E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Type 2 Diabetes Mellitus. |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Body processes [G] - Metabolic Phenomena [G03] |
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 HbA1c after 24 weeks of treatment when added to metformin in subjects who have inadequately controlled T2DM despite current treatment with stable 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 metformin on postprandial serum glucose (PPG) and to determine the effect of ranolazine when added to metformin on fasting serum glucose (FSG). Evaluate the effect of ranolazine when added to metformin on serum C-peptide, serum insulin, and plasma glucagon. Evaluate the PK of ranolazine and the safety objective of the study is to evaluate the safety and tolerability of ranolazine when added to metformin in subjects who have inadequately controlled T2DM despite current treatment with stable 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 |
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. Metformin therapy at a stable total daily dose ≥ 1500 mg and ≤ 2550 mg in addition to diet and exercise for ≥8 weeks prior to Screening.
5. Body mass index (BMI) 25 to 45 kg/m2, inclusive, at Screening.
6. HbA1c within the following ranges, based on current metformin dose as specified in the protocol.
7. Fasting serum C-peptide ≥ 0.8 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 (+ 2 days). A one-time central laboratory re-test of FSG is allowed for subjects with an initial central laboratory FSG between 125 mg/dL and 129 mg/dL who are otherwise eligible as determined by the Investigator.
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 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% compliance in 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.
1. History or current diagnosis of type 1 diabetes mellitus.
2. History of diabetic ketoacidosis, ketosis-prone diabetes, or hyperosmolar hyperglycemic coma.
3. History of severe hypoglycemia (≥ 1 episode within 3 months prior to Screening or ≥ 2 episodes within 6 months prior to Screening), defined as hypoglycemia requiring third 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 the subject unsuitable to participate in this study.
5. Any clinically significant CV or cerebrovascular event, eg, MI, ACS, recent revascularization (including coronary artery bypass graft procedures [CABG] or percutaneous coronary intervention [PCI]), transient ischemic attack (TIA), or ischemic stroke ≤ 3 months prior to Screening.
6. History of congestive heart failure defined as New York Heart Association (NYHA) stage III or IV and/or known left ventricular ejection fraction ≤ 40%.
7. 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/or Randomization.
8. 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 (e.g., ziprasidone).
9. History of bariatric surgery at any time in the past or any other surgery within 2 months prior to Screening; or planning to undergo surgery during the study (planned minor surgery may be acceptable upon approval of the Medical Monitor).
10. Any other hospitalization in the 14 days prior to Screening or planned hospitalization at any time during the study.
11. Significant weight change (≥ 5%) < 2 months prior to Screening, or enrollment in a weight loss program which is not in the maintenance phase at Screening.
12. Undergoing any type of dialysis at Screening or planning to undergo any type of dialysis during the course of the study.
13. Serum creatinine concentration ≥ 1.5 mg/dL for males or ≥ 1.4 mg/dL for females at Screening.
14. History of liver cirrhosis (Child-Pugh Class A, B, or C).
15. Active liver disease and/or significant abnormal liver function defined as aspartate aminotransferase (AST) > 3x upper limit of the normal range (ULN) and/or alanine aminotransferase (ALT) > 3x ULN and /or serum total bilirubin > 2.0 mg/dL.
16. Positive blood screen for hepatitis C antibody or hepatitis B surface antigen.
17. Hemoglobin < 12 g/dL for males or < 11g/dL for females at Screening.
18. History of alcohol or drug abuse (in the investigator’s opinion) within 1 year prior to Screening.
19. Clinical hypothyroidism (subjects that have an abnormal thyroid stimulating hormone [TSH] value at screening will be further evaluated by free T4 [fT4]; subjects with an abnormal fT4 will be excluded).
20. History of malignancy (except for treated non-melanoma skin cancer and treated adenocarcinoma in situ of the uterine cervix) within 5 years prior to Screening.
21. 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.
22. Use of any non-insulin anti-hyperglycemic therapy (other than metformin [see inclusion criterion #4]) for more than 14 days (consecutive or not) during the 12 weeks (24 weeks for thiazolidinediones) prior to Screening and/or use of any anti-hyperglycemic therapy other than metformin, at any dose, at any time during the 4 weeks prior to Randomization.
23. Treatment with chronic insulin, within 24 weeks prior to Screening (except for one temporary period of daily insulin injections no longer than 7 days).
24. Previous history of intolerance to metformin including metformin-induced lactic Acidosis.
Please see protocol for remainder of Principal Exclusion Criteria. |
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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.
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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 ordered 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.
The additional endpoints of this study are the following:
Change from Baseline in weight by visit.
Change from Baseline in HbA1c by visit.
Proportion of subjects achieving HbA1c < 7% by visit.
Change from Baseline in 2-hour and 3-hour PPG by visit.
Change from Baseline in FSG by visit.
Change from Baseline in fasting serum insulin by visit.
Change from Baseline in fasting serum C-peptide by visit.
Change from Baseline in fasting plasma glucagon by visit.
Change from Baseline in PPG area under the curve AUC0-3hr by visit.
Change from Baseline in PPG net incremental AUC0-3hr by visit.
Change from Baseline in postprandial serum insulin AUC0-3hr by visit.
Change from Baseline in postprandial serum C-peptide AUC0-3hr by visit.
Change from Baseline in postprandial plasma glucagon AUC0-3hr by visit. |
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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
| Information not present in EudraCT |
E.8.4 | The trial involves multiple sites in the Member State concerned | Information not present in EudraCT |
E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 18 |
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 |
Argentina |
Canada |
Czech Republic |
Hungary |
Israel |
Korea, Republic of |
Mexico |
Poland |
Romania |
South Africa |
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 | 0 |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 0 |
E.8.9.2 | In all countries concerned by the trial months | 9 |
E.8.9.2 | In all countries concerned by the trial days | 0 |