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Plus Epicatechin Duchenne Muscular Dystrophy in Non-ambulatory Adolescents

Primary Purpose

Duchenne Muscular Dystrophy

Status

Completed

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

(+)- Epicatechin

About this trial

This is an interventional treatment trial for Duchenne Muscular Dystrophy focused on measuring Pediatric, muscle disease, Duchenne muscular dystrophy, cardiomyopathy

Eligibility Criteria

8 Years - 17 Years (Child)MaleDoes not accept healthy volunteers

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.

Sites / Locations

UC Davis Medical Center

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Arm Label

Cohort 1

Cohort 2

Cohort 3

Arm Description

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

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

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

Outcomes

Primary Outcome Measures

Pharmacokinetics Outcome: Absolute Values of (+)-Epicatechin Serum Concentration, Pre-dose (Trough) and 2 Hours Post-dose (Peak)

Pharmacokinetic evaluation for dose-response evaluation.

Pharmacokinetics Outcome: Absolute Values of (+)-Epicatechin Serum Concentration, Pre-dose (Trough) and 2 Hours Post-dose (Peak)

Pharmacokinetic evaluation for dose-response evaluation.

Laboratory Outcome: Absolute Plasma Follistatin:Myostatin Ratio at Baseline, Week 4 and Week 8

Evaluation of follistatin:myostatin ratio from plasma samples.

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.

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.

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).

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).

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).

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).

Secondary Outcome Measures

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.

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).

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.

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".

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).

Full Information

NCT ID

NCT02964377

First Posted

November 7, 2016

Last Updated

November 22, 2021

Sponsor

Craig McDonald, MD

Collaborators

Cardero Therapeutics, Inc.

1. Study Identification

Unique Protocol Identification Number

NCT02964377

Brief Title

Plus Epicatechin Duchenne Muscular Dystrophy in Non-ambulatory Adolescents

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

November 2021

Overall Recruitment Status

Completed

Study Start Date

November 2016 (Actual)

Primary Completion Date

July 2018 (Actual)

Study Completion Date

July 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor-Investigator

Name of the Sponsor

Craig McDonald, MD

Collaborators

Cardero Therapeutics, Inc.

4. Oversight

Data Monitoring Committee

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Duchenne Muscular Dystrophy

Keywords

Pediatric, muscle disease, Duchenne muscular dystrophy, cardiomyopathy

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

15 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Cohort 1

Arm Type

Experimental

Arm Description

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

Arm Title

Cohort 2

Arm Type

Experimental

Arm Description

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

Arm Title

Cohort 3

Arm Type

Experimental

Arm Description

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

Intervention Type

Drug

Intervention Name(s)

(+)- Epicatechin

Primary Outcome Measure Information:

Title

Pharmacokinetics Outcome: Absolute Values of (+)-Epicatechin Serum Concentration, Pre-dose (Trough) and 2 Hours Post-dose (Peak)

Description

Pharmacokinetic evaluation for dose-response evaluation.

Time Frame

Pre-dose and 2 hours post-dose at baseline

Title

Pharmacokinetics Outcome: Absolute Values of (+)-Epicatechin Serum Concentration, Pre-dose (Trough) and 2 Hours Post-dose (Peak)

Description

Pharmacokinetic evaluation for dose-response evaluation.

Time Frame

Week 4

Title

Laboratory Outcome: Absolute Plasma Follistatin:Myostatin Ratio at Baseline, Week 4 and Week 8

Description

Evaluation of follistatin:myostatin ratio from plasma samples.

Time Frame

Baseline, Week 4 and Week 8

Title

Clinical Outcome: Mean Percent of Baseline Cardiac Ejection Fraction by MRI

Description

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.

Time Frame

Week 8

Title

Safety: Number of Participants Who Experienced Treatment-Related Laboratory Abnormalities

Description

Time Frame

Study duration (8 weeks)

Title

Laboratory Outcome: Absolute Values of Nitric Oxide (AU) Measured by ELISA

Description

Proteomics evaluation of plasma biomarkers to confirm intervention-responsive pathophysiological pathways, using enzyme-linked immunosorbent assay (ELISA).

Time Frame

Baseline, Week 4, Week 8

Title

Laboratory Outcome: Absolute Values of Carbonylation (AU) Measured by ELISA

Description

Proteomics evaluation of plasma biomarkers to confirm intervention-responsive pathophysiological pathways, using enzyme-linked immunosorbent assay (ELISA).

Time Frame

Baseline, Week 4, Week 8

Title

Laboratory Outcome: Absolute Values of Follistatin (AU) Measured by ELISA

Description

Proteomics evaluation of plasma biomarkers to confirm intervention-responsive pathophysiological pathways, using enzyme-linked immunosorbent assay (ELISA).

Time Frame

Baseline, Week 4, Week 8

Title

Laboratory Outcome: Absolute Values of Myostatin (AU) Measured by ELISA

Description

Proteomics evaluation of plasma biomarkers to confirm intervention-responsive pathophysiological pathways, using enzyme-linked immunosorbent assay (ELISA).

Time Frame

Baseline, Week 4, Week 8

Secondary Outcome Measure Information:

Title

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

Description

Time Frame

Baseline, Week 4, Week 8

Title

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

Description

Time Frame

Baseline, Week 4, Week 8

Title

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

Description

Time Frame

Baseline, Week 4, Week 8

Title

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

Description

Time Frame

Baseline to Week 4 and Week 8

Title

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

Description

Time Frame

Change from Baseline to Week 4 and Week 8

Other Pre-specified Outcome Measures:

Title

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

Description

Cardiac MRI using tagged imaging detects changes in heart muscle contractility in people with DMD. It measures how the heart deforms throughout the cardiac cycle, and is used to calculate strain on the heart muscle. Peak strain is a measure of distortion in the heart muscle during contraction versus when it is at rest. Mid-ventricular peak circumferential strain is a sensitive marker of cardiac function and can detect effects of therapeutic interventions. Strain is expressed in the negative, so more negative measurements indicate a healthy state while less negative measurements (closer to zero) indicate an unhealthy state.

Time Frame

Baseline, Week 8

10. Eligibility

Sex

Male

Minimum Age & Unit of Time

8 Years

Maximum Age & Unit of Time

17 Years

Accepts Healthy Volunteers

Eligibility Criteria

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.

Facility Information:

Facility Name

UC Davis Medical Center

City

Sacramento

State/Province

California

ZIP/Postal Code

95817

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

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Plus Epicatechin Duchenne Muscular Dystrophy in Non-ambulatory Adolescents

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