Aernoud Fiolet

104 Chapter 4 Tertiary outcomes: (1) New onset or first recurrence of symptomatic or asymptomatic atrial fibrillation or atrial flutter. (2) Newonset of diabetes: Initiation of medication for the treatment of glucose control or fasting glucose ≥126 mg/dl (≥7 mmol/L) or Hb1Ac ≥6.5% or 2 hour post oral glucose tolerance test value of 11.1 mmol/L (WHO criteria). (3) Venous thrombo-embolism including new deep- vein thrombosis and/or pulmonary embolism as evidenced by imaging. Adjudication of outcomes All potential primary and secondary events are assessed by members of an independentAdjudication Committee comprised of 6members (3 each inAustralia and the Netherlands) with expertise in cardiology and neurology. In addition, all cases of suspected myotoxicity are reviewed by an independent expert adjudicator. Data and safety monitoring The Data and Safety Monitoring Board (DSMB) is comprised of 5 independent members with expertise in trial methodology, CV disease and biostatistics. Per protocol the trial will continue until all participants have been followed for at least 12months and the required number of 331 primary events has been accrued unless the Steering Committee is advised otherwise by the DSMB. The full mandate of the DSMB is described in a separate charter. Statistical considerations The sample size determination for the study was event-driven, i.e. based on a requirement for the number of patients reaching the primary efficacy endpoint. Design assumptions included a 10% drop-out rate after the open label run-in phase, a per annum rate for the composite primary endpoint in the control group of 2.6% and a hazard ratio of 0.70. It was estimated that the occurrence of at least 331 composite primary endpoints would provide the trial with 90% power to statistically detect the expected treatment benefit at a two-sided significance level of 0.05. Based on these assumptions the sample size was set at 5447 randomized participants. In accordance with the intent-to-treat principle outlined in the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for human use — the ICH Harmonized Tripartite Guideline Statistical Principles for Clinical Trials E9, the primary analyses for efficacy will be based on time to first event for the primary composite end-point in all randomized patients who took at least 1 tablet of their assigned trial medication using events