Australian public assessment for Ibuprofen - Therapeutic Goods ...

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Table 13. CPI-CL-008 A, B and C: Patient disposition. AusPAR Caldolor Ibuprofen Phebra Pty Ltd PM-2010-02393-3-1 Final 2 January 2013 Therapeutic Goods Administration Population 008A 008B 008C Placebo q6h Caldolor 400 mg q6h Caldolor 800 mg q6h Placebo q6h Caldolor 800 mg q6h Placebo q6h Caldolor 800 mg Screened nr nr nr nr nr nr nr Randomised 134 134 138 153 166 92 106 AT na na na na na 86 99 ITT 134 134 138 153 166 84 95 EEP 115 111 116 137 150 64 77 AH 58 50 53 137* 150* na na Discontinued 134 134 138 153 166 86 99 Completed 0 0 0 0 0 0 0 nr = not reported; na = not applicable; * No ‘AH’ population was defined but all patients in 008B had undergone abdominal hysterectomy. In CPI-CL-008A, B and C, all patients had study medication discontinued prior to Day 5. Most early discontinuations were due to cessation of IV access and/or commencement of oral analgesia. Protocol violations In CPI-CL008A, protocol violations were recorded in 86 (64%), 88 (66%) and 95 (69%) of the patients randomised to placebo, Caldolor 400 mg and Caldolor 800 mg, respectively. These violations most commonly involved errors in the timing of study drug administration (more than 1 h before or after the scheduled time), or the receipt of restricted medications. Other protocol violations involved failure to observe exclusion criteria, consenting errors and randomisation according to the wrong age or weight stratum. Amongst the 17 randomised patients who should have been excluded due to factors such as creatinine clearance
Baseline data AusPAR Caldolor Ibuprofen Phebra Pty Ltd PM-2010-02393-3-1 Final 2 January 2013 Therapeutic Goods Administration In CPI-CL-008A, the majority of patients were female (79%), and Caucasian (86%). The mean age was 45 years. A total of 295 patients (73%) underwent abdominal surgery, of whom 161 (40% of the ITT population) were women who had an abdominal hysterectomy; 111 patients (27%) had orthopaedic surgery. Each of the three geographical regions (USA, Australia and the RSA) contributed about one-third of the ITT population. In CPI-CL-008B, all of the patients were women who underwent an abdominal hysterectomy in the USA. The mean age was 42 years. About half of the patients (55%) were Black, 39% were Caucasian and 6% were Hispanic. In CPI-CL-008C, the majority of patients were female (65%), and Caucasian (86%). The mean age of 61 years was higher than in the other studies. Some 71% of the patients were enrolled in the USA and the remainder in the RSA. 50% of the patients underwent knee replacement; 22% hip replacement; 19% knee arthroplasty and 9% hip arthroplasty. Baseline (pre-treatment) pain severity was not measured in any of the studies, as the first dose of study medication was given before the patients were conscious of pain in 008A and B and before the onset of pain in 008C. However, the types of surgery that were undertaken would be expected to produce moderate to severe pain in the absence of analgesia. Results for the primary efficacy outcome An FDA inspection identified concerns regarding the primary outcome data from one site that participated in both CPI-CL008A and B. Most of these issues involved CPI-CL-008B. According to the publicly available FDA reviews, there were discrepancies between the source documents and the submitted data listings for the primary endpoint (24-h morphine usage) for 4 patients. One of the patients was in enrolled in 008A and the other 3 in 008B. Also, the treatment assignments of 2 patients enrolled in 008A were unblinded to the study staff and 2 ineligible patients were enrolled in 008B. These findings led the FDA to request a reanalysis of the primary outcome data from CPI- CL-008B, excluding all data from the site concerned. The FDA statistical reviewer also performed a reanalysis that excluded only the 5 patients with suspect data for the primary outcome. The reanalyses did not alter the study conclusions. The exclusion of data from Site 2 in CPI-CL-008B slightly reduced the between-treatment difference for the primary endpoint and raised the corresponding p-value, which nevertheless remained well below 0.05. Other outcomes were not affected. For completeness, both the original analysis and the reanalyses will be presented in this report. Morphine usage Total morphine usage in the 24 h following the first dose of study medication (which was given intra-operatively at the initiation of skin closure) was the primary efficacy outcome in CPI-CL-008A and B. In CPI-CL-008A, only Caldolor 800 mg q6h and not Caldolor 400 mg q6h was significantly superior to placebo at the α=0.05 level in respect of this outcome (Table 14). Page 49 of 118
Page 1 and 2: Australian Public Assessment Report
Page 3 and 4: Contents AusPAR Caldolor Ibuprofen
Page 5 and 6: AusPAR Caldolor Ibuprofen Phebra Pt
Page 11 and 12: Carcinogenicity AusPAR Caldolor Ibu
Page 13 and 14: Nonclinical summary and conclusions
Page 31 and 32: Time to afebrility (temp
Page 39 and 40: Table 12. CPI-CL-006: Patient dispo
Page 41 and 42: Other efficacy studies IND 32803 Au
Page 47: AusPAR Caldolor Ibuprofen Phebra Pt
Page 57 and 58: Dose-response and non-pivotal effic
Page 59 and 60: Combined indications AusPAR Caldolo
Page 79 and 80: continued next page AusPAR Caldolor
Page 85 and 86: IVIb = Caldolor. AusPAR Caldolor Ib
Page 89 and 90: Table 37. IND 32803 (Sepsis syndrom
Page 95 and 96: Pivotal studies AusPAR Caldolor Ibu
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AusPAR Caldolor Ibuprofen Phebra Pt
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Pharmacovigilance plan AusPAR Caldo
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Table 44. Other efficacy outcomes.
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Caldolor is indicated for the reduc
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