Duchenne Muscular Dystrophy
Conditions
Keywords
Pediatric, muscle disease, Duchenne muscular dystrophy, cardiomyopathy
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.
Interventions
DRUG(+)- Epicatechin
Sponsors
Cardero Therapeutics, Inc.
Craig McDonald, MD
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
8 Years to 17 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Laboratory Outcome: Absolute Values of Myostatin (AU) Measured by ELISA | Baseline, Week 4, Week 8 | Proteomics evaluation of plasma biomarkers to confirm intervention-responsive pathophysiological pathways, using enzyme-linked immunosorbent assay (ELISA). |
| Laboratory Outcome: Absolute Plasma Follistatin:Myostatin Ratio at Baseline, Week 4 and Week 8 | 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 | Week 8 | 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 | Study duration (8 weeks) | 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 | Baseline, Week 4, Week 8 | 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 | Baseline, Week 4, Week 8 | 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 | Baseline, Week 4, Week 8 | Proteomics evaluation of plasma biomarkers to confirm intervention-responsive pathophysiological pathways, using enzyme-linked immunosorbent assay (ELISA). |
| Pharmacokinetics Outcome: Absolute Values of (+)-Epicatechin Serum Concentration, Pre-dose (Trough) and 2 Hours Post-dose (Peak) | Pre-dose and 2 hours post-dose at baseline | Pharmacokinetic evaluation for dose-response evaluation. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Outcome: Percent of Normalized Upper Extremity Reachable Surface Area at Week 4 and Week 8 | Baseline, Week 4, 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 | Baseline, Week 4, Week 8 | 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 | Baseline, Week 4, Week 8 | 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 | Baseline to Week 4 and Week 8 | 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 | Change from Baseline to Week 4 and Week 8 | 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). |
Other
| Measure | Time frame | Description |
|---|---|---|
| Clinical Outcome: Mean Strain Index (Ecc%) of Cardiac Mid-Ventricular Strain by MRI | Baseline, Week 8 | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1 (+)- Epicatechin at 25mg/day twice per day | 5 |
| Cohort 2 (+)- Epicatechin at 25mg/day three times per day | 5 |
| Cohort 3 (+)- Epicatechin at 75mg/day at two times per day. | 5 |
| Total | 15 |
Baseline characteristics
| Characteristic | Cohort 1 | Cohort 2 | Cohort 3 | Total |
|---|---|---|---|---|
| Age, Continuous | 13.2 years STANDARD_DEVIATION 3.1 | 11.9 years STANDARD_DEVIATION 3 | 13.2 years STANDARD_DEVIATION 2.9 | 12.8 years STANDARD_DEVIATION 2.8 |
| Race and Ethnicity Not Collected | — | — | — | 0 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 5 Participants | 5 Participants | 5 Participants | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 5 | 0 / 5 | 0 / 5 |
| other Total, other adverse events | 4 / 5 | 2 / 5 | 4 / 5 |
| serious Total, serious adverse events | 0 / 5 | 0 / 5 | 0 / 5 |
Outcome results
Primary
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.
Time frame: Week 8
Population: Missing data due to poor image quality.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 | Clinical Outcome: Mean Percent of Baseline Cardiac Ejection Fraction by MRI | 98.19 percentage | Standard Deviation 14.92 |
| Cohort 2 | Clinical Outcome: Mean Percent of Baseline Cardiac Ejection Fraction by MRI | 96.23 percentage | Standard Deviation 9.66 |
| Cohort 3 | Clinical Outcome: Mean Percent of Baseline Cardiac Ejection Fraction by MRI | 92.27 percentage | Standard Deviation 14.98 |
Primary
Laboratory Outcome: Absolute Plasma Follistatin:Myostatin Ratio at Baseline, Week 4 and Week 8
Evaluation of follistatin:myostatin ratio from plasma samples.
Time frame: Baseline, Week 4 and Week 8
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 | Laboratory Outcome: Absolute Plasma Follistatin:Myostatin Ratio at Baseline, Week 4 and Week 8 | Week 4 | 3.61 Ratio of follistatin to myostatin (AU) | Standard Deviation 0.78 |
| Cohort 1 | Laboratory Outcome: Absolute Plasma Follistatin:Myostatin Ratio at Baseline, Week 4 and Week 8 | Baseline | 1.82 Ratio of follistatin to myostatin (AU) | Standard Deviation 0.71 |
| Cohort 1 | Laboratory Outcome: Absolute Plasma Follistatin:Myostatin Ratio at Baseline, Week 4 and Week 8 | Week 8 | 4.02 Ratio of follistatin to myostatin (AU) | Standard Deviation 1.55 |
| Cohort 2 | Laboratory Outcome: Absolute Plasma Follistatin:Myostatin Ratio at Baseline, Week 4 and Week 8 | Week 4 | 3.41 Ratio of follistatin to myostatin (AU) | Standard Deviation 1.24 |
| Cohort 2 | Laboratory Outcome: Absolute Plasma Follistatin:Myostatin Ratio at Baseline, Week 4 and Week 8 | Baseline | 1.76 Ratio of follistatin to myostatin (AU) | Standard Deviation 0.74 |
| Cohort 2 | Laboratory Outcome: Absolute Plasma Follistatin:Myostatin Ratio at Baseline, Week 4 and Week 8 | Week 8 | 3.94 Ratio of follistatin to myostatin (AU) | Standard Deviation 1.23 |
| Cohort 3 | Laboratory Outcome: Absolute Plasma Follistatin:Myostatin Ratio at Baseline, Week 4 and Week 8 | Baseline | 3.31 Ratio of follistatin to myostatin (AU) | Standard Deviation 0.91 |
| Cohort 3 | Laboratory Outcome: Absolute Plasma Follistatin:Myostatin Ratio at Baseline, Week 4 and Week 8 | Week 8 | 5.7 Ratio of follistatin to myostatin (AU) | Standard Deviation 0.65 |
| Cohort 3 | Laboratory Outcome: Absolute Plasma Follistatin:Myostatin Ratio at Baseline, Week 4 and Week 8 | Week 4 | 5.26 Ratio of follistatin to myostatin (AU) | Standard Deviation 0.87 |
Comparison: Baseline vs. Week 4 (Cohort 1)p-value: <0.0001Regression, Linear
Comparison: Baseline vs. Week 4 (Cohort 2)p-value: <0.0001Regression, Linear
Comparison: Baseline vs. Week 4 (Cohort 3)p-value: <0.0001Regression, Linear
Comparison: Baseline vs. Week 8 (Cohort 1)p-value: <0.0001Regression, Linear
Comparison: Baseline vs. Week 8 (Cohort 2)p-value: <0.0001Regression, Linear
Comparison: Baseline vs. Week 8 (Cohort 3)p-value: <0.0001Regression, Linear
Primary
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).
Time frame: Baseline, Week 4, Week 8
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 | Laboratory Outcome: Absolute Values of Carbonylation (AU) Measured by ELISA | Week 4 | 9.95 AU | Standard Deviation 1.72 |
| Cohort 1 | Laboratory Outcome: Absolute Values of Carbonylation (AU) Measured by ELISA | Baseline | 12.85 AU | Standard Deviation 2.38 |
| Cohort 1 | Laboratory Outcome: Absolute Values of Carbonylation (AU) Measured by ELISA | Week 8 | 9.07 AU | Standard Deviation 1.41 |
| Cohort 2 | Laboratory Outcome: Absolute Values of Carbonylation (AU) Measured by ELISA | Week 4 | 12.2 AU | Standard Deviation 2.08 |
| Cohort 2 | Laboratory Outcome: Absolute Values of Carbonylation (AU) Measured by ELISA | Baseline | 15.7 AU | Standard Deviation 1.74 |
| Cohort 2 | Laboratory Outcome: Absolute Values of Carbonylation (AU) Measured by ELISA | Week 8 | 10.47 AU | Standard Deviation 1.91 |
| Cohort 3 | Laboratory Outcome: Absolute Values of Carbonylation (AU) Measured by ELISA | Baseline | 12.45 AU | Standard Deviation 3.91 |
| Cohort 3 | Laboratory Outcome: Absolute Values of Carbonylation (AU) Measured by ELISA | Week 8 | 6.64 AU | Standard Deviation 1.05 |
| Cohort 3 | Laboratory Outcome: Absolute Values of Carbonylation (AU) Measured by ELISA | Week 4 | 7.18 AU | Standard Deviation 2.74 |
Comparison: Baseline vs. Week 4p-value: <0.0001Regression, Linear
Comparison: Baseline vs. Week 4p-value: <0.0001Regression, Linear
Comparison: Baseline vs. Week 4p-value: <0.0001Regression, Linear
Comparison: Baseline vs. Week 8p-value: <0.0001Regression, Linear
Comparison: Baseline vs. Week 8p-value: <0.0001Regression, Linear
Comparison: Baseline vs. Week 8p-value: <0.0001Regression, Linear
Primary
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).
Time frame: Baseline, Week 4, Week 8
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 | Laboratory Outcome: Absolute Values of Follistatin (AU) Measured by ELISA | Week 4 | 891.43 AU | Standard Deviation 278.51 |
| Cohort 1 | Laboratory Outcome: Absolute Values of Follistatin (AU) Measured by ELISA | Baseline | 527.24 AU | Standard Deviation 282.06 |
| Cohort 1 | Laboratory Outcome: Absolute Values of Follistatin (AU) Measured by ELISA | Week 8 | 951.43 AU | Standard Deviation 312.39 |
| Cohort 2 | Laboratory Outcome: Absolute Values of Follistatin (AU) Measured by ELISA | Week 4 | 795.71 AU | Standard Deviation 352.83 |
| Cohort 2 | Laboratory Outcome: Absolute Values of Follistatin (AU) Measured by ELISA | Baseline | 555.71 AU | Standard Deviation 382.28 |
| Cohort 2 | Laboratory Outcome: Absolute Values of Follistatin (AU) Measured by ELISA | Week 8 | 914.29 AU | Standard Deviation 350.17 |
| Cohort 3 | Laboratory Outcome: Absolute Values of Follistatin (AU) Measured by ELISA | Baseline | 1011.25 AU | Standard Deviation 247.39 |
| Cohort 3 | Laboratory Outcome: Absolute Values of Follistatin (AU) Measured by ELISA | Week 8 | 1351.25 AU | Standard Deviation 148.95 |
| Cohort 3 | Laboratory Outcome: Absolute Values of Follistatin (AU) Measured by ELISA | Week 4 | 1356.25 AU | Standard Deviation 117.13 |
Comparison: Baseline vs. Week 4p-value: <0.0001Regression, Linear
Comparison: Baseline vs. Week 4p-value: <0.0001Regression, Linear
Comparison: Baseline vs. Week 8p-value: <0.0001Regression, Linear
Comparison: Baseline vs. Week 8p-value: <0.0001Regression, Linear
Comparison: Baseline vs. Week 8p-value: <0.0001Regression, Linear
Comparison: Baseline vs. Week 4p-value: <0.0001Regression, Linear
Primary
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).
Time frame: Baseline, Week 4, Week 8
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 | Laboratory Outcome: Absolute Values of Myostatin (AU) Measured by ELISA | Baseline | 282.33 AU | Standard Deviation 69.7 |
| Cohort 1 | Laboratory Outcome: Absolute Values of Myostatin (AU) Measured by ELISA | Week 4 | 247.67 AU | Standard Deviation 66.94 |
| Cohort 1 | Laboratory Outcome: Absolute Values of Myostatin (AU) Measured by ELISA | Week 8 | 247.07 AU | Standard Deviation 69.7 |
| Cohort 2 | Laboratory Outcome: Absolute Values of Myostatin (AU) Measured by ELISA | Week 4 | 239 AU | Standard Deviation 90.2 |
| Cohort 2 | Laboratory Outcome: Absolute Values of Myostatin (AU) Measured by ELISA | Baseline | 302.33 AU | Standard Deviation 91.15 |
| Cohort 2 | Laboratory Outcome: Absolute Values of Myostatin (AU) Measured by ELISA | Week 8 | 233.67 AU | Standard Deviation 78.47 |
| Cohort 3 | Laboratory Outcome: Absolute Values of Myostatin (AU) Measured by ELISA | Week 4 | 263.67 AU | Standard Deviation 56.16 |
| Cohort 3 | Laboratory Outcome: Absolute Values of Myostatin (AU) Measured by ELISA | Week 8 | 241.67 AU | Standard Deviation 51.67 |
| Cohort 3 | Laboratory Outcome: Absolute Values of Myostatin (AU) Measured by ELISA | Baseline | 316.6 AU | Standard Deviation 88.7 |
Comparison: Baseline vs. Week 4p-value: 0.012Regression, Linear
Comparison: Baseline vs. Week 4p-value: <0.0001Regression, Linear
Comparison: Baseline vs. Week 4p-value: <0.0001Regression, Linear
Comparison: Baseline vs. Week 8p-value: 0.01Regression, Linear
Comparison: Baseline vs. Week 8p-value: <0.0001Regression, Linear
Comparison: Baseline vs. Week 8p-value: <0.0001Regression, Linear
Primary
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).
Time frame: Baseline, Week 4, Week 8
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 | Laboratory Outcome: Absolute Values of Nitric Oxide (AU) Measured by ELISA | Week 4 | 0.82 AU | Standard Deviation 0.31 |
| Cohort 1 | Laboratory Outcome: Absolute Values of Nitric Oxide (AU) Measured by ELISA | Baseline | 0.65 AU | Standard Deviation 0.17 |
| Cohort 1 | Laboratory Outcome: Absolute Values of Nitric Oxide (AU) Measured by ELISA | Week 8 | 0.99 AU | Standard Deviation 0.28 |
| Cohort 2 | Laboratory Outcome: Absolute Values of Nitric Oxide (AU) Measured by ELISA | Week 4 | 1.06 AU | Standard Deviation 0.16 |
| Cohort 2 | Laboratory Outcome: Absolute Values of Nitric Oxide (AU) Measured by ELISA | Baseline | 0.63 AU | Standard Deviation 0.14 |
| Cohort 2 | Laboratory Outcome: Absolute Values of Nitric Oxide (AU) Measured by ELISA | Week 8 | 1.14 AU | Standard Deviation 0.15 |
| Cohort 3 | Laboratory Outcome: Absolute Values of Nitric Oxide (AU) Measured by ELISA | Baseline | 0.57 AU | Standard Deviation 0.21 |
| Cohort 3 | Laboratory Outcome: Absolute Values of Nitric Oxide (AU) Measured by ELISA | Week 8 | 0.92 AU | Standard Deviation 0.3 |
| Cohort 3 | Laboratory Outcome: Absolute Values of Nitric Oxide (AU) Measured by ELISA | Week 4 | 0.93 AU | Standard Deviation 0.36 |
Comparison: Baseline vs. Week 4p-value: 0.002Regression, Linear
Comparison: Baseline vs. Week 4p-value: <0.001Regression, Linear
Comparison: Baseline vs. Week 4p-value: <0.0001Regression, Linear
Comparison: Baseline vs. Week 8p-value: <0.0001Regression, Linear
Comparison: Baseline vs. Week 8p-value: <0.0001Regression, Linear
Comparison: Baseline vs. Week 8p-value: <0.0001Regression, Linear
Primary
Pharmacokinetics Outcome: Absolute Values of (+)-Epicatechin Serum Concentration, Pre-dose (Trough) and 2 Hours Post-dose (Peak)
Pharmacokinetic evaluation for dose-response evaluation.
Time frame: Pre-dose and 2 hours post-dose at baseline
Population: One Cohort 3 participant post-dose sample was missed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 | Pharmacokinetics Outcome: Absolute Values of (+)-Epicatechin Serum Concentration, Pre-dose (Trough) and 2 Hours Post-dose (Peak) | Trough | 15.1 nM | Standard Deviation 10.4 |
| Cohort 1 | Pharmacokinetics Outcome: Absolute Values of (+)-Epicatechin Serum Concentration, Pre-dose (Trough) and 2 Hours Post-dose (Peak) | Peak | 481.2 nM | Standard Deviation 477.6 |
| Cohort 2 | Pharmacokinetics Outcome: Absolute Values of (+)-Epicatechin Serum Concentration, Pre-dose (Trough) and 2 Hours Post-dose (Peak) | Trough | 33.9 nM | Standard Deviation 7.9 |
| Cohort 2 | Pharmacokinetics Outcome: Absolute Values of (+)-Epicatechin Serum Concentration, Pre-dose (Trough) and 2 Hours Post-dose (Peak) | Peak | 551.2 nM | Standard Deviation 284.9 |
| Cohort 3 | Pharmacokinetics Outcome: Absolute Values of (+)-Epicatechin Serum Concentration, Pre-dose (Trough) and 2 Hours Post-dose (Peak) | Trough | 20.6 nM | Standard Deviation 43.6 |
| Cohort 3 | Pharmacokinetics Outcome: Absolute Values of (+)-Epicatechin Serum Concentration, Pre-dose (Trough) and 2 Hours Post-dose (Peak) | Peak | 3899.3 nM | Standard Deviation 1217.6 |
p-value: 0.0482t-test, 2 sided
p-value: 0.0075t-test, 2 sided
p-value: 0.0083t-test, 2 sided
Primary
Pharmacokinetics Outcome: Absolute Values of (+)-Epicatechin Serum Concentration, Pre-dose (Trough) and 2 Hours Post-dose (Peak)
Pharmacokinetic evaluation for dose-response evaluation.
Time frame: Week 4
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 | Pharmacokinetics Outcome: Absolute Values of (+)-Epicatechin Serum Concentration, Pre-dose (Trough) and 2 Hours Post-dose (Peak) | Trough | 84.2 nM | Standard Deviation 47.6 |
| Cohort 1 | Pharmacokinetics Outcome: Absolute Values of (+)-Epicatechin Serum Concentration, Pre-dose (Trough) and 2 Hours Post-dose (Peak) | Peak | 742.8 nM | Standard Deviation 442.7 |
| Cohort 2 | Pharmacokinetics Outcome: Absolute Values of (+)-Epicatechin Serum Concentration, Pre-dose (Trough) and 2 Hours Post-dose (Peak) | Trough | 163.8 nM | Standard Deviation 84.5 |
| Cohort 2 | Pharmacokinetics Outcome: Absolute Values of (+)-Epicatechin Serum Concentration, Pre-dose (Trough) and 2 Hours Post-dose (Peak) | Peak | 601 nM | Standard Deviation 357 |
| Cohort 3 | Pharmacokinetics Outcome: Absolute Values of (+)-Epicatechin Serum Concentration, Pre-dose (Trough) and 2 Hours Post-dose (Peak) | Trough | 179.1 nM | Standard Deviation 398.1 |
| Cohort 3 | Pharmacokinetics Outcome: Absolute Values of (+)-Epicatechin Serum Concentration, Pre-dose (Trough) and 2 Hours Post-dose (Peak) | Peak | 5590.8 nM | Standard Deviation 1729.9 |
p-value: 0.0127t-test, 2 sided
p-value: 0.0202t-test, 2 sided
p-value: 0.0007t-test, 2 sided
Primary
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.
Time frame: Study duration (8 weeks)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1 | Safety: Number of Participants Who Experienced Treatment-Related Laboratory Abnormalities | 1 Participants |
| Cohort 2 | Safety: Number of Participants Who Experienced Treatment-Related Laboratory Abnormalities | 0 Participants |
| Cohort 3 | Safety: Number of Participants Who Experienced Treatment-Related Laboratory Abnormalities | 2 Participants |
Secondary
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.
Time frame: Baseline, Week 4, Week 8
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 | Clinical Outcome: Mean Maximal Attained Revolutions Per 6-minute Cycle Test | Week 8 | 199 revolutions | Standard Deviation 96.6 |
| Cohort 1 | Clinical Outcome: Mean Maximal Attained Revolutions Per 6-minute Cycle Test | Week 4 | 194.4 revolutions | Standard Deviation 80.4 |
| Cohort 1 | Clinical Outcome: Mean Maximal Attained Revolutions Per 6-minute Cycle Test | Baseline | 177.4 revolutions | Standard Deviation 112.4 |
| Cohort 2 | Clinical Outcome: Mean Maximal Attained Revolutions Per 6-minute Cycle Test | Week 8 | 387 revolutions | Standard Deviation 54 |
| Cohort 2 | Clinical Outcome: Mean Maximal Attained Revolutions Per 6-minute Cycle Test | Baseline | 362.6 revolutions | Standard Deviation 82.8 |
| Cohort 2 | Clinical Outcome: Mean Maximal Attained Revolutions Per 6-minute Cycle Test | Week 4 | 415 revolutions | Standard Deviation 77.2 |
| Cohort 3 | Clinical Outcome: Mean Maximal Attained Revolutions Per 6-minute Cycle Test | Week 8 | 356.8 revolutions | Standard Deviation 275.4 |
| Cohort 3 | Clinical Outcome: Mean Maximal Attained Revolutions Per 6-minute Cycle Test | Week 4 | 348.2 revolutions | Standard Deviation 222.3 |
| Cohort 3 | Clinical Outcome: Mean Maximal Attained Revolutions Per 6-minute Cycle Test | Baseline | 330.8 revolutions | Standard Deviation 172.5 |
Comparison: Baseline vs. Week 8p-value: 0.054Regression, Linear
Comparison: Baseline vs. Week 4p-value: 0.009Regression, Linear
Secondary
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.
Time frame: Baseline, Week 4, Week 8
Population: Missing data due to equipment malfunction
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 | Clinical Outcome: Percent of Normalized Upper Extremity Reachable Surface Area at Week 4 and Week 8 | Week 4 | 63.7 % normalized reachable surface area | Standard Deviation 44.4 |
| Cohort 1 | Clinical Outcome: Percent of Normalized Upper Extremity Reachable Surface Area at Week 4 and Week 8 | Baseline | 44 % normalized reachable surface area | Standard Deviation 33.9 |
| Cohort 1 | Clinical Outcome: Percent of Normalized Upper Extremity Reachable Surface Area at Week 4 and Week 8 | Week 8 | 47.9 % normalized reachable surface area | Standard Deviation 51.2 |
| Cohort 2 | Clinical Outcome: Percent of Normalized Upper Extremity Reachable Surface Area at Week 4 and Week 8 | Week 4 | 84.4 % normalized reachable surface area | Standard Deviation 32.9 |
| Cohort 2 | Clinical Outcome: Percent of Normalized Upper Extremity Reachable Surface Area at Week 4 and Week 8 | Baseline | 89.9 % normalized reachable surface area | Standard Deviation 24.6 |
| Cohort 2 | Clinical Outcome: Percent of Normalized Upper Extremity Reachable Surface Area at Week 4 and Week 8 | Week 8 | 92.7 % normalized reachable surface area | Standard Deviation 35.4 |
| Cohort 3 | Clinical Outcome: Percent of Normalized Upper Extremity Reachable Surface Area at Week 4 and Week 8 | Baseline | 33 % normalized reachable surface area | Standard Deviation 23.2 |
| Cohort 3 | Clinical Outcome: Percent of Normalized Upper Extremity Reachable Surface Area at Week 4 and Week 8 | Week 8 | 41.5 % normalized reachable surface area | Standard Deviation 26.7 |
| Cohort 3 | Clinical Outcome: Percent of Normalized Upper Extremity Reachable Surface Area at Week 4 and Week 8 | Week 4 | 35.8 % normalized reachable surface area | Standard Deviation 21.4 |
Secondary
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).
Time frame: Baseline, Week 4, Week 8
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 | Clinical Outcome: Total Score Using Performance of the Upper Limb Assessment | Week 8 | 22 score on a scale | Standard Deviation 5.8 |
| Cohort 1 | Clinical Outcome: Total Score Using Performance of the Upper Limb Assessment | Week 4 | 21.4 score on a scale | Standard Deviation 6.8 |
| Cohort 1 | Clinical Outcome: Total Score Using Performance of the Upper Limb Assessment | Baseline | 19.8 score on a scale | Standard Deviation 5.4 |
| Cohort 2 | Clinical Outcome: Total Score Using Performance of the Upper Limb Assessment | Week 4 | 32 score on a scale | Standard Deviation 5.8 |
| Cohort 2 | Clinical Outcome: Total Score Using Performance of the Upper Limb Assessment | Baseline | 30.8 score on a scale | Standard Deviation 6.8 |
| Cohort 2 | Clinical Outcome: Total Score Using Performance of the Upper Limb Assessment | Week 8 | 31.8 score on a scale | Standard Deviation 5.4 |
| Cohort 3 | Clinical Outcome: Total Score Using Performance of the Upper Limb Assessment | Baseline | 27 score on a scale | Standard Deviation 10.6 |
| Cohort 3 | Clinical Outcome: Total Score Using Performance of the Upper Limb Assessment | Week 8 | 25.6 score on a scale | Standard Deviation 11.4 |
| Cohort 3 | Clinical Outcome: Total Score Using Performance of the Upper Limb Assessment | Week 4 | 26.8 score on a scale | Standard Deviation 9.9 |
Comparison: Baseline vs. Week 4p-value: 0.01Regression, Linear
Comparison: Baseline vs. Week 4p-value: 0.019Regression, Linear
Comparison: Baseline vs. Week 8p-value: <0.001Regression, Linear
Comparison: Baseline vs. Week 8p-value: 0.05Regression, Linear
Secondary
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).
Time frame: Change from Baseline to Week 4 and Week 8
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 | Person-Reported Outcome: Mean Person-Reported Outcome Measure Upper Limb (PROM-UL) Functional Capacity Score | Week 4 | 64 score on a scale | Standard Deviation 14.5 |
| Cohort 1 | Person-Reported Outcome: Mean Person-Reported Outcome Measure Upper Limb (PROM-UL) Functional Capacity Score | Baseline | 73.6 score on a scale | Standard Deviation 19.8 |
| Cohort 1 | Person-Reported Outcome: Mean Person-Reported Outcome Measure Upper Limb (PROM-UL) Functional Capacity Score | Week 8 | 62.6 score on a scale | Standard Deviation 15 |
| Cohort 2 | Person-Reported Outcome: Mean Person-Reported Outcome Measure Upper Limb (PROM-UL) Functional Capacity Score | Week 4 | 87.4 score on a scale | Standard Deviation 7.6 |
| Cohort 2 | Person-Reported Outcome: Mean Person-Reported Outcome Measure Upper Limb (PROM-UL) Functional Capacity Score | Baseline | 88.4 score on a scale | Standard Deviation 7.9 |
| Cohort 2 | Person-Reported Outcome: Mean Person-Reported Outcome Measure Upper Limb (PROM-UL) Functional Capacity Score | Week 8 | 87.6 score on a scale | Standard Deviation 6.3 |
| Cohort 3 | Person-Reported Outcome: Mean Person-Reported Outcome Measure Upper Limb (PROM-UL) Functional Capacity Score | Baseline | 79.2 score on a scale | Standard Deviation 24.1 |
| Cohort 3 | Person-Reported Outcome: Mean Person-Reported Outcome Measure Upper Limb (PROM-UL) Functional Capacity Score | Week 8 | 78.8 score on a scale | Standard Deviation 18.5 |
| Cohort 3 | Person-Reported Outcome: Mean Person-Reported Outcome Measure Upper Limb (PROM-UL) Functional Capacity Score | Week 4 | 82.8 score on a scale | Standard Deviation 20.2 |
Comparison: Baseline vs. Week 4p-value: 0.006Regression, Linear
Comparison: Baseline vs. Week 8p-value: 0.002Regression, Linear
Secondary
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.
Time frame: Baseline to Week 4 and Week 8
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 | Person-Reported Outcome: Upper Extremity Standardized Mean Score Using Pediatric Outcomes Data Collection Instrument (PODCI) Quality of Life Instrument | Week 4 | 31.2 score on a scale | Standard Deviation 16.4 |
| Cohort 1 | Person-Reported Outcome: Upper Extremity Standardized Mean Score Using Pediatric Outcomes Data Collection Instrument (PODCI) Quality of Life Instrument | Baseline | 32 score on a scale | Standard Deviation 12.9 |
| Cohort 1 | Person-Reported Outcome: Upper Extremity Standardized Mean Score Using Pediatric Outcomes Data Collection Instrument (PODCI) Quality of Life Instrument | Week 8 | 36.2 score on a scale | Standard Deviation 12.3 |
| Cohort 2 | Person-Reported Outcome: Upper Extremity Standardized Mean Score Using Pediatric Outcomes Data Collection Instrument (PODCI) Quality of Life Instrument | Week 4 | 74.6 score on a scale | Standard Deviation 18.3 |
| Cohort 2 | Person-Reported Outcome: Upper Extremity Standardized Mean Score Using Pediatric Outcomes Data Collection Instrument (PODCI) Quality of Life Instrument | Baseline | 62.6 score on a scale | Standard Deviation 24.6 |
| Cohort 2 | Person-Reported Outcome: Upper Extremity Standardized Mean Score Using Pediatric Outcomes Data Collection Instrument (PODCI) Quality of Life Instrument | Week 8 | 71 score on a scale | Standard Deviation 21.6 |
| Cohort 3 | Person-Reported Outcome: Upper Extremity Standardized Mean Score Using Pediatric Outcomes Data Collection Instrument (PODCI) Quality of Life Instrument | Baseline | 66 score on a scale | Standard Deviation 22.3 |
| Cohort 3 | Person-Reported Outcome: Upper Extremity Standardized Mean Score Using Pediatric Outcomes Data Collection Instrument (PODCI) Quality of Life Instrument | Week 8 | 62.6 score on a scale | Standard Deviation 32.1 |
| Cohort 3 | Person-Reported Outcome: Upper Extremity Standardized Mean Score Using Pediatric Outcomes Data Collection Instrument (PODCI) Quality of Life Instrument | Week 4 | 72.6 score on a scale | Standard Deviation 21.3 |
Comparison: Baseline vs. Week 8p-value: 0.025Regression, Linear
Comparison: Baseline vs. Week 4p-value: 0.026Regression, Linear
Other Pre-specified
Clinical Outcome: Mean Strain Index (Ecc%) of Cardiac Mid-Ventricular Strain by MRI
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
Population: 3 of the participants were unable to undergo the procedure and thus were not included in the analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 | Clinical Outcome: Mean Strain Index (Ecc%) of Cardiac Mid-Ventricular Strain by MRI | Baseline | -16.65 Ecc% | Standard Deviation 4.31 |
| Cohort 1 | Clinical Outcome: Mean Strain Index (Ecc%) of Cardiac Mid-Ventricular Strain by MRI | Week 8 | -16.8 Ecc% | Standard Deviation 1.39 |
| Cohort 2 | Clinical Outcome: Mean Strain Index (Ecc%) of Cardiac Mid-Ventricular Strain by MRI | Baseline | -17.38 Ecc% | Standard Deviation 2.17 |
| Cohort 2 | Clinical Outcome: Mean Strain Index (Ecc%) of Cardiac Mid-Ventricular Strain by MRI | Week 8 | -17.67 Ecc% | Standard Deviation 2.9 |
| Cohort 3 | Clinical Outcome: Mean Strain Index (Ecc%) of Cardiac Mid-Ventricular Strain by MRI | Baseline | -11.46 Ecc% | Standard Deviation 1.34 |
| Cohort 3 | Clinical Outcome: Mean Strain Index (Ecc%) of Cardiac Mid-Ventricular Strain by MRI | Week 8 | -10.71 Ecc% | Standard Deviation 6 |