Safety and Tolerability Study of Cycloset in Treatment of Type 2 Diabetes
Cycloset, a new quick-release oral formulation of bromocriptine mesylate, effectively reduces blood sugar by the proposed mechanism of reversing many of the metabolic alterations associated with insulin resistance and obesity by resetting central (hypothalamic) circadian organization of monoamine neuronal activities.
The primary analysis of this study will test the hypothesis that the rate of all-cause severe adverse events for those receiving usual drug therapy for diabetes management plus Cycloset is not greater than that for usual drug therapy plus placebo by more than an acceptable margin. While the primary purpose of this study is to establish the safety profile of Cycloset in type 2 diabetes, any potential positive cardiovascular benefits will be evaluated as well.
Type 2 Diabetes Mellitus
Drug: Usual Diabetes Therapy plus placebo
|Study Design:||Allocation: Randomized
Endpoint Classification: Safety Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
|Official Title:||A Randomized, Double-Blind, Placebo-Controlled Trial to Assess Safety and Tolerability During Treatment of Type 2 Diabetes (T2DM) With Usual Diabetes Therapy (UDT) and Either Cycloset or Placebo|
- Subjects Experiencing Serious Adverse Events [ Time Frame: From baseline to week 52. ] [ Designated as safety issue: Yes ]Number of subjects reporting all-cause Serious Adverse Events (SAEs) for usual drug therapy plus Cycloset vs. that for usual drug therapy (UDT) plus placebo from baseline to week 52.
- Number of Subjects Experiencing Serious Cardiovascular Adverse Events [ Time Frame: Baseline to week 52. ] [ Designated as safety issue: Yes ]The secondary safety endpoint is number subjects with occurrences of first cardiovascular SAE (myocardial infarction, stroke, in-patient hospitalization for heart failure, angina or revascularization surgery).
- Change in HbA1c From Baseline to Week 24 in Subjects Failing Treatment With Metformin Plus a Sulfonylurea [ Time Frame: Baseline to week 24 ] [ Designated as safety issue: No ]
Change in HbA1c from baseline to week 24 in subjects failing treatment with metformin plus a sulfonylurea with failure defined as having a baseline HbA1c value of ≥ 7.5%. Change was measured at week 24 after randomization in subjects having no major protocol violations.
Change is reported as the absolute difference in % HbA1c.
- Change in HbA1c From Baseline to Week 24 for Subjects With a Baseline HbA1c of ≥ 7.5% Who Were Taking at Least One Oral Hypoglycemia Agent (OHA) at Baseline. [ Time Frame: Baseline to week 24 ] [ Designated as safety issue: No ]The difference between Cycloset and placebo in the change in HbA1c from baseline to Week 24 was analyzed for subjects with a baseline HbA1c of ≥ 7.5% who were taking at least one oral hypoglycemia agent (OHA) at baseline. The primary analysis was based on subjects from the evaluable per protocol efficacy (EPPE) analysis set with a secondary analysis using subjects from the intent to treat efficacy (ITTE) analysis set for subjects completing 24 weeks of treatment. Change is reported as the absolute difference in % HbA1c.
|Study Start Date:||July 2004|
|Study Completion Date:||January 2007|
|Primary Completion Date:||January 2007 (Final data collection date for primary outcome measure)|
Experimental: Usual Diabetes Therapy plus placebo
Usual diabetes therapy plus placebo
Drug: Usual Diabetes Therapy plus placebo
Placebo tablet taken orally once in the morning, beginning with one tablet daily, titrated up by 1 tablet each week to a maximum of 6 tablets daily
Other Name: placebo
|Experimental: Drug Cycloset||
Usual diabetes therapy plus Cycloset
Other Name: bromocriptine mesylate
Bromocriptine mesylate, an ergot derivative, is a sympatholytic dopamine D2 receptor agonist that can exert inhibitory effects on serotonin turnover in the central nervous system. It has been proposed that bromocriptine can reverse many of the metabolic alterations associated with insulin resistance and obesity by resetting central (hypothalamic) circadian organization of monoamine neuronal activities.
While Cycloset has demonstrated efficacy by reducing HbA1c, fasting and post-prandial glucose and fasting and post-prandial triglycerides, the relatively small numbers of individuals treated for type 2 diabetes during the controlled Phase III clinical trials of Cycloset did not allow for a full evaluation of the safety profile. Since persons with diabetes are already at higher risk for cardiovascular disease, it is important to examine more fully the spectrum of potential adverse or positive effects from Cycloset in a large sample of persons with diabetes. Accordingly, the present study is designed to investigate the clinical safety of treatment with Cycloset in a broad population of persons with type 2 diabetes.
To determine in subjects with type 2 diabetes mellitus receiving Usual Diabetes Therapy (UDT) consisting of either diet, oral hypoglycemic agents (OHA) (no more than 2), or insulin (with or without no more than 1 OHA) plus either Placebo or Cycloset:
- Whether add-on therapy with Cycloset results in all-cause rate of serious adverse events, which are not higher than add-on therapy with Placebo.
Whether add-on therapy with Cycloset results in disease-specific rate of serious cardiovascular adverse events, which are not higher than add-on therapy with Placebo.
While the primary purpose of this study is to establish the safety profile of Cycloset in type 2 diabetes, any potential positive cardiovascular benefits will be evaluated as well.
Other clinical measures:
- The impact (either positive or negative) of Cycloset on HbA1c, fasting plasma glucose, weight, triglycerides lipids, blood pressure and patient tolerability after 12 months of therapy.
Furthermore, Hba1c changes from baseline to 24 weeks between Cycloset and Placebo among subjects with a baseline Hba1c of >= 7.5% among the following subgroups:
A. Treated at baseline with any Oral hypoglycemic agent (OHA) including injectable insulin secretagogues B. Metformin plus or minus one OHA or injectable insulin secretagogue C. Sulphonylurea plus or minus one OHA or injectable insulin secretagogue D. Treated at baseline with Metformin and one sulphonylurea