Plus Epicatechin Duchenne Muscular Dystrophy in Non-ambulatory Adolescents

NCT02964377 | Completed Phase 1 Results

• 1 other identifier: 951753
• Study Type: interventional
• Target: 15
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Duchenne Muscular Dystrophy

Keywords

Pediatric; muscle disease; Duchenne muscular dystrophy; cardiomyopathy

Outcome Measures

Primary Outcomes (9)

• 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 Outcomes (5)

• Clinical Outcome: Percent of Normalized Upper Extremity Reachable Surface Area at Week 4 and Week 8

  Baseline, Week 4, Week 8

• Clinical Outcome: Total Score Using Performance of the Upper Limb Assessment

  Baseline, Week 4, Week 8

• Clinical Outcome: Mean Maximal Attained Revolutions Per 6-minute Cycle Test

  Baseline, Week 4, Week 8

• Person-Reported Outcome: Upper Extremity Standardized Mean Score Using Pediatric Outcomes Data Collection Instrument (PODCI) Quality of Life Instrument

  Baseline to Week 4 and Week 8

• Person-Reported Outcome: Mean Person-Reported Outcome Measure Upper Limb (PROM-UL) Functional Capacity Score

  Change from Baseline to Week 4 and Week 8

Other Outcomes (1)

• Clinical Outcome: Mean Strain Index (Ecc%) of Cardiac Mid-Ventricular Strain by MRI

  Baseline, Week 8

Study Arms (3)

Cohort 1

EXPERIMENTAL

8-weeks open-label (+)- Epicatechin at 25mg/day twice per day,

Drug: (+)- Epicatechin

Cohort 2

EXPERIMENTAL

8-weeks open-label (+)- Epicatechin at 25mg/day three times per day

Drug: (+)- Epicatechin

Cohort 3

EXPERIMENTAL

8-weeks open-label (+)- Epicatechin at 75mg/day at two times per day

Drug: (+)- Epicatechin

Interventions

(+)- Epicatechin DRUG

Cohort 1; Cohort 2; Cohort 3

Eligibility Criteria

• Age: 8 Years - 17 Years
• Sex: male
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Craig McDonald, MD: lead
• Cardero Therapeutics, Inc.: collaborator

Study Sites (1)

UC Davis Medical Center

Sacramento, California, 95817, United States

Location

MeSH Terms

Conditions

Muscular Dystrophy, Duchenne; Muscular Diseases; Cardiomyopathies

Interventions

Catechin

Condition Hierarchy (Ancestors)

Muscular Dystrophies; Muscular Disorders, Atrophic; Musculoskeletal Diseases; Neuromuscular Diseases; Nervous System Diseases; Genetic Diseases, X-Linked; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Heart Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Chromans; Benzopyrans; Pyrans; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Flavonoids; Chromones; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Results Point of Contact

• Title: Dr. Craig McDonald, Professor and Chair
• Organization: UC Davis Health

cmmcdonald@ucdavis.edu

(916) 734-4293

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor and Chair of Department of Physical Rehabilitation

Study Record Dates

• First Submitted: November 7, 2016
• First Posted: November 16, 2016
• Study Start: November 1, 2016
• Primary Completion: July 1, 2018
• Study Completion: July 1, 2018
• Last Updated: December 21, 2021
• Results First Posted: December 21, 2021

Record last verified: 2021-11

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)