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Phase 4: Investigational Study to Evaluate Metformin XR Monotherapy Versus Metformin IR Monotherapy in Subjects With Type 2 Diabetes

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ClinicalTrials.gov Identifier: NCT01864174
Recruitment Status : Completed
First Posted : May 29, 2013
Results First Posted : July 21, 2017
Last Update Posted : November 28, 2019
Sponsor:
Information provided by (Responsible Party):
Bristol-Myers Squibb

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double (Participant, Investigator);   Primary Purpose: Treatment
Condition Type 2 Diabetes Mellitus
Interventions Drug: Metformin XR
Drug: Metformin IR
Drug: Placebo matching with Metformin XR
Drug: Placebo matching with Metformin IR
Enrollment 1736
Recruitment Details 1736 enrolled at 148 study sites in North America, Europe, and South Africa.Lead in period=794. Reasons not entered: 1 AE, 17 WC, 4 lost to FU, 3 NC, 911 SC, 4 ARS, 1 other. Adverse event=-AE, Withdrew consent=WC, Follow-up=FU, poor/non-compliance=NC, No longer met study criteria=SC, Administrative reason by sponsor=ARS.
Pre-assignment Details 570 completed lead-in period and were eligible for randomization. 568 randomized. Non-randomized: 1 AE, 27 WC, 3 lost to FU, 7 NC, 159 SC, 8 ARS, 3 other.
Arm/Group Title Metformin XR Metformin IR
Hide Arm/Group Description

Participants received Metformin XR and Placebo matching with Metformin XR

Metformin Extended Release (XR) 500 mg tablets (500-2000 mg per day) by mouth twice daily (BID) for 24 weeks

Placebo matching with Metformin XR 0 mg tablets by mouth twice daily (BID) for 24 weeks.

Participants received Metformin IR and Placebo matching with Metformin IR.

Metformin Immediate Release (IR) 500 mg tablets (500-2000 mg per day) by mouth twice daily (BID) for 24 weeks

Placebo matching with Metformin IR 0 mg tablets by mouth twice daily (BID) for 24 weeks.

Period Title: Double Blind Treatment - All Treated
Started 283 285
Completed 268 271
Not Completed 15 14
Reason Not Completed
Removed due to site non-compliance             15             14
Period Title: Double Blind - Compliant Randomized
Started 268 271
Completed 245 245
Not Completed 23 26
Reason Not Completed
Adverse Event             6             1
Subject Request to Discontinue Treatment             2             0
Subject Withdrew Consent             4             5
Death             1             0
Lost to Follow-up             3             10
Poor/Non-compliance             1             0
Other             6             10
Period Title: Off Treatment Follow-Up
Started 9 1
Completed 6 1
Not Completed 3 0
Reason Not Completed
Other             2             0
Subject Withdrew Consent             1             0
Arm/Group Title Metformin XR Metformin IR Total
Hide Arm/Group Description

Participants received Metformin XR and Placebo matching with Metformin XR

Metformin Extended Release (XR) 500 mg tablets (500-2000 mg per day) by mouth twice daily (BID) for 24 weeks

Placebo matching with Metformin XR 0 mg tablets by mouth twice daily (BID) for 24 weeks.

Participants received Metformin IR and Placebo matching with Metformin IR.

Metformin Immediate Release (IR) 500 mg tablets (500-2000 mg per day) by mouth twice daily (BID) for 24 weeks

Placebo matching with Metformin IR 0 mg tablets by mouth twice daily (BID) for 24 weeks.

Total of all reporting groups
Overall Number of Baseline Participants 268 271 539
Hide Baseline Analysis Population Description
All Treated Data Set (n=568) are the randomized participants who received at least 1 dose of study drug during the double blind treatment period (up to rescue). 29 participants were excluded from the baseline Randomized Data Set; therefore, the number of participants included in the baseline population is 539. n = number of evaluable participants
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 268 participants 271 participants 539 participants
56.8  (10.69) 55.3  (10.34) 56.0  (10.53)
Age, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 268 participants 271 participants 539 participants
< 65 years 198 226 424
>= 65 years 70 45 115
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 268 participants 271 participants 539 participants
Female
122
  45.5%
122
  45.0%
244
  45.3%
Male
146
  54.5%
149
  55.0%
295
  54.7%
Race/Ethnicity, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 268 participants 271 participants 539 participants
White 227 225 452
Black or African American 22 19 41
Asian 17 20 37
Other 2 7 9
1.Primary Outcome
Title Adjusted Mean Change From Baseline in HbA1c
Hide Description Mean change in glycated hemoglobin (HbA1c) from baseline to Week 24 in the double-blind treatment period.
Time Frame Baseline and Week 24
Hide Outcome Measure Data
Hide Analysis Population Description
Randomized participants who took at least one dose of double-blind study medication in the treatment group to which they were randomized with non-missing baseline and Week 24 values who were not excluded due to non-compliance.
Arm/Group Title Metformin XR Metformin IR
Hide Arm/Group Description:

Participants received Metformin XR and Placebo matching with Metformin XR

Metformin Extended Release (XR) 500 mg tablets (500-2000 mg per day) by mouth twice daily (BID) for 24 weeks

Placebo matching with Metformin XR 0 mg tablets by mouth twice daily (BID) for 24 weeks.

Participants received Metformin IR and Placebo matching with Metformin IR.

Metformin Immediate Release (IR) 500 mg tablets (500-2000 mg per day) by mouth twice daily (BID) for 24 weeks

Placebo matching with Metformin IR 0 mg tablets by mouth twice daily (BID) for 24 weeks.

Overall Number of Participants Analyzed 237 237
Mean (Standard Error)
Unit of Measure: percent
-0.93  (0.0485) -0.96  (0.0480)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Metformin XR, Metformin IR
Comments [Not Specified]
Type of Statistical Test Non-Inferiority or Equivalence (legacy)
Comments The study provided 90% power to demonstrate noninferiority in change from baseline mean HbA1c at Week 24, with an assumed standard deviation (SD) of 1.0%, a non-inferiority margin of 0.3%, and 2-sided alpha of 0.05 for the primary comparison
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.03
Confidence Interval (2-Sided) 95%
-0.10 to 0.17
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.0687
Estimation Comments METFORMIN XR VS METFORMIN IR
2.Primary Outcome
Title Number of Participants With Death, Serious Adverse Events (SAEs), SAEs Related to Study Therapy, SAEs Leading to Discontinuation, Adverse Events (AEs) Related to Study Therapy, and AEs Leading to Discontinuation
Hide Description SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. Treatment-related=having certain, probable, possible, or missing relationship to study drug. All listed events are treatment emergent, which is defined as nonserious and serious AEs with an onset from Day 1 of the double-blind treatment up to and including 4 days and 30 days respectively, after the last dose date of double-blind study. randomized.
Time Frame Date of first dose (Day 1) up to 30 post last dose of study drug (approx. 28 weeks)
Hide Outcome Measure Data
Hide Analysis Population Description
Treated participants; All participants who took at least one dose of double-blind study medication in the treatment group they were randomized to unless participants had never received the double-blind study medication they were randomized. Those participants were included in the treatment group based on the first treatment received.
Arm/Group Title Metformin XR Metformin IR
Hide Arm/Group Description:

Participants received Metformin XR and Placebo matching with Metformin XR

Metformin Extended Release (XR) 500 mg tablets (500-2000 mg per day) by mouth twice daily (BID) for 24 weeks

Placebo matching with Metformin XR 0 mg tablets by mouth twice daily (BID) for 24 weeks.

Participants received Metformin IR and Placebo matching with Metformin IR.

Metformin Immediate Release (IR) 500 mg tablets (500-2000 mg per day) by mouth twice daily (BID) for 24 weeks

Placebo matching with Metformin IR 0 mg tablets by mouth twice daily (BID) for 24 weeks.

Overall Number of Participants Analyzed 283 285
Measure Type: Number
Unit of Measure: participants
Death 1 0
SAE 8 10
SAEs Related to Study Therapy 1 1
SAEs Leading to Discontinuation 0 1
AEs Related to Study Therapy 30 25
AEs Leading to Discontinuation 10 7
3.Secondary Outcome
Title Mean Change in Fasting Plasma Glucose (FPG)
Hide Description The mean change in fasting plasma glucose (FPG) from baseline to Week 24 in the double-blind treatment period was assessed. The lack of glycemic control criteria for initiation of rescue medication during Week 12 to Week 24 was having a FPG > 200 mg/dL (11.1 mmol/L). mg/dL = milligrams per deciliter; mmol/L = millimole per Liter
Time Frame Baseline and Week 24
Hide Outcome Measure Data
Hide Analysis Population Description
Randomized participants who took at least one dose of double-blind study medication in the treatment group to which they were randomized with non-missing baseline and Week 24 values and who were not excluded due to non-compliance.
Arm/Group Title Metformin XR Metformin IR
Hide Arm/Group Description:

Participants received Metformin XR and Placebo matching with Metformin XR

Metformin Extended Release (XR) 500 mg tablets (500-2000 mg per day) by mouth twice daily (BID) for 24 weeks

Placebo matching with Metformin XR 0 mg tablets by mouth twice daily (BID) for 24 weeks.

Participants received Metformin IR and Placebo matching with Metformin IR.

Metformin Immediate Release (IR) 500 mg tablets (500-2000 mg per day) by mouth twice daily (BID) for 24 weeks

Placebo matching with Metformin IR 0 mg tablets by mouth twice daily (BID) for 24 weeks.

Overall Number of Participants Analyzed 228 229
Mean (Standard Error)
Unit of Measure: mg/dL
-21.1  (1.803) -20.6  (1.789)
4.Secondary Outcome
Title Mean Change in Mean Daily Glucose (MDG)
Hide Description The mean change in Mean Daily Glucose (MDG) from baseline to Week 24 in the double-blind treatment period was assessed. Prior to the Day 1 visit (between Week -1 and Day 1) and in the week before the Week 24/Study Termination and Rescue or Early Treatment Termination visit, participants performed 7-point finger stick blood glucose monitoring (before and 2 hours after 3 meals per day, and at bedtime) for 3 consecutive days in order to determine their MDG.
Time Frame Baseline and Week 24
Hide Outcome Measure Data
Hide Analysis Population Description
Randomized participants who took at least one dose of double-blind study medication in the treatment group to which they were randomized with non-missing baseline and Week 24 last observation carried forward (LOCF) results who were not excluded due to non-compliance.
Arm/Group Title Metformin XR Metformin IR
Hide Arm/Group Description:

Participants received Metformin XR and Placebo matching with Metformin XR

Metformin Extended Release (XR) 500 mg tablets (500-2000 mg per day) by mouth twice daily (BID) for 24 weeks

Placebo matching with Metformin XR 0 mg tablets by mouth twice daily (BID) for 24 weeks.

Participants received Metformin IR and Placebo matching with Metformin IR.

Metformin Immediate Release (IR) 500 mg tablets (500-2000 mg per day) by mouth twice daily (BID) for 24 weeks

Placebo matching with Metformin IR 0 mg tablets by mouth twice daily (BID) for 24 weeks.

Overall Number of Participants Analyzed 211 218
Mean (Standard Error)
Unit of Measure: mg/dL
-24.68  (1.5813) -27.05  (1.555)
5.Secondary Outcome
Title Percent of Participants With HbA1c < 7%
Hide Description Percent of participants achieving a therapeutic glycemic response (defined as HbA1c < 7.0%) at Week 24 in the double-blind treatment period.
Time Frame Week 24
Hide Outcome Measure Data
Hide Analysis Population Description
Randomized participants who took at least one dose of double-blind study medication in the treatment group to which they were randomized with non-missing baseline and Week 24 values who were not excluded due to non-compliance.
Arm/Group Title Metformin XR Metformin IR
Hide Arm/Group Description:

Participants received Metformin XR and Placebo matching with Metformin XR

Metformin Extended Release (XR) 500 mg tablets (500-2000 mg per day) by mouth twice daily (BID) for 24 weeks

Placebo matching with Metformin XR 0 mg tablets by mouth twice daily (BID) for 24 weeks.

Participants received Metformin IR and Placebo matching with Metformin IR.

Metformin Immediate Release (IR) 500 mg tablets (500-2000 mg per day) by mouth twice daily (BID) for 24 weeks

Placebo matching with Metformin IR 0 mg tablets by mouth twice daily (BID) for 24 weeks.

Overall Number of Participants Analyzed 237 237
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percent of participants
70.9
(65.5 to 76.3)
72.0
(66.3 to 77.7)
Time Frame From Day 1 up to 30 days post last dose (approx. 28 weeks)
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Metformin XR Metformin IR
Hide Arm/Group Description

Participants received Metformin XR and Placebo matching with Metformin XR

Metformin Extended Release (XR) 500 mg tablets (500-2000 mg per day) by mouth twice daily (BID) for 24 weeks

Placebo matching with Metformin XR 0 mg tablets by mouth twice daily (BID) for 24 weeks.

Participants received Metformin IR and Placebo matching with Metformin IR.

Metformin Immediate Release (IR) 500 mg tablets (500-2000 mg per day) by mouth twice daily (BID) for 24 weeks

Placebo matching with Metformin IR 0 mg tablets by mouth twice daily (BID) for 24 weeks.

All-Cause Mortality
Metformin XR Metformin IR
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Metformin XR Metformin IR
Affected / at Risk (%) Affected / at Risk (%)
Total   8/283 (2.83%)   10/285 (3.51%) 
Blood and lymphatic system disorders     
Hypocoagulable state  1  1/283 (0.35%)  0/285 (0.00%) 
Cardiac disorders     
Angina unstable  1  1/283 (0.35%)  0/285 (0.00%) 
Eye disorders     
Diplopia  1  0/283 (0.00%)  1/285 (0.35%) 
Gastrointestinal disorders     
Abdominal pain lower  1  0/283 (0.00%)  1/285 (0.35%) 
Upper gastrointestinal haemorrhage  1  1/283 (0.35%)  0/285 (0.00%) 
Hepatobiliary disorders     
Cholecystitis  1  0/283 (0.00%)  1/285 (0.35%) 
Cholecystitis acute  1  0/283 (0.00%)  1/285 (0.35%) 
Cholelithiasis  1  1/283 (0.35%)  0/285 (0.00%) 
Infections and infestations     
Pulmonary tuberculosis  1  0/283 (0.00%)  1/285 (0.35%) 
Respiratory tract infection  1  0/283 (0.00%)  1/285 (0.35%) 
Injury, poisoning and procedural complications     
Delayed recovery from anaesthesia  1  1/283 (0.35%)  0/285 (0.00%) 
Laceration  1  0/283 (0.00%)  1/285 (0.35%) 
Overdose  1  2/283 (0.71%)  0/285 (0.00%) 
Metabolism and nutrition disorders     
Diabetes mellitus inadequate control  1  0/283 (0.00%)  1/285 (0.35%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Malignant melanoma in situ  1  1/283 (0.35%)  0/285 (0.00%) 
Prostatic adenoma  1  0/283 (0.00%)  1/285 (0.35%) 
Squamous cell carcinoma  1  1/283 (0.35%)  0/285 (0.00%) 
Nervous system disorders     
Cerebral haemorrhage  1  1/283 (0.35%)  0/285 (0.00%) 
Cerebral infarction  1  0/283 (0.00%)  1/285 (0.35%) 
Renal and urinary disorders     
Ureterolithiasis  1  0/283 (0.00%)  1/285 (0.35%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 19.0
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Metformin XR Metformin IR
Affected / at Risk (%) Affected / at Risk (%)
Total   25/283 (8.83%)   22/285 (7.72%) 
Gastrointestinal disorders     
Diarrhoea  1  25/283 (8.83%)  22/285 (7.72%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 19.0
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.
Bristol-Myers Squibb Co. agreements with investigators vary; constant is our right to embargo communications regarding trial results prior to public release for a period ≤60 days from submittal for review. We will not prohibit investigators from publishing, but will prohibit the disclosure of previously undisclosed confidential information other than study results, and request postponement of single-center publications until after disclosure of the clinical trial's primary publication.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Bristol-Myers Squibb Study Director
Organization: Bristol-Myers Squibb
EMail: Clinical.Trials@bms.com
Layout table for additonal information
Responsible Party: Bristol-Myers Squibb
ClinicalTrials.gov Identifier: NCT01864174     History of Changes
Other Study ID Numbers: CV181-206
2012-004531-23 ( EudraCT Number )
First Submitted: May 24, 2013
First Posted: May 29, 2013
Results First Submitted: May 31, 2017
Results First Posted: July 21, 2017
Last Update Posted: November 28, 2019