Safety and Tolerability Study of Cycloset in Treatment of Type 2 Diabetes

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

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.

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:

1. 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.

2. 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:

3. 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

Inclusion Criteria:

• Type 2 diabetes
• age 30-80 years
• body mass index < 43 kg/m2
• HbA1c ≤ 10% for at least 12 weeks prior to screening
• stable diabetes therapeutic regimen consisting of either diet, oral hypoglycemic agents (no more than 2), or insulin (with or without no more than 1 oral hypoglycemic agent) for 4 weeks prior to randomization

Exclusion Criteria:

• Subject who had taken prescription sympathomimetic drugs within seven (7) days prior to the first screening visit. Prescription sympathomimetic drugs were not allowed for any period greater than ten (10) consecutive days during the course of the study. Other ergot alkaloid derivatives or anti-migraine medications such as zolmitriptan (Zomig) and sumatriptan (Imitrex) were not permitted during the study.

• Subject who had a history of alcoholism or drug abuse in the three (3) years prior to the first screening visit.

• Subject who had a known hypersensitivity to any of the formulation components of the study drug.

• Subject who had received any experimental drug or used an experimental device in the 30 days prior to the first screening visit or would do so during the study.

• Subject who was pregnant or lactating women or women planning to become pregnant during the study. Women of childbearing potential had to have a negative pregnancy test at screening. Women who became pregnant were discontinued from the study.

• Subject who had given donations of blood during the 30 days prior to the screening visit. Donation of blood also was prohibited during the study and for 30 days after completion of the study.

• Subjects with clinically significant major organ system disease, such as

  • seizure disorder
  • significant gastroparesis or orthostatic hypotension (autonomic neuropathy)
  • cerebrovascular accident in the previous 6 months
  • uncontrolled hypertension (systolic BP >160 or diastolic BP > 100 at screening)
  • coronary artery bypass graft or coronary angioplasty in the previous 3 months, myocardial infarction in the previous 6 months, or unstable angina pectoris (chest pain at rest, worsening chest pain, or admission to the ER or hospital for chest pain) within the previous 3 months
  • congestive heart failure defined by NYHA as Class III or IV
  • clinical nephrotic syndrome, or renal impairment with a serum creatinine > 1.4 mg/dl if female receiving treatment with metformin, > 1.5 mg/dl if male receiving treatment with metformin, and > 1.6 mg/dl in not on metformin
  • impaired liver function, including having AST or ALT greater than three times the upper limit of normal
  • active infection (e.g., HIV, hepatitis), or a history of severe infection during the 30 days prior to screening
  • major surgical operation during the 30 days prior to screening
  • cancer, other than non-melanoma skin or non metastatic prostate cancer within the past 5 years
  • Any concurrent illness, other than diabetes mellitus, not controlled by a stable therapeutic regimen

• Working rotating, varying or night shifts

• Patients taking unapproved herbal supplements that may be associated with a risk of cardiovascular events (such as ephedra, yohimbe etc)

• Patients who had started therapy with an erectile dysfunction drug within 2 weeks prior to screening; patients could not begin treatment with an erectile dysfunction drug during the study period; patients previously taking erectile dysfunction drugs could do so only under medical supervision.

• Subjects with circumstances or abnormalities (e.g., blindness or a history of non-compliance) that would interfere with the interpretation of safety or efficacy data or completion of the study.

• Clinically significant abnormalities (values outside the normal range) on screening central laboratory evaluation unless discussed with and approved by the study principal investigator or Sponsor medical monitor.