International clinical trial to determine whether treatment with RVX000222 as compared to placebo increases time to occurrence of cardiac events in patients with Diabetes Mellitus and with a history of atherosclerotic cardiovascular disease.

• Register: EUCTR
• Last refreshed on: 10 December 2019
• Main ID: EUCTR2015-002040-14-HR
• Date of registration: 10/11/2015
• Prospective Registration: No
• Primary sponsor: Resverlogix Corp.
• Public title: International clinical trial to determine whether treatment with RVX000222 as compared to placebo increases time to occurrence of cardiac events in patients with Diabetes Mellitus and with a history of atherosclerotic cardiovascular disease.
• Scientific 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) - BETonMACE
• Date of first enrolment: 27/10/2015
• Target sample size: 2400
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2015-002040-14
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: no; Single blind: no; Double blind: yes; Parallel group: yes; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: no; Placebo: yes; Other: no; Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Argentina, Australia, Belgium, Bulgaria, Croatia, Germany, Hungary, Israel, Mexico, Netherlands, Poland, Russian Federation, Serbia, Slovakia, Taiwan

Contacts

• Name: Clinical Development
• Affiliation: Resverlogix Corp

• Name: Clinical Development
• Affiliation: Resverlogix Corp

Key inclusion & exclusion criteria

Inclusion criteria:
1. Male and female subjects age 18 and over with documented diagnosed T2DM and a CAD event of either unstable angina or myocardial infarction, not less than 7 days and no more than 90 days prior to Visit 1. In order to have sufficient number of clinical
events, the number of subjects with unstable angina will be limited to 25% of the total
number of subjects
-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 or associated referral areas, occurring at rest or with minimal exertion
b. ECG changes consistent with acute myocardial ischemia based upon at least one of the following:
i. new or presumed new ST elevation
ii. new or presumed new ST depression
iii. new or presumed new T-wave inversion
c. Objective evidence of obstructive coronary artery disease based upon at least one of the following:
i. new or presumed new evidence of myocardial ischemia or infarction by perfusion imaging
ii. new or presumed new regional wall motion abnormality
iii. current evidence of at least one 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
- Previous MI 7-90 days before screening, treated with or without a percutaneous
coronary intervention (PCI). For a qualifying event of MI, two of the following
three criteria must be satisfied:
a. Characteristic ischemic chest pain or pain in associated referral areas
b. Dynamic elevation of troponin T or I or CKMB, if troponin T or I is unavailable at the local lab (at least above the upper limit of normal for the laboratory)
c. Development of new Q-waves in at least two adjacent electrocardiogram (ECG) leads or development of a new dominant R wave in V1
2. Documented diagnosis of T2DM (one or more of the following criteria must be met):
-Documented history of T2DM
-History of taking diabetes medication
-HbA1c =6.5% at Visit 1
3. For males HDL-C of <40 mg/dL (1.04 mmol/L) and for females HDL-C of <45 mg/dL (1.17 mmol/L) at Visit 1.
4. In the opinion of the Investigator, subjects currently not on high intensity statin therapy will be able to start rosuvastatin according to the protocol at Visit 1.
5. In the opinion of the Investigator, subjects currently on statin therapy other than atorvastatin or rosuvastatin can be switched to rosuvastatin according to the protocol at Visit 1. High intensity statin therapy doses should remain unchanged during the study period if at all possible.
6. Female subjects must meet one of the following:
-If of childbearing potential, female subjects must have a negative urine pregnancy test and be willing and able to use medically acceptable non-hormonal method of birth control (non-hormonal intrauterine device, condom, or diaphragm) or remain abstinent from Screening until Follow-up Visit.

Exclusion criteria:
1. Heart disease which, in the opinion of the investigator, will within 90 days of Visit 1 likely require coronary bypass, PCI, cardiac transplantation, surgical repair and/or replacement.
2. Previous or current diagnosis of severe heart failure (New York Heart Association Class IV) or a documented left ventricular ejection fraction (LVEF) of <25% as determined by contrast left ventriculography, radionuclide ventriculography or echocardiography. The absence of a LVEF measurement in a subject without a previous or current diagnosis of heart failure does not prohibit entry into the study.
3. Subjects with evidence of cardiac electrophysiologic instability including a history of uncontrolled ventricular arrhythmias, uncontrolled atrial fibrillation/flutter or uncontrolled supraventricular tachycardias with a ventricular response heart rate of >100 beats per minute at rest within 4 weeks prior to Visit 1.
4. Coronary artery bypass grafting (CABG) within 90 days prior to Visit 1.
5. Evidence of severe renal impairment as determined by any one of the following:
-an eGFR <30 mL/min/1.7m2 at Visit 1
-a current need for dialysis
6. Uncontrolled hypertension defined as 2 consecutive measurements of sitting blood pressure of systolic >180 mm Hg or diastolic >100 mm Hg at Visit 1.
7. Current or recent (within 12 months prior to Visit 1) treatment with immunosuppressants (e.g., cyclosporine).
8. Use of fibrates at any dose or niacin/nicotinic acid 250 mg or more within 30 days prior to Visit 1.
9. A known allergy or sensitivity to any ingredient in the investigational medicinal product.
10. History of intolerance to atorvastatin or rosuvastatin.This exclusion criterion applies to subjects with a history of intolerance to the statin to which they would be assigned at screening
11. Triglycerides >400 mg/dL (4.52 mmol/L) at Visit 1.
12. Any medical or surgical condition which might significantly alter the absorption, distribution, metabolism or excretion of medication including, but not limited to any of the following: untreated or incompletely treated thyroid dysfunction, cholecystitis, Crohn’s disease, ulcerative colitis, or any gastric bypass alteration.
13. Evidence of cirrhosis from liver imaging or biopsy, a history of hepatic encephalopathy, esophageal or gastric varices, active hepatitis, or prior porta-caval shunt procedure, or a Child-Pugh score of at least 5 points.
-Any one of the following liver enzymes that is >1.5x the upper limit of normal range (ULN) by central lab at Visit 1
a. Alanine aminotransferase (ALT)
b. Aspartate aminotransferase (AST)
14. A total bilirubin that is >ULN by central lab at Visit 1.
15. History of malignancy of any organ system, treated or untreated, within the past 2 years whether or not there is evidence of local recurrence or metastases, with the exception of localized basal cell carcinoma of the skin.
16. History or evidence of drug or alcohol abuse within 12 months of Visit 1, in the opinion of the investigator.
17. Female subjects who are pregnant.
18. Any condition which, in the opinion of the investigator, may plac

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Secondary cardiovascular disease (CVD) prevention in type 2 diabetes mellitus (T2DM) subjects with low high-density lipoprotein cholesterol (HDL-C) at high risk for MACE.
MedDRA version: 20.0 Level: LLT Classification code 10051614 Term: Arteriosclerotic cardiovascular disease System Organ Class: 100000004866
MedDRA version: 20.0 Level: LLT Classification code 10051615 Term: Atherosclerotic cardiovascular disease System Organ Class: 100000004866

Therapeutic area: Diseases [C] - Cardiovascular Diseases [C14]

Intervention(s)

Product Name: RVX000222
Product Code: RVX000222
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: apabetalone
Current Sponsor code: RVX000222
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 100-
Pharmaceutical form of the placebo: Capsule, hard
Route of administration of the placebo: Oral use

Primary Outcome(s)

Primary end point(s): The primary endpoint will be time from randomization to the first occurrence of adjudication-confirmed MACE narrowly defined as a single composite endpoint of CV Death or Non-fatal MI or Stroke.

Main Objective: To evaluate if treatment with RVX000222 as compared to placebo increases time to the first occurrence of narrowly defined MACE. Narrowly defined MACE is defined as a single composite endpoint of CV death or Non-fatal MI or Stroke.

Timepoint(s) of evaluation of this end point: Primary endpoints will be assessed until end of study treatment (104 weeks) or when the 250th event occurs, whichever occurs first.

Secondary Objective: - To evaluate if treatment with RVX000222 increases time to the first occurrence of broadly defined MACE in comparison to placebo
-To evaluate if tretment with RVX000222 increases time to the first occurrence of fatal or non-fatal MI, or fatal or non-fatal stroke
- To evaluate treatment group difference in all-cause mortality
- To evaluate changes in lipoprotein concentrations including apoA-I, apolipoprotein B (apoB), LDL-C, HDL-C, and triglyceride (TG) over time within and between treatment groups
- To evaluate changes in DM variables including glycated hemoglobin (HbA1c), fasting glucose, and fasting insulin over time within and between treatment groups
- To evaluate changes in ALP over time within and between treatment groups including isoforms for whole population and quartiles of ALP baseline concentration
- Assess changes in kidney function
- To evaluate the safety and tolerability

Secondary Outcome(s)

Secondary end point(s): 1. Time from randomization to the first occurrence of adjudication-confirmed MACE broadly defined between treatment groups.
Broadly defined MACE is the occurrence of any of the following events:
-CV death
-Non-fatal MI
-Hospitalization for CVD events which include:
-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 events prior to randomization
- Stroke
2. Time from randomization to fatal or non-fatal MI, or fataal or non-fatal stroke
3. Time from randomization to CV Death or Non-fatal MI
4. Time from randomization to Non-fatal MI
5. Time from randomization to CV Death
6. Time from randomization to Stroke
7. All-cause mortality
Other Secondary Endpoints:
-The percent change in apoA-I, apoB, LDL-C, HDL-C, and TG over time within and between treatment groups
-The change from baseline in HbA1c, fasting glucose, and fasting insulin within and between treatment groups
-Changes in ALP within and between treatment groups for all subjects and according to quartiles of ALP baseline concentration
-Changes from baseline in kidney function in subgroup population with estimated glomerular filtration rate <60 mL/min/1.7 m2 within and between treatment groups

Timepoint(s) of evaluation of this end point: Secondary endpoints will be assessed when the 250th event occurs

Secondary ID(s)

2015-002040-14-BE

RVX222-CS-015

Source(s) of Monetary Support

Resverlogix Corp

Ethics review

Status: Approved
Approval date:
Contact: