The results from EVOLVE: Treatment with cinacalcet does not improve hard outcomes in dialysis patients.

The announcement by Amgen of the top-line results of EVOLVE today caught me by surprise - or maybe not. Still another RCT showing that should have worked based on observational data turns out to be negative.

EVOLVE (EValuation Of Cinacalcet HCl Therapy to Lower CardioVascular Events) is a Phase 3 trial, which evaluated cinacalcet (Sensipar) for the reduction of the risk of mortality and cardiovascular (CV) events among 3,883 patients with secondary hyperparathyroidism (HPT) and chronic kidney disease (CKD) receiving dialysis.

EVOLVE is a randomized, double-blind, placebo-controlled Phase 3 study of 3,883 patients from 22 countries with secondary HPT and CKD receiving dialysis. The trial was event driven. The PI is Dr. Glenn Chertow from Stanford. The trial was designed to determine if treatment with cinacalcet compared to placebo decreases the risk of all-cause mortality and CV morbidity. The trial consisted of a 30-day screening phase, a titration phase with visits every 2 weeks, and a follow-up phase with visits every 8 weeks. The cinacalcet dose in the treatment arm could be escalated sequentially from 30 to 180 mg/d. Following the screening phase, patients were randomized to the cinacalcet or placebo. A paper in CJASN in 2007 provides details on study design.

The key result of this study is that it was negative, i.e., was null for the primary composite primary events time to the composite event comprising all-cause mortality or first non-fatal cardiovascular event, including myocardial infarction, hospitalization for unstable angina, heart failure or peripheral vascular event.

The most frequently reported adverse events in the cinacalcet arm of the trial were nausea, vomiting and hypocalcemia.

The bottom-line is that treatment targeted at reducing PTH with cinacalcet does not result in improved hard endpoints such as death and cardiovascular complications. This study reinforces the importance of assessing hard endpoints in large well designed and adequately powered RCTs rather than relying on observational studies to determine the role of interventions.. and before spending billions of dollars.