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 (or TZDs in the 24 weeks) 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 (or TZDs in the 24 weeks) 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 or TZDs (eg, rosiglitazone or pioglitazone) for at least 24 weeks prior to Screening
5. Body mass index (BMI) 25 kg/m2 to 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). 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 determinedby the Investigator.
8. Fasting serum C-peptide ≥ 0.8 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 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 |
- Diabetes- Specific Exclusions:
1. History of or current diagnosis of type 1 diabetes mellitus
2. History of diabetic ketoacidosis, ketosis-prone diabetes, or hyperosmolar hyperglycemic coma
3.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
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. History of any clinically significant cardiovascular or cerebrovascular event ≤ 3 months prior to Screening
6. Inadequately controlled or unstable hypertension as defined by SBP > 160 mmHg or 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 planning to undergo surgery during the study. Subjects with a planned minor surgery may be enrolled upon approval by the Medical Monitor.
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 or on a weight-loss program and is not in the maintenance phase at Screening
11. 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 at any time during the course of the study
12. History of liver cirrhosis (Child-Pugh Class A, B, or C).
13. Active liver disease and/or significant abnormal liver function defined as AST> 3x ULN and/or ALT> 3x ULN and/or serum total bilirubin > 2.0 mg/dL
14. History of cancer (except non-melanomic skin cancers or cervical in situ) within 5 years prior to Screening.
15. History of alcohol or other drug abuse < 12 months prior to Screening
16. 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:
17. Prior treatment with open-label ranolazine or known hypersensitivity or intolerance to ranolazine
18. Treatment with strong or moderate CYP3A inhibitors or P-gp inhibitors within 14 days prior to Randomization
19. Treatment with CYP3A inducers or P-gp inducers within 14 days prior to Randomization
20. Treatment with CYP3A4 substrates with a narrow therapeutic range within 14 days prior to Randomization
21. Treatment with simvastatin at a daily dose of > 20 mg or lovastatin at a daily dose > 40 mg, within 14 days prior to Randomization
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 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 the following:
• Change from Baseline in incremental change of 2-hour PPG at Week 24
• Change from Baseline in FSG at Week 24 or change from Baseline in 2-hour PPG at 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 | 7 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 42 |
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 |
Belarus |
Czech Republic |
Hungary |
Israel |
Mexico |
Poland |
Romania |
Russian Federation |
Serbia |
Slovakia |
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 |