Plus Epicatechin Duchenne Muscular Dystrophy in Non-ambulatory Adolescents

Study Overview
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Brief Summary
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This single center open-label pilot study will enroll 15 non-ambulatory children with Duchenne muscular dystrophy at least 8 years of age and who demonstrate pre-clinical cardiomyopathy (defined as a cardiac ejection fraction >55% with abnormal LV strain by cardiac MRI). They will receive (+)-epicatechin at one of three doses during an 8-week dose-ranging study with assessments at baseline, 2 Weeks, 4weeks, and 8 weeks. The study will determine optimal dosing for future cardiac efficacy studies based on serum / plasma biomarker response using follistatin: myostatin ratio, nitrite/nitrate ratio, cardiac troponins and cardiac BNP. Secondary endpoints will include additional biomarker assessments by SOMAscanTM, cardiac functional evaluations by cardiac MRI (LV strain), and echocardiogram (LV strain by speckle tracking) and measures of strength, range of motion and mobility, and clinical safety assessments. Results of secondary endpoint analysis will be used to refine design of subsequent clinical trials powered to detect changes in clinical outcomes.

Official Title
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A Single Center Dose Ranging Pilot Study of (+)-Epicatechin in Non-ambulatory Adolescents With Duchenne Muscular Dystrophy and Pre-symptomatic Cardiac Dysfunction

Conditions
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Duchenne Muscular Dystrophy

Intervention / Treatment
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* Drug: (+)- Epicatechin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male Age 8 years to 17 years Non-Ambulatory (unable to complete 10m run/walk under 10s) Weight </=100Kg Diagnosis of DMD confirmed by at least one the following: Dystrophin immunofluorescence and/or immunoblot showing complete dystrophin deficiency, and clinical picture consistent with typical DMD, or Gene deletions test positive (missing one or more exons) of the dystrophin gene, where reading frame can be predicted as 'out-of-frame', and clinical picture consistent with typical DMD, or Complete dystrophin gene sequencing showing an alteration (point mutation, duplication, or other mutation resulting in a stop codon mutation) that can be definitely associated with DMD, with a typical clinical picture of DMD, or Positive family history of DMD confirmed by one of the criteria listed above in a sibling or maternal uncle, and clinical picture typical of DMD. Cardiac ejection fraction >55% on echocardiogram Use of nutritional, herbal and antioxidant supplements taken with the intent of maintaining or improving skeletal muscle strength or functional mobility has been discontinued at least 4 weeks prior to screening (daily multivitamin use is acceptable). Glucocorticoid therapy, if used, must have a stable weight-based dose for at least 3 months prior to enrollment Cardiac therapy, if used, includes prophylactic ACE inhibitors, aldosterone receptor antagonists (e.g. spironolactone, eplerenone, etc.), and/or beta-blocker therapy, and must be stable for 3 months prior to enrollment. Hematology profile within normal range. Baseline laboratory safety chemistry profile within typical range for DMD (elevated ALT / AST acceptable in the absence of elevated GGT, elevated CK acceptable). Exclusion Criteria: Inability to complete cardiac or strength, range of motion and mobility assessments per protocol Current enrollment in another treatment clinical trial. History of significant concomitant illness or significant impairment of renal or hepatic function. Use of regular daily aspirin or other medication with antiplatelet effects within 3 weeks of first dose of study medication. Cardiac symptoms that, in the opinion of the investigator, may be suggestive of imminent moderate to severe cardiac events, irrespective of LVEF.

Ages Eligible for Study
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Minimum Age: 8 Years
Maximum Age: 17 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: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>8-weeks open-label (+)- Epicatechin at 25mg/day twice per day, | Drug: (+)- Epicatechin<br> <br> |
| Experimental: Cohort 2<br>8-weeks open-label (+)- Epicatechin at 25mg/day three times per day | Drug: (+)- Epicatechin<br> <br> |
| Experimental: Cohort 3<br>8-weeks open-label (+)- Epicatechin at 75mg/day at two times per day | Drug: (+)- Epicatechin<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics Outcome: Absolute Values of (+)-Epicatechin Serum Concentration, Pre-dose (Trough) and 2 Hours Post-dose (Peak) | Pharmacokinetic evaluation for dose-response evaluation. | Pre-dose and 2 hours post-dose at baseline | 
| Pharmacokinetics Outcome: Absolute Values of (+)-Epicatechin Serum Concentration, Pre-dose (Trough) and 2 Hours Post-dose (Peak) | Pharmacokinetic evaluation for dose-response evaluation. | Week 4 | 
| Laboratory Outcome: Absolute Plasma Follistatin:Myostatin Ratio at Baseline, Week 4 and Week 8 | Evaluation of follistatin:myostatin ratio from plasma samples. | Baseline, Week 4 and Week 8 | 
| Clinical Outcome: Mean Percent of Baseline Cardiac Ejection Fraction by MRI | Evaluation of change in cardiac volume and performance, as measured by the mean percent of baseline ejection fraction using Cardiac MRI, measured at 8 weeks. | Week 8 | 
| Safety: Number of Participants Who Experienced Treatment-Related Laboratory Abnormalities | Treatment-related laboratory abnormalities, defined as values outside of the typical range for Duchenne Muscular Dystrophy. Safety laboratory tests included blood chemistry panel, complete blood count w/ differential panel, & urinalysis assessments for clinical safety monitoring. | Study duration (8 weeks) | 
| Laboratory Outcome: Absolute Values of Nitric Oxide (AU) Measured by ELISA | Proteomics evaluation of plasma biomarkers to confirm intervention-responsive pathophysiological pathways, using enzyme-linked immunosorbent assay (ELISA). | Baseline, Week 4, Week 8 | 
| Laboratory Outcome: Absolute Values of Carbonylation (AU) Measured by ELISA | Proteomics evaluation of plasma biomarkers to confirm intervention-responsive pathophysiological pathways, using enzyme-linked immunosorbent assay (ELISA). | Baseline, Week 4, Week 8 | 
| Laboratory Outcome: Absolute Values of Follistatin (AU) Measured by ELISA | Proteomics evaluation of plasma biomarkers to confirm intervention-responsive pathophysiological pathways, using enzyme-linked immunosorbent assay (ELISA). | Baseline, Week 4, Week 8 | 
| Laboratory Outcome: Absolute Values of Myostatin (AU) Measured by ELISA | Proteomics evaluation of plasma biomarkers to confirm intervention-responsive pathophysiological pathways, using enzyme-linked immunosorbent assay (ELISA). | Baseline, Week 4, Week 8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Outcome: Percent of Normalized Upper Extremity Reachable Surface Area at Week 4 and Week 8 | Quantitative upper extremity reachable workspace will be assessed using the XBox Kinect system. The KINECT Upper Extremity Reachable Workspace test measures surface area of a reachable workspace bubble, normalized to the size of the individual, noted as the RSA or Reachable Surface Area. The Total RSA measure is the sum of four quadrants dividing superior and inferior medial and lateral spaces. A total score of 1 indicates a typical reachable workspace, while lower scores indicate restrictions in one or more of the four quadrants. | Baseline, Week 4, Week 8 | 
| Clinical Outcome: Total Score Using Performance of the Upper Limb Assessment | The standardized Performance of Upper Limb (PUL) measure will be assessed at baseline and after 4 & 8 weeks. The Performance of the Upper Limb module is an observer-administered performance battery of upper extremity mobility tasks for the shoulder (upper, 6 items, 12 points), elbow (middle, 9 items, 17 points) and wrist/hand (distal, 7 items, 13 points). Higher scores indicate higher level of function. Total score ranges from 0-42 points and is the sum of the scores for the three subscales (10 upper, 10 mid, and 14 distal). | Baseline, Week 4, Week 8 | 
| Clinical Outcome: Mean Maximal Attained Revolutions Per 6-minute Cycle Test | The Assisted Six-Minute Cycle Test is an ergometer-based assessment of upper limb function. Test results indicate the maximum number of ergometer revolutions achieved in six-minutes, with higher numbers indicating a greater degree of functional capacity. | Baseline, Week 4, Week 8 | 
| Person-Reported Outcome: Upper Extremity Standardized Mean Score Using Pediatric Outcomes Data Collection Instrument (PODCI) Quality of Life Instrument | The PODCI instrument was developed by Daltroy and colleagues with support by the Pediatric Orthopaedic Society of North America (POSNA). The PODCI is a 108-item questionnaire that evaluates global functioning in the pediatric orthopedic population utilizing four components: upper extremity functioning, transfers and basic mobility, sports and physical functioning and a comfort/pain score. Global functioning is assessed by the average of the four previous scores. All scales are scored from zero to 100, with 100 representing the highest level of functioning and least pain. The PODCI asks questions such as During the last week, was it easy or hard for you to … lift heavy books. | Baseline to Week 4 and Week 8 | 
| Person-Reported Outcome: Mean Person-Reported Outcome Measure Upper Limb (PROM-UL) Functional Capacity Score | The Performance of Upper Limb module (PUL) for DMD was designed according to a specific contextual framework of upper limb function in both ambulant and non-ambulant individuals with DMD. The UL-PROM closely linked to this motor performance based clinician-reported outcome measure, was developed to evaluate manual ability related to activities of daily living (ADL) that cannot be observed in a clinical setting. Items were selected in relation to the different domains of the PUL from proximal to distal performance in order to cover the full range of upper limb functions. The questionnaire consists of 33 items covering four domains (3 points each for Food/Nutrition 7 items, Self Care 8 items, Household/Environment 6 items, Leisure/Communication 12 items). Higher scores indicate greater function, with total score being a sum of the subscale scores (Ranging from 0 to 99). | Change from Baseline to Week 4 and Week 8 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pediatric, muscle disease, Duchenne muscular dystrophy, cardiomyopathy