Modulation of SERCA2a of Intra-myocytic Calcium Trafficking in Heart Failure With Reduced Ejection Fraction

Phase 1

Recruiting

Conditions: Congestive Heart Failure
Heart Failure, Systolic
Heart Failure
HFrEF - Heart Failure With Reduced Ejection Fraction

Brief Summary: It is believed that targeted SERCA2a enzyme replacement in HFrEF patients will correct defective intracellular Ca2+ hemostasis, resulting in improved cardiac contractile function and energetics which will, in turn, translate to improved clinical outcomes. Additionally, it is hypothesized that correcting SERCA2a dysfunction will also improve coronary blood flow through correction of the impaired endothelium-dependent nitric oxide-mediated vasodilatation observed in heart failure.

Detailed Description: MUSIC-HFrEF1 is an interventional study of SRD-001, an adeno-associated virus serotype 1 (AAV1) vector expressing the transgene for sarco(endo)plasmic reticulum Ca2+ ATPase 2a isoform (SERCA2a), in anti-AAV1 neutralizing antibody (NAb) negative subjects with ischemic or non-ischemic cardiomyopathy and New York Heart Association (NYHA) class III/IV symptoms of heart failure with reduced ejection fraction (HFrEF).

The Phase 1 trial is an open-label, uncontrolled study investigating two doses of SRD-001 at 3E13 and 4.5E13 viral genomes (vg) in 3-4 participants at each dose level.

The Phase 2 trial is a randomized, double-blind, placebo-controlled trial with prospective assignment to a single dose of either SRD-001 or placebo in a 1:1 ratio and a total sample size of N=50.

Recruitment & Eligibility

Inclusion Criteria

Main

Exclusion Criteria

Restrictive cardiomyopathy, hypertrophic cardiomyopathy, acute myocarditis, pericardial disease, amyloidosis, infiltrative cardiomyopathy, uncorrected thyroid disease or discrete left ventricular (LV) aneurysm
Prior heart transplantation, left ventricular reduction surgery (LVRS), cardiomyoplasty, passive restraint device (e.g., CorCap™ Cardiac Support Device), mechanical circulatory support device (MCSD) or cardiac shunt
Likely to receive cardiac resynchronization therapy, cardiomyoplasty, LVRS, conventional revascularization procedure or valvular repair in the 6 months following treatment
Likely need for an immediate heart transplant or MCSD implant due to hemodynamic instability
Inadequate hepatic and renal function
Diagnosis of, or treatment for, any cancer within the last 5 years except for basal cell carcinoma or carcinomas in situ where surgical excision was considered curative

Arm && Interventions

Group	Intervention	Description
SRD-001	SRD-001	3E13 or 4.5E13 vg; one-time intracoronary infusion
Placebo	Placebo	One-time intracoronary infusion

Primary Outcome Measures

Name	Time	Method
Change from baseline in LV function/remodeling	Baseline to Month 6 and Month 12	Left ventricular end systolic volume (LVESV) as assessed by echocardiography
Rate of adverse events	6 and 12 months	Treatment-emergent adverse events
Change from baseline in symptomatic parameters	Baseline to Month 6 and Month 12	Quality of life as assessed by Kansas City Cardiomyopathy Questionnaire: 0-24, very poor to poor; 25-49, poor to fair; 50-74, fair to good; and 75-100, good to excellent
Change from baseline in physical parameter	Baseline to Month 6 and Month 12	Distance walked during the 6MWT
Rate of recurrent events	Baseline to Month 6 and Month 12	HF-related hospitalization, ambulatory worsening heart failure, all-cause death, MCSD and transplant

Secondary Outcome Measures

Name	Time	Method
Incidence of abnormal laboratory test results	Baseline to Month 6 and Month 12	Hematologic, serum chemistries, NT-proBNP and troponin
Incidence of abnormal ECG results	Baseline to Month 6 and Month 12	New arrhythmias
Proportion of subjects who complete the trial	12 months	Those who complete the trial vs withdraw consent, are lost to follow-up, or withdrawn due to an AE or other reason
Concomitant medication use	6 and 12 months	Changes in heart failure related medications
Incidence of abnormal findings from interrogation of implantable cardioverter defibrillator	Baseline to Month 6 and Month 12	New arrhythmias
Incidence of abnormal physical examination findings	Baseline to Month 6 and Month 12	Change from baseline in physical examination findings

Locations (5): University of Texas Southwestern Medical Center
🇺🇸
Dallas, Texas, United States
University of Washington Medicine
🇺🇸
Seattle, Washington, United States
San Diego Cardiac Center
🇺🇸
San Diego, California, United States
University of California, San Francisco
🇺🇸
San Francisco, California, United States
Washington University in Saint Louis
🇺🇸
Saint Louis, Missouri, United States