Clinical trial NCT01425359: Type 2 Diabetes Evaluation of Ranolazine in Subjects With Chronic Stable Angina
Official title: A Phase 4, Randomized, Double-Blind, Placebo-Controlled, Parallel Study of Ranolazine in Subjects With Chronic Stable Angina and Coronary Artery Disease With a History of Type 2 Diabetes Mellitus
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Angina Pectoris
Coronary Artery Disease
Type 2 Diabetes Mellitus
Keywords: Chronic angina
Angina pectoris
Coronary artery disease
Type 2 Diabetes Mellitus
Lead sponsor: Gilead Sciences
Sponsor class: INDUSTRY
First posted: 2011-08-30
Enrollment: 949
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study will evaluate the effect of ranolazine compared to placebo on the average weekly angina frequency in subjects with chronic stable angina and coronary artery disease (CAD) who have a history of type 2 diabetes mellitus (T2DM), and whether ranolazine can reduce the frequency of angina (chest pain) attacks, compared to a placebo. Subjects will be asked to record their daily angina episodes in a diary at the end of each study day. Ranolazine is approved for the treatment of chronic angina, and is not approved for the treatment of T2DM.

Detailed description: Participants who meet the eligibility criteria at screening will enter a 4-to 6-week Qualifying Period. The allowed concomitant antianginal medication(s) must be maintained at a stable dose throughout the study. Participants will document the number of angina episodes, number of sublingual nitroglycerin doses taken, and a dyspnea score (on a scale from 1 to 5) on a daily basis in a diary. Participants eligible to stay in the study after the Qualifying Period will enter the 8-week double-blind dosing phase. Participants will have study visits at the end of Weeks 2 and 8. Participants will continue to document the number of angina episodes and number of sublingual nitroglycerin doses taken as well as a dyspnea score on a daily basis by the end of each day in their diary. In addition, participants will be called during Week 2 and at the end of Week 5 to encourage compliance. A safety follow-up phone call will be made 14 days after the last study visit or early discontinuation.

Eligibility criteria: Inclusion Criteria:

* Written informed consent
* Males and females aged at least 18 years
* At least a 3-month history of chronic stable angina triggered by physical effort and relieved by rest and/or sublingual nitroglycerin
* CAD documented by one or more of the following:

  1. Angiographic evidence of ≥ 50% stenosis of one or more major coronary arteries
  2. History of myocardial infarction (MI) documented by positive myocardial muscle creatine kinase (CK-MB) enzymes, troponins, or electrocardiogram (ECG) changes
  3. Cardiac imaging study or exercise test diagnostic for CAD
* Treatment with up to 2 antianginal therapies at a stable dose for at least 2 weeks prior to the Qualifying Period.
* Documented history of T2DM
* Willing to maintain stable tobacco usage habits throughout the study
* Willing to maintain stable activity levels throughout the study
* Females of childbearing potential must agree to utilize highly effective contraception methods from Screening throughout the duration of study treatment and for 14 days following the last dose of study drug.

Exclusion Criteria:

* New York Heart Association (NYHA) Class III and IV
* Acute coronary syndrome in the prior 2 months or planned coronary revascularization during the study period
* Stroke or transient ischemic attack within 6 months prior to Screening
* QTc \> 500 milliseconds
* Uncontrolled hypertension (seated systolic blood pressure \> 180 mmHg or diastolic blood pressure \> 110 mmHg)
* Systolic blood pressure \< 100 mmHg
* Clinically significant hepatic impairment
* Prior treatment with ranolazine, or known hypersensitivity or intolerance to ranolazine
* Females who are breastfeeding
* Positive serum pregnancy test
* Participation in another investigational drug or device study within 1 month prior to Screening
* Current treatment with trimetazidine, ivabradine, or nicorandil. Subjects will need to discontinue these medications 2 weeks prior to the Qualifying Period.
* Current treatment with potent inhibitors of cytochrome (CYP)3A (eg, ketoconazole, itraconazole, clarithromycin, nefazodone, nelfinavir, ritonavir, indinavir, and saquinavir)
* Current treatment with CYP3A and P glycoprotein (Pgp) inducers (eg, rifampicin/rifampin, carbamazepine, and St. John's wort \[Hypericum perforatum\])
* Current treatment with CYP3A4 substrates with a narrow therapeutic range (eg, cyclosporine, tacrolimus, and sirolimus)
* Subjects taking simvastatin who cannot reduce the dose to 20 mg once daily or who cannot switch to another statin
* Current treatment with Class I or III antiarrhythmic medications
* History of illicit drug use or alcohol abuse within 1 year of Screening
* Any other conditions that, in the opinion of the investigator, are likely to prevent compliance with the study protocol or pose a safety concern if the subject participates in the study

Primary outcomes:
measure: Average Weekly Angina Frequency Over the Last 6 Weeks of Treatment
timeFrame: 6 weeks
Secondary outcomes:
measure: Average Weekly Frequency of Sublingual Nitroglycerin Use Over the Last 6 Weeks of Treatment
timeFrame: 6 weeks
measure: Percentage of Weeks Participants Achieved at Least a 50% Reduction in Angina Frequency
timeFrame: 6 weeks
measure: Percentage of the Last 6 Weeks on Treatment During Which the Angina Frequency Was ≤ 50% of the Baseline Average Weekly Angina Frequency
timeFrame: 6 weeks
measure: Change From Baseline in the Short-Form 36® (SF-36) Mental and Physical Component Scores
timeFrame: Up to 8 weeks
measure: Patient's Global Impression of Change (PGIC) Scale Score
timeFrame: 8 weeks
Other outcomes:
Locations:
city: Little Rock
country: United States
facility: Cardiology and Medicine Clinic
state: Arkansas
city: Merced
country: United States
facility: Merced Heart Associates
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 Research Center
state: California
city: Hollywood
country: United States
facility: South Florida Research Solutions, LLC
state: Florida
city: Jacksonville
country: United States
facility: Baptist Heart Specialist
state: Florida
city: Winter Haven
country: United States
facility: Clinical Research of Central Florida
state: Florida
city: Augusta
country: United States
facility: Masters of Clinical Research, Inc.
state: Georgia
city: Columbus
country: United States
facility: Columbus Cardiology Associates
state: Georgia
city: Elizabethtown
country: United States
facility: Central Cardiology Associates
state: Kentucky
city: Owensboro
country: United States
facility: Research Integrity, LLC
state: Kentucky
city: Alexandria
country: United States
facility: Alexandria Cardiology Clinic
state: Louisiana
city: Mandeville
country: United States
facility: Clinical Trials Management, LLC
state: Louisiana
city: Alpena
country: United States
facility: Endeavor Medical Research, PLC
state: Michigan
city: Minneapolis
country: United States
facility: Minneapolis Heart Institute Foundation
state: Minnesota
city: Edgewater
country: United States
facility: Cross Country Cardiology
state: New Jersey
city: Jackson
country: United States
facility: Kore CV Research
state: Tennessee
city: Johnson City
country: United States
facility: Wellmont Cardiovascular Associates Heart Institute
state: Tennessee
city: Houston
country: United States
facility: Med-Tech Research
state: Texas
city: Humble
country: United States
facility: Humble Cardiology Associates
state: Texas
city: Gomel
country: Belarus
facility: State Institution "Gomel regional clinical hospital"
city: Minsk
country: Belarus
facility: State Inst Rep Scientific and Practical center
city: Sofia
country: Bulgaria
facility: Diagnostic Consultative Center, Ascendent Cardiological Out-Patient Office
city: Sofia
country: Bulgaria
facility: MHAT "Tsar Boris III"
city: Sofia
country: Bulgaria
facility: National Cardiology Center, Cardiology Clinic - III
city: Sofia
country: Bulgaria
facility: MHAT "Vita", Cardiology Department
city: Sofia
country: Bulgaria
facility: UMHAT "Tsaritsa Yoanna" - ISUL, Cardiology Clinic
city: Sofia
country: Bulgaria
facility: Military Medical Academy, Clinic of Cardiology and Intesive Care
city: New Market
country: Canada
facility: SKDS Research Inc
state: Ontario
city: Sudbury
country: Canada
facility: Dr. Roger Labonté Professional Medicine Corp.
state: Ontario
city: Toronto
country: Canada
facility: Aniol Gupta MD
state: Ontario
city: Montreal
country: Canada
facility: Montréal General Hospital
state: Quebec
city: Lancaster
country: Canada
facility: High Desert Medical Group
city: Montreal
country: Canada
facility: Montreal Heart Institute
city: Ontario
country: Canada
facility: London Road Diagnostic Clinic and Medical Centre
city: Saint John's
country: Canada
facility: Topsail Road Medical Clinic
city: Brno
country: Czech Republic
facility: Vojenska Nemocnice Brno
city: Kladno
country: Czech Republic
facility: Cardiocentrum Kladno s.r.o.
city: Praha 4
country: Czech Republic
facility: Poliklinika Modrany - Kardiologie
city: Praha 5
country: Czech Republic
facility: Fakultní Nemocnice v Motole
city: Praha 5
country: Czech Republic
facility: Corintez s.r.o.
city: Príbram
country: Czech Republic
facility: Centrum klinického výzkumu, s.r.o.
city: Slaný
country: Czech Republic
facility: Nemocnice Slaný
city: Tbilisi
country: Georgia
facility: Tbilisi State Medical University Alexandre Aladashvili University Clinic
city: Tbilisi
country: Georgia
facility: Amtel Hospital First Clinical LLC
city: Tbilisi
country: Georgia
facility: Clinic "Guli"
city: Tbilisi
country: Georgia
facility: Cardio-Reanimation Clinic LTD
city: Tbilisi
country: Georgia
facility: Emergency Cardiology Center by Academician G. Chapidze LTD
city: Tbilisi
country: Georgia
facility: Tbilisi Heart and Vascular Clinic LTD
city: Tbilisi
country: Georgia
facility: Multiprofile Clinical Hospital of Tbilisi #2 LTD
city: Berlin
country: Germany
facility: Charité Campus Virchow Klinikum
city: Bielefeld
country: Germany
facility: Städtische Kliniken Bielefeld
city: Dortmund
country: Germany
facility: Sankt Johannes-Hospital Dortmund
city: Göttingen
country: Germany
facility: Universitätsklinikum Göttingen
city: Heidelberg
country: Germany
facility: Gemeinschaftspraxis fur Kardiologie
city: Mannheim
country: Germany
facility: Praxis Fur Innere Medizin Kardiologie, Pneumologic und Allergologie
city: Mannheim
country: Germany
facility: Universitätsmedizin Mannheim
city: Ashkelon
country: Israel
facility: Barzilai Medical Center, Cardiology Dept.
city: Be'er Ya'aqov
country: Israel
facility: Assaf Harofeh Medical Centre
city: Jerusalem
country: Israel
facility: Shaare Zedek Medical Center
city: Rehovot
country: Israel
facility: Kaplan Medical Center
city: Safed
country: Israel
facility: Ziv Medical Center
city: Tel Aviv
country: Israel
facility: Tel Aviv Souraski Medical Center
city: Lódz
country: Poland
facility: MULTI-MED PLUS Sp. z o.o.
state: Lodzkie
city: Skierniewice
country: Poland
facility: Niepubliczny Zakład Opieki Zdrowotnej Przychodnia Zdrowia "Zadębie"
state: Lodzkie
city: Puławy
country: Poland
facility: KO-MED Marek Konieczny
state: Lubelskie
city: Kraków
country: Poland
facility: Specjalistyczna Praktyka Lekarska Leszek Bryniarski
state: Malopolskie
city: Kraków
country: Poland
facility: NZOZ Revita Poradnia Kardiologiczna
state: Malopolskie
city: Warszawa
country: Poland
facility: Instytut Kardiologii
state: Mazowieckie
city: Warszawa
country: Poland
facility: Instytut Kardiologii
state: Mazowieckie
city: Gdynia
country: Poland
facility: NZOZ Sródmiescie Sp z o.o.
state: Pomorskie
city: Gdansk
country: Poland
facility: Pomorskie Centra Kardiologiczne S.A.
city: Grodzisk, Mazowiecki
country: Poland
facility: S.P. Specjalistyczny Szpital Zachodni im.JP II
city: Krakow
country: Poland
facility: Krakowski Szpital Specjalistyczny im.JPII
city: Warszawa
country: Poland
facility: Synexus SCM Sp. z o.o. Oddział w Warszawie
city: Warszawa
country: Poland
facility: Centrum Badawcze Współczenej Terapii
city: Zabrze
country: Poland
facility: Slaskie Centrum Chorób Serca w Zabrzu
city: Pushkin
country: Russian Federation
facility: City Hospital #38 named after Semashko N.A
state: St. Petersburg
city: Barnaul
country: Russian Federation
facility: Altay Regional Cardiologycal Dispensary
city: Chita
country: Russian Federation
facility: "Chita State Medical Academy" Curative-Diagnostic Clinic department
city: Ekaterinburg
country: Russian Federation
facility: Sverdlovsky Regional Clinical Hospital of Wars Veterans
city: Kemerovo
country: Russian Federation
facility: Municipal Institution of Healthcare "Kemerovo Cardiology Dispensary"
city: Kemerovo
country: Russian Federation
facility: Non-state Institution of healthcare "Department hospital on station Kemerovo of OAO "Russian Railway"
city: Kirovsk
country: Russian Federation
facility: Medical centre "Delis", LLC
city: Moscow
country: Russian Federation
facility: Federal State Institution "National Research Center for Preventive Medicine"
city: Moscow
country: Russian Federation
facility: State healthcare institution of Moscow "City Clinical hospital#15 named after O.M.Filatov"
city: Moscow
country: Russian Federation
facility: State Healthcare institution of Moscow"Cardiology Dispensary #2"
city: Moscow
country: Russian Federation
facility: First Moscow State Medical University I.M. Sechenov
city: Moscow
country: Russian Federation
facility: State Budget Educational Institution of High Professional Education First Moscow State Medical University... #1, Cardiology Clinic, Hospital Therapy Department
city: Moscow
country: Russian Federation
facility: State Budget Educational Institution of High Professional Education First Moscow State Medical University... #1, Cardiology Clinic, Hospital Therapy Department
city: Moscow
country: Russian Federation
facility: Moscow City Clinical Hospital #51
city: Moscow
country: Russian Federation
facility: FGU Central Clinical Hospital with Polyclinic of President Administrative Department of RF
city: Moscow
country: Russian Federation
facility: Moscow State University of Medicine and Dentistry based on Moscow City Clinical Hospital #71
city: Moscow
country: Russian Federation
facility: City Clinical Hospital named after S.P.Botkin
city: Moscow
country: Russian Federation
facility: State Institution of Moscow Healthcare "City Clinical Hospital named after S.P. Botkin"
city: Moscow
country: Russian Federation
facility: Moscow State Institution of Health "City Clinical Hospital #81"
city: Moscow
country: Russian Federation
facility: Federal State Institution "Outpatient department #3" of President Management department of Russian Federation
city: Novosibirsk
country: Russian Federation
facility: State Novosibirsk Regional Clinical Hospital
city: Penza
country: Russian Federation
facility: Regional Clinical Hospital named after N.N.Burdenko
city: Perm
country: Russian Federation
facility: State Institution of Healthcare Perm Regional Hospital for War Veterans
city: Ryazan
country: Russian Federation
facility: State Healthcare Institution "Ryazan regional clinical cardiological dispensary"
city: Saratov
country: Russian Federation
facility: "Clinical hospital named after S.R.Mirotvortsev"
city: Smolensk
country: Russian Federation
facility: Educational Institution of Higher Vocational Education "Smolensk State Medical Academy" on the base of Municipal Medicoprophylactic Institution "Hospital of Emergency Medical Care",
city: St. Petersburg
country: Russian Federation
facility: FGU Central Clinical Hospital with Polyclinic of President Administrative Department of RF
city: St. Petersburg
country: Russian Federation
facility: Federal State Educational Institution of High Professional Education "Military Medical Academy n.a. S.M. Kirov" of the Ministry of Defence of Russia
city: St. Petersburg
country: Russian Federation
facility: International Medical Center "SOGAZ", LLC
city: St. Petersburg
country: Russian Federation
facility: State Healthcare institution "Municipal Out-patient Clinic #109"
city: St. Petersburg
country: Russian Federation
facility: Saint-Petersburg State Healthcare Institution
city: St. Petersburg
country: Russian Federation
facility: Federal Heart, Blood and Endocrinology Centre n.a. Almazov
city: St. Petersburg
country: Russian Federation
facility: Institution and Address: "Medical Research Institute", LLC
city: St. Petersburg
country: Russian Federation
facility: Federal Heart, Blood and Endocrinology Centre n.a. Almazov
city: St. Petersburg
country: Russian Federation
facility: State Institution of Healthcare "City Hospital #40 of Kurortniy administrative district
city: Voronezh
country: Russian Federation
facility: Autonomous healthcare institution of Voronezh region "Voronezh regional clinic consultative and diagnostic centre"
city: Yaroslavl
country: Russian Federation
facility: Municipal Institution of Healthcare "Clinical Hospital #8 of Yaroslavl"
city: Belgrade
country: Serbia
facility: Cardiology Clinic, Clinical Center Serbia
city: Sremska Kamenica
country: Serbia
facility: Institute of Cardiovascular Diseases
city: Bardejov
country: Slovakia
facility: ALIAN, s.r.o.
city: Bratislava
country: Slovakia
facility: Cardioconsult, s.r.o.
city: Bratislava
country: Slovakia
facility: Kardiovaskulárne centrum, s.r.o.
city: Košice
country: Slovakia
facility: CARDIO D&R, s.r.o.
city: Lučenec
country: Slovakia
facility: KARDIOMED, s.r.o.
city: Nitra
country: Slovakia
facility: Kardiocentrum Nitra, s.r.o.
city: Golnik
country: Slovenia
facility: University Clinic of Respiratory and Allergic Diseases Golnik
city: Ljubljana
country: Slovenia
facility: University Klinicni Center Ljubljana
city: Murska Sobota
country: Slovenia
facility: General Hospital Murska Sobota
city: Donetsk
country: Ukraine
facility: Donetsk National Medical University, Department of Internal Medicine #1 based on Department of Emergency Cardiology and Rehabilitation of Institute of Urgent and Recovery Surgery named after V. K. Gusak
city: Kharkiv
country: Ukraine
facility: Central Clinical Hospital of Ukrzaliznitsia, Cardiology department
city: Kharkiv
country: Ukraine
facility: Kharkiv Medical Academy of Postgraduate Education, Department of cardiology and functional diagnostics based on City Clinical Hospital #8, Department of Cardiology #2
city: Kyiv
country: Ukraine
facility: Central polyclinic of Pechersk district, Department of cardiology
city: Kyiv
country: Ukraine
facility: Kyiv City Clinical Hospital #1, Department of Emergency Cardiology
city: Kyiv
country: Ukraine
facility: Kyiv city clinical hospital #5
city: Kyiv
country: Ukraine
facility: Department of Diabetology of National Medical Academy of Postgraduate Education named after P.L.Shupyk based on Day Time Hospital of Administration of Medical Service and Rehabilitation of "ARTEM" SHC
city: Kyiv
country: Ukraine
facility: SI "Institute of Gerontology of AMS of Ukraine"
city: Lviv
country: Ukraine
facility: Lviv National Medical University named after Danylo Halytsky, Department of Propaedeutics of Internal Medicine #1 based on Polyclinic Department of Municipal City Clinical Hospital #5
city: Odessa
country: Ukraine
facility: SI Odessa Regional Cardiological Dispensary
Study officials:
affiliation: Gilead Sciences
name: Patrick Yue, MD
role: STUDY_DIRECTOR
References:
citation: Arnold SV, Kosiborod M, Li Y, Jones PG, Yue P, Belardinelli L, Spertus JA. Comparison of the Seattle Angina Questionnaire With Daily Angina Diary in the TERISA Clinical Trial. Circ Cardiovasc Qual Outcomes. 2014 Nov;7(6):844-50. doi: 10.1161/CIRCOUTCOMES.113.000752. Epub 2014 Sep 23.
citation: Roubinian NH, Escobar GJ, Liu V, Gardner MN, Carson JL, Kleinman SH, Murphy EL; NHLBI Recipient Epidemiology and Donor Evaluation Study (REDS-III). Decreased red blood cell use and mortality in hospitalized patients. JAMA Intern Med. 2014 Aug;174(8):1405-7. doi: 10.1001/jamainternmed.2014.2889. No abstract available.
citation: Kosiborod M, Arnold SV, Spertus JA, McGuire DK, Li Y, Yue P, Ben-Yehuda O, Katz A, Jones PG, Olmsted A, Belardinelli L, Chaitman BR. Evaluation of ranolazine in patients with type 2 diabetes mellitus and chronic stable angina: results from the TERISA randomized clinical trial (Type 2 Diabetes Evaluation of Ranolazine in Subjects With Chronic Stable Angina). J Am Coll Cardiol. 2013 May 21;61(20):2038-45. doi: 10.1016/j.jacc.2013.02.011. Epub 2013 Mar 10.