Trial Outcomes & Findings for Safety and Tolerability Study of Cycloset in Treatment of Type 2 Diabetes (NCT NCT00377676)

Last Updated: 2016-06-10

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

3095 participants

Primary outcome timeframe

From baseline to week 52.

Results posted on

2016-06-10

Participant Flow

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

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).

Participant milestones

Participant milestones
Measure	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.	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.
Overall Study STARTED	2054	1016
Overall Study COMPLETED	1093	694
Overall Study NOT COMPLETED	961	322

Reasons for withdrawal

Reasons for withdrawal
Measure	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.	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.
Overall Study Adverse Event	498	107
Overall Study Protocol Violation	33	27
Overall Study Death	5	2
Overall Study Withdrawal by Subject	187	72
Overall Study Lost to Follow-up	120	56
Overall Study Other	118	58

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Cycloset n=2054 Participants 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.	Placebo n=1016 Participants 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 n=3070 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants
Age, Categorical Between 18 and 65 years	1453 Participants n=99 Participants	701 Participants n=107 Participants	2154 Participants n=206 Participants
Age, Categorical >=65 years	601 Participants n=99 Participants	315 Participants n=107 Participants	916 Participants n=206 Participants
Age, Continuous	60.2 years STANDARD_DEVIATION 10 • n=99 Participants	59.5 years STANDARD_DEVIATION 10 • n=107 Participants	59.7 years STANDARD_DEVIATION 10 • n=206 Participants
Sex: Female, Male Female	913 Participants n=99 Participants	418 Participants n=107 Participants	1331 Participants n=206 Participants
Sex: Female, Male Male	1141 Participants n=99 Participants	598 Participants n=107 Participants	1739 Participants n=206 Participants
Region of Enrollment United States	2054 participants n=99 Participants	1016 participants n=107 Participants	3070 participants n=206 Participants

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Cycloset n=2054 Participants 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.	Placebo n=1016 Participants 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.
Subjects Experiencing Serious Adverse Events	176 participants	98 participants

SECONDARY outcome

Timeframe: Baseline to week 52.

Population: intent to treat

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).

Outcome measures

Outcome measures
Measure	Cycloset n=2054 Participants 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.	Placebo n=1016 Participants 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.
Number of Subjects Experiencing Serious Cardiovascular Adverse Events	31 Subjects	30 Subjects

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Cycloset n=177 Participants 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.	Placebo n=90 Participants 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.
Change in HbA1c From Baseline to Week 24 in Subjects Failing Treatment With Metformin Plus a Sulfonylurea	-0.49 percent Standard Deviation 0.8	-0.04 percent Standard Deviation 1

SECONDARY outcome

Timeframe: Baseline to week 24

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

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.

Outcome measures

Outcome measures
Measure	Cycloset n=261 Participants 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.	Placebo n=151 Participants 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.
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	0.041 percent Standard Deviation 1.2

Adverse Events

Cycloset

Serious events: 176 serious events

Other events: 1611 other events

Deaths: 0 deaths

Placebo

Serious events: 98 serious events

Other events: 430 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Cycloset n=2054 participants at risk 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.	Placebo n=1016 participants at risk 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.
Gastrointestinal disorders nausea	32.2% 661/2054 • Number of events 661 • 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).	7.6% 77/1016 • Number of events 77 • 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).
Gastrointestinal disorders vomiting	8.1% 167/2054 • Number of events 167 • 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).	3.1% 32/1016 • Number of events 32 • 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).
Nervous system disorders Dizziness	14.8% 303/2054 • Number of events 303 • 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).	6.2% 63/1016 • Number of events 63 • 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).
Nervous system disorders headache	11.4% 235/2054 • Number of events 235 • 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).	8.3% 84/1016 • Number of events 84 • 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).
General disorders Fatigue	13.9% 285/2054 • Number of events 285 • 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).	6.7% 68/1016 • Number of events 68 • 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).
Gastrointestinal disorders constipation	5.8% 119/2054 • Number of events 119 • 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).	5.1% 52/1016 • Number of events 52 • 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).
Endocrine disorders hypoglycemia	6.9% 141/2054 • Number of events 141 • 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).	5.3% 54/1016 • Number of events 54 • 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).

Additional Information

Richard Scranton

VeroScience

Phone: 401 816-0525

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee 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.
Publication restrictions are in place

Restriction type: OTHER

Measure	Cycloset n=2054 participants at risk 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.	Placebo n=1016 participants at risk 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.
Cardiac disorders Cardiac Disorders	2.5% 51/2054 • Number of events 51 • 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).	3.6% 37/1016 • Number of events 37 • 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).
Infections and infestations Infection	1.3% 27/2054 • Number of events 27 • 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).	1.3% 13/1016 • Number of events 13 • 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).
Nervous system disorders Nervous	1.3% 26/2054 • Number of events 26 • 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).	1.4% 14/1016 • Number of events 14 • 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).
General disorders General disorders and adminstrative site conditions	0.68% 14/2054 • Number of events 14 • 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).	0.89% 9/1016 • Number of events 9 • 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).
Gastrointestinal disorders Gastrointestinal	0.63% 13/2054 • Number of events 13 • 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).	0.89% 9/1016 • Number of events 9 • 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).
Vascular disorders Vascular disorders	0.49% 10/2054 • Number of events 10 • 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).	0.79% 8/1016 • Number of events 8 • 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).
Respiratory, thoracic and mediastinal disorders Respiratory	0.63% 13/2054 • Number of events 13 • 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).	0.30% 3/1016 • Number of events 3 • 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).
Injury, poisoning and procedural complications Injury	0.58% 12/2054 • Number of events 12 • 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).	0.30% 3/1016 • Number of events 3 • 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).
Musculoskeletal and connective tissue disorders Musculoskeletal and connective tissue	0.54% 11/2054 • Number of events 11 • 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).	0.39% 4/1016 • Number of events 4 • 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).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Neoplasm	0.39% 8/2054 • Number of events 8 • 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).	0.20% 2/1016 • Number of events 2 • 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).
Endocrine disorders Endocrine disorders	0.24% 5/2054 • Number of events 5 • 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).	0.39% 4/1016 • Number of events 4 • 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).
Metabolism and nutrition disorders Metabolism	0.34% 7/2054 • Number of events 7 • 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).	0.20% 2/1016 • Number of events 2 • 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).
Renal and urinary disorders Renal	0.29% 6/2054 • Number of events 6 • 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).	0.30% 3/1016 • Number of events 3 • 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).
Hepatobiliary disorders Hepatobiliary	0.19% 4/2054 • Number of events 4 • 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).	0.10% 1/1016 • Number of events 1 • 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).
Psychiatric disorders Pyschiatric	0.19% 4/2054 • Number of events 4 • 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).	0.10% 1/1016 • Number of events 1 • 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).
Reproductive system and breast disorders Reproductive	0.19% 4/2054 • Number of events 4 • 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).	0.00% 0/1016 • 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).
Eye disorders Eye	0.00% 0/2054 • 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).	0.20% 2/1016 • Number of events 2 • 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).