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    Summary
    EudraCT Number:2015-002040-14
    Sponsor's Protocol Code Number:RVX222-CS-015
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2017-04-10
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedNetherlands - Competent Authority
    A.2EudraCT number2015-002040-14
    A.3Full title of the trial
    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)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    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.
    A.3.2Name or abbreviated title of the trial where available
    BETonMACE
    A.4.1Sponsor's protocol code numberRVX222-CS-015
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02586155
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorResverlogix Corp.
    B.1.3.4CountryCanada
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportResverlogix Corp
    B.4.2CountryCanada
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationResverlogix Corp
    B.5.2Functional name of contact pointClinical Development
    B.5.3 Address:
    B.5.3.1Street Address44 Montgomery Street, Suite 2150
    B.5.3.2Town/ citySan Francisco
    B.5.3.3Post codeCA 94104
    B.5.3.4CountryUnited States
    B.5.4Telephone number001415470 5600
    B.5.5Fax number001415470 5600
    B.5.6E-mailmsweeney@resverlogix.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameRVX000222
    D.3.2Product code RVX000222
    D.3.4Pharmaceutical form Capsule, hard
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNapabetalone
    D.3.9.2Current sponsor codeRVX000222
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboCapsule, hard
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    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.
    E.1.1.1Medical condition in easily understood language
    Prevention of cardiovascular events in type 2 diabetes mellitus patients with low high-density lipoprotein cholesterol levels and at high risk for major adverse cardiovascular events
    E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10051614
    E.1.2Term Arteriosclerotic cardiovascular disease
    E.1.2System Organ Class 100000022953
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10051615
    E.1.2Term Atherosclerotic cardiovascular disease
    E.1.2System Organ Class 100000022953
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    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.
    E.2.2Secondary objectives of the trial
    -To evaluate if treatment with RVX000222 increases time to the first occurrence of broadly defined MACE in comparison to placebo
    -To evaluate if treatment 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 in population with baseline estimated glomerular filtration rate <60 mL/min/1.7m2
    -To evaluate the safety and tolerability of RVX000222
    E.2.3Trial contains a sub-study No
    E.3Principal 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 related to index ACS event including 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 quality 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 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:
    a. 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 (nonhormonal
    intrauterine device, condom, or diaphragm) or remain abstinent from Screening until Follow-up Visit.
    b. Be of non-child-bearing potential: post-surgical sterilization or post-menopausal.
    7. Have given signed informed consent to participate in this study.
    E.4Principal 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 an 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 estimated Glomerular Filtration Rate less than 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 (Appendix A)
    - Any one of the following liver enzymes that is >1.5xULN by central lab at Visit 1
    i. ALT
    ii. 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 place the subject at higher risk from his/her participation in the study, or is likely to prevent the subject from complying with the requirements of the study or completing the study.
    19. Use of other investigational drugs and devices within 30 days or 5 half-lives of Visit 1, whichever is longer.
    20. History of noncompliance to medical regimens or unwillingness to comply with the study protocol.
    21. Any condition that in the opinion of the investigator would confound the evaluation and interpretation of efficacy and/or safety data.
    22. Persons directly involved in the execution of this protocol.
    E.5 End points
    E.5.1Primary 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.
    E.5.1.1Timepoint(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.
    E.5.2Secondary 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:
    o Unstable angina AND evidence of new or presumed new progressive obstructive coronary disease, OR
    o 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 fatal 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/1.7m2 within and between treatment groups
    E.5.2.1Timepoint(s) of evaluation of this end point
    Secondary endpoints will be assessed when the 250th event occurs
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA86
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Argentina
    Belgium
    Bulgaria
    Croatia
    Germany
    Hungary
    Israel
    Mexico
    Netherlands
    Poland
    Russian Federation
    Serbia
    Slovakia
    Taiwan
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months5
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months9
    E.8.9.2In all countries concerned by the trial days7
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 1440
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 960
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations No
    F.3.3.1Women of childbearing potential not using contraception Information not present in EudraCT
    F.3.3.2Women of child-bearing potential using contraception Information not present in EudraCT
    F.3.3.3Pregnant women Information not present in EudraCT
    F.3.3.4Nursing women Information not present in EudraCT
    F.3.3.5Emergency situation Information not present in EudraCT
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state30
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 1716
    F.4.2.2In the whole clinical trial 2400
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    None
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2017-04-10
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-06-29
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2019-07-04
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