HOPE-Duchenne (Halt cardiomyOPathy progrEssion in Duchenne)

Study Overview
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Brief Summary
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Male subjects with cardiomyopathy secondary to Duchenne muscular dystrophy (DMD) meeting all inclusion and no exclusion criteria will be randomized. All subjects will be at least 12 years of age. They will be randomized in a 1:1 manner to either intracoronary infusion of CAP-1002 in three coronary arteries supplying the three major cardiac territories of the left ventricle of the heart (anterior, lateral, inferior/posterior) or usual care. In the active treatment arm, all three major cardiac territories will be treated (infused) during a single procedure in an open-label fashion.

Detailed Description
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Approximately 24, and not more than 30, subjects will be randomized into the study, in two sequential enrollment groups. Safety data from Group 1 will undergo a Data Safety Monitoring Board (DSMB) review prior to initiation of enrollment for Group 2. The first 6-8 randomized subjects will comprise Group 1, and will include a minimum of 3 subjects completing intracoronary infusion with CAP-1002. The DSMB will conduct a review of interim safety data through 72 hours post-Day 0 for at least 3 infused subjects and for at least 6 subjects overall. Enrollment of Group 2 will begin per DSMB recommendations following their review of the 72 hour safety data from Group 1. Group 2 will include approximately 18 subjects. Screening and randomization will continue until at total of 12 subjects are infused with CAP 1002 or 30 subjects are randomized into the study, whichever comes first. All subjects assigned to the active treatment arm will receive an intended total dose of up to 75 million (M) CAP-1002 cells infused as 25M cells into each of the three left ventricle cardiac territories (anterior, lateral, inferior/posterior). Subjects randomized to receive usual care will continue to be cared for and treated in whatever manner the investigator deems most appropriate for the subject on an ongoing basis, and will receive no infusion. Randomization will take place within 30 days of the first screening procedure. After completion of the screening procedures, eligible subjects randomized to active treatment arm will receive CAP-1002 administered via intracoronary infusion on Day 0. Day 0 for eligible subjects randomized to the usual care arm will occur 7 days after the date of randomization. All randomized subjects will have a follow-up telephone call on Study Day 3, and study visits at Weeks 2 and 6, and at Months 3, 6 and 12 post Day 0.

Official Title
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A Randomized, Open-label Study of the Safety and Efficacy of Multi- Vessel Intracoronary Delivery of Allogeneic Cardiosphere-Derived Cells in Patients With Cardiomyopathy Secondary to Duchenne Muscular Dystrophy

Conditions
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Duchenne Muscular Dystrophy, Cardiomyopathy

Intervention / Treatment
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* Drug: Allogeneic Cardiosphere-Derived Cells (CAP-1002)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male subjects 18 years of age or older must be able to provide informed consent and follow up with protocol procedures. Male subjects at least 12 years of age but younger than 18 years of age must be able to provide assent with parent or guardian providing permission for study participation. Only male subjects will be randomized into this study. Documented diagnosis of Duchenne Muscular Dystrophy by genetic mutation analysis. Cardiomyopathy with left ventricular scar by LGE in at least 4 segments as assessed by contrast-enhanced MRI and EF >35% at the time of screening. Use of evidence based medical-therapy in accordance with the DMD Care Considerations Working Group guidelines for the management of DMD, for at least three months prior to signing the consent form (or, providing assent) or documented contraindication or intolerance or patient preference. Subjects must be taking systemic glucocorticoids for at least six months prior to screening. Subjects must be 12 years of age or older at time of screening Subjects must be appropriate candidates for cardiac catheterization and intracoronary infusion of CAP-1002, in the judgement of the site's interventional cardiologist. Exclusion Criteria: Therapy with intravenous inotropic or vasoactive medications at the time of screening. Inability to undergo cardiac catheterization and/or MRI without general anesthesia. Immunologic incompatibility with all available Master Cell Banks (MCBs) by single-antigen bead (SAB) serum antibody profiling. Planned or likely major surgery in the next 12 months after planned randomization. Left Ventricular Assist Devices (LVAD) or those subjects actively in the process of acquiring a LVAD. Contraindication to cardiac MRI. Known hypersensitivity to contrast agents. Estimated glomerular filtration rate (GFR) <60 mL/min, as calculated by the CKD-EPI cystatin C equation (Inker, Schmid et al. 2012). Active infection not responsive to treatment. Active systemic allergic reaction(s), connective tissue disease or autoimmune disorder(s). History of cardiac tumor or cardiac tumor demonstrated on screening MRI. History of previous stem cell therapy. History of use of medications listed in Appendix 3 within 3 months prior to signing the ICF / Assent through completion of the study infusion. Known moderate-to-severe aortic stenosis/insufficiency or severe mitral stenosis/regurgitation. Current active alcohol or drug abuse. Known history of Human Immunodeficiency Virus (HIV) infection. Known history of chronic viral hepatitis. Abnormal liver function (ALT/AST >10 times the upper reference range) and/or abnormal hematology (hematocrit <25%, WBC <3000 μl, platelets <100,000 μl) studies without a reversible, identifiable cause. Known hypersensitivity to bovine products. Known hypersensitivity to dimethyl sulfoxide (DMSO). Uncontrolled diabetes (HbA1c >9.0). Inability to comply with protocol-related procedures, including required study visits. Any condition or other reason that, in the opinion of the Investigator or Medical Monitor, would render the subject unsuitable for the study. Currently receiving investigational treatment on another clinical study or expanded access protocol, including any of the following: Received investigational intervention within 30 days prior to randomization Treatment and/or an incomplete follow-up to treatment with any investigational cell based therapy within 6 months prior to randomization Active participation in other research therapy for cardiovascular repair/regeneration

Ages Eligible for Study
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Minimum Age: 12 Years

Sexes Eligible for Study
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Male

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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Allogeneic Cardiosphere-Derived Cells (CAP-1002)<br>CAP-1002 is an investigational product consisting of allogeneic cardiosphere-derived cells (CDCs). All subjects assigned to the active treatment arm will receive an intended total dose of 75 million (M) CAP-1002 cells infused as 25M cells into each of the three left ventricle cardiac territories (anterior, lateral, inferior/posterior). If any of the three coronary arteries are deemed by the infusing Investigator to supply less than 30% of the left ventricular myocardium, the infusing Investigator may choose to infuse only 12.5M cells into that coronary artery or arteries. Therefore the full dose of CAP-1002 delivered may range from 50M cells to 75M cells provided that all three arteries are infused. | Drug: Allogeneic Cardiosphere-Derived Cells (CAP-1002)<br>* Intracoronary delivery of Allogeneic Cardiosphere-Derived Cells (CAP-1002)<br>* Other names: CAP-1002;|
| No Intervention: Usual Care<br>Subjects randomized to receive usual care will continue to be cared for and treated in whatever manner the investigator deems most appropriate for the subject on an ongoing basis, and will receive no infusion. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability composite of CAP-1002 will be established as described below. | Will be established by summaries of the occurrence of changes in coronary blood flow events, major cardiac events, laboratory assessments, vital signs, physical examination, ECG, and the occurrence of major adverse events. | 72 hours post infusion of allogeneic cardiosphere-derived cells | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cardiac Structural composite assessed as: Absolute and relative change in parameters measured by cardiac MRI |  | 12 months post infusion of CAP-1002 or randomization to the usual care arm | 
| Functional composite assessed as: Serial change in mobility measurements and Performance of Upper Limb (PUL) scale, spirometry, and 6-minute walk test (6MWT) when deemed appropriate by the Investigator. |  | 12 months post infusion of CAP-1002 or randomization to the usual care arm | 
| Quality of Life composite assessed as: Change in PedsQL (Pediatric Quality of Life Inventory), including the cardiac module, and PODCI Adolescent Questionnaire. |  | 12 months post infusion of CAP-1002 or randomization to the usual care arm | 
| Biomarkers composite assessed as: Osteopontin, ST2, IL-10, Galectin-3, and exploratory biomarkers (if consented/provided assent). |  | 12 months post infusion of CAP-1002 or randomization to the usual care arm | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Duchenne Muscular Dystrophy, Cardiomyopathy