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 Table 9. Estimates of treatment effect on causes of hospitalisation in the RS-BB-dose Subgroup analysis of the secondary endpoints in the RSBBdose population showed that for the endpoint of all-cause mortality there was no or negligible effect in favour of ivabradine in all the pre-specified subgroups except for the subgroups of “females”, “ischaemic cause”, “NYHA Class II”, “no hypertension” and “baseline HR ≥ 77 bpm”. No analysis for statistical significance was presented. All the interaction tests had p-values higher than 0.05. For the endpoint of cardiovascular death, results were similar, showing no or negligible effect in favour of ivabradine in all the pre specified subgroups except for the subgroups of “females”, “ischaemic cause”, “NYHA Class II”, “no hypertension” and “baseline HR ≥ 77 bpm”, and in addition also in the subgroups of “age ≥65 years”, and “no DM”. No analysis for statistical significance was presented. For the endpoint of hospitalisation for worsening heart failure, subgroups analysis showed an effect in favour of ivabradine in all the pre specified subgroups except the subgroup of “age ≥ 65 years”. Analyses of the secondary endpoints relating to effects on symptoms in the RS population showed that with regards to changes in NYHA class, 27.6% (887/ 3216) of patients in the ivabradine group improved by ≥ 1 NYHA class relative to baseline, compared with 24% (776/ 3234) of patients in the placebo group (p = 0.001). Patientreported Global Assessment improved in 72% of patients in the ivabradine group, compared with 68% in the placebo group (p = 0.0005). The Physician-reported Global Assessment improved in 61% of patients in the ivabradine group compared with 57% in the placebo group (p = 0.0011). With regards to effect on heart rate changes, results showed that overall in the RS population between baseline and Day 28, the mean (± SD) change in HR was -15.4 (± 10.7) bpm in the ivabradine group compared with -4.6 (± 10.6) bpm in the placebo group, giving a difference in the change in heart rate between the ivabradine and placebo groups of - 10.9 (95% CI [-11.4, -10.4]) bpm after 28 days of dosing. This difference was found to be statistically significant. This difference was maintained throughout the study. At the last post randomisation visit, the difference in the change in heart rate between the ivabradine and placebo groups was - 8.1 (95% CI [-8.7, -7.5]) bpm (a mean [± SD] change in HR of - 12.0 [± 13.3] bpm and -4.1 [± 12.9] bpm in the ivabradine and placebo groups respectively). Similar results were observed in the RSBBdose population. Analysis of HR changes in the subgroup “age ≥ 75 years” gave similar results. The mean (±SD) change in HR from baseline to Day 28 was -14.6 (± 10.0) bpm in the ivabradine group and -4.8 (± 10.2) bpm in the placebo group, respectively, giving a statistically significant between-group difference of -10.2 bpm (95% CI [-11.6, -8.8]). At the last post randomisation visit, the mean (± SD) change in HR from baseline was -9.6 ± 13.3 bpm in the ivabradine group and -3.5 ± 12.5 bpm in the placebo group, giving a statistically significant between-group difference of –6.7 bpm (95% CI [-8.4, -4.9]). Other efficacy studies Not applicable. Page 26 of 101
Analyses performed across trials (pooled analyses and meta-analyses) Not applicable. AusPAR Coralan Ivabradine Servier Laboratories (Australia) Pty Ltd PM-2010-03269-3-3 Final 31 October 2012 Therapeutic Goods Administration Evaluator’s summary and conclusions on clinical efficacy for the proposed new indication (for use in patients with symptomatic chronic heart failure) Overall, the study design and study inclusion and exclusion criteria were appropriate and consistent with the TGA adopted EU guidelines on the clinical investigation of drugs for treatment of cardiac failure 7, and aimed to recruit a study population of adult patients with chronic heart failure, with NYHA Class II to IV, on stable and optimal CHF medications, with reduced LVEF of ≤ 35% and who were in sinus rhythm with a resting HR of ≥ 70 bpm. No rationale was given for the choice of a baseline HR criterion of ≥ 70 bpm. The starting dose and the dose titration of the study drug, based on the recommended starting dose and dose titration guidelines for use of ivabradine in patients with chronic stable angina (currently approved indication), were appropriate. The target dose of 7.5 mg b.d was based on the result of a clinical study on ivabradine which showed that this dose would decrease resting HR by approximately 10 bpm. The study primary endpoint (composite endpoint of time to first event of cardiovascular death or hospitalisation for worsening heart failure) differs from the primary endpoints recommended by the EMA guidelines on the clinical investigation of drugs for treatment of cardiac failure (improvement in symptoms, cardiovascular morbidity and all-cause mortality), although the recommended primary endpoints were present in the study secondary endpoints. The main flaw in the study design was the maintenance of study treatment blinding, given that ivabradine but not placebo would lead to a reduction in heart rate. Study investigators and patients would be able to differentiate between ivabradine and placebo based on the presence or absence of reduction in heart rate. The Endpoint Validation Committee which adjudicated the primary and secondary endpoints relating to hospitalisations and deaths was blinded to both the treatment group and baseline heart rate. This would maintain the blind for these endpoints. However, the endpoints relating to clinical symptoms (change in NYHA class and global assessment of heart condition) and the safety endpoints of adverse events reporting could have been affected. Overall, in the RS analysis population baseline demographic characteristics, baseline disease characteristics, and main background treatments for heart failure were comparable between the 2 treatment groups and generally comparable with the CHF patient profile in clinical practice in terms of the aetiology of CHF and background treatment regimen. However, the overall mean age (± SD) of the study population was relatively young at 60.4 (± 11.4) years. Only 38.0% were ≥ 65 years of age, 23.1% (1500/ 6505) were ≥ 70 years of age and 11.1% were ≥ 75 years of age. As a majority (62%) of the study population was < 65 years of age, this raises the question of whether the study efficacy results could be extrapolated to the CHF patient population in clinical practice. The majority of the patients in the study were in NYHA Classes II (48.7%) and III (49.5%), and only 1.7% (n=111) were in NYHA Class IV. Although this is consistent with the incidence of the different NYHA Classes of patients in clinical practice, it may affect the ability of the study results to be extrapolated to the sub-population of patients in NYHA Class IV. Efficacy analysis results showed that in the RS population there was an 18% relative risk reduction in the incidence of the primary composite endpoint of cardiovascular death or hospitalisation for worsening heart failure in the ivabradine group compared to the placebo group and this reduction was found to be statistically significant at 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 17 and 18: Table 1. Analysis Sets and Subsets
Page 25: Table 6. Causes of deaths by treatm
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
Page 67 and 68: Safety specification AusPAR Coralan
Page 69 and 70: 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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