Modulation of SERCA2a of Intra-Myocytic Calcium Trafficking in Cardiomyopathy Secondary to Duchenne Muscular Dystrophy

Official title

A Phase 1b, Open-Label, Controlled Trial Evaluating the Safety and Efficacy of SRD-001 (AAV1/SERCA2a) in Subjects With Cardiomyopathy Secondary to Duchenne Muscular Dystrophy

Overview

This research study is testing whether an experimental drug, called SRD-001, is safe and helps the weakened heart of patients with Duchenne muscular dystrophy (DMD) regain its ability to effectively pump blood to the rest of the body. SRD-001 is a form of gene therapy. The goal of SRD-001 gene therapy is to provide the heart muscle cells with extra copies of the SERCA2a gene so that they can produce more SERCA2a protein to help the heart muscle cells squeeze/contract better. Researchers will compare SRD-001 treated participants with no-treatment participants; all participants will continue to take their current heart medications. All participants will be followed very closely for 2 years and undergo cardiac magnetic resonance imaging of their heart at baseline, year 1 and year 2 along with assessment of upper limb function and lung function. After the 2 years of close follow-up, all participants will roll over into long-term follow-up where they will be called biannually for information on their current medical status.

Detailed description

This phase 1b, multi-center, non-randomized, open-label, ascending dose escalation, no-intervention-control trial will assess the safety and explore the efficacy of SRD-001 administered as a one-time antegrade epicardial coronary artery infusion for the treatment of participants with cardiomyopathy secondary to DMD. SRD-001 is an AAV1 vector expressing the transgene for SERCA2a. Twelve participants will be assigned to either active treatment with SRD-001 or no-intervention based upon their neutralizing antibody status. The objectives of the trial are (1) to evaluate the safety of a one-time intracoronary administration of SRD-001 in participants with cardiomyopathy due to DMD; and (2) to explore the impact of SRD-001 on heart and skeletal muscle function and quality of life. After screening to determine eligibility, participants will be sequentially assigned to low dose SRD-001, high dose SRD-001 or no-intervention. Participants assigned to active treatment with SRD-001 will under cardiac catheterization and angiography just prior to the intracoronary infusion of SRD-001 and spend overnight int he hospital for observation.

Interventions

• Genetic SRD-001
  SRD-001 is an adeno-associated virus serotype 1 (AAV1) based gene therapy designed to deliver a copy of the gene encoding the human sarcoplasmic/endoplasmic reticulum Ca(2+) ATPase 2a (SERCA2a). It is administered as a one-time intracoronary infusion.

Primary outcome measures

• Rate of all-cause mortality [Time frame: From Day 1 to Week 52 and Week 104]
• Rate and severity of related treatment-emergent adverse events [Time frame: From Day 1 to Week 52 and Week 104]
• Rate and severity of all treatment-emergent adverse events [Time frame: From Day 1 to Week 52 and Week 104]
• Rate of cell-mediated immune reaction [Time frame: From Day 1 to Week 52]

Secondary outcome measures (2)

• Change, including normal/abnormal shifts, in 12-lead electrocardiogram (ECG) [Time frame: From Day 1 to Week 52 and Week 104]
• Change, including normal/abnormal shifts, in laboratory evaluations [Time frame: From Day 1 to Week 52 and Week 104]

Eligibility criteria

Inclusion criteria

• Diagnosis of DMD with confirmatory genetic testing
• Cardiomyopathy with left ventricular scar in at least 3 of 16 segments
• Left ventricular ejection fraction < 40%
• Individualized, optimized cardiac medical therapy and glucocorticoid treatment for at least 12 months prior to enrollment
• Willing and able to provide informed consent

Exclusion criteria

• Abnormal blood pressure
• Non-DMD-related liver function test elevations
• Cystatin C ≥ 1.2 mg/L
• Thrombocytopenia
• Anemia
• Inadequate pulmonary function

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 3 centers

• The University of Kansas Medical Center — Kansas City
• Cincinnati Children's Hospital Medical Center — Cincinnati
• Nationwide Children's Hospital — Columbus

Identifiers

NCT: NCT06224660 · SRD-001-1004

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗