Clinical Study Report - Calidad de Información CFR

Clinical Study Report 

A multicentre, open-label, therapeutic and 

exploratory trial to evaluate the safety and efficacy 

of platelet glycoprotein (GP) IIb/IIIa receptor 

blocker (Clotinab) in high-risk patients with 

Percutaneous Coronary Intervention (PCI) 

Study No. Clotinab_II 

Study drug Clotinab 

Indication 

High-risk patients with acute blood vessel thrombosis who will undergo 


Study period 17-MAY-2005 ~ 01-DEC-2005 

Sponsor : ISU ABXIS CO., LTD. 

Writers: 

CSR writer : Ae-Jin, Lim 

Biostatistician : Ik-Seong, Choi 

Lifecord Stat-Korea 

Report status Version 1.0_Eng 

Report version 

date 

08-MAR-2006 

Coordinating Investigator : 

Prof. Yang-Soo, Jang 

Severance Hospital / Dept. of Cardiology 

Institute/Department : 

Severance Hospital / Dept. of Cardiology 

Asan Medical Center / Dept. of Cardiology 

Chonnam National University Hospital 

/ Dept. of Cardiology 

This study was conducted in accordance with ICH/GCP and LSK SOPs for clinical 

investigation and documentation. The information in this document is the property 

of ISU ABXIS Co., Ltd. and is confidential. Neither the document nor information 

contained therein may be passed on, reproduced or disclosed outside ISU ABXIS 

Co., Ltd. without the written consent of the company. 

CSR_Clotinab_II 1 

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1.1. Principal investigator’s signature page 

PRINCIPAL OR COORDINATING 

INVESTIGATORS SIGNATURES 

OR SPONSOR’S RESPONSIBLE MEDICAL OFFICER 

STUDY TITLE: A multicentre, open-label, therapeutic and exploratory 

trial to evaluate the safety and efficacy of platelet 

glycoprotein (GP) IIb/IIIa receptor blocker (Clotinab) in 

high-risk patients with Percutaneous Coronary 

Intervention (PCI) 

STUDY 

AUTHOR(S): 

Yang-Soo, Jang; Young-Hak, Kim; Myung-Ho, Jeong 

I have read this report and confirm that to the best of my knowledge 

it accurately describes the conduct and results of the study 

INVESTIGATOR: 

DATE: 

Name 

Signature 


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1.2. Signature page 

WRITER 

CSR Writer 

Biostatistician 

REVIEWER 

Study Manager 

CR Manager 

Stat Manager 

APPROVAL 

Clinical Operation 

Director 

Biostatistics 

Director 

Sponsor 

Ae-Jin, Lim 

LSK 

Ik-Seong, Choi 

Date Signature 

LSK Date Signature 

Sook-Hyun, Im 

LSK 

Ji-Hoon, Hwang 

LSK 

Hee-Jeong, Shim 



LSK Date Signature 

Yong-Kwan, Jun 

LSK 

Sung-Jae, Kim 

LSK 

Mook, Kim 



ISU ABXIS Co., Ltd. Date Signature 


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2. Synopsis 

Sponsor: ISU ABXIS Co.,Ltd 

Study number: Clotinab_II 

Version date: 08-MAR-2006 

Name of finished drug : Name of activeingredient : Study period : 

Clotinab Abciximab 17-MAY-2005 ~ 01-DEC-2005 

Name of Study 

Institutes/ 

Principal 

investigators 

A multicentre, open-label, therapeutic and exploratory trial to evaluate the safety 

and efficacy of platelet glycoprotein (GP) IIb/IIIa receptor blocker (Clotinab) in 

high-risk patients with Percutaneous Coronary Intervention (PCI) 

Severance Hospital : Yang-Soo, Jang 

Asan Medical Center : Young-Hak, Kim 

Chonnam National University Hospital : Myung-Ho, Jeong 

Study period 17-MAY-2005 ~ 01-DEC-2005 

Objective 

Study design 

Sample size- 

Planned: 

Sample size— 

Enrolled: 

Indication 

investigational 

drug 

The objective of this trial is to evaluate the efficacy and safety of Clotinab, an 

investigational drug, to prevent ischemic cardiac complications in high-risk 

patients who will undergo Percutaneous Coronary Intervention (PCI) 

To obtain the data of safety and efficacy of Clotinab, a single arm, multi-centre, 

open-label, clinical trial of Clotinab is performed with the first 30 patients. After 

completing 30 pateints, a randomized multi-centre open-label clinical trial is 

followed with 40 patients assigned to the Clotinab group and 30 assigned to the 

ReoPro ® group. Data from the ReoPro ® group is used as a reference point for 

decisions rule and is not aimed to compare the two groups. When the first 30 

subjects in Clotinab group complete the trial, results from analyzing the safety and 

efficacy data are submitted to KFDA. Regardless of the analysis results, the clinical 

trial is to be continued according to the study plan. 

Clotinab: 70 subjects, ReoPro ® : 30 subjects 

Total of 112 were recuited to keep in consideration that dropout becomes 10%. 

Clotinab: 84, ReoPro ® : 40, Total:124 

High-risk patients with acute blood vessel thrombosis who will undergo 


Clotinab 


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Comparator ReoPro ® 

Inclusion / 

Exclusion 

criteria 

Inclusion criteria 

(1) Patients aged between 19 and 80 

(2) Patients meeting one of the following conditions and who will undergo PCI: 

1) Patients showing ischemic ST change in electrocardiogram among patients 

as well as refractory to drug treatment in resting phase and with recurrent 

angina pectoris 

2) Post-infarction angina patients within 7 days from myocardial infarction 

attack refractory to drug treatment and showing ischemic ST change in 

electrocardiogram 

3) Acute Q-Wave myocardial infarction within 12 hours after the attack, which 

require direct intervention procedure 

4) Acute Q-Wave myocardial infarction within 12 hours after the attack, which 

require another rescue intervention after failure to thrombolytic therapy 

5) Classification of vascular lesions according to the coronary arteriostenosis 

(ACC/AHA) criteria defined by angiography* 

- Two Type B lesion characteristics 

- One Type C lesion characteristic 

- Females aged over 65 with one Type B lesion characteristic 

- Diabetics with one lesion Type B characteristic 

(3) Subjects who have signed the informed consent form 

Exclusion criteria 

(1) Patients to whom PCI cannot be administered within 24 hours from receiving 

the investigational product 

(2) Occlusion of the left main coronary artery is ≥ 50 % and bypass surgery is 

applicable 

(3) Culprit lesion in the bypass graft 

(4) Major surgery or trauma within recent 6 weeks 

(5) Gastrointestinal or genitourinary bleeding of clinical significance within recent 

six weeks 


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Inclusion / 

Exclusion 

criteria 

(6) History of cerebrovascular attack within two years, or cerebrovascular attack 

with a significant residual neurological deficit 

(7) Patients who require oral anticoagulants during the trial 

(8) Patients who have been administrated oral anticoagulants within 7 days 

(permissible if prothrombin time is controlled to ≤ 1.2 times before the 

procedure) 

(9) Severe uncontrollable hypertension (SBP > 180mm Hg or DBP > 100mm Hg) 

(10) Retinal hemorrhage within recent 6 weeks 

(11) Bleeding diathesis (i.e. internal bleeding or hemostatic disorder) 

(12) Thrombocytopenia (< 100,000 cells/mL) 

(13) Hypersensitivity to the test drug or murine protein, or history of 

hypersensitivity 

(14) Patients who had participated in other clinical trial within 30 days 

(15) Intracranial neoplasm, arteriovenous malformation, or aneurysm 

(16) History or diagnosis of vasculitis 

(17) Severe renal dysfunction (Creatinine is two times higher than the upper limit 

of normal of each center.) or hepatic disorder 

(GOT, GPT is three times higher than the upper limit of normal.) 

(18) Pregnancy, breast feeding, or females of childbearing age without using a 

proper contraceptive 

(19) Alcohol addictive, drug misuse or abuse, or patients who are not able to 

participate in the trial due to psychological or emotional problem 

(20) Patients whose voluntary participation in the trial may be influenced by the 

investigator 

(21) Patients who can’t take antiplatelet drugs 

(22) Patients who might die of other disease than cardiac disease during the trial 

(23) Patients who the investigator judges ineligible due to other than the situations 

above 

(24) Use of dextran intravenously before PCI or intent to use it during PCI 


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Concomitant 

therapy 

Investigational 

drug 

administered 

Comparator 

administered 

Treatment 

method 

Evaluation 

Methods 

Statistical 

Methods 

Concomitant administration of asprin and heparin; 

With aspirin, Plavix ® (Clopidogrel) of 300-450 mg as initial dose (if necessary) and 

75-100 mg/day as maintenance dose was permissible) 

0.25 mg/kg of Clotinab is administered IV bolus 10 minutes to 6 hours prior to 

PCI, followed by a continuous infusion of 0.125 mg/kg/min (Max 10 ug/min) for 12 

hours. 

0.25 mg/kg of ReoPro ® is administered IV bolus 10 minutes to 6 hours prior to 

PCI, followed by a continuous infusion of 0.125 mg/kg/min (Max 10 ug/min) for 12 

hours. 

After screening and confirmation of eligibility, patients who signed the informed 

consent were hospitalized prior to a procedure and administered investigational 

product and treated with PCI on day 1. After the procedure, subjects had stayed in 

the hospital for observation. On the Day 30(+7) from discharge, they visited the 

hospital for the safety and efficacy assessment. 

Efficacy Assessment 

� Primary endpoint 

① Death(due to heart disease) 

② Recurrence of myocardial infarction 

③ Recurrent ischemic symptoms which require emergency revascularization 

such as PCI, CABG, IABP 

� Secondary endpoint 

New change in electrocardiogram which indicates the status of ischemia 

Safety Assessment 

Bleeding, thrombocytopenia, change in Hb/Hct, HACA(human antichimetric 

antibody) development, adverse event etc. 

Primary efficacy endpoint 

The number and proportion of subjects experiencing the MACE were presented. 

The frequency, proportion and its exact 95% C.I. for subjects by MACE types were 


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calculated. Frequency and proportion of MACE onset were summarized by MI 

(Myocardial infarction) and ACC/AHA classification. Chi-square test or Fisher’s 

exact test was performed to compare Clotinab and ReoPro ® . The efficacy 

interpretation followed the decision rule below. 

 

Case A1. PP population 

If nine or fewer patients among seventy six subjects treated with Clotinab 

experience MACE, then the MACE onset rate is estimated to be below 20% and 

Clotinab is considered to be effective. 

Case A2. ITT population 

If ten or fewer patients among eighty four subjects treated with Clotinab 



Case A3. FAS population 

If ten or fewer patients among eighty three subjects treated with Clotinab 



Case B 

If the number of MACE patients is over the defined number in each population, 

efficacy of Clotinab is evaluated after adjusting the critical value based on the 

MACE onset rate in ReoPro ® . 

Secondary efficacy endpoint 

-New change in electrocardiogram that indicates the status of ischemia 

Frequency, proportion and 95% exact C.I. of new changes from pre-administration 

to post-administration in electrocardiogram (yes/no) were presented. Fisher’s exact 

test was performed to find the differences between two groups. Frequency was 


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Efficacy results 

presented and McNemar’s test was applied to determine if the changes in 

electrocardiogram from pre- to post-administration is significant. 

Safety endpoints 

– Bleeding, thrombocytopenia, change in Hb/Hct, adverse event 

Frequency, proportion and 95% exact C.I. for each endpoint were presented. 

The primary efficacy endpoint is the onset of MACE within 30(+7) days from the 

study drug administration following the PCI procedure. The MACE includes the 

death related to heart disease, the recurrence of myocardial infarction (MI) and 

the emergency revascularization. 

No patient among 84 patients in the Clotinab group experienced the primary 

efficacy measure, the MACE. Whether we analyze the PP population, ITT 

population, or FAS population, the same conclusion is reached. Clotinab is effecitve 

in preventing the MACE event. The upper bound of 95% confidence interval is all 

below 5% regardless of the analysis population, indicating that the MACE rate 

among patients undergoing the PCI procedure will be less than 5% if also treated 

with Clotinab. Only one Clotinab patient experienced a new change in 

electrocardiogram. The rate of the status of ischemia indicated by 

electrocardiogram in the Clotinab patients at day 30(+7) dropped significantly by 

about 17-21%, depending on the analysis population, from the baseline. No 

Clotinab patient experienced major bleeding event. We can conclude that Clotinab 

is effective and safe in preventing the MACE in patients undergoing the PCI 

procedure. 

Two patient among 40 patients in the ReoPro ® group experienced the MACE. The 

upper bound of 95% confidence interval is about 16.9-18.7% depending on the 

analysis population. This indicates that less than 20% of the patients undergoing 

the PCI proceudre will experience the MACE if also treated with ReoPro ® . Only one 

patient experienced a new change in electrocardiogram. The rate of the status of 

ischemia indicated by electrocardiogram in the ReoPro ® group at dqy 30(+7) 


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Safety results 

dropped significantly by about 24-27%, depending on the analysis population, 

from the baseline. Three ReoPro ® patients experienced major bleeding event. The 

major bleeding rate is signifcantly higher in the ReoPro ® group than in the 

Clotinab group. 

The intention of this clinical study is not designed to compare the efficacy or 

safety of Clotinab and ReoPro ® in patients undergoing the PCI procedure. Thus we 

do not make a statement about which treatment is more effective and safer. 

Nevertheless we can conclude that Clotinab is effective and safe in preventing the 

MACE in patients undergoing the PCI procedure. 

Based on TIMI criteria, no major bleeding occurred in Clotinab, but 3 subjects 

(7.50%) experienced major bleeding in ReoPro ® . The number of subjects with 

minor bleeding was 11(13.25%) for Clotinab and 5(12.50%) for ReoPro ® . The 

number of subjects with clinically insignificant bleeding was 11(13.25%) for 

Clotinab and 9(22.50%) for ReoPro ® . 

Number of patients with overall bleeding based on TIMI criteria showed no 

significant difference between Clotinab and ReoPro ® in each time point. (See Table 

12.2:2) However number of patients with major bleeding showed significant 

difference(p=0.0326). 

No significant results were reported in thrombocytopenia, change in Hb/Hct, 

HACA, adverse event, laboratory data. 

Serious adverse events were occurred to 7 subjects[{Clotinab 3(3.61%), 95% 

exact C.I.(0.75%, 10.20%)}, {ReoPro ® 4(10.00%), 95% exact C.I.(2.79%, 

23.66%)}] as follows. Prolongation of existing hospitalization: 2 patients, lifethreatening: 

1 subject in Clotinab. Death: 2 subjects, life-threatening: 2 subjects in 

ReoPro ® . But Investigators concluded these 7 cases were not related to study 

drug, and there was no significant difference between Clotinab and ReoPro ® in 

SAE occurrence rate(P=0.1521). 


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Conclusion 

Clotinab is expected to be effective to prevent ischemic heart complications for 

high-risk patients who undergo Percutaneous Coronary Intervention(PCI). The 

probability of MACE onset in Clotinab is estimated to be below 5%. There was no 

clinically significant result in safety variables. In conclusion, Clotinab will be a 

effective medicine to prevent ischemic cardiac complications for high-risk patients 

who undergo Percutaneous Coronary Intervention. 


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3. Table of contents 

1. Cover Page ………………………………………………………………………………………………………………….1 

1.1. Principal investigator’s signature page .................................................................... 2 

1.2. Signature page..................................................................................................... 3 

2. Synopsis ....................................................................................................................... 4 

3. Table of contents ..........................................................................................................12 

4. List of abbreviations and definition of terms ....................................................................17 

5. Ethics ..........................................................................................................................18 

5.1. Institutional review board (IRB) ............................................................................18 

5.2. Ethical conduct of the study .................................................................................18 

5.3. Patient information and consent............................................................................18 

6. Investigators and study administrative structure ..............................................................18 

7. Introduction..................................................................................................................20 

8. Study objective.............................................................................................................21 

9. Investigational plan.......................................................................................................21 

9.1. Overall study design and plan - description ............................................................21 

9.3. Selection of study population................................................................................24 

9.3.1. Inclusion criteria ........................................................................................24 

9.3.2. Exclusion criteria ........................................................................................24 

9.3.3. Removal of patients from therapy or assessment ..........................................25 

9.4. Treatments..........................................................................................................26 

9.4.1. Dosage and administration method of investigational product ........................26 

9.4.2. Identity of investigational products ..............................................................26 

9.4.2.1. Product name, generic name of main active ingredient, composition of raw 

material and formulation ......................................................................................26 

9.4.2.2. Packaging and labeling of investigational product .......................................27 

9.4.2.3. Management of investigational product .....................................................28 

9.4.3. Methd of assigning patients to treatment groups...........................................28 

9.4.4. Treatment method......................................................................................29 

9.4.4.1 Percutaneous coronary intervention (PCI) procedure ...................................29 

9.4.4.2 Actions to thrombocytopenia .....................................................................29 

9.4.5. Concomitant therapy and restrictions ...........................................................29 

9.4.5.1. Concomitant therapy................................................................................29 

9.4.5.2. Restrictions on concomitant medication .....................................................30 

9.5. Efficacy and safety variables.................................................................................30 


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9.5.1. Efficacy and safety measurements assessed .................................................31 

9.5.1.1. Efficacy measurement assessed................................................................31 

9.5.1.2. Safety measurement assessed ..................................................................33 

9.5.2. Appropriateness of measurements ...............................................................35 

9.5.3. Primary efficacy variable .............................................................................35 

9.6. Data quality assurance .........................................................................................35 

9.7. Statistical methods planned in the protocol and determination of sample size............36 

9.7.1. Statistical and Analytical Plans .....................................................................37 

9.7.1.1. General principle for statistical analysis ......................................................37 

9.7.1.2. Analysis of Demographic and Baseline characteristics..................................37 

9.7.1.3. Efficacy Analysis ......................................................................................37 

9.7.1.4. Safety endpoint and analysis.....................................................................38 

9.7.1.5. Missing data............................................................................................40 

9.7.2. Determination of sample size.......................................................................40 

10. Study patients ............................................................................................................42 

10.1. Disposition of patients........................................................................................42 

10.2. Protocol deviations.............................................................................................44 

11. Efficacy evaluation ......................................................................................................45 

11.1. Data sets analysed.............................................................................................45 

11.2. Demographic and other baseline characteristics....................................................46 

11.2.1. Demographic characteristics ......................................................................46 

11.2.2. Baseline characteristics .............................................................................54 

11.2.3. Medication administered prior to trial .........................................................60 

11.2.4. Medication administered during trial...........................................................60 

11.3. Efficacy results, tabulations, and analysis.............................................................61 

11.3.1. Primary efficacy analysis ...........................................................................61 

11.3.2. Secondary efficacy analysis .......................................................................65 

11.3.3. By-patient displays ...................................................................................72 

11.3.4. Efficacy conclusions..................................................................................72 

12. Safety evaluation ........................................................................................................73 

12.1. Extent of exposure.............................................................................................73 

12.2. Bleeding............................................................................................................73 

12.3. Thrombocytopenia .............................................................................................77 

12.4. Change in Hb/Hct ..............................................................................................78 

12.5. HACA (Human antichimetric antibody) .................................................................80 

12.6. Adverse Event ...................................................................................................82 


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12.6.1. Brief summary of Adverse Event ................................................................82 

12.6.2. Display of adverse events..........................................................................83 

12.6.3. Analysis of adverse events ........................................................................92 

12.6.4. Listing of adverse events by patient ...........................................................92 

12.7. Serious adverse events, and other significant adverse events.................................92 

12.8. Clinical laboratory evaluation...............................................................................97 

12.8.1. Listing of indivisual laboratory measurements by patient..............................97 

12.8.2. Evaluation of each laboratory parameter.....................................................97 

12.9. Vital signs, physical findings and other observations related to safety.....................97 

12.10. Safety conclusions............................................................................................98 

13. Discussion and overall conclusions................................................................................99 

14. Reference list............................................................................................................103 

15. Tables referred to but not included in the text..............................................................106 


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LIST OF IN-TEXT TABLES & FIGURE 

TABLE 6.1: 1 LIST OF ALL PARTICIPATING INVESTIGATORS AND PHARMACISTS........................................20 

TABLE 10.1:1 DISPOSITION OF SUBJECTS...................................................................................43 

FIGURE 10.1:1 DISPOSITION OF SUBJECTS .................................................................................44 

TABLE 10.2:1 LISTING OF SUBJECTS WITH MAJOR PROTOCOL DEVIATION .............................................45 

TABLE 11.2.1:1 DISTRIBUTION OF SUBJECTS BY DISEASES (CAN SELECT MORE THEN ONE ITEM)-ITT ..........47 

TABLE 11.2.1:2 DISTRIBUTION OF SUBJECTS BY DISEASES (CAN SELECT MORE THEN ONE ITEM)-FAS .........47 

TABLE 11.2.1:3 DISTRIBUTION OF SUBJECTS BY DISEASES (CAN SELECT MORE THEN ONE ITEM)-PP ...........48 

TABLE 11.2.1:4 SUBJECT DEMOGRAPHICS (ITT, I)........................................................................48 

TABLE 11.2.1:4 SUBJECT DEMOGRAPHICS (ITT, II).......................................................................50 

TABLE 11.2.1:5 SUBJECT DEMOGRAPHICS (FAS, I) .......................................................................51 

TABLE 11.2.1:5 SUBJECT DEMOGRAPHICS (FAS, II)......................................................................52 

TABLE 11.2.1:6 SUBJECT DEMOGRAPHICS (PP, I) .........................................................................53 

TABLE 11.2.1:6 SUBJECT DEMOGRAPHICS (PP, II)........................................................................54 

TABLE 11.2.2:1 PRE-TRIAL INTERVIEW (ITT)..............................................................................55 

TABLE 11.2.2:2 PRE-TRIAL INTERVIEW (FAS) .............................................................................56 

TABLE 11.2.2:3 PRE-TRIAL INTERVIEW (PP) ...............................................................................57 

TABLE 11.2.2:4 MEDICAL HISTORY (ITT) ..................................................................................58 

TABLE 11.2.2:5 MEDICAL HISTORY (FAS)..................................................................................59 

TABLE 11.2.2:6 MEDICAL HISTORY (PP) ...................................................................................60 

TABLE 11.3.1:1 MAJOR ADVERSE CARDIAC EVENT (MACE)-PP .......................................................62 

TABLE 11.3.1:2 MAJOR ADVERSE CARDIAC EVENT (MACE) IN THE SUBGROUPS-PP...............................63 

TABLE 11.3.1:3 MAJOR ADVERSE CARDIAC EVENT (MACE)-ITT ......................................................63 

TABLE 11.3.1:4 MAJOR ADVERSE CARDIAC EVENT (MACE) IN THE SUBGROUPS-ITT .............................64 

TABLE 11.3.1:5 MAJOR ADVERSE CARDIAC EVENT (MACE)-FAS......................................................64 

TABLE 11.3.1:6 MAJOR ADVERSE CARDIAC EVENT (MACE) IN THE SUBGROUPS-FAS.............................65 

TABLE 11.3.2:1 NEW CHANGE IN ELECTROCARDIOGRAM WHICH INDICATES THE STATUS OF ISCHEMIA -PP.....66 

TABLE 11.3.2:2 THE CHANGE ELECTROCARDIOGRAM BETWEEN PRE- AND POST- INJECTION OF THE 

INVESTIGATIONAL DRUG –PP ............................................................................................67 

TABLE 11.3.2:3 NEW CHANGE IN ELECTROCARDIOGRAM WHICH INDICATES THE STATUS OF ISCHEMIA –ITT...68 


INVESTIGATIONAL DRUG -ITT............................................................................................69 

TABLE 11.3.2:5 NEW CHANGE IN ELECTROCARDIOGRAM WHICH INDICATES THE STATUS OF ISCHEMIA –FAS ..70 



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INVESTIGATIONAL DRUG -FAS ...........................................................................................71 

TABLE 12.2:1 BLEEDING........................................................................................................75 

TABLE 12.2:2 NUMBER OF PATIENTS WITH BLEEDING EVENTS ...........................................................76 

TABLE 12.2:3 NUMBER OF PATIENTS WITH MAJOR BLEEDING EVENTS BY TOTAL HEPARIN BOLUS DOSE ..........76 

TABLE 12.2:4 DESCRIPTION OF PATIENTS WITH MAJOR BLEEDING......................................................76 

TABLE 12.2:5 NUMBER OF PATIENTS WITH MAJOR BLEEDING EVENTS BY GENDER AND WEIGHT ..................77 

TABLE 12.3:1 THROMBOCYTOPENIA ..........................................................................................78 

TABLE 12.4:1 HB/HCT – CLOTINAB ..........................................................................................79 

TABLE 12.4:2 HB/HCT – REOPRO ® ..........................................................................................80 

TABLE 12.5:1 CLOTINAB HACA RESULTS....................................................................................81 

TABLE 12.5:2 HACA(HUMAN ANTICHIMETRIC ANTIBODY) DEVELOPMENT. ............................................81 

TABLE 12.6.1:1 SUMMARY OF ADVERSE EVENTS...........................................................................83 

TABLE 12.6.2:1 NUMBER OBSERVED AND RATE, WITH SUBJECT IDENTIFICATIONS-CLOTINAB .....................85 

TABLE 12.6.2:2 NUMBER OBSERVED AND RATE, WITH SUBJECT IDENTIFICATIONS-REOPRO ® ......................89 

TABLE 12.7:1 SUBJECTS WITH SERIOUS ADVERSE EVENTS ..............................................................94 

TABLE 12.7:2 SUBJECTS WITH AES LEAD TO DEATH.......................................................................95 

TABLE 12.7:3 SUBJECTS WITH AES LEAD TO IP DOSAGE CHANGE/TEMPORARILY DISCONTINUED .................95 

TABLE 12.7:4 SUBJECTS WITH AES LEAD TO IP PERMANENTLY DISCONTINUED ......................................96 


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4. List of abbreviations and definition of terms 

ACC American College of Cardiology 

AE Adverse Event 

AHA American Heart Association 

BUN Blood Urea Nitrogen 

CABG Coronary Artery Bypass Graft 

CBC Complete Blood Count 

C.I. Confidence Interval 

CRF Case Record(Report) Form 

DBP Diastolic Blood Pressure 

EKG Electrocardiogram 

GOT(AST) Glutamic Oxaloacetic Transaminase (Aspartate Transaminase) 

GPT(ALT) Glutamic Pyruvic Transaminase (Alanine Transaminase) 

HACA Human anti-Chimeric Antibody 

IRB Institutional Review Board 

ITT Intention-to-Treated 

KGCP Korean Good Clinical Practice 

MACE Major Adverse Cardiac Event 

MI Myocardial Infarction 

PP Per-protocol 

PTCA Percutaneous Transluminal Coronary Angioplasty 

PCI Percutaneous Coronary Intervention 

RBC Red Blood Cell 

SAE Serious Adverse Event 

SBP Systolic Blood Pressure 

SOP Standard Operating Procedure 

WBC White Blood Cell 


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5. Ethics 

5.1. Institutional review board (IRB) 

This clinical trial was carried out after the protocol, informed consent, subject information and 

advertisement were reviewed and approved by/from IRB. Details regarding IRB’s composition 

and member’s list are shown in Appendix 16.1.3. 

5.2. Ethical conduct of the study 

This clinical trial was conducted in accordance with the ICH/GCP guidelines and clinical trial 

protocol as well as in accordance with principles of Declaration of Helsinki. 

5.3. Patient information and consent 

Prior to patient participating in the trial, all trial related information was explained and written 

informed consent was obtained from each patient. Each patient was also informed that they 

could withdraw their consent at any time at will. 

Any individual medical information obtained as a result of the study would be considered 

confidential and protected. 

The subject information sheets and informed consent form are provided in Appendix16.1.1. 

6. Investigators and study administrative structure 

There are 3 Institutes for this trial including Severance Hospital. All labaratory tests were 

performed at each trial center without centrallaboratory, except HACA analysis whice was done 

at the Lab of ISU ABXIS Co., Ltd. 

All curricula vitae form principal investigator, investigator and person who involved in this trial of 

the institute were shown in Appendix 16.1.4. 

Investigational product was manufactured and shipped to sites by ISU ABXIS Co., Ltd. All 

documents related to this procedure were kept by ISU ABXIS Co., Ltd. 


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Coordination investigator : 

Prof. Yang-Soo, Jang 

Dept. of Cardiology / Severance Hospital 

#134, Sinchon-dong, Seodaemun-gu, Seoul, Korea 

Principal investigator : 

Prof. Young-Hak, Kim 

Dept. of Cardiology / Asan Medical Center 

#388-1, Pungnap-2-dong, Songpa-gu, Seoul, Korea 

Principal investigator : 

Prof. Myung-Ho, Jeong 

Dept. of Cardiology / Chonnam National University Hospital 

#8, Hak-dong, Dong-gu, Gwangju, Korea 

Study Manager : 

Sook-Hyun, Im 

Clinical research team / Lifecord Stat-Korea 

14Fl. Paradise venture Bldg, #708-33 Yeoksam-dong, Gangnam-gu, Seoul, Korea 

Randomization Allocation Staffs : 

Kyoung-A, Kim / Byeong-Kwan, Park 

Statistics team / Lifecord Stat-Korea 


Database Administrator : 

Min-Geol, Jang 

Data management team / Lifecord Stat-Korea 


Statistician : 

Ik-Seong, Choi 

Statistics team / Lifecord Stat-Korea 



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On site Monitoring : 

Eun-Kyoung, Oh / Ae-Jin, Lim 

Clinical research team / Lifecord Stat-Korea 


Table 6.1: 1 List of all participating investigators and pharmacists 

Institutes 

Severance 

Hospital 

Asan 

Medical 

Center 

Chonnam 

National University 

Hospital 

7. Introduction 

Principal 

investigators 

Yang-Soo, Jang 

Young-Hak, Kim 

Myung-Ho, Jeong 

Investigators Pharmacists Monitor 

Young-Guk, Ko 

Tae-Soo. Kang 

Dong-Hoon. Choi 

Seung-Jung. Park 

Seong-Wook. Park 

Jae-Joong. Kim 

Myeong-Ki. Hong 

Cheol-Whan. Lee 

Weon. Kim 

Ju-Han. Kim 

Young-Joon. Hong 

Ah-Young, Kim 

Si-Hyun, Park 

Ji-Won, Yoon 

Hye-Won, Lee 

Young-Sun, Ki 

Eun-Kyoung, Oh 

Ae-Jin, Lim 


Ae-Jin, Lim 


Ae-Jin, Lim 

Coronary diseases like angina pectoris and myocardial infarction have been rising very fast for 

the past 10 years, making it one of the leading causes of adult death in Korea 1) . Coronary 

disease clinically turns up as angina pectoris, ischemia without pain, myocardial infarction, or 

sudden death. In the past coronary artery bypass surgery was one of the main medical 

procedures, but in recent years PCI is the one. After PCI acute complications (about 5%) such 

as tunica intima dissection, thrombogenesis, or vasoconstriction and chronic complications (10- 

25%) like re-stenosis still remain issues. 

Platelet-mediated thrombosis is known to account for pathophysiology of acute coronary 

symptoms 3) and for acute vascular obstruction as well 4)-6) . Administrating asprin to patients who 

will undergo angioplasty reduces risk of acute vascular obstruction, but is relatively weak in 

inhibiting platelet aggregation. Ischemic symptom in 10 – 20% of high-risk patients treated with 

asprin is a persistent problem 7) . 


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Abciximab, one of platelet glycoprotein (GP) IIb/IIIa receptor blockers, was developed by Coller 

in 1985 and named as 7E3. It is a chimeric human monoclonal antibody 8) . Abciximab is a strong 

inhibitor against platelet coagulation 7) . It binds to platelet surface GP IIb/IIIa receptor 

competitively with adhesive molecules such as fibrinogen and von Willebrand etc. and blocks 

the final stage of platelet coagulation. Various large-scale studies have found that Abciximab 

improves outcome of PCI and diabetes, decreases the incidence of short-term or long-term 

death, and reduces Major Adverse Cardiac Event (MACE). 

Inserting antiplatelet GP IIb/IIIa DNA into Chinese hamster’s ovary cell produces Clotinab, a 

product made in ISU ABXIS CO., LTD. Since it contains identical active ingredient as ReoPro ® on 

the domestic market, it is expected that Clotinab has same efficacy to ReoPro ® as a platelet GP 

IIb/IIIa receptor inhibitor. Therefore, this theraputic and exploratory clinical trial was designed 

to investigate the preventive effect on ischemic heart complications and safety of adjuvant use 

of Clotinab with asprin and heparin in high-risk acute coronary thrombotic patients who will 

undergo PCI. 

8. Study objective 

The objective of this trial is to evaluate the efficacy and safety of Clotinab, an investigational 

drug, to prevent ischemic cardiac complications in high-risk patients who will undergo 


9. Investigational plan 

9.1. Overall study design and plan - description 

This trial is to proceed in two stages. The first stage is a single arm, multi-centre, open-label, 

study of Clotinab. Thirty eligible patients are to be admitted in the first stage. The secod stage 

is a randomized multi-centre open-label clinical trial with 40 patients to be allocated to the 

Clotinab group and 30 to the ReoPro ® group. Data from the ReoPro ® group is used as a 

reference point for decision rule. No comparison between two treatment groups is intended. 

When the first first stage is over, safety and efficacy results are to be submitted to KFDA, and 

regardless of the results, the clinical trial is to continue 


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The clinical trial was activated on May 17, 2005. First thirty eligible patients were to be 

admitted to the Clotinab group without randomization. However, the PCI procedure failed in 

one patient (C003). One additional patient was admitted to the Clotinab group, making the size 

of the first stage thirty-one. Afterwards ninety-three patients were randomized between 

Clotinab and ReoPro ® . A total of 124 patients were admitted into the trial. Efficacy and safety 

results from the first stage were submitted as an interim report to the KFDA in August 2005. 

The screening period was 1 day to 2 weeks. Day 1 is the date of baseline examination and PCI 

administration. The screening examination may replace the baseline examination. Patients were 

followed four weeks post PCI and treatment. 

Ten minutes to six hours prior to PCI, 0.25 mg/kg of Clotinab was administered IV bolus, 

followed by a 12-hour infusion of 0.125 mg/kg/min (Max 10 ug/min) dissolved in sterile saline of 

0.9 % or dextrose of 5 % . 

While hospitalized for recuperation from the PCI procedure, patients were examined according 

to the protocol. Post PCI assessment of efficacy and safety was performed at 12h, 24h, day 3, 

and either on the date of discharge or one day before the discharge. If day 3 falls on the date 

of discharge, the assessment of the date of discharge was not recorded in the CRF. 

Patients made the return visit on day30(+7) to be examined according to the protocol and 

evaluated for efficacy and safety. Aspirin and heparin were prescribed together, and other oral 

anticoagulants as well as Dextran were prohibited throughout the trial period. All the 

concomittant medications and all the observed adverse events were recorded in the CRF. 


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Test items 

Study flow chart 

* Women in reproductive age were examined for pregnancy using the urine-HCG test. 

Subject basic 

information 

Visits 

Pre interview 

/Medical history 

Inclusion/Exclusion 

Criteria 

Screening 

(-2week~ 

Day 1) 

Urine HCG v * 

v 

v 

v 

Pre- 

Dose 

0 

hr 

Day 1 ~ Day 2 (post-dose) 

1 

hr 

2 

hr 


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3 

hr 

4 

hr 

6 

hr 

12 

hr 

18 

hr 

24 

hr 

Day 

3 

(One day 

before) 

Discharge 

Vital signs v v v v v v v v v v v v v 

ECGs v v v v v v v 

Physical examination v v v v 

Platelet v v v v v v v 

Hemoglobin, 

Hematocrit v v v v v v v 

WBC,RBC, 

WBC diff. v v v v v v 

Serum Chemistry v v v v 

Troponin, 

CK-MB v v v v v v v 

Urinalysis v v v v 

Efficacy assessment 

(MACE) 

Day 

30 

(+7) 

v v v v v 

Safety assessment v v v v v 

HACA v v v 

Concomitant 

Medication 

v v v v v v v 

Adverse events v v v v v v 

Administration of 

study drug 

PT v 

ACT or APTT v v 

v 

Performed prior to PCI procedure, and 

depend on the heparin concomitant 

therapy during the procedure 

v v v

9.2. Discussion of study design, including the choice of control groups 

Inserting antiplatelet GP IIb/IIIa DNA into Chinese hamster’s ovary cell produces Clotinab, a 

product made in ISU ABXIS CO., LTD. Since it contains identical active ingredient as ReoPro ® , a 

platelet GP IIb/IIIa receptor inhibitor, which is already on the domestic market, Clotinab is 

expected to have the same efficacy as ReoPro ® . Therefore, this theraputic and exploratory 

clinical trial was designed to investigate the preventive effect on ischemic heart complications 

and safety of adjuvant use of Clotinab with asprin and heparin in high-risk acute coronary 

thrombotic patients who will undergo PCI. 

9.3. Selection of study population 

9.3.1. Inclusion criteria 

(1) Patients aged between 19 and 80 

(2) Patients meeting one of the following conditions and who will undergo PCI: 

1) Patients showing ischemic ST change in electrocardiogram among patients as well as 

refractory to drug treatment in resting phase or with recurrent angina pectoris 

2) Post-infarction angina patients within 7 days from myocardial infarction attack refractory 

to drug treatment and showing ischemic ST change in electrocardiogram 

3) Acute Q-Wave myocardial infarction within 12 hours after the attack, which requires 

direct intervention procedure 

4) Acute Q-Wave myocardial infarction within 12 hours after the attack, which requires 

another rescue intervention after failure to thrombolytic therapy 

5) Classification of vascular lesions according to the coronary arteriostenosis (ACC/AHA) 

criteria defined by angiography* 

- Two type B lesion characteristics 

- One type C lesion characteristic 

- Females aged over 65 with one Type B lesion characteristic 

- Diabetics with one lesion Type B characteristic 

(3) Subjects who have signed the informed consent form 

9.3.2. Exclusion criteria 

(1) Patients to whom PCI cannot be administered within 24 hours from receiving the 

investigational product 

(2) Occlusion of the left main coronary artery is ≥ 50 % and bypass surgery is applicable 


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(3) Culprit lesion in the bypass graft 

(4) Major surgery or trauma within recent 6 weeks 

(5) Gastrointestinal or genitourinary bleeding of clinical significance within recent six weeks 

(6) History of cerebrovascular attack within two years, or cerebrovascular attack with a 

significant residual neurological deficit 

(7) Patients who require oral anticoagulants during the trial 

(8) Patients who have been administrated oral anticoagulants within 7 days (permissible if 

prothrombin time is controlled to ≤ 1.2 times before the procedure) 

(9) Severe uncontrollable hypertension (SBP > 180mm Hg or DBP > 100mm Hg) 

(10) Retinal hemorrhage within recent 6 weeks 

(11) Bleeding diathesis (i.e. internal bleeding or hemostatic disorder) 

(12) Thrombocytopenia (< 100,000 cells/mL) 

(13) Hypersensitivity to the test drug or murine protein, or history of hypersensitivity 

(14) Patients who had participated in other clinical trial within 30 days 

(15) Intracranial neoplasm, arteriovenous malformation, or aneurysm 

(16) History or diagnosis of vasculitis 

(17) Severe renal dysfunction (Creatinine is two times higher than the upper limit of normal of 

each center.) or hepatic disorder 

(GOT, GPT is three times higher than the upper limit of normal.) 

(18) Pregnancy, breast feeding, or females of childbearing age without using a proper 

contraceptive 

(19) Alcohol addictive, drug misuse or abuse, or patients who are not able to participate in the 

trial due to psychological or emotional problem 

(20) Patients whose voluntary participation in the trial may be influenced by the investigator 

(21) Patients who can’t take antiplatelet drugs 

(22) Patients who might die of other disease than cardiac disease during the trial 

(23) Patients who the investigator judges ineligible due to other than the situations above 

(24) Use of dextran intravenously before PCI or intent to use it during PCI 

9.3.3. Removal of patients from therapy or assessment 

Subjects might drop/be discontinued due to the following reasons: 

(1) Dropout Criteria 

1) When a subject or legal agent withdraws the consent (The withdrawal will not 

jeopardize suject’s future treatment or care.) 

2) Failure to follow up after treatment with the investigational medication 


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(2) Discontinuation Criteria 

1) When the investigation medication is found to be toxic, which requires the drug to be 

discontinued 

2) When the investigator determines that continuous participation of the subject in the 

clinical trial is harmful to the subject’s health, well-being or reliability of trial results 

3) When the investigator determines that the progression of a participant’s disease has 

made the continuing participation diffcult 

4) Violations against the protocol 

- Patients not clearing all the exclusion criteria 

- Use of restricted concomitant medication 

- Termination of the trial before the last visit 

(3) Actions for Discontinuation or Violations against Protocol 

Reasons of dropout should be recorded in the subject’s source documents and CRF. Follow-up 

should be done to find out if adverse event is a reason for dropout. If so, it should be recorded 

according to the guideline for onset of adverse event 

If a subject did not pay a visit to the site as scheduled during the trial, the subject contacted on 

the phone or by mail to find out his or her health condition and reason why he or she did not 

show up. 

9.4. Treatments 

9.4.1. Dosage and administration method of investigational product 

Ten minutes to six hours prior to PCI, 0.25 mg/kg of Clotinab was administered IV bolus, 

followed by a 12-hour infusion of 0.125 mg/kg/min (Max 10 ug/min) dissolved in sterile saline 

of 0.9 % or dextrose of 5 %. 

9.4.2. Identity of investigational products 

9.4.2.1. Product name, generic name of main active ingredient, 

composition of raw material and formulation 


Ver. 1.0_Eng

Product Name Clotinab 

Generic Name Abciximab 

Composition of 

Raw Material 

Investigational drug 

- 1 ml contains 

Abciximab --------------------------------------------------------------- 2mg 

(Host cell: CHO DG44 cell) 

(Vector: Plasmid combined with heavy & light Chain = pdCMV-dhfr1, 

human γ1 constant region DNA, and human κ constant region DNA) 

Packing Unit 5 mL (10 mg), 2.5 mL (5 mg) 

Appearance 

and 

Formulation 

Clear and colorless solution in a clear and colorless vial 

Storage Vials should be stored at 2 to 8°C. Do not freeze. 

Product Name ReoPro ® 

Generic Name Abciximab 

Composition of 

Raw Material 

Packing Unit 5 mL (10 mg) 

Appearance 

and 

Formulation 

Comparator 

- 1 ml contains 

Abciximab --------------------------------------------------------------- 2mg 

(Host: SP2/0-Ag14 cell : SP2/0 cell) 

(Vector: Plasmid combined with light chain-pACY184, pSV2neo, and 

human κ constant region DNA: Plasmind combined with heavy chainpSV2gpt, 

and human γ1 constant region DNA) 

Clear and colorless solution in a clear and colorless vial 

Storage Vials should be stored at 2 to 8°C. Do not freeze. 

9.4.2.2. Packaging and labeling of investigational product 

The package and label of investigational product used in this trial included the recording as the 

followings; 

- Description that the item is “for clinical trial use” 

- Code name(s) of the product or generic name(s) of the active ingredient(s) 

- Manufacturing number and expiration date 

- Manufacturer (ISU ABXIS CO., Ltd.) 

- Store at 2 to 8°C. Do not freeze. 


Ver. 1.0_Eng

9.4.2.3. Management of investigational product 

The pharmacist in charge of investigational drugs took the responsibility for receiving, storing, 

preparing, taking care of and returning the drugs. 

The pharmacists made sure of receiving study drug, double-checked number of the drugs 

received on an invoice, signed the invoice, and took good care of the drug. He/she assured that 

the investigational drug was administered to eligible subjects per protocol only and kept a 

correct record of study drug given and managed. Unused investigational drugs should be kept 

until the sponsor makes a decision on discarding or collecting them. Managing pharmacists 

submited a copy of the record on all the unused drug, used/unused vials, labels, and drug 

management to the clinical trial monitor. 

9.4.3. Methd of assigning patients to treatment groups 

(1) A randomization list was made using a block randomization method. To create a 4:3 

allocation ratio between the treatment and control group, a block of size 7 was used for 

each center. The size of the block was not specified in the protocol or known to 

investigators. 

(2) Procedure 

When an eligible patient satisfying the inclusion/exclusion criteria was registered, the 

investigator filled up a request form for randomization allocation, faxed the form to Lifecord 

Stat-Korea (LSK), and called to ask whether the staff in charge of randomization allocation 

had received the request form. The staff at LSK wrote a randomization code, faxed the form 

back to the investigator, and called to confirm the randomization. 

Or the investigator called the LSK staff in charge of randomization allocation. The LSK staff 

gave the investigator the randomization code immediately. The investigator confirmed the 

randomization code by submitting the randomization request form to LSK via fax and 

making a call to the LSK staff. The LSK staff checked request form and signed and sent the 

form, back to the investigator via fax. The LSK staff confirmed whether the investigator had 

received the signed form. 

Both LSK staff in charge of randomization allocation and investigator kept a copy of the 

completed randomization request form (Details are shown in Appendix 16.1.6). 

Staff in charge in randomization allocation: 

Lifecord Stat-Korea(LSK) 


Ver. 1.0_Eng

Biostatisitician Kyoung-A Kim, Byeong-Kwan Park 

02-546-1008(Ext. 527), 02-546-0081 

9.4.4. Treatment method 

9.4.4.1 Percutaneous coronary intervention (PCI) procedure 

Coronary angiography or PCI was performed through femoral artery. Coronary angiography was 

performed via a 5~7 F guide catheter, and PCI was administered via a 6~8 F guide catheter. 

Through the catheter, a soft tipped, steerable guidewire (0.014'' (0.36 mm) diameter) was 

passed down the coronary artery, across the stenosis, and into a distal branch. A balloon 

catheter was then passed over the guidewire and positioned at the stenosis. After a balloon 

catheter inflates, a stent catheter was inserted if the remaing part of stenosis was over 35% or 

vascular obstruction occurred due to detachment from coronary or thrombus. Type of stent was 

selected at the doctor’s discretion. According to Thrombolysis in Myocardial Infarction (TIMI), 

coronary blood flow was scaled into 0 to 3 before and after the procedure. 

9.4.4.2 Actions to thrombocytopenia 

(1) Observe thrombocytopenia everyday until the platelet count becomes normal. 

(2) Stop administrating heparin and asprin if the platelet count is lower than 60,000 cells/㎕. 

(3) Transfuse platelet if the platelet count is lower than 50,000 cells/㎕. 

9.4.5. Concomitant therapy and restrictions 

9.4.5.1. Concomitant therapy 

(1) The investigator recorded all concomitant treatments on CRF. This record included the name 

of drugs, daily total dose, route of administration, onset and stop date of administration, 

and the indication. 

(2) Aspirin and heparin were used concomitantly as follows: 

1) Aspirin 

At least 2 hours before PCI, aspirin is administered, followed by oral administration of 

100-300 mg/day. In addition to asprin, Plavix® (Clopidogrel) may be administered 

with initial dosage of 300 - 450 mg (if necessary) and maintance dosage of 75 – 100 

mg/day. 


Ver. 1.0_Eng

2) Heparin 

- Heparin bolus administration prior to PCI procedure 

If the activated clotting time (ACT) of a subject prior to the PCI procedure is below 

200 seconds, heparin bolus is administrated to the artery access site according to 

the following regimen: 

ACT < 150 seconds: administer 70 U/㎏heparin 

ACT = 150 to 199 seconds: administer 50 U/㎏heparin 

ACT ≥ 200 seconds: administer no heparin 

- Additional heparin bolus administration during PCI procedure 

If the ACT is below 200 seconds, additional 20 U/kg heparin bolus is given to 

achieve and maintain an ACT of > 200 seconds during the procedure. If the ACT is 

still below 200 seconds, additional 20 U/kg heparin bolus is given until the ACT 

reaches longer than 200 seconds. 

- Heparin injection after the PCI procedure is performed at the investigator’s discretion. 

(3) The investigator recorded all concomitant treatments on CRF including antihypertensive 

drug (for example, Nitrates, β-adrenergic receptor blocker, Ca channel blocker, ACE inhibitor 

etc.). This record included the name of drugs, daily total dose, route of administration , onset 

and stop date of administration, and the indication. 

9.4.5.2. Restrictions on concomitant medication 

Following medications may have an effect on the trial, and were prohibited during the trial 

period. 

- Oral anticoagulants 

- Dextran (Concomitant use of dextran intravenously prior to PCI or during PCI was 

contraindicatd.) 

9.5. Efficacy and safety variables 

Efficacy endpoints 

(1) Primary efficacy endpoint 


Ver. 1.0_Eng

The primary efficacy endpoint is the onset of major adverse cardiac event (MACE) within 

30(+7) days from the study drug administration following the PCI procedure. The MACE 

includes the death related to heart disease, the recurrence of myocardial infarction (MI) and the 

emergency revascularization. 

(2) Secondary efficacy endpoint 

New change in electrocardiogram that indicates the status of ischemia 


(1) Bleeding 

(2) Thrombocytopenia 

(3) Change in Hb/Hct 

(4) HACA (human antichimetric antibody) development 

(5) Adverse event 

9.5.1. Efficacy and safety measurements assessed 

9.5.1.1. Efficacy measurement assessed 

Primary efficacy measurement assessed 

(1) Death 

Investigator classified the cause of death into ‘cardiovascular cause’ or ‘non-cardiovascular 

cause’ (If non-cardiovascular causes could not be clearly established, the cause of death was 

classified as ‘cardiovascular cause’). 

(2) Recurrence of Myocardial infarction (MI) 

MI was broadly categorized as STEMI or NSTEMI, and NSTEMI was further categorized 

according to the hospitalization status. 

1) STEMI 

It meets both criteria below: 

- CK-MB > 3 times the upper limit of normal value and increase of >50 % in the 

second sample over the first sample when two samples are collected at two 

different times. 

- New Q wave on the EKG of > 0.04 second duration or a depth > one-fourth of the 


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2) NSTEMI 

corresponding R wave amplitude, or both in two or more contiguous leads or reelevation 

in ST segment > 0.1 mV. 

① MI occurs during hospitalization and satisfies one of the following criteria: 

- CK-MB > 3 times the upper limit of normal value and increase of >50 % in the 

second sample over the first sample when two samples are collected at two 

different times. 


corresponding R wave amplitude, or both in two or more contiguous leads or ST 

segment elevation > 0.1 mV. 

② MI occurs following the discharge from hospital and satisfies one of the following 

criteria: 

- CK-MB > 2 times the upper limit of normal value 


corresponding R wave amplitude, or both in two or more contiguous leads or ST 

segment elevation > 0.1 mV. 

(3) Emergency Revascularization 

1) The second PCI after removing the guidewire while still in the catheterization laboratory 

was considered as the primary outcome. The return to the catheterization laboratory 

for emergency revascularization to treat recurrent ischemia was also considered as the 

primary outcome. A scheduled PCI (staged procedures) was not considered as the 

primary outcome. 

2) The coronary artery bypass graft to treat ischemia following the failed PCI was 

considered as the primary outcome. The elective surgery to treat pre-existing multi-vessel 

disease was not considered as the primary outcome. 

Secondary efficacy measurement assessed 

New change in electrocardiogram was decided by investigator’s decision about the ECG result. 


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9.5.1.2. Safety measurement assessed 

(1) Bleeding 

According to the TIMI criteria, bleeding is categorized into ‘major bleeding’, ‘minor bleeding’, 

or ‘clinically insignificant bleeding’. To measure the quantity of bleeding, the quantity of 

change in hemoglobin and hematocrit was adjusted according to whole blood and 

concentrated red blood cell (RBC) infused within 48 hours from the measurement. 

1) Major bleeding: Intracranial bleeding or decrease in hemoglobin count ≥ 5 g/dL (or 

decrease in hematocrit ≥ 15% if hemoglobin count is not available) 

2) Minor bleeding: - Spontaneous bleeding like gross hematuria or hematemesis 

- Spontaneous or iatrogenic bleeding observed with decrease in 

hemoglobin count ≥ 3 g/dL (or decrease in hematocrit ≥ 10% if 

hemoglobin count is not available) 

- Impossible to identify bleeding site with decrease in hemoglobin count 

≥ 4 g/dL (or decrease in hematocrit ≥ 12% if hemoglobin count is not 

available) 

3) Clinically insignificant bleeding: Minor bleeding not meeting the criteria above 


The following two criteria should be met: 

1) Decrease in the platelet count ≥ 25% when compared to the baseline count 

2) Platelet count < 100,000 

(3) Change in Hb/Hct 

(4) Human antichimetric antibody (HACA) development 

See HACA report in Appendix 16.1.9 for HACA test method 

(5) Adverse event 

1) Definition 

Adverse events (AEs) in clinical trials are defined as untoward and unintended signs, symptoms, 

or clinical effects which clinical trial participants experience during the observation period of the 

clinical trial. It is not necessary that AEs have to be causally related to the study drug. Adverse 


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events whose causal reations to the study drug cannot be excluded are defined as adverse drug 

reactions (ADRs). 

2) Observation period 

The observation period in this study starts when the subject signs the informed consent form 

is signed, and ends 14 days after the last protocol visit is made. 

3) Method 

i) The principal investigator and the sub-investigator have a responsibility for recording all 

AEs observed during the clnical trial. AEs should be recorded in medical terms if possible. If 

it is not possible, then signs or symptoms should be described based on observations by 

the principal investigator/sub-investigator or reported by the subject. 

ii) Regardless of causal relationship to the study drug, all AEs should be thoroughly monitored 

until they are resolved. Thair outcomes have to be evaluated. 

iii) Symptoms, signs, onset and termination dates, severity, actions taken, and serious AEs 

should be recorded in CRF. AEs’ causal relationships to the study drug have to be assessed. 

4) Severity of AE 

i) Mild: An AE is considered mild if it does not infere with everyday activities. The subject may 

not recognize a mild AE. Most mild AEs do not require treatment. 

ii) Moderate: An AE is considered moderate if it interferes with normal daily activities. A 

moderate AE may make the subject uncomfortable. The subject may keep participating in 

the trial, but may need treatment. 

iii) Severe: An AE is considered severe if it prevents the subjects from normal daily activities. 

A severe AE makes the subject very uncomfortable. The subject may stop the treatment,. 

The subject may be treated for the AE or may even have to be hospitalized. 

5) Causal Relationship to Study Drug 

i) Definite: Onset of AE is associated with administrating time of the study drug. The study 

drug explains onset of AE most directly than other factors. 

ii) Probable: Therer is association between onset of AE and administrating time of the study 

drug. The study drug explains onset of AE more than other factors. 

iii) Possible: Therer is association between onset of AE and administrating time of the study 

drug, however other possible factors explain onset of AE as much as the study drug does. 

iv) Improbable: Therer is no reasonable relationship between onset of AE and administrating 

time or type of the study drug, or there exists other probable cause. 


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v) None: AE occurs independently from administrating time of the study drug. 

vi) Unknown: Impossible to evaluate 

6) Treatment for AE 

All the patients experiencing AEs should be monitored until AE-related symptoms disappear and 

observed changes are satisfactorily explained. All observed outcomes of AEs are recorded in the 

AE section of CRF. 

9.5.2. Appropriateness of measurements 

The MACE occurrence rate in the high-risk patient group is commonly used as an efficacy 

endpoint(variable) and well-established in the clinical trial of abxicimab. 

9.5.3. Primary efficacy variable 

The primary efficacy endpoints is the onset of major adverse cardiac event (MACE) within 30 

(+7) days from the study drug administration following the PCI procedure. 

9.6. Data quality assurance 

Clinical laboratory tests and electrocardiogram readings were carried at participating medical 

centers, not at a central laboratory. All centers were certified by the quality control program of 

Korea Society of Clinical Pathologists. 

Investigational products, protocol, monitoring procedures and others were reviewed and 

discussed at the investigators’ meeting before activating the clinical trial. Also , at the initiation 

meeting of each institution, detailed information about the protocol, CRF, ICH-GCP was provided 

to the involved staff. 

The Sponsor supplied case report form(CRF)s to clinical trial centers. A copy would be kept at 

the cetner, and the original was sent to the sponsor. 

The clinical trial data were recorded in the CRF. All the records were written with a black ball 

point pen. When correction was needed, a single line was drawn, correction was made without 

erasing or whiting-out the record, and investigator’s signature and date of correction were 

entered. Investigators verified and signed CRF entries. CRF entries were verified against 


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source data document, If there were any discrepancies, they were noted on the CRF, and 

investigators took corrective actions. All the medical records were made avaible for review and 

clarification.. 

The pharmacist was delegated IP management by the principal investigator. The pharemacit 

received IP, checked the quantity, and managed IP in general. IP adminstration followed the 

protocol and instruction. Unused IP was retrieved by Sponsor; every unused drug, used/unused 

vials, labels, and copies of IP management document were sent to the monitor at the end of 

the trial. 

During the trial, monitors visited study centers regularly to mointor whether the trial was 

following the protocol, standard operation procedures, KGCP, and related regulations and 

guidliens. The source document was made to monitors, auditors, and IRB. Monitors could 

always access the entire source documents including CRFs, copies of laboratory result, and 

medical test results, and verified CRF entries and signed consents against the source document. 

The investigator collected and recorded all the AEs. The investigator reported SAEs to IRBs and 

the sponsor according to the “Chapter 17. Guidelines for adverse events” of the protocol. The 

SAE recporting procedure is consistent with the LSK SOP and related regulations. 

Data were transferred into database using DMSys 4.0, SigmaSoft International, Florida USA, by 

two entry persons. File comparison was performed. Medical Dictionary for Drug Regulatory 

Affairs(MedDRA) and Drug Reference list (Anatomic Therapeutic Chemical code:ATC code) were 

used to perform the medical coding of adverse events and medications. 

Data clarification forms (DCFs) were issued to query CRF entries. Consistency between essential 

documents for trial master files and essential documents for investigator site files was 

maintained. Corrections of CRF entries were reviewed and approved by the investigators. 

The datebase was locked on Februaty 08 th , 2006. 

9.7. Statistical methods planned in the protocol and determination of 

sample size 


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9.7.1. Statistical and Analytical Plans 

9.7.1.1. General principle for statistical analysis 

1) A one-sided significance test was applied to the primary efficacy endpoint at α = 0.05. All 

other significance tests was two-sided at α = 0.05. 

2) The efficacy analysis was the per protocol (PP) analysis. 

3) All statistical analysis was carried out by SAS ® Version 9.1, SAS institute, Cary, NC, USA. 

Exact confidence interval was computed by StatXact version 4.0, Cytel software corp. 

4) All confidence interval was presented by 95% exact confidence interval. 

9.7.1.2. Analysis of Demographic and Baseline characteristics 

Demographic variables (age, height, weight, sex) and baseline variables (medical history, 

concomitant medication) were summarized by treatment group. Descriptive statistics were 

produced for baseline demographic variables. Mean, standard deviation, median, and maximum 

and minimum were presented for continuous variables, and frequencies and proportions were 

generated for categorical variables. 

Continuous variables were compared using t-test or Wilcoxon rank sum test by treatment 

group. Categorical variables were compared using chi-square test or Fisher’s exact test. 

9.7.1.3. Efficacy Analysis 

Primary efficacy endpoint and analysis 

(1) Primary Efficacy Endpoint 

The primary efficacy endpoint was the onset of major adverse cardiac event (MACE) within 


included the death related to heart disease, the recurrence of myocardial infarction (MI) and the 


(2) Analysis methods 

The number and proportion of subjects experiencing the MACE were presented. The frequency, 

proportion and its exact 95% C.I. for subjects by MACE types were calculated. Frequency and 

proportion of MACE onset were summarized by MI (Myocardial infarction) and ACC/AHA 

classification. Chi-square test or Fisher’s exact test was performed to compare Clotinab and 

ReoPro ® . The efficacy interpretation followed the decision rule below. 

 


Ver. 1.0_Eng

Case A1. PP population 

If nine or fewer patients among seventy six subjects treated with Clotinab experience MACE, 

then the MACE onset rate is estimated to be below 20% and Clotinab is considered to be 

effective.. 

Case A2. ITT population 

If ten or fewer patients among eighty four subjects treated with Clotinab experience MACE, 


effective 

Case A3. FAS population 

If ten or fewer patients among eighty three subjects treated with Clotinab experience MACE, 


effective. 

Case B 

If the number of MACE patients is over the defined number in each population, efficacy of 

Clotinab is evaluated after adjusting the critical value based on the MACE onset rate in ReoPro ® . 

Secondary efficacy endpoint and analysis 

(1) Endpoint 

New change in electrocardiogram that indicates the status of ischemia. 

(2) Analysis methods 

Frequency, proportion and 95% exact C.I. of new changes from pre-administration to postadministration 

in electrocardiogram (yes/no) were presented. Fisher’s exact test was performed 

to find the differences between two groups. Frequency was presented and McNemar’s test was 

applied to determine if the changes in electrocardiogram from pre- to post-administration is 

significant. 

9.7.1.4. Safety endpoint and analysis 


(1) Bleeding 

According to the TIMI criteria, bleeding is categorized into ‘major bleeding’, ‘minor bleeding’, 

or ‘insignificant bleeding’. To measure the quantity of bleeding, the quantity of change in 

hemoglobin and hematocrit was adjusted according to whole blood and concentrated red 


Ver. 1.0_Eng

lood cell (RBC) infused within 48 hours from the measurement 

1) Major bleeding: Intracranial bleeding or decrease in hemoglobin count ≥ 5 g/dL (or 

decrease in hematocrit ≥ 15% if hemoglobin count is not available) 

2) Minor bleeding: - Spontaneous bleeding like gross hematuria or hematemesis 

- Spontaneous or iatrogenic bleeding observed with decrease in 

hemoglobin count ≥ 3 g/dL (or decrease in hematocrit ≥ 10% if 

hemoglobin count is not available) 

- Impossible to identify bleeding site with decrease in hemoglobin count 

≥ 4 g/dL (or decrease in hematocrit ≥ 12% if hemoglobin count is not 

available) 

3) Clinically insignificant bleeding: Minor bleeding not meeting the criteria above 

According to this category, frequency, proportion and its 95% exact C.I. were presented for 

Clotinab and ReoPro ® . Wilcoxon-Mann-Whitney test was performed for the differences in two 

study groups. 

For the major bleeding, frequency and proportion were described by Heparin dose, sex and 

weight. 


Details were described for the subjects whose platelet count < 100.000 and platelet count is 

decreased by ≥25% when compared to the baseline count. Frequency, proportion and its 95% 

C.I. were calculated. 

(3) Change of Hb/Hct 

Descriptive statistics (mean, standard deviation, median, minimum, maximum) were described 

by group and visit. Friedman Test was performed to test whether there is a significant 

difference in each time point. 

(4) HACA (human antichimetric antibody) development 

Frequency and proportion were presented for the patients showing positive response in HACA 

development by group. Fisher’s exact test was used to compare the positive response rate of 

Clotinab and ReoPro ® . 


Ver. 1.0_Eng

(5) Adverse Event 

The table summarized for the adverse events which occurred after the administration of the 

investigational drug or comparator drug. Other adverse events were reported in the listing. All 

adverse event were coded by system organ class (SOC) and preferred term(PT) using 

MedDRA(Medical Dictionary for Regulatory Activities)8.0 ® . Frequency and proportion by these 

codes were generated in two groups. For the relationship with the study drug, frequency was 

calculated by group for adverse events which were related to the study drug (Definite, Probable, 

Possible) and were not related to the study drug (Improbable, None, Unknown). Frequency, 

proportion (95% exact C.I.) were presented for the number of adverse event and the number 

of subjects with adverse events occurred at least once. Serious adverse events were 

summarized using the following category: adverse event results in death or stopping of study 

drug. 

(6) Laboratory data 

The descriptive statistics (mean, standard deviation, median, minimum, maximum) were 

presented by group and visit for continuous variables such as hematology, serum chemistry and 

vital sign. Frequency and proportion of status (normal/clinically insignificant abnormal/clinically 

significant abnormal) in each visit compared to screening or baseline were described for 

categorical variables such as urine test status. 

9.7.1.5. Missing data 

If a subject terminated the trial early or did not make the final visit, the efficacy and safety data 

should be collected as much as possible. If the efficacy data could not be obtained, they were 

treated as missind data. 

9.7.2. Determination of sample size 

ReoPro ® developed abroad was approved in the country and is currently on the domestic 

market. Clotinab, a platelet IIb/IIIa inhibitor, which was developed by ISUABXIX Ltd. has same 

active ingredient as ReoPro ® and is expected to have a similar efficacy to ReoPro ® . 

The clinical trial is designed to prove that event rate of the primary efficacy endpoint of Clotinab 

is below 20%. The followings are the statistical null hypothesis and alternative hypothesis in the 

phase Ⅱ of the clinical trial on Clotinab. 


Ver. 1.0_Eng

H0 : p ≥ 0.2 versus HA : p < 0.2 

That is, it is assumed that the event rate is over 0.2 and Clotinab doesn’t have efficacy until the 

efficacy of Clotinab is tested. If the null hypothesis is rejected by the clinical trial, it is concluded 

that the event rate of Clotinab is below 0.2. 

The clinical trial set the event rate of 9 % 14) . Data distribute binomially and sample size and 

critical value were obtained using the calculating process below. Because the data are binomial, 

not continuous and can’t satisfy significance level and power exactly at 0.05 and 0.80, the 

closest significance level and power were selected. 

Sample Size and Calculating Process for Critical Value 

Notations: 

X: Number of subjects to whom the event occurs out of N subjects 

P: event rate 

Number of subjects was calculated under the following condition. 

α = Pr( X ≤ k | H 

0 

: P = 

Power = Pr( X ≤ k | H 

A 

0. 

2) 

: P = 

= 1 − 

0. 

09) 

n 

∑ 

C 

x= 

k + 1 

n 

x 

= 1 − 

p 

x 

n 

∑ 

x= 

k + 1 

( 1 − p) 

C 

0. 

05 


Ver. 1.0_Eng 

n 

x 

p 

x 

n− 

x 

≤ 

( 1 − p) 

n− 

x 

≥ 

0. 

80 

n and k that satisfy the conditions above are 70 and 8. Significance leve is 0.04371 and power 

is 0.82407. 

Because ReoPro ® is on the market with already proved efficacy, 30 subjects is recuited for the 

drug to get a reference point for decisions rule (When n=30, t distribution approaches to 

normal distribution. Namely, when sample size is 30, sample distribution approaches to 

distribution of population). 

Total of 112 is recuited to keep in consideration that dropout becomes 10%. When the number

of subjects enrolled reaches to 70 in the Clotinab group and 30 in the ReoPro ® group, the trial 

is terminated. 

10. Study patients 

10.1. Disposition of patients 

A total of 124 patients were screened for this trial at 3 centers. First 31 patients were assigned 

to Clotinab treatment without randomization. Afterwards, ninety-three patients were admitted 

and randomized into Clotinab and ReoPro ® groups, 53 into Clotinab group and 40 into ReoPro ® 

group. Of 124 subjects screened, 1 subject(Y022) was dropped before the treatment started, 

because the patient was found ineligible after the study entry. After study medications and PCI 

procedures were administered to 123 patients, one Clotinab subject (C025) withdrew the 

consent, and dropped out of the trial. Disposition status of 124 patients screened are shown in 

Table 10.1:1 and Figure 10.1:1. 


Ver. 1.0_Eng

Table 10.1:1 Disposition of Subjects 

Clotinab ReoPro ® 

1 2 3 1 2 3 Total 

Planed 112 

Screened 21 46 17 11 20 9 124 

Non-randomized 7 20 4 0 0 0 31 

Treated 7 20 4 0 0 0 31 

Non-Treated 0 0 0 0 0 0 0 

Randomized 14 26 13 11 20 9 93 

Treated 14 25 13 11 20 9 92 

Non-Treated 

Status 

0 1 0 0 0 0 1 

Completed 21 45 16 11 20 9 122 

Withdrawal 

Reason for withdrawal 

1 1 2 

Adverse event 

Drop out by investigator’s decision 

Protocol violation 

Consent withdrawal 

Follow-up failure 

1 1 

Others 

Efficacy populations 

1 1 

ITT (Intention-To-Treat Analysis) 21 46 17 11 20 9 124 

FAS(Full analysis set) 21 45 17 11 20 9 123 

PP (Per-Protocol Analysis) 21 41 14 11 17 8 112 

Safety populations 21 45 17 11 20 9 123 

1: Severance Hospital, School of Medicine, Yonsei University., 2: Asan Medical Centre, 3: 

Chonnam National University Hospital 


Ver. 1.0_Eng

Figure 10.1:1 Disposition of subjects 

N=1 

PCI failure 

N=31 

Patients ISU301 treated 

N=30 

Completed 

N=76(ISU301) 

PP 

DISPOSITION OF PATIENTS 

N=51 

Completed 

N=124 

Patients screened 

N=52 

ISU301 

treated 

N=53 

ISU301 

N=1 

Withdrawal 

N=52) N=1 

N=8, Major violation 

1) N=23) 10.2. Protocol deviations 

N=93 

Patients randomized 

N=1 

Withdrawal 

(SF but RDZ) 

N=40 

ReoPro 

N=40 

Completed 

N=36(ReoPro) 

PP 

N=4, Major violation 4) 

Protocol deviations were reviewed at a blind meeting (08-Feb-2006) after database lock(08- 

Feb-2006). Details of protocol deviations related to the efficacy endpoint were recorded in the 

minutes of “Protocol Deviation Meeting” (See Appendix 16.2.2). 

There were 12 subject with major protocol deviation, one 1) was for CABG treatment after PCI 

failure, Five Clotinab patients 2) who completed the trial were considered to be major protocol 

deviations; of the five, 4 patients did not clear ‘exclusion criteria No.17’ , and 1 patient made 

the study-completion return visit on Day10. rather than on Day 30. Two 3) patients dropped out 

of the study: 1 subject withdrew the consent on Day 2, 1 randomized subject was dropped out 

who should have been a screening-failure. Four ReoPro ® patients 4) were considered major 

protocol violations; 3 subjects did not clear ‘exclusion criteria No.17’, and 1 subject was given a 

deviant amount of the drug because of an accidental disconnection of IV line during IP 

administration. Details are shown in Figure 10.1:1 and Table 10.2:1. 


Ver. 1.0_Eng

Table 10.2:1 Listing of subjects with major protocol deviation 

NO. Subject ID Group Comment 

1 C003 Clotinab CABG after PCI failure 

2 C017 Clotinab Deviation of exclusion criteria No.17 

3 C025 Clotinab Consent withdrawal 

4 Y008 Clotinab Deviation of exclusion criteria No.17 



7 Y020 Clotinab Early study-completion visit (day10) 

8 Y022 Clotinab Screening failure but RDZ 

9 C007 ReoPro ® Deviation of exclusion criteria No.17 

10 Y024 ReoPro ® Treatment amount and method of IP(line disconnected) 

11 Y047 ReoPro ® Deviation of exclusion criteria No.17 

12 Y063 ReoPro ® Deviation of exclusion criteria No.17 

11. Efficacy evaluation 

11.1. Data sets analysed 

The analysis was done with the following 4 populations: 

1) ITT(Intention-to-treat) Population 

2) FAS(Full Analysis) Population 

3) PP(Per-Protocol) Population 

4) Safety Population 

Since the main objective of this study, like most phase Ⅱ clinical trials, was to explore whether 

the study drug had a promising activity, it was hard to achieve the objective if analysis included 

ineligible subjects or subjects to whom the investigational medicine could not be administered 

during the PCI procedure. Thus, PP analysis was the main analysis to evaluate the efficacy of 

the drug. PP population included subjects who completed the trial but excluded ineligible 

subjects, subjects to whom the investigational medicine could not be administered during the 

PCI procedure and subjects with serious protocol violations. The analyses with FAS (Full 

analysis set) and ITT (Intention to treat) populations were also given and compared. 

The ITT group consisted of all the stage 1 participants with signed consent forms and all the 

stage 2 participants with signed consent forms and randomized treatment assignment. All the 


Ver. 1.0_Eng

ITT subjects to whom the study drug had been administered make up the FAS. All the FAS 

subjects who had completed the trial without serious protocol violation became the PP set. 

The safety population consisted of the study participants to whom the study drug was 

administered even partially. The analysis was done according to the drugs actually received. 

Of 124 subjects including 31 Clotinab patients from the stage 1, 84 subjects received Clotinab, 

and 40 received ReoPro ® . The ITT set consisited of all 124 patients. The FAS consisted of 123, 

83 Clotinab patients and 40 ReoPro ® patients. The PP set consisted of 112 patients, 76 Clotinab 

patients and 36 ReoPro ® patients. 

The FAS population was the safety analysis set. 

Details are shown in Appendix 16.2.2. 

11.2. Demographic and other baseline characteristics 

11.2.1. Demographic characteristics 

The distribution of subjects by diseases based on the coronary arteriostenosis ACC/AHA criteria 

defined by angiography is as follows: 67 patients had one type C lesion characteristic,; 40 

patients had two type B lesion characteristics; 26 patients were refractory to drug treatmentin 

resting phase and with recurrent angina pectoris, and showed ischemic ST change in 

electrocardiogram; and 22 post-infarction angina patients were within 7 days after myocardial 

infarction attack that is refractory to drug treatment, and showed ischemic ST change in 

electrocardiogram. There was no significant difference in the distribution of disease status 

between two drug groups (Tables 11.2.1.1-3). 

Demographic characteristics of study participants were summarized in Table 11.2.1:4. There 

were 98 male patients and 26 female patients. The mean age was 58.8±10.50, the mean 

height 165.2±7.82cm and 165.1±8.00cm, and the mean weight was 68.7±12.09kg. There was 

no significant difference in these variables between two treatment groups. 

Demographic characteristics for the FAS population and the PP population were summarized in 

Table 11.2.1:5 and Table 11.2.1.6. There was no significant difference between two different 

groups in the FAS population or in the PP population. 

The Clotinab group was recruited in two stages, first 31 patients without randomization and 


Ver. 1.0_Eng

1) 

2) 

3) 

4) 

next 53 patients with randomization. Characteristics of the first stage patients and the second 

stage patients are summarized in Table 11.2.1:4. and Table 11.2.1:5 These two groups and the 

ReoPro ® group do not show any statistically significant difference. 

Table 11.2.1:1 Distribution of Subjects by Diseases (can select more then one item)-ITT 

Items 

Ischemic ST change in electrocardiogram plus being refractory to drug treatment in 

resting phase or with recurrent angina pectoris 

Ischemic ST change in electrocardiogram plus post-infarction angina patients within 7 

days after myocardial infarction attack that is refractory to drug treatment 

Acute Q-Wave myocardial infarction within 12 hours after the attack, which require 



another procedure after failure to thrombolytic therapy 

Clotinab 

(N= 84) 

ReoPro ® 

(N= 40) 


Ver. 1.0_Eng 

P-value 

18 8 0.8551 a) 

16 6 0.5813 a) 

6 4 0.7258 b) 

4 2 1.0000 b) 

5) Two type B lesion characteristics* 29 11 0.4341 a) 

6) One type C lesion characteristic* 45 22 0.8814 a) 

7) Females aged over 65 with one type B lesion characteristic* 4 1 1.0000 b) 

8) Diabetics with one lesion type B characteristic* 6 6 0.1990 b) 

1) 

2) 

3) 

4) 

* The Coronary arteriostenosis ACC/AHA classification defined by angiography 

a) P-value from Chi-square test b) Fisher’s exact test 

Table 11.2.1:2 Distribution of Subjects by Diseases (can select more then one item)-FAS 

Items 


resting phase or with recurrent angina pectoris 

Ischemic ST change in electrocardiogram plus post-infarction angina patients within 7 

days after myocardial infarction attack that is refractory to drug treatment 





Clotinab 

(N= 83) 

ReoPro ® 

(N= 40) 

P-value 

17 8 0.9504 a) 

16 6 0.5620 a) 

6 4 0.7266 b) 

4 2 1.0000 b) 


6) One Type C lesion characteristic* 45 22 0.9349 a)



1) 

2) 

3) 

4) 



Table 11.2.1:3 Distribution of Subjects by Diseases (can select more then one item)-PP 

Items 


resting phase orwith recurrent angina pectoris 

Ischemic ST change in electrocardiogram among post-infarction angina patients within 

7 days after myocardial infarction attack that is refractory to drug treatment 





Clotinab 

(N= 76) 

ReoPro ® 

(N= 36) 


Ver. 1.0_Eng 

P-value 

16 8 0.8880 a) 

12 6 0.9060 a) 

5 3 0.7103 b) 

4 0 0.3034 b) 


6) One type C lesion characteristic* 41 20 0.8732 a) 





Table 11.2.1:4 Subject demographics (ITT, I) 

Demographic Variable Clotinab ReoPro ® Total P-value 

N 84 40 

Sex 

124 

Male 68 ( 81.0%) 30 ( 75.0%) 98 ( 79.0%) 0.4466 2) 

Female 16 ( 19.0%) 10 ( 25.0%) 26 ( 21.0%) 

Age (year) 

N 84 40 124 

Mean 58.7 59.0 58.8 

Median 60.0 60.0 60.0 0.8931 1) 

SD 10.57 10.47 10.50 

Min 30.0 37.0 30.0

Max 77.0 77.0 77.0 

Height (cm) 

N 82 a) 40 122 

Mean 165.3 165.1 165.2 

Median 165.0 167.2 165.0 0.9046 1) 

SD 7.77 8.00 7.82 

Min 143.3 148.0 143.3 

Max 178.0 178.5 178.5 

Weight (Kg) 

N 83 b) 40 123 

Mean 68.3 69.7 68.7 

Median 66.7 69.3 67.4 0.5412 1) 

SD 11.29 13.70 12.09 

Min 45.0 43.0 43.0 

Max 100.0 106.0 106.0 

1) P-value from T-test, 2) P-value from Chi-square test 

a) The height measurement was missing in two patients b) The weight measurementwas missing in one 

patient 


Ver. 1.0_Eng

Table 11.2.1:4 Subject demographics (ITT, II) 

Demographic Variable Clotinab a) Clotinab b) ReoPro ® Total P-value 

N 31 53 40 124 

Sex 

Male 27 ( 87.1%) 41 ( 77.4%) 30 ( 75.0%) 98 ( 79.0%) 0.5311 2) 

Female 4 ( 12.9%) 12 ( 22.6%) 10 ( 25.0%) 26 ( 21.0%) 

Age (year) 

N 31 53 40 124 

Mean 59.8 58.0 59.0 58.8 

Median 59.0 60.0 60.0 60.0 0.7461 1) 

SD 9.45 11.21 10.47 10.50 

Min 37.0 30.0 37.0 30.0 

Max 77.0 74.0 77.0 77.0 

Height (cm) 

N 31 51 c) 40 122 

Mean 166.7 164.4 165.1 165.2 

Median 170.0 164.0 167.2 165.0 0.6357 1) 

SD 7.43 7.91 8.00 7.82 

Min 150.0 143.3 148.0 143.3 

Max 177.0 178.0 178.5 178.5 

Weight (Kg) 

N 31 52 d) 40 123 

Mean 70.3 67.1 69.7 68.7 

Median 69.1 65.5 69.3 67.4 0.7017 1) 

SD 9.89 11.97 13.70 12.09 

Min 50.0 45.0 43.0 43.0 

Max 86.3 100.0 106.0 106.0 

1) P-value from ANOVA 2) P-value from Chi-square test a) Stage i b) Stage ii 

c) The height measurement was missing in two patients d) The weight measurement was missing in one 

patient 


Ver. 1.0_Eng

Table 11.2.1:5 Subject demographics (FAS, I) 


N 83 40 123 

Male 67 ( 80.7%) 30 ( 75.0%) 97 ( 78.9%) 0.4665 2) 

Female 16 ( 19.3%) 10 ( 25.0%) 26 ( 21.1%) 


Ver. 1.0_Eng 

Sex 

Age (year) 

N 83 40 123 

Mean 58.7 59.0 58.8 

Median 60.0 60.0 60.0 0.9017 1) 

SD 10.63 10.47 10.54 

Min 30.0 37.0 30.0 

Max 77.0 77.0 77.0 

Height (cm) 

N 81 a) 40 121 

Mean 165.2 165.1 165.1 

Median 165.0 167.2 165.0 0.9610 1) 

SD 7.76 8.00 7.81 

Min 143.3 148.0 143.3 

Max 178.0 178.5 178.5 

Weight (Kg) 

N 82 b) 40 122 

Mean 68.2 69.7 68.7 

Median 66.6 69.3 67.4 0.5217 1) 

SD 11.34 13.70 12.13 

Min 45.0 43.0 43.0 

Max 100.0 106.0 106.0 


a) The height measurement was missing in two patients b) The weight measurement was missing in one 

patient

Table 11.2.1:5 Subject demographics (FAS, II) 


N 31 52 40 123 


Ver. 1.0_Eng 

Sex 

Male 27 ( 87.1%) 40 ( 76.9%) 30 ( 75.0%) 97 ( 78.9%) 0.5106 2) 

Female 4 ( 12.9%) 12 ( 23.1%) 10 ( 25.0%) 26 ( 21.1%) 

Age (year) 

N 31 52 40 123 

Mean 59.8 58.1 59.0 58.8 

Median 59.0 60.0 60.0 60.0 0.7550 1) 

SD 9.45 11.32 10.47 10.54 

Min 37.0 30.0 37.0 30.0 

Max 77.0 74.0 77.0 77.0 

Height (cm) 

N 31 50 c) 40 121 

Mean 166.7 164.2 165.1 165.1 

Median 170.0 164.0 167.2 165.0 0.6446 1) 

SD 7.43 7.87 8.00 7.81 

Min 150.0 143.3 148.0 143.3 

Max 177.0 178.0 178.5 178.5 

Weight (Kg) 

N 31 51 d) 40 122 

Mean 70.3 66.9 69.7 68.7 

Median 69.1 65.0 69.3 67.4 0.7107 1) 

SD 9.89 12.05 13.70 12.13 

Min 50.0 45.0 43.0 43.0 

Max 86.3 100.0 106.0 106.0 



patient

Table 11.2.1:6 Subject demographics (PP, I) 


N 76 36 112 

Male 60 ( 78.9%) 27 ( 75.0%) 87 ( 77.7%) 0.6394 2) 

Female 16 ( 21.1%) 9 ( 25.0%) 25 ( 22.3%) 


Ver. 1.0_Eng 

Sex 

Age (year) 

N 76 36 112 

Mean 59.5 58.3 59.1 

Median 60.5 58.5 60.0 0.5651 1) 

SD 10.35 10.38 10.33 

Min 30.0 37.0 30.0 

Max 77.0 77.0 77.0 

Height (cm) 

N 74 a) 36 110 

Mean 164.7 165.2 164.9 

Median 164.7 167.9 165.0 0.7496 1) 

SD 7.83 7.91 7.82 

Min 143.3 148.0 143.3 

Max 178.0 178.5 178.5 

Weight (Kg) 

N 75 b) 36 111 

Mean 67.4 69.5 68.1 

Median 66.0 69.5 67.0 0.3959 1) 

SD 11.20 13.33 11.91 

Min 45.0 43.0 43.0 

Max 100.0 106.0 106.0 


a) The height measurement was missing in two patients b) The weight measurement was missing in one 

patient

Table 11.2.1:6 Subject demographics (PP, II) 


N 26 50 36 112 


Ver. 1.0_Eng 

Sex 

Male 22 ( 84.6%) 38 ( 76.0%) 27 ( 75.0%) 87 ( 77.7%) 0.6746 2) 

Female 4 ( 15.4%) 12 ( 24.0%) 9 ( 25.0%) 25 ( 22.3%) 

Age (year) 

N 26 50 36 112 

Mean 61.0 58.7 58.3 59.1 

Median 60.5 60.5 58.5 60.0 0.5694 1) 

SD 9.29 10.86 10.38 10.33 

Min 37.0 30.0 37.0 30.0 

Max 77.0 74.0 77.0 77.0 

Height (cm) 

N 26 48 c) 36 110 

Mean 165.7 164.1 165.2 164.9 

Median 169.2 164.0 167.9 165.0 0.5215 1) 

SD 7.49 8.03 7.91 7.82 

Min 150.0 143.3 148.0 143.3 

Max 175.0 178.0 178.5 178.5 

Weight (Kg) 

N 26 49 d) 36 111 

Mean 68.8 66.7 69.5 68.1 

Median 66.5 65.0 69.5 67.0 0.5525 1) 

SD 9.77 11.92 13.33 11.91 

Min 50.0 45.0 43.0 43.0 

Max 86.3 100.0 106.0 106.0 



patient 

11.2.2. Baseline characteristics 

Data from pre-trial interviews are summarized in Tables 11.2.2:1 to 11.2.2.3 for the ITT, FAS, 

and PP population by treatment group. Of 124 registered patients 43 were smokers (34.68%). 

No one uses alcohol or drug. Contraceptive was applicable to no one. There was no evidence of 

signiticant difference between two treatment groups.

Medical history data are summarized in Tables 11.2.2:4 to 11.2.2:6 for the ITT, FAS, and PP 

population. Of 124 registered patients, 28 (22.58%) have history of endocrine disease, 

11(8.87%) have some allergy, 8 (6.45%) have history of gastrointestinal/hepatobiliary disease, 

and 8(6.45%) have history of neurological/mental disorder. Other diseases or disorders are all 

below a 5% prevalence rate. Two treatment groups are not significantly different 

Table 11.2.2:1 Pre-trial interview (ITT) 

Demographic Variable Clotinab ReoPro ® Total 

N 

Smoking 

84 40 124 

Yes 30(35.71%) 13(32.50%) 43(34.68%) 

No 54(64.29%) 27(67.50%) 81(65.32%) 

Cigarettes/Day 

N 27* 13 40 

Mean 20.5 21.5 20.9 

Median 20.0 20.0 20.0 

SD 14.31 8.01 12.51 

Min 2.0 10.0 2.0 

Max 60.0 40.0 60.0 

Alcoholic 

Yes 0( 0.00%) 0( 0.00%) 0( 0.00%) 

No 84(100.0%) 40(100.0%) 124(100.0%) 

Drug abuser 

Yes 0( 0.00%) 0( 0.00%) 0( 0.00%) 

No 84(100.0%) 40(100.0%) 124(100.0%) 

Contraception 

Not applicable 16 10 26 

Male 68 30 98 

Not applicable :Menopause, hysterectomy, salpingectomy 

*Difference in number of patients is due to missing data. 


Ver. 1.0_Eng

Table 11.2.2:2 Pre-trial interview (FAS) 


N 83 40 123 

Smoking 

Yes 30(36.14%) 13(32.50%) 43(34.96%) 

No 53(63.86%) 27(67.50%) 80(65.04%) 


N 27* 13 40 

Mean 20.5 21.5 20.9 

Median 20.0 20.0 20.0 

SD 14.31 8.01 12.51 

Min 2.0 10.0 2.0 

Max 60.0 40.0 60.0 

Alcoholic 

Yes 0( 0.00%) 0( 0.00%) 0( 0.00%) 

No 83(100.0%) 40(100.0%) 123(100.0%) 

Drug abuser 

Yes 0( 0.00%) 0( 0.00%) 0( 0.00%) 

No 83(100.0%) 40(100.0%) 123(100.0%) 

Contraception 


Male 67 30 97 




Ver. 1.0_Eng

Table 11.2.2:3 Pre-trial interview (PP) 


N 76 36 112 

Smoking 

Yes 25(32.89%) 12(33.33%) 37(33.04%) 

No 51(67.11%) 24(66.67%) 75(66.96%) 


N 23* 12 35 

Mean 21.7 20.0 21.1 

Median 20.0 20.0 20.0 

SD 14.94 6.03 12.52 

Min 2.0 10.0 2.0 

Max 60.0 30.0 60.0 

Alcoholic 

Yes 0( 0.00%) 0( 0.00%) 0( 0.00%) 

No 76(100.0%) 36(100.0%) 112(100.0%) 

Drug abuser 

Yes 0( 0.00%) 0( 0.00%) 0( 0.00%) 

No 76(100.0%) 36(100.0%) 112(100.0%) 

Contraception 


Male 60 27 87 




Ver. 1.0_Eng

Table 11.2.2:4 Medical History (ITT) 

ITEM Clotinab 

(N=84) 

ReoPro ® 

(N=40) 


Ver. 1.0_Eng 

Total 

(N=124) 

Allergy 5( 5.95%) 6(15.00%) 11( 8.87%) 

Peripheral vascular 1( 1.19%) 0( 0.00%) 1( 0.81%) 

Skin/mucous membrane 0( 0.00%) 2( 5.00%) 2( 1.61%) 

Eye 0( 0.00%) 1( 2.50%) 1( 0.81%) 

Ear,nose,throat 1( 1.19%) 1( 2.50%) 2( 1.61%) 

Respiratory 4( 4.76%) 1( 2.50%) 5( 4.03%) 

Musculoskeletal(Excluding hernia) 1( 1.19%) 3( 7.50%) 4( 3.23%) 

Infectious Disease 1( 1.19%) 0( 0.00%) 1( 0.81%) 

Gastrointestinal/hepatobiliary 6( 7.14%) 2( 5.00%) 8( 6.45%) 

Endocrine 18(21.43%) 10(25.00%) 28(22.58%) 

Kidney/genitourinary 3( 3.57%) 0( 0.00%) 3( 2.42%) 

Neuro/Mental 5( 5.95%) 3( 7.50%) 8( 6.45%) 

Neoplasm 0( 0.00%) 0( 0.00%) 0( 0.00%) 

Fracture 0( 0.00%) 0( 0.00%) 0( 0.00%) 

Major operation 0( 0.00%) 0( 0.00%) 0( 0.00%) 

Others 3( 3.57%) 0( 0.00%) 3( 2.42%)

Table 11.2.2:5 Medical History (FAS) 

ITEM Clotinab 

(N=83) 

ReoPro ® 

(N=40) 


Ver. 1.0_Eng 

Total 

(N=123) 

Allergy 5( 6.02%) 6(15.00%) 11( 8.94%) 



Eye 0( 0.00%) 1( 2.50%) 1( 0.81%) 


Respiratory 4( 4.82%) 1( 2.50%) 5( 4.07%) 




Endocrine 17(20.48%) 10(25.00%) 27(21.95%) 


Neuro/Mental 5( 6.02%) 3( 7.50%) 8( 6.50%) 

Neoplasm 0( 0.00%) 0( 0.00%) 0( 0.00%) 

Fracture 0( 0.00%) 0( 0.00%) 0( 0.00%) 


Others 3( 3.61%) 0( 0.00%) 3( 2.44%)

Table 11.2.2:6 Medical History (PP) 

ITEM Clotinab 

(N=76) 

ReoPro ® 

(N=36) 


Ver. 1.0_Eng 

Total 

(N=112) 

Allergy 4( 5.26%) 5(13.89%) 9( 8.04%) 



Eye 0( 0.00%) 1( 2.78%) 1( 0.89%) 


Respiratory 4( 5.26%) 1( 2.78%) 5( 4.46%) 




Endocrine 16(21.05%) 10(27.78%) 26(23.21%) 


Neuro/Mental 4( 5.26%) 3( 8.33%) 7( 6.25%) 

Neoplasm 0( 0.00%) 0( 0.00%) 0( 0.00%) 

Fracture 0( 0.00%) 0( 0.00%) 0( 0.00%) 


Others 3( 3.95%) 0( 0.00%) 3( 2.68%) 

11.2.3. Medication administered prior to trial 

Antithrombotic agents were the most frequently used medication within 7 days before the study. 

All 124 patients used some antithrombotic agents. 116 patients (93.65%) used some cardiac 

therapy. 100 patients (80.65%) used beta blocking agents. See Table 15.1 for other drug uses 

and details. See also Table 15.3 and 15.5 for prior drug therapy history in the FAS and PP 

population. 

11.2.4. Medication administered during trial 

All 123 patients (patient Y022 withdrew from the trial after randomization, thus not considered 

here) used antithrombotic agents during the trial. 118 out of 123 (95.93%) used some cardiac 

therapy. 101 out of 123 (82.11%) used beta blocking agents. See Table 15.2 for other drug 

uses and details. See Table 15.4 and 15.6 for concomitant medications in the FAS and PP 

population.

11.3. Efficacy results, tabulations, and analysis 

11.3.1. Primary efficacy analysis 

The primary efficacy endpoint is the onset of major adverse cardiac event (MACE) within 


includes the death related to heart disease, the recurrence of myocardial infarction (MI) and the 


The number of Clotinab patients experiencing MACE was 0 among 76 PP patients. The MACE 

rate is 0.00%, and its 95% exact C.I. is (0.00%, 4.74%). Note that the upper confidence bound 

is below 5%. The number of ReoPro ® patients experiencing MACE was 2 (C021 and Y056) 

among 36 PP patients. The observed MACE rate is 5.56%, and its 95% exact C.I. (0.68%, 

18.66%). Note that the upper confidence bound is below 20%. See Table 11.3.1:1 for more 

details. The two ReoPro ® patients experiencing MACE had two type B lesion characteristics 

according to ACC/AHA criteria defined by angiography and acute Q-Wave myocardial infarction 

within 12 hours after the attack, which requires direct intervention procedure. (See Table 

11.3.1:2) 

The ITT population analysis shows little variation from the PP analysis. None of 84 Clotinab 

subjects experienced MACE. The observed MACE rate is 0.0% and its 95% exact C.I. (0.00%, 

4.30%). Two of 40 ReoPro ® subjects experienced. The observed MACE rate is 5.00%, and its 

95% exact C.I. is (0.61%, 16.92%) (See Table 11.3.1:3). 

The FAS population of 123 patients produced an almost identical result as the ITT population. 

The MACE rate of 83 Clotinab patients was 0, and its 95% exact C.I. is (0.00%, 4.35%), and 

the MACE rate of 40 ReoPro ® patients is 5.00%, and its 95% exact C.I. is (0.61%, 16.92%). 

(See Table 11.3.1:6). 

The protocol presented the decision rule for 70 subjects. However the decision rule was 

modified to maintain the significance level 5% for the number of subjects different from 70. 

The number of PP Clotinab patients is 76, and if the number of MACE cases is ≤9 (called the 

cutoff point), then the treatment is considered effective at the 20% response rate. The number 

of ITT Clotinab patients is 84, and the number of FAS Clotinab patients is 83. The cutoff point 

for the number of subjects 83 and 84, is the same, 10 


Ver. 1.0_Eng

Treatment 

Group 

Clotinab 

(N=76) 

ReoPro ® 

(N=36) 

The number of Clotinab subjects who experienced MACE was 0. Therefore, regardless of the 

analysis population, we can conclude that Clotinab is effective, and that the MACE onset rate in 

patients treated with Clotinab is below 5%. 

Table 11.3.1:1 Major Adverse Cardiac Event (MACE)-PP 

MACE 12hr 24hr Day 3 

Death due to cardiac 

disease 

Recurrence of 

myocardial infarction 

Emergency 

revascularization 

(One day 

before) 

Discharge 

Day 

30(+7) 

0 0 0 0 0 0 

0 0 0 0 0 0 

0 0 0 0 0 0 


Ver. 1.0_Eng 

Total 

Cut off 

Value 

Total 0 0 0 0 0 0

Angina (%) 

Table 11.3.1:2 Major Adverse Cardiac Event (MACE) in the Subgroups-PP 

Ischemic ST change in electrocardiogram plus being 

refractory to drug treatment in resting phase or with 

recurrent angina pectoris 

Ischemic ST change in electrocardiogram among postinfarction 

angina patients within 7 days after myocardial 

infarction attack that is refractory to drug treatment 

MI (%) 

Acute Q-Wave myocardial infarction within 12 hours after 

the attack, which require direct intervention procedure 

Acute Q-Wave myocardial infarction within 12hours after the 

attack, which require another procedure after failure to 

thormbolytic therapy 

ACC/AHA classification (%) 

Clotinab 

(N=76) 

MACE 

ReoPro ® (N=36) 

MACE 


Ver. 1.0_Eng 

Total 

0(0.00%) 0(0.00%) 0 

0(0.00%) 0(0.00%) 0 

0(0.00%) 2(5.56%) 2* 

0(0.00%) 0(0.00%) 0 

Two type B lesion characteristics 0(0.00%) 2(5.56%) 2* 

One type C lesion characteristic 0(0.00%) 0(0.00%) 0 

Females aged over 65 with one type B lesion characteristic 0(0.00%) 0(0.00%) 0 

Diabetics with one lesion type B characteristic 0(0.00%) 0(0.00%) 0 

Treatment 

Group 

Clotinab 

(N=84) 

ReoPro ® 

(N=40) 

* C021, Y056 

Table 11.3.1:3 Major Adverse Cardiac Event (MACE)-ITT 



disease 

Recurrence of 


Emergency 


(One day 

before) 

Discharge 

Day 

30(+7) 

0 0 0 0 0 0 

0 0 0 0 0 0 

0 0 0 0 0 0 

Total 

Cut off 

Value 

Total 0 0 0 0 0 0

Angina (%) 

Total 0 0 0 0 2(5.00%) 2(5.00%) 

Table 11.3.1:4 Major Adverse Cardiac Event (MACE) in the Subgroups-ITT 







MI (%) 



Acute Q-Wave myocardial infarction within 12hours after the 

attack, which require another procedure after failure to 

thormbolytic therapy 


Clotinab 

(N=84) 

MACE 


MACE 


Ver. 1.0_Eng 

Total 

0(0.00%) 0(0.00%) 0 

0(0.00%) 0(0.00%) 0 

0(0.00%) 2(5.00%) 2* 

0(0.00%) 0(0.00%) 0 



Females aged over 65 with one type B lesion characteristic 0(0.00%) 0(0.00%) 0 


* C021, Y056 

Treatment 

Group 

Clotinab 

(N=83) 

ReoPro ® 

(N=40) 

Table 11.3.1:5 Major Adverse Cardiac Event (MACE)-FAS 



disease 

Recurrence of 


Emergency 


(One day 

before) 

Discharge 

Day 

30(+7) 

Total 

0 0 0 0 0 0 

0 0 0 0 0 0 

0 0 0 0 0 0 

Cut off 

Value 

Total 0 0 0 0 0 0

Angina (%) 

Emergency 


0 0 0 0 0 0 

Total 0 0 0 0 2(5.00%) 2(5.00%) 

Table 11.3.1:6 Major Adverse Cardiac Event (MACE) in the Subgroups-FAS 







MI (%) 



Acute Q-Wave myocardial infarction within 12hours after 

the attack, which require another procedure after failure 

to thormbolytic therapy 


Clotinab (N=83) 

MACE 


MACE 


Ver. 1.0_Eng 

Total 

0(0.00%) 0(0.00%) 0 

0(0.00%) 0(0.00%) 0 

0(0.00%) 2(5.00%) 2* 

0(0.00%) 0(0.00%) 0 



Females aged 

characteristic 

over 65 with one type B lesion 

0(0.00%) 0(0.00%) 0 


* C021, Y056 

11.3.2. Secondary efficacy analysis 

The secondary efficacy endpoint is a new change in electrocardiogram that indicates the status 

of ischemia. One Clotinab patient (Y038) showed a new change twice at 24 hour and day3. No 

other Clotinab subject showed a new change. One ReoPro ® patient (A015) showed a new 

change three times at 12 hour, 24 hour, and day 3. No other ReoPro ® patient showed a new 

change. See Table 11.3.2:1, Table 11.3.2:3, Table 11.3.2:5. 

At the baseline, 75 of 76 Clotinab PP patients had electrocardiogram, and 1 missed it. 28 

(37.3%) indicated the status of ischemia while 47 while the rest indicated other conditions. The 

ischmia rate was more or less constant until discharge; 36.1% at 12 hour, 35.2% at 24 hour, 

36.2% at day 3, and 38.3% at one day prior to discharge, and 20.0% at day 30(+7). (See

Baseline 

Table 11.3.2:1) 

At the baseline, 35 of ReoPro ® PP patients had electrocardiogram, and 1 missed it. 17 (48.6%) 

indicated the status of ischemia while 18 indicated other conditions. The ischemia rate indicated 

by electrocardiogram stayed more or less constant until discharge; 47.1% at 12 hour, 47.1% at 

24 hour, 48.6% at day 3, and 48.6% at one day prior to discharge, and 21.2% at day 30(+7). 

(See Table 11.3.2:1). 

The drop of the status of ischemia rate in the Clotinab group from 37.3% at baseline to 20.0% 

at day 30(+7) is statistically significant, p-value=0.0003. The drop in the ReoPro ® group from 

48.6% to 21.2% is also statistically significant, p-value=0.0126. (See Table 11.3.2:2). The 

electrocardiogram data in the ITT population (Table 11.3.2:3 and 11.3.2:4) and FAS population 

(Table 11.3.2:5 and 11.3.2:6) show similar results as in the PP population. 

Table 11.3.2:1 New change in electrocardiogram which indicates the status of ischemia -PP 

n † /N 

Clotinab 

#(%) of new 

change 


Ver. 1.0_Eng 

n † /N 

Myocardial ischemia 28/75(37.33%) 17/35(48.57%) 

Other 47/75(62.67%) 18/35(51.43%) 

Missing 1/76(1.32%) 1/36( 2.78%) 

ReoPro ® 

#(%) of new 

change 

12hr 26/72(36.11%) 0(0.00%) 16/34(47.06%) 1(6.25%) 

Exact 95%C.I. (0.00%,13.23%) (0.16%, 30.23%) 

24hr 24/67(35.82%) 1(4.17%) 16/34(47.06%) 1(6.25%) 

Exact 95%C.I. (0.11%, 21.12%) (0.16%, 30.23%) 

Day 3 25/68(36.76%) 1(4.00%) 17/35(48.57%) 1(5.88%) 

Exact 95%C.I. (0.10%, 20.35%) (0.15%, 28.69%) 

(one day before) 

Discharge 

27/70(38.57%) 1*(3.70%) 17/35(48.57%) 1*(5.88%) 

Exact 95%C.I. (0.09%, 18.97%) (0.15%, 28.69%) 

Discharge on day3 or 

day4 

16 1* 13 1* 

Discharge after day4 11 0 4 0 

Day 30(+7) 

14/70(20.00%) 0(0.00%) 7/33(21.21%) 0(0.00%) 

Exact 95%C.I. (0.00%, 23.16%) (0.00%, 40.96%) 

Total number of events 2 3 

p-value 

Total number of subjects 1(1.32%) 1(2.78%) 0.5415 a)

Visit 

12hr 

Baseline 

C.I. : confidence interval, * Patients with Subject ID “A015, Y038” has visited on Day3 and was 

discharged on the same day, a) P-value from Fisher’s exact test. N † : Patients whose 

electrocardiogram indicates the status of Myocardial ischemia, N: # of ECG , Other: 

Normal, Abnormal in clinically insignificant, Abnormal in clinically significant other 

than myocardial ischemia. Exaxt 95%C.I. presented for proportion of new 

changeTable 11.3.2:2 The change electrocardiogram between pre- and post- 

injection of the investigational drug –PP 

Clotinab 

(N=76, Missing=1) 

Abnormal with 

Other Total P-value 

MI 

Abnormal with 

MI 

ReoPro ® 


Abnormal with MI 24 2 14 2 


Other 4 42 0.4142 3 15 0.6547 

Total 28 44 72(Missing=4) 17 17 34(Missing=1) 

24hr 


Other 6 38 0.5271 4 14 0.7055 


Day 3 


Other 4 40 0.7055 3 15 1.0000 



Discharge 


Other 6 41 0.3173 3 16 0.6547 


Day 30(+7) 


Other 13 43 0.0003 11 15 0.0126 


MI: myocardial ischemia 

Other: Normal, Abnormal in clinically insignificant, Abnormal in clinically significant other than myocardial 

ischemia., P-value from McNemar’s Test, Difference in number of patients is due to missing data. 


Ver. 1.0_Eng

Baseline 

Table 11.3.2:3 New change in electrocardiogram which indicates the status of ischemia – 

ITT 

n † /N 

Clotinab 

#(%) of new 

change 


Ver. 1.0_Eng 

n † /N 


Other 49/83(59.04%) 19/39(48.72%) 

Missing 1/84(1.19%) 1/40(2.50%) 

ReoPro ® 

#(%) of new 

change 

12hr 30/79(37.97%) 0(0.00%) 19/38(50.00%) 1( 5.26%) 

Exact 95%C.I. (0.00%, 11.57%). (0.13%, 26.03%) 

24hr 27/73(36.99%) 1( 3.70%) 19/38(50.00%) 1( 5.26%) 

Exact 95%C.I. (0.09%, 18.97%) (0.13%, 26.03%) 

Day 3 29/73(39.73%) 1( 3.45%) 19/38(50.00%) 1( 5.26%) 

Exact 95%C.I. (0.09%, 17.76%) (0.13%, 26.03%) 

(one day before) Discharge 31/75(41.33%) 1*( 3.23%) 19/38(50.00%) 1*( 5.26%) 

Exact 95%C.I. (0.08%, 16.70%) (0.13%, 26.03%) 


day4 

19 1* 15 1* 


Day 30(+7) 15/76(19.74%) 0(0.00%) 10/37(27.03%) 0(0.00%) 

Exact 95%C.I. (0.00%, 21.80) (0.00%, 30.85%) 


p-value 

Total number of subjects 1(1.19%) 1(2.50%) 0.5429 a) 

C.I. : confidence interval, * Patients with subject ID “A015, Y038” has visited on Day3 and was discharged 

on the same day, a) P-value from Fisher’s exact test. N † : Patients whose electrocardiogram indicates the 

status of Myocardial ischemia, N: # of ECG , Other: Normal, Abnormal in clinically insignificant, Abnormal 

in clinically significant other than myocardial ischemia. Exaxt 95%C.I. presented for proportion of new 

change

Visit 

12hr 

Baseline 

Table 11.3.2:4 The change electrocardiogram between pre- and post- injection of the 

investigational drug -ITT 

Abnormal with 

MI 

Clotinab 



Abnormal with 

MI 

ReoPro ® 




Other 5 44 0.2568 3 16 0.6547 


24hr 


Other 7 40 0.3657 4 15 0.7055 


Day 3 


Other 4 41 0.7055 3 16 1.0000 



Discharge 


Other 8 41 0.2482 3 17 0.6547 


Day 30(+7) 


Other 16 45

Baseline 

Table 11.3.2:5 New change in electrocardiogram which indicates the status of ischemia – 

FAS 

n † /N 

Clotinab 

#(%) of new 

change 


Ver. 1.0_Eng 

n † /N 


Other 49/82(59.76%) 19/39(48.72%) 

Missing 1/83(1.20%) 1/40(2.50%) 

ReoPro ® 

#(%) of new 

change 

12hr 30/79(37.97%) 0(0.00%) 19/38(50.00%) 1(5.26%) 

Exact 95%C.I. (0.00%, 11.57%) ( 0.13%, 26.03%) 

24hr 27/73(36.99%) 1(3.70%) 19/38(50.00%) 1(5.26%) 

Exact 95%C.I. ( 0.09%, 18.97%) ( 0.13%, 26.03%) 

Day 3 29/73(39.73%) 1(3.45%) 19/38(50.00%) 1(5.26%) 

Exact 95%C.I. ( 0.09%, 17.76%) ( 0.13%, 26.03%) 

(one day before) Discharge 31/75(41.33%) 1*(3.23%) 19/38(50.00%) 1*(5.26%) 

Exact 95%C.I. ( 0.08%, 16.70%) ( 0.13%, 26.03%) 


day4 

19 1* 15 1* 


Day 30(+7) 15/76(19.74%) 0(0.00%) 10/37(27.03%) 0(0.00%) 

Exact 95%C.I. (0.00%, 21.80%) (0.00%, 30.85%) 


p-value 

Total number of subjects 1(1.20%) 1(2.50%) 0.5464 a) 

C.I. : confidence interval, * Patients with Subject ID “A015, Y038” has visited on Day3 and was discharged 

on the same day, a) P-value from Fisher’s exact test. n † : Patients whose electrocardiogram indicates the 

status of Myocardial ischemia, N: # of ECG , Other: Normal, Abnormal in clinically insignificant, Abnormal 

in clinically significant other than myocardial ischemia. Exaxt 95%C.I. presented for proportion of new 

change

Visit 

12hr 

Table 11.3.2:6 The change electrocardiogram between pre- and post- injection of the 

investigational drug -FAS 

Baseline 

Abnormal with 

MI 

Clotinab 



Abnormal with 

MI 

ReoPro ® 




Other 5 44 0.2568 3 16 0.6547 


24hr 


Other 7 40 0.3657 4 15 0.7055 


Day 3 


Other 4 41 0.7055 3 16 1.0000 



Discharge 


Other 8 42 0.1317 3 17 0.6547 


Day 30(+7) 


Other 16 45

11.3.3. By-patient displays 

See Appendix 16.4 

11.3.4. Efficacy conclusions 

The primary efficacy endpoint is the onset of MACE within 30(+7) days from the study drug 

administration following the PCI procedure. The MACE includes the death related to heart 

disease, the recurrence of myocardial infarction (MI) and the emergency revascularization. 

No patient among 84 patients in the Clotinab group experienced the primary efficacy measure, 

the MACE. Whether we analyze the PP population, ITT population, or FAS population, the same 

conclusion is reached. Clotinab is effecitve in preventing the MACE event. The upper bound of 

95% confidence interval is all below 5% regardless of the analysis population, indicating that 

the MACE rate among patients undergoing the PCI procedure will be less than 5% if also 

treated with Clotinab. Only one Clotinab patient experienced a new change in electrocardiogram. 

The rate of the status of ischemia indicated by electrocardiogram in the Clotinab patients at day 

30(+7) dropped significantly by about 17-21%, depending on the analysis population, from the 

baseline. No Clotinab patient experienced major bleeding event. We can conclude that Clotinab 

is effective and safe in preventing the MACE in patients undergoing the PCI procedure. 

Two patient among 40 patients in the ReoPro ® group experienced the MACE. The upper bound 

of 95% confidence interval is about 16.9-18.7% depending on the analysis population. This 

indicates that less than 20% of the patients undergoing the PCI proceudre will experience the 

MACE if also treated with ReoPro ® . Only one patient experienced a new change in 

electrocardiogram. The rate of the status of ischemia indicated by electrocardiogram in the 

ReoPro ® group at dqy 30(+7) dropped significantly by about 24-27%, depending on the 

analysis population, from the baseline. Three ReoPro ® patients experienced major bleeding 

event. The major bleeding rate is signifcantly higher in the ReoPro ® group than in the Clotinab 

group. 

The intention of this clinical study is not designed to compare the efficacy or safety of Clotinab 

and ReoPro ® in patients undergoing the PCI procedure. Thus we do not make a statement 

about which treatment is more effective and safer. Nevertheless we can conclude that Clotinab 



Ver. 1.0_Eng

12. Safety evaluation 

Eighty-three patients received Clotinab, and forty received ReoPro ® . These one hundred and 

twenth-three patints constituted the safety evaluation population. 

12.1. Extent of exposure 

The patient was administered 0.25mg/kg of Clotinab via IV bolus 10 minutes to six hours prior 

to the PCI procedure. Then a 12-hour infusion of 0.125 mg/kg/min (Max 10 ug/min) dissolved 

in sterile saline of 0.9 % or dextrose of 5 % followed. 

12.2. Bleeding 

Bleeding was checked at 12 hr., 24 hr., day 3, the day before discharge, and day 30(+7), and 

was categorized into ‘major bleeding’, ‘minor bleeding’ or ‘clinically insignificant bleeding’ 

according to the TIMI criteria. Bleeding categories, bleeding checking time, and treatment 

groups were crossclassified. Because bleeding categories are ordinal, namely demonstrating 

severity, it was tested statistically whether one treatment group experienced bleeding more 

severely than the other group. Bleeding data were also summarized according by treatment 

group, by heparin dose, by gender and body weight. (See Table 12.2:1~Table 12.2:5) 

No Clotinab patient had major bleeding episode whereas three ReoPro ® ( C010, Y051, Y053) 

had major bleeding .event. When the number of patients having major bleeding event of the 

Clotinab group is compared to the ReoPro ® group, the Fisher’s exact test shows a p-value of 

0.0326. 

Four bleeding categories, ‘no bleeding’, ‘clinically insignificant bleeding’, ‘minor bleeding’, and 

‘major bleeding’ are ordered in severity. At each bleeding checking time, severity of bleeding 

was compared between two treatment groups using the Wilcoxon-Mann-Whitney test. At no 

time point, there was significant difference in bleeding severity between two treatment groups. 

(See Table 12.2:2.) 

Two patients (Y051, Y053) with major bleedingevent were administered haparin dose ≤5,000U. 

The other patient (C010) was not given heparin(See Table 12.2:3). Demographic details of 

these three patients are given in Table 12.2:4. All three were older than 59 years of age. Two 


Ver. 1.0_Eng

were female and one was male. Table 12.2:5 is added to show major bleeding events by 

treatment group, gender, age class, and weight class. 

There was no significant difference in severity of bleeding between the two treatment groups. 

However, when just the major bleeding was considered, the major bleeding rate of the ReoPro ® 

group was significantly higher than that of the Clotinab group (p=0.0326). 


Ver. 1.0_Eng

Bleeding 

Number of 

Patients 

Table 12.2:1 Bleeding 

CSR_Clotinab_II 

75 

Ver. 1.0_Eng 

12hr 24hr Day 3 


(One day 

before) 

Discharge 

Day 

30(+7) 

Total c) 12hr 24hr Day 3 

(One day 

before) 

Discharge 

83 83 83 83 83 40 40 40 40 40 

Major bleeding 0(0.00%) 0(0.00%) 0(0.00%) 0(0.00%) 0(0.00%) 0 

(0.00%) 

P-value for 

Clotinab vs 

® a) 

ReoPro 

0.0326 

Minor bleeding 4( 4.82%) 5( 6.02%) 6( 7.23%) 5( 6.02%) 1( 1.20%) 11 

(13.25%) 

%change vs +92.77% -19.68% +44.58% +20.48% -51.81% +6.02% 

ReoPro ® 

P-value vs 

® b) 

ReoPro 

Clinically 

insignificant 

bleeding 

%change vs 

ReoPro ® 

P-value for 

Clotinab vs 

® b) 

ReoPro 

0.9074 

4( 4.82%) 6( 7.23%) 3( 3.61%) 1( 1.20%) 0(0.00%) 11 

(13.25%) 

-51.81% +189.16% -63.86% -75.90% -41.10% 

0.1929 

Day 

30(+7) 

Total c) 

0(0.00%) 1( 2.50%) 1( 2.50%) 2( 5.00%) 0(0.00%) 3 

(7.50%) 

1( 2.50%) 3( 7.50%) 2( 5.00%) 2( 5.00%) 1( 2.50%) 5 

(12.50%) 

4(10.00%) 2( 5.00%) 4(10.00%) 2( 5.00%) 1( 2.50%) 9 

(22.50%) 

a) P-value from Fisher’s exact test. b) P-value from Chi-square test. C) Total: Total number of patients with at least one bleeding event throughout the trial

Table 12.2:2 Number of patients with bleeding events 

Bleeding No bleeding Insignificant 

bleeding 

Minor 

bleeding 

Major 

bleeding 

Total P-value 

12h 

Clotinab 75(90.36%) 4( 4.82%) 4(8.82%) 0(0.00%) 83 

ReoPro ® 35(87.50%) 4(10.00%) 1(2.50%) 0(0.00%) 40 0.6744 

24hr 

Clotinab 72(86.75%) 6(7.23%) 5(6.02%) 0(0.00%) 83 

ReoPro ® 34(85.00%) 2(5.00%) 3(7.50%) 1(2.50%) 40 0.7288 

Day3 

Clotinab 74(89.16%) 3(3.61%) 6(7.23%) 0(0.00%) 83 

ReoPro ® 33(82.50%) 4(10.00%) 2(5.00%) 1(2.50%) 40 0.3272 

Discharge 

Clotinab 77(92.77%) 1(1.20%) 5(6.02%) 0(0.00%) 83 

ReoPro ® 34(85.00%) 2(5.00%) 2(5.00%) 2(5.00%) 40 0.1694 

Day30(+7) 

Clotinab 82(98.80%) 0(0.00%) 1(1.20%) 0(0.00%) 83 

ReoPro ® 38(95.00%) 1(2.50%) 1(2.50%) 0(0.00%) 40 0.2067 

P-value from Wilcoxon-Mann-Whitney test(Useing statXact-4) 

Table 12.2:3 Number of patients with major bleeding events by total heparin bolus dose 

Bleeding 

Clotinab 

(N=83) 

ReoPro ® 

(N=40) 

Total P-value 

Pts receiving heparin 77 32 109 

Pts with major bleeding among 

heparin recipients 

0(0.00%) 2( 6.25%) 

Pts not receiving heparin 

6 

8 

14 

Pts with mahor bleeding among 

heparin non-recipients 

0(0.00%) 1(12.5%) 

1 

Pts receiving ≤ 5.000U 48 18 66 

Pts with major bleeding 0(0.00%) 2(11.11%) 2 0.0713 

Pts receiving > 5.000U 29 14 43 

Pts with major bleeding 0(0.00%) 0(0.00%) 0 

Pts: Patients, Only includes patients who received heparin, P-value from Fisher’s exact test. 

Table 12.2:4 Description of patients with major bleeding 

Subjiect 

number 

Subject initial 

Treatment 

group 

SEX AGE 

Height 

(cm) 

Weight 

(kg) 

C010 NIN ReoPro ® Female 77 148 43 

Y051 LIJ ReoPro ® Male 59 170 61 

Y053 HYS ReoPro ® Female 67 157 53 


Ver. 1.0_Eng

Table 12.2:5 Number of patients with major bleeding events by Gender and Weight 

Bleeding Clotinab ReoPro ® Total P-value 

All man 68 30 98 

Major bleeding 0(0.00%) 1(3.33%) 1 0.3061 

Men ≤ 75Kg 50 21 71 


Men > 75Kg 18 9 27 

Major bleeding 0(0.00%) 0(0.00%) 0 

All women 16 a) 10 26 


Women ≤ 55Kg 6 4 10 


Women > 55Kg 9 6 15 

Major bleeding 0(0.00%) 0(0.00%) 0 

Pts: Patients, P-value from Fisher’s exact test. 

a) 

One woman did not have weight recorded; this patient was iincluded in this analysis. 

12.3. Thrombocytopenia 

If the platelet count is decreased by ≥25% compared to the baseline count, and if the platelet 

count is

Table 12.3:1 Thrombocytopenia 

Treatment Time N * 

Clotinab 

#(%) of 

Thrombocytopenia 


Ver. 1.0_Eng 

N * 

ReoPro ® 

#(%) of 

Thrombocytopenia 

12hr 79 4( 5.06%) 39 0(0.00%) 

Exact 95% C.I. (1.40%,12.46%) (0.00%, 9.03%) 

24hr 80 1( 1.25%) 39 0(0.00%) 

Exact 95% C.I. (0.03%, 6.77%) (0.00%, 9.03%) 

Day 3 80 1( 1.25%) 40 0(0.00%) 

Exact 95% C.I. (0.03%, 6.77%) (0.00%, 8.81%) 

(One day before) Discharge 74 1( 1.35%) 35 0(0.00%) 

Exact 95% C.I. (0.03%, 7.30%) (0.00%, 10.00%) 


day4 

42 0 13 0 


Day 30(+7) 81 0(0.00%) 38 0(0.00%) 

Exact 95% C.I. (0.00%, 4.45%) (0.00%, 9.25%) 


P-value 

Total number of subjects 4(4.82%) 0(0.00%) 0.3028 

N: Number of subjects at each treatment time. 

p-value from Fisher’s exact test, * Difference in number of patients is due to missing data. 

12.4. Change in Hb/Hct 

Hb/Hct data were collected at the baseline, 12 hour, 24 hour, day 3, one day prior to discharge, 

and day 30(+7). Descriptive statistics (mean, standard deviation, median, minimum, maximum) 

were presented at each observation time point per tretment group. The Friedman test was 

applied to determine if there was significant variation in Hb and Hct over the study period. The 

signifance test was applied to each treatment group separtely. Both Hb and Hct showed 

statistically significant variations in each treatment group (See Table 12.4:1, Table 12.4:2). 

Significant variations in Hb and Hct were expected. Hb and Hct levels were generally lowered by 

about 1.5mg% after the PCI proceudre, and recover within a month from the proceudre. 

Significant variations in Hb and Hct are statistically significant but clinically expected.

Hb 

Hct 

Table 12.4:1 Hb/Hct – Clotinab 

Hb/Hct N b) Mean SD Med Min Max P-value a) 

Baseline 84 13.69 1.43 13.80 10.2 17.0 

12 hr 79 12.66 1.32 12.70 8.7 15.1 

24 hr 80 12.41 1.32 12.50 8.0 14.9

Hb 

Hct 

Table 12.4:2 Hb/Hct – ReoPro ® 

Hb/Hct N b) Mean SD Med Min Max P-value a) 

Baseline 40 13.88 1.34 13.75 10.1 16.8 

12 hr 39 12.63 1.33 12.40 10.6 15.3 

24 hr 39 12.30 1.39 12.10 9.8 15.1

egion-specific) or C region (constant region specific) was set to ‘positive’ and response by Fab 

cleavage region (five C-terminal amino acids of c7E3, peptide compounding Fab(CDKTH) was 

set to ‘negative’. If not inhibited by Clotinab then it was defined as ‘unknown’. Evaluation results 

are summarized in Table 12.5:1. 

Table 12.5:1 Clotinab HACA results 


Number of subjects 83 40 

V region (anti-variable region) 4 0 

C region (constant region) 2 1 

Fab cleavage region 5 1 

Unassessable 2 2 

Incidence (%) of immune responses 7.2 2.5 

Out of 83 subjects in Clotinab and 40 in ReoPro ® , the number of subjects whose results were 

higher than cut off value or increased more than twice at 30 days after the administration 

compared to the pre-administration in IgG screening was 13, 4 in Clotinab and ReoPro ® , 

respectively. 

After neutralization for the subjects who selected by IgG screening, 6 subjects {7.2%, 95% 

exact C.I.(2.70%, 15.07%)}among Clotinab group (83 subjects) were confirmed as HACA 

seropositive, and among these subjects, 4 were V region and 2 were C region. 1 subjects 

{2.5%, 95% exact C.I.(0.06%, 13.16%)}among ReoPro ® group (40 subjects) was confirmed 

as HACA seropositive and C region. (Details are in HACA report (Appendix 16.1.9)) 

However, there was no significant difference between Clotinab and ReoPro ® for HACA 

seropositive response rate. (P=0.4255. See Table 12.5.2 ). 

Table 12.5:2 HACA(human antichimetric antibody) development. 

HACA Clotinab ReoPro ® P-value 

Number of subjects 83 40 

Number of Subjects with 

positive response 

6 1 

Positive response rate (%) 7.2% 2.5% 0.4255 

Exact 95% C.I. (2.70%, 15.07%) (0.06%, 13.16%) 

P-value from Fisher’s exact test. 


Ver. 1.0_Eng

12.6. Adverse Event 

Adverse events included untoward events observed after the study drug administration and preexisting 

symptoms or conditions worsend after the study drug administration. Pre-existing 

symptoms or conditions that did not change during the trial were noted in the listing of adverse 

events (Table 15.13) All adverse event were coded by system organ class(SOC) and preferred 

term(PT) using MedDRA(Medical Dictionary for Regulatory Activities)8.0 ® . If the causal 

relationship of an adverse event to the treatment is ‘definite’, ‘probable’ or ‘possible’, the 

adverse event is considered ‘related to the study drug’. If the relationship is ‘improbable’, ‘none’ 

or uUnknown’, then the adverse event is considered ‘not-related to the study drug’. 

12.6.1. Brief summary of Adverse Event 

Summary of adverse event was shown below(See Table 12.6.1:1). 

Seventy-two patients {86.75%, 95% exact C.I.(77.52%, 93.19%)} among 83 Clotinab patients 

experienced one or more adverse events. Five patients had adverse events related to the 

study drug {6.02%, 95% exact C.I.(1.98%, 13.50%)}. 

Those seventy-two patients experienced a total of two hundred forty-two adverse events, an 

average of 3.4 AEs per patient. 228 were considered mild, 6 moderate, and 8 severe. 8 AEs 

were considered ‘related to the study drug’. 6 AEs were mild, and 2 were severe. 

Thirty-three patients {82.50%, 95% exact C.I.(67.22%, 92.66%)} among 40 ReoPro ® patients, 

experienced one or more AEs. One patient had adverse event related to the study drug {2.50%, 

95% exact C.I.(0.06%, 13.16%)}. 

Those thirty-three patients experienced a total of 137 adverse events, an average of 4.2 AEs 

per patient. 129 were considered mild, and 8 were severe . One AE which was mild was 

considered ‘related to the study drug’. 

A chi-square test for the proportion of the patients experiencing adverse event at least once, 

showed no significant difference between two groups (P=0.5325). Fisher’s exact test for the 

proportion of the subjects experiencing study-drug-related adverse events at least once, 

showed no significant difference between two groups (P=0.6627). 


Ver. 1.0_Eng

Clotinab 

(N=83) 

ReoPro ® 

(N=40) 

Table 12.6.1:1 Summary of Adverse Events 

Subjects with 

AE[%] 

(All) 

72[86.75%] 

(77.52%, 

93.19%) a) 

33[82.50%] 

(67.22%, 

92.66%) a) 

a) Exact 95% confidence interval 

Number of adverse events 

and severity 

(All) 

Subjects with 

AE[%] 

(drugrelated) 

Number of adverse events 

and severity 

(Drug-related) 

Mild 228 5[6.02%] Mild 6 

Moderate 6 (1.98%, Moderate 0 

Severe 8 13.50%) Severe 2 

NA 0 NA 0 

Total 242 

a) 

Total 8 

Mild 129 1[2.50%] Mild 1 

Moderate 0 (0.06%, Moderate 0 

Severe 8 13.16%) Severe 0 

NA 0 NA 0 

a) 

Total 137 

12.6.2. Display of adverse events 

The number and proportion of adverse events by body system were given below. 

Total 1 

Coded by system organ class for Clotinab: 

Fifty-five patients (66.27%) among 83 Clotinab treated patients experienced adverse events in 

general disorders and administration site conditions. 25 (31.12%) suffered AEs in nervous 

system disorders{25 (30.12%)}, 21 (25.30%) suffered AEs in musculoskeletal and connective 

tissue disorder. 21 (25.30%) suffered AEs in cardiac disorders. (See Table 15.9) 

Coded by system organ class for ReoPro ® : 

Twenty-eight patients (70.00%) among 40 ReoPro ® patients experienced adverse events in 

general disorders and administration site condition. 14 (35.00% suffered AEs in gastrointestinal 

disorders., 14 (35.00%) suffered AEs in cardiac disorders (See Table 15.9) 

Coded by preferred term for Clotinab: 

Twenty-seven patients (32.53%) among 83 Clotinab patients seperienced adverse events of 

wound secretion. 22 (26.51%) suffered AEs of catheter site hematoma, and 16 (19.28%) 

suffered AEs of catheter site hemorrhage, brining catheter site related AEs up to 38 (45.78%).. 

(See Table 12.6.2:1) 

Coded by preferred term for ReoPro ® : 


Ver. 1.0_Eng

Seventeen patients (42.50%) among 40 ReoPro ® patients experienced adverse events of 

wound secretion{17 (42.50%)}. 10 (25.00%) suffered AEs of catheter site hematoma, and 5 

(12.50%) suffered AEs of catheter site hemorrhage, bringing catheter related AEs to 15 

(37.50%). 10 (25.00%) had AEs of headache. (See Table 12.6.2:1) 

Five patients had eight AEs related to Clotinab, Three had thrombocytopenia, two had wound 

secretion , two had catheter site hematoma, and one had application site bleeding. One patient 

had one AE related to ReoPro ® The patient had aspartate aminotransferase increase(See Table 

12.6.2:1). 


Ver. 1.0_Eng

Body system 

Blood and lymphatic 

system disorders 

Table 12.6.2:1 Number observed and rate, with subject identifications-Clotinab 


85 

Ver. 1.0_Eng 

Leukocytosis 

Mild Moderate Severe Total Total 

Related NR Related NR Related NR Related NR R+NR 

1(1.20%) 1 1 

Thrombocytopenia 2(2.41%) 1(1.20%) 1(1.20%) 3 1 4 

Cardiac disorders Arrhythmia 1(1.20%) 1 1 

Brady cardia 1(1.20%) 1 1 

Chest discomfort 9(10.84%) 1(1.20%) 10 10 

Chest pain 7(8.43%) 7 7 

Dyspnoea 4(4.82%) 1(1.20%) 5 5 

Palpitations 1(1.20%) 1 1 

Eye disorders Xerophthalmia 1(1.20%) 1 1 

Gastrointestinal disorders Abdominal discomfort 4(4.82%) 4 4 

General disorders and 

administration site 

conditions 

Abdominal pain upper 1(1.20%) 1 1 

Constipation 3(3.61%) 3 3 

Dyspepsia 7(8.43%) 7 7 

Gastritis erosive 1(1.20%) 1 1 

Nausea 6(7.23%) 6 6 

Vomiting 

Application site bleeding 

1(1.20%) 1 1 

1(1.20%) 5(6.02%) 1 5 6

Body system 



conditions 

Musculoskeletal and 

connective tissue disorders 


86 

Ver. 1.0_Eng 

Application site pain 



6(7.23%) 6 6 

Catheter site hematoma 1(1.20%) 18(21.7%) 1(1.20%) 1(1.20%) 1(1.20%) 2 20 22 

Catheter site hemorrhage 

16(19.3%) 16 16 

Cold sweat 4(4.82%) 4 4 

Facial pain 1(1.20%) 1 1 

Feeling cold 5(6.02%) 5 5 

Feeling hot 1(1.20%) 1 1 

Influenza like illness 3(3.61%) 3 3 

Injection site 

hemorrhage 

1(1.20%) 1 1 

Pyrexia 

Wound secretion 

2(2.41%) 2 2 

Arthralgia 

2(2.41%) 24(28.9%) 1(1.20%) 2 25 27 

1(1.20%) 

1 1 

Back pain 12(14.5%) 1(1.20%) 13 13 

Buttock pain 1(1.20%) 1 1 

Flank pain 1(1.20%) 1 1 

Limb discomfort 1(1.20%) 1 1 

Musculoskeletal 

discomfort 

1(1.20%) 1 1 

Myalgia 3(3.61%) 3 3

Body system 


87 

Ver. 1.0_Eng 





Shoulder pain 

1(1.20%) 1 1 

Nervous system disorders Burning sensation 1(1.20%) 1 1 

Dizziness 5(6.02%) 5 5 

Headache 14(16.9%) 1(1.20%) 15 15 

Hypoaesthesia 3(3.61%) 3 3 

Migraine 1(1.20%) 1 1 

Paraesthesia 3(3.61%) 3 3 

Psychiatric disorders Anxiety 

Sleep disorder 

1(1.20%) 1 1 

Renal and urinary 

disorders 

Respiratory, thoracic and 

mediastinal disorders 

Skin and subcutaneous 

tissue disorders 

Dysuria 

3(3.61%) 3 3 

7(8.43%) 1(1.20%) 8 8 

Hematuria 1(1.20%) 1 1 

Cough 

3(3.61%) 3 3 

Dyspnoea 1(1.20%) 1 1 

Haemoptysis 3(3.61%) 3 3 

Nasopharyngitis 1(1.20%) 1 1 

Tachypnoea 1(1.20%) 1 1 

Excoriation 

1(1.20%) 1 1 

Pruritus 3(3.61%) 3 3 

Rash 5(6.02%) 5 5 

Rash macular 1(1.20%) 1 1 

Urticaria 2(2.41%) 2 2 

Vascular disorders Epistaxis 2(2.41%) 2 2

Body system 


88 

Ver. 1.0_Eng 



Vascular disorders Gingival bleeding 3(3.61%) 3 3 

Haemorrhage 3(3.61%) 3 3 

Hypertension 2(2.41%) 2 2 

NR = not related

Table 12.6.2:2 Number observed and rate, with subject identifications-ReoPro ® 

Body system 


89 

Ver. 1.0_Eng 



Cardiac disorders Cardiac tamponade 2(5.00%) 2 2 

Chest discomfort 6(15.0%) 6 6 

Chest pain 7(17.5%) 7 7 

Dyspnoea 1(2.50%) 1(2.50%) 2 2 

Myocardial ischaemia 1(2.50%) 1 1 

Palpitations 1(2.50%) 1 1 

Tachycardia 1(2.50%) 1 1 

Gastrointestinal disorders Abdominal discomfort 2(5.00%) 2 2 



conditions 

Abdominal pain upper 1(2.50%) 1 1 

Constipation 2(5.00%) 2 2 

Diarrhoea 1(2.50%) 1 1 

Dyspepsia 3(7.50%) 3 3 

Gastoesophageal reflux 

disease 

1(2.50%) 1 1 

Nausea 6(15.0%) 6 6 

Vomiting 5(12.5%) 5 5 

Application site bleeding 2(5.00%) 2(5.00%) 4 4 

Application site pain 4(10.0%) 4 4 

Asthenia 2(5.00%) 2 2

Body system 


90 

Ver. 1.0_Eng 





conditions 

Catheter site hematoma 10(25.0%) 10 10 

Catheter site hemorrhage 5(12.5%) 5 5 

Cold sweat 2(5.00%) 2 2 

Death 2(5.00%) 2 2 

Face oedema 1(2.50%) 1 1 

Feeling cold 2(5.00%) 2 2 

Feeling hot 1(2.50%) 1 1 

Pyrexia 1(2.50%) 1 1 

Wound secretion 17(42.5%) 17 17 

Investigations Aspartate 

aminotransferase 

increased 

1(2.50%) 1 1 



Back pain 7(17.5%) 7 7 

Flank pain 1(2.50%) 1 1 

Pain in extremity 1(2.50%) 1 1 

Nervous system disorders Burning sensation 2(5.00%) 2 2 

Dizziness 3(7.50%) 3 3 

Headache 10(25.0%) 10 10 

Psychiatric disorders Sleep disorder 1(2.50%) 1 1 



Dysuria 5(12.5%) 5 5 

Hematuria 2(5.00%) 2 2 



Pulmonary tuberculosis 1(2.50%) 1 1 



Erythema 1(2.50%) 1 1 

Pruritus 1(2.50%) 1 1 

Pruritus generalised 1(2.50%) 1 1

Body system 


91 

Ver. 1.0_Eng 





Urticaria 1(2.50%) 1 1 

Vascular disorders Gingival bleeding 4(10.0%) 4 4 

Haemorrhage 2(5.00%) 1(2.50%) 3 3 

NR = not related

12.6.3. Analysis of adverse events 

Most frequent adverse events in the Clotinab and ReoPro ® group were related to general 

disorders and administration site conditions. Most frequent adverse events related to the PCI 

procedure were wound secretion and catheter site hematoma, catheter site hemorrhage in both 

treatment groups. 

The proportion of patients experiencing adverse event at least once was not significantly 

different between Clotinab and ReoPro ® (p-value=0.5325) The proportion of patients 

experiencing adverse events related to the study drug at least once was not significantly 

different between two groups (p-value=0.6627). 

Three Clotinab patients (3.61%) experienced drug-related thrombocytopenia, two patients 

(2.41%) wound secretion 2(2.41%), two patients (2.41%) catheter site hematoma, and one 

patient (1.20%) application site bleeding. One ReoPro ® patient (2.50%) experienced aspartate 

aminotransferase increase. 

12.6.4. Listing of adverse events by patient 

See Table 15.12. 

12.7. Serious adverse events, and other significant adverse events 

Serious adverse events occurred in 7 patients; two deaths (C021, Y056), life-threatening AEs in 

3 subjects (C010, C020, A032), and 2 prolonged hospitalizations (A020, Y045) (refer to Table 

12.7:1). 

The subject C021 (LSD, female, 67 years old), who had taken medication for non-insulin 

dependent diabetes mellitus, hypertension, were treated with ReoPro ® followed by PCI on 13- 

Sep-2005, then discharged on 01-Oct-2005. On 08-Oct-2005, no femoral pulse, mental 

deepening occurred to the subject. CPR was done and emergent medications were administered, 

but the subject was dead. It was assumed that the death was caused by ventricular arrhythmia, 

and the investigator concluded this was definitely not related to the study drug. 


Ver. 1.0_Eng

The subject Y056 (KMC, male, 57 years old), who had chronic superficial gastritis/erosion, 

hypertension, coronary artery occlusive disease, r/o reactive pulmonary TBc, were treated with 

ReoPro ® followed by PCI for STEMI on 10-Oct-2005, then discharged on 14-Oct-2005. On 12- 

Nov-2005, the subject visited the emergency room due to a chest pain. CPR was done and 

emergent medications were administered for no pulsation, no respiration, pupil full dilation, but 

the subject was dead. The investigator concluded this was definitely not related to the study 

drug. 

Of the life-threatening adverse events, there were 1 case of cardiac tamponade (C010, 

ReoPro ® ) during PCI, 1 case of cardiac tamponade (C032, ReoPro ® ) on day 21 post PCI and 1 

case of transient bradycardia with hypotension due to “no-reflow phenomenon” after stenting 

(C020, Clotinab). 

Of the adverse events of prolongation of hospitalization, there were 1 case of dyspnea (A020, 

Clotinab) on day 2, 1 case of urinary difficulty (Y045, Clotinab) on day 23. These events were 

treated appropriately soon, all subjects were recovered and completed all the schedule of the 

study. The investigator concluded this was definitely not related to the study drug. 

There were adverse events causing volume change/temporary discontinuation of treatment of 

study drug to 5 subjects (3 cases of catheter site hematoma, 2 cases of wound secretion) 

during the study. And there were adverse events causing study drug discontinuation in 5 

subjects (3 cases of catheter site hematoma, 3 cases of wound secretion, 1 case of application 

site bleeding, 1 case of haemorrhage, 1 case of gingival bleeding and 1 case of epistaxis) (refer 

to table 12.7:3, table 12.7:4). 


Ver. 1.0_Eng

Subjec 

t ID 

Table 12.7:1 Subjects with Serious Adverse Events 

Treatmen 

t Sex Age System Organ Class Preferred term 

A020 Clotinab Fem 

ale 


94 

Ver. 1.0_Eng 

Onset 

date Onset time 

Resolution 

date 

Resolutio 

n time Severity 

Seriousness 

72 Cardiac disorders Dyspnoea 08/05/05 12:00 08/08/05 UK:UK Severe Yes Medication 

prescribed 

A032 ReoPro ® Male 50 Cardiac disorders Cardiac 

tamponade 

C010 ReoPro ® Fem 

ale 

C020 Clotinab Fem 

ale 

C021 ReoPro ® Fem 

ale 

77 Cardiac disorders Cardiac 

tamponade 

Action 

taken Causality Outcome 

None Recovered, 

without 

sequelae 

10/04/05 11:00 10/06/05 18:00 Severe Yes No None Recovered, 

without 

sequelae 

08/01/05 14:UK 08/04/05 UK:UK Severe Yes No None Recovered, 

without 

sequelae 

67 Cardiac disorders Bradycardia 09/13/05 09:15 09/13/05 09:25 Severe Yes No None Recovered, 

without 

sequelae 

67 Cardiac disorders Dyspnoea 10/08/05 UK:UK 10/09/05 02:30 Severe Yes Medication 

prescribed 

None Death 

Y045 Clotinab Male 67 



conditions 



Y056 ReoPro ® Male 57 General disorders and 


conditions 

Death 10/09/05 02:30 10/09/05 02:30 Severe Yes Medication 

prescribed 

Dysuria 09/12/05 UK:UK 09/18/05 UK:UK Severe Yes Medication 

prescribed 

Death 11/12/05 UK:UK 11/12/05 UK:UK Severe Yes Medication 

prescribed 

None Death 


without 

sequelae 

None Death

Subject 

ID 

Table 12.7:2 Subjects with AEs lead to death 

Treatme 

nt Sex Age System Organ Class 

® Fem- 

C021 ReoPro 

ale 

Y056 ReoPro ® Male 57 

Subject 

ID 


95 

Ver. 1.0_Eng 

Preferred 

term 

Onset 

date 

Onset 

time 

Resoluti 

on date 

Resoluti 

on time Severity 

Seriousness 

67 Cardiac disorders Dyspnoea 10/08/05 UK:UK 10/09/05 02:30 Severe Yes 

General disorders and administration 

site conditions 

General disorders and administration 


Table 12.7:3 Subjects with AEs lead to IP dosage change/temporarily discontinued 

Treatm 

ent Sex Age 

A004 Clotinab Male 55 


A026 Clotinab Female 

64 

Y042 Clotinab Male 59 

® Fem- 

Y062 ReoPro 

ale 

68 

System Organ 

Class 

General disorders 

and administration 














Preferred 

term 

Catheter site 

hematoma 

Catheter site 

hematoma 

Catheter site 

hematoma 

Wound 

secretion 

Wound 

secretion 

Death 10/09/05 02:30 10/09/05 02:30 Severe Yes 

Death 11/12/05 UK:UK 11/12/05 UK:UK Severe Yes 

Onset 

date 

Onset 

time 

Resolution 

date 

Resoluti 

on time Severity 

06/23/05 11:45 06/23/05 15:20 Mild No 

07/04/05 UK:UK UK/UK/UK UK:UK 

중등도 

(Moderate) 

08/29/05 07:50 08/29/05 15:40 Mild No 

08/30/05 17:10 08/30/05 22:30 Mild No 

10/20/05 21:30 10/20/05 23:35 Mild No 

Action 


Medication 

prescribed 

Medication 

prescribed 

Medication 

prescribed 

None Death 

None Death 

None Death 

Seriousness 

Action taken Causality Outcome 

No 

IP dosage 

change/temporarily 

discontinued 

IP dosage 


discontinued 

IP dosage 


discontinued 

IP dosage 


discontinued 

IP dosage 


discontinued 

Improbable 

Improbable 

Improbable 

Improbable 

Improbable 

Recovered 

, without 

sequelae 

Recovered 

, without 

sequelae 

Recovered 

, without 

sequelae 

Recovered 

, without 

sequelae 

Recovered 

, without 

sequelae

Subject 

ID 

Table 12.7:4 Subjects with AEs lead to IP permanently discontinued 

Treatm 

ent Sex Age System Organ Class Preferred term 


A022 Clotinab Female 

54 

C024 Clotinab Male 48 

Y046 Clotinab Female 

® Fem- 

C010 ReoPro 

ale 

56 


96 

Ver. 1.0_Eng 



conditions 



conditions 



conditions 



conditions 



conditions 



conditions 



conditions 

Catheter site 

hematoma 

Onset 

date 

Onset 

time 

Resolution 

date 

Resolution 

time Severity 

Seriousness 

08/03/05 UK:UK UK/UK/UK UK:UK Severe No 

Wound secretion 08/03/05 UK:UK 08/03/05 01:35 Mild No 

Catheter site 

hematoma 

08/04/05 11:50 08/04/05 18:00 Severe No 

Wound secretion 08/04/05 11:50 08/04/05 18:00 Severe No 

Catheter site 

hematoma 

Application site 

bleeding 

10/12/05 20:25 10/23/05 UK:UK Mild No 

10/12/05 UK:UK 10/13/05 UK:UK Mild No 

Wound secretion 09/12/05 22:30 09/13/05 07:00 Mild No 

Vascular disorders Epistaxis 09/12/05 23:30 09/13/05 13:30 Mild No 

Vascular disorders Gingival bleeding 09/10/05 01:40 09/13/05 13:30 Mild No 

77 Vascular disorders Haemorrhage 08/02/05 UK:UK 09/02/05 UK:UK Severe No 

Action 


IP 

permanently 

discontinued 

IP 

permanently 

discontinued 

IP 

permanently 

discontinued 

IP 

permanently 

discontinued 

IP 

permanently 

discontinued 

IP 

permanently 

discontinued 

IP 

permanently 

discontinued 

IP 

permanently 

discontinued 

IP 

permanently 

discontinued 

IP 

permanently 

discontinued 

Possible 

Possible 

Improbable 

Improbable 

Possible 

Possible 

Improbable 

Improbable 

Improbable 

Improbable 

Recovered, 

without 

sequelae 

Recovered, 

without 

sequelae 

Recovered, 

without 

sequelae 

Recovered, 

without 

sequelae 

Recovered, 

without 

sequelae 

Recovered, 

without 

sequelae 

Recovered, 

without 

sequelae 

Recovered, 

without 

sequelae 

Recovered, 

without 

sequelae 

Recovered, 

without 

sequelae

12.8. Clinical laboratory evaluation 

The descriptive statistics (mean, standard deviation, median, minimum, maximum) were 

presented by group and visit for continuous variables such as hematology, serum chemistry, 

coagulation and cardiac marker(See Table 15.13, Table 15.14). Clinical laboratoy tests and 

cardiac marker tests were done at the basline, 12 hour, 24 hour, day 3, one day before 

discharge, and day 30(+7). For the Friedman test, a nonparametric method for blocked data, 

was done for each treatment group. Each patient is considered a block. The Friedman test 

determines if variariations in test results over the time are significant. The significance test was 

done separately for each treatment group. The frequency and proportion of status 

(normal/clinically insignificant abnormal/clinically significant abnormal) in the urinalysis and 

coagulation analysis at day 3, one day before discharge, and day 30(+7) visit compared to the 

screening or baseline status were described (Table 15.15-17). 

12.8.1. Listing of indivisual laboratory measurements by patient 

See Appendix 16.4 

12.8.2. Evaluation of each laboratory parameter 

The Clotinab group showed significant variations over the time in all the hematology and serum 

chemistry tests except for SGPT and sodium. The ReoPro ® also showed significant variations 

over the time in all the hematology, and serum chemistry test except for glucose and 

triglyceride. These significant variations were not considered clinically important. No noteworthy 

difference between Clotinab and ReoPro ® group existed considering a similar tendency in both 

groups. 

12.9. Vital signs, physical findings and other observations related to 

safety 

Vital signs were measured at the baseline, 1 hour, 2 hour, 3 hour, 4 hour, 6 hour, 12 hour, 18 

hour, 24 hour, day 3, one day before discharge, and day 30(+7). Descriptive statistics of 

baseline observations and changes from the baseline (mean, standard deviation, median, 

minimum, maximum) were presented per measurement time for each treatment group 

separately. For the Friedman test, a nonparametric method for blocked data, was done for each 


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97

treatment group. Each patient is considered a block (See Table 15.18). But these significant 

variations in body temperature, pulse rate, and respiration rate were considered to have no 

clinical meaning. And the variations of systolic blood pressure were due to medications given 

such as vasodilator, beta blocker, ACE inhibitor to lower myocardial oxygen consumption just 

after hospitalization, and thus variations in systolic blood pressure are considered normal one, 

not related to investigational drug. 

The physical examination was done at the baseline/screening, day 3, one day before discharge, 

and day 30(+7). Physical examination results during the study were cross classified against the 

baseline for each treatment group separatley (See Table 15.19, Table 15.20). Nothing particular 

was noteworthy. 

12.10. Safety conclusions 

Based on TIMI criteria, no major bleeding occurred in Clotinab, but 3 subjects (7.50%) 

experienced major bleeding in ReoPro ® . The number of subjects with minor bleeding was 

11(13.25%) for Clotinab and 5(12.50%) for ReoPro ® . The number of subjects with clinically 

insignificant bleeding was 11(13.25%) for Clotinab and 9(22.50%) for ReoPro ® . 

Number of patients with overall bleeding based on TIMI criteria showed no significant 

difference between Clotinab and ReoPro ® in each time point. (See Table 12.2:2) However 

number of patients with major bleeding showed significant difference. (p=0.0326) 

No significant results were reported in thrombocytopenia, change in Hb/Hct, HACA, adverse 

event, laboratory data. 

Serious adverse events were occurred to 7 subjects[{Clotinab 3(3.61%), 95% exact C.I.(0.75%, 

10.20%)}, {ReoPro ® 4(10.00%), 95% exact C.I.(2.79%, 23.66%)}] as follows. Prolongation of 

existing hospitalization: 2 patients, life-threatening: 1 subject in Clotinab. Death: 2 subjects, 

life-threatening: 2 subjects in ReoPro ® . But Investigators concluded these 7 cases were not 

related to study drug, and there was no significant difference between Clotinab and ReoPro ® in 



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13. Discussion and overall conclusions 

The platelet glycoprotein (GP) IIb/IIIa receptor blocker is the strongest known inhibitor against 

the last step of platelet coagulation 7) . In the process of platelet formation in coronary arteries, 

the platelet glycoprotein (GP) IIb/IIIa receptor is activated after changing forms in platelet 

which has been activated by collagen, thrombin, adenosine diphosphate. And it acts as a 

receptor of fibrinogen and von Willebrand factor, which is dissolved in blood. After that, the 

platelet glycoprotein (GP) IIb/IIIa receptor approched by fibrinogen is activated by changing 

structure, and forms thrombus by formation of crossbinding 28)29) . Accordingly, the GP IIb/IIIa 

receptor is thought of as the most important factor of acute thrombogenesis in coronary 

arteries, and we can decrease thrombogenesis by inhibiting the binding between fibrinogen and 

GP IIb/IIIa receptor, resulting in blocking the crossbinding of platelets 29) . 

Representative platelet GPIIb/IIIa receptor blockers currently used in clinical practiice are 

abciximab(ReoPro ® ) which is chimeric human-murine monoclonal antibody fragment, 

eptifibatide(Integrilin) which is a peptide, and Tirofiban(Aggrastat ® ) and Lamifiban which is a 

peptidimimetric. 20)-26) . Among them, Abxicimab has an affinity for vitronectin receptor existing in 

vascular smooth muscle cell, endothelial cell, platelet, etc, differently from low-molecular weight 

glycoprotein IIb/IIIa receptor blockers. Inhibiting vitronectin receptor prevents restenosis by 

restricting cellular movement and proliferation of vascular smooth muscle after acute vascular 

damage 29)-33) . 

The effect of platelet glucoprotein IIb/IIIa receptor blocker has been proved in many clinical 

trials such as the PRAGON trial 34) , PRISM trial 25) , PRISM-PLUS trial 26) and PURSUIT trial 24) etc. It 

is known that the glycoprotein IIb/IIIa receptor blocker decreases complication in high-risk 

patient groups such as with vascular acute obstruction as in the EPIC trial 20) by using abxicimab 

(ReoPro ® ), and it could decrease acute ischemic complication without increase of hemorrhagic 

complication by using low-dose heparin in the EPILOG trial 21) . 

It was reported that ReoPro ® was effective in case of prolonged door-to-needle time situation in 

patients with myocardial infarction in the ReoMI trial 35) . In the GUSTO-III trial, 36) it was 

presented that ReoPro ® decreased the 30-day death rate in MI patients who failed 

thrombolytics treatment. There are few efficacy results of ReoPro ® for preventing restenosis 

after percutaneous coronary intervention, but it was proved that ReoPro ® had an efficacy in 

patients with diabetes mellitus in the EPISTENT trial 37) . But it was reported that there ware rare 


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effects of stenting for restenosis in the ERASER trial 38) . 

This study was designed multicentre, open-label study to evaluate the efficacy and safety of 

Clotinab to improve ischemic cardiac complications in high-risk patients who will undergo 

Percutaneous Coronary Intervention (PCI)). Since it (Clotinab) contains identical active 

ingredient as ReoPro ® on the domestic market, it is expected that Clotinab has same efficacy to 

ReoPro ® as a platelet GP IIb/IIIa receptor inhibitor. this theraputic and exploratory clinical trial 

was designed to investigate the preventive effect on ischemic heart complications and safety of 

adjuvant use of Clotinab with asprin and heparin in high-risk acute coronary thrombotic patients 

who will undergo PCI. 

The primary efficacy endpoint is the onset of MACE within 30(+7) days from the study drug 

administration following the PCI procedure. The MACE includes the death related to heart 

disease, the recurrence of myocardial infarction (MI) and the emergency revascularization. 

No patient among 84 patients in the Clotinab group experienced the primary efficacy measure, 

the MACE. Whether we analyze the PP population, ITT population, or FAS population, the same 

conclusion is reached. Clotinab is effecitve in preventing the MACE event. The upper bound of 

95% confidence interval is all below 5% regardless of the analysis population, indicating that 

the MACE rate among patients undergoing the PCI procedure will be less than 5% if also 

treated with Clotinab. Only one Clotinab patient experienced a new change in electrocardiogram. 

The rate of the status of ischemia indicated by electrocardiogram in the Clotinab patients at day 

30(+7) dropped significantly by about 17-21%, depending on the analysis population, from the 

baseline. No Clotinab patient experienced major bleeding event. We can conclude that Clotinab 


Two patient among 40 patients in the ReoPro ® group experienced the MACE. The upper bound 

of 95% confidence interval is about 16.9-18.7% depending on the analysis population. This 

indicates that less than 20% of the patients undergoing the PCI proceudre will experience the 

MACE if also treated with ReoPro ® . Only one patient experienced a new change in 

electrocardiogram. The rate of the status of ischemia indicated by electrocardiogram in the 

ReoPro ® group at dqy 30(+7) dropped significantly by about 24-27%, depending on the 

analysis population, from the baseline. Three ReoPro ® patients experienced major bleeding 

event. The major bleeding rate is signifcantly higher in the ReoPro ® group than in the Clotinab 

group. 


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100

The intention of this clinical study is not designed to compare the efficacy or safety of Clotinab 

and ReoPro ® in patients undergoing the PCI procedure. Thus we do not make a statement 

about which treatment is more effective and safer. Nevertheless we can conclude that Clotinab 


Bleeding, thrombocytopenia, change in Hb/Hct, HACA(human antichimetric antibody) 

development, adverse event and other data were analyzed to evaluate the safety of Clotinab 

Based on TIMI criteria, no major bleeding occurred in Clotinab, but 3 subjects (7.50%) 

experienced major bleeding in ReoPro ® . The number of subjects with minor bleeding was 

11(13.25%) for Clotinab and 5(12.50%) for ReoPro ® . The number of subjects with clinically 

insignificant bleeding was 11(13.25%) for Clotinab and 9(22.50%) for ReoPro ® . 

Number of patients with overall bleeding based on TIMI criteria showed no significant 

difference between Clotinab and ReoPro ® in each time point. (See Table 12.2:2) However 

number of patients with major bleeding showed significant difference. (p=0.0326) 

No significant results were reported in thrombocytopenia, change in Hb/Hct, HACA, adverse 

event, laboratory data. 

Most frequent adverse events in the Clotinab and ReoPro ® group were related to general 

disorders and administration site conditions. Most frequent adverse events related to the PCI 

procedure were wound secretion and catheter site hematoma, catheter site hemorrhage in both 

treatment groups. 

The proportion of patients experiencing adverse event at least once was not significantly 

different between Clotinab and ReoPro ® (p-value=0.5325) The proportion of patients 

experiencing adverse events related to the study drug at least once was not significantly 

different between two groups (p-value=0.6627). 

Three Clotinab patients (3.61%) experienced drug-related thrombocytopenia, two patients 

(2.41%) wound secretion 2(2.41%), two patients (2.41%) catheter site hematoma, and one 

patient (1.20%) application site bleeding. One ReoPro ® patient (2.50%) experienced aspartate 

aminotransferase increase. 

Serious adverse events were occurred to 7 subjects[{Clotinab 3(3.61%), 95% exact C.I.(0.75%, 


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101

10.20%)}, {ReoPro ® 4(10.00%), 95% exact C.I.(2.79%, 23.66%)}] as follows. Prolongation of 

existing hospitalization: 2 patients, life-threatening: 1 subject in Clotinab. Death: 2 subjects, 

life-threatening: 2 subjects in ReoPro ® . But Investigators concluded these 7 cases were not 

related to study drug, and there was no significant difference between Clotinab and ReoPro ® in 


Observing the vital sign and laboratory data, significant differences were shown in each time 

point for Clotinab and ReoPro ® . However, they were not clinically significant differences. 

Clotinab is expected to be effective to prevent ischemic heart complications for high-risk 

patients who undergo Percutaneous Coronary Intervention(PCI). The probability of MACE onset 

in Clotinab is estimated to be below 5%. There was no clinically significant result in safety 

variables. In conclusion, Clotinab will be a effective medicine to prevent ischemic cardiac 

complications for high-risk patients who undergo Percutaneous Coronary Intervention. 


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14. Reference list 

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장기 임상 결과 [대한내과학회지 : 제65권 제6호 2003] 

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57권 제1호 1999] 

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(6) Harker LA. Role of platelets and thrombosis in mechanisms of acute occlusion and restenosis 

after angioplasty. Am J Cardiol 1987:60:20B-28B. 

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conformation and/or microenviroment of the platelet glycoprotein IIb/IIIa complex J clin 

Invest 1985;76:101-8. 

(9) 고위험군 급성 심근경색증 환자의 관상동맥 중재술시 혈소판 당단백 IIb/IIIa 수용체 차 

단제(Abciximab: ReoPro ® )의 구제적 사용 [Korean Circulation J 2001;31(5):492-499]. 

(10) 급성 심근경색 환자에서 일차적 관동맥 중재술시 Abciximab의 사용이 좌심실 재형성 

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(11) 급성 관상동맥 증후군 환자에서 저분자량 헤파린과 혈소판 당단백 Ⅱb/ Ⅲ a 억제제의 

병합요법의 장기 임상효과 [대한순환기학회지 : 2003;33 (7):559-567]. 

(12) 신증후군 환자에서 혈전에 의한 급성 심근경색증의 성공적인 Abciximab 치료 [대한순 

환기학회지 : 2003;33(6):523-527]. 

(13) Long-term clinical benefits of a platelet glycoprotein IIb/IIIa receptor blocker, abciximab 

(ReoPro ® ), in high-risk diabetic patients undergoing percutaneous coronary intervention 

[ Korean J Intern Med. 2003 Sep;18(3):129-37]. 

(14) Randomized trial of coronary intervention with antibody against platelet IIb/IIIa integrin 

for reduction of clinical restenosis: results at six months. The EPIC Investigators. Lancet. 

1994 Apr 9;343(8902):881-6. 

(15) Randomized placebo-controlled trial of abciximab before and during coronary intervention 

in refractory unstable angina: the CAPTURE Study. Lancet. 1997 May 17;349(9063):1429- 

35. 

(16) Randomized placebo-controlled and balloon-angioplasty-controlled trial to assess safety of 


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coronary stenting with use of platelet glycoprotein-IIb/IIIa blockade. The EPISTENT 

Investigators. Evaluation of Platelet IIb/IIIa Inhibitor for Stenting. Lancet. 1998 Jul 

11;352(9122):87-92. 

(17) Complementary clinical benefits of coronary-artery stenting and blockade of platelet 

glycoprotein IIb/IIIa receptors. Evaluation of Platelet IIb/IIIa Inhibition in Stenting 

Investigators. N Engl J Med. 1999 Jul 29;341(5):319-27. 

(18) Platelet glycoprotein IIb/IIIa inhibition with coronary stenting for acute myocardial 

infarction. N Engl J Med. 2001 Jun 21;344(25):1895-903. 

(19) Comparison of angioplasty with stenting, with or without abciximab, in acute myocardial 

infarction. N Engl J Med. 2002 Mar 28;346(13):957-66. 

(20) EPIC(Evaluation of 7E3 in Preventing Ischemic Complications) Investigators. Use of a 

monoclonal antibody directed against the platelet glycoprotein IIb/IIIa receptor in high-risk 

coronary angioplasty. N Engl J Med 1994:330:956-61. 

(21) EPILOG(Evaluation in PTCA to improve Long-Term outcome GP IIb/IIIa Blockade Study 

Group) Investigators. Platelet glycoprotein IIb/IIIa receptor blockade and low-dose heparin 

daring percutaneous coronary revascularization. N Engl J Med 1997:336:1689-96. 

(22) IMPACT-II(Integrilin to Minimize Pletelet Aggregation and Coronary Thrombosis-II) trial 

Investigators. Randomizde placebo-controlled trial of effect of eptifibatide on complications 

of percutaneous coronary intervention. IMPACT-II Lancet 1997:349:1422-8. 

(23) RESTORE (Randomized Efficacy Study of Tirofiban for Outcomes and REstenosis) 

Investigators. Effects of platelet glycoprotein IIb/IIIa blockade with tirofiban on adverse 

cardiac events in patients with unstable angina or acute myocardial infarction undergoing 

coronary angioplasty. Circulation 1997:96:1445-53. 

(24) PURSUIT(Pletelet Glycoprotein IIb/IIIa in Unstable Angina Receptor Suppression Using 

Integrilin Therapy) Trial Investigators. Inhibition of platelet glycoprotein IIb/IIIa with 

eptifibatide in patients with acute coronary artery syndromes. N Engl J Med 1998:389:436- 

42. 

(25) Platelet Receptor Inhibition in ischemic Syndrome Management(PRISM) study investigators. 

A comparison of aspirin plus tirofiban with aspirin plus heparin for unstable angina. N Engl 

J Med 1998:338:1498-505. 

(26) Platelet Receptor Inhibition in ischemic Syndrome Management in Patients Limited by 

Unstable Sings and Symptoms(PRISM-PLUS) Study Investigators. Inhibition of the platelet 

glycoprotein IIb/IIIa receptor with tirofiban in unstable angina and non-Q wave myocardial 

infarction. N Engl J Med 1998:338:1448-97. 

(27) Weitz JI, Bates S.Beyond heparin and aspirin: New treatments for unstable angina and 

non-Q wave myocardial infarction. Arch Intern Med 2000:160:749-58. 


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(28) Willerson JT, Golino P, Eidt J, Campbell WB, Buja LM. Specific platelet mediators and 

unstable coronary artery. Experimental evidence and potential clinical implications. 

Circulation 1989:80:198-205. 

(29) Frishman WH, Burns B, Atac B, Alturk N, Altajar B, Lerrik K. Novel antiplatelet therapies for 

treatment of patients with ischemic heart disease : Inhibitors of the platelet glycoprotein 

IIb/IIIa integrin receptor. Am Heart J 1995:130:877-92. 

(30) Nakada MT, Jordan RE, Knight DM. abciximab (ReoPro ® chimeric 7E3 Fab) cross-specificity 

with [alpha]V[beta]3 integr-in receptors:A potential mechanism for the prevention of 

restenosis. J Am Coll Cardiol 1997:29:A243. 

(31) Reverter JC, Beguin S, Kessels H, Kuman R, Hemlar HC, Coller BS. Inhibition of plateletmedicaated. 

tissue factor-induced thrombin generation by the mouse/human chimeric 7E3 

antibody. Potential implications for the effect of c7E3 Fab treatment of an acute thrombosis 

and “cllinical restenosis” , J Clin Invest 1996:98:863-74. 

(32) Marijianowski MM, Nakada MT, Sundell BI, Kelly AB, Jordan RE, Jakubowski JA, et al. 

Abciximab reduces vascular lesion formation in non-human primates. J Am Coll Cardiol. 

1999:33:69A. 

(33) Bishop GG, McPherson JA, Sanders J, Feldman MJ, Gimple LW, Ragosta A, et al. 

[alpha]V[beta]3 receptor blockade reduces restenosis following balloon angioplasty in the 

atherosderotic rabbit. J Am Coll Cardiol 1999:33:31A. 

(34) The PARAGON(Platelet IIb/IIIa Antagonism for the Reduction of Acute doronary syndrome 

events in a Global Organization Network) Investigators. International, randomized, 

controlled trial of Lamifiban (a platelet glycoprotein IIb/IIIa inhibitor), heparin, or both in 

unstable angina. Circulation. 1998:97:2386-95. 

(35) Makkar R, Goff B, Eigler N, Sebastian M, Fischell T, Sarr L, et al. Effect of glycoprotein 

IIb/IIIa inhibition without thrombolytic therapy in acute myocardial infarction : Results of 

ReoMI pilot study. Cathet Cardiovasc Interv 1999:48:430-4. 

(36) Miller JM, Smalling R, Ohman EM, BOde C, Betrin A, Kleiman NS, et al. Effectiveness of 

early coronary angioplasty and abciximab for failed thrombolysis (reteplase or alteplase 

during myocardial infarction. Am J Cardiol 1999:84:779-84. 

(37) EPISTENT(Evaluation of Platelet IIb/IIIa Inhibitor or Stenting) trial investigators. 

Randomized placebo-controlled and ballon-angioplasty-controlled trial to assess safety of 

coronary stenting with use of platelet glycoprotein-Iib/IIIa blockade. Lancet 1998:352:87- 

92. 

(38) The ERASER(Evaluation of Reo-Pro ® And Stenting to Eliminate Restenosis) study 

Investigators. Acute platelet inhibition with abciximab does not reduce in-stent 

restenosis(ERASER study). Criculation 1999:100:799-806. 


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15. Tables referred to but not included in the text 

TABLE 15. 1 MEDICATION ADMINISTERED WITHIN 7DAYS BEFORE TRIAL (ITT) ....................................107 

TABLE 15. 2 CONCOMITANT MEDICATION - ADMINISTERED DURING TRIAL (ITT) ..................................109 

TABLE 15. 3 MEDICATION - ADMINISTERED WITHIN 7DAYS BEFORE TRIAL (FAS)..................................111 

TABLE 15. 4 CONCOMITANT MEDICATION - ADMINISTERED DURING TRIAL (FAS) ..................................113 

TABLE 15. 5 MEDICATION - ADMINISTERED WITHIN 7 DAYS BEFORE TRIAL (PP)...................................115 

TABLE 15. 6 CONCOMITANT MEDICATION - ADMINISTERED DURING TRIAL (PP)....................................117 

TABLE 15. 7 DISPOSITION OF SUBJECTS BY SITE AND TREATMENT ....................................................119 

TABLE 15. 8 NUMBER OF PATIENTS WITH MAJOR BLEEDING EVENTS BY INITIAL HEPARIN BOLUS DOSE .........120 

TABLE 15. 9 THE RATE OF ADVERSE EVENT BY BODY SYSTEM..........................................................121 

TABLE 15. 10 NUMBER OBSERVED AND RATE, WITH SUBJECT IDENTIFICATIONS- CLOTINAB......................125 

TABLE 15. 11 NUMBER OBSERVED AND RATE, WITH SUBJECT IDENTIFICATIONS-REOPRO ® ......................136 

TABLE 15. 12 SUBJECT LIST OF ALL ADVERSE EVENTS ...................................................................142 

TABLE 15. 13 LABORATORY DATA ...........................................................................................183 

TABLE 15. 14 CARDIAC MARKER ............................................................................................197 

TABLE 15. 15 URINALYSIS-CLOTINAB ......................................................................................199 

TABLE 15. 16 URINALYSIS-REOPRO ® ......................................................................................201 

TABLE 15. 17 COAGULATION .................................................................................................203 

TABLE 15. 18 VITAL SIGN.....................................................................................................204 

TABLE 15. 19 PHYSICAL EXAMINATION-CLOTINAB .......................................................................207 

TABLE 15. 20 PHYSICAL EXAMINATION -REOPRO ® ......................................................................209 

TABLE 15. 21 LISTING OF SUBJECTS WITH MINOR PROTOCOL VIOLATIONS ..........................................211 


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Table 15. 1 Medication administered within 7days before trial (ITT) 

Items Statistic 

Clotinab ReoPro ® Total 

Total number of subjects (N=84) (N=40) (N=124) 

Level1 Level2 

alimentary tract and metabolism antidiarrheals, intestinal antiinflammatory/antiinfective 

agents 

N(%) 1( 1.19%) 0( 0.00%) 1( 0.81%) 

bile and liver therapy N(%) 0( 0.00%) 1( 2.50%) 1( 0.81%) 

digestives, incl. enzymes N(%) 3( 3.57%) 4(10.00%) 7( 5.65%) 

drugs for acid related disorders N(%) 31(36.90%) 11(27.50%) 42(33.87%) 

drugs for functional gastrointestinal disorders N(%) 4( 4.76%) 4(10.00%) 8( 6.45%) 

drugs used in diabetes N(%) 12(14.29%) 7(17.50%) 19(15.32%) 

laxatives N(%) 1( 1.19%) 0( 0.00%) 1( 0.81%) 

mineral supplements N(%) 5( 5.95%) 2( 5.00%) 7( 5.65%) 

other alimentary tract and metabolism products N(%) 1( 1.19%) 2( 5.00%) 3( 2.42%) 

tonics N(%) 1( 1.19%) 0( 0.00%) 1( 0.81%) 

vitamins N(%) 2( 2.38%) 1( 2.50%) 3( 2.42%) 

antiinfectives for systemic use antibacterials for systemic use N(%) 0( 0.00%) 2( 5.00%) 2( 1.61%) 

antimycobacterials N(%) 1( 1.19%) 0( 0.00%) 1( 0.81%) 

antibacterials for systemic use N(%) 3( 3.57%) 0( 0.00%) 3( 2.42%) 

blood and blood forming organs antithrombotic agents N(%) 84(100.0%) 40(100.0%) 124(100.0%) 

blood substitutes and perfusion solutions N(%) 2( 2.38%) 1( 2.50%) 3( 2.42%) 

cardiovascular system agents acting on the renin-angiotensin system N(%) 44(52.38%) 20(50.00%) 64(51.61%) 

beta blocking agents N(%) 69(82.14%) 31(77.50%) 100(80.65%) 

calcium channel blockers N(%) 36(42.86%) 23(57.50%) 59(47.58%) 

cardiac therapy N(%) 79(94.05%) 37(92.50%) 116(93.55%) 

diuretics N(%) 9(10.71%) 6(15.00%) 15(12.10%) 

peripheral vasodilators N(%) 1( 1.19%) 0( 0.00%) 1( 0.81%) 

serum lipid reducing agents N(%) 54(64.29%) 19(47.50%) 73(58.87%) 

genito urinary system and sex hormones urologicals N(%) 1( 1.19%) 0( 0.00%) 1( 0.81%) 

musculo-skeletal system antiinflammatory and antirheumatic products N(%) 3( 3.57%) 1( 2.50%) 4( 3.23%) 

drugs for treatment of bone diseases N(%) 1( 1.19%) 0( 0.00%) 1( 0.81%) 


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Level1 Level2 

nervous system analgesics N(%) 27(32.14%) 11(27.50%) 38(30.65%) 

anesthetics N(%) 5( 5.95%) 1( 2.50%) 6( 4.84%) 

anti-parkinson drugs N(%) 1( 1.19%) 0( 0.00%) 1( 0.81%) 

antiepileptics N(%) 1( 1.19%) 1( 2.50%) 2( 1.61%) 

psychoanaleptics N(%) 2( 2.38%) 0( 0.00%) 2( 1.61%) 

psycholeptics N(%) 60(71.43%) 26(65.00%) 86(69.35%) 

respiratory system antihistamines for systemic use N(%) 59(70.24%) 25(62.50%) 84(67.74%) 

cough and cold preparations N(%) 3( 3.57%) 0( 0.00%) 3( 2.42%) 

drugs for obstructive airway dieases N(%) 4( 4.76%) 0( 0.00%) 4( 3.23%) 

sensory organs ophthalmologicals N(%) 0( 0.00%) 1( 2.50%) 1( 0.81%) 

systemic hormonal preparations, excl. sex 

hormones and insulins 

corticosteroids for systemic use N(%) 18(21.43%) 8(20.00%) 26(20.97%) 

thyroid therapy N(%) 0( 0.00%) 1( 2.50%) 1( 0.81%) 


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Table 15. 2 Concomitant medication - administered during trial (ITT) 




Level1 Level2 

alimentary tract and metabolism antiemetics and antinauseants N(%) 0( 0.00%) 1( 2.50%) 1( 0.81%) 


digestives, incl. enzymes N(%) 10(11.90%) 5(12.50%) 15(12.20%) 


drugs for functional gastrointestinal disorders N(%) 18(21.43%) 10(25.00%) 28(22.76%) 


laxatives N(%) 5( 5.95%) 3( 7.50%) 8( 6.50%) 

mineral supplements N(%) 7( 8.33%) 6(15.00%) 13(10.57%) 

stomatological preparations N(%) 1( 1.19%) 0( 0.00%) 1( 0.81%) 

tonics N(%) 1( 1.19%) 0( 0.00%) 1( 0.81%) 

vitamins N(%) 2( 2.38%) 1( 2.50%) 3( 2.44%) 

antiinfectives for systemic use antibacterials for systemic use N(%) 10(11.90%) 4(10.00%) 14(11.38%) 


antineoplastic and immunomodulating agents endocrine therapy N(%) 1( 1.19%) 0( 0.00%) 1( 0.81%) 

blood and blood forming organs antianemic preparations N(%) 2( 2.38%) 0( 0.00%) 2( 1.63%) 

antithrombotic agents N(%) 83(98.81%) 40(100.0%) 123(100.0%) 


other hematological agents N(%) 1( 1.19%) 0( 0.00%) 1( 0.81%) 


antihypertensives N(%) 1( 1.19%) 0( 0.00%) 1( 0.81%) 




diuretics N(%) 13(15.48%) 5(12.50%) 18(14.63%) 



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Level1 Level2 

cardiovascular system serum lipid reducing agents N(%) 68(80.95%) 31(77.50%) 99(80.49%) 

dermatologicals antibiotics and chemotherapeutics for dermatological 

use 

N(%) 1( 1.19%) 0( 0.00%) 1( 0.81%) 

antifungals for dermatological use N(%) 1( 1.19%) 0( 0.00%) 1( 0.81%) 

corticosteroids, dermatological preparations N(%) 4( 4.76%) 0( 0.00%) 4( 3.25%) 

preparations for treatment of wounds and ulcers N(%) 1( 1.19%) 0( 0.00%) 1( 0.81%) 


musculo-skeletal system antiinflammatory and antirheumatic products N(%) 13(15.48%) 6(15.00%) 19(15.45%) 


topical products for joint and muscular pain N(%) 2( 2.38%) 4(10.00%) 6( 4.88%) 


anesthetics N(%) 6( 7.14%) 6(15.00%) 12( 9.76%) 



other nervous system drugs N(%) 1( 1.19%) 0( 0.00%) 1( 0.81%) 




cough and cold preparations N(%) 9(10.71%) 0( 0.00%) 9( 7.32%) 

drugs for obstructive airway diseases N(%) 5( 5.95%) 0( 0.00%) 5( 4.07%) 

nasal preparations N(%) 2( 2.38%) 1( 2.50%) 3( 2.44%) 






various all other therapeutic products N(%) 1( 1.19%) 0( 0.00%) 1( 0.81%) 


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Table 15. 3 Medication - administered within 7days before trial (FAS) 




Level1 Level2 


agents 

N(%) 1( 1.20%) 0( 0.00%) 1( 0.81%) 


digestives, incl. enzymes N(%) 3( 3.61%) 4(10.00%) 7( 5.69%) 


drugs for functional gastrointestinal disorders N(%) 4( 4.82%) 4(10.00%) 8( 6.50%) 


laxatives N(%) 1( 1.20%) 0( 0.00%) 1( 0.81%) 

mineral supplements N(%) 5( 6.02%) 2( 5.00%) 7( 5.69%) 

other alimentary tract and metabolism products N(%) 1( 1.20%) 2( 5.00%) 3( 2.44%) 

tonics N(%) 1( 1.20%) 0( 0.00%) 1( 0.81%) 

vitamins N(%) 2( 2.41%) 1( 2.50%) 3( 2.44%) 

antiinfectives for systemic use antibacterials for systemic use N(%) 0( 0.00%) 2( 5.00%) 2( 1.63%) 


antibacterials for systemic use N(%) 3( 3.61%) 0( 0.00%) 3( 2.44%) 

blood and blood forming organs antithrombotic agents N(%) 83(100.0%) 40(100.0%) 123(100.0%) 






diuretics N(%) 9(10.84%) 6(15.00%) 15(12.20%) 


serum lipid reducing agents N(%) 53(63.86%) 19(47.50%) 72(58.54%) 


musculo-skeletal system antiinflammatory and antirheumatic products N(%) 3( 3.61%) 1( 2.50%) 4( 3.25%) 



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Level1 Level2 


anesthetics N(%) 5( 6.02%) 1( 2.50%) 6( 4.88%) 






cough and cold preparations N(%) 3( 3.61%) 0( 0.00%) 3( 2.44%) 

drugs for obstructive airway dieases N(%) 4( 4.82%) 0( 0.00%) 4( 3.25%) 







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Table 15. 4 Concomitant medication - administered during trial (FAS) 




Level1 Level2 

alimentary tract and metabolism antiemetics and antinauseants N(%) 0( 0.00%) 1( 2.50%) 1( 0.81%) 


digestives, incl. enzymes N(%) 10(12.05%) 5(12.50%) 15(12.20%) 


drugs for functional gastrointestinal disorders N(%) 18(21.69%) 10(25.00%) 28(22.76%) 


laxatives N(%) 5( 6.02%) 3( 7.50%) 8( 6.50%) 

mineral supplements N(%) 7( 8.43%) 6(15.00%) 13(10.57%) 

stomatological preparations N(%) 1( 1.20%) 0( 0.00%) 1( 0.81%) 

tonics N(%) 1( 1.20%) 0( 0.00%) 1( 0.81%) 

vitamins N(%) 2( 2.41%) 1( 2.50%) 3( 2.44%) 

antiinfectives for systemic use antibacterials for systemic use N(%) 10(12.05%) 4(10.00%) 14(11.38%) 


antineoplastic and immunomodulating agents endocrine therapy N(%) 1( 1.20%) 0( 0.00%) 1( 0.81%) 

blood and blood forming organs antianemic preparations N(%) 2( 2.41%) 0( 0.00%) 2( 1.63%) 

antithrombotic agents N(%) 83(100.0%) 40(100.0%) 123(100.0%) 


other hematological agents N(%) 1( 1.20%) 0( 0.00%) 1( 0.81%) 


antihypertensives N(%) 1( 1.20%) 0( 0.00%) 1( 0.81%) 




diuretics N(%) 13(15.66%) 5(12.50%) 18(14.63%) 



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Level1 Level2 

cardiovascular system serum lipid reducing agents N(%) 68(81.93%) 31(77.50%) 99(80.49%) 


use 

N(%) 1( 1.20%) 0( 0.00%) 1( 0.81%) 

antifungals for dermatological use N(%) 1( 1.20%) 0( 0.00%) 1( 0.81%) 

corticosteroids, dermatological preparations N(%) 4( 4.82%) 0( 0.00%) 4( 3.25%) 

preparations for treatment of wounds and ulcers N(%) 1( 1.20%) 0( 0.00%) 1( 0.81%) 


musculo-skeletal system antiinflammatory and antirheumatic products N(%) 13(15.66%) 6(15.00%) 19(15.45%) 


topical products for joint and muscular pain N(%) 2( 2.41%) 4(10.00%) 6( 4.88%) 


anesthetics N(%) 6( 7.23%) 6(15.00%) 12( 9.76%) 



other nervous system drugs N(%) 1( 1.20%) 0( 0.00%) 1( 0.81%) 




cough and cold preparations N(%) 9(10.84%) 0( 0.00%) 9( 7.32%) 

drugs for obstructive airway diseases N(%) 5( 6.02%) 0( 0.00%) 5( 4.07%) 

nasal preparations N(%) 2( 2.41%) 1( 2.50%) 3( 2.44%) 






various all other therapeutic products N(%) 1( 1.20%) 0( 0.00%) 1( 0.81%) 


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Table 15. 5 Medication - administered within 7 days before trial (PP) 




Level1 Level2 


agents 

1( 1.32%) 0( 0.00%) 1( 0.89%) 

bile and liver therapy 0( 0.00%) 1( 2.78%) 1( 0.89%) 

digestives, incl. enzymes 3( 3.95%) 4(11.11%) 7( 6.25%) 

drugs for acid related disorders 26(34.21%) 10(27.78%) 36(32.14%) 

drugs for functional gastrointestinal disorders 3( 3.95%) 4(11.11%) 7( 6.25%) 

drugs used in diabetes 12(15.79%) 7(19.44%) 19(16.96%) 

laxatives 1( 1.32%) 0( 0.00%) 1( 0.89%) 

mineral supplements 4( 5.26%) 2( 5.56%) 6( 5.36%) 

other alimentary tract and metabolism products 1( 1.32%) 2( 5.56%) 3( 2.68%) 

tonics 1( 1.32%) 0( 0.00%) 1( 0.89%) 

vitamins 2( 2.63%) 1( 2.78%) 3( 2.68%) 

antiinfectives for systemic use antibacterials for systemic use 0( 0.00%) 2( 5.56%) 2( 1.79%) 

antimycobacterials 1( 1.32%) 0( 0.00%) 1( 0.89%) 

antibacterials for systemic use 1( 1.32%) 0( 0.00%) 1( 0.89%) 

blood and blood forming organs antithrombotic agents 76(100.0%) 36(100.0%) 112(100.0%) 

blood substitutes and perfusion solutions 1( 1.32%) 0( 0.00%) 1( 0.89%) 

cardiovascular system agents acting on the renin-angiotensin system 37(48.68%) 18(50.00%) 55(49.11%) 

beta blocking agents 62(81.58%) 28(77.78%) 90(80.36%) 

calcium channel blockers 34(44.74%) 22(61.11%) 56(50.00%) 

cardiac therapy 72(94.74%) 33(91.67%) 105(93.75%) 

diuretics 8(10.53%) 6(16.67%) 14(12.50%) 

serum lipid reducing agents 47(61.84%) 17(47.22%) 64(57.14%) 

genito urinary system and sex hormones urologicals 1( 1.32%) 0( 0.00%) 1( 0.89%) 

musculo-skeletal system antiinflammatory and antirheumatic products 3( 3.95%) 0( 0.00%) 3( 2.68%) 

drugs for treatment of bone diseases 1( 1.32%) 0( 0.00%) 1( 0.89%) 

nervous system analgesics 23(30.26%) 11(30.56%) 34(30.36%) 


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Level1 Level2 

nervous system anesthetics 4( 5.26%) 1( 2.78%) 5( 4.46%) 

anti-parkinson drugs 1( 1.32%) 0( 0.00%) 1( 0.89%) 

antiepileptics 1( 1.32%) 1( 2.78%) 2( 1.79%) 

psychoanaleptics 1( 1.32%) 0( 0.00%) 1( 0.89%) 

psycholeptics 52(68.42%) 24(66.67%) 76(67.86%) 

respiratory system antihistamines for systemic use 51(67.11%) 24(66.67%) 75(66.96%) 

cough and cold preparations 3( 3.95%) 0( 0.00%) 3( 2.68%) 

drugs for obstructive airway dieases 3( 3.95%) 0( 0.00%) 3( 2.68%) 

sensory organs ophthalmologicals 0( 0.00%) 1( 2.78%) 1( 0.89%) 



corticosteroids for systemic use 14(18.42%) 8(22.22%) 22(19.64%) 

thyroid therapy 0( 0.00%) 1( 2.78%) 1( 0.89%) 


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Table 15. 6 Concomitant medication - administered during trial (PP) 




Level1 Level2 

alimentary tract and metabolism antiemetics and antinauseants 0( 0.00%) 1( 2.78%) 1( 0.89%) 

bile and liver therapy 2( 2.63%) 2( 5.56%) 4( 3.57%) 

digestives, incl. enzymes 10(13.16%) 5(13.89%) 15(13.39%) 

drugs for acid related disorders 29(38.16%) 13(36.11%) 42(37.50%) 

drugs for functional gastrointestinal disorders 15(19.74%) 10(27.78%) 25(22.32%) 

drugs used in diabetes 15(19.74%) 8(22.22%) 23(20.54%) 

laxatives 4( 5.26%) 2( 5.56%) 6( 5.36%) 

mineral supplements 6( 7.89%) 5(13.89%) 11( 9.82%) 

stomatological preparations 1( 1.32%) 0( 0.00%) 1( 0.89%) 

tonics 1( 1.32%) 0( 0.00%) 1( 0.89%) 

vitamins 2( 2.63%) 1( 2.78%) 3( 2.68%) 

antiinfectives for systemic use antibacterials for systemic use 8(10.53%) 4(11.11%) 12(10.71%) 

antimycobacterials 1( 1.32%) 0( 0.00%) 1( 0.89%) 

antineoplastic and immunomodulating agents endocrine therapy 1( 1.32%) 0( 0.00%) 1( 0.89%) 

blood and blood forming organs antianemic preparations 2( 2.63%) 0( 0.00%) 2( 1.79%) 

antithrombotic agents 76(100.0%) 36(100.0%) 112(100.0%) 

blood substitutes and perfusion solutions 2( 2.63%) 2( 5.56%) 4( 3.57%) 

other hematological agents 1( 1.32%) 0( 0.00%) 1( 0.89%) 

cardiovascular system agents acting on the renin-angiotensin system 42(55.26%) 23(63.89%) 65(58.04%) 

antihypertensives 1( 1.32%) 0( 0.00%) 1( 0.89%) 

beta blocking agents 64(84.21%) 28(77.78%) 92(82.14%) 

calcium channel blockers 42(55.26%) 25(69.44%) 67(59.82%) 

cardiac therapy 75(98.68%) 35(97.22%) 110(98.21%) 

diuretics 9(11.84%) 5(13.89%) 14(12.50%) 

serum lipid reducing agents 63(82.89%) 28(77.78%) 91(81.25%) 


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Level1 Level2 


use 

1( 1.32%) 0( 0.00%) 1( 0.89%) 

antifungals for dermatological use 1( 1.32%) 0( 0.00%) 1( 0.89%) 

corticosteroids, dermatological preparations 3( 3.95%) 0( 0.00%) 3( 2.68%) 

genito urinary system and sex hormones urologicals 3( 3.95%) 0( 0.00%) 3( 2.68%) 

musculo-skeletal system antiinflammatory and antirheumatic products 12(15.79%) 5(13.89%) 17(15.18%) 

drugs for treatment of bone diseases 1( 1.32%) 0( 0.00%) 1( 0.89%) 

topical products for joint and muscular pain 2( 2.63%) 4(11.11%) 6( 5.36%) 

nervous system analgesics 37(48.68%) 19(52.78%) 56(50.00%) 

anesthetics 6( 7.89%) 6(16.67%) 12(10.71%) 

anti-parkinson drugs 1( 1.32%) 0( 0.00%) 1( 0.89%) 

antiepileptics 1( 1.32%) 1( 2.78%) 2( 1.79%) 

other nervous system drugs 1( 1.32%) 0( 0.00%) 1( 0.89%) 

psychoanaleptics 2( 2.63%) 0( 0.00%) 2( 1.79%) 

psycholeptics 10(13.16%) 5(13.89%) 15(13.39%) 

respiratory system antihistamines for systemic use 19(25.00%) 10(27.78%) 29(25.89%) 

cough and cold preparations 7( 9.21%) 0( 0.00%) 7( 6.25%) 

drugs for obstructive airway diseases 4( 5.26%) 0( 0.00%) 4( 3.57%) 

nasal preparations 2( 2.63%) 1( 2.78%) 3( 2.68%) 

sensory organs ophthalmologicals 0( 0.00%) 1( 2.78%) 1( 0.89%) 



corticosteroids for systemic use 10(13.16%) 5(13.89%) 15(13.39%) 

thyroid therapy 0( 0.00%) 1( 2.78%) 1( 0.89%) 


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Table 15. 7 Disposition of subjects by site and treatment 

Treatment 

Group 

Clotinab 

ReoPro ® 

Sites Enrollment ITT FAS PP 

Asan Medical Centre 21 21 21 21 

Severance Hospital 46 46 45 41 

Chonnam National University Hospital 17 17 17 14 

Total 84 84 83 76 

Asan Medical Centre 11 11 11 11 

Severance Hospital 20 20 20 17 

Chonnam National University Hospital 9 9 9 8 

Total 40 40 40 36 

Total 124 124 123 112 


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Table 15. 8 Number of patients with major bleeding events by initial heparin bolus dose 

Bleeding Clotinab ReoPro ® Total P-value 

Pts receiving heparin 77 32 109 

Pts receiving ≤ 5.000U 50 18 68 

Pts with major bleeding 0(0.00%) 2(11.11%) 2 0.0672 

Pts receiving > 5.000U 27 14 41 

Pts with major bleeding 0(0.00%) 0(0.00%) 0 

Pts: Patients, Only includes patients who received heparin, P-value from Chi-square test. 


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Table 15. 9 The rate of adverse event by Body System 

Number of subjects (%) 


Body system/Preferred term 

with Adverse Events 

Clotinab 

ReoPro 

with Adverse Events related Drug 

(N=83) 

® 

Clotinab 

ReoPro 

(N=40) 

(N=83) 

® 

(N=40) 

Blood and lymphatic system disorders 5( 6.02%) 3(3.61%) 

Leukocytosis 1( 1.20%) 

Thrombocytopenia 4( 4.82%) 3(3.61%) 

Cardiac disorders 21(25.30%) 14(35.00%) 

Arrhythmia 1( 1.20%) 

Bradycardia 1( 1.20%) 

Cardiac tamponade 2( 5.00%) 

Chest discomfort 10(12.05%) 6(15.00%) 

Chest pain 7( 8.43%) 7(17.50%) 

Dyspnoea 5( 6.02%) 2( 5.00%) 

Myocardial ischaemia 1( 2.50%) 

Palpitations 1( 1.20%) 1( 2.50%) 

Tachycardia 1( 2.50%) 

Eye disorders 1( 1.20%) 

Xerophthalmia 1( 1.20%) 

Gastrointestinal disorders 20(24.10%) 14(35.00%) 

Abdominal discomfort 4( 4.82%) 2( 5.00%) 

Abdominal pain upper 1( 1.20%) 1( 2.50%) 

Constipation 3( 3.61%) 2( 5.00%) 

Diarrhoea 1( 2.50%) 

Dyspepsia 7( 8.43%) 3( 7.50%) 

Gastoesophageal reflux disease 1( 2.50%) 

Gastritis erosive 1( 1.20%) 

Nausea 6( 7.23%) 6(15.00%) 

Vomiting 1( 1.20%) 5(12.50%) 

General disorders and administration site 

conditions 

55(66.27%) 28(70.00%) 2(2.41%) 

Application site bleeding 6( 7.23%) 4(10.00%) 1(1.20%) 


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Clotinab 

ReoPro 


(N=83) 

® 

Clotinab 

ReoPro 

(N=40) 

(N=83) 

® 

(N=40) 

Application site pain 6( 7.23%) 4(10.00%) 

Asthenia 2( 5.00%) 

Catheter site hematoma 22(26.51%) 10(25.00%) 2(2.41%) 

Catheter site hemorrhage 16(19.28%) 5(12.50%) 

Cold sweat 4( 4.82%) 2( 5.00%) 

Death 2( 5.00%) 

Face oedema 1( 2.50%) 

Facial pain 1( 1.20%) 

Feeling cold 5( 6.02%) 2( 5.00%) 

Feeling hot 1( 1.20%) 1( 2.50%) 

Influenza like illness 3( 3.61%) 

Injection site hemorrhage 1( 1.20%) 

Pyrexia 2( 2.41%) 1( 2.50%) 

Wound secretion 27(32.53%) 17(42.50%) 2(2.41%) 

Investigations 1( 2.50%) 1(2.50%) 

Aspartate aminotransferase 

increased 

1( 2.50%) 1(2.50%) 

Musculoskeletal and connective tissue 


21(25.30%) 8(20.00%) 

Arthralgia 1( 1.20%) 

Back pain 13(15.66%) 7(17.50%) 

Buttock pain 1( 1.20%) 

Flank pain 1( 1.20%) 1( 2.50%) 

Limb discomfort 1( 1.20%) 

Musculoskeletal discomfort 1( 1.20%) 

Myalgia 3( 3.61%) 

Pain in extremity 1( 2.50%) 

Shoulder pain 1( 1.20%) 

Nervous system disorders 25(30.12%) 11(27.50%) 

Burning sensation 1( 1.20%) 2( 5.00%) 

Dizziness 5( 6.02%) 3( 7.50%) 


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Clotinab 

ReoPro 

(N=83) 

® 

(N=40) 

Headache 15(18.07%) 10(25.00%) 

Hypoaesthesia 3( 3.61%) 

Migraine 1( 1.20%) 

Paraesthesia 3( 3.61%) 

Psychiatric disorders 4( 4.82%) 1( 2.50%) 

Anxiety 1( 1.20%) 

Sleep disorder 3( 3.61%) 1( 2.50%) 

Renal and urinary disorders 9(10.84%) 7(17.50%) 

Dysuria 8( 9.64%) 5(12.50%) 

Hematuria 1( 1.20%) 2( 5.00%) 

Respiratory, thoracic and mediastinal 


8( 9.64%) 1( 2.50%) 

Cough 3( 3.61%) 

Dyspnoea 1( 1.20%) 

Haemoptysis 3( 3.61%) 

Nasopharyngitis 1( 1.20%) 

Pulmonary tuberculosis 1( 2.50%) 

Tachypnoea 1( 1.20%) 

Skin and subcutaneous tissue disorders 10(12.05%) 4(10.00%) 

Erythema 1( 2.50%) 

Excoriation 1( 1.20%) 

Pruritus 3( 3.61%) 1( 2.50%) 

Pruritus generalised 1( 2.50%) 

Rash 5( 6.02%) 

Rash macular 1( 1.20%) 

Urticaria 2( 2.41%) 1( 2.50%) 

Vascular disorders 10(12.05%) 7(17.50%) 

Epistaxis 2( 2.41%) 

Gingival bleeding 3( 3.61%) 4(10.00%) 

Haemorrhage 3( 3.61%) 3( 7.50%) 



Clotinab 

ReoPro 

(N=83) 

® 

(N=40) 


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Clotinab 

ReoPro 


(N=83) 

® 

Clotinab 

ReoPro 

(N=40) 

(N=83) 

® 

(N=40) 

Vascular disorders Hypertension 2( 2.41%) 

Total 242 137 8 1 


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Table 15. 10 Number observed and rate, with subject identifications-Clotinab 

Body system 



Blood and lymphatic Leukocytosis 1(1.20%) 


Y059 

Thrombocytopenia 2(2.41%) 1(1.20%) 

1(1.20%) 

A011 

Y044 

A006 

A020 

Cardiac disorders Arrhythmia 1(1.20%) 

C003 

Bradycardia 1(1.20%) 

C020 

Chest discomfort 9(10.84%) 

1(1.20%) 

A003 

A006 

A020 

A022 

C017 

Y008 

Y012 

Y061 

Y064 

A001 

Cardiac disorders Chest pain 7(8.43%) 

A004 

A019 

A025 

C026 

Y014 

Y027 

Y028 

1 1 

3 1 4 

1 1 

1 1 

10 10 

7 7 


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Body system 

Cardiac disorders Dyspnoea 4(4.82%) 

C003 

Y016 

Y028 

Y041 

Cardiac disorders Palpitations 1(1.20%) 

C026 

Eye disorders Xerophthalmia 1(1.20%) 

Y013 

Gastrointestinal disorders Abdominal discomfort 4(4.82%) 

A003 

A020 

A022 

Y044 

Abdominal pain upper 1(1.20%) 

Y038 

Constipation 3(3.61%) 

A021 

C003 

Y004 

Dyspepsia 7(8.43%) 

C017 

Y008 

Y012 

Y019 

Y028 

Y045 

Y059 

Gastritis erosive 1(1.20%) 

Y046 



1(1.20%) 

A020 

5 5 

1 1 

1 1 

4 4 

1 1 

3 3 

7 7 

1 1 


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Body system 

Gastrointestinal disorders Nausea 6(7.23%) 

A020 

A025 

C018 

C026 

Y028 

Y054 

Vomiting 1(1.20%) 

A020 



conditions 

Application site bleeding 1(1.20%) 

C024 



5(6.02%) 

C004 

C025 

C026 

Y020 

Y028 

Application site pain 6(7.23%) 

C013 

C020 

Y014 

Y027 

Y028 

Y031 

6 6 

1 1 

1 5 6 

6 6 


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conditions 

Body system 

Catheter site hematoma 1(1.20%) 

C024 



18(21.7%) 

A004 

A009 

A020 

A026 

A028 

A031 

C004 

C020 

Y002 

Y012 

Y014 

Y015 

Y017 

Y025 

Y034 

Y049 

Y059 

Y066 

1(1.20%) 

A013 

1(1.20%) 

A019 

1(1.20%) 

A022 

2 20 22 


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conditions 



conditions 

Body system 

Catheter site hemorrhage 16(19.3%) 

A003 

A005 

A006 

A013 

A019 

A020 

A022 

A028 

C005 

C020 

C022 

Y042 

Y049 

Y059 

Y061 

Y064 

Cold sweat 4(4.82%) 

A019 

C003 

Y016 

Y061 

Facial pain 1(1.20%) 

C013 

Feeling cold 5(6.02%) 

A007 

C026 

Y008 

Y031 

Y055 

Feeling hot 1(1.20%) 

C002 



16 16 

4 4 

1 1 

5 5 

1 1 


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conditions 

Body system 

Influenza like illness 3(3.61%) 

A009 

Y011 

Y046 


1(1.20%) 

hemorrhage 

Y005 

Pyrexia 2(2.41%) 

Y046 

Y052 

Wound secretion 2(2.41%) 

A019 

C024 



24(28.9%) 

A013 

A021 

A028 

A031 

C002 

C009 

C013 

C018 

C020 

Y012 

Y013 

Y031 

Y032 

Y034 

Y038 

Y042 

Y046 

1(1.20%) 

A022 

3 3 

1 1 

2 2 

2 25 27 


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conditions 



Body system 

Wound secretion Y049 

Y054 

Y055 

Y059 

Y060 

Y061 

Y064 

Arthralgia 1(1.20%) 

Y057 

Back pain 12(14.5%) 

C020 

Y004 

Y005 

Y006 

Y012 

Y014 

Y019 

Y034 

Y042 

Y055 

Y059 

Y060 

Buttock pain 1(1.20%) 

Y028 

Flank pain 1(1.20%) 

Y061 

Limb discomfort 1(1.20%) 

A005 


discomfort 



1(1.20%) 

C017 

1(1.20%) 

C002 

1 1 

13 13 

1 1 

1 1 

1 1 

1 1 


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Body system 

Myalgia 3(3.61%) 

C026 

Y044 

Y057 

Musculoskeletal and Shoulder pain 1(1.20%) 


Y064 

Nervous system disorders Burning sensation 1(1.20%) 

Y052 

Dizziness 5(6.02%) 

A017 

C017 

Y002 

Y042 

Y044 

Nervous system disorders Headache 14(16.9%) 

A009 

A019 

C001 

C017 

C024 

C026 

Y016 

Y017 

Y028 

Y031 

Y038 

Y041 

Y044 

Y055 



1(1.20%) 

A004 

3 3 

1 1 

1 1 

5 5 

15 15 


Ver. 1.0_Eng

Body system 

Hypoaesthesia 3(3.61%) 

A001 

C013 

Y016 

Migraine 1(1.20%) 

Y045 

Paraesthesia 3(3.61%) 

Y005 

Y012 

Y027 

Psychiatric disorders Anxiety 1(1.20%) 

Y008 

Sleep disorder 3(3.61%) 

C003 

Y004 

Y045 





Dysuria 7(8.43%) 

C014 

C018 

C026 

Y014 

Y015 

Y027 

Y064 

Haematuria 1(1.20%) 

Y045 

Cough 3(3.61%) 

C020 

C022 

Y057 



1(1.20%) 

C002 

3 3 

1 1 

3 3 

1 1 

3 3 

8 8 

1 1 

3 3 


Ver. 1.0_Eng

Body system 

Respiratory, thoracic and Dyspnoea 1(1.20%) 


Y008 

Haemoptysis 3(3.61%) 

A017 

C020 

Y007 

Nasopharyngitis 1(1.20%) 

Y004 

Tachypnoea 1(1.20%) 

Y016 

Skin and subcutaneous Excoriation 1(1.20%) 


A019 

Skin and subcutaneous Pruritus 3(3.61%) 


Y005 

Y020 

Y032 

Rash 5(6.02%) 

C017 

Y015 

Y018 

Y020 

Y032 

Rash macular 1(1.20%) 

Y035 

Urticaria 2(2.41%) 

A001 

A004 

Vascular disorders Epistaxis 2(2.41%) 

C020 

Y046 



1 1 

3 3 

1 1 

1 1 

1 1 

3 3 

5 5 

1 1 

2 2 

2 2 


Ver. 1.0_Eng

Body system 

Vascular disorders Gingival bleeding 3(3.61%) 

A031 

Y016 

Y028 

Haemorrhage 3(3.61%) 

A013 

A022 

C003 

Hypertension 2(2.41%) 

C026 

Y061 

*NR = not related 



3 3 

3 3 

2 2 


Ver. 1.0_Eng

Table 15. 11 Number observed and rate, with subject identifications-ReoPro ® 

Body system 



Cardiac disorders Cardiac tamponade 2(5.00%) 

A032 

C010 

Chest discomfort 6(15.0%) 

A008 

A010 

A032 

C016 

C023 

Y023 

Chest pain 7(17.5%) 

A015 

A024 

C010 

C011 

C023 

Y037 

Y056 

Dyspnoea 1(2.50%) 

1(2.50%) 

Y023 

C021 

Myocardial ischaemia 1(2.50%) 

A015 

Palpitations 1(2.50%) 

Y024 

Tachycardia 1(2.50%) 

Y056 

Gastrointestinal disorders Abdominal discomfort 2(5.00%) 

A010 

Y063 

2 2 

6 6 

7 7 

2 2 

1 1 

1 1 

1 1 

2 2 


Ver. 1.0_Eng

Body system 

Gastrointestinal disorders Abdominal pain upper 1(2.50%)A 

014 

Constipation 2(5.00%) 

C021 

Y047 

Diarrhoea 1(2.50%) 

A014 

Dyspepsia 3(7.50%) 

A032 

Y033 

Y040 

Gastoesophageal reflux 

1(2.50%) 

disease 

Y053 

Nausea 6(15.0%) 

A014 

A032 

C010 

C016 

C021 

Y050 

Vomiting 5(12.5%) 

A014 

C010 

C021 

Y023 

Y058 

General disorders and Application site bleeding 2(5.00%) 


C016 

conditions 

Y023 



2(5.00%) 

Y051 

Y053 

1 1 

2 2 

1 1 

3 3 

1 1 

6 6 

5 5 

4 4 


Ver. 1.0_Eng



conditions 



conditions 

Body system 



Application site pain 4(10.0%) 

A032 

C010 

Y056 

Y058 

Asthenia 2(5.00%)A 

032 

C016 

Catheter site hematoma 10(25.0%) 

A010 

A015 

A016 

A027 

A032 

C012 

Y026 

Y040 

Y050 

Y062 

Catheter site hemorrhage 5(12.5%) 

A030 

A032 

C012 

C023 

Y053 

Cold sweat 2(5.00%) 

C016 

C021 

Death 2(5.00%) 

C021 

Y056 

4 4 

2 2 

10 10 

5 5 

2 2 

2 2 


Ver. 1.0_Eng

Body system 

Face oedema 1(2.50%) 

Y026 

Feeling cold 2(5.00%)A 

014 

C023 

Feeling hot 1(2.50%)A 

032 

Pyrexia 1(2.50%)A 

032 

General disorders and Wound secretion 17(42.5%) 


A010 

conditions 

A015 

A027 

A029 

C012 

C021 

Y023 

Y024 

Y037 

Y043 

Y047 

Y048 

Y050 

Y051 

Y058 

Y062 

Y063 

Investigations Aspartate 

1(2.50%) 


increased 

Y023 



1 1 

2 2 

1 1 

1 1 

17 17 

1 1 


Ver. 1.0_Eng



Body system 

Back pain 7(17.5%) 

C021 

Y037 

Y047 

Y050 

Y053 

Y058 

Y062 

Flank pain 1(2.50%) 

C010 

Pain in extremity 1(2.50%) 

Y037 

Nervous system disorders Burning sensation 2(5.00%) 

Y047 

Y050 

Dizziness 3(7.50%) 

A010 

A032 

Y037 

Nervous system disorders Headache 10(25.0%) 

A008 

A032 

C010 

C016 

C021 

C023 

Y023 

Y037 

Y047 

Y050 



7 7 

1 1 

1 1 

2 2 

3 3 

10 10 


Ver. 1.0_Eng

Body system 

Psychiatric disorders Sleep disorder 1(2.50%) 

C021 


Dysuria 5(12.5%) 


A014 

A015 

A032 

Y029 

Y040 

Hematuria 2(5.00%) 

Y056 

C021 

Respiratory, thoracic and Pulmonary tuberculosis 1(2.50%) 


Y056 

Skin and subcutaneous Erythema 1(2.50%) 


A024 

Pruritus 1(2.50%) 

C011 

Pruritus generalised 1(2.50%) 

Y026 

Urticaria 1(2.50%) 

A030 

Vascular disorders Gingival bleeding 4(10.0%) 

Y043 

Y051 

Y053 

Y058 

*NR = not related 

Haemorrhage 2(5.00%) 

C021 

Y023 



1 1 

5 5 

2 2 

1 1 

1 1 

1 1 

1 1 

1 1 

4 4 

1(2.50%) 

C010 3 3 


Ver. 1.0_Eng

Table 15. 12 Subject list of all adverse events 

Subject list of all adverse events 

Subjec 

t ID 

Treatment 

IP 

administration 

Sex Age 

System Organ 

Class 

Preferred term Severity 

Serious 

-ness 

Action 

taken 

Causality Outcome 

Y059 Clotinab After Male 49 Blood and lymphatic Leukocytosis Mild No Medication None Recovered, 



prescribed 

without sequelae 

A006 Clotinab After Female 77 Blood and lymphatic Thrombocytopenia Mild No No Improbable Recovered, 




A011 Clotinab After Male 60 Blood and lymphatic Thrombocytopenia Mild No No Possible Recovered, 




A020 Clotinab After Female 72 Blood and lymphatic Thrombocytopenia Severe No No Possible Recovered, 




Y044 Clotinab After Male 74 Blood and lymphatic Thrombocytopenia Mild No No Probable Recovered, 




Y044 Clotinab After Male 74 Blood and lymphatic Thrombocytopenia Mild No No Probable Recovered, 




C003 Clotinab After Male 58 Cardiac disorders Arrhythmia Mild No No None Recovered, 



Y052 Clotinab Before Male 55 Cardiac disorders Bradycardia Severe No Medication None Recovered, 


prescribed 


C020 Clotinab After Female 67 Cardiac disorders Bradycardia Severe Yes No None Recovered, 



A032 ReoPro ® After Male 50 Cardiac disorders Cardiac tamponade Severe Yes No None Recovered, 



C010 ReoPro ® After Female 77 Cardiac disorders Cardiac tamponade Severe Yes No None Recovered, 



Y048 ReoPro ® Before Male 71 Cardiac disorders Chest discomfort Mild No Medication None Recovered, 


prescribed 


A001 Clotinab Before Male 54 Cardiac disorders Chest discomfort Mild No Medication None Recovered, 


prescribed 


A001 Clotinab After Male 54 Cardiac disorders Chest discomfort Severe No Medication None Recovered, 


prescribed 



Ver. 1.0_Eng


Subjec 

t ID 

Treatment 

IP 


Sex Age 

System Organ 

Class 


Serious 

-ness 

Action 

taken 


A003 Clotinab After Male 47 Cardiac disorders Chest discomfort Mild No No None Recovered, 



A003 Clotinab After Male 47 Cardiac disorders Chest discomfort Mild No Medication None Recovered, 


prescribed 


A006 Clotinab After Female 77 Cardiac disorders Chest discomfort Mild No No None Recovered, 






A009 Clotinab Before Male 56 Cardiac disorders Chest discomfort Moderate No No None Recovered, 






A022 Clotinab After Female 54 Cardiac disorders Chest discomfort Mild No Medication None Recovered, 


prescribed 


A026 Clotinab Before Female 64 Cardiac disorders Chest discomfort Mild No Medication None Recovered, 


prescribed 


A031 Clotinab Before Male 41 Cardiac disorders Chest discomfort Mild No No None Recovered, 



C017 Clotinab After Male 32 Cardiac disorders Chest discomfort Mild No Medication None Recovered, 


prescribed 


C025 Clotinab Before Male 51 Cardiac disorders Chest discomfort Mild No Medication None Recovered, 


prescribed 


Y006 Clotinab Before Male 66 Cardiac disorders Chest discomfort Mild No Medication None Recovered, 


prescribed 


Y008 Clotinab After Male 65 Cardiac disorders Chest discomfort Mild No No None Recovered, 



Y011 Clotinab Before Male 63 Cardiac disorders Chest discomfort Mild No No None Recovered, 



Y012 Clotinab After Male 52 Cardiac disorders Chest discomfort Mild No No Improbable Recovered, 




Ver. 1.0_Eng


Subjec 

t ID 

Treatment 

IP 


Sex Age 

System Organ 

Class 


Serious 

-ness 

Action 

taken 


Y046 Clotinab Before Female 56 Cardiac disorders Chest discomfort Mild No No None Recovered, 



Y061 Clotinab After Male 58 Cardiac disorders Chest discomfort Mild No No None Recovered, 



Y064 Clotinab After Female 74 Cardiac disorders Chest discomfort Mild No Medication None Recovered, 


prescribed 


A008 ReoPro ® After Male 56 Cardiac disorders Chest discomfort Mild No Medication None Recovered, 


prescribed 


A010 ReoPro ® After Male 72 Cardiac disorders Chest discomfort Mild No No None Recovered, 



A015 ReoPro ® Before Male 39 Cardiac disorders Chest discomfort Mild No Medication None Recovered, 


prescribed 


A032 ReoPro ® After Male 50 Cardiac disorders Chest discomfort Mild No No None Recovered, 



C016 ReoPro ® After Male 37 Cardiac disorders Chest discomfort Mild No Medication None Recovered, 


prescribed 


C023 ReoPro ® After Male 52 Cardiac disorders Chest discomfort Mild No Medication None Recovered, 


prescribed 


Y023 ReoPro ® After Male 66 Cardiac disorders Chest discomfort Mild No No None Recovered, 



A004 Clotinab After Male 55 Cardiac disorders Chest pain Mild No Medication None Recovered, 


prescribed 


A019 Clotinab After Male 71 Cardiac disorders Chest pain Mild No No None Recovered, 



A025 Clotinab After Male 46 Cardiac disorders Chest pain Mild No No None Recovered, 



A025 Clotinab After Male 46 Cardiac disorders Chest pain Mild No Medication None Recovered, 


prescribed 


C003 Clotinab Before Male 58 Cardiac disorders Chest pain Mild No Medication None Recovered, 


prescribed 



Ver. 1.0_Eng


Subjec 

t ID 

Treatment 

IP 


Sex Age 

System Organ 

Class 


Serious 

-ness 

Action 

taken 


C026 Clotinab After Male 57 Cardiac disorders Chest pain Mild No Medication None Recovered, 


prescribed 


Y006 Clotinab Before Male 66 Cardiac disorders Chest pain Mild No No None Recovered, 



Y014 Clotinab After Male 52 Cardiac disorders Chest pain Mild No No None Recovered, 



Y021 Clotinab Before Male 62 Cardiac disorders Chest pain Mild No Medication None Recovered, 


prescribed 


Y027 Clotinab After Female 62 Cardiac disorders Chest pain Mild No Medication None Recovered, 


prescribed 


Y028 Clotinab After Female 63 Cardiac disorders Chest pain Mild No Medication None Recovered, 


prescribed 




prescribed 




prescribed 


Y046 Clotinab Before Female 56 Cardiac disorders Chest pain Mild No Medication None Recovered, 


prescribed 


Y052 Clotinab Before Male 55 Cardiac disorders Chest pain Severe No Medication None Recovered, 


prescribed 


Y057 Clotinab Before Male 70 Cardiac disorders Chest pain Mild No No None Recovered, 



Y060 Clotinab Before Female 70 Cardiac disorders Chest pain Mild No Medication None Recovered, 


prescribed 


A014 ReoPro ® Before Female 64 Cardiac disorders Chest pain Mild No Medication None Recovered, 


prescribed 


A015 ReoPro ® After Male 39 Cardiac disorders Chest pain Mild No Medication None Recovered, 


prescribed 


A024 ReoPro ® After Male 55 Cardiac disorders Chest pain Mild No Medication None Recovered, 


prescribed 



Ver. 1.0_Eng


Subjec 

t ID 

Treatment 

IP 


Sex Age 

System Organ 

Class 


Serious 

-ness 

Action 

taken 


C010 ReoPro ® After Female 77 Cardiac disorders Chest pain Mild No No None Recovered, 



C011 ReoPro ® After Male 47 Cardiac disorders Chest pain Mild No Medication None Recovered, 


prescribed 


C015 ReoPro ® Before Male 75 Cardiac disorders Chest pain Mild No Medication None Recovered, 


prescribed 


C023 ReoPro ® After Male 52 Cardiac disorders Chest pain Mild No Medication None Recovered, 


prescribed 


Y037 ReoPro ® After Male 68 Cardiac disorders Chest pain Mild No No None Recovered, 



Y056 ReoPro ® After Male 57 Cardiac disorders Chest pain Mild No Medication None Recovered, 


prescribed 


Y063 ReoPro ® Before Male 73 Cardiac disorders Chest pain Mild No Medication None Recovered, 


prescribed 


Y065 ReoPro ® Before Male 54 Cardiac disorders Chest pain Mild No Medication None Recovered, 


prescribed 


A020 Clotinab After Female 72 Cardiac disorders Dyspnoea Severe Yes Medication None Recovered, 


prescribed 


C003 Clotinab After Male 58 Cardiac disorders Dyspnoea Mild No No None Recovered, 



Y009 Clotinab Before Male 58 Cardiac disorders Dyspnoea Mild No Medication None Recovered, 


prescribed 


Y011 Clotinab Before Male 63 Cardiac disorders Dyspnoea Mild No No None Recovered, 



Y016 Clotinab After Male 61 Cardiac disorders Dyspnoea Mild No Medication None Recovered, 


prescribed 


Y028 Clotinab After Female 63 Cardiac disorders Dyspnoea Mild No No None Recovered, 



Y041 Clotinab After Male 48 Cardiac disorders Dyspnoea Mild No No None Recovered, 




Ver. 1.0_Eng


Subjec 

t ID 

Treatment 

IP 


Sex Age 

System Organ 

Class 


Serious 

-ness 

Action 

taken 


A014 ReoPro ® Before Female 64 Cardiac disorders Dyspnoea Mild No Medication None Recovered, 


prescribed 


C021 ReoPro ® After Female 67 Cardiac disorders Dyspnoea Severe Yes Medication None Death 


prescribed 

Y023 ReoPro ® After Male 66 Cardiac disorders Dyspnoea Mild No No None Recovered, 



A015 ReoPro ® After Male 39 Cardiac disorders Myocardial ischaemia Mild No No None Recovered, 



C026 Clotinab After Male 57 Cardiac disorders Palpitations Mild No No None Recovered, 



Y024 ReoPro ® After Female 71 Cardiac disorders Palpitations Mild No No None Recovered, 



Y056 ReoPro ® After Male 57 Cardiac disorders Tachycardia Mild No No None Recovered, 



Y053 ReoPro ® Before Female 67 Endocrine disorders Diabetes mellitus Mild No Medication None AE, No more 


prescribed 

progress 

Y013 Clotinab After Male 43 Eye disorders Xerophthalmia Mild No Medication None Recovered, 


prescribed 


A003 Clotinab After Male 47 Gastrointestinal Abdominal discomfort Mild No No None Recovered, 




A020 Clotinab After Female 72 Gastrointestinal Abdominal discomfort Mild No Medication None Recovered, 



prescribed 


A022 Clotinab After Female 54 Gastrointestinal Abdominal discomfort Mild No Medication None Recovered, 



prescribed 


A025 Clotinab Before Male 46 Gastrointestinal Abdominal discomfort Mild No No None Recovered, 




Y013 Clotinab Before Male 43 Gastrointestinal Abdominal discomfort Mild No No None Recovered, 




Y044 Clotinab After Male 74 Gastrointestinal Abdominal discomfort Mild No Medication None Recovered, 



prescribed 



Ver. 1.0_Eng


Subjec 

t ID 

Treatment 

IP 


Sex Age 

System Organ 

Class 

A010 ReoPro ® After Male 72 Gastrointestinal 



Y063 ReoPro ® After Male 73 Gastrointestinal 



Y038 Clotinab After Male 63 Gastrointestinal 



Y046 Clotinab Before Female 56 Gastrointestinal 



Y052 Clotinab Before Male 55 Gastrointestinal 






A014 ReoPro ® After Female 64 Gastrointestinal 



A001 Clotinab Before Male 54 Gastrointestinal 



A021 Clotinab After Male 60 Gastrointestinal 



A022 Clotinab Before Female 54 Gastrointestinal 



C003 Clotinab After Male 58 Gastrointestinal 









C021 ReoPro ® After Female 67 Gastrointestinal 



C023 ReoPro ® Before Male 52 Gastrointestinal 




Serious 

-ness 

Action 

taken 


Abdominal discomfort Mild No Medication None Recovered, 

prescribed 


Abdominal discomfort Mild No No None Recovered, 


Abdominal pain upper Mild No Medication None AE, No more 

prescribed 

progress 

Abdominal pain upper Mild No Medication None AE, No more 

prescribed 

progress 

Abdominal pain upper Mild No Medication None Recovered, 

prescribed 



prescribed 



prescribed 


Constipation Mild No No None Recovered, 


Constipation Mild No Medication None Recovered, 

prescribed 



prescribed 



prescribed 


Constipation Mild No Medication None AE, No more 

prescribed 

progress 


prescribed 


Constipation Mild No No None Recovered, 



prescribed 



Ver. 1.0_Eng


Subjec 

t ID 

Treatment 

IP 


Sex Age 

System Organ 

Class 



















Y028 Clotinab After Female 63 Gastrointestinal 












C019 ReoPro ® Before Male 38 Gastrointestinal 



Y033 ReoPro ® After Female 68 Gastrointestinal 






Y048 ReoPro ® Before Male 71 Gastrointestinal 







Serious 

-ness 

Action 

taken 



prescribed 


Diarrhoea Mild No Medication None Recovered, 

prescribed 


Dyspepsia Mild No No None Recovered, 


Dyspepsia Mild No Medication None Recovered, 

prescribed 


Dyspepsia Mild No No Improbable Recovered, 


Dyspepsia Mild No No None Recovered, 



prescribed 



prescribed 



prescribed 



prescribed 



prescribed 


Dyspepsia Mild No Medication None AE, No more 

prescribed 

progress 


prescribed 



prescribed 


Gastoesophageal reflux Mild No Medication None Recovered, 

disease 

prescribed 



Ver. 1.0_Eng


Subjec 

t ID 

Treatment 

IP 


Sex Age 

System Organ 

Class 




A020 Clotinab After Female 72 Gastrointestinal 












C020 Clotinab Before Female 67 Gastrointestinal 



























C016 ReoPro ® After Male 37 Gastrointestinal 




Serious 

-ness 

Action 

taken 


Gastritis erosive Mild No Medication None AE, No more 

prescribed 

progress 

Nausea Mild No Medication None Recovered, 

prescribed 


Nausea Mild No No None Recovered, 



prescribed 



prescribed 





prescribed 


Nausea Mild No Medication Improbable Recovered, 

prescribed 



prescribed 





prescribed 



prescribed 



prescribed 



prescribed 



prescribed 



Ver. 1.0_Eng


Subjec 

t ID 

Treatment 

IP 


Sex Age 

System Organ 

Class 







A020 Clotinab After Female 72 Gastrointestinal 





















C004 Clotinab After Male 68 General disorders and 



conditions 

C024 Clotinab After Male 48 General disorders and 



conditions 

C025 Clotinab After 


Male 51 General disorders and 


conditions 


Serious 

-ness 

Action 

taken 


Nausea Mild No Medication Improbable Recovered, 

prescribed 



prescribed 


Vomiting Mild No Medication None Recovered, 

prescribed 



prescribed 



prescribed 


Vomiting Mild No No None Recovered, 


Vomiting Mild No Medication Improbable Recovered, 

prescribed 


Vomiting Mild No No None Recovered, 



prescribed 


Application site bleeding Mild No No Improbable Recovered, 


Application site bleeding Mild No IP 

permanentl 

y 

discontinue 

d 

Possible Recovered, 





Ver. 1.0_Eng


Subjec 

t ID 

Treatment 

IP 




Y020 Clotinab After 




C016 ReoPro ® After 


Y023 ReoPro ® After 












Sex Age 

System Organ 

Class 



conditions 



conditions 

Female 63 General disorders and 


conditions 



conditions 



conditions 



conditions 



conditions 



conditions 



conditions 



conditions 


Serious 

-ness 

Action 

taken 








Application site bleeding Mild No No None Recovered, 




Application site bleeding Severe No No Improbable Recovered, 


Application site bleeding Severe No No Improbable Recovered, 


Application site pain Mild No Medication 

prescribed 


prescribed 


prescribed 


Ver. 1.0_Eng 






without sequelae


Subjec 

t ID 

Treatment 

IP 








A032 ReoPro ® After 








C025 Clotinab Before 




Y060 Clotinab Before 


Sex Age 

System Organ 

Class 



conditions 



conditions 



conditions 



conditions 



conditions 



conditions 



conditions 



conditions 



conditions 



conditions 


Serious 

-ness 

Action 

taken 


prescribed 


prescribed 


prescribed 


prescribed 


prescribed 



Ver. 1.0_Eng 











Application site pain Mild No No None Recovered, 


Application site pain Mild No No None Recovered, 


Asthenia Mild No No None Recovered, 





without sequelae


Subjec 

t ID 

Treatment 

IP 






A004 Clotinab After 










Sex Age 

System Organ 

Class 



conditions 



conditions 



conditions 



conditions 



conditions 



conditions 



conditions 


Serious 

-ness 

Action 

taken 




Asthenia Mild No Medication 

prescribed 

Catheter site hematoma Mild No IP dosage 

change/te 

mporarily 

discontinue 

d 


Ver. 1.0_Eng 



Improbable Recovered, 


Catheter site hematoma Mild No No None Recovered, 


Catheter site hematoma Moderate No IP dosage 

change/te 

mporarily 

discontinue 

d 

Catheter site hematoma Severe No IP 

permanentl 

y 

discontinue 

d 





Catheter site hematoma Mild No No Improbable Recovered, 

without sequelae


Subjec 

t ID 

Treatment 

IP 


















Sex Age 

System Organ 

Class 



conditions 



conditions 



conditions 



conditions 



conditions 



conditions 



conditions 



conditions 


Serious 

-ness 

Action 

taken 

Catheter site hematoma Severe No IP 

permanentl 

y 

discontinue 

d 

Catheter site hematoma Mild No IP dosage 

change/te 

mporarily 

discontinue 

d 














Catheter site hematoma Mild No IP 

permanentl 

y 

discontinue 

d 






Ver. 1.0_Eng


Subjec 

t ID 

Treatment 

IP 






















Sex Age 

System Organ 

Class 



conditions 



conditions 



conditions 



conditions 



conditions 



conditions 



conditions 



conditions 



conditions 



conditions 


Serious 

-ness 

Action 

taken 























Ver. 1.0_Eng


Subjec 

t ID 

Treatment 

IP 






















Sex Age 

System Organ 

Class 



conditions 



conditions 



conditions 



conditions 



conditions 



conditions 



conditions 



conditions 



conditions 



conditions 


Serious 

-ness 

Action 

taken 




















Catheter site 

hemorrhage 

Mild No No None Recovered, 



Ver. 1.0_Eng


Subjec 

t ID 

Treatment 

IP 






A007 Clotinab Before 
















Sex Age 

System Organ 

Class 



conditions 



conditions 



conditions 



conditions 



conditions 



conditions 



conditions 



conditions 



conditions 



conditions 


Catheter site 

hemorrhage 

Catheter site 

hemorrhage 

Catheter site 

hemorrhage 

Catheter site 

hemorrhage 

Catheter site 

hemorrhage 

Catheter site 

hemorrhage 

Catheter site 

hemorrhage 

Catheter site 

hemorrhage 

Catheter site 

hemorrhage 

Catheter site 

hemorrhage 

Serious 

-ness 

Action 

taken 


Mild No No Improbable Recovered, 




Mild No No None AE, No more 

progress 
















Ver. 1.0_Eng


Subjec 

t ID 

Treatment 

IP 






















Sex Age 

System Organ 

Class 



conditions 



conditions 



conditions 



conditions 



conditions 



conditions 



conditions 



conditions 



conditions 



conditions 


Catheter site 

hemorrhage 

Catheter site 

hemorrhage 

Catheter site 

hemorrhage 

Catheter site 

hemorrhage 

Catheter site 

hemorrhage 

Catheter site 

hemorrhage 

Catheter site 

hemorrhage 

Catheter site 

hemorrhage 

Catheter site 

hemorrhage 

Catheter site 

hemorrhage 

Serious 

-ness 

Action 

taken 























Ver. 1.0_Eng


Subjec 

t ID 

Treatment 

IP 




















Y023 ReoPro ® Before 


Sex Age 

System Organ 

Class 



conditions 



conditions 



conditions 



conditions 



conditions 



conditions 



conditions 



conditions 



conditions 



conditions 


Catheter site 

hemorrhage 

Serious 

-ness 

Action 

taken 




Cold sweat Mild No No None Recovered, 






Cold sweat Mild No Medication 

prescribed 


Ver. 1.0_Eng 











Cold sweat Moderate No Medication 

prescribed 


without sequelae


Subjec 

t ID 

Treatment 

IP 


Y050 ReoPro ® Before 




















Sex Age 

System Organ 

Class 



conditions 



conditions 



conditions 



conditions 



conditions 



conditions 



conditions 



conditions 



conditions 



conditions 


Serious 

-ness 

Action 

taken 




Death Severe Yes Medication 

prescribed 

Death Severe Yes Medication 

prescribed 

Drug hypersensitivity Mild No Medication 

prescribed 

Face oedema Mild No Medication 

prescribed 

Facial pain Mild No Medication 

prescribed 

Feeling cold Mild No Medication 

prescribed 


prescribed 


prescribed 

None Death 

None Death 


Ver. 1.0_Eng 













Feeling cold Mild No No None Recovered, 

without sequelae


Subjec 

t ID 

Treatment 

IP 






















Sex Age 

System Organ 

Class 



conditions 



conditions 



conditions 



conditions 



conditions 



conditions 



conditions 



conditions 



conditions 



conditions 


Serious 

-ness 

Action 

taken 





prescribed 


prescribed 


Ver. 1.0_Eng 









Feeling hot Mild No Medication 

prescribed 



Feeling hot Mild No No None Recovered, 


Influenza like illness Mild No No None Recovered, 


Influenza like illness Mild No Medication 

prescribed 

Influenza like illness Mild No Medication 

prescribed 

None AE, No more 

progress 


without sequelae


Subjec 

t ID 

Treatment 

IP 




















Sex Age 

System Organ 

Class 



conditions 



conditions 



conditions 



conditions 



conditions 



conditions 



conditions 



conditions 



conditions 



hemorrhage 

Serious 

-ness 

Action 

taken 




Pyrexia Mild No Medication 

prescribed 

Pyrexia Mild No Medication 

prescribed 


Ver. 1.0_Eng 





Pyrexia Mild No No None Recovered, 


Pyrexia Mild No No None Recovered, 


Wound secretion Mild No No Improbable Recovered, 


Wound secretion Mild No IP 

permanentl 

y 

discontinue 

d 





Wound secretion Severe No IP 

permanentl 

y 

discontinue 

d 


without sequelae


Subjec 

t ID 

Treatment 

IP 






















Sex Age 

System Organ 

Class 



conditions 



conditions 



conditions 



conditions 



conditions 



conditions 



conditions 



conditions 



conditions 



conditions 


Serious 

-ness 

Action 

taken 






Wound secretion Mild No No None Recovered, 










Wound secretion Mild No No Possible Recovered, 







Ver. 1.0_Eng


Subjec 

t ID 

Treatment 

IP 




















Sex Age 

System Organ 

Class 



conditions 



conditions 



conditions 



conditions 



conditions 



conditions 



conditions 



conditions 



conditions 


Serious 

-ness 

Action 

taken 










Wound secretion Mild No IP dosage 

change/te 

mporarily 

discontinue 

d 

Wound secretion Mild No IP 

permanentl 

y 

discontinue 

d 












Ver. 1.0_Eng


Subjec 

t ID 

Treatment 

IP 






















Sex Age 

System Organ 

Class 



conditions 



conditions 



conditions 



conditions 



conditions 



conditions 



conditions 



conditions 



conditions 



conditions 


Serious 

-ness 

Action 

taken 























Ver. 1.0_Eng


Subjec 

t ID 

Treatment 

IP 






















Sex Age 

System Organ 

Class 



conditions 



conditions 



conditions 



conditions 



conditions 



conditions 



conditions 



conditions 



conditions 



conditions 


Serious 

-ness 

Action 

taken 























Ver. 1.0_Eng


Subjec 

t ID 

Treatment 

IP 






Sex Age 

System Organ 

Class 



conditions 



conditions 


Serious 

-ness 

Action 

taken 

Wound secretion Mild No IP dosage 

change/te 

mporarily 

discontinue 

d 






Y013 Clotinab Before Male 43 Hepatobiliary disorders Hepatitis Mild No Medication Improbable Recovered, 


prescribed 


Y023 ReoPro ® After Male 66 Investigations Aspartate 

Mild No No Possible Recovered, 



increased 


Y057 Clotinab After Male 70 Musculoskeletal and 

Arthralgia Mild No Medication None Recovered, 


connective tissue 


prescribed 


C002 Clotinab After Male 70 Musculoskeletal and 

Back pain Severe No Medication None Recovered, 




prescribed 


C020 Clotinab After Female 67 Musculoskeletal and 

Back pain Mild No Medication None Recovered, 




prescribed 



Back pain Mild No Medication None Recovered, 




prescribed 



Back pain Mild No No None Recovered, 






Back pain Mild No No None Recovered, 






Ver. 1.0_Eng


Subjec 

t ID 

Treatment 

IP 






















Sex Age 

System Organ 

Class 

Male 52 Musculoskeletal and 
























Female 70 Musculoskeletal and 







Serious 

-ness 

Action 

taken 

Back pain Mild No Medication 

prescribed 


prescribed 


prescribed 


prescribed 


prescribed 


prescribed 


prescribed 


prescribed 


prescribed 


prescribed 



Ver. 1.0_Eng 




















without sequelae


Subjec 

t ID 

Treatment 

IP 






















Sex Age 

System Organ 

Class 
































Serious 

-ness 

Action 

taken 


prescribed 


prescribed 


prescribed 


prescribed 


prescribed 


prescribed 

Buttock pain Mild No Medication 

prescribed 

Flank pain Mild No Medication 

prescribed 



Ver. 1.0_Eng 

















Flank pain Mild No No None Recovered, 


Limb discomfort Mild No No None Recovered, 

without sequelae


Subjec 

t ID 

Treatment 

IP 
























Sex Age 

System Organ 

Class 

























Male 55 Nervous system 








discomfort 

Serious 

-ness 

Action 

taken 




Myalgia Mild No Medication 

prescribed 


prescribed 


prescribed 


Ver. 1.0_Eng 







Neck pain Mild No No None Recovered, 


Pain in extremity Mild No No None Recovered, 


Pain in extremity Mild No Medication 

prescribed 



Shoulder pain Mild No No None Recovered, 


Burning sensation Mild No No None Recovered, 


Burning sensation Mild No Medication None Recovered, 

prescribed 


Burning sensation Mild No No None Recovered, 

without sequelae


Subjec 

t ID 

Treatment 

IP 


Sex Age 

System Organ 

Class 

A017 Clotinab After Female 71 Nervous system 



C017 Clotinab After Male 32 Nervous system 



C020 Clotinab Before Female 67 Nervous system 



Y002 Clotinab After Female 71 Nervous system 



Y006 Clotinab Before Male 66 Nervous system 



Y042 Clotinab After Male 59 Nervous system 






Y046 Clotinab Before Female 56 Nervous system 



A010 ReoPro ® After Male 72 Nervous system 



A015 ReoPro ® Before Male 39 Nervous system 









C019 ReoPro ® Before Male 38 Nervous system 



Y037 ReoPro ® After Male 68 Nervous system 



Y050 ReoPro ® Before Male 65 Nervous system 




Serious 

-ness 

Action 

taken 


Dizziness Mild No No None Recovered, 






Dizziness Mild No Medication Improbable Recovered, 

prescribed 




















Dizziness Mild No No None AE, No more 

progress 




Ver. 1.0_Eng


Subjec 

t ID 

Treatment 

IP 


Sex Age 

System Organ 

Class 

A003 Clotinab Before Male 47 Nervous system 



A004 Clotinab After Male 55 Nervous system 






A005 Clotinab Before Female 56 Nervous system 















A025 Clotinab Before Male 46 Nervous system 






C003 Clotinab Before Male 58 Nervous system 






C020 Clotinab Before Female 67 Nervous system 










Serious 

-ness 

Action 

taken 


Headache Mild No No None Recovered, 


Headache Moderate No No None Recovered, 




Headache Mild No Medication None Recovered, 

prescribed 





prescribed 



prescribed 



prescribed 





prescribed 



prescribed 





prescribed 



prescribed 



prescribed 



Ver. 1.0_Eng


Subjec 

t ID 

Treatment 

IP 


Sex Age 

System Organ 

Class 















































Serious 

-ness 

Action 

taken 





prescribed 





prescribed 



prescribed 



prescribed 


Headache Mild No Medication Improbable Recovered, 

prescribed 



prescribed 



prescribed 



prescribed 



prescribed 



prescribed 



prescribed 



prescribed 





Ver. 1.0_Eng


Subjec 

t ID 

Treatment 

IP 


Sex Age 

System Organ 

Class 
















C010 ReoPro ® After Female 77 Nervous system 









C016 ReoPro ® After Male 37 Nervous system 






C021 ReoPro ® After Female 67 Nervous system 



C023 ReoPro ® After Male 52 Nervous system 













Serious 

-ness 

Action 

taken 



prescribed 



prescribed 



prescribed 



prescribed 



prescribed 





prescribed 



prescribed 



prescribed 



prescribed 



prescribed 



prescribed 





prescribed 



prescribed 



Ver. 1.0_Eng


Subjec 

t ID 

Treatment 

IP 


Sex Age 

System Organ 

Class 


Serious 

-ness 

Action 

taken 






prescribed 


Y065 ReoPro ® Before Male 54 Nervous system 




prescribed 


A001 Clotinab After Male 54 Nervous system Hypoaesthesia Mild No No None Recovered, 




C013 Clotinab After Male 35 Nervous system Hypoaesthesia Mild No No None Recovered, 




Y016 Clotinab After Male 61 Nervous system Hypoaesthesia Mild No No None Recovered, 





Migraine Mild No Medication None Recovered, 



prescribed 



Paraesthesia Mild No No None Recovered, 





Paraesthesia Mild No No None Recovered, 





Paraesthesia Mild No Medication None Recovered, 



prescribed 


Y008 Clotinab After Male 65 Psychiatric disorders Anxiety Mild No Medication None AE, No more 


prescribed 

progress 

Y053 ReoPro ® Before Female 67 Psychiatric disorders Anxiety Mild No Medication None Recovered, 


prescribed 


C003 Clotinab After Male 58 Psychiatric disorders Sleep disorder Mild No Medication None Recovered, 


prescribed 


Y004 Clotinab After Male 76 Psychiatric disorders Sleep disorder Mild No Medication None Recovered, 


prescribed 


Y045 Clotinab After Male 67 Psychiatric disorders Sleep disorder Mild No No None Recovered, 



C021 ReoPro ® After Female 67 Psychiatric disorders Sleep disorder Mild No Medication None Recovered, 


prescribed 



Ver. 1.0_Eng


Subjec 

t ID 

Treatment 

IP 


Sex Age 

System Organ 

Class 


Serious 

-ness 

Action 

taken 


Y048 ReoPro ® Before Male 71 Psychiatric disorders Sleep disorder Mild No No None Recovered, 



A012 Clotinab Before Male 62 Renal and urinary 

Dysuria Mild No Medication None Recovered, 



prescribed 


A031 Clotinab Before Male 41 Renal and urinary 

Dysuria Mild No No None Recovered, 




C002 Clotinab After Male 70 Renal and urinary 

Dysuria Moderate No No None Recovered, 













prescribed 







Y013 Clotinab Before Male 43 Renal and urinary 




prescribed 


Y014 Clotinab After Male 52 Renal and urinary 





Y015 Clotinab After Female 68 Renal and urinary 






Dysuria Mild No Medication None AE, No more 



prescribed 

progress 







Dysuria Severe Yes Medication None Recovered, 



prescribed 







A014 ReoPro ® After Female 64 Renal and urinary 






Ver. 1.0_Eng


Subjec 

t ID 

Treatment 

IP 


Sex Age 

System Organ 

Class 

A015 ReoPro ® After Male 39 Renal and urinary 



A032 ReoPro ® After Male 50 Renal and urinary 



Y029 ReoPro ® After Female 62 Renal and urinary 



Y040 ReoPro ® After Female 64 Renal and urinary 



Y045 Clotinab After Male 67 Renal and urinary 



Y056 ReoPro ® After Male 57 Renal and urinary 



C021 ReoPro ® After Female 67 Renal and urinary 



C020 Clotinab After Female 67 Respiratory, thoracic and 



C022 Clotinab After Male 71 Respiratory, thoracic and 



Y057 Clotinab After Male 70 Respiratory, thoracic and 



Y060 Clotinab Before Female 70 Respiratory, thoracic and 






A017 Clotinab After Female 71 Respiratory, thoracic and 



C020 Clotinab After Female 67 Respiratory, thoracic and 







Serious 

-ness 

Action 

taken 










Haematuria Mild No No Improbable Recovered, 


Haematuria Mild No No Improbable Recovered, 


Hematuria Mild No No None Recovered, 


Cough Mild No No None Recovered, 


Cough Mild No Medication None Recovered, 

prescribed 


Cough Mild No Medication None Recovered, 

prescribed 


Cough Mild No No None Recovered, 


Dyspnoea Mild No No None Recovered, 


Haemoptysis Mild No No Improbable Recovered, 


Haemoptysis Mild No No None Recovered, 


Haemoptysis Mild No Medication Improbable AE, No more 

prescribed 

progress 


Ver. 1.0_Eng


Subjec 

t ID 

Treatment 

IP 


























C019 ReoPro ® Before 






Sex Age 

System Organ 

Class 

Male 76 Respiratory, thoracic and 








Male 56 Skin and subcutaneous 























Serious 

-ness 

Action 

taken 


Nasopharyngitis Mild No Medication None AE, No more 

prescribed 

progress 

Pulmonary tuberculosis Mild No No None AE, No more 

progress 

Rales Mild No Medication None Recovered, 

prescribed 


Tachypnoea Mild No No None Recovered, 


Blister Mild No No None Recovered, 


Erythema Mild No No None Recovered, 


Excoriation Mild No Medication None Recovered, 

prescribed 


Pruritus Mild No No None Recovered, 


Pruritus Mild No Medication Improbable AE, No more 

prescribed 

progress 

Pruritus Mild No Medication None AE, No more 

prescribed 

progress 

Pruritus Mild No Medication Improbable Recovered, 

prescribed 


Pruritus Mild No Medication None Recovered, 

prescribed 


Pruritus Mild No Medication None Recovered, 

prescribed 


Pruritus generalised Mild No Medication Improbable Recovered, 

prescribed 


Rash Mild No Medication None Recovered, 

prescribed 



Ver. 1.0_Eng


Subjec 

t ID 

Treatment 

IP 


Sex Age 

System Organ 

Class 


Serious 

-ness 

Action 

taken 


Y015 Clotinab After Female 68 Skin and subcutaneous 

Rash Mild No No None Recovered, 




Y018 Clotinab After Male 61 Skin and subcutaneous 




prescribed 



Rash Mild No Medication None AE, No more 



prescribed 

progress 


Rash Mild No Medication Improbable Recovered, 



prescribed 


C019 ReoPro ® Before Male 38 Skin and subcutaneous 




prescribed 


Y035 Clotinab After Female 67 Skin and subcutaneous Rash macular Mild No Medication Improbable Recovered, 



prescribed 


A001 Clotinab After Male 54 Skin and subcutaneous Urticaria Mild No Medication None Recovered, 



prescribed 


A004 Clotinab After Male 55 Skin and subcutaneous Urticaria Mild No Medication None Recovered, 



prescribed 


A030 ReoPro ® After Male 48 Skin and subcutaneous Urticaria Mild No Medication None Recovered, 



prescribed 


A015 ReoPro ® Before Male 39 Vascular disorders Conjunctival 

Mild No Medication Improbable Recovered, 


haemorrhage 

prescribed 


C008 Clotinab Before Male 52 Vascular disorders Ear haemorrhage Mild No No None Recovered, 



C020 Clotinab After Female 67 Vascular disorders Epistaxis Mild No No None Recovered, 



Y004 Clotinab Before Male 76 Vascular disorders Epistaxis Mild No No None Recovered, 



Y046 Clotinab After Female 56 Vascular disorders Epistaxis Mild No IP Improbable Recovered, 


permanentl 

y 

discontinue 

d 



Ver. 1.0_Eng


Subjec 

t ID 

Treatment 

IP 


Sex Age 

System Organ 

Class 


Serious 

-ness 

Action 

taken 


A031 Clotinab After Male 41 Vascular disorders Gingival bleeding Mild No No Improbable Recovered, 



Y016 Clotinab After Male 61 Vascular disorders Gingival bleeding Mild No No Improbable Recovered, 



Y028 Clotinab After Female 63 Vascular disorders Gingival bleeding Mild No No Improbable Recovered, 



Y046 Clotinab Before Female 56 Vascular disorders Gingival bleeding Mild No IP Improbable Recovered, 


permanentl 

y 

discontinue 

d 


Y043 ReoPro ® After Male 55 Vascular disorders Gingival bleeding Mild No No Improbable Recovered, 



Y051 ReoPro ® After Male 59 Vascular disorders Gingival bleeding Mild No No Improbable Recovered, 



Y053 ReoPro ® After Female 67 Vascular disorders Gingival bleeding Mild No No Improbable Recovered, 



Y058 ReoPro ® After Female 58 Vascular disorders Gingival bleeding Mild No No Improbable Recovered, 



A013 Clotinab After Male 70 Vascular disorders Haemorrhage Moderate No No Improbable Recovered, 



A022 Clotinab After Female 54 Vascular disorders Haemorrhage Moderate No Medication Improbable Recovered, 


prescribed 


C003 Clotinab After Male 58 Vascular disorders Haemorrhage Moderate No No None Recovered, 



C010 ReoPro ® After Female 77 Vascular disorders Haemorrhage Severe No IP Improbable Recovered, 


permanentl 

y 

discontinue 

d 



Ver. 1.0_Eng


Subjec 

t ID 

Treatment 

IP 


Sex Age 

System Organ 

Class 


Serious 

-ness 

Action 

taken 


C021 ReoPro ® After Female 67 Vascular disorders Haemorrhage Mild No No Improbable Recovered, 



Y023 ReoPro ® After Male 66 Vascular disorders Haemorrhage Mild No No Improbable Recovered, 



C026 Clotinab After Male 57 Vascular disorders Hypertension Mild No Medication None Recovered, 


prescribed 


Y061 Clotinab After Male 58 Vascular disorders Hypertension Mild No Medication None Recovered, 


prescribed 



Ver. 1.0_Eng

Table 15. 13 Laboratory Data 

WBC 

RBC 

Item 


(Hematology) N * Mean SD Med Min Max p-value N * Mean SD Med Min Max p-value 

Baseline 84 7.55 2.66 6.93 3.60 15.80 40 7.73 2.31 7.00 4.10 13.20 

12 hr 79 8.18 2.55 7.70 4.67 18.80 39 8.49 1.73 8.50 5.40 13.40 

Day 3 80 7.26 1.85 7.00 3.81 12.55

Change 4 81 0.05 0.40 0.02 -1.37 1.39 39 -0.09 0.40 -0.05 -1.12 0.56 

Change1=12hr-Baseline, Change2=day3- Baseline, Change3=(One day before) Discharge - Baseline, Change4=day30- Baseline. 

p-value from Friedman test, * Difference in number of patients is due to missing data. The data from one day prior to discharge, if diffent form day3 were not 

included in the Friedman test because most patients were discharged from the hospital on day3 or day4. Including those data in the Friedman test would have 

created many missing obserbations. 


Ver. 1.0_Eng

PLT 

Neutro. 

(seg) 

Table 15. 13 Laboratory Data (Continued) 

Item 



Baseline 84 214.43 44.01 209.50 119.00 319.00 40 236.45 52.59 231.00 143.00 372.00 

4 hr 82 198.43 57.15 203.00 70.00 389.00 40 219.95 56.58 210.50 132.00 358.00 

12 hr 79 192.20 55.15 194.00 62.00 367.00

Change 1 62 6.77 11.95 7.20 -31.90 31.60 30 7.64 12.67 8.50 -24.30 30.70 

Change 2 67 3.07 11.61 2.20 -31.80 26.80 33 2.55 11.41 4.40 -27.90 19.00 

Change 3 67 2.37 12.12 3.30 -31.80 26.40 33 -0.44 11.80 2.80 -27.90 19.00 

Change 4 68 -3.09 12.32 -1.50 -34.10 28.10 34 -6.38 12.83 -3.60 -49.40 8.10 

Change1*=4hr- Baseline, Change2*=12hr- Baseline, Change3*=24hr- Baseline Change4*=day3- Baseline, Change5*=(One day before) Discharge - Baseline, 

Change6*=day30- Baseline, Change1=12hr- Baseline, Change2=Day3- Baseline, Change3=(One day before) Discharge - Baseline, Change4=day30- Baseline . 

p-value from Friedman test , * Difference in number of patients is due to missing data. The data from one day prior to discharge, if diffent form day3 were not 




Ver. 1.0_Eng

Table 15.13 Laboratory Data (Continued) 

Lympho. 

Mono. 

Item 



Baseline 71 28.61 9.31 29.00 9.00 51.80 35 28.43 10.81 30.70 11.70 52.80 

12hr 64 21.95 7.69 21.40 5.20 45.00 31 20.47 7.38 20.00 6.00 33.80 

Day 3 78 25.33 6.82 24.00 8.50 47.10

Change1=12hr- Baseline, Change2=Day3- Baseline, Change3=(One day before) Discharge- Baseline, Change4=day30- Baseline 





Ver. 1.0_Eng


Eosino. 

Baso. 

Item 



Baseline 71 2.91 3.16 2.10 0.10 18.10 35 2.37 2.02 1.80 0.10 10.10 

12hr 64 2.08 2.67 1.25 0.00 15.60 31 1.32 1.10 1.00 0.00 5.00 

Day 3 78 3.31 3.09 2.55 0.20 15.80

Change1=12hr- Baseline, Change2=Day3- Baseline, Change3=(One day before) Discharge- Baseline, Change4=day30- Baseline 





Ver. 1.0_Eng

SGOT 

(AST) 

SGPT 

(ALT) 


Item 


(Serum Chemistry) N * Mean SD Med Min Max p-value N * Mean SD Med Min Max p-value 

Glucose 

Screening 84 41.24 51.23 26.00 11.00 355.00 40 45.20 43.40 28.50 13.00 211.00 

12 hr 81 40.64 36.22 27.00 11.00 238.00 38 51.74 62.70 28.00 13.00 335.00 

Day 3 79 38.72 34.89 27.00 11.00 219.00 0.0244 38 31.66 21.01 26.00 11.00 109.00 0.0463 

Day 30(+7) 80 24.69 14.57 22.00 11.00 138.00 39 24.36 9.93 21.00 13.00 56.00 

Change 1 81 -1.30 49.08 -3.00 -251.00 181.00 38 5.45 62.36 -3.00 -87.00 308.00 

Change 2 79 0.61 46.71 -1.00 -283.00 191.00 38 -10.79 38.38 -4.00 -151.00 72.00 

Change 3 80 -16.51 55.10 -3.00 -337.00 112.00 39 -21.31 45.77 -4.00 -194.00 24.00 

Screening 84 30.02 21.21 25.00 8.00 142.00 40 27.55 13.72 25.50 7.00 69.00 

12 hr 81 30.07 19.32 24.00 7.00 102.00 38 28.79 17.63 25.00 8.00 81.00 

Day 3 79 34.68 30.78 26.00 6.00 227.00 0.1868 38 26.29 15.98 23.00 8.00 80.00 0.0489 

Day 30(+7) 80 26.31 16.03 21.00 5.00 91.00 39 27.44 22.80 21.00 7.00 143.00 

Change 1 81 -0.35 15.10 -2.00 -40.00 67.00 38 1.13 15.25 -3.00 -21.00 49.00 

Change 2 79 4.82 22.21 -2.00 -35.00 85.00 38 -0.79 14.69 -3.50 -32.00 41.00 

Change 3 80 -4.15 21.14 -1.00 -70.00 69.00 39 -0.23 25.39 0.00 -34.00 125.00 

Screening 81 128.25 56.79 109.00 71.00 382.00 39 128.90 59.21 110.00 64.00 393.00 

12 hr 73 124.19 37.48 114.00 75.00 261.00 36 134.89 41.75 128.00 76.00 289.00 

Day 3 72 119.31 38.80 104.50 74.00 271.00 0.0009 36 131.25 52.11 108.00 53.00 288.00 0.1465 

Day 30(+7) 80 112.34 32.78 100.50 76.00 237.00 39 116.31 47.25 101.00 50.00 279.00 

Change 1 71 -1.76 45.60 0.00 -207.00 78.00 35 17.14 35.88 21.00 -65.00 101.00 

Change 2 71 -7.93 55.04 -3.00 -205.00 151.00 35 3.77 49.33 -4.00 -164.00 108.00 

Change 3 77 -15.38 44.89 -12.00 -188.00 76.00 38 -9.42 61.45 -5.50 -287.00 120.00 

Change1=12hr-screening, Change2=Day3- screening, Change3=day30- screening 

p-value from Friedman test, * Difference in number of patients is due to missing data. 


Ver. 1.0_Eng


Item 

(Serum Chemistry) N * 

Cholesterol 

Triglyceride 

BUN 


Mean SD Med Min Max p-value N * Mean SD Med Min Max p-value 

Screening 72 172.29 43.43 166.00 102.00 304.00 37 169.97 32.75 162.00 109.00 239.00 

12 hr 74 157.12 34.51 153.00 98.00 254.00 35 157.29 27.32 153.00 110.00 213.00 

Day 3 75 152.13 32.40 153.00 90.00 251.00



Item 

(Serum Chemistry) 

N * Mean SD Med Min Max p-value N * Mean SD Med Min Max p-value 

Creatinine Screening 84 0.95 0.18 0.95 0.50 1.50 40 0.97 0.18 1.00 0.70 1.40 

12 hr 80 0.93 0.19 0.90 0.50 1.60 38 0.95 0.17 0.95 0.70 1.30 

Day 3 79 0.92 0.16 0.90 0.50 1.40


Item 


Alk. 

Phosphata 



Screening 73 64.30 16.11 61.00 34.00 131.00 38 69.37 26.42 67.50 29.00 166.00 

12 hr 80 59.15 14.51 57.00 35.00 118.00 38 61.21 21.29 57.00 28.00 137.00 

se Day 3 79 63.73 15.69 60.00 37.00 122.00



Item 



Potassium Screening 82 4.14 0.38 4.10 3.30 5.10 40 4.06 0.39 4.00 3.60 5.00 

12 hr 78 3.98 0.37 3.90 3.30 5.80 38 3.78 0.31 3.80 2.90 4.60 

Day 3 76 4.09 0.37 4.10 3.20 5.40 38 3.94 0.38 3.95 3.10 4.80 

Day 30(+7) 80 4.44 0.37 4.40 3.70 5.60



Item 



Uric acid Screening 64 5.63 1.23 5.50 2.20 10.10 35 5.81 1.58 6.00 0.80 8.70 

12 hr 78 5.31 1.27 5.10 2.60 10.90 38 5.40 1.39 5.40 1.00 8.30 

Day 3 77 5.14 1.17 5.10 2.80 9.20

Table 15. 14 Cardiac Marker 


Item 

(Cardiac Marker) 

N * Mean SD Med Min Max p-value N * 

Mean SD Med Min Max p-value 

Troponin Baseline 81 4.87 23.33 0.10 0.01 204.39 38 2.56 6.89 0.20 0.01 38.13 

12 hr 78 3.45 11.98 0.20 0.01 91.60 39 5.78 18.88 0.90 0.01 112.13 

24 hr 80 3.08 7.35 0.25 0.01 46.93 39 3.96 9.08 0.85 0.01 47.61 

Day 3 81 2.10 4.78 0.25 0.01 28.16

CK-MB Change 4 81 -5.50 23.11 -0.42 -120.90 76.47 39 -16.15 42.54 -1.20 -220.63 7.53 

Change 5 78 -6.89 22.03 -0.24 -125.60 20.50 39 -16.48 42.67 -0.10 -220.51 5.40 

Change1=12hr-Baseline, Change2=24hr- Baseline, Change3=day3- Baseline, Change4=(One day before) Discharge- Baseline. Change4=day30- Baseline , 





Ver. 1.0_Eng

Table 15. 15 Urinalysis-Clotinab 

ITEM (Urinalysis) Day 3 (One day before) Discharge Day 30(+7) 

Normal Insig. Sig. Normal Insig. Sig. Normal Insig. Sig. 

Screening 

Abnormal Abnormal 



Specific Normal 60 0 0 63 0 0 65 0 0 

gravity Insig. Abnormal. 0 0 0 0 0 0 0 0 0 

Sig. Abnormal 0 0 0 0 0 0 0 0 0 

PH Normal 59 0 0 61 1 0 64 0 0 

Insig. Abnormal. 1 0 0 1 0 0 1 0 0 

Sig. Abnormal 0 0 0 0 0 0 0 0 0 

Protein Normal 56 0 1 59 1 0 62 0 0 


Sig. Abnormal 0 0 0 0 0 0 0 0 0 

Glucose Normal 41 2 1 45 1 1 49 0 0 


Sig. Abnormal 3 1 0 4 0 0 2 1 1 

Ketone Normal 56 1 0 59 0 0 60 1 0 


Sig. Abnormal 0 0 0 0 0 0 0 0 0 

RBC Normal 46 7 2 49 7 1 57 1 0 


Sig. Abnormal 0 0 0 0 0 0 0 0 0 

Sig. : Significant , Insig. Insignificant, Difference in number of patients is due to missing data. 


Ver. 1.0_Eng

Table 15. 15 Urinalysis-Clotinab (Continued) 



Screening 




Bilirubin Normal 59 1 0 62 1 0 65 0 0 


Sig. Abnormal 0 0 0 0 0 0 0 0 0 

Urobilnogen Normal 54 4 0 58 3 0 63 0 0 


Sig. Abnormal 0 0 0 0 0 0 0 0 0 

Nitrite Normal 60 0 0 63 0 0 65 0 0 


MICROSCOPY 

Sig. Abnormal 0 0 0 0 0 0 0 0 0 

RBC Normal 43 3 1 44 4 0 49 2 0 


Sig. Abnormal 0 0 0 0 0 0 0 0 0 

WBC Normal 42 3 1 43 4 0 49 1 0 


Sig. Abnormal 0 0 0 0 0 0 0 0 0 

Squamous Normal 47 2 0 49 2 0 53 0 0 

cell Insig. Abnormal. 0 0 0 0 0 0 0 0 0 

Sig. Abnormal 0 0 0 0 0 0 0 0 0 



Ver. 1.0_Eng

Table 15. 16 Urinalysis-ReoPro ® 



Screening 




Specific Normal 25 1 0 26 1 0 27 0 0 

gravity Insig. Abnormal. 0 0 0 0 0 0 0 0 0 

Sig. Abnormal 0 0 0 0 0 0 0 0 0 

PH Normal 26 0 0 27 0 0 27 0 0 


Sig. Abnormal 0 0 0 0 0 0 0 0 0 

Protein Normal 24 0 0 25 0 0 25 1 0 


Sig. Abnormal 0 0 0 0 0 0 0 0 0 

Glucose Normal 21 3 0 22 3 0 24 1 0 


Sig. Abnormal 0 0 1 0 0 1 0 0 1 

Ketone Normal 22 1 0 23 1 0 24 0 0 


Sig. Abnormal 0 0 0 0 0 0 0 0 0 

RBC Normal 17 4 0 18 3 0 21 2 0 


Sig. Abnormal 0 0 0 0 0 0 0 0 0 



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Table 15. 16 Urinalysis-ReoPro ® (Continued) 



Screening 




Bilirubin Normal 26 0 0 27 0 0 26 1 0 


Sig. Abnormal 0 0 0 0 0 0 0 0 0 

Urobilnogen Normal 24 2 0 23 4 0 27 0 0 


Sig. Abnormal 0 0 0 0 0 0 0 0 0 

Nitrite Normal 23 3 0 25 2 0 27 0 0 


MICROSCOPY 

Sig. Abnormal 0 0 0 0 0 0 0 0 0 

RBC Normal 17 2 0 18 1 0 21 1 0 


Sig. Abnormal 0 0 0 0 0 0 0 0 0 

WBC Normal 19 2 0 20 2 0 22 3 0 


Sig. Abnormal 0 0 0 0 0 0 0 0 0 

Squamous Normal 18 2 0 19 1 0 21 0 0 

cell Insig. Abnormal. 1 0 0 1 0 0 1 1 0 

Sig. Abnormal 0 0 0 0 0 0 0 0 0 



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Table 15. 17 Coagulation 

ITEM(APTT or ACT) Day 3 (One day before) Discharge Day 30(+7) 

Baseline 

Normal Insig. 

Abnormal 

Sig. 

Abnormal 

Normal Insig. 

Abnormal 

Sig. 

Abnormal 

Normal Insig. 

Abnormal 

Clotinab Normal 40 6 0 44 3 0 42 3 0 


Sig. Abnormal 0 0 0 0 0 0 0 0 0 

ReoPro ® Normal 26 4 0 27 4 0 25 4 0 


Sig. Abnormal 0 0 0 0 0 0 0 0 0 



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Sig. 

Abnormal

Table 15. 18 Vital sign 

Systolic 

blood 

pressure:( 

Item 


N * Mean SD Med Min Max P-value N * Mean SD Med Min Max P-value 

Baseline 82 124.39 20.20 120.0 89.0 180.0

Table 15. 18 Vital sign (continued) 


Item 

N * Mean SD Med Min Max P-value N * Mean SD Med Min Max P-value 

Pulse rate Baseline 82 67.02 10.48 68.0 46.0 105.0 0.0004 40 70.43 13.18 65.5 50.0 120.0 0.0653 

(beats /min) Change 1 80 -0.50 12.89 0.0 -58.0 24.0 36 -0.94 12.61 1.0 -22.0 41.0 

Change 2 81 -0.12 13.83 0.0 -55.0 34.0 39 1.33 15.55 3.0 -25.0 48.0 

Change 3 82 -0.06 14.15 1.0 -52.0 35.0 40 -0.75 13.54 1.0 -23.0 33.0 

Change 4 81 1.32 13.81 3.0 -52.0 30.0 39 -0.31 13.51 0.0 -25.0 32.0 

Change 5 80 -0.18 12.54 1.5 -48.0 33.0 40 1.30 13.82 1.0 -26.0 40.0 

Change 6 82 -1.96 11.74 -2.0 -48.0 19.0 40 -0.08 12.98 1.0 -26.0 33.0 

Change 7 80 0.26 12.65 0.5 -45.0 45.0 38 -0.87 12.56 -1.0 -25.0 22.0 

Change 8 81 0.85 12.73 2.0 -45.0 28.0 40 3.30 15.37 4.0 -24.0 42.0 

Change 9 81 2.67 11.92 4.0 -47.0 34.0 40 3.28 12.02 3.0 -22.0 32.0 

Change 10 81 2.17 12.44 2.0 -45.0 47.0 40 1.63 11.73 3.0 -28.0 23.0 

Change 11 80 0.60 13.96 1.5 -42.0 41.0 38 -2.50 13.99 -1.5 -28.0 24.0 

Body Baseline 79 36.17 0.39 36.2 35.0 37.0

Table 15. 18 Vital sign (continued) 

Item 


N * Mean SD Med Min Max P-value N * 

Mean SD Med Min Max P-value 

Respiration Baseline 79 19.25 2.27 20.0 12.0 29.0

Table 15. 19 Physical examination-Clotinab 

ITEM 

Day3 (One day before) Discharge Day30 

Screening Normal Abnormal Normal Abnormal Normal Abnormal 

General 

appearance 

Normal 73 4 75 2 76 1 

Abnormal 4 0 4 0 4 0 

Nutrition Normal 80 1 81 0 81 0 

Abnormal 0 0 0 0 0 0 

Skin/mucous 

membrane 

Normal 68 12 69 11 76 4 

Abnormal 1 0 1 0 1 0 

Eye Normal 81 0 80 1 81 0 

Abnormal 0 0 0 0 0 0 

Ear,nose,throat Normal 80 0 80 0 80 0 

Abnormal 1 0 1 0 1 0 

Thyroid Normal 81 0 81 0 81 0 

Abnormal 0 0 0 0 0 0 

Lung Normal 76 2 77 1 78 0 

Abnormal 3 0 3 0 3 0 

Heart/circulatory Normal 75 6 81 0 80 1 

Abnormal 0 0 0 0 0 0 

Abdomen Normal 78 1 79 0 78 1 

Abnormal 1 1 2 0 1 1 

Kidney/urinary Normal 78 1 79 0 79 0 

Abnormal 1 1 1 1 2 0 

Difference in number of patients is due to missing data. 


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Table 15. 19 Physical examination -Clotinab (Cont.) 

ITEM 



Neuro/mental Normal 71 7 77 1 76 2 

Abnormal 3 0 3 0 3 0 

Spinal/extremities Normal 77 2 77 2 79 0 

Abnormal 2 0 2 0 2 0 

Peripheral 

circulation 

Normal 80 1 80 1 81 0 

Abnormal 0 0 0 0 0 0 

Lymphatic system Normal 81 0 81 0 81 0 

Abnormal 0 0 0 0 0 0 

Others Normal 76 4 79 1 80 0 

Abnormal 0 1 0 1 0 1 



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Table 15. 20 Physical examination -ReoPro ® 

ITEM 



General 

appearance 

Normal 34 1 35 0 34 0 

Abnormal 3 2 5 0 4 0 

Nutrition Normal 40 0 40 0 38 0 

Abnormal 0 0 0 0 0 0 

Skin/mucous 

membrane 

Normal 34 5 34 5 36 1 

Abnormal 0 1 0 1 1 0 

Eye Normal 38 1 38 1 37 0 

Abnormal 1 0 1 0 1 0 

Ear,nose,throat Normal 39 0 39 0 37 0 

Abnormal 1 0 1 0 1 0 

Thyroid Normal 40 0 40 0 38 0 

Abnormal 0 0 0 0 0 0 

Lung Normal 39 1 39 1 38 0 

Abnormal 0 0 0 0 0 0 

Heart/circulatory Normal 39 1 39 1 37 1 

Abnormal 0 0 0 0 0 0 

Abdomen Normal 36 3 39 0 36 1 

Abnormal 1 0 1 0 1 0 

Kidney/urinary Normal 39 0 39 0 37 0 

Abnormal 1 0 1 0 1 0 



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Table 15. 20 Physical examination - ReoPro ® (Cont.) 

ITEM 



Neuro/mental Normal 34 4 36 2 35 1 

Abnormal 0 2 0 2 2 0 

Spinal/extremities Normal 36 3 37 2 37 0 

Abnormal 1 0 1 0 1 0 

Peripheral 

circulation 

Normal 40 0 40 0 38 0 

Abnormal 0 0 0 0 0 0 

Lymphatic system Normal 40 0 40 0 38 0 

Abnormal 0 0 0 0 0 0 

Others Normal 38 1 39 0 37 0 

Abnormal 1 0 1 0 1 0 



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Table 15. 21 Listing of subjects with minor protocol violations 


1 A001 Clotinab AB 

2 A002 Clotinab A 

3 A003 Clotinab Deviation of the treatment amount and method of IP 2, Deviation of Aspirin treatment 

time, AB 

4 A004 Clotinab B 


6 A009 Clotinab Deviation of the treatment amount and method of IP 2, A 


8 A012 Clotinab Deviation of the treatment amount and method of IP 2, AB 

9 A013 Clotinab Deviation of the treatment amount and method of IP 3, Deviation of Aspirin treatment 

time, A 

10 A017 Clotinab Deviation of Aspirin treatment time, A 

11 A018 Clotinab Deviation of Aspirin treatment time, AB 


13 A020 Clotinab Deviation of the treatment amount and method of IP 2, Action to thrombocytopenia, 

Deviation of Aspirin treatment time, Follow-up, A 


15 A022 Clotinab Deviation of the treatment amount and method of IP 2, Deviation of the treatment amount 

and method of IP 3, AB 


17 A026 Clotinab Deviation of Aspirin treatment time, AB 

18 A028 Clotinab AB 


20 C001 Clotinab AB 

21 C002 Clotinab Date of Informed Consent, Deviation of the treatment amount and method of IP 4, 

Deviation of Aspirin treatment time, B 

22 C004 Clotinab B 

23 C005 Clotinab Deviation of the treatment amount and method of IP 1, B 




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26 C009 Clotinab N 

27 C013 Clotinab Deviation of Aspirin treatment time, Follow-up, B 

28 C014 Clotinab Deviation of Aspirin treatment time, X 

29 C018 Clotinab Deviation of the treatment amount and method of IP 1, Deviation of the treatment amount 

and method of IP 4, Follow-up, N 

30 C020 Clotinab X 

31 C022 Clotinab MACE deviatons, X 

32 C024 Clotinab Deviation of the treatment amount and method of IP 1, Deviation of the treatment amount 

and method of IP 3, B 

33 C026 Clotinab Deviation of the treatment amount and method of IP 1, B 

34 Y001 Clotinab Deviation of the treatment amount and method of IP 4 , AB 

35 Y002 Clotinab A 

36 Y003 Clotinab Deviation of the treatment amount and method of IP 4, A 

37 Y004 Clotinab Deviation of the treatment amount and method of IP 4, Deviation of Aspirin treatment 

time, 

Follow-up,AB 

38 Y005 Clotinab Deviation of the treatment amount and method of IP 1, AB 

39 Y006 Clotinab Deviation of Aspirin treatment time,A 




43 Y012 Clotinab Deviation of Aspirin treatment time, Follow-up, AB 


45 Y015 Clotinab Follow-up,AB 

46 Y016 Clotinab AB 


48 Y018 Clotinab Deviation of the treatment amount and method of IP 4, Deviation of Aspirin treatment 

time, A 


50 Y021 Clotinab Follow-up, A 





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66 Y052 Clotinab B 





71 Y060 Clotinab Follow-up, AB 


73 Y064 Clotinab Follow-up, A 

74 Y066 Clotinab Follow-up, AB 

75 A008 ReoPro ® A 

76 A010 ReoPro ® Deviation of Aspirin treatment time,B 

77 A014 ReoPro ® AB 

78 A015 ReoPro ® Deviation of the treatment amount and method of IP 3, Deviation of the treatment amount 

and method of IP 4, A 


80 A023 ReoPro ® Deviation of the treatment amount and method of IP 4, Deviation of Aspirin treatment 

time, AB 

81 A024 ReoPro ® B 





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85 A032 ReoPro ® Deviation of the treatment amount and method of IP 3, Follow-up, A 

86 C010 ReoPro ® Deviation of the treatment amount and method of IP 3,N 

87 C011 ReoPro ® N 

88 C012 ReoPro ® N 

89 C015 ReoPro ® X 

90 C016 ReoPro ® Deviation of the treatment amount and method of IP 4, X 

91 C019 ReoPro ® Deviation of the treatment amount and method of IP 3, Deviation of the treatment amount 

and method of IP 4, X 

92 C021 ReoPro ® Follow-up, X 

93 C023 ReoPro ® B 

94 Y023 ReoPro ® Deviation of Aspirin treatment time, AB* 

95 Y026 ReoPro ® Deviation of concomitant medication, AB 

96 Y029 ReoPro ® AB 

97 Y030 ReoPro ® A 

98 Y033 ReoPro ® Deviation of Aspirin treatment time,AB 

99 Y036 ReoPro ® Deviation of the treatment amount and method of IP 4, Deviation of concomitant 

medication, AB 

100 Y037 ReoPro ® Deviation of the treatment amount and method of IP 4, AB 

101 Y040 ReoPro ® B 

102 Y043 ReoPro ® Deviation of Aspirin treatment time, A 





107 Y056 ReoPro ® Action to thrombocytopenia(SAE:Death), A 

108 Y058 ReoPro ® Deviation of Aspirin treatment time ,AB 

109 Y062 ReoPro ® Deviation of the treatment amount and method of IP 3, Deviation of the treatment amount 

and method of IP 4, AB 

110 Y065 ReoPro ® Follow-up, AB 

Deviation type A : Heparin treatment without previous ACT measurement 

Deviation type B : Heparin treatment but no ACT result afterward 

Deviation type AB : Heparin treatment without previous ACT measurement, no ACT result afterward 

Deviation type AB * : Heparin treatment without previous ACT measurement, no ACT result afterward (no ACT measurement) 


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Deviation type N : no ACT measurement & no Heparin treatment 

Deviation type X : ACT measurement but no Heparin treatment 


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Clinical Study Report - Calidad de Información CFR

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