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

Phase 1

Completed

Conditions: Becker Muscular Dystrophy

Interventions: Drug: (-)-epicatechin

Registration Number: NCT01856868

Lead Sponsor: Craig McDonald, MD

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

Detailed Description: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: Male

Target Recruitment: 7

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%

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment with Epicatechin	(-)-epicatechin	Purified nutritional extract (-)-epicatechin 100mg/day orally for 8 weeks.

Primary Outcome Measures

Name	Time	Method
Mean Change From Baseline in Muscle Tissue Myogenin at 8 Weeks	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).
Mean Change From Baseline in Muscle Tissue Dysferlin at 8 Weeks	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).
Mean Change From Baseline in Cristae-associated Mitofillin Levels at 8 Weeks	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.
Mean Change From Baseline in Muscle Tissue Myf5 at 8 Weeks	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).
Mean Change From Baseline in Muscle Tissue LKB1 at 8 Weeks	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) .
Mean Change From Baseline in Muscle Tissue MyoD at 8 Weeks	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).
Mean Change From Baseline in Muscle Tissue MEF2a at 8 Weeks	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).
Mean Change From Baseline in Muscle Tissue AMPK at 8 Weeks	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).
Mean Change From Baseline in Muscle Tissue Follistatin at 8 Weeks	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).
Mean Change From Baseline in Muscle Tissue Utrophin at 8 Weeks	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).
Change From Baseline in Muscle Tissue PGC1alpha (AU) at 8 Weeks	Baseline and 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.
Mean Change From Baseline in Muscle Tissue Myostatin at 8 Weeks	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).

Secondary Outcome Measures

Name	Time	Method
Change From Baseline in Stand From Supine at 8 Weeks	Baseline and 8 Weeks	Muscle burst function will be assessed by time function tests.
-(-)Epicatechin Pharmacokinetics	8 Weeks	Pharmacokinetics sequentially after dosing will be measured.
Change From Baseline in Knee Extension at 8 Weeks	Baseline and 8 Weeks	Knee extension will be assessed using an isokinetic dynamometer.
Participants With Abnormal Treatment-Related Laboratory Assessments	8 weeks	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.
Change From Baseline in 6-Minute Walk Distance at 8 Weeks	Baseline and 8 Weeks	Muscle function will be assessed by measuring the 6-minute walk distance
Change From Baseline in Elbow Flexion at 8 Weeks	Baseline and 8 Weeks	Elbow flexion will be assessed using an isokinetic dynamometer.