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 the study is to:
• Determine the effect of ranolazine on hemoglobin A1c
(HbA1c) after 24 weeks of treatment when added to
glimepiride in subjects who have inadequately controlled type
2 diabetes mellitus (T2DM) despite current treatment with
stable sulfonylurea (SU) or metformin therapy in addition to
diet and exercise |
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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 when added to glimepiride
on postprandial serum glucose (PPG)
• Determine the effect of ranolazine when added to glimepiride
on fasting serum glucose (FSG)
The additional objectives of the study are to:
• Evaluate the effect of ranolazine when added to glimepiride on
each of the following parameters: serum C-peptide, serum
insulin, and plasma glucagon
• Evaluate the pharmacokinetics (PK) of ranolazine
The safety objective of the study is to:
• Evaluate the safety and tolerability of ranolazine when added to
glimepiride in subjects who have inadequately controlled
T2DM despite current treatment with stable SU or metformin
therapy in addition to diet and exercise |
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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, 18 to 75 years old, inclusive
3. Documented history of T2DM
4. Receiving one of the following SU or metformin therapies in addition to diet and exercise for at least 90 days prior to Screening:
a. glimepiride at a daily dose of ≥ 2 mg and ≤ 4 mg
b. glimepiride at a daily dose of ≥ 1 mg and ≤ 2 mg for subjects with severe renal impairment (eGFR < 30 mL/min/1.73m2 by the modification of diet in renal disease [MDRD] method)
c. glipizide, glyburide, or glibenclamide (or equivalent) at a daily dose of ≥ 7.5 mg
d. gliclazide at a daily dose of > 160 mg (or > 60 mg for the MR formulation)
e. metformin at a daily dose of ≥ 1500 mg
5. Body mass index (BMI) 27 kg/m2 to 45 kg/m2, inclusive, at Screening
6. HbA1c 7% to 10%, inclusive, at Screening and the end of the Qualifying Period (Day 14 + 2 days)
7. C-peptide > 1 ng/mL at Screening
8. FSG ≥ 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)
9. Able and willing to comply with all study procedures during the course of the study
10. Females of child-bearing potential must have a negative serum 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 in dosing during the Qualifying Period |
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E.4 | Principal exclusion criteria |
Disease-specific:
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 prior to Screening
4. Clinically significant complications of diabetes that in the judgment of the investigator would make the subject unsuitable to participate in this study
Medical:
5. Any clinically significant CV or cerebrovascular event (eg, MI, ACS, recent revascularization [including coronary artery bypass graft procedures or percutaneous coronary intervention], transient ischemic attack, or ischemic stroke) ≤ 3 months prior
to Screening
6. Inadequately controlled or unstable hypertension as defined by a systolic blood pressure (SBP) > 160 mmHg or diastolic blood pressure (DBP) > 100 mmHg at Screening and at 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 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 during the 8 weeks prior to Screening 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:
16. Use of OHAs other than SU agents or metformin, including but not limited to dipeptidyl peptidase-4 inhibitors (eg, saxagliptin and sitagliptin) and glucagon-like peptide-mimetics (eg, exenatide) < 3 months prior to Screening. Use of
thiazolidinediones (TZDs) (eg, rosiglitazone or pioglitazone) < 6 months prior to Screening
17. Previous history of intolerance of glimepiride (as a single-agent therapy)
18. Prior treatment with open-label ranolazine, or known hypersensitivity or intolerance to ranolazine or any of its excipients
19. Treatment with strong or moderate CYP3A inhibitors within 14 days prior to Randomization
20. Treatment with CYP3A inducers or P-gp inducers within 14 days prior to Randomization
21. Treatment with CYP3A4 substrates with a narrow therapeutic range (eg, cyclosporine, tacrolimus, or sirolimus) within 14 days prior to Randomization
22. Treatment with simvastatin at a dose of > 20 mg daily within 14 days prior to Randomization
23. Weight loss medication or anti-obesity medication (prescription or non-prescription) < 3 months prior to Screening
24. Treatment with niacin > 200 mg daily; if receiving ≤ 200 mg daily, should be on stable doses for ≥ 3 months prior to Screening
25. 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.
26. If receiving thyroid replacement therapy, should be on stable doses for at least 6 weeks prior to Randomization
Laboratory tests:
27. Hemoglobin < 12 g/dL for males or < 11g/dL for females at Screening
Other:
28. Participation in another clinical study involving an investigational drug or device < 30 days prior to Screening; participation in another clinical study involving an OHA < 90 days prior to Screening
29. Donation of blood < 2 months prior to Screening or plans to donate blood while participating in the study
30. Females who are pregnant or are breastfeeding
31. Other condition(s) that, in the opinion of the investigator, would compromise the safety of the subject, prevent compliance with the study protocol (including the ability to comply with MMTT), or 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 the following:
• Change from Baseline in HbA1c at Week 24 of Treatment Period |
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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 PPG through Week 24 of Treatment Period
• Change from Baseline in FSG through Week 24 of Treatment Period |
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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 | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 27 |
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 |
Malaysia |
Russian Federation |
Serbia |
South Africa |
Taiwan |
Thailand |
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 |