Trial Outcomes & Findings for Phase 4: Investigational Study to Evaluate Metformin XR Monotherapy Versus Metformin IR Monotherapy in Subjects With Type 2 Diabetes (NCT NCT01864174)

NCT ID: NCT01864174

Last Updated: 2019-11-29

Results Overview

Mean change in glycated hemoglobin (HbA1c) from baseline to Week 24 in the double-blind treatment period.

Recruitment status

COMPLETED

Study phase

PHASE4

Target enrollment

1736 participants

Primary outcome timeframe

Baseline and Week 24

Results posted on

2019-11-29

Participant Flow

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.

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.

Participant milestones

Participant milestones
Measure	Metformin XR 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.	Metformin IR 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.
Double Blind Treatment - All Treated STARTED	283	285
Double Blind Treatment - All Treated COMPLETED	268	271
Double Blind Treatment - All Treated NOT COMPLETED	15	14
Double Blind - Compliant Randomized STARTED	268	271
Double Blind - Compliant Randomized COMPLETED	245	245
Double Blind - Compliant Randomized NOT COMPLETED	23	26
Off Treatment Follow-Up STARTED	9	1
Off Treatment Follow-Up COMPLETED	6	1
Off Treatment Follow-Up NOT COMPLETED	3	0

Reasons for withdrawal

Reasons for withdrawal
Measure	Metformin XR 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.	Metformin IR 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.
Double Blind Treatment - All Treated Removed due to site non-compliance	15	14
Double Blind - Compliant Randomized Adverse Event	6	1
Double Blind - Compliant Randomized Subject Request to Discontinue Treatment	2	0
Double Blind - Compliant Randomized Subject Withdrew Consent	4	5
Double Blind - Compliant Randomized Death	1	0
Double Blind - Compliant Randomized Lost to Follow-up	3	10
Double Blind - Compliant Randomized Poor/Non-compliance	1	0
Double Blind - Compliant Randomized Other	6	10
Off Treatment Follow-Up Other	2	0
Off Treatment Follow-Up Subject Withdrew Consent	1	0

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Metformin XR n=268 Participants 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.	Metformin IR n=271 Participants 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 n=539 Participants Total of all reporting groups
Age, Continuous	56.8 years STANDARD_DEVIATION 10.69 • n=5 Participants	55.3 years STANDARD_DEVIATION 10.34 • n=7 Participants	56.0 years STANDARD_DEVIATION 10.53 • n=5 Participants
Age, Customized < 65 years	198 participants n=5 Participants	226 participants n=7 Participants	424 participants n=5 Participants
Age, Customized >= 65 years	70 participants n=5 Participants	45 participants n=7 Participants	115 participants n=5 Participants
Sex: Female, Male Female	122 Participants n=5 Participants	122 Participants n=7 Participants	244 Participants n=5 Participants
Sex: Female, Male Male	146 Participants n=5 Participants	149 Participants n=7 Participants	295 Participants n=5 Participants
Race/Ethnicity, Customized White	227 participants n=5 Participants	225 participants n=7 Participants	452 participants n=5 Participants
Race/Ethnicity, Customized Black or African American	22 participants n=5 Participants	19 participants n=7 Participants	41 participants n=5 Participants
Race/Ethnicity, Customized Asian	17 participants n=5 Participants	20 participants n=7 Participants	37 participants n=5 Participants
Race/Ethnicity, Customized Other	2 participants n=5 Participants	7 participants n=7 Participants	9 participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline and Week 24

Population: 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.

Mean change in glycated hemoglobin (HbA1c) from baseline to Week 24 in the double-blind treatment period.

Outcome measures

Outcome measures
Measure	Metformin XR n=237 Participants 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.	Metformin IR n=237 Participants 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.
Adjusted Mean Change From Baseline in HbA1c	-0.93 percent Standard Error 0.0485 • Interval -1.02 to -0.83	-0.96 percent Standard Error 0.0480 • Interval -1.05 to -0.87

PRIMARY outcome

Timeframe: Date of first dose (Day 1) up to 30 post last dose of study drug (approx. 28 weeks)

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Metformin XR n=283 Participants 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.	Metformin IR n=285 Participants 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.
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 Death	1 participants	0 participants
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 SAE	8 participants	10 participants
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 SAEs Related to Study Therapy	1 participants	1 participants
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 SAEs Leading to Discontinuation	0 participants	1 participants
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 AEs Related to Study Therapy	30 participants	25 participants
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 AEs Leading to Discontinuation	10 participants	7 participants

SECONDARY outcome

Timeframe: Baseline and Week 24

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

Outcome measures

Outcome measures
Measure	Metformin XR n=228 Participants 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.	Metformin IR n=229 Participants 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.
Mean Change in Fasting Plasma Glucose (FPG)	-21.1 mg/dL Standard Error 1.803	-20.6 mg/dL Standard Error 1.789

SECONDARY outcome

Timeframe: Baseline and Week 24

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Metformin XR n=211 Participants 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.	Metformin IR n=218 Participants 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.
Mean Change in Mean Daily Glucose (MDG)	-24.68 mg/dL Standard Error 1.5813	-27.05 mg/dL Standard Error 1.555

SECONDARY outcome

Timeframe: Week 24

Percent of participants achieving a therapeutic glycemic response (defined as HbA1c \< 7.0%) at Week 24 in the double-blind treatment period.

Outcome measures

Outcome measures
Measure	Metformin XR n=237 Participants 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.	Metformin IR n=237 Participants 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.
Percent of Participants With HbA1c < 7%	70.9 percent of participants Interval 65.5 to 76.3	72.0 percent of participants Interval 66.3 to 77.7

Adverse Events

Metformin XR

Serious events: 8 serious events

Other events: 25 other events

Deaths: 0 deaths

Metformin IR

Serious events: 10 serious events

Other events: 22 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Metformin XR n=283 participants at risk 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.	Metformin IR n=285 participants at risk 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.
Gastrointestinal disorders Diarrhoea	8.8% 25/283 • From Day 1 up to 30 days post last dose (approx. 28 weeks)	7.7% 22/285 • From Day 1 up to 30 days post last dose (approx. 28 weeks)

Additional Information

Bristol-Myers Squibb Study Director

Bristol-Myers Squibb

Email: [email protected]

Results disclosure agreements

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

Restriction type: OTHER

Measure	Metformin XR n=283 participants at risk 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.	Metformin IR n=285 participants at risk 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.
Blood and lymphatic system disorders Hypocoagulable state	0.35% 1/283 • From Day 1 up to 30 days post last dose (approx. 28 weeks)	0.00% 0/285 • From Day 1 up to 30 days post last dose (approx. 28 weeks)
Cardiac disorders Angina unstable	0.35% 1/283 • From Day 1 up to 30 days post last dose (approx. 28 weeks)	0.00% 0/285 • From Day 1 up to 30 days post last dose (approx. 28 weeks)
Eye disorders Diplopia	0.00% 0/283 • From Day 1 up to 30 days post last dose (approx. 28 weeks)	0.35% 1/285 • From Day 1 up to 30 days post last dose (approx. 28 weeks)
Gastrointestinal disorders Abdominal pain lower	0.00% 0/283 • From Day 1 up to 30 days post last dose (approx. 28 weeks)	0.35% 1/285 • From Day 1 up to 30 days post last dose (approx. 28 weeks)
Gastrointestinal disorders Upper gastrointestinal haemorrhage	0.35% 1/283 • From Day 1 up to 30 days post last dose (approx. 28 weeks)	0.00% 0/285 • From Day 1 up to 30 days post last dose (approx. 28 weeks)
Hepatobiliary disorders Cholecystitis	0.00% 0/283 • From Day 1 up to 30 days post last dose (approx. 28 weeks)	0.35% 1/285 • From Day 1 up to 30 days post last dose (approx. 28 weeks)
Hepatobiliary disorders Cholecystitis acute	0.00% 0/283 • From Day 1 up to 30 days post last dose (approx. 28 weeks)	0.35% 1/285 • From Day 1 up to 30 days post last dose (approx. 28 weeks)
Hepatobiliary disorders Cholelithiasis	0.35% 1/283 • From Day 1 up to 30 days post last dose (approx. 28 weeks)	0.00% 0/285 • From Day 1 up to 30 days post last dose (approx. 28 weeks)
Infections and infestations Pulmonary tuberculosis	0.00% 0/283 • From Day 1 up to 30 days post last dose (approx. 28 weeks)	0.35% 1/285 • From Day 1 up to 30 days post last dose (approx. 28 weeks)
Infections and infestations Respiratory tract infection	0.00% 0/283 • From Day 1 up to 30 days post last dose (approx. 28 weeks)	0.35% 1/285 • From Day 1 up to 30 days post last dose (approx. 28 weeks)
Injury, poisoning and procedural complications Delayed recovery from anaesthesia	0.35% 1/283 • From Day 1 up to 30 days post last dose (approx. 28 weeks)	0.00% 0/285 • From Day 1 up to 30 days post last dose (approx. 28 weeks)
Injury, poisoning and procedural complications Laceration	0.00% 0/283 • From Day 1 up to 30 days post last dose (approx. 28 weeks)	0.35% 1/285 • From Day 1 up to 30 days post last dose (approx. 28 weeks)
Injury, poisoning and procedural complications Overdose	0.71% 2/283 • From Day 1 up to 30 days post last dose (approx. 28 weeks)	0.00% 0/285 • From Day 1 up to 30 days post last dose (approx. 28 weeks)
Metabolism and nutrition disorders Diabetes mellitus inadequate control	0.00% 0/283 • From Day 1 up to 30 days post last dose (approx. 28 weeks)	0.35% 1/285 • From Day 1 up to 30 days post last dose (approx. 28 weeks)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Malignant melanoma in situ	0.35% 1/283 • From Day 1 up to 30 days post last dose (approx. 28 weeks)	0.00% 0/285 • From Day 1 up to 30 days post last dose (approx. 28 weeks)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Prostatic adenoma	0.00% 0/283 • From Day 1 up to 30 days post last dose (approx. 28 weeks)	0.35% 1/285 • From Day 1 up to 30 days post last dose (approx. 28 weeks)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Squamous cell carcinoma	0.35% 1/283 • From Day 1 up to 30 days post last dose (approx. 28 weeks)	0.00% 0/285 • From Day 1 up to 30 days post last dose (approx. 28 weeks)
Nervous system disorders Cerebral haemorrhage	0.35% 1/283 • From Day 1 up to 30 days post last dose (approx. 28 weeks)	0.00% 0/285 • From Day 1 up to 30 days post last dose (approx. 28 weeks)
Nervous system disorders Cerebral infarction	0.00% 0/283 • From Day 1 up to 30 days post last dose (approx. 28 weeks)	0.35% 1/285 • From Day 1 up to 30 days post last dose (approx. 28 weeks)
Renal and urinary disorders Ureterolithiasis	0.00% 0/283 • From Day 1 up to 30 days post last dose (approx. 28 weeks)	0.35% 1/285 • From Day 1 up to 30 days post last dose (approx. 28 weeks)