AusPAR: Ivabradine - Therapeutic Goods Administration

AusPAR Coralan Ivabradine Servier Laboratories (Australia) Pty Ltd PM-2010-03269-3-3
Final 31 October 2012
Therapeutic Goods Administration
recommended beta blockers and is relevant in the selection of patient population
for which the extended indication may be applicable.
Sample size
The number of pre-specified events (PSEs) required and the sample size were estimated
based on the time to occurrence of the first event of cardiovascular death or
hospitalisation for worsening heart failure, in order to detect a true difference between
placebo and ivabradine groups using a two-sided log-rank test at a significance level of
5%. The sample size and follow-up durations were modified by protocol amendments
twice during the study to accommodate new data relating to the estimated expected rate
of clinical outcomes in this patient population.
The original protocol estimated that a sample size of 5500 patients with 1220 PSEs was
required for the detection of a 17% relative risk reduction of the primary composite
endpoint, assuming 90% power and a significance level of 5%. This estimation assumed an
annual incidence rate of the primary composite endpoint in the placebo group of 14%, and
an incidence of non-cardiovascular death of 1% in both groups. The mean follow-up
duration was expected to be 2 years.
A protocol amendment increased the calculated sample size to 7000 patients and
proposed to continue the study until at least 1600 PSEs had occurred. This increased
powering of the study was based on an anticipated smaller relative risk reduction of the
primary composite endpoint of 15%, following the BEAUTIFUL study14 results which
suggested a possible lower effect of ivabradine on heart failure endpoints than previously
expected.
A later amendment was made in view of the number of primary composite endpoints
already observed up until that time. As this was an event-driven trial, the amendment
proposed that recruitment could be stopped when approximately 6500 patients had been
randomised. This would allow the detection of a 15% relative risk reduction of the
primary composite endpoint (90% power and 1600 PSEs), with an expected mean followup
of 2.25 years.
For the subset analysis in the RSBBdose population, it was anticipated that approximately
47% of the overall population would be treated with at least half of the target daily dose of
beta blocker at randomisation and that there should be a minimum of 3000 patients in
that group. This was expected to result in at least 633 events, allowing the detection of a
relative risk reduction of 20% in favour of ivabradine, with an 80% power, when assuming
an annual incidence rate of the primary composite endpoint of 14% in placebo group and
an incidence of non-cardiovascular death of 1% at 2.25 years.
Comment: As the sample size adjustment was based on the results of an external
trial and treatment blinding was preserved, it was congruent with the TGA adopted
ICH E9 guidelines 15 which allowed for sample size adjustments when there are
changes to the assumptions which underlay the original design and sample size
calculations. As the increase in sample size was based on the results of an external
trial, it is not anticipated to affect the Type I error rate.
Statistical methods
For the primary composite endpoint, the superiority of ivabradine over placebo was
tested using a Cox proportional hazards model, adjusted for beta blocker intake at
14 Fox K, et al. Ivabradine for patients with stable coronary artery disease and left-ventricular systolic
dysfunction (BEAUTIFUL): a randomised, double-blind, placebo-controlled trial. Lancet 372:807–816,
2008.
15 TGA-adopted ICH Topic E9: Note for Guidance on Statistical Principles for Clinical Trials. September
1998.
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