Angina Pectoris, Coronary Artery Disease, Type 2 Diabetes Mellitus
Conditions
Keywords
Chronic angina, Angina pectoris, Coronary artery disease, Type 2 Diabetes Mellitus
Brief summary
This study will evaluate the effect of ranolazine compared to placebo on the average weekly angina frequency in subjects with chronic stable angina and coronary artery disease (CAD) who have a history of type 2 diabetes mellitus (T2DM), and whether ranolazine can reduce the frequency of angina (chest pain) attacks, compared to a placebo. Subjects will be asked to record their daily angina episodes in a diary at the end of each study day. Ranolazine is approved for the treatment of chronic angina, and is not approved for the treatment of T2DM.
Detailed description
Participants who meet the eligibility criteria at screening will enter a 4-to 6-week Qualifying Period. The allowed concomitant antianginal medication(s) must be maintained at a stable dose throughout the study. Participants will document the number of angina episodes, number of sublingual nitroglycerin doses taken, and a dyspnea score (on a scale from 1 to 5) on a daily basis in a diary. Participants eligible to stay in the study after the Qualifying Period will enter the 8-week double-blind dosing phase. Participants will have study visits at the end of Weeks 2 and 8. Participants will continue to document the number of angina episodes and number of sublingual nitroglycerin doses taken as well as a dyspnea score on a daily basis by the end of each day in their diary. In addition, participants will be called during Week 2 and at the end of Week 5 to encourage compliance. A safety follow-up phone call will be made 14 days after the last study visit or early discontinuation.
Interventions
DRUGRanolazine
Sponsors
Gilead Sciences
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Written informed consent * Males and females aged at least 18 years * At least a 3-month history of chronic stable angina triggered by physical effort and relieved by rest and/or sublingual nitroglycerin * CAD documented by one or more of the following: 1. Angiographic evidence of ≥ 50% stenosis of one or more major coronary arteries 2. History of myocardial infarction (MI) documented by positive myocardial muscle creatine kinase (CK-MB) enzymes, troponins, or electrocardiogram (ECG) changes 3. Cardiac imaging study or exercise test diagnostic for CAD * Treatment with up to 2 antianginal therapies at a stable dose for at least 2 weeks prior to the Qualifying Period. * Documented history of T2DM * Willing to maintain stable tobacco usage habits throughout the study * Willing to maintain stable activity levels throughout the study * Females of childbearing potential must agree to utilize highly effective contraception methods from Screening throughout the duration of study treatment and for 14 days following the last dose of study drug.
Exclusion criteria
* New York Heart Association (NYHA) Class III and IV * Acute coronary syndrome in the prior 2 months or planned coronary revascularization during the study period * Stroke or transient ischemic attack within 6 months prior to Screening * QTc \> 500 milliseconds * Uncontrolled hypertension (seated systolic blood pressure \> 180 mmHg or diastolic blood pressure \> 110 mmHg) * Systolic blood pressure \< 100 mmHg * Clinically significant hepatic impairment * Prior treatment with ranolazine, or known hypersensitivity or intolerance to ranolazine * Females who are breastfeeding * Positive serum pregnancy test * Participation in another investigational drug or device study within 1 month prior to Screening * Current treatment with trimetazidine, ivabradine, or nicorandil. Subjects will need to discontinue these medications 2 weeks prior to the Qualifying Period. * Current treatment with potent inhibitors of cytochrome (CYP)3A (eg, ketoconazole, itraconazole, clarithromycin, nefazodone, nelfinavir, ritonavir, indinavir, and saquinavir) * Current treatment with CYP3A and P glycoprotein (Pgp) inducers (eg, rifampicin/rifampin, carbamazepine, and St. John's wort \[Hypericum perforatum\]) * Current treatment with CYP3A4 substrates with a narrow therapeutic range (eg, cyclosporine, tacrolimus, and sirolimus) * Subjects taking simvastatin who cannot reduce the dose to 20 mg once daily or who cannot switch to another statin * Current treatment with Class I or III antiarrhythmic medications * History of illicit drug use or alcohol abuse within 1 year of Screening * Any other conditions that, in the opinion of the investigator, are likely to prevent compliance with the study protocol or pose a safety concern if the subject participates in the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Average Weekly Angina Frequency Over the Last 6 Weeks of Treatment | 6 weeks | Average weekly angina frequency was defined as the total number of angina episodes reported during the last 6 weeks of treatment divided by 6 weeks. For subjects who terminated with less than 6 weeks of treatment, frequency was calculated as the total number of angina episodes reported during the treatment period divided by the subject's actual duration of treatment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Average Weekly Frequency of Sublingual Nitroglycerin Use Over the Last 6 Weeks of Treatment | 6 weeks | Average weekly frequency of sublingual nitroglycerin use was defined as the total number reported during the last 6 weeks of treatment divided by the duration corresponding to the last 6 weeks of treatment. |
| Percentage of Weeks Participants Achieved at Least a 50% Reduction in Angina Frequency | 6 weeks | For each participant, the percentage of the last 6 weeks on treatment during which the angina frequency was less than or equal to 50% of the baseline average weekly angina frequency was determined. |
| Percentage of the Last 6 Weeks on Treatment During Which the Angina Frequency Was ≤ 50% of the Baseline Average Weekly Angina Frequency | 6 weeks | — |
| Change From Baseline in the Short-Form 36® (SF-36) Mental and Physical Component Scores | Up to 8 weeks | The range of each health domain score is 0-100, with 0 indicating a poorer health state and 100 indicating a better health state. An increase in score indicates an improvement in health state. Participants were asked to complete the survey at randomization (prior to receiving treatment), and at end of treatment visit (Week 8) or early study drug discontinuation or early termination visit. The survey asked participants for responses specific to the preceding 4 weeks prior to completing the survey. |
| Patient's Global Impression of Change (PGIC) Scale Score | 8 weeks | The PGIC was completed at the end of treatment/last visit.The PGIC scale measures the change in the participant's overall status since the beginning of the study on a scale ranging from 1 (no change or worse) to 7 (very much improved). |
Countries
Belarus, Bulgaria, Canada, Czechia, Georgia, Germany, Israel, Poland, Russia, Serbia, Slovakia, Slovenia, Ukraine, United States
Participant flow
Recruitment details
Participants were enrolled at a total of 116 study sites in North America, Europe, and Asia. The first participant was screened on 05 October 2011. The last participant observation occurred on 25 October 2012.
Pre-assignment details
1142 participants entered the qualifying period.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Qualifying phase: Participants entered a 2-week washout period if needed to discontinue antianginal drugs (except beta-blockers) followed by placebo to match ranolazine (1 tablet twice daily) during a 4-week run-in period. Participants with at least 85% adherence to documentation requirements (angina frequency and sublingual nitroglycerin use) over the last 21 days of the placebo run-in period were randomized to the treatment period.
Treatment Period: Placebo to match ranolazine (Day 1: 1 tablet in the evening; Days 2-7: 1 tablet twice daily; 2 tablets twice daily thereafter) for up to 8 weeks. | 474 |
| Ranolazine Qualifying phase: Participants entered a 2-week washout period if needed to discontinue antianginal drugs (except beta-blockers) followed by placebo to match ranolazine (1 tablet twice daily) during a 4-week run-in period. Participants with at least 85% adherence to documentation requirements (angina frequency and sublingual nitroglycerin use) over the last 21 days of the placebo run-in period were randomized to the treatment period.
Treatment period: Ranolazine tablets (Day 1: 1 × 500 tablet in the evening; Days 2-7: 1 × 500 mg twice daily; 2 × 500 mg twice daily thereafter) for up to 8 weeks. | 470 |
| Total | 944 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 9 | 8 |
| Overall Study | Death | 0 | 1 |
| Overall Study | Did Not Meet Qualifying Criteria | 3 | 5 |
| Overall Study | Investigator's Discretion | 2 | 0 |
| Overall Study | Protocol Violation | 1 | 2 |
| Overall Study | Randomized but Not Treated | 2 | 3 |
| Overall Study | Revascularization | 0 | 1 |
| Overall Study | Subject Withdrew Consent | 1 | 2 |
| Overall Study | Unsatisfactory Response | 1 | 0 |
Baseline characteristics
| Characteristic | Ranolazine | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 63 years STANDARD_DEVIATION 8.6 | 64 years STANDARD_DEVIATION 8.5 | 64 years STANDARD_DEVIATION 8.5 |
| Age, Customized 65 - 74 years | 160 participants | 170 participants | 330 participants |
| Age, Customized < 65 years | 264 participants | 249 participants | 513 participants |
| Age, Customized ≥ 75 years | 46 participants | 55 participants | 101 participants |
| Body Mass Index | 31.3 kg/m^2 STANDARD_DEVIATION 5.01 | 31.1 kg/m^2 STANDARD_DEVIATION 4.9 | 31.2 kg/m^2 STANDARD_DEVIATION 4.96 |
| Glycosylated hemoglobin (HbA1c) | 7.3 percent HbA1c in blood STANDARD_DEVIATION 1.5 | 7.3 percent HbA1c in blood STANDARD_DEVIATION 1.53 | 7.3 percent HbA1c in blood STANDARD_DEVIATION 1.52 |
| Race/Ethnicity, Customized Asian | 1 participants | 1 participants | 2 participants |
| Race/Ethnicity, Customized Black or African American | 5 participants | 2 participants | 7 participants |
| Race/Ethnicity, Customized Hispanic or Latino | 4 participants | 5 participants | 9 participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 462 participants | 464 participants | 926 participants |
| Race/Ethnicity, Customized Not Reported | 3 participants | 3 participants | 6 participants |
| Race/Ethnicity, Customized Unknown | 1 participants | 2 participants | 3 participants |
| Race/Ethnicity, Customized White | 464 participants | 471 participants | 935 participants |
| Region of Enrollment Belarus | 0 participants | 1 participants | 1 participants |
| Region of Enrollment Bulgaria | 11 participants | 9 participants | 20 participants |
| Region of Enrollment Canada | 1 participants | 2 participants | 3 participants |
| Region of Enrollment Czech Republic | 6 participants | 3 participants | 9 participants |
| Region of Enrollment Georgia | 40 participants | 36 participants | 76 participants |
| Region of Enrollment Germany | 2 participants | 1 participants | 3 participants |
| Region of Enrollment Israel | 14 participants | 10 participants | 24 participants |
| Region of Enrollment Poland | 40 participants | 53 participants | 93 participants |
| Region of Enrollment Russian Federation | 263 participants | 281 participants | 544 participants |
| Region of Enrollment Serbia | 2 participants | 3 participants | 5 participants |
| Region of Enrollment Slovakia | 9 participants | 12 participants | 21 participants |
| Region of Enrollment Slovenia | 1 participants | 0 participants | 1 participants |
| Region of Enrollment Ukraine | 69 participants | 53 participants | 122 participants |
| Region of Enrollment United States | 15 participants | 12 participants | 27 participants |
| Sex: Female, Male Female | 180 Participants | 182 Participants | 362 Participants |
| Sex: Female, Male Male | 290 Participants | 292 Participants | 582 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 474 | 0 / 470 |
| serious Total, serious adverse events | 20 / 474 | 16 / 470 |
Outcome results
Primary
Average Weekly Angina Frequency Over the Last 6 Weeks of Treatment
Average weekly angina frequency was defined as the total number of angina episodes reported during the last 6 weeks of treatment divided by 6 weeks. For subjects who terminated with less than 6 weeks of treatment, frequency was calculated as the total number of angina episodes reported during the treatment period divided by the subject's actual duration of treatment.
Time frame: 6 weeks
Population: Full Analysis Set (FAS): randomized participants who received at least 1 dose of randomized study drug with at least 1 postbaseline primary efficacy measurement and did not have any major eligibility violations. Participants were included in the FAS if they did not discontinue study drug prior to Day 14.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Average Weekly Angina Frequency Over the Last 6 Weeks of Treatment | 5.2 angina attacks per week | Standard Deviation 4.73 |
| Ranolazine | Average Weekly Angina Frequency Over the Last 6 Weeks of Treatment | 4.5 angina attacks per week | Standard Deviation 4.32 |
p-value: 0.008Generalized linear model
Secondary
Average Weekly Frequency of Sublingual Nitroglycerin Use Over the Last 6 Weeks of Treatment
Average weekly frequency of sublingual nitroglycerin use was defined as the total number reported during the last 6 weeks of treatment divided by the duration corresponding to the last 6 weeks of treatment.
Time frame: 6 weeks
Population: Full Analysis Set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Average Weekly Frequency of Sublingual Nitroglycerin Use Over the Last 6 Weeks of Treatment | 3.6 nitroglycerin uses per week | Standard Deviation 5.35 |
| Ranolazine | Average Weekly Frequency of Sublingual Nitroglycerin Use Over the Last 6 Weeks of Treatment | 2.9 nitroglycerin uses per week | Standard Deviation 4.34 |
p-value: 0.003Generalized linear model
Secondary
Change From Baseline in the Short-Form 36® (SF-36) Mental and Physical Component Scores
The range of each health domain score is 0-100, with 0 indicating a poorer health state and 100 indicating a better health state. An increase in score indicates an improvement in health state. Participants were asked to complete the survey at randomization (prior to receiving treatment), and at end of treatment visit (Week 8) or early study drug discontinuation or early termination visit. The survey asked participants for responses specific to the preceding 4 weeks prior to completing the survey.
Time frame: Up to 8 weeks
Population: Participants in the Full Analysis Set with available data were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in the Short-Form 36® (SF-36) Mental and Physical Component Scores | Mental Component Score | 1.2 units on a scale | Standard Error 0.37 |
| Placebo | Change From Baseline in the Short-Form 36® (SF-36) Mental and Physical Component Scores | Physical Component Score | 1.9 units on a scale | Standard Error 0.25 |
| Ranolazine | Change From Baseline in the Short-Form 36® (SF-36) Mental and Physical Component Scores | Mental Component Score | 1.0 units on a scale | Standard Error 0.39 |
| Ranolazine | Change From Baseline in the Short-Form 36® (SF-36) Mental and Physical Component Scores | Physical Component Score | 2.8 units on a scale | Standard Error 0.26 |
Secondary
Patient's Global Impression of Change (PGIC) Scale Score
The PGIC was completed at the end of treatment/last visit.The PGIC scale measures the change in the participant's overall status since the beginning of the study on a scale ranging from 1 (no change or worse) to 7 (very much improved).
Time frame: 8 weeks
Population: Participants in the Full Analysis Set with available data were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Patient's Global Impression of Change (PGIC) Scale Score | 3.9 units on a scale | Standard Error 0.07 |
| Ranolazine | Patient's Global Impression of Change (PGIC) Scale Score | 4.0 units on a scale | Standard Error 0.07 |
Secondary
Percentage of the Last 6 Weeks on Treatment During Which the Angina Frequency Was ≤ 50% of the Baseline Average Weekly Angina Frequency
Time frame: 6 weeks
Population: Full Analysis Set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percentage of the Last 6 Weeks on Treatment During Which the Angina Frequency Was ≤ 50% of the Baseline Average Weekly Angina Frequency | 50 percentage of weeks | Standard Error 1.4 |
| Ranolazine | Percentage of the Last 6 Weeks on Treatment During Which the Angina Frequency Was ≤ 50% of the Baseline Average Weekly Angina Frequency | 54 percentage of weeks | Standard Error 1.3 |
Secondary
Percentage of Weeks Participants Achieved at Least a 50% Reduction in Angina Frequency
For each participant, the percentage of the last 6 weeks on treatment during which the angina frequency was less than or equal to 50% of the baseline average weekly angina frequency was determined.
Time frame: 6 weeks
Population: Participants in the Full Analysis Set with available data were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percentage of Weeks Participants Achieved at Least a 50% Reduction in Angina Frequency | 41 percentage of weeks | Standard Deviation 36 |
| Ranolazine | Percentage of Weeks Participants Achieved at Least a 50% Reduction in Angina Frequency | 46 percentage of weeks | Standard Deviation 35 |