AusPAR: Ivabradine - Therapeutic Goods Administration

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AusPAR Coralan Ivabradine Servier Laboratories (Australia) Pty Ltd PM-2010-03269-3-3 Final 31 October 2012 Therapeutic Goods Administration were randomised. Of these 6558 patients, 7 (2 in the ivabradine and 5 in the placebo group) who did not meet the inclusion criteria but were given randomisation numbers were not given any study drug and were not included in the Randomised Set. A further 46 patients, all of the patients recruited in the two Polish centres were excluded from all analysis sets for concerns over invalid data due to misconduct. The total number of patients retained in the Randomised Set (RS) was therefore 6505. Of these, 3241 patients were randomised to ivabradine and 3264 to placebo. (Please refer to Figure 3 below). Figure 3. Participant flow The RSBBdose dataset comprised of 3181 patients (48.9% of the RS), 1581 patients (48.8% of the RS) in the ivabradine group and 1600 patients (49.0% of the RS) in the placebo group. Analysis sets and subsets are presented in Table 1. Page 16 of 101
Table 1. Analysis Sets and Subsets AusPAR Coralan Ivabradine Servier Laboratories (Australia) Pty Ltd PM-2010-03269-3-3 Final 31 October 2012 Therapeutic Goods Administration Comment: The Randomised Set (RS) is in keeping with the ITT analysis population. The exclusion from the RS of the 7 subjects who were allocated randomised numbers but were actually not included in the study due to not satisfying the inclusion criteria was appropriate. However, the exclusion from the RS of patients of the two centres which were found to have major GCP deficiencies [such as fake source documents, and falsified copies of source documents in order to allow inclusion of ineligible patients]occurred post randomisation and could potentially introduce bias to the analysis. There were no details supplied by the sponsor in the CSR or in the responses to EMA as to whether the exclusion occurred after unblinding. That the number of patients involved was small (0.70%, 46/6558) and that it was approximately evenly distributed between the 2 treatment groups, might mitigate any potential bias to a certain extent. In addition, in response to the query by EMA on this issue, the sponsor provided an analysis of the primary composite endpoint that included these 46 patients and it showed that the results were similar to the results of the analysis that excluded these 46 patients. 18, 19 Major protocol violations/deviations Protocol deviations were defined before study unblinding and were grouped into three categories: deviations that may affect primary efficacy criterion assessment, deviations that may affect safety assessment and other deviations that may affect study management. Overall, 312 patients had at least one protocol deviation at inclusion: 150 patients (4.6%) in the ivabradine group compared with 162 patients (5.0%) in the placebo group. Overall, 367 protocol deviations were observed before or at inclusion, with 214 deviations relating to observations which could have impacted the efficacy assessment, 134 deviations which could have impacted the safety assessment and 19 deviations which could have impacted the study management. The incidences of the protocol deviations were comparable 18 Response to EMA queries question no. 14. Analysis which included the 46 patients showed a relative risk reduction in favour of ivabradine of 18% (hazard ratio 0.82, 95% CI [075-090], p
Page 1 and 2: Australian Public Assessment Report
Page 3 and 4: Contents AusPAR Coralan Ivabradine
Page 5 and 6: Product background AusPAR Coralan I
Page 7 and 8: AusPAR Coralan Ivabradine Servier L
Page 15: AusPAR Coralan Ivabradine Servier L
Page 25 and 26: Table 6. Causes of deaths by treatm
Page 27 and 28: Analyses performed across trials (p
Page 31 and 32: Table 10. (ii) Pre-specified subgro
Page 37 and 38: Patient exposure AusPAR Coralan Iva
Page 39 and 40: Treatment-related adverse events (a
Page 41 and 42: Table 15. Continued AusPAR Coralan
Page 49 and 50: Clinical summary and conclusions Fi
Page 63 and 64: Table 25. Incidence of TEAEs by age
Page 65 and 66: Second round benefit-risk assessmen
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Safety specification AusPAR Coralan
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CL3-067 (Follow up Measure; Ophthal
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AusPAR Coralan Ivabradine Servier L
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Risk management plan AusPAR Coralan
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Table 35 AusPAR Coralan Ivabradine
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Therapeutic Goods Administration PO
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AusPAR: Ivabradine - Therapeutic Goods Administration

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