A randomized, double-blind, placebo-controlled trial to assess safety and tolerability during treatment of type 2 diabetes with usual diabetes therapy and either Cycloset™ or placebo

Background: Cycloset™ is a quick-release formulation of bromocriptine mesylate, a dopamine agonist, which in animal models of insulin resistance and type 2 diabetes acts centrally to reduce resistance to insulin- mediated suppression of hepatic glucose output and tissue glucose disposal. In such animals, bromocriptine also reduces hepatic triglyceride synthesis and free fatty acid mobilization, manifesting decreases in both plasma triglycerides and free fatty acids. In clinical trials, morning administration of Cycloset™ either as monotherapy or adjunctive therapy to sulfonylurea or insulin reduces HbA1c levels relative to placebo by 0.55–1.2. Cycloset™ therapy also reduces plasma triglycerides and free fatty acid by approximately 25% and 20%, respectively, among those also receiving sulfonylurea therapies. The effects of once-daily morning Cycloset™ therapy on glycemic control and plasma lipids are demonstrable throughout the diurnal portion of the day (7 a.m. to 7 p.m.) across postprandial time points. Methods/Design: 3,095 individuals were randomized in a 2:1 ratio into a one year trial aimed to assess the safety and efficacy of Cycloset™ compared to placebo among individuals receiving a variety of treatments for type 2 diabetes. Eligibility criteria for this randomized placebo controlled trial included: age 30–80, HbA1c ≤ 10%, diabetes therapeutic regimen consisting of diet or no more than two hypoglycemic agents or insulin with or without one additional oral agent (usual diabetes therapy; UDT). The primary safety endpoint will test the hypothesis that the rate of all-cause serious adverse events after one year of usual diabetes therapy (UDT) plus Cycloset™ is not greater than that for UDT plus placebo by more than an acceptable margin defined as a hazard ratio of 1.5 with a secondary endpoint analysis of the difference in the rate of serious cardiovascular events, (myocardial infarction, stroke, coronary revascularization or hospitalization for or angina or congestive heart failure). Efficacy analyses will evaluate effects of Cycloset™ versus placebo on change from baseline in HbA1c, fasting glucose, body weight, waist circumference, blood pressure and plasma lipids. Discussion: This study will extend the current data on Cycloset™ safety, tolerability and efficacy in individuals with type 2 diabetes to include its effects in combination with thiazolodinediones, insulin secretagogues, metformin, alpha-glucosidase inhibitors and exogenous insulin regimens. Trial registration: clinical trials.gov NCT0037767