Type 2 Diabetes Mellitus
Conditions
Brief summary
This is a randomized, double-blind, placebo-controlled, parallel-group, multicenter study to determine the effect of ranolazine when added to metformin on glycemic control in adults with type 2 diabetes mellitus (T2DM) who are inadequately controlled despite current treatment with stable metformin therapy in addition to diet and exercise.
Interventions
DRUGRanolazine
Ranolazine tablet(s) administered orally
Placebo to match ranolazine for the duration of the study
DRUGMetformin
Metformin tablet(s) administered orally once daily
DRUGPlacebo to match metformin
Placebo to match metformin for the duration of the study
BEHAVIORALDiet
Participants are instructed to continue the diet regimen prescribed by their physician.
BEHAVIORALExercise
Participants are instructed to continue the exercise regimen prescribed by their physician.
Sponsors
Gilead Sciences
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Documented history of T2DM * Metformin therapy at a stable total daily dose ≥ 1500 mg and ≤ 2550 mg in addition to diet and exercise for ≥ 8 weeks prior to Screening * Body mass index (BMI) 25 to 45 kg/m\^2, inclusive, at Screening * HbA1c within specified ranges at Screening and at the end of the Qualifying Period based on current metformin dose * C-peptide ≥ 0.8 ng/mL at Screening * Fasting serum glucose (FSG) ≥ 130 mg/dL (7.2 mmol/L) and ≤ 240 mg/dL (13.3 mmol/L) at Screening and at the end of the Qualifying Period
Exclusion criteria
* Type 1 diabetes mellitus * History of diabetic ketoacidosis, ketosis-prone diabetes, or hyperosmolar hyperglycemic coma * History of severe hypoglycemia * Any clinically significant cardiovascular or cerebrovascular event ≤ 3 months prior to Screening * History of congestive heart failure * Corrected QT interval (QTc) \> 500 msec by ECG at Screening, a personal or family history of QTc prolongation, congenital long QT syndrome, or individuals who are receiving drugs that prolong the QTc interval, such as Class Ia or Class III antiarrhythmic agents, erythromycin, and certain antipsychotics (eg, ziprasidone) * Serum creatinine concentration ≥ 1.5 mg/dL for males or ≥ 1.4 mg/dL for females at Screening * Active liver disease and/or significant abnormal liver function defined as aspartate aminotransferase (AST) \> 3 x upper limit of the normal range (ULN) and/or alanine aminotransferase (ALT) \> 3 x ULN and/or serum total bilirubin \> 2.0 mg/dL * Use of any non-insulin antihyperglycemic therapy (other than metformin) for more than 14 days (consecutive or not) during the 12 weeks (24 weeks for thiazolidinediones) prior to Screening and/or use of any antihyperglycemic therapy other than metformin, at any dose, at any time during the 4 weeks prior to randomization * Treatment with chronic insulin within 24 weeks prior to Screening (except for one temporary period of daily insulin injections no longer than 7 days) * Treatment with strong or moderate cytochrome P450 3A (CYP3A) inhibitors or P-glycoprotein (P-gp) inhibitors within 14 days prior to randomization * Treatment with CYP3A inducers or P-gp inducers within 14 days prior to randomization * Treatment with simvastatin or lovastatin at a dose \> 20 mg or \> 40 mg daily, respectively, within 14 days prior to randomization
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Week 24 | Baseline; Week 24 | The average (mean) change from baseline in HbA1c at Week 24 was analyzed. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Fasting Serum Glucose at Week 24 | Baseline; Week 24 | The average (mean) change from baseline in fasting serum glucose at Week 24 was analyzed. |
| Change From Baseline in 2-hour Postprandial Serum Glucose at Week 24 | Baseline; Week 24 | The average (mean) change from baseline in 2-hour postprandial serum glucose at Week 24 was analyzed. Mixed Meal Tolerance Test (MMTT) Full Analysis Set: randomized participants who received at least one dose of study treatment with a baseline and at least one postbaseline measurement of serum glucose at T=120 minutes during the MMTT, administered under fasting conditions, excluding participants with major eligibility protocol violations; analyzed based on the randomized treatment regardless of actual treatment received. |
Countries
Canada, Czechia, Hungary, India, Israel, Mexico, Poland, Russia, South Africa, Ukraine, United States
Participant flow
Recruitment details
Participants were enrolled (during the Qualifying Period) at a total of 112 study sites in Canada, Europe, Asia, Mexico, South Africa, and the United States. The first participant was screened on 28 June 2012. The last participant observation occurred on 01 October 2013.
Pre-assignment details
580 participants entered the qualifying period; 442 participants were randomized and treated, and comprise the Safety Analysis Set. Of these, 20 participants were excluded due to major eligibility criteria protocol violation or because the participant had no postbaseline data; the remaining 422 participants comprise the Full Analysis Set.
Participants by arm
| Arm | Count |
|---|---|
| Placebo+Metformin Qualifying period: Metformin 1000 mg (2 x 500 mg tablets) twice daily plus placebo to match ranolazine twice daily for either 2 or 8 weeks (dependent on metformin dose and HbA1c level at Screening) and participants who were ≥ 80% compliant and meeting eligibility criteria continued to the treatment period.
Treatment period: Metformin 1000 mg (2 x 500 mg tablets) twice daily plus placebo to match ranolazine twice daily through Week 24.
Participants were required to maintain their diet and exercise regimen. | 222 |
| Ranolazine+Metformin Qualifying period: Metformin 1000 mg (2 x 500 mg tablets) twice daily plus placebo to match ranolazine twice daily for either 2 or 8 weeks (dependent on metformin dose and HbA1c level at Screening) and participants who were ≥ 80% compliant and meeting eligibility criteria continued to the treatment period.
Treatment period: Ranolazine 500 mg (1 x 500 mg tablet) twice daily plus metformin 500 mg/metformin placebo (1 x 500 mg tablet active metformin plus 1 placebo tablet) twice daily on Days 1 through 7, followed by ranolazine 1000 mg (2 x 500 mg tablets) twice daily plus metformin 500 mg/metformin placebo (1 x 500 mg tablet active metformin plus 1 placebo tablet) twice daily from Day 8 through Week 24.
Participants were required to maintain their diet and exercise regimen. | 220 |
| Total | 442 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 5 | 7 |
| Overall Study | Hyperglycemia | 0 | 1 |
| Overall Study | Investigator's Discretion | 2 | 2 |
| Overall Study | Lost to Follow-up | 4 | 3 |
| Overall Study | Protocol Violation | 9 | 5 |
| Overall Study | Subject Non-compliance | 14 | 6 |
| Overall Study | Subject Withdrew Consent | 6 | 11 |
Baseline characteristics
| Characteristic | Total | Placebo+Metformin | Ranolazine+Metformin |
|---|---|---|---|
| Age, Continuous | 56 years STANDARD_DEVIATION 9.1 | 56 years STANDARD_DEVIATION 8.9 | 56 years STANDARD_DEVIATION 9.3 |
| Body Mass Index (BMI) | 31.4 kg/m^2 STANDARD_DEVIATION 4.71 | 31.2 kg/m^2 STANDARD_DEVIATION 4.46 | 31.6 kg/m^2 STANDARD_DEVIATION 4.95 |
| Duration of Diabetes | 6.5 years STANDARD_DEVIATION 5.34 | 6.7 years STANDARD_DEVIATION 5.31 | 6.4 years STANDARD_DEVIATION 5.37 |
| Estimated glomerular filtration rate (eGFR) | 90.4 mL/min/1.73m^2 STANDARD_DEVIATION 20.91 | 90.8 mL/min/1.73m^2 STANDARD_DEVIATION 20.01 | 89.9 mL/min/1.73m^2 STANDARD_DEVIATION 21.82 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 90 Participants | 53 Participants | 37 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 347 Participants | 166 Participants | 181 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 5 Participants | 3 Participants | 2 Participants |
| Fasting Serum Glucose (FSG) | 169.4 mg/dL STANDARD_DEVIATION 34.42 | 170.0 mg/dL STANDARD_DEVIATION 35.97 | 168.8 mg/dL STANDARD_DEVIATION 32.86 |
| Glycosylated hemoglobin (HbA1c) | 8.09 percent HbA1c in blood STANDARD_DEVIATION 0.71 | 8.09 percent HbA1c in blood STANDARD_DEVIATION 0.729 | 8.10 percent HbA1c in blood STANDARD_DEVIATION 0.692 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 2 participants | 2 participants | 0 participants |
| Race/Ethnicity, Customized Asian | 106 participants | 52 participants | 54 participants |
| Race/Ethnicity, Customized Black or African American | 19 participants | 8 participants | 11 participants |
| Race/Ethnicity, Customized Other | 2 participants | 0 participants | 2 participants |
| Race/Ethnicity, Customized White | 313 participants | 160 participants | 153 participants |
| Region of Enrollment Canada | 4 participants | 1 participants | 3 participants |
| Region of Enrollment Czech Republic | 1 participants | 0 participants | 1 participants |
| Region of Enrollment Hungary | 16 participants | 8 participants | 8 participants |
| Region of Enrollment India | 93 participants | 44 participants | 49 participants |
| Region of Enrollment Israel | 3 participants | 2 participants | 1 participants |
| Region of Enrollment Mexico | 10 participants | 6 participants | 4 participants |
| Region of Enrollment Poland | 5 participants | 0 participants | 5 participants |
| Region of Enrollment Russian Federation | 86 participants | 37 participants | 49 participants |
| Region of Enrollment South Africa | 11 participants | 7 participants | 4 participants |
| Region of Enrollment Ukraine | 64 participants | 35 participants | 29 participants |
| Region of Enrollment United States | 149 participants | 82 participants | 67 participants |
| Sex: Female, Male Female | 219 Participants | 98 Participants | 121 Participants |
| Sex: Female, Male Male | 223 Participants | 124 Participants | 99 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 14 / 222 | 18 / 220 |
| serious Total, serious adverse events | 2 / 222 | 3 / 220 |
Outcome results
Primary
Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Week 24
The average (mean) change from baseline in HbA1c at Week 24 was analyzed.
Time frame: Baseline; Week 24
Population: Participants in the Full Analysis Set (randomized participants who received ≥ 1 dose of study treatment with a baseline and at least one postbaseline measurement of HbA1c, excluding participants with major eligibility violations, and analyzed based on randomized treatment, regardless of actual treatment received) with available data were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo+Metformin | Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Week 24 | HbA1c at Week 24 | 7.86 percent of HbA1c in blood | Standard Deviation 1.003 |
| Placebo+Metformin | Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Week 24 | Change from baseline in HbA1c at Week 24 | -0.20 percent of HbA1c in blood | Standard Deviation 0.949 |
| Ranolazine+Metformin | Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Week 24 | HbA1c at Week 24 | 7.72 percent of HbA1c in blood | Standard Deviation 1.069 |
| Ranolazine+Metformin | Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Week 24 | Change from baseline in HbA1c at Week 24 | -0.37 percent of HbA1c in blood | Standard Deviation 0.916 |
Comparison: Assuming a common standard deviation of 1.2%, an effective sample size of 400 would provide at least 90% power to detect a statistically significant treatment difference of -0.4% (ranolazine vs. placebo) for the reduction of HbA1c from baseline at Week 24 based on a 2-sided alpha of 0.05 and 1:1 randomization.p-value: 0.30695% CI: [-0.31, 0.1]Mixed Effects Model Analysis
Secondary
Change From Baseline in 2-hour Postprandial Serum Glucose at Week 24
The average (mean) change from baseline in 2-hour postprandial serum glucose at Week 24 was analyzed. Mixed Meal Tolerance Test (MMTT) Full Analysis Set: randomized participants who received at least one dose of study treatment with a baseline and at least one postbaseline measurement of serum glucose at T=120 minutes during the MMTT, administered under fasting conditions, excluding participants with major eligibility protocol violations; analyzed based on the randomized treatment regardless of actual treatment received.
Time frame: Baseline; Week 24
Population: Participants in the MMTT Full Analysis Set with available data were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo+Metformin | Change From Baseline in 2-hour Postprandial Serum Glucose at Week 24 | -4 mg/dL | Standard Deviation 54 |
| Ranolazine+Metformin | Change From Baseline in 2-hour Postprandial Serum Glucose at Week 24 | 7 mg/dL | Standard Deviation 58.2 |
Secondary
Change From Baseline in Fasting Serum Glucose at Week 24
The average (mean) change from baseline in fasting serum glucose at Week 24 was analyzed.
Time frame: Baseline; Week 24
Population: Participants in the Full Analysis Set with available data were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo+Metformin | Change From Baseline in Fasting Serum Glucose at Week 24 | -3 mg/dL | Standard Deviation 44.7 |
| Ranolazine+Metformin | Change From Baseline in Fasting Serum Glucose at Week 24 | 3 mg/dL | Standard Deviation 42.5 |