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 guarantee for the accuracy and reliability of the data of the 46 patients from these centres. The closure of the centres has thus been decided.” The clinical study reviewed in this evaluation was otherwise in compliance with GCP guidelines. Pharmacokinetics No new PK data was provided in this submission. Pharmacodynamics No new PD data was provided in this submission. Efficacy Dosage selection for the pivotal studies The sponsor has stated that the starting dose of ivabradine in the pivotal SHIFT study was based on the recommended starting dose for ivabradine in patients with chronic stable angina (currently approved indication). The dose titration according to heart rate and symptoms of bradycardia was also based on the dosing guidelines for use of ivabradine in patients with chronic stable angina. Proposed new indication for use in patients with symptomatic chronic heart failure Pivotal SHIFT study Study design, objectives, locations and dates The SHIFT study was a randomised, double blind, placebo controlled, multi centre morbidity-mortality study, evaluating the effects of ivabradine on cardiovascular events in patients with symptomatic CHF and left ventricular systolic dysfunction. The primary objective was to demonstrate the superiority of ivabradine over placebo in the reduction of cardiovascular mortality or hospitalisation for worsening heart failure (primary composite endpoint), in patients with symptomatic CHF and a reduced left ventricular ejection fraction (LVEF) and who were concurrently receiving optimal recommended therapy for CHF. The secondary objectives were to assess the effects of ivabradine compared to placebo on the primary composite endpoint in patients receiving at least half of the optimal daily dose of beta blockers at randomisation, on mortality endpoints (all-cause mortality, cardiovascular mortality, and mortality from heart failure), on morbidity endpoints (all-cause hospitalisation, cardiovascular hospitalisation and hospitalisation for worsening heart failure) and on functional capacity and clinical symptoms of heart failure. The study was conducted at 625 centres in 37 countries, the majority of the centres being in Europe. The study started on 26 September 2006 (first visit, first patient) and was completed on 19 April 2010 (last visit, last patient). The study design had two parallel and balanced treatment arms. Randomisation was stratified on beta blocker intake (yes/no) at time of randomisation and on centre. The study was event driven and designed to terminate after at least 1600 primary composite endpoints had occurred. The study was divided into two periods: a run-in period of two weeks (from selection visit [ASSE] to inclusion visit [D000]) to confirm the eligibility of Page 8 of 101
AusPAR Coralan Ivabradine Servier Laboratories (Australia) Pty Ltd PM-2010-03269-3-3 Final 31 October 2012 Therapeutic Goods Administration patients and their clinical stability, and during which no study treatment was dispensed, and a post randomisation period which included a titration period and a follow-up period. The titration period had scheduled visits at 2 weeks (D014) and 4 weeks (D028). The follow-up period had a first visit at 4 months (M004) and then every 4 months thereafter until the end-of-study visit. Figure 1. Treatment periods. Ivabradine ASSE: selection visit. D000: inclusion visit Inclusion and exclusion criteria The main inclusion criteria were male or female adult patients (≥ 18 years of age) with symptomatic CHF 4, (with NYHA Class II, III or IV 5) for at least 4 weeks prior to the selection visit, in stable clinical condition, with optimal and unchanged CHF medications and dosages for ≥ 4 weeks prior to the selection visit, and with documented hospital admission for worsening heart failure within 12 months before the selection visit. Patients also needed electrocardiographic (ECG) documentation of sinus rhythm with resting heart rate (HR) ≥ 70 beats per minute (bpm) at study selection visit. In addition, at Visit D000 (inclusion visit at the end of the 2-week run-in period), patients had to have a documented sinus rhythm and HR ≥ 70 bpm on a recent (within 24 hours) resting standard 12-lead ECG and had documented left ventricular ejection fraction (LVEF) ≤ 35% within 3 months before Visit D000. Main exclusion criteria were patients with recent (less than 2 months prior to selection visit) myocardial infarction or coronary revascularisation, had scheduled coronary 4 All aetiologies of CHF were included, except congenital heart disease, severe aortic or mitral stenosis, severe aortic regurgitation, or severe primary mitral regurgitation 5 New York Heart Association functional classification of heart failure. NYHA Class I: No symptoms and no limitation in ordinary physical activity. NYHA Class II: Mild symptoms (mild shortness of breath and/or angina) and slight limitation during ordinary activity. NYHA Class III: Marked limitation in activity due to symptoms, even during less-than-ordinary activity, e.g. walking short distances (20–100 m). Comfortable only at rest. NYHA Class IV: Severe limitations. Experiences symptoms even while at rest. Mostly bedbound patients. Page 9 of 101
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: AusPAR Coralan Ivabradine Servier L
Page 11 and 12: AusPAR Coralan Ivabradine Servier L
Page 17 and 18: Table 1. Analysis Sets and Subsets
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
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AusPAR Coralan Ivabradine Servier L
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Table 25. Incidence of TEAEs by age
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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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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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