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

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ClinicalTrials.gov Identifier: NCT00377676
Recruitment Status : Completed
First Posted : September 18, 2006
Results First Posted : October 28, 2011
Last Update Posted : June 10, 2016
Sponsor:
Information provided by (Responsible Party):
VeroScience

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Type 2 Diabetes Mellitus
Interventions Drug: Cycloset
Drug: Usual Diabetes Therapy plus placebo
Enrollment 3095
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).
Arm/Group Title Cycloset Placebo
Hide 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 [1] 1016
Completed 1093 694
Not Completed 961 322
Reason Not Completed
Adverse Event             498             107
Protocol Violation             33             27
Death             5             2
Withdrawal by Subject             187             72
Lost to Follow-up             120             56
not specified             118             58
[1]
25 subjects did not receive study drug - thus 3070 were randomized and received drug
Arm/Group Title Cycloset Placebo Total
Hide 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 Number of Baseline Participants 2054 1016 3070
Hide Baseline Analysis Population Description
[Not Specified]
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 2054 participants 1016 participants 3070 participants
<=18 years
0
   0.0%
0
   0.0%
0
   0.0%
Between 18 and 65 years
1453
  70.7%
701
  69.0%
2154
  70.2%
>=65 years
601
  29.3%
315
  31.0%
916
  29.8%
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 2054 participants 1016 participants 3070 participants
60.2  (10) 59.5  (10) 59.7  (10)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 2054 participants 1016 participants 3070 participants
Female
913
  44.4%
418
  41.1%
1331
  43.4%
Male
1141
  55.6%
598
  58.9%
1739
  56.6%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 2054 participants 1016 participants 3070 participants
2054 1016 3070
1.Primary Outcome
Title Subjects Experiencing Serious Adverse Events
Hide 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.
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Cycloset Placebo
Hide 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.
Overall Number of Participants Analyzed 2054 1016
Measure Type: Number
Unit of Measure: participants
176 98
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Cycloset, Placebo
Comments [Not Specified]
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 [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.02
Confidence Interval (1-Sided) 95%
1.27
Estimation Comments cycloset to placebo
2.Secondary Outcome
Title Number of Subjects Experiencing Serious Cardiovascular Adverse Events
Hide 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.
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
intent to treat
Arm/Group Title Cycloset Placebo
Hide 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.
Overall Number of Participants Analyzed 2054 1016
Measure Type: Number
Unit of Measure: Subjects
31 30
Show Statistical Analysis 1 Hide 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 [Not Specified]
Statistical Test of Hypothesis P-Value <0.05
Comments [Not Specified]
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Cox Proportional Hazard
Estimated Value .58
Confidence Interval (2-Sided) 95%
.35 to .96
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Change in HbA1c From Baseline to Week 24 in Subjects Failing Treatment With Metformin Plus a Sulfonylurea
Hide 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
Show Outcome Measure DataHide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 177 90
Least Squares Mean (Standard Deviation)
Unit of Measure: percent
-0.49  (0.8) -0.04  (1)
Show Statistical Analysis 1 Hide 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 [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.5
Parameter Dispersion
Type: Standard Deviation
Value: 1.4
Estimation Comments [Not Specified]
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.
Hide 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
Show Outcome Measure DataHide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 261 151
Least Squares Mean (Standard Deviation)
Unit of Measure: percent
-0.41  (0.9) 0.041  (1.2)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Cycloset, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.5
Estimation Comments [Not Specified]
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).
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Cycloset Placebo
Hide 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 (%) Affected / at Risk (%)
Total   --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
Cycloset Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   176/2054 (8.57%)      98/1016 (9.65%)    
Cardiac disorders     
Cardiac Disorders  1 [1]  51/2054 (2.48%)  51 37/1016 (3.64%)  37
Endocrine disorders     
Endocrine disorders  1 [2]  5/2054 (0.24%)  5 4/1016 (0.39%)  4
Eye disorders     
Eye  1 [3]  0/2054 (0.00%)  0 2/1016 (0.20%)  2
Gastrointestinal disorders     
Gastrointestinal  1 [4]  13/2054 (0.63%)  13 9/1016 (0.89%)  9
General disorders     
General disorders and adminstrative site conditions  1 [5]  14/2054 (0.68%)  14 9/1016 (0.89%)  9
Hepatobiliary disorders     
Hepatobiliary  1  4/2054 (0.19%)  4 1/1016 (0.10%)  1
Infections and infestations     
Infection  1 [6]  27/2054 (1.31%)  27 13/1016 (1.28%)  13
Injury, poisoning and procedural complications     
Injury  1  12/2054 (0.58%)  12 3/1016 (0.30%)  3
Metabolism and nutrition disorders     
Metabolism  1 [7]  7/2054 (0.34%)  7 2/1016 (0.20%)  2
Musculoskeletal and connective tissue disorders     
Musculoskeletal and connective tissue  1  11/2054 (0.54%)  11 4/1016 (0.39%)  4
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Neoplasm  1  8/2054 (0.39%)  8 2/1016 (0.20%)  2
Nervous system disorders     
Nervous  1 [8]  26/2054 (1.27%)  26 14/1016 (1.38%)  14
Psychiatric disorders     
Pyschiatric  1  4/2054 (0.19%)  4 1/1016 (0.10%)  1
Renal and urinary disorders     
Renal  1 [9]  6/2054 (0.29%)  6 3/1016 (0.30%)  3
Reproductive system and breast disorders     
Reproductive  1  4/2054 (0.19%)  4 0/1016 (0.00%)  0
Respiratory, thoracic and mediastinal disorders     
Respiratory  1 [10]  13/2054 (0.63%)  13 3/1016 (0.30%)  3
Vascular disorders     
Vascular disorders  1 [11]  10/2054 (0.49%)  10 8/1016 (0.79%)  8
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA (8.0)
[1]
Cardiac Disorders include: Coronary Artery Disease, Chest Pain, Cardiac failure congestive, Myocardial Infarction, Angina Unstable, Atrial Fibrillation, Syncope, Acute Myocardial Infarction
[2]
Endocrine disorders include: hypoglycemia
[3]
Eye disorders include: retinal detachment
[4]
Gastrointestinal disorders include: Gastrointestinal hemorrhage
[5]
General disorders and administrative site conditions include: Chest pain, non-cardiac chest pain
[6]
Infection includes: Pneumonia, Cellulitis, Diverticulitis
[7]
Metabolism and nutrition disorders include: Dehydration
[8]
Nervous system disorders include: Syncope, Cerebrovascular accident, Transient ischemic attack
[9]
Renal and urinary disorders include: acute renal failure
[10]
Respiratory, thoracic and mediastinal disorders include: Chronic obstructive pulmonary disease
[11]
Vascular disorders include: Carotid artery stenosis
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Cycloset Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   1611/2054 (78.43%)      430/1016 (42.32%)    
Endocrine disorders     
hypoglycemia  1  141/2054 (6.86%)  141 54/1016 (5.31%)  54
Gastrointestinal disorders     
nausea  1  661/2054 (32.18%)  661 77/1016 (7.58%)  77
vomiting  1  167/2054 (8.13%)  167 32/1016 (3.15%)  32
constipation  1  119/2054 (5.79%)  119 52/1016 (5.12%)  52
General disorders     
Fatigue  1  285/2054 (13.88%)  285 68/1016 (6.69%)  68
Nervous system disorders     
Dizziness  1  303/2054 (14.75%)  303 63/1016 (6.20%)  63
headache  1  235/2054 (11.44%)  235 84/1016 (8.27%)  84
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA (8.0)
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.
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
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.
Results Point of Contact
Name/Title: Richard Scranton
Organization: VeroScience
Phone: 401 816-0525
Responsible Party: VeroScience
ClinicalTrials.gov Identifier: NCT00377676     History of Changes
Other Study ID Numbers: 165-AD-04-03-US-1
First Submitted: September 14, 2006
First Posted: September 18, 2006
Results First Submitted: November 8, 2010
Results First Posted: October 28, 2011
Last Update Posted: June 10, 2016