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
To determine this primary endpoint, “pre-specified events” (PSEs) were collected by
investigators in the Clinical Study Record Form (CRF). PSEs were defined as “death of any
cause” and “hospitalisation of any cause”. Details of the death or hospitalisation were to be
indicated in the CRF. An independent Endpoint Validation Committee (EVC), blinded to
treatment group and baseline heart rate, then adjudicated the clinical PSEs occurring in
the study population according to the definitions of the study endpoints described in the
EVC Charter. The EVC could confirm or reject an investigator-notified PSE. The EVC could
also adjudicate an endpoint differently from the PSE proposed and they could create new
endpoints. The results of these adjudications were used for the efficacy analyses. (Please
refer to Figure 2 below).
Figure 2. Description of the adjudicated endpoints
Secondary efficacy outcomes included
• non-composite endpoints on mortality: death from any cause, cardiovascular death,
and death from heart failure
• non-composite endpoints on hospitalisations: hospitalisation for any cause,
cardiovascular hospitalisation, and hospitalisation for worsening heart failure
• composite endpoint of the time to first event of cardiovascular death, hospitalisation
for worsening heart failure, or hospitalisation for non-fatal myocardial infarction
• changes from baseline in functional capacity (NYHA class), global assessment of heart
condition (Patient and Physician Global Assessment scores), and heart rates.
Comment: The TGA adopted EU guidelines on the clinical investigation of drugs for
treatment of cardiac failure 7 recommend that the primary endpoints of heart failure
treatment studies be improvement in symptoms, cardiovascular morbidity and allcause
mortality. This is based on the principle that main objectives are to
demonstrate improvement in cardiovascular morbidity and clinical symptoms and
no adverse effect on overall mortality. The study primary endpoint differs from the
recommended primary endpoint. Although the components of these recommended
endpoints were present in the secondary endpoints, the study was powered for the
primary endpoint. Whether the analysis of these components in the secondary
endpoints allowed adequate and robust demonstration of improvement in
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