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

• Sponsor: VeroScience (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00377676
• Collaborator: (none)
• Enrollment: 3,095
• Arms: 2
• Duration (Months): 30

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Type 2 Diabetes Mellitus	Drug: Cycloset; Drug: Usual Diabetes Therapy plus placebo	Phase 3

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:

1. 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:

1. 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

Study Design

• Study Type: Interventional
• Actual Enrollment: 3095 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, 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
• Study Start Date: Jul 1, 2004
• Actual Primary Completion Date: Jan 1, 2007
• Actual Study Completion Date: Jan 1, 2007

Arms and Interventions

Arm	Intervention/Treatment
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 Names: placebo
Experimental: Drug Cycloset	Drug: Cycloset; Usual diabetes therapy plus Cycloset; Other Names: bromocriptine mesylate

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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).

2. 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.

3. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 30 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts 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.

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• VeroScience

Investigators

• Principal Investigator: Michael Gaziano, MAVERIC
• Principal Investigator: Richard E Scranton, MD MPH, VeroScience

Study Documents (Full-Text)

None provided.

More Information

Publications

• Scranton RE, Gaziano JM, Rutty D, Ezrokhi M, Cincotta A. 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. BMC Endocr Disord. 2007 Jun 25;7:3.

• Responsible Party: VeroScience
• ClinicalTrials.gov Identifier: NCT00377676
• Other Study ID Numbers: 165-AD-04-03-US-1
• First Posted: Sep 18, 2006
• Last Update Posted: Jun 10, 2016
• Last Verified: May 1, 2016

• Keywords provided by VeroScience: diabetes; diabetes mellitus
• Additional relevant MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2; Bromocriptine

Study Results

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 Detail	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).

Arm/Group Title	Cycloset	Placebo
Arm/Group Description	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.	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.
Period Title: Overall Study
STARTED	2054	1016
COMPLETED	1093	694
NOT COMPLETED	961	322

Baseline Characteristics

Arm/Group Title	Cycloset	Placebo	Total
Arm/Group Description	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.	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.	Total of all reporting groups
Overall Participants	2054	1016	3070
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	1453 70.7%	701 69%	2154 70.2%
>=65 years	601 29.3%	315 31%	916 29.8%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	60.2 (10)	59.5 (10)	59.7 (10)
Sex: Female, Male (Count of Participants)
Female	913 44.4%	418 41.1%	1331 43.4%
Male	1141 55.6%	598 58.9%	1739 56.6%
Region of Enrollment (participants) [Number]
United States	2054 100%	1016 100%	3070 100%

Outcome Measures

1. Primary Outcome

Title	Subjects Experiencing Serious Adverse Events
Description	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.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cycloset	Placebo
Arm/Group Description	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.	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.
Measure Participants	2054	1016
Number [participants]	176 8.6%	98 9.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cycloset, Placebo
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	In order to test the primary hypothesis at a one-sided alpha = .05 and have a power of 0.9, when the non-inferiority margin is 1.5, the total number of subjects with all-cause SAEs that must be observed during the study was found to be 235. Assuming the placebo rate is 0.08, the required sample size was found to be 2991.
Statistical Test of Hypothesis	p-Value	<0.05
	Comments	Using the Lan and Demets alpha spending function for O'Brien-Fleming boundaries and the overall one-sided significance level of 5%, a level of 0.04068 was to be used at the interim analysis and 0.03938 at the time of the final analysis.
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.02
	Confidence Interval	(1-Sided) 95%; to 1.27
	Parameter Dispersion	Type: Value:
	Estimation Comments	cycloset to placebo

2. Secondary Outcome

Title	Number of Subjects Experiencing Serious Cardiovascular Adverse Events
Description	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.

Outcome Measure Data

Analysis Population Description

intent to treat

Arm/Group Title	Cycloset	Placebo
Arm/Group Description	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.	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.
Measure Participants	2054	1016
Number [Subjects]	31	30

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cycloset, Placebo
	Comments	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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.05
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	.58
	Confidence Interval	(2-Sided) 95%; .35 to .96
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Change in HbA1c From Baseline to Week 24 in Subjects Failing Treatment With Metformin Plus a Sulfonylurea
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Cycloset	Placebo
Arm/Group Description	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.	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.
Measure Participants	177	90
Least Squares Mean (Standard Deviation) [percent]	-0.49 (0.8)	-0.04 (1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cycloset
	Comments	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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.5
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Standard Deviation; Value: 1.4
	Estimation Comments

4. Secondary Outcome

Title	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.
Description	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

Outcome Measure Data

Analysis Population Description

randomized subjects with a baseline HbA1c of >= 7.5 taking one or two oral diabetes agents (not insulin)

Arm/Group Title	Cycloset	Placebo
Arm/Group Description	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.	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.
Measure Participants	261	151
Least Squares Mean (Standard Deviation) [percent]	-0.41 (0.9)	0.041 (1.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cycloset, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.5
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	Expected study duration was 52 weeks. Adverse event data were collected from the day of first treatment dose to within 30 days of the last course of treatment or the date of the last contact (whichever was earlier).
Arm/Group Title	Cycloset		Placebo
Arm/Group Description	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.		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.
All Cause Mortality
	Cycloset		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Cycloset		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	176/2054 (8.6%)		98/1016 (9.6%)
Cardiac disorders
Cardiac Disorders	51/2054 (2.5%)	51	37/1016 (3.6%)	37
Endocrine disorders
Endocrine disorders	5/2054 (0.2%)	5	4/1016 (0.4%)	4
Eye disorders
Eye	0/2054 (0%)	0	2/1016 (0.2%)	2
Gastrointestinal disorders
Gastrointestinal	13/2054 (0.6%)	13	9/1016 (0.9%)	9
General disorders
General disorders and adminstrative site conditions	14/2054 (0.7%)	14	9/1016 (0.9%)	9
Hepatobiliary disorders
Hepatobiliary	4/2054 (0.2%)	4	1/1016 (0.1%)	1
Infections and infestations
Infection	27/2054 (1.3%)	27	13/1016 (1.3%)	13
Injury, poisoning and procedural complications
Injury	12/2054 (0.6%)	12	3/1016 (0.3%)	3
Metabolism and nutrition disorders
Metabolism	7/2054 (0.3%)	7	2/1016 (0.2%)	2
Musculoskeletal and connective tissue disorders
Musculoskeletal and connective tissue	11/2054 (0.5%)	11	4/1016 (0.4%)	4
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasm	8/2054 (0.4%)	8	2/1016 (0.2%)	2
Nervous system disorders
Nervous	26/2054 (1.3%)	26	14/1016 (1.4%)	14
Psychiatric disorders
Pyschiatric	4/2054 (0.2%)	4	1/1016 (0.1%)	1
Renal and urinary disorders
Renal	6/2054 (0.3%)	6	3/1016 (0.3%)	3
Reproductive system and breast disorders
Reproductive	4/2054 (0.2%)	4	0/1016 (0%)	0
Respiratory, thoracic and mediastinal disorders
Respiratory	13/2054 (0.6%)	13	3/1016 (0.3%)	3
Vascular disorders
Vascular disorders	10/2054 (0.5%)	10	8/1016 (0.8%)	8
Other (Not Including Serious) Adverse Events
	Cycloset		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1611/2054 (78.4%)		430/1016 (42.3%)
Endocrine disorders
hypoglycemia	141/2054 (6.9%)	141	54/1016 (5.3%)	54
Gastrointestinal disorders
nausea	661/2054 (32.2%)	661	77/1016 (7.6%)	77
vomiting	167/2054 (8.1%)	167	32/1016 (3.1%)	32
constipation	119/2054 (5.8%)	119	52/1016 (5.1%)	52
General disorders
Fatigue	285/2054 (13.9%)	285	68/1016 (6.7%)	68
Nervous system disorders
Dizziness	303/2054 (14.8%)	303	63/1016 (6.2%)	63
headache	235/2054 (11.4%)	235	84/1016 (8.3%)	84

Limitations/Caveats

Thus HbA1c was only performed on a subset of patients defined as failing (HbA1c >= 7.5) and who were on oral diabetes medications. Forced titration of study drug may have lead to a greater number of discontinuations.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

After FDA filing, Principal Liaison shall be free to publish the results of the Study subject only to the provisions of Section 7 regarding Veroscience Proprietary Information. The Principal Liaison shall furnish Veroscience with a copy of any proposed publication for review and comment prior to submission for publication, at least thirty (30) days prior to submission for manuscripts and at least fifteen (15) days prior to submission for abstracts.