E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10049194 |
E.1.2 | Term | Stable angina pectoris |
E.1.2 | System Organ Class | 10007541 - Cardiac disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate the efficacy of ranolazine compared to placebo on the average weekly angina frequency in subjects with a history of type 2 diabetes mellitus (T2DM) and coronary artery disease (CAD) and chronic stable angina who remain symptomatic despite treatment with 1 or 2 concomitant antianginal agent(s). |
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E.2.2 | Secondary objectives of the trial |
a) To evaluate the efficacy of ranolazine compared to placebo on average weekly frequency of sublingual nitroglycerin (SL NTG) use
b) To evaluate the efficacy of ranolazine compared to placebo on angina-free days
c) To evaluate the efficacy of ranolazine compared to placebo on proportion of subjects achieving at least a 50% reduction in the average weekly angina frequency
d) To evaluate the efficacy of ranolazine compared to placebo on health-related QoL
e) To evaluate the safety and tolerability of ranolazine compared to placebo |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Written informed consent
2. Males and females aged at least 18 years
3. At least a 3-month history of chronic stable angina triggered by physical effort and relieved by rest and/or SL NTG
4. CAD documented by one or more of the following:
a. Evidence, either by invasive coronary angiograms or noninvasive CT coronary angiograms, of ≥ 50% stenosis of one or more major coronary arteries
b. History of myocardial infarction (MI) documented by positive CK-MB enzymes, troponins, or electrocardiogram (ECG) changes
c. Cardiac imaging study or exercise test diagnostic for CAD
d. History of coronary revascularization procedure
5. Treatment with 1 or 2 antianginal therapies at a stable dose for at least 2 weeks prior to the 4-week single-blind placebo run-in period. Allowed antianginals are the following:
• beta-blocker (except sotalol)
• CCB
• dihydropyridine
• non-dihydropyridine (diltiazem at a dose of at least 180 mg daily or verapamil at a dose of at least 180 mg daily)
• LAN
6. Documented history of T2DM
7. Willing to maintain stable tobacco usage habits throughout the study
8. Willing to maintain stable activity levels throughout the study
9. 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. |
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E.4 | Principal exclusion criteria |
1. New York Heart Association (NYHA) Class III and IV
2. Acute coronary syndrome in the prior 2 months or planned coronary revascularization during the study period
3. Stroke or transient ischemic attack within 6 months prior to Screening
4. QTc > 500 milliseconds
5. Uncontrolled hypertension (seated systolic blood pressure > 180 mmHg or diastolic blood pressure > 110 mmHg)
6. Systolic blood pressure < 100 mmHg
7. Clinically significant hepatic impairment
8. Prior treatment with ranolazine, or known hypersensitivity or intolerance to ranolazine
9. Females who are breastfeeding
10. Positive serum pregnancy test
11. Participation in another investigational drug or device study within 1 month prior to Screening
12. Current treatment with trimetazidine, ivabradine, or nicorandil. Subjects will need to discontinue these medications 2 weeks prior to initiating the 4-week single-blind, placebo run-in period.
13. Current treatment with strong inhibitors of CYP3A (eg, ketoconazole, itraconazole, clarithromycin, nefazodone, nelfinavir, ritonavir, indinavir, and saquinavir)
14. Current treatment with CYP3A and Pgp inducers (eg, rifampicin/rifampin, carbamazepine, and St. John’s wort [Hypericum perforatum])
15. Current treatment with CYP3A4 substrates with a narrow therapeutic range (eg, cyclosporine, tacrolimus, and sirolimus)
16. Subjects taking simvastatin who cannot reduce the dose to 20 mg once daily or who cannot switch to another statin
17. Current treatment with Class I or III antiarrhythmic medications
18. History of illicit drug use or alcohol abuse within 1 year of Screening
19. 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
20. Severe renal impairment defined as creatinine clearance or estimated glomerular filtration rate (eGFR) < 30 mL/min as calculated by Cockcroft-Gault formula or Modification of Diet in Renal Disease (MDRD) equation, respectively
21. Subjects taking greater than a total of 1000 mg daily of metformin who cannot reduce the dose to a maximum total of 1000 mg daily (additional anti-diabetic medications may be added as clinically indicated to allow subjects to decrease their metformin dose and maintain glycemic control)
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E.5 End points |
E.5.1 | Primary end point(s) |
Average weekly angina frequency over the last 6 weeks of treatment |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
1. Average weekly frequency of SL NTG use over the last 6 weeks of treatment
2. Angina-free days over the last 6 weeks of treatment
3. Proportion of subjects achieving at least a 50% reduction in the average weekly angina frequency
4. Change from baseline in the SF-36 Mental Component Score
5. Change from baseline in the SF-36 Physical Component Scores
6. Patient’s Global Impression of Change (PGIC) scale score |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 7 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 50 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Austria |
Belarus |
Bulgaria |
Canada |
Czech Republic |
Georgia |
Germany |
Israel |
Poland |
Romania |
Russian Federation |
Serbia |
Singapore |
Slovakia |
Slovenia |
Ukraine |
United States |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 4 |
E.8.9.2 | In all countries concerned by the trial days | 0 |