Long-term safety and efficacy of anacetrapib in patients with atherosclerotic vascular disease.

AIMS: REVEAL was the first randomized controlled trial to demonstrate that adding cholesteryl ester transfer protein inhibitor therapy to intensive statin therapy reduced the risk of major coronary events. We now report results from extended follow-up beyond the scheduled study treatment period. METHODS AND RESULTS: A total of 30 449 adults with prior atherosclerotic vascular disease were randomly allocated to anacetrapib 100 mg daily or matching placebo, in addition to open-label atorvastatin therapy. After stopping the randomly allocated treatment, 26 129 survivors entered a post-trial follow-up period, blind to their original treatment allocation. The primary outcome was first post-randomization major coronary event (i.e. coronary death, myocardial infarction, or coronary revascularization) during the in-trial and post-trial treatment periods, with analysis by intention-to-treat. Allocation to anacetrapib conferred a 9% [95% confidence interval (CI) 3-15%; P = 0.004] proportional reduction in the incidence of major coronary events during the study treatment period (median 4.1 years). During extended follow-up (median 2.2 years), there was a further 20% (95% CI 10-29%; P < 0.001) reduction. Overall, there was a 12% (95% CI 7-17%, P < 0.001) proportional reduction in major coronary events during the overall follow-up period (median 6.3 years), corresponding to a 1.8% (95% CI 1.0-2.6%) absolute reduction. There were no significant effects on non-vascular mortality, site-specific cancer, or other serious adverse events. Morbidity follow-up was obtained for 25 784 (99%) participants. CONCLUSION: The beneficial effects of anacetrapib on major coronary events increased with longer follow-up, and no adverse effects emerged on non-vascular mortality or morbidity. These findings illustrate the importance of sufficiently long treatment and follow-up duration in randomized trials of lipid-modifying agents to assess their full benefits and potential harms. TRIAL REGISTRATION: International Standard Randomized Controlled Trial Number (ISRCTN) 48678192; ClinicalTrials.gov No. NCT01252953; EudraCT No. 2010-023467-18.

Randomized Evaluation of the Effects of Anacetrapib through Lipid-modification (REVEAL)-A large-scale, randomized, placebo-controlled trial of the clinical effects of anacetrapib among people with established vascular disease: Trial design, recruitment, and baseline characteristics.

Patients with prior vascular disease remain at high risk for cardiovascular events despite intensive statin-based treatment. Inhibition of cholesteryl ester transfer protein by anacetrapib reduces low-density lipoprotein (LDL) cholesterol by around 25% to 40% and more than doubles high-density lipoprotein (HDL) cholesterol. However, it is not known if these apparently favorable lipid changes translate into reductions in cardiovascular events. METHODS: The REVEAL study is a randomized, double-blind, placebo-controlled clinical trial that is assessing the efficacy and safety of adding anacetrapib to effective LDL-lowering treatment with atorvastatin for an average of at least 4years among patients with preexisting atherosclerotic vascular disease. The primary assessment is an intention-to-treat comparison among all randomized participants of the effects of allocation to anacetrapib on major coronary events (defined as the occurrence of coronary death, myocardial infarction, or coronary revascularization). RESULTS: Between August 2011 and October 2013, 30,449 individuals in Europe, North America, and China were randomized to receive anacetrapib 100mg daily or matching placebo. Mean (SD) age was 67 (8) years, 84% were male, 88% had a history of coronary heart disease, 22% had cerebrovascular disease, and 37% had diabetes mellitus. At the randomization visit (after at least 8weeks on a protocol-defined atorvastatin regimen), mean plasma LDL cholesterol was 61 (15) mg/dL and HDL cholesterol was 40 (10) mg/dL. INTERPRETATION: The REVEAL trial will provide a robust evaluation of the clinical efficacy and safety of adding anacetrapib to an effective statin regimen. Results are anticipated in 2017.

Designing a seamless phase II/III clinical trial using early outcomes for treatment selection: an application in multiple sclerosis.

In recent years adaptive seamless phase II/III designs (ASDs) allowing treatment or dose selection at an interim analysis have gained much attention because of their potential to save development costs and to shorten time-to-market of a new compound compared to conventional drug development programmes with separate trials for individual phases. In this paper, we describe an ASD with treatment selection based on early outcome data, specifically considering the situation where no final outcomes are observed at the time of the interim analysis. Bringing together combination tests for adaptive designs and the closure principle for multiple testing, control of the familywise type I error rate in the strong sense is achieved. Furthermore, a simulation model is proposed based on standardized test statistics that allows the generation of virtual trials for a variety of outcomes. We use this simulation model to investigate the actual type I error rate of the proposed testing procedure and find that the familywise type I error rate is controlled as expected. The method is often conservative, with the degree of conservatism depending on the correlation between early and late outcome, the true mean values of the early outcome in the different treatment groups and the selection rule. The investigations are motivated and illustrated by an application of the proposed design and simulation model to progressive multiple sclerosis.