Type 2 Diabetes Mellitus
Conditions
Keywords
diabetes, diabetes mellitus
Brief summary
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.
Detailed description
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
Interventions
DRUGCycloset
Usual diabetes therapy plus Cycloset
DRUGUsual 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
Sponsors
VeroScience
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
30 Years to 80 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Subjects Experiencing Serious Adverse Events | From baseline to week 52. | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects Experiencing Serious Cardiovascular Adverse Events | Baseline to week 52. | 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 | Baseline to week 24 | 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. | Baseline to week 24 | 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. |
Participant flow
Recruitment details
Patients were recruited from 74 centers across the United States and Puerto Rico, including 19 Veterans Affairs (VA) hospitals. First patient enrolled: 23 August 2004 Last patient completed: 25 January 2007
Pre-assignment details
4,074 subjects were screened, 3,095 randomized 2:1 to Cycloset or placebo. 3,095 were analyzed for safety and 3,070 for all other analyses.The most common reason given for screen failure due to protocol ineligibility was an elevated creatinine (24.7% of all screen failures).
Participants by arm
| Arm | Count |
|---|---|
| Cycloset During the first week of the dose titration period, subjects were instructed to take 1 tablet of study drug daily (0.8 mg Cycloset). If the dose was tolerated, subjects were to have their dose of study drug increased to 2 tablets of study drug per day. The daily dose of study drug was to be increased at a rate of 1 tablet per week, up to a target dose level of 6 tablets per day at Week 6. | 2,054 |
| Placebo During the first week of the dose titration period, subjects were instructed to take 1 tablet of study drug daily (1 placebo tablet). If the dose was tolerated, subjects were to have their dose of study drug increased to 2 tablets of study drug per day. The daily dose of study drug was to be increased at a rate of 1 tablet per week, up to a target dose level of 6 tablets per day at Week 6. | 1,016 |
| Total | 3,070 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 498 | 107 |
| Overall Study | Death | 5 | 2 |
| Overall Study | Lost to Follow-up | 120 | 56 |
| Overall Study | Other | 118 | 58 |
| Overall Study | Protocol Violation | 33 | 27 |
| Overall Study | Withdrawal by Subject | 187 | 72 |
Baseline characteristics
| Characteristic | Placebo | Cycloset | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 315 Participants | 601 Participants | 916 Participants |
| Age, Categorical Between 18 and 65 years | 701 Participants | 1453 Participants | 2154 Participants |
| Age, Continuous | 59.5 years STANDARD_DEVIATION 10 | 60.2 years STANDARD_DEVIATION 10 | 59.7 years STANDARD_DEVIATION 10 |
| Region of Enrollment United States | 1016 participants | 2054 participants | 3070 participants |
| Sex: Female, Male Female | 418 Participants | 913 Participants | 1331 Participants |
| Sex: Female, Male Male | 598 Participants | 1141 Participants | 1739 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 1,611 / 2,054 | 430 / 1,016 |
| serious Total, serious adverse events | 176 / 2,054 | 98 / 1,016 |
Outcome results
Primary
Subjects Experiencing Serious Adverse Events
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.
Time frame: From baseline to week 52.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cycloset | Subjects Experiencing Serious Adverse Events | 176 participants |
| Placebo | Subjects Experiencing Serious Adverse Events | 98 participants |
p-value: <0.05Regression, Cox
Secondary
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.
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.
Time frame: Baseline to week 24
Population: randomized subjects with a baseline HbA1c of \>= 7.5 taking one or two oral diabetes agents (not insulin)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Cycloset | 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. | -0.41 percent | Standard Deviation 0.9 |
| Placebo | 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. | 0.041 percent | Standard Deviation 1.2 |
p-value: <0.001ANOVA
Secondary
Change in HbA1c From Baseline to Week 24 in Subjects Failing Treatment With Metformin Plus a Sulfonylurea
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.
Time frame: Baseline to week 24
Population: subjects with baseline HbA1c of \>= 7.5 and taking both metformin/sulfonylurea but not insulin. Analysis was conducted for those completing 24 weeks of treatment and on the ITT using the LOCF for those not completing 24 weeks of treatment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Cycloset | Change in HbA1c From Baseline to Week 24 in Subjects Failing Treatment With Metformin Plus a Sulfonylurea | -0.49 percent | Standard Deviation 0.8 |
| Placebo | Change in HbA1c From Baseline to Week 24 in Subjects Failing Treatment With Metformin Plus a Sulfonylurea | -0.04 percent | Standard Deviation 1 |
Comparison: If the standard deviation of HbA1c level is about 1.0% and the baseline and 24 week scores have a correlation of 0.50 then the effect size is 0.5%/1.0% = 0.50. For the metformin/SU analysis, 160 subjects assuming a standard deviation of 1.0% would provide a power of 90% power to detect differences in mean changes of 0.5% or larger.p-value: <0.001ANOVA
Secondary
Number of Subjects Experiencing Serious Cardiovascular Adverse Events
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).
Time frame: Baseline to week 52.
Population: intent to treat
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cycloset | Number of Subjects Experiencing Serious Cardiovascular Adverse Events | 31 Subjects |
| Placebo | Number of Subjects Experiencing Serious Cardiovascular Adverse Events | 30 Subjects |
Comparison: In order to test the hypothesis for serious cardiovascular adverse events as for the primary endpoint at a one-sided alpha = 0.5 when the non-inferiority margin is 1.5, the final sample size of 3000 to 3300 subjects was to provide at least 62% power, assuming a hypothetical rate of events of 3.43%, or 103 to 113 cardiovascular SAEs. Upon demonstration of non-inferiority - a 2 sided using 95% CI was used to assess for superiority.p-value: <0.0595% CI: [0.35, 0.96]Regression, Cox