Public Assessment Report for paediatric studies submitted in ...

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Multicenter, Randomized, Double-blind, Double-Dummy, Parallel-Group, Active/Active Comparator/placebo study. Phase III. Location: 13 centers in the Unites States and one in Mexico. • Study population /Sample size Male or premenarchal females, 4-11 years of age, with asthma (ATS definition) requiring chronic pharmacotherapy for at least 6 months prior to screening. Patients had to demonstrate a baseline FEV1 (or PEFR for 4-5 years olds who could not adequately perform spirometry) of 50-80% of predicted normal value and show reversibility (≥15% increase in FEV1 (or PEFR if patients qualified on PEFR) following inhalation of 2 actuations of VENTOLIN MDI. 142 patients were blindly randomized into 3 groups: 45 patients in the Placebo group, 49 patients in the albuterol DISKUS group and 48 patients in the albuterol MDI group. There were no statistically significant differences between all groups regarding age, sex, duration of chronic renal failure, post transplant periods. • Treatments During the treatment period, patients were randomized to albuterol DISKUS, albuterol MDI, or placebo given four times daily. The treatment per age group was as follows: 2 capsules (500mg) daily up to 1 year of age 3 capsules (750mg) daily from 1 year to 5 years of age 3-6 capsules (750-1500 mg) daily over 5 years of age Total duration of the study: 4 weeks. Outcomes/endpoints The primary measures of efficacy were the peak within 30 min. of dosing of percent of predicted PEFR and FEV1 measured by change from baseline. Secondary measures of efficacy consisted of serial PEFR and FEV1 measurements. Other measurements of efficacy included patient-conducted determinations of morning peak expiratory flow rates (PEFR), use of back-up medication (VENTOLIN MDI), patient-rated asthma symptoms (including night time awakenings). Safety assessments included clinical adverse events, clinical laboratory tests, vital signs, 12-lead electrocardiograms, and physical examinations. FEV1 and PEFR measurements were recorded at each visit as the primary assessments of efficacy. FEV1 is defined as forced expiratory volume in one second. PEFR is defined as peak expiratory flow rate. • Statistical Methods Enrollment was planned for 120 patients (40 per treatment group). Data from previous studies have suggested that a reasonable assumption for the standard deviation of percent of predicted FEV1 measured in paediatric patients is 12%. Use a two-sample t-test and a significance level of 0.05, 40 patients per treatment group would provide at least 80% power in detecting a difference of 7.5% in percent of predicted FEV1 for any pairwise treatment comparison. This sample size would also provide at least 80% power to show a difference of 11% in percent of predicted PEFR (based on a standard deviation of 18%). It was anticipated that up to 10% of patients enrolled in the study would be aged 4 or 5 years, and therefore would not perform serial FEV1 measurements. Assuming the standard deviation of percent Salbutamol Final Public Assessment Report RO/W/0001/pdWS/001 Page 12/76
of predicted FEV1 to be 12%, the resulting sample size of 36 6-11 year-old patients per treatment group would provide al least 80% power of detecting a difference of 7.9% in percent of predicted FEV1. The primary efficacy endpoints were the peak effect, measured as the change from baseline in maximum percent of predicted FEV1 value (for patients aged 6-11) and percent of predicted PEFR value (for patients aged 4-11) observed within 30 minutes of dosing. Other measures of efficacy included FEV1 and PEFR at each of the time points on Day 1 and Week 4 and summary measures for 6-hour serial measurements (repeat measures, area under the curve and weighted average); functions of FEV1 and PEFR; diary card results, including morning PEFR, back-up VENTOLIN use, night time awakenings, asthma symptom scores and asthma exacerbations. The primary efficacy measures were analyzed using analysis of covariance with the percent of predicted same-day baseline as the covariate. The model included terms for treatment, investigator and baseline covariate. Results Safety results: Overall, both albuterol DISKUS and albuterol MDI were well tolerated and showed comparable effects to placebo with QID dosing over 4 weeks. There were no deaths reported during the study. There was one serious status asthmaticus adverse event (patient on albuterol DISKUS) which was not considered related to the study drug.No statistically significant differences were observed among the three treatment groups for the incidence of adverse events. The four adverse events that were thought by the investigator to be possibly, probably or almost certainly drug related were in the placebo group. None of the laboratory, vital sign, EKG, or physical examination results demonstrated a safety concern. Efficacy results Albuterol DISKUS and albuterol MDI, administered QID, were significantly more effective than placebo with QID dosing over 4-week treatment period in paediatric patients aged 4-11 years. At treatment Day 1 and Treatment week 4, albuterol DISKUS and albuterol MDI exhibited a significantly (p≤0.006) higher mean peak effect within 30 min of dosing compared to placebo as measured by the change from same-day baseline in percent of predicted PEFR and FEV1. Albuterol DISKUS and albuterol MDI demonstrated comparable efficacy over the 4-week treatment period. This was demonstrated by comparable increases in both of the primary efficacy endpoints, peak within 30 min, of dosing measured as a change from baseline of percent of predicted PEFR for patients aged 4-11 and FEV1 for patients aged 6-11. Both albuterol DISKUS and albuterol MDI demonstrated efficacy through the 2-3 hour interval based on PEFR and FEV1. The subgroup analysis of the 4-8 and 9-11 year olds demonstrated similar results as the total age group analysis. Albuterol DISKUS and albuterol MDI were numerically greater than placebo for all endpoints comprising the analysis of functions of 6-hour serial PEFR and FEV1, with the exception of time to maximum effect. Overall statistical significance was achieved for onset of effect, duration of effect, onset of maximum effect and WAVE ≥15% at Treatment Day 1 and for subjects achieving response, onset of effect, offset of effect and maximum effect at Treatment Week 4. Where overall significance was achieved, pairwise comparison showed both albuterol groups were significantly better than placebo at Treatment Day 1 and Treatment Week 4 (p≤0,044). Albuterol DISKUS and albuterol MDI were similar at Treatment Day 1 and Treatment Week 4 except onset of effect and duration of effect at Treatment Week 4 (p=0,028 and p=0,049, respectively) favoring albuterol DISKUS. In general there was agreement between the PEFR results and the FEV1 results. There was no overall significance demonstrated between the three treatment groups as measured by morning PEFR values, use of back-up VENTOLIN, asthma symptoms, and night time awakenings requiring treatment with back-up VENTOLIN. A great number of patients who received albuterol MDI experienced exacerbations (25% total number and 17% out of clinic) during the study compared to those who received albuterol DISKUS (14% Salbutamol Final Public Assessment Report RO/W/0001/pdWS/001 Page 13/76
Page 1 and 2: Public Assessment Report for paedia
Page 3 and 4: Pharmacovigilance and PSUR Name: Da
Page 5 and 6: Rapid-acting inhaled β 2 -agonists
Page 7 and 8: The MAHs are requested to submit a
Page 9 and 10: Neonatal onset of symptoms (associa
Page 11: Study Code: RID/CT/84 (D140/B16); D
Page 15 and 16: central laboratory where this clini
Page 17 and 18: DISKUS 200 mcg compared to albutero
Page 19 and 20: Study period 25 Nov 1996 - 28 May 1
Page 21 and 22: Investigational products for this s
Page 23 and 24: 180mcg 1 inhalation of 90mcg (Can B
Page 25 and 26: Efficacy results Primary efficacy v
Page 27 and 28: At Week 4, mean changes from baseli
Page 29 and 30: In the ITT population the daytime a
Page 31 and 32: This study demonstrated similar saf
Page 33 and 34: Protocol deviations were summarised
Page 35 and 36: The overall (based on all evaluable
Page 37 and 38: Three studies regarding the clinica
Page 39 and 40: The improvment in PEF was 51 L. min
Page 41 and 42: eported by the ≤ 6 year age group
Page 43 and 44: suitable for this age because young
Page 45 and 46: In the group treated with salbutamo
Page 47 and 48: common complaints associated with h
Page 49 and 50: although being gradually replaced b
Page 51 and 52: Based on the data submitted, the MA
Page 53 and 54: Inhaled Table 1 Key Differences bet
Page 55 and 56: GDS wording National SmPCs with sig
Page 57 and 58: GDS wording National SmPCs with sig
Page 59 and 60: Question 4 (Rapporteur): With regar
Page 61 and 62: Question 3 In case of divergences b
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United Kingdom: Salbulin MDPI Novol
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2. Completely depress the coloured
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The harmonised SmPC as outcome of t
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Assessment of the Applicant’s res
Page 71 and 72:
SALBUTAMOL WZF POLFA 2 mg SALBUTAMO
Page 73 and 74:
symptoms. Increased consumption of
Page 75 and 76:
sympathomimetic amines. High doses
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