Type 2 Diabetes Mellitus
Conditions
Brief summary
The purpose of this study is determine if Metformin XR monotherapy in subjects with type 2 diabetes is non-inferior to Metformin IR monotherapy
Interventions
DRUGMetformin XR
DRUGMetformin IR
DRUGPlacebo matching with Metformin XR
DRUGPlacebo matching with Metformin IR
Sponsors
Bristol-Myers Squibb
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
For more information regarding BMS clinical trial participation, please visit www.BMSStudyConnect.com Inclusion Criteria: * Men and women, aged ≥18 years old at time of enrollment * Treatment naive subjects with type 2 diabetes mellitus with inadequate glycemic (HbA1c ≥7.0% and ≤9.2% obtained at screening visit) control on diet and exercise alone * Women must have a negative serum or urine test within 24 hours prior to start of investigational product
Exclusion criteria
* History of ketoacidosis, lactic acidosis or hyperosmolar non-ketonic coma * Symptoms of poorly controlled diabetes, including but not limited to marked polyuria and polydipsia with \>10% weight loss during last 3 months * Serum creatinine ≥1.50 mg/dL (133 μmol/L) for male subjects; serum creatinine ≥1.40 mg/dL (124 μmol/L for female subjects)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Adjusted Mean Change From Baseline in HbA1c | Baseline and Week 24 | Mean change in glycated hemoglobin (HbA1c) from baseline to Week 24 in the double-blind treatment period. |
| 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 | Date of first dose (Day 1) up to 30 post last dose of study drug (approx. 28 weeks) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change in Fasting Plasma Glucose (FPG) | 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 |
| Mean Change in Mean Daily Glucose (MDG) | Baseline and Week 24 | 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. |
| Percent of Participants With HbA1c < 7% | Week 24 | Percent of participants achieving a therapeutic glycemic response (defined as HbA1c \< 7.0%) at Week 24 in the double-blind treatment period. |
Countries
Canada, Czechia, Germany, Hungary, Poland, Puerto Rico, Romania, South Africa, United Kingdom, United States
Participant flow
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.
Participants by arm
| Arm | Count |
|---|---|
| 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. | 268 |
| 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. | 271 |
| Total | 539 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Double Blind - Compliant Randomized | Adverse Event | 6 | 1 |
| Double Blind - Compliant Randomized | Death | 1 | 0 |
| Double Blind - Compliant Randomized | Lost to Follow-up | 3 | 10 |
| Double Blind - Compliant Randomized | Other | 6 | 10 |
| Double Blind - Compliant Randomized | Poor/Non-compliance | 1 | 0 |
| Double Blind - Compliant Randomized | Subject Request to Discontinue Treatment | 2 | 0 |
| Double Blind - Compliant Randomized | Subject Withdrew Consent | 4 | 5 |
| Double Blind Treatment - All Treated | Removed due to site non-compliance | 15 | 14 |
| Off Treatment Follow-Up | Other | 2 | 0 |
| Off Treatment Follow-Up | Subject Withdrew Consent | 1 | 0 |
Baseline characteristics
| Characteristic | Metformin XR | Metformin IR | Total |
|---|---|---|---|
| Age, Continuous | 56.8 years STANDARD_DEVIATION 10.69 | 55.3 years STANDARD_DEVIATION 10.34 | 56.0 years STANDARD_DEVIATION 10.53 |
| Age, Customized < 65 years | 198 participants | 226 participants | 424 participants |
| Age, Customized >= 65 years | 70 participants | 45 participants | 115 participants |
| Race/Ethnicity, Customized Asian | 17 participants | 20 participants | 37 participants |
| Race/Ethnicity, Customized Black or African American | 22 participants | 19 participants | 41 participants |
| Race/Ethnicity, Customized Other | 2 participants | 7 participants | 9 participants |
| Race/Ethnicity, Customized White | 227 participants | 225 participants | 452 participants |
| Sex: Female, Male Female | 122 Participants | 122 Participants | 244 Participants |
| Sex: Female, Male Male | 146 Participants | 149 Participants | 295 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 25 / 283 | 22 / 285 |
| serious Total, serious adverse events | 8 / 283 | 10 / 285 |
Outcome results
Primary
Adjusted Mean Change From Baseline in HbA1c
Mean change in glycated hemoglobin (HbA1c) from baseline to Week 24 in the double-blind treatment period.
Time frame: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Metformin XR | Adjusted Mean Change From Baseline in HbA1c | -0.93 percent | Standard Error 0.0485 |
| Metformin IR | Adjusted Mean Change From Baseline in HbA1c | -0.96 percent | Standard Error 0.048 |
95% CI: [-0.1, 0.17]
Primary
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=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)
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.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Metformin XR | 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 |
| Metformin XR | 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 |
| Metformin XR | 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 |
| Metformin XR | 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 |
| Metformin XR | 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 |
| Metformin XR | 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 |
| Metformin IR | 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 | 0 participants |
| Metformin IR | 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 | 25 participants |
| Metformin IR | 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 | 7 participants |
| Metformin IR | 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 | 1 participants |
| Metformin IR | 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 | 10 participants |
| Metformin IR | 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 |
Secondary
Mean Change in Fasting Plasma Glucose (FPG)
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
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 and who were not excluded due to non-compliance.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Metformin XR | Mean Change in Fasting Plasma Glucose (FPG) | -21.1 mg/dL | Standard Error 1.803 |
| Metformin IR | Mean Change in Fasting Plasma Glucose (FPG) | -20.6 mg/dL | Standard Error 1.789 |
Secondary
Mean Change in Mean Daily Glucose (MDG)
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
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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Metformin XR | Mean Change in Mean Daily Glucose (MDG) | -24.68 mg/dL | Standard Error 1.5813 |
| Metformin IR | Mean Change in Mean Daily Glucose (MDG) | -27.05 mg/dL | Standard Error 1.555 |
Secondary
Percent of Participants With HbA1c < 7%
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
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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Metformin XR | Percent of Participants With HbA1c < 7% | 70.9 percent of participants |
| Metformin IR | Percent of Participants With HbA1c < 7% | 72.0 percent of participants |