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

Study Overview
=================
Brief Summary
-----------------
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.

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.

Official Title
-----------------
A Phase III Multi-Center, Double-Blind, Randomized, Parallel Group, 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)

Conditions
-----------------
Diabetes Mellitus, Type 2, Coronary Artery Disease

Intervention / Treatment
-----------------
* Drug: Apabetalone
* Drug: Placebo
* Drug: Atorvastatin
* Drug: Rosuvastatin


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: • ACS event of either unstable angina or myocardial infarction 7-90 days prior Visit 1: Unstable angina: for a qualifying unstable angina event, each of components (a), (b), and (c) must be satisfied: a.) Characteristic ischemic pain or discomfort in chest/associated referral areas, occurring at rest/with minimal exertion b.) ECG changes consistent with acute myocardial ischemia based on new/presumed ST elevation/depression or T-wave inversion c.) Objective evidence of obstructive CAD based on 1+ of the following: i. New/presumed new evidence of myocardial ischemia/infarction by perfusion imaging ii. New/presumed new regional wall motion abnormality iii. Current evidence of at least 1 epicardial coronary artery stenosis ≥70% by coronary angiography iv. Need for coronary revascularization for the index ACS event, including a percutaneous coronary intervention (PCI) with or without coronary stenting. Prior MI 7-90 days prior screening treated with or without a percutaneous coronary intervention (PCI). For a qualifying event of MI 2 of the following 3 criteria must be satisfied: a.) Characteristic ischemic chest pain/pain in associated referral areas b.) Dynamic elevation of troponin T/I or CKMB if troponinT/I is unavailable at local lab (at least >ULN for lab) c.) 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, and/or 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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: High-Intensity statin therapy+RVX000222<br>Daily dose 100 mg capsule b.i.d. with high-intensity statin therapy (atorvastatin or rosuvastatin) | Drug: Apabetalone<br>* 100 mg capsule<br>* Other names: RVX000222;Drug: Atorvastatin<br>* High-Intensity Statin<br>* Other names: Lipitor;Drug: Rosuvastatin<br>* High-Intensity Statin<br>* Other names: Crestor;|
| Active Comparator: High-Intensity statin therapy+Placebo<br>Placebo (for RVX000222 100 mg capsule) b.i.d. with high-intensity statin therapy (atorvastatin or rosuvastatin) | Drug: Placebo<br>* Capsule manufactured to mimic RVX000222 100 mg capsule<br>* Other names: Placebo (for RVX000222);Drug: Atorvastatin<br>* High-Intensity Statin<br>* Other names: Lipitor;Drug: Rosuvastatin<br>* High-Intensity Statin<br>* Other names: Crestor;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of First Occurrence of Adjudication-confirmed Narrowly Defined MACE | Incidence of first occurrence of MACE narrowly defined as a single composite endpoint of Cardiovascular (CV) Death (including undetermined cause of death) or Non-fatal Myocardial Infarction (MI) or Stroke. If a subject has multiple events, only the first event contributing to the composite endpoint is counted. | 120 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of First Occurrence of Adjudication-confirmed Broadly Defined MACE | First occurrence of MACE broadly defined as a single composite endpoint of Cardiovascular Death (CVD) (including undetermined cause of death) or Non-fatal Myocardial Infarction (MI), Stroke, or Hospitalization for CVD events (including unstable angina and evidence of new or presumed new progressive obstructive coronary disease or emergency revascularization procedures at any time and urgent revascularization procedures ≥30 days after the index event as defined by Hicks et al., 2014) . If a subject has multiple events, only the first event contributing to the composite endpoint is counted. | 120 weeks | 
| Incidence of Hospitalization for Congestive Heart Failure (CHF) |  | 120 weeks | 
| Incidence of All-cause Mortality |  | 120 weeks | 
| Change in Apolipoprotein A1 (ApoA-I) Concentration From Baseline Over Time Within and Between Treatment Groups |  | 120 weeks | 
| Change in Apolipoprotein B (apoB) Concentration From Baseline Over Time Within and Between Treatment Groups |  | 120 weeks | 
| Change in LDL-C Concentration From Baseline Over Time Within and Between Treatment Groups |  | 120 weeks | 
| Change in HDL-C Concentration From Baseline Over Time Within and Between Treatment Groups |  | 120 weeks | 
| Change in Triglyceride (TG) Concentration From Baseline Over Time Within and Between Treatment Groups |  | 120 weeks | 
| Change in Hemoglobin (Hb) A1c From Baseline Over Time Within and Between Treatment Groups |  | 120 weeks | 
| Change in Glucose From Baseline Over Time Between and Within Treatment Groups |  | 120 weeks | 
| Change in Alkaline Phosphatase (ALP) From Baseline Over Time Within and Between Treatment Groups |  | 172 weeks | 
| Change in C Reactive Protein (CRP) Concentration From Baseline Over Time Within and Between Treatment Groups |  | 52 weeks | 
| Change in Estimated Glomerular Filtration Rate (eGFR) From Baseline Over Time Within and Between Treatment Groups for Subjects With Impaired Renal Function at Baseline (eGFR <60 mL/Min/1.7m2) |  | 120 weeks |