Download JACC-HF Online Appendix 1- Study Oversight

CUPID 2: AAV1/SERCA2a in Heart Failure
Greenberg, et al.
Online Appendix 1- Study Oversight
CUPID Clinical Endpoints Committee (CEC)
Responsibilities:
The CEC provides independent, consistent and unbiased adjudication of all potential of protocoldefined study events using clearly defined standardized criteria for heart failure hospitalization.
The CEC also evaluates whether the decisions and timing regarding LVAD and heart transplant
are in accord with current heart failure practice guidelines. This committee will remain blinded
to treatment assignment throughout the study.
CEC Committee Chairman:
Akshay Desai M.D., MPH, Brigham and Women’s Hospital Clinical Endpoint Center
CUPID Data Monitoring Committee (DMC)
Responsibilities:
The DMC is responsible for safeguarding the interests of trial participants, assessing the safety
and efficacy data during the trial, monitoring the overall conduct of the clinical trial and
providing recommendations for enhancing the integrity of the trial.
Members and affiliations:
Jeffrey S. Borer, M.D., Chair, Professor of Medicine, Cell Biology, Radiology and Surgery
Chief, Division of Cardiovascular Medicine,
Director, The Howard Gilman Institute for Heart Valve Diseases and the
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Schiavone Cardiovascular Translational Research Institute State University of
New York Downstate Medical Center, New York, NY
Lloyd Fisher, M.D., Ph.D., Professor Emeritus, Department of Biostatistics, University of
Washington, Kenmore, WA
Alan B. Miller, M.D., Professor of Medicine, Division of Cardiology, University of Florida
Health Science Center, Jacksonville, FL
Ian Sarembock, M.D., Ch.B., M.B., Service Line Executive Medical Director & Co-Director,
Heart & Vascular Center at The Christ Hospital, Cincinnati, OH
Karl Swedberg, M.D., Ph.D., Senior Physician, Department of Medicine, Sahlgrenska University
Hospital-Östra, Göteborg, Sweden
CUPID Executive Steering Committee
Responsibilities:
The Executive Steering Committee is responsible for overseeing the conduct of the clinical trial,
to provide information, insight and feedback to the DMC and CEC and to provide medical and
scientific advice on all aspects of this study and other issues that arise during the clinical
development of AAV1/SERCA2a.
Members and affiliations:
Barry Greenberg, M.D. (Chair); Professor of Medicine, Director, Advanced Heart Failure
Treatment Program, University of California, San Diego, San Diego CA
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Javed Butler, M.D., MPH, FACC, FAHA, Professor of Medicine, Division of Cardiology,
Director, Heart Failure Research, Emory University School of Medicine, Atlanta,
GA
G. Michael Felker, M.D., MHS, Associate Professor of Medicine, Division of Cardiovascular
Medicine, Duke University, Durham, NC
Adriaan Voors, M.D., Ph.D., Professor of Cardiology, University Medical Center Groningen,
Groningen, The Netherlands
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Online Tables Full Study Inclusion / Exclusion Criteria
Online Table 1
Inclusion Criteria
Unless otherwise specified, screening must be performed within 30 days prior to administration
of investigational medicinal product on Day 0 except as noted under Inclusion Criteria #1
and 4. Subjects must meet the following criteria to be eligible for the study:
1. Negative neutralizing AAV1 antibodies (NAb) (titer <1:2 or equivocal) within 90 days of
screening.
2. 18-80 years of age, inclusive, at the time of signing the informed consent.
3. Chronic systolic HF due to ischemic or non-ischemic cardiomyopathy. Subjects with
ischemic cardiomyopathy must have at least one major coronary vessel with TIMI grade 3
flow. If a subject has not undergone coronary angiography within 2 months, this criterion
may be assessed after the subject is randomized and undergoes angiography just prior to the
planned infusion of investigational medicinal product.
a. Hypertrophic cardiomyopathy is excluded.
b. Toxic and alcoholic cardiomyopathies are allowed as long as toxin or alcohol
exposure has been eliminated and a sufficient amount of time has elapsed to ruleout spontaneous recovery.
4. Left ventricular ejection fraction (LVEF) ≤35% anytime during the 60-day window prior to
administration of investigational medicinal product.
5. Diagnosis of NYHA class II, III or IV HF for a minimum of 90 days prior to screening.
6. Individualized, maximal, optimized HF therapy consistent with American College of
Cardiology/American Heart Association and European Society of Cardiology practice
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guidelines for the treatment of chronic heart failure(ACC/AHA/ESC HF guidelines) and as
updated from time to time:
a. Medical therapy as appropriate to the individual subject including oral diuretic,
angiotensin-converting enzyme (ACE) inhibitor (or angiotensin-receptor blocker
(ARB) if ACE intolerant) and, as tolerated, beta blocker at approved dosages as
labeled in the respective package insert. The choice of beta blocker is limited to
those approved for heart failure in all participating countries (bisoprolol,
carvedilol or sustained release metoprolol succinate). Unless contraindicated or
not tolerated, the addition of an aldosterone antagonist should be considered in the
absence of hyperkalemia and significant renal dysfunction and according to
evolving standards; the final decision is at the discretion of the investigator.
Dosing of the above medications must be stable for a minimum of 30 days prior
to screening, although up- or down-titration of diuretics, as medically indicated, is
permitted. Enrollment of any subject with any deviation from this combination
must be preapproved by the medical monitor.
b. Resynchronization therapy, if clinically indicated according to ACC/AHA/ESC
HF guidelines, must have been implanted at least 6 months prior to screening.
c. Implantable cardioverter defibrillator (ICD), if clinically indicated according to
ACC/AHA/ESC HF guidelines, must have been implanted a minimum of 30 days
prior to screening.
d. Cardiac rehabilitation should be consistent with the Agency for Health Care
Policy and Research Clinical Practice Guideline, Number 17, Cardiac
Rehabilitation. This does not imply that the potential candidate must be enrolled
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in a cardiac rehabilitation program at screening or in the future.
7. All women of childbearing potential must have a negative urine pregnancy test prior to
administration of investigational medicinal product and agree to use adequate contraception
(defined as oral or injectable contraceptives, intrauterine devices, surgical sterilization or a
combination of a condom and spermicide) or limit sexual activity to vasectomized partner for
3 months after administration of investigational medicinal product. Men capable of fathering
a child must agree to use barrier contraception (combination of a condom and spermicide) or
limit activity to post-menopausal, surgically sterilized, or a contraception-practicing partner,
for 3 months after administration of investigational medicinal product.
8. Ability to understand and comply with study requirements as evidenced by providing signed
written informed consent form and Release of Medical Information Form.
9. Presence of at least one of the following risk factors:
a. Hospitalization for heart failure within 6 months of screening, or in lieu of
hospitalization, at least 2 outpatient interventions for the intended treatment of
signs and symptoms of worsening heart failure (e.g., intravenous diuretics,
peripheral ultrafiltration)
b. NT-proBNP >1200 pg/mL (BNP >225 pg/mL) within 30 days of screening; if
subject is in atrial fibrillation, NT-proBNP >1600 pg/mL (BNP >275 pg/mL)
within 30 days of screening
10. In Germany only: Medically indicated for diagnostic angiography at the clinician’s
discretion.
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Online Table 2
Exclusion Criteria
Subjects meeting any of the following criteria will be excluded from the study:
1. Any intravenous (IV) therapy with positive inotropes, vasodilators or diuretics within
30 days prior to screening.
2. Restrictive cardiomyopathy, obstructive cardiomyopathy, acute myocarditis, pericardial
disease, amyloidosis, infiltrative cardiomyopathy, uncorrected thyroid disease or discrete LV
aneurysm.
3. Cardiac surgery, percutaneous coronary intervention (PCI) or valvuloplasty within 30 days
prior to screening.
4. Myocardial infarction (e.g., ST elevation MI [STEMI] or large non-STEMI) within 90 days
prior to screening. Large non-STEMI shall be defined >3x ULN for CK-MB or >5x ULN for
troponin.
5. Prior heart transplant, left ventricular reduction surgery (LVRS), cardiomyoplasty, passive
restraint device (e.g., CorCap™ Cardiac Support Device, Acorn Cardiovascular Inc., St.
Paul, MN), surgically implanted LVAD or cardiac shunt.
6. Likely need for an immediate heart transplant or LVAD implant due to hemodynamic
instability.
7. Prior CABG is not considered ideal for inclusion in the study; however, a potential candidate
can be reviewed on a case-by-case basis. Ideally, the orifice of the graft should be easy to
engage with a catheter and the graft should perfuse a significant amount of potentially viable
myocardium.
8. Known hypersensitivity to contrast agents used for angiography; history of, or likely need
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for, high dose steroid pretreatment prior to contrast angiography.
9. Significant, in the opinion of the investigator, left main or ostial right coronary luminal
stenosis.
10. Liver function tests (ALT, AST, alkaline phosphatase) >3x Upper Limit of Normal (ULN)
within 30 days prior to investigational medicinal product administration or known intrinsic
liver disease (e.g., cirrhosis, chronic hepatitis B or hepatitis C virus infection).
11. Current or likely need for hemodialysis within 12 months following enrollment or current
GFR ≤20 mL/minute/1.73 m2 estimated by MDRD calculation.
12. Bleeding diathesis or thrombocytopenia defined as platelet count <50,000 platelets/μL.
13. Anemia defined as hemoglobin <9 g/dL, provided that there is no evidence of bleeding.
14. Known AIDS or HIV seropositive status, or a previous diagnosis of immunodeficiency with
an absolute neutrophil count <1000 cells/mm3.
15. Diagnosis of, or treatment for, any cancer other than basal cell carcinoma within the last
5 years. (Past medical history of cancer is not exclusionary as long as subject has been
disease-free for at least 5 years since the time of diagnosis and treatment).
16. Previous participation in a study of gene transfer; however, if the study was unblinded or
documentation otherwise exists that the subject was randomized to the placebo control group
and did not receive active gene transfer agent, the subject may be considered for this study.
17. Receiving investigational intervention or participating in another clinical study within
30 days or within 5 half-lives of the investigational drug administration prior to screening.
Exception may be made if the individual is enrolled in a non-therapeutic observational study
(registry) or the observational portion of a therapeutic study where the sponsoring authority
authorizes enrollment.
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18. Pregnant or breast-feeding.
19. Recent history of psychiatric disease, including drug or alcohol abuse, that is likely to impair,
in the opinion of the investigator, the subject’s ability to comply with protocol-mandated
procedures.
20. Other concurrent medical condition(s) that, while not explicitly excluded by the protocol,
could jeopardize the safety of the subject or objectives of the study.
Table abbreviations:
AIDS
Acquired immunodeficiency syndrome
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
BNP
B-Type natriuretic peptide
CABG
Coronary artery bypass graft(s)
HIV
Human immunodeficiency virus
LV
Left ventricular or left ventricle
MI
Myocardial infarction
NAb
Neutralizing AAV1 antibodies
NT-proBNP
N-terminal pro B type natriuretic peptide
TIMI
Thrombolysis In Myocardial Infarction TIMI Grade Flow is a scoring system
from 0-3 referring to levels of coronary blood flow
STEMI
ST segment elevation myocardial infarction
ULN
Upper Limit of Normal
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