Use of (-)-Epicatechin in the Treatment of Becker Muscular Dystrophy (Pilot Study)

Study Overview
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Brief Summary
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(-)-Epicatechin will be evaluated for the treatment of progressive muscle loss and impaired skeletal muscle function in Becker Muscular Dystrophy (BMD) patients.

Detailed Description
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This is a proof-of-concept phase 1/2a pilot and endpoint development study that is designed to provide initial evidence of biological activity of (-)-epicatechin. Primary endpoints include initial assessment of tissue-specific evidence of efficacy from muscle biopsy samples. Secondary endpoints include measures of strength and physical function, and safety and adverse event data. Pilot endpoints include assessment of mRNA and miRNA peripheral blood profiles and validation of non-invasive near-infrared spectroscopy (NIRS) muscle perfusion studies during exercise and a recumbent cycle exercise test that may be employed as endpoints in future clinical trials. This single center open-label pilot study will enroll 10 adults with genetically-confirmed Becker muscular dystrophy, who will receive the purified nutritional extract (-)-epicatechin 100mg/day orally for 8 weeks. After screening visits, participants will be enrolled in the study if they meet all inclusion criteria. They will be evaluated at baseline and at screening, day 1, and weeks 1, 2, 4 and 8.

Official Title
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An Open-label Pilot Study of Purified Tea-derived Epicatechin to Improve Mitochondrial Function, Strength and Skeletal Muscle Exercise Response in Becker Muscular Dystrophy.

Conditions
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Becker 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 18 years to 60 years Average to low daily physical activity Ability to ambulate for 75 meters without assistive devices Diagnosis of BMD confirmed by at least one the following: Dystrophin immunofluorescence and/or immunoblot showing partial dystrophin deficiency, and clinical picture consistent with typical BMD, or Gene deletions test positive (missing one or more exons) of the dystrophin gene, where reading frame can be predicted as 'in-frame', and clinical picture consistent with typical BMD, 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 BMD, with a typical clinical picture of BMD, or Positive family history of BMD confirmed by one of the criteria listed above in a sibling or maternal uncle, and clinical picture typical of BMD. Nutritional, herbal and antioxidant supplements taken with the intent of maintaining or improving skeletal muscle strength or functional mobility have been discontinued at least 2 weeks prior to screening (daily multivitamin use is acceptable). Hematology profile within normal range Baseline laboratory safety chemistry profile within normal range No plan to change exercise regimen during study participation Exclusion Criteria: Currently enrolled 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. Regular participation in vigorous exercise. Symptomatic heart failure with cardiac ejection fraction <25%

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment with Epicatechin<br>Purified nutritional extract (-)-epicatechin 100mg/day orally for 8 weeks. | Drug: (-)-epicatechin<br>* purified nutritional extract (-)-epicatechin 100mg/day orally for 8 weeks.<br>* Other names: dietary supplement;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Muscle Tissue PGC1alpha (AU) at 8 Weeks | Western blot measurement of the transcriptional coactivator gene PGC1alpha involved in mitochondrial biogenesis will be assessed using relative band intensities of the pre-treatment (Baseline) and post-treatment (8 Weeks) specimens with digitally quantified using ImageJ software. | Baseline and 8 Weeks | 
| Mean Change From Baseline in Muscle Tissue AMPK at 8 Weeks | Western blot measurement of AMPK will be assessed using relative band intensities of the pre-treatment and post-treatment specimens with digitally quantified using ImageJ software). | 8 weeks | 
| Mean Change From Baseline in Muscle Tissue LKB1 at 8 Weeks | Western blot measurement of LKB1 will be assessed using relative band intensities of the pre-treatment and post-treatment specimens with digitally quantified using ImageJ software) . | 8 weeks | 
| Mean Change From Baseline in Cristae-associated Mitofillin Levels at 8 Weeks | Western blot measurement of Mitofillin will be assessed using relative band intensities of the pre-treatment and post-treatment specimens with digitally quantified using ImageJ software. | 8 weeks | 
| Mean Change From Baseline in Muscle Tissue Follistatin at 8 Weeks | Regulators of muscle growth and regeneration including follistatin will be assessed by Western using relative band intensities of the pre-treatment and post-treatment specimens with digitally quantified using ImageJ software). | 8 weeks | 
| Mean Change From Baseline in Muscle Tissue Myostatin at 8 Weeks | Regulators of muscle growth and regeneration including myostatin will be assessed by Western using relative band intensities of the pre-treatment and post-treatment specimens with digitally quantified using ImageJ software). | 8 weeks | 
| Mean Change From Baseline in Muscle Tissue Myogenin at 8 Weeks | Modulators of skeletal muscle regeneration by Western will include myogenin will be assessed using relative band intensities of the pre-treatment and post-treatment specimens with digitally quantified using ImageJ software). | 8 weeks | 
| Mean Change From Baseline in Muscle Tissue Myf5 at 8 Weeks | Modulators of skeletal muscle regeneration My5 will be assessed by Western using relative band intensities of the pre-treatment and post-treatment specimens with digitally quantified using ImageJ software). | 8 weeks | 
| Mean Change From Baseline in Muscle Tissue MyoD at 8 Weeks | Modulators of skeletal muscle regeneration MyoD will be assessed by Western using relative band intensities of the pre-treatment and post-treatment specimens with digitally quantified using ImageJ software). | 8 weeks | 
| Mean Change From Baseline in Muscle Tissue MEF2a at 8 Weeks | Modulators of skeletal muscle regeneration MEF2a will be assessed by Western using relative band intensities of the pre-treatment and post-treatment specimens with digitally quantified using ImageJ software). | 8 weeks | 
| Mean Change From Baseline in Muscle Tissue Dysferlin at 8 Weeks | Structure associated indicators including dysferlin will be assessed by Western using relative band intensities of the pre-treatment and post-treatment specimens with digitally quantified using ImageJ software). | 8 weeks | 
| Mean Change From Baseline in Muscle Tissue Utrophin at 8 Weeks | Structure associated indicators including utrophin will be assessed by Western using relative band intensities of the pre-treatment and post-treatment specimens with digitally quantified using ImageJ software). | 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| -(-)Epicatechin Pharmacokinetics | Pharmacokinetics sequentially after dosing will be measured. | 8 Weeks | 
| Participants With Abnormal Treatment-Related Laboratory Assessments | Standard safety monitoring of plasma hematologic, hepatologic, renal and metabolic parameters will be assessed. Abnormal will be defined as values outside of typical range for patients with Becker Muscular Dystrophy. | 8 weeks | 
| Change From Baseline in Knee Extension at 8 Weeks | Knee extension will be assessed using an isokinetic dynamometer. | Baseline and 8 Weeks | 
| Change From Baseline in 6-Minute Walk Distance at 8 Weeks | Muscle function will be assessed by measuring the 6-minute walk distance | Baseline and 8 Weeks | 
| Change From Baseline in Stand From Supine at 8 Weeks | Muscle burst function will be assessed by time function tests. | Baseline and 8 Weeks | 
| Change From Baseline in Elbow Flexion at 8 Weeks | Elbow flexion will be assessed using an isokinetic dynamometer. | Baseline and 8 Weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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BMD, Becker muscular dystrophy, epicatechin, clinical trial, neuromuscular disease