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

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Phase 1/2 Trial of the Safety and Efficacy of SRD-001 (AAV1/SERCA2a) in Subjects With Heart Failure With Reduced Ejection Fraction

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

Intervention / Treatment
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* Biological: SRD-001
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Main Inclusion Criteria: Chronic ischemic or non-ischemic cardiomyopathy NYHA class III/IV LVEF ≤35% Guideline-directed medical therapy for heart failure; ICD 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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SRD-001<br>3E13 or 4.5E13 vg; one-time intracoronary infusion | Biological: SRD-001<br>* AAV1/SERCA2a<br>|
| Placebo Comparator: Placebo<br>One-time intracoronary infusion | Drug: Placebo<br>* SRD-001 matching placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in symptomatic parameters | New York Heart Association classification (I, II, III or IV) | Baseline to Month 6 and Month 12 | 
| Change from baseline in symptomatic parameters | 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 | Baseline to Month 6 and Month 12 | 
| Change from baseline in physical parameter | Distance walked during the 6MWT | Baseline to Month 6 and Month 12 | 
| Change from baseline in LV function/remodeling | Left ventricular end systolic volume (LVESV) as assessed by echocardiography | Baseline to Month 6 and Month 12 | 
| Rate of recurrent events | HF-related hospitalization, ambulatory worsening heart failure, all-cause death, MCSD and transplant | Baseline to Month 6 and Month 12 | 
| Rate of adverse events | Treatment-emergent adverse events | 6 and 12 months | 

Secondary Outcome Measures

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