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

• ClinicalTrials.gov Identifier: NCT01856868
• Recruitment Status: Completed
• First Posted: May 17, 2013
• Results First Posted: December 22, 2021
• Last Update Posted: December 22, 2021
• Sponsor: Craig McDonald, MD
• Collaborator: Cardero Therapeutics, Inc.
• Information provided by (Responsible Party): Craig McDonald, MD, University of California, Davis

Study Description

Brief Summary:

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

Condition or disease	Intervention/treatment	Phase
Becker Muscular Dystrophy	Drug: (-)-epicatechin	Phase 1; Phase 2

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 7 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-label Pilot Study of Purified Tea-derived Epicatechin to Improve Mitochondrial Function, Strength and Skeletal Muscle Exercise Response in Becker Muscular Dystrophy.
• Study Start Date: May 2013
• Actual Primary Completion Date: September 2018
• Actual Study Completion Date: September 2018

Arms and Interventions

Arm	Intervention/treatment
Experimental: Treatment with Epicatechin; Purified nutritional extract (-)-epicatechin 100mg/day orally for 8 weeks.	Drug: (-)-epicatechin; purified nutritional extract (-)-epicatechin 100mg/day orally for 8 weeks.; Other Name: dietary supplement

Outcome Measures

Primary Outcome Measures :

1. Change From Baseline in Muscle Tissue PGC1alpha (AU) at 8 Weeks [ Time Frame: 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.
2. Mean Change From Baseline in Muscle Tissue AMPK at 8 Weeks [ Time Frame: 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).
3. Mean Change From Baseline in Muscle Tissue LKB1 at 8 Weeks [ Time Frame: 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) .
4. Mean Change From Baseline in Cristae-associated Mitofillin Levels at 8 Weeks [ Time Frame: 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.
5. Mean Change From Baseline in Muscle Tissue Follistatin at 8 Weeks [ Time Frame: 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).
6. Mean Change From Baseline in Muscle Tissue Myostatin at 8 Weeks [ Time Frame: 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).
7. Mean Change From Baseline in Muscle Tissue Myogenin at 8 Weeks [ Time Frame: 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. Mean Change From Baseline in Muscle Tissue Myf5 at 8 Weeks [ Time Frame: 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).
9. Mean Change From Baseline in Muscle Tissue MyoD at 8 Weeks [ Time Frame: 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).
10. Mean Change From Baseline in Muscle Tissue MEF2a at 8 Weeks [ Time Frame: 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).
11. Mean Change From Baseline in Muscle Tissue Dysferlin at 8 Weeks [ Time Frame: 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).
12. Mean Change From Baseline in Muscle Tissue Utrophin at 8 Weeks [ Time Frame: 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).

Secondary Outcome Measures :

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

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 60 Years (Adult)
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: No

Criteria

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%

Contacts and Locations

Locations

United States, California

University of California, Davis

Sacramento, California, United States, 95817

Sponsors and Collaborators

Craig McDonald, MD

Cardero Therapeutics, Inc.

Investigators

• Principal Investigator: Craig M McDonald, MD; University of California, Davis
• Study Director: Erik K Henricson, MPH; University of California, Davis

  Study Documents (Full-Text)

Documents provided by Craig McDonald, MD, University of California, Davis:

Study Protocol and Statistical Analysis Plan  [PDF] March 8, 2013

Informed Consent Form  [PDF] March 24, 2014

More Information

Additional Information:

UC Davis Neuromuscular Research Center 

• Responsible Party: Craig McDonald, MD, Professor and Chairman, Department of Physical Medicine and Rehabilitation, University of California, Davis
• ClinicalTrials.gov Identifier: NCT01856868
• Other Study ID Numbers: 454352
• First Posted: May 17, 2013
• Results First Posted: December 22, 2021
• Last Update Posted: December 22, 2021
• Last Verified: November 2021

Keywords provided by Craig McDonald, MD, University of California, Davis:

BMD; Becker muscular dystrophy; epicatechin; clinical trial; neuromuscular disease

Additional relevant MeSH terms:

Muscular Dystrophies; Muscular Dystrophy, Duchenne; Muscular Disorders, Atrophic; Muscular Diseases; Musculoskeletal Diseases; Neuromuscular Diseases; Nervous System Diseases; Genetic Diseases, Inborn; Genetic Diseases, X-Linked