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] - Nutritional and Metabolic Diseases [C18] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10067585 |
E.1.2 | Term | Type 2 diabetes mellitus |
E.1.2 | System Organ Class | 10027433 - Metabolism and nutrition 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 |
The primary objective of this study is to:
• Determine the effect of ranolazine monotherapy on HbA1c in subjects with T2DM who are inadequately controlled with diet and exercise alone and who are treatment naïve to
antihyperglycemic therapy or have not received antihyperglycemic therapy in the 90 days prior to Screening |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives of the study are to:
• Determine the effect of ranolazine monotherapy on postprandial glucose (PPG)
• Determine the effect of ranolazine monotherapy on fasting serum glucose (FSG)
The additional objectives of the study are to:
• Evaluate the effect of ranolazine monotherapy on each of the following endpoints: serum C-peptide, serum insulin, plasma glucagon
• Evaluate the pharmacokinetics (PK) of ranolazine
The safety objective of the study is to:
• Evaluate the safety and tolerability of ranolazine monotherapy in subjects who are treatment naïve to antihyperglycemic therapy or have not received antihyperglycemic therapy in the 90 days prior to Screening |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Subjects must meet all of the following inclusion criteria to be eligible for participation in this study.
1. Written informed consent
2. Males and females, 18 to 75 years old, inclusive
3. Documented history of T2DM
4. Treatment naïve to antihyperglycemic therapy or having received no prior treatment with antihyperglycemic therapy for at least 90 days prior to Screening
5. Body mass index (BMI) 27-45 kg/m2 inclusive at Screening
6. HbA1c 7% - 10% inclusive, at Screening and at the end of Qualifying Period (Day 14 +2 days)
7. FSG of ≥ 130 mg/dL (7.2 mmol/L) and ≤ 240 mg/dL (13.3 mmol/L) at Screening and at the end of Qualifying Period (Day 14 +2 days)
8. C-peptide > 1.0 ng/mL at Screening
9. Ability and willingness to comply with all study procedures during the course of the study
10. Females of child-bearing potential must have a negative pregnancy test at Screening (unless surgically sterile or > 2 years post-menopausal) 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
11. At least 80% compliant with dosing during the Qualifying Period
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E.4 | Principal exclusion criteria |
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study:
- Diabetes- Specific Exclusions:
1. History of Type 1 Diabetes Mellitus
2. History of acute or chronic ketoacidosis, ketosis-prone diabetes, or hyperosmolar hyperglycemic coma
3. History of a severe episode of hypoglycemia (eg, requiring assistance of another person or active intervention of any kind) < 3 months before Screening
4. Clinically significant complications of diabetes that, in the judgment of the investigator, would make subjects unsuitable to participate in this study
- Medical Exclusions:
5. Any clinically significant cardiovascular or cerebrovascular event ≤ 3 months prior to Screening
6. 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.
7. 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)
8. History of bariatric surgery at any time in the past or any other surgery < 2 months before Screening, or any planned surgery, that, in the opinion of the investigator, might have an effect on glucose homeostasis
9. Any other hospitalization in the 14 days prior to Screening or planned hospitalization at any time during the study.
10. Significant weight change (± 5%) < 2 months prior to Screening
11. Undergoing any type of dialysis at Screening or planning to undergo any type of dialysis at any time during the course of the study
12. History of liver cirrhosis
13. History of substance abuse < 12 months prior to Screening
14. Excessive alcohol consumption that, in the opinion of the investigator, would likely affect the subject’s glucose homeostasis
15. 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
- Medications Exclusions:
16. Prior treatment with open-label ranolazine or known hypersensitivity or intolerance to ranolazine
17. Treatment with strong or moderate CYP3A inhibitors within 14 days prior to Randomization
18. Treatment with CYP3A inducers or P-gp inducers within 14 days prior to Randomization
19. Treatment with CYP3A4 substrates with a narrow therapeutic range within 14 days prior to Randomization
20. Treatment with simvastatin at a daily dose of > 20 mg within 14 days prior to Randomization
21. Treatment with a thiazolidinedione (TZD) (eg, rosiglitazone or pioglitazone) within 6 months of Screening.
22. Weight-loss medication or anti-obesity medication (prescription or non-prescription) < 3 months prior to Screening
23. 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
24. Expected or current treatment with systemic corticosteroids (oral or injectable) for a > 14 days from Screening through the end of the Treatment Period. Topical or inhaled corticosteroid formulations are permitted at any time during the study
25. If receiving thyroid replacement therapy, should be on stable doses for at least 6 weeks prior to Randomization
- Laboratory Test Exclusions:
26. Hemoglobin < 12 g/dL for males; or < 11 g/dL for females, at Screening
- Other Exclusions:
27. 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
28. Donation of blood < 2 months prior to Screening or plans to donate blood while participating in the study
29. Females who are pregnant or breastfeeding
30. 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
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint of this study is:
• Change from Baseline in HbA1c at Week 24 |
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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) |
The secondary efficacy endpoints of this study are:
• Change from Baseline in postprandial serum glucose through Week 24
• Change from Baseline in fasting serum glucose through Week 24 |
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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 | Yes |
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) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
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 | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 28 |
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 |
Russian Federation |
Serbia |
South Africa |
Ukraine |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
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 | 4 |
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 |