Ranolazine When Added to Glimepiride in Subjects With Type 2 Diabetes Mellitus
Type 2 Diabetes Mellitus
About this trial
This is an interventional treatment trial for Type 2 Diabetes Mellitus focused on measuring Type 2 Diabetes Mellitus
Eligibility Criteria
Inclusion Criteria:
- Written informed consent
- Males and females, 18 to 75 years old, inclusive
- Documented history of T2DM
Receiving one of the following sulfonylurea or metformin therapies in addition to diet and exercise for at least 90 days prior to Screening:
- glimepiride at a daily dose of ≥ 2 mg and ≤ 4 mg
- glipizide, glyburide, or glibenclamide (or equivalent) at a daily dose of ≥ 7.5 mg
- gliclazide at a daily dose of > 160 mg (or ≥ 60 mg for the modified release [MR] formulation)
- metformin at a daily dose of ≥ 1500 mg
- Body mass index (BMI) 25 kg/m2 to 45 kg/m2, inclusive, at Screening
- HbA1c 7% to 10%, inclusive, at Screening and the end of the Qualifying Period (Day 14)
- Fasting Serum C-peptide ≥ 0.8 ng/mL at Screening
- Fasting serum glucose (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): A one-time central laboratory re-test of FSG is allowed in subjects with an initial central laboratory FSG ≥ 120 mg/dL (6.7 mmol/L) and < 130 mg/dL (7.2 mmol/L) who are otherwise eligible as determined by the investigator.
- Able and willing to comply with all study procedures during the course of the study
- 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.
- At least 80% compliant in dosing during the Qualifying Period
Exclusion Criteria:
- History of or current diagnosis of type 1 diabetes mellitus
- History of diabetic ketoacidosis, ketosis-prone diabetes, or hyperosmolar hyperglycemic coma
- 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
- Clinically significant complications of diabetes that in the judgment of the investigator would make the subject unsuitable to participate in this study
- History of any clinically significant cardiovascular (CV) or cerebrovascular event (eg, myocardial infarction [MI], acute coronary syndrome [ACS], recent revascularization [including coronary artery bypass graft procedures or percutaneous coronary intervention], transient ischemic attack, or ischemic stroke) ≤ 3 months prior to Screening
- 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
- Prolonged QT interval corrected for heart rate (QTc) interval > 500 msec by electrocardiogram (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)
- History of bariatric surgery at any time in the past or 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.
- Any other hospitalization in the 14 days prior to Screening or planned hospitalization at any time during the study
- Significant weight change (± 5%) < 2 months prior to Screening or enrollment in a weight-loss program other than a maintenance phase at Screening.
- 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 during the course of the study
- History of liver cirrhosis (Child-Pugh Class A, B or C)
- Active liver disease and/or significant abnormal liver function defined as aspartate aminotransferase (AST) > 3 x upper limit of the normal range (ULN) and/or alanine aminotransferase (ALT) > 3 x ULN and/or serum total bilirubin > 2.0 mg/dL
- History of cancer (except nonmelanomic skin cancers or cervical in situ) within 5 years prior to Screening
- History of alcohol or other drug abuse < 12 months prior to Screening
- 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
- Use of antihyperglycemic agents other than sulfonylurea agents or metformin, including but not limited to dipeptidyl peptidase-4 inhibitors (eg, saxagliptin and sitagliptin), glucagon-like peptide-mimetics (eg, exenatide), or insulin < 3 months prior to Screening; use of thiazolidinediones (TZDs) (eg, rosiglitazone or pioglitazone) < 24 weeks prior to Screening
- Previous history of intolerance of glimepiride (as a single-agent therapy)
- Prior treatment with open-label ranolazine, or known hypersensitivity or intolerance to ranolazine or any of its excipients
- Treatment with strong or moderate cytochrome P (CYP)3A inhibitors or P-glycoprotein (P-gp) inhibitors within 14 days prior to randomization
- Treatment with CYP3A inducers or P-gp inducers within 14 days prior to randomization
- Treatment with CYP3A4 substrates with a narrow therapeutic range (eg, cyclosporine, tacrolimus, or sirolimus) within 14 days prior to Randomization
- Treatment with simvastatin at a dose of > 20 mg daily or lovastatin at a dose of > 40 mg daily within 14 days prior to Randomization
- Weight loss medication or anti-obesity medication (prescription or non-prescription) < 3 months prior to Screening
- Treatment with niacin > 200 mg daily; if receiving ≤ 200 mg daily, should be on stable doses for ≥ 3 months prior to Screening
- 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.
- If receiving thyroid replacement therapy, should be on stable doses for at least 6 weeks prior to randomization
- Hemoglobin < 12 g/dL for males or < 11 g/dL for females at Screening
- Participation in another clinical study involving an investigational drug or device < 30 days prior to Screening; participation in another clinical study involving an oral antihyperglycemic agent (OHA) < 90 days prior to Screening
- Donation of blood < 2 months prior to Screening or plans to donate blood while participating in the study
- Females who are pregnant or are breastfeeding
- Other condition(s) that, in the opinion of the investigator, would compromise the safety of the individual, prevent compliance with the study protocol (including the ability to comply with Mixed Meal Tolerance Test [MMTT]), or compromise the quality of the clinical study
Sites / Locations
- Clinical Research Advantage/Desert Clinical Research, LLC
- Desert Sun Clinical Research, LLC
- Eclipse Clinical Research
- Paul W. Davis, MD, PA
- Southland Clinical Research Center, Inc.
- Valley Research
- Del Rosario Medical Clinic, Inc.
- Scripps Whittier Diabetes Institute
- National Research Institute
- Spectrum Clinical Research Institute, Inc
- Sacramento Heart and Vascular Medical Associates
- Infosphere Clinical Research
- PAB Clinical Research
- Florida Research Network, LLC
- NewPhase Clinical Trials, Inc.
- Suncoast Clinical Research
- Regenerate Clinical Trials
- Comprehensive Clinical Development, Inc.
- Clinical Research of Central Florida
- Synergy Therapeutic Partners
- CTL Research
- Cedar-Crosse Research Center
- LaPorte County Institute for Clinical Research
- L-MARC Research Center
- Horizon Research Group of Opelousas
- MD Medical Research
- IRC Clinics, Inc
- Endeavor Medical Research, PLC
- Associated Internal Medicine Specialists, P.C.
- Albuquerque Clinical Trials
- PMG Research of Charlotte
- PharmQuest
- Clinical Inquest Center, Ltd.
- Infinity Research Group, LLC
- Southeastern Research Associates, Inc.
- HCCA Clinical Research Solution
- Holston Medical Group
- New Phase Research & Development
- The University of Texas Southwestern Medical Center at Dallas
- Excel Clinical Research, LLC
- Texas Center for Drug Development, Inc.
- Humble Cardiology Associates
- Cetero Research
- Cetero Research
- Highland Clinical Research
- Jean Brown Research
- Interni oddeleni
- Drug Research Center
- Synexus Hungary Ltd
- Markhot Ferenc Hospital
- Kanizsai Dorottya Hospital
- Borbanya Praxis Kft., Outpatient Clinic
- Medifarma 98
- Hospital Universiti Sains Malaysia
- NZOZ Centrum Badan Klinicznych
- Centrum Terapii Wspolczesnej J.M. Jasnorzewska Sp. Komandytowo - Akcyjna
- NZOZ Centrum Medyczne Szpital Sw. Rodziny
- NZOZ Polimedica
- Centrum Badan Klinicznych PI-House Sp. z o.o.
- LANDA - Specjalistyczne Gabinety Lekarskie
- SPZOZ Uniwersytecki Szpital Kliniczny Nr 1 im. Norberta Barlickiego Uniwersytetu Medycznego w Łodzi, Oddział Kliniczny Diabetologii
- NZOZ Centrum Badan Klinicznych Oswiecim
- Spital Clinic Judetean de Urgenta Oradea Stationarul 1
- Consultmed SRL
- CMI Morosanu V. Magdalena
- Centru Medical Dr. Negrisanu
- Tehnomed Trading Srl
- O.D. Medica Srl
- Institutul de Diabet, Nutritie si Boli Metabolice "Dr. N. C. Paulescu"
- Institutul National De Diabet, Nutritie Si Boli Metabolice "Prof. Dr. N.C. Paulescu"
- CMI Mateescu S. Ana-Maria
- Spitalul Clinic Judetean de Urgenta "Sf. Apostol Andrei" Galati
- Diabmed Dr. Popescu Alexandrina SRL
- 3rd Central Military Clinical Hospital named after A.A.Vishnevskogo
- GOU VPO "Chita State Medical Academy" of Minzdravsocrazvitie RF
- "Clinic of New Medical Technology" Company Limited
- The Urals State Medical Academy
- Kemerovo Regional Clinical Hospital
- "Krasnoyarsk State Medical University n.a. Prof. V.F. Voyno-Yasenetsky
- State Healthcare Institution of Moscow "Cardiologival Dispensary #2 of Management Department of South Administrative District"
- Central Clinical Hospital of Russian Academy of Sciences
- Medical Sanitary Unit of Minestry of Internal Affairs of Russia in Moscow
- City Clinical Hospital # 13 of Avtozavodsky District of Nizhniy Novgorod
- Novosibirsk State Medical University
- Scientific Research Institute of Physiology of Siberian Department RAMS
- City Hospital # 38 named after N A Semashko
- Rostov State Medical University
- Ryazan State Medical University
- Center "Diabetes", LLC
- Smolensk State Medical Academy, Sanatorium-Preventorium
- Medinet, LLC
- North-Western State Medical Unversity n.a. I.I.Mechnikov
- Saint-Petersburg City Outpatient Clinic#37
- Military Medical Academy named after S.M. Kirov
- Saint-Petersburg state budgetary healthcare institution "City Polyclinic #109"
- Alexanders City Hospital
- Clinical Hospital #122 n.a. Sokolov of FMBA
- ANO "Medical Centre "XXI century"
- St. Elizabeth City Hospital
- Krestovsky Island Medical Institute, LLC
- Federal Centre of Heart, Blood and Endocrinology named after V.A. Almazov
- International Medical Center "SOGAZ", LLC
- Saint-Petersburg City Pokrovskaya Hospital
- Tyumen State Medical Academy
- Voronezh Regional Clinical Hospital #1
- City Hospital named after N.A.Semashko
- Clinical Hospital for Emergency Care named after N.V. Solovyov
- Medical Sanitary Unit of Novo-Yaroslavsky Oil Refinery
- Yaroslavl Regional Clinical Hospital
- Clinical Center of Serbia
- Zvezdara University Medical Center
- Clinical Center of Kragujevac
- METABOLKLINIK s.r.o.
- Metabolic Center of Dr. Katarina Raslova Ltd.
- ARETEUS s.r.o., Diabetologicka ambulancia
- ENDIAMED s.r.o
- MediVet s.r.o.
- Newkwa Medical Centre
- Drs. Naiker and Naicker Inc.
- Centre for Diabetes and Endocrinology Suite 1
- Centre for Diabetes, Asthma and Allergy
- Soweto Clinical Trial Centre
- Centre fro Diabetes and Endocrinology (Pty) Ltd
- Aliwal Shoal Medical & Clinical Trial Centre
- Paarl Research Centre
- Helderberg Clinical Trials Centre
- Tiervlei Trial Centre
- Chulalongkorn University
- Phramongkutklao Hospital
- Rajavithi Hospital
- Songklanagarind Hospital
- City Clinical Hospital#9, Dnipropetrovsk State Medical Academy
- Educational Scientific Medical Centre "University clinic" of Donetsk National Medical University n.a. M.Gorkiy
- Administration of Medical Service and Rehabilitation of "ARTEM" State Holding Company
- National Medical University n.a. O.O. Bogomolets, Chair of Family Medicine based on Outpatient Clinic # 2 of Shevchenkovsky District
- V. P. Komissarenko Institute of Endocrinology and Metabolism of AMS of Ukraine
- Municipal Institution Lutsk City Clinical Hospital
- Lviv Regional Endocrinology Dispensary
- Odessa State Medical University
- Zhytomyr Regional Clinical Hospital
Arms of the Study
Arm 1
Arm 2
Experimental
Placebo Comparator
Ranolazine+glimepiride
Placebo+glimepiride
Glimepiride stabilization period (up to 8 weeks): participants not on stable glimepiride will receive glimepiride 2 mg once daily, and if tolerated the dose will be increased on Day 8 (+ 2 days) to 4 mg once daily. Qualifying period: participants will receive placebo to match ranolazine twice daily in addition to glimepiride for 14 days (+ 2 days) and if ≥ 80% compliant and meeting eligibility criteria will continue to the treatment period. Treatment period: participants will be randomized to receive ranolazine 500 mg twice daily plus glimepiride 4 mg once daily on Days 1 through 7, followed by ranolazine 1000 mg twice daily plus glimepiride 4 mg once daily from Day 8 (or by Day 16 if not well tolerated) through Week 24. Participants will be required to maintain their diet and exercise regimen.
Glimepiride stabilization period (up to 8 weeks): participants not on stable glimepiride will receive glimepiride 2 mg once daily, and if tolerated the dose will be increased on Day 8 (+ 2 days) to 4 mg once daily. Qualifying period: participants will receive placebo to match ranolazine twice daily in addition to glimepiride for 14 days (+ 2 days) and if ≥ 80% compliant and meeting eligibility criteria will continue to the treatment period. Treatment period: participants will be randomized to receive placebo to match ranolazine plus glimepiride 4 mg once daily for 24 weeks. Participants will be required to maintain their diet and exercise regimen.