Type 2 Diabetes Mellitus
Conditions
Keywords
Type 2 Diabetes Mellitus
Brief summary
This is a randomized, double-blind, placebo-controlled, parallel-group, multi-center study to determine the effect of ranolazine when given as monotherapy on glycemic control in subjects with type 2 diabetes mellitus (T2DM) who were inadequately controlled with diet and exercise alone and who are treatment naive to antihyperglycemic therapy or have not received antihyperglycemic therapy in the 90 days (or thiazolidinediones \[TZDs\] for at least 24 weeks) prior to screening, and to characterize the relationship between HbA1c reduction and other glycemic parameters in subjects with T2DM.
Interventions
DRUGRanolazine
Ranolazine tablets administered orally twice daily.
DRUGPlacebo
Placebo to match ranolazine administered orally twice daily.
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
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Written informed consent * Males and females, 18 to 75 years old, inclusive * Documented history of T2DM * Treatment naïve to antihyperglycemic therapy or having received no prior treatment with antihyperglycemic therapy for at least 90 days (TZDs for at least 24 weeks) prior to screening * Body mass index (BMI) 25 kg/m2 to 45 kg/m2 inclusive at screening * HbA1c 7% - 10%, inclusive at screening and at the end of the Qualifying Period (Day 14 +2 days) * Fasting serum glucose (FSG) of ≥ 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 (Day 14 +2 days). A one-time central laboratory re-test of FSG is allowed in subjects with an initial central laboratory FSG ≥ 125 mg/dL (6.9 mmol/L) and \< 130 mg/dL (7.2 mmol/L) who are otherwise eligible as determined by the investigator. * Fasting serum C-peptide ≥ 0.8 ng/mL at screening * Able and willing to comply with all study procedures during the course of the study * Females of child-bearing potential must have a negative pregnancy test at screening and must agree to use highly effective contraception methods from screening throughout the duration of the Treatment Period and for 14 days following the last dose of study drug * At least 80% compliant with dosing during the Qualifying Period
Exclusion criteria
* History of or current diagnosis of type 1 diabetes mellitus * History of diabetic ketoacidosis, ketosis-prone diabetes, or hyperosmolar hyperglycemic coma * History of a severe episode of hypoglycemia (≥ 1 episode within 3 months prior to screening or ≥ 2 episodes within 6 months prior to screening), defined as hypoglycemia requiring 3rd party assistance to actively administer carbohydrate, glucagon, or other resuscitative actions due to severe impairment in consciousness or behavior * Clinically significant complications of diabetes that, in the judgment of the investigator, would make the subject unsuitable to participate in this study * History of any clinically significant cardiovascular or cerebrovascular event (eg, myocardial infarction \[MI\], acute coronary syndrome \[ACS\], recent coronary revascularization \[including coronary artery bypass graft procedures or percutaneous coronary intervention\], transient ischemic attack or ischemic stroke) ≤ 3 months prior to screening * Inadequately controlled or unstable hypertension as defined by systolic blood pressure (SBP) \> 160 mmHg or diastolic blood pressure (DBP) \> 100 mmHg at screening and randomization * Prolonged QTc interval \> 500 msec by ECG at screening, a personal or family history of QTc prolongation, congenital long QT syndrome, or subjects who are receiving drugs that prolong the QTc interval, such as Class Ia or Class III antiarrhythmic agents, erythromycin, and certain antipsychotics (eg, ziprasidone) * History of bariatric surgery at any time in the past or any other surgery \< 2 months before screening, or planning to undergo surgery during the study. Subjects with a planned minor surgery may be enrolled upon approval by the Medical Monitor. * Any other hospitalization in the 14 days prior to screening or planned hospitalization at any time during the study * Significant weight change (± 5%) \< 2 months prior to screening or on a weight-loss program and is not in the maintenance phase at screening * Severe renal impairment, defined as an estimated glomerular filtration rate (eGFR) by the Modification of Diet in Renal Disease (MDRD) equation \< 30 mL/min/1.73 m2 at screening or undergoing any type of dialysis at screening or planning to undergo any type of dialysis during the course of the study. * History of liver cirrhosis (Child-Pugh Class A, B or C) * Active liver disease and/or significant abnormal liver function defined as aspartate aminotransferase (AST) \> 3x upper limit of the normal range (ULN) and/or alanine aminotransferase (ALT) \> 3x ULN and/or serum total bilirubin \> 2.0 mg/dL * History of cancer (except non-melanomic skin cancers or cervical in situ) within 5 years prior to screening * History of alcohol or other drug abuse \< 12 months prior to screening * Any other clinically significant existing medical or psychiatric condition, including clinically significant laboratory abnormalities, or one requiring further evaluation that, in the opinion of the investigator, could interfere with conduct of the study or interpretation of the data * Prior treatment with open-label ranolazine or known hypersensitivity or intolerance to ranolazine or any of its excipients * Treatment with strong or moderate cytochrome (CYP)3A 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 CYP3A4 substrates with a narrow therapeutic range (eg, cyclosporine, tacrolimus, sirolimus) within 14 days prior to randomization * Treatment with simvastatin at a daily dose \> 20 mg or lovastatin at a daily dose \> 40 mg, within 14 days prior to randomization * Weight-loss medication or anti-obesity medication (prescription or nonprescription) \< 3 months prior to screening * Treatment with niacin \> 200 mg daily; if receiving ≤ 200 mg daily, should be on stable doses for ≥ 90 days prior to screening and for the duration of the study * Expected or current treatment with systemic corticosteroids (oral or injectable) for \> 14 days from screening through the end of the Treatment Period. Topical or inhaled corticosteroid formulations are permitted at any time during the study * If receiving thyroid replacement therapy, should be on stable doses for at least 6 weeks prior to randomization * Hemoglobin \< 12 g/dL for males; or \< 11 g/dL for females, at screening * Participation in another clinical study involving an investigational drug or device \< 30 days prior to screening; participation in another clinical study involving an antihyperglycemic therapy \< 90 days prior to screening * Donation of blood \< 2 months prior to screening; plans to donate blood while participating in the study * Females who are pregnant or breastfeeding * Other condition(s) that, in the opinion of the investigator, would compromise the safety of the subject, would prevent compliance with the study protocol (including the ability to comply with Mixed Meal Tolerance Test \[MMTT\]), or would compromise the quality of the clinical study
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. |
| Percentage of Participants With HbA1c < 7% at Week 24 | Week 24 | — |
| 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 time \[T\] = 120 minutes during the MMTT, administered under fasting conditions, excluding participants with major eligibility protocol violations and analyzed based on the randomized treatment regardless of actual treatment received. |
| Change From Baseline in Incremental Change of 2-hour Postprandial Serum Glucose at Week 24 | Baseline; Week 24 | The average (mean) change from baseline in incremental change of 2-hour postprandial serum glucose at Week 24 was analyzed. |
Countries
Czechia, Hungary, Poland, Romania, Russia, Serbia, Slovakia, South Africa, Ukraine, United States
Participant flow
Recruitment details
Participants were enrolled at a total of 113 study sites in the United States, South Africa, Europe, and Russia. The first participant was screened on 15 November 2011. The last participant observation occurred on 21 October 2013.
Pre-assignment details
605 participants entered the qualifying period; 465 were randomized, and 464 were randomized and treated (Safety Analysis Set). Of these, 8 were excluded due to major eligibility criteria protocol violation or had baseline but no on-treatment data; thus, 456 were included in the Full Analysis Set.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Qualifying Period: Placebo to match ranolazine (1 tablet twice daily) for 14 days.
Treatment Period: Placebo to match ranolazine (Days 1-7: 1 tablet twice daily; 2 tablets twice daily thereafter) for up to 24 weeks.
Participants were required to maintain their diet and exercise regimen. | 232 |
| Ranolazine Qualifying Period: Placebo to match ranolazine (1 tablet twice daily) for 14 days.
Treatment Period: Ranolazine tablets (Days 1-7: 1 × 500 mg twice daily; 2 × 500 mg twice daily thereafter) for up to 24 weeks.
Participants were required to maintain their diet and exercise regimen. | 232 |
| Total | 464 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event Other than Hyperglycemia | 3 | 10 |
| Overall Study | Hyperglycemia | 5 | 2 |
| Overall Study | Investigator's Discretion | 3 | 1 |
| Overall Study | Lost to Follow-up | 4 | 1 |
| Overall Study | Protocol Violation | 5 | 1 |
| Overall Study | Randomized but Not Treated | 0 | 1 |
| Overall Study | Subject Noncompliance | 8 | 15 |
| Overall Study | Subject Withdrew Consent | 6 | 3 |
Baseline characteristics
| Characteristic | Placebo | Ranolazine | Total |
|---|---|---|---|
| Age, Continuous | 56 years STANDARD_DEVIATION 9.3 | 55 years STANDARD_DEVIATION 9.5 | 56 years STANDARD_DEVIATION 9.4 |
| Age, Customized < 65 years | 197 participants | 199 participants | 396 participants |
| Age, Customized ≥ 65 years | 35 participants | 33 participants | 68 participants |
| Body Mass Index | 32.8 kg/m^2 STANDARD_DEVIATION 4.85 | 32.8 kg/m^2 STANDARD_DEVIATION 4.75 | 32.8 kg/m^2 STANDARD_DEVIATION 4.8 |
| Duration of Diabetes | 3.0 years STANDARD_DEVIATION 4 | 3.0 years STANDARD_DEVIATION 4.29 | 3.0 years STANDARD_DEVIATION 4.14 |
| Estimated glomerular filtration rate (eGFR) | 83.3 mL/min/1.73m^2 STANDARD_DEVIATION 18.4 | 84.5 mL/min/1.73m^2 STANDARD_DEVIATION 18.8 | 83.9 mL/min/1.73m^2 STANDARD_DEVIATION 18.59 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 31 Participants | 29 Participants | 60 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 201 Participants | 202 Participants | 403 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Fasting Serum Glucose | 171.5 mg/dL STANDARD_DEVIATION 34.45 | 172.1 mg/dL STANDARD_DEVIATION 34.32 | 171.8 mg/dL STANDARD_DEVIATION 34.35 |
| Glycosylated hemoglobin (HbA1c) | 8.01 percent HbA1c in blood STANDARD_DEVIATION 0.727 | 8.06 percent HbA1c in blood STANDARD_DEVIATION 0.732 | 8.04 percent HbA1c in blood STANDARD_DEVIATION 0.729 |
| Race/Ethnicity, Customized Asian | 10 participants | 9 participants | 19 participants |
| Race/Ethnicity, Customized Black or African-American | 10 participants | 9 participants | 19 participants |
| Race/Ethnicity, Customized Not Permitted | 1 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized Other | 2 participants | 1 participants | 3 participants |
| Race/Ethnicity, Customized White | 209 participants | 213 participants | 422 participants |
| Region of Enrollment Hungary | 12 participants | 9 participants | 21 participants |
| Region of Enrollment Poland | 7 participants | 11 participants | 18 participants |
| Region of Enrollment Romania | 10 participants | 11 participants | 21 participants |
| Region of Enrollment Russian Federation | 83 participants | 82 participants | 165 participants |
| Region of Enrollment Serbia | 0 participants | 2 participants | 2 participants |
| Region of Enrollment Slovakia | 8 participants | 13 participants | 21 participants |
| Region of Enrollment South Africa | 11 participants | 13 participants | 24 participants |
| Region of Enrollment Ukraine | 39 participants | 36 participants | 75 participants |
| Region of Enrollment United States | 62 participants | 56 participants | 118 participants |
| Sex: Female, Male Female | 113 Participants | 123 Participants | 236 Participants |
| Sex: Female, Male Male | 119 Participants | 109 Participants | 228 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 31 / 232 | 28 / 232 |
| serious Total, serious adverse events | 7 / 232 | 6 / 232 |
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 subjects with major eligibility violations and analyzed based on the randomized treatment regardless of actual treatment received) with available data were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Week 24 | HbA1c at Week 24 | 7.70 percent of HbA1c in blood | Standard Deviation 1.183 |
| Placebo | Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Week 24 | Change from baseline in HbA1c at Week 24 | -0.27 percent of HbA1c in blood | Standard Deviation 1.027 |
| Ranolazine | Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Week 24 | HbA1c at Week 24 | 7.26 percent of HbA1c in blood | Standard Deviation 1.101 |
| Ranolazine | Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Week 24 | Change from baseline in HbA1c at Week 24 | -0.80 percent of HbA1c in blood | Standard Deviation 1.02 |
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 -0.5% (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: <0.000195% CI: [-0.76, -0.36]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 time \[T\] = 120 minutes during the MMTT, administered under fasting conditions, excluding participants with major eligibility protocol violations and analyzed based on the randomized treatment regardless of actual treatment received.
Time frame: Baseline; Week 24
Population: Participants in the Mixed Meal Tolerance Test (MMTT) Full Analysis Set with available data were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in 2-hour Postprandial Serum Glucose at Week 24 | 2 mg/dL | Standard Deviation 65.1 |
| Ranolazine | Change From Baseline in 2-hour Postprandial Serum Glucose at Week 24 | -19 mg/dL | Standard Deviation 53.8 |
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 | Change From Baseline in Fasting Serum Glucose at Week 24 | 1 mg/dL | Standard Deviation 42.2 |
| Ranolazine | Change From Baseline in Fasting Serum Glucose at Week 24 | -7 mg/dL | Standard Deviation 37.5 |
Secondary
Change From Baseline in Incremental Change of 2-hour Postprandial Serum Glucose at Week 24
The average (mean) change from baseline in incremental change of 2-hour postprandial serum glucose at Week 24 was analyzed.
Time frame: Baseline; Week 24
Population: Participants in the Mixed Meal Tolerance Test (MMTT) Full Analysis Set with available data were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Incremental Change of 2-hour Postprandial Serum Glucose at Week 24 | -1 mg/dL | Standard Deviation 47.7 |
| Ranolazine | Change From Baseline in Incremental Change of 2-hour Postprandial Serum Glucose at Week 24 | -12 mg/dL | Standard Deviation 37.9 |
Secondary
Percentage of Participants With HbA1c < 7% at Week 24
Time frame: Week 24
Population: Participants in the Full Analysis Set with Baseline HbA1c ≥ 7% and available data were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With HbA1c < 7% at Week 24 | 25.6 percentage of participants |
| Ranolazine | Percentage of Participants With HbA1c < 7% at Week 24 | 41.2 percentage of participants |