Clinical trial NCT01494987: Ranolazine When Added to Glimepiride in Subjects With Type 2 Diabetes Mellitus
Official title: A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Efficacy and Safety of Ranolazine When Added to Glimepiride in Subjects With Type 2 Diabetes Mellitus
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Type 2 Diabetes Mellitus
Keywords: Type 2 Diabetes Mellitus
Lead sponsor: Gilead Sciences
Sponsor class: INDUSTRY
First posted: 2011-12-19
Enrollment: 431
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a randomized, double-blind, placebo-controlled, parallel-group, multi-center study to determine the effect of ranolazine when added to glimepiride on glycemic control in adults with type 2 diabetes mellitus (T2DM) who are inadequately controlled despite current treatment with stable sulfonylurea or metformin therapy in addition to diet and exercise.


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:

  1. glimepiride at a daily dose of ≥ 2 mg and ≤ 4 mg
  2. glipizide, glyburide, or glibenclamide (or equivalent) at a daily dose of ≥ 7.5 mg
  3. gliclazide at a daily dose of \> 160 mg (or ≥ 60 mg for the modified release \[MR\] formulation)
  4. 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

Primary outcomes:
measure: Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Week 24
timeFrame: Baseline; Week 24
Secondary outcomes:
measure: Change From Baseline in Incremental Change of 2-hour Postprandial Serum Glucose at Week 24
timeFrame: Baseline; Week 24
measure: Change From Baseline in Fasting Serum Glucose at Week 24
timeFrame: Baseline; Week 24
measure: Change From Baseline in 2-hour Postprandial Serum Glucose at Week 24
timeFrame: Baseline; Week 24
Other outcomes:
Locations:
city: Mesa
country: United States
facility: Clinical Research Advantage/Desert Clinical Research, LLC
state: Arizona
city: Tucson
country: United States
facility: Desert Sun Clinical Research, LLC
state: Arizona
city: Tucson
country: United States
facility: Eclipse Clinical Research
state: Arizona
city: Pine Bluff
country: United States
facility: Paul W. Davis, MD, PA
state: Arkansas
city: Fountain Valley
country: United States
facility: Southland Clinical Research Center, Inc.
state: California
city: Fresno
country: United States
facility: Valley Research
state: California
city: Huntington Park
country: United States
facility: Del Rosario Medical Clinic, Inc.
state: California
city: La Jolla
country: United States
facility: Scripps Whittier Diabetes Institute
state: California
city: Los Angeles
country: United States
facility: National Research Institute
state: California
city: Moreno Valley
country: United States
facility: Spectrum Clinical Research Institute, Inc
state: California
city: Sacramento
country: United States
facility: Sacramento Heart and Vascular Medical Associates
state: California
city: West Hills
country: United States
facility: Infosphere Clinical Research
state: California
city: Brandon
country: United States
facility: PAB Clinical Research
state: Florida
city: Gainesville
country: United States
facility: Florida Research Network, LLC
state: Florida
city: Miami Beach
country: United States
facility: NewPhase Clinical Trials, Inc.
state: Florida
city: New Port Richey
country: United States
facility: Suncoast Clinical Research
state: Florida
city: South Miami
country: United States
facility: Regenerate Clinical Trials
state: Florida
city: St. Petersburg
country: United States
facility: Comprehensive Clinical Development, Inc.
state: Florida
city: Winter Haven
country: United States
facility: Clinical Research of Central Florida
state: Florida
city: Atlanta
country: United States
facility: Synergy Therapeutic Partners
state: Georgia
city: Eagle
country: United States
facility: CTL Research
state: Idaho
city: Chicago
country: United States
facility: Cedar-Crosse Research Center
state: Illinois
city: Michigan City
country: United States
facility: LaPorte County Institute for Clinical Research
state: Indiana
city: Louisville
country: United States
facility: L-MARC Research Center
state: Kentucky
city: Eunice
country: United States
facility: Horizon Research Group of Opelousas
state: Louisiana
city: Oxon Hill
country: United States
facility: MD Medical Research
state: Maryland
city: Towson
country: United States
facility: IRC Clinics, Inc
state: Maryland
city: Alpena
country: United States
facility: Endeavor Medical Research, PLC
state: Michigan
city: Battle Creek
country: United States
facility: Associated Internal Medicine Specialists, P.C.
state: Michigan
city: Albuquerque
country: United States
facility: Albuquerque Clinical Trials
state: New Mexico
city: Charlotte
country: United States
facility: PMG Research of Charlotte
state: North Carolina
city: Greensboro
country: United States
facility: PharmQuest
state: North Carolina
city: Beavercreek
country: United States
facility: Clinical Inquest Center, Ltd.
state: Ohio
city: Oklahoma City
country: United States
facility: Infinity Research Group, LLC
state: Oklahoma
city: Taylors
country: United States
facility: Southeastern Research Associates, Inc.
state: South Carolina
city: Franklin
country: United States
facility: HCCA Clinical Research Solution
state: Tennessee
city: Kingsport
country: United States
facility: Holston Medical Group
state: Tennessee
city: Knoxville
country: United States
facility: New Phase Research & Development
state: Tennessee
city: Dallas
country: United States
facility: The University of Texas Southwestern Medical Center at Dallas
state: Texas
city: Houston
country: United States
facility: Excel Clinical Research, LLC
state: Texas
city: Houston
country: United States
facility: Texas Center for Drug Development, Inc.
state: Texas
city: Humble
country: United States
facility: Humble Cardiology Associates
state: Texas
city: San Antonio
country: United States
facility: Cetero Research
state: Texas
city: San Antonio
country: United States
facility: Cetero Research
state: Texas
city: Salt Lake City
country: United States
facility: Highland Clinical Research
state: Utah
city: Salt Lake City
country: United States
facility: Jean Brown Research
state: Utah
city: Havirov
country: Czech Republic
facility: Interni oddeleni
state: Moravskoslezsky kraj
city: Balatonfüred
country: Hungary
facility: Drug Research Center
city: Budapest
country: Hungary
facility: Synexus Hungary Ltd
city: Eger
country: Hungary
facility: Markhot Ferenc Hospital
city: Nagykanizsa
country: Hungary
facility: Kanizsai Dorottya Hospital
city: Nyíregyháza
country: Hungary
facility: Borbanya Praxis Kft., Outpatient Clinic
city: Nyíregyháza
country: Hungary
facility: Medifarma 98
city: Kubang Kerian
country: Malaysia
facility: Hospital Universiti Sains Malaysia
state: Kelantan
city: Wroclaw
country: Poland
facility: NZOZ Centrum Badan Klinicznych
state: Dolnoslaskie
city: Lodz
country: Poland
facility: Centrum Terapii Wspolczesnej J.M. Jasnorzewska Sp. Komandytowo - Akcyjna
state: Lodzkie
city: Lodz
country: Poland
facility: NZOZ Centrum Medyczne Szpital Sw. Rodziny
state: Lodzkie
city: Zgierz
country: Poland
facility: NZOZ Polimedica
state: Lodzkie
city: Gdansk
country: Poland
facility: Centrum Badan Klinicznych PI-House Sp. z o.o.
state: Pomorskie
city: Krakow
country: Poland
facility: LANDA - Specjalistyczne Gabinety Lekarskie
city: Lodz
country: Poland
facility: SPZOZ Uniwersytecki Szpital Kliniczny Nr 1 im. Norberta Barlickiego Uniwersytetu Medycznego w Łodzi, Oddział Kliniczny Diabetologii
city: Oswięcim
country: Poland
facility: NZOZ Centrum Badan Klinicznych Oswiecim
city: Oradea
country: Romania
facility: Spital Clinic Judetean de Urgenta Oradea Stationarul 1
state: Jud Bihor
city: Iasi
country: Romania
facility: Consultmed SRL
state: Jud. Iasi
city: Galati
country: Romania
facility: CMI Morosanu V. Magdalena
state: Judetul Galati
city: Timisoara
country: Romania
facility: Centru Medical Dr. Negrisanu
state: Judical Timis
city: Bucharest
country: Romania
facility: Tehnomed Trading Srl
city: Bucharest
country: Romania
facility: O.D. Medica Srl
city: Bucuresti
country: Romania
facility: Institutul de Diabet, Nutritie si Boli Metabolice "Dr. N. C. Paulescu"
city: Bucuresti
country: Romania
facility: Institutul National De Diabet, Nutritie Si Boli Metabolice "Prof. Dr. N.C. Paulescu"
city: Constanta
country: Romania
facility: CMI Mateescu S. Ana-Maria
city: Galati
country: Romania
facility: Spitalul Clinic Judetean de Urgenta "Sf. Apostol Andrei" Galati
city: Ploiesti
country: Romania
facility: Diabmed Dr. Popescu Alexandrina SRL
city: Arkhangelskoe
country: Russian Federation
facility: 3rd Central Military Clinical Hospital named after A.A.Vishnevskogo
city: Chita
country: Russian Federation
facility: GOU VPO "Chita State Medical Academy" of Minzdravsocrazvitie RF
city: Dzerzhinskiy
country: Russian Federation
facility: "Clinic of New Medical Technology" Company Limited
city: Ekaterinburg
country: Russian Federation
facility: The Urals State Medical Academy
city: Kemerovo
country: Russian Federation
facility: Kemerovo Regional Clinical Hospital
city: Krasnoyarsk
country: Russian Federation
facility: "Krasnoyarsk State Medical University n.a. Prof. V.F. Voyno-Yasenetsky
city: Moscow
country: Russian Federation
facility: State Healthcare Institution of Moscow "Cardiologival Dispensary #2 of Management Department of South Administrative District"
city: Moscow
country: Russian Federation
facility: Central Clinical Hospital of Russian Academy of Sciences
city: Moscow
country: Russian Federation
facility: Medical Sanitary Unit of Minestry of Internal Affairs of Russia in Moscow
city: Nizhniy Novgorod
country: Russian Federation
facility: City Clinical Hospital # 13 of Avtozavodsky District of Nizhniy Novgorod
city: Novosibirsk
country: Russian Federation
facility: Novosibirsk State Medical University
city: Novosibirsk
country: Russian Federation
facility: Scientific Research Institute of Physiology of Siberian Department RAMS
city: Pushkin
country: Russian Federation
facility: City Hospital # 38 named after N A Semashko
city: Rostov-on-Don
country: Russian Federation
facility: Rostov State Medical University
city: Ryazan
country: Russian Federation
facility: Ryazan State Medical University
city: Samara
country: Russian Federation
facility: Center "Diabetes", LLC
city: Smolensk
country: Russian Federation
facility: Smolensk State Medical Academy, Sanatorium-Preventorium
city: St. Petersburg
country: Russian Federation
facility: Medinet, LLC
city: St. Petersburg
country: Russian Federation
facility: North-Western State Medical Unversity n.a. I.I.Mechnikov
city: St. Petersburg
country: Russian Federation
facility: Saint-Petersburg City Outpatient Clinic#37
city: St. Petersburg
country: Russian Federation
facility: Military Medical Academy named after S.M. Kirov
city: St. Petersburg
country: Russian Federation
facility: Saint-Petersburg state budgetary healthcare institution "City Polyclinic #109"
city: St. Petersburg
country: Russian Federation
facility: Alexanders City Hospital
city: St. Petersburg
country: Russian Federation
facility: Clinical Hospital #122 n.a. Sokolov of FMBA
city: St. Petersburg
country: Russian Federation
facility: ANO "Medical Centre "XXI century"
city: St. Petersburg
country: Russian Federation
facility: St. Elizabeth City Hospital
city: St. Petersburg
country: Russian Federation
facility: Krestovsky Island Medical Institute, LLC
city: St. Petersburg
country: Russian Federation
facility: Federal Centre of Heart, Blood and Endocrinology named after V.A. Almazov
city: St. Petersburg
country: Russian Federation
facility: International Medical Center "SOGAZ", LLC
city: St. Petersburg
country: Russian Federation
facility: Saint-Petersburg City Pokrovskaya Hospital
city: Tyumen
country: Russian Federation
facility: Tyumen State Medical Academy
city: Voronezh
country: Russian Federation
facility: Voronezh Regional Clinical Hospital #1
city: Yaroslavl
country: Russian Federation
facility: City Hospital named after N.A.Semashko
city: Yaroslavl
country: Russian Federation
facility: Clinical Hospital for Emergency Care named after N.V. Solovyov
city: Yaroslavl
country: Russian Federation
facility: Medical Sanitary Unit of Novo-Yaroslavsky Oil Refinery
city: Yaroslavl
country: Russian Federation
facility: Yaroslavl Regional Clinical Hospital
city: Belgrade
country: Serbia
facility: Clinical Center of Serbia
city: Belgrade
country: Serbia
facility: Zvezdara University Medical Center
city: Kragujevac
country: Serbia
facility: Clinical Center of Kragujevac
city: Bratislava
country: Slovakia
facility: METABOLKLINIK s.r.o.
state: Bratislavsky kraj
city: Bratislava
country: Slovakia
facility: Metabolic Center of Dr. Katarina Raslova Ltd.
state: Bratislavsky kraj
city: Trebisov
country: Slovakia
facility: ARETEUS s.r.o., Diabetologicka ambulancia
state: Kosicky kraj
city: Dolny Kubin
country: Slovakia
facility: ENDIAMED s.r.o
state: Zilinsky kraj
city: Malacky
country: Slovakia
facility: MediVet s.r.o.
city: Newlands West
country: South Africa
facility: Newkwa Medical Centre
state: Durban
city: Overport
country: South Africa
facility: Drs. Naiker and Naicker Inc.
state: Durban
city: Durban
country: South Africa
facility: Centre for Diabetes and Endocrinology Suite 1
city: Johannesburg
country: South Africa
facility: Centre for Diabetes, Asthma and Allergy
city: Johannesburg
country: South Africa
facility: Soweto Clinical Trial Centre
city: Johannesburg
country: South Africa
facility: Centre fro Diabetes and Endocrinology (Pty) Ltd
city: Kwa Zulu Natal
country: South Africa
facility: Aliwal Shoal Medical & Clinical Trial Centre
city: Paarl, Cape Town
country: South Africa
facility: Paarl Research Centre
city: Somerset West
country: South Africa
facility: Helderberg Clinical Trials Centre
city: Western Cape
country: South Africa
facility: Tiervlei Trial Centre
city: Patumwan
country: Thailand
facility: Chulalongkorn University
state: Bangkok
city: Bangkok
country: Thailand
facility: Phramongkutklao Hospital
city: Bangkok
country: Thailand
facility: Rajavithi Hospital
city: Songkla
country: Thailand
facility: Songklanagarind Hospital
city: Dnipropetrovsk
country: Ukraine
facility: City Clinical Hospital#9, Dnipropetrovsk State Medical Academy
city: Donetsk
country: Ukraine
facility: Educational Scientific Medical Centre "University clinic" of Donetsk National Medical University n.a. M.Gorkiy
city: Kyiv
country: Ukraine
facility: Administration of Medical Service and Rehabilitation of "ARTEM" State Holding Company
city: Kyiv
country: Ukraine
facility: National Medical University n.a. O.O. Bogomolets, Chair of Family Medicine based on Outpatient Clinic # 2 of Shevchenkovsky District
city: Kyiv
country: Ukraine
facility: V. P. Komissarenko Institute of Endocrinology and Metabolism of AMS of Ukraine
city: Lutsk
country: Ukraine
facility: Municipal Institution Lutsk City Clinical Hospital
city: Lviv
country: Ukraine
facility: Lviv Regional Endocrinology Dispensary
city: Odesa
country: Ukraine
facility: Odessa State Medical University
city: Zhytomyr
country: Ukraine
facility: Zhytomyr Regional Clinical Hospital
Study officials:
affiliation: Gilead Sciences
name: Patrick Yue, MD
role: STUDY_DIRECTOR
References: