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Effect of RVX000222 on Time to Major Adverse Cardiovascular Events in High-Risk T2DM Subjects With CAD (BETonMACE)

This study is currently recruiting participants.
See Contacts and Locations
Verified July 2016 by Resverlogix Corp
Sponsor:
Collaborators:
PPD
ICON plc
Medidata Solutions
Information provided by (Responsible Party):
Resverlogix Corp
ClinicalTrials.gov Identifier:
NCT02586155
First received: October 21, 2015
Last updated: July 20, 2016
Last verified: July 2016
  Purpose
The purpose of this study is to determine whether bromodomain extraterminal domain (BET) inhibition treatment with RVX000222 in high-risk type 2 diabetes mellitus patients with coronary artery disease increases the time to major adverse cardiovascular events.

Condition Intervention Phase
Diabetes Mellitus, Type 2 Coronary Artery Disease Cardiovascular Diseases Drug: RVX000222 Drug: Placebo (for RVX000222) Drug: atorvastatin Drug: rosuvastatin Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Prevention
Official Title: A Phase III Multi-Center, Double-Blind, Randomized, Parallel Group, up to 104 Weeks Dosing, Placebo-Controlled Clinical Trial in High-Risk Type 2 Diabetes Mellitus (T2DM) Subjects With Coronary Artery Disease (CAD) to Determine Whether Bromodomain Extraterminal Domain (BET) Inhibition Treatment With RVX000222 Increases the Time to Major Adverse Cardiovascular Events (MACE)

Resource links provided by NLM:


Further study details as provided by Resverlogix Corp:

Primary Outcome Measures:
  • Time to first occurrence of adjudication-confirmed narrowly defined MACE [ Time Frame: 120 weeks ]
    Narrowly defined MACE(major adverse cardiac event) is defined as a single composite endpoint of CV death or non-fatal MI or stroke


Secondary Outcome Measures:
  • Time to first occurrence of adjudication-confirmed broadly defined MACE [ Time Frame: 120 weeks ]
    Broadly defined MACE (major adverse cardiac event) is the occurrence of any of the following: CV death, non-fatal MI, hospitalization for CVD events, or stroke

  • Group difference in all-cause mortality [ Time Frame: 120 weeks ]
  • Percent change in apoA-I concentration over time within and between treatment groups [ Time Frame: 120 weeks ]
  • Percent change in apoB concentration over time within and between treatment groups [ Time Frame: 120 weeks ]
  • Percent change in LDL-C concentration over time within and between treatment groups [ Time Frame: 120 weeks ]
  • Percent change in HDL-C concentration over time within and between treatment groups [ Time Frame: 120 weeks ]
  • Percent change in TG concentration over time within and between treatment groups [ Time Frame: 120 weeks ]
  • Change in HbA1c over time within and between treatment groups [ Time Frame: 120 weeks ]
  • Change in fasting glucose over time within and between treatment groups [ Time Frame: 120 weeks ]
  • Change in fasting insulin over time within and between treatment groups [ Time Frame: 120 weeks ]
  • Change in alkaline phosphatase (ALP) over time within and between treatment groups [ Time Frame: 120 weeks ]
    including isoforms for whole population and quartiles of ALP baseline concentration

  • Change in kidney function in population [ Time Frame: 120 weeks ]
    baseline estimated glomerular filtration rate (eGFR) <60 mL/min/1.7m2

  • Incidence of AEs and Serious AEs within and between treatment groups [ Time Frame: 120 weeks ]

Other Outcome Measures:
  • Percent change in hsCRP within and between treatment groups [ Time Frame: 120 weeks ]
  • Percent change in fibrinogen within and between treatment groups [ Time Frame: 120 weeks ]
  • Transcription (messenger RNA [mRNA]) change in whole blood [ Time Frame: 6 weeks ]
  • Health Related Quality of Life (HRQOL) as measured using the EQ-5D-5L [ Time Frame: 122 weeks ]

Estimated Enrollment: 2400
Study Start Date: October 2015
Estimated Study Completion Date: October 2018
Estimated Primary Completion Date: September 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: High-Intensity statin therapy+RVX000222
Daily dose 100 mg capsule b.i.d. with high-intensity statin therapy (atorvastatin or rosuvastatin)
Drug: RVX000222
100 mg capsule
Other Name: apabetalone
Drug: atorvastatin
High-Intensity Statin
Other Name: Lipitor
Drug: rosuvastatin
High-Intensity Statin
Other Name: Crestor
Active Comparator: High-Intensity statin therapy+Placebo
Placebo (for RVX000222 100 mg capsule) b.i.d. with high-intensity statin therapy (atorvastatin or rosuvastatin)
Drug: Placebo (for RVX000222)
Capsule manufactured to mimic RVX000222 100 mg capsule
Other Name: placebo
Drug: atorvastatin
High-Intensity Statin
Other Name: Lipitor
Drug: rosuvastatin
High-Intensity Statin
Other Name: Crestor

Detailed Description:

The majority (75%) of deaths in subjects with diabetes mellitus (DM) are due to atherosclerotic cardiovascular disease (CVD). Recent studies suggest a major adverse cardiovascular event (MACE) rate of >11% over 18 months in type 2 diabetes mellitus (T2DM) despite a baseline LDL-C of <2.1 mmol/L. Bromodomains (BRDs) are a family of evolutionary conserved protein-interaction modules that play key functions in chromatin organization and regulation of gene transcription. One recognized family of bromodomain-containing proteins is the bromodomain and extra-terminal (BET) family. BET inhibition represents a novel, epigenetic approach to treat CAD.

RVX000222 affects biological processes important in atherosclerosis and acute coronary events via selective inhibition of BET proteins. RVX000222 is available as a capsule formulation with standard excipients and established stability.

The BETonMACE study will focus on prevention of subsequent MACE in subjects with CAD and DM with high intensity statin therapy as co-medication.

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • CAD event 7-90 days prior Visit 1 w/ 1+ of following 3 primary criteria:
  • Unstable angina w/ each of the following: 1. characteristic ischemic pain or discomfort in chest/associated referral areas, occurring at rest/with minimal exertion 2. ECG changes consistent with acute myocardial ischemia based on new/presumed ST elevation/depression or T-wave inversion 3. objective evidence of obstructive CAD based on 1+ of the following: a. new/presumed new evidence of myocardial ischemia/infarction by perfusion imaging b. new/presumed new regional wall motion abnormality c. current evidence of at least 1 epicardial coronary artery stenosis ≥70% by coronary angiography d. need for coronary revascularization related to index ACS event
  • History of PCI w/ or w/o coronary stenting to treat acute coronary syndrome 7-90 days prior Visit 1
  • Prior MI 7-90 days prior screening w/ 2 of following 3 criteria: 1. characteristic ischemic chest pain/pain in associated referral areas 2. Elevation of troponin T/I or CKMB if troponinT/I is unavailable at local lab (at least >ULN for lab) 3. Development of new Q-waves in ≥2 adjacent ECG leads or development of new dominant R wave in V1
  • Documented diagnosis of T2DM (1+ of the following criteria)
  • Documented history of T2DM
  • History of taking diabetes medication
  • HbA1c ≥6.5% at Visit 1
  • For males HDL-C<40 mg/dL(1.04 mmol/L), for females HDL-C<45 mg/dL(1.17 mmol/L) at Visit 1
  • Subjects currently not on high intensity statin therapy could start rosuvastatin at Visit 1 and those currently on therapy besides atorvastatin/rosuvastatin can be switched to rosuvastatin at Visit 1
  • Female subjects of non-childbearing potential (post-surgical sterilization/post-menopausal) or if childbearing potential have neg urine pregnancy test and be willing and able to use non-hormonal birth control (non-hormonal IUD, condom or diaphragm) or remain abstinent from Screening to Follow-up Visit
  • Give signed informed consent

Exclusion Criteria:

  • Heart disease which will w/in 90 days of Visit 1 likely need coronary bypass, PCI, cardiac transplantation, surgical repair and/or replacement
  • Previous/current diagnosis of severe heart failure or documented LVEF<25% determined by contrast left ventriculography, radionuclide ventriculography or echocardiography. Absence of LVEF measurement in subject w/out a previous/current diagnosis of heart failure does not exclude entry into study
  • Evidence of cardiac EP instability incl. history of uncontrolled ventricular arrhythmias, atrial fibrillation/flutter or supraventricular tachycardias w/ a ventricular response HR>100bpm at rest w/in 4 wks prior Visit 1
  • CABG w/in 90 days prior Visit 1
  • Evidence of severe renal impairment as determined by either eGFR<30 mL/min/1.7m2 at Visit 1 or current need for dialysis
  • Uncontrolled hypertension defined as 2 consecutive measurements of sitting BP of systolic>180 mmHg or diastolic>100 mmHg at Visit 1
  • Treatment w/ immunosuppressants w/in 12 mos prior Visit 1
  • Use of fibrates at any dose or niacin/nicotinic acid 250+ mg w/in 30 days prior Visit 1
  • Known allergy/sensitivity to any ingredient in IMP
  • History of intolerance to atorvastatin/rosuvastatin
  • Triglycerides>400 mg/dL (4.52 mmol/L) at Visit 1
  • Any medical/surgical condition which might significantly alter absorption, distribution, metabolism or excretion of medication
  • Evidence of cirrhosis from liver imaging/biopsy, history of hepatic encephalopathy, esophageal/gastric varices, active hepatitis or prior porta-caval shunt procedure or a Child-Pugh score of ≥5 points
  • ALT/AST>1.5xULN by central lab at Visit 1
  • Tot. bilirubin>ULN by central lab at Visit 1
  • History of malignancy of any organ syst treated/untreated w/in the past 2 yrs whether or not there is evidence of local recurrence/metastases except localized basal skin cell carcinoma
  • History/evidence of drug/alcohol abuse w/in 12 mos of Visit 1
  • Pregnancy
  • Any condition which may place subject at higher risk from his/her participation in the study or is likely to prevent subject from completing/complying w/ requirements of study
  • Use of other investigational drugs and devices w/in 30 days or 5 half-lives of Visit 1, whichever is longer
  • History of noncompliance to medical regimens or unwillingness to comply w/ study protocol
  • Any condition that would confound the evaluation/interpretation of efficacy and/or safety data
  • Persons directly involved in execution of this protocol
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02586155

Contacts
Contact: Heather Berns 403.254.9252

Locations
Israel
Lady Davis Carmel Medical Center Recruiting
Haifa, Israel, 34362
Contact: Basil Lewis, MD         
Sponsors and Collaborators
Resverlogix Corp
PPD
ICON plc
Medidata Solutions
Investigators
Study Chair: Kausik Ray, MD Imperial College London
  More Information

Responsible Party: Resverlogix Corp
ClinicalTrials.gov Identifier: NCT02586155     History of Changes
Other Study ID Numbers: RVX222-CS-015
Study First Received: October 21, 2015
Last Updated: July 20, 2016

Additional relevant MeSH terms:
Diabetes Mellitus
Cardiovascular Diseases
Coronary Artery Disease
Myocardial Ischemia
Coronary Disease
Diabetes Mellitus, Type 2
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Heart Diseases
Arteriosclerosis
Arterial Occlusive Diseases
Vascular Diseases
Atorvastatin Calcium
Rosuvastatin Calcium
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Anticholesteremic Agents
Hypolipidemic Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Lipid Regulating Agents
Enzyme Inhibitors

ClinicalTrials.gov processed this record on August 22, 2017