Becker Muscular Dystrophy
Conditions
Keywords
BMD, Becker muscular dystrophy, epicatechin, clinical trial, neuromuscular disease
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.
Interventions
DRUG(-)-epicatechin
purified nutritional extract (-)-epicatechin 100mg/day orally for 8 weeks.
Sponsors
Cardero Therapeutics, Inc.
Craig McDonald, MD
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to 60 Years
Healthy volunteers
No
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%
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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). |
| 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). |
| 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 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 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 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). |
| 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 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 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 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 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 Knee Extension at 8 Weeks | Baseline and 8 Weeks | Knee extension will be assessed using an isokinetic dynamometer. |
| 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 Stand From Supine at 8 Weeks | Baseline and 8 Weeks | Muscle burst function will be assessed by time function tests. |
| Change From Baseline in Elbow Flexion at 8 Weeks | Baseline and 8 Weeks | Elbow flexion will be assessed using an isokinetic dynamometer. |
| -(-)Epicatechin Pharmacokinetics | 8 Weeks | Pharmacokinetics sequentially after dosing will be measured. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Treatment With Epicatechin Purified nutritional extract (-)-epicatechin 100mg/day orally for 8 weeks.
(-)-epicatechin: purified nutritional extract (-)-epicatechin 100mg/day orally for 8 weeks. | 7 |
| Total | 7 |
Baseline characteristics
| Characteristic | Treatment With Epicatechin |
|---|---|
| 6-Minute Walk Distance (m) | 372 meters STANDARD_DEVIATION 87.2 |
| Age, Continuous | 46.6 years STANDARD_DEVIATION 9.5 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 7 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Forced Vital Capacity (%) | 93.4 % STANDARD_DEVIATION 12.5 |
| Height (cm) | 179.2 centimeters STANDARD_DEVIATION 4.3 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 7 Participants |
| Region of Enrollment United States | 7 participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 7 Participants |
| Time to Climb 4 Stairs (s) | 7.4 seconds STANDARD_DEVIATION 7.4 |
| Time to Run 10m (s) | 7.9 seconds STANDARD_DEVIATION 7.9 |
| Time to Stand (s) | 5.5 seconds STANDARD_DEVIATION 2.3 |
| Weight (kg) | 83.2 kilograms STANDARD_DEVIATION 18.3 |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 6 |
| other Total, other adverse events | 6 / 6 |
| serious Total, serious adverse events | 0 / 6 |
Outcome results
Primary
Change From Baseline in Muscle Tissue PGC1alpha (AU) at 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.
Time frame: Baseline and 8 Weeks
Population: One participant sustained a fall at home that resulted in a minor injury just prior to the 8 week evaluation and declined undergoing the 8 week biopsy. Thus, only 6 participants were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment With Epicatechin | Change From Baseline in Muscle Tissue PGC1alpha (AU) at 8 Weeks | Baseline | 0.55 AU | Standard Deviation 0.3 |
| Treatment With Epicatechin | Change From Baseline in Muscle Tissue PGC1alpha (AU) at 8 Weeks | 8 Weeks | 0.86 AU | Standard Deviation 0.17 |
p-value: 0.0434t-test, 2 sided
Primary
Mean Change From Baseline in Cristae-associated Mitofillin Levels at 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.
Time frame: 8 weeks
Population: One participant sustained a fall at home that resulted in a minor injury just prior to the 8 week evaluation and declined undergoing the 8 week biopsy. Thus, only 6 participants were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment With Epicatechin | Mean Change From Baseline in Cristae-associated Mitofillin Levels at 8 Weeks | Baseline | 1.05 AU | Standard Deviation 0.36 |
| Treatment With Epicatechin | Mean Change From Baseline in Cristae-associated Mitofillin Levels at 8 Weeks | Week 8 | 1.33 AU | Standard Deviation 0.3 |
p-value: 0.0078t-test, 2 sided
Primary
Mean Change From Baseline in Muscle Tissue AMPK at 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).
Time frame: 8 weeks
Population: One participant sustained a fall at home that resulted in a minor injury just prior to the 8 week evaluation and declined undergoing the 8 week biopsy. Thus, only 6 participants were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment With Epicatechin | Mean Change From Baseline in Muscle Tissue AMPK at 8 Weeks | Baseline | 0.76 AU | Standard Deviation 0.48 |
| Treatment With Epicatechin | Mean Change From Baseline in Muscle Tissue AMPK at 8 Weeks | Week 8 | 1.06 AU | Standard Deviation 0.52 |
p-value: 0.0185t-test, 2 sided
Primary
Mean Change From Baseline in Muscle Tissue Dysferlin at 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).
Time frame: 8 weeks
Population: One participant sustained a fall at home that resulted in a minor injury just prior to the 8 week evaluation and declined undergoing the 8 week biopsy. Thus, only 6 participants were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment With Epicatechin | Mean Change From Baseline in Muscle Tissue Dysferlin at 8 Weeks | Baseline | 0.65 AU | Standard Deviation 0.26 |
| Treatment With Epicatechin | Mean Change From Baseline in Muscle Tissue Dysferlin at 8 Weeks | Week 8 | 0.91 AU | Standard Deviation 0.25 |
p-value: 0.0371t-test, 2 sided
Primary
Mean Change From Baseline in Muscle Tissue Follistatin at 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).
Time frame: 8 weeks
Population: One participant sustained a fall at home that resulted in a minor injury just prior to the 8 week evaluation and declined undergoing the 8 week biopsy. Thus, only 6 participants were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment With Epicatechin | Mean Change From Baseline in Muscle Tissue Follistatin at 8 Weeks | Baseline | 0.83 AU | Standard Deviation 0.37 |
| Treatment With Epicatechin | Mean Change From Baseline in Muscle Tissue Follistatin at 8 Weeks | Week 8 | 1.11 AU | Standard Deviation 0.36 |
p-value: 0.0025t-test, 2 sided
Primary
Mean Change From Baseline in Muscle Tissue LKB1 at 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) .
Time frame: 8 weeks
Population: One participant sustained a fall at home that resulted in a minor injury just prior to the 8 week evaluation and declined undergoing the 8 week biopsy. Thus, only 6 participants were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment With Epicatechin | Mean Change From Baseline in Muscle Tissue LKB1 at 8 Weeks | Baseline | 0.67 AU | Standard Deviation 0.17 |
| Treatment With Epicatechin | Mean Change From Baseline in Muscle Tissue LKB1 at 8 Weeks | Week 8 | 0.88 AU | Standard Deviation 0.24 |
p-value: 0.0434t-test, 2 sided
Primary
Mean Change From Baseline in Muscle Tissue MEF2a at 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).
Time frame: 8 weeks
Population: One participant sustained a fall at home that resulted in a minor injury just prior to the 8 week evaluation and declined undergoing the 8 week biopsy. Thus, only 6 participants were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment With Epicatechin | Mean Change From Baseline in Muscle Tissue MEF2a at 8 Weeks | Baseline | 0.63 AU | Standard Deviation 0.15 |
| Treatment With Epicatechin | Mean Change From Baseline in Muscle Tissue MEF2a at 8 Weeks | Week 8 | 0.78 AU | Standard Deviation 0.12 |
p-value: 0.0182t-test, 2 sided
Primary
Mean Change From Baseline in Muscle Tissue Myf5 at 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).
Time frame: 8 weeks
Population: One participant sustained a fall at home that resulted in a minor injury just prior to the 8 week evaluation and declined undergoing the 8 week biopsy. Thus, only 6 participants were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment With Epicatechin | Mean Change From Baseline in Muscle Tissue Myf5 at 8 Weeks | Baseline | 1.07 AU | Standard Deviation 0.08 |
| Treatment With Epicatechin | Mean Change From Baseline in Muscle Tissue Myf5 at 8 Weeks | Week 8 | 1.232 AU | Standard Deviation 0.13 |
p-value: 0.0238Wilcoxon (Mann-Whitney)
Primary
Mean Change From Baseline in Muscle Tissue MyoD at 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).
Time frame: 8 weeks
Population: One participant sustained a fall at home that resulted in a minor injury just prior to the 8 week evaluation and declined undergoing the 8 week biopsy. Thus, only 6 participants were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment With Epicatechin | Mean Change From Baseline in Muscle Tissue MyoD at 8 Weeks | Baseline | 0.87 AU | Standard Deviation 0.34 |
| Treatment With Epicatechin | Mean Change From Baseline in Muscle Tissue MyoD at 8 Weeks | Week 8 | 1.21 AU | Standard Deviation 0.34 |
p-value: 0.0321t-test, 2 sided
Primary
Mean Change From Baseline in Muscle Tissue Myogenin at 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).
Time frame: 8 weeks
Population: One participant sustained a fall at home that resulted in a minor injury just prior to the 8 week evaluation and declined undergoing the 8 week biopsy. Thus, only 6 participants were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment With Epicatechin | Mean Change From Baseline in Muscle Tissue Myogenin at 8 Weeks | Baseline | 0.89 AU | Standard Deviation 0.18 |
| Treatment With Epicatechin | Mean Change From Baseline in Muscle Tissue Myogenin at 8 Weeks | Week 8 | 1.20 AU | Standard Deviation 0.19 |
p-value: 0.031t-test, 2 sided
Primary
Mean Change From Baseline in Muscle Tissue Myostatin at 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).
Time frame: 8 weeks
Population: One participant sustained a fall at home that resulted in a minor injury just prior to the 8 week evaluation and declined undergoing the 8 week biopsy. Thus, only 6 participants were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment With Epicatechin | Mean Change From Baseline in Muscle Tissue Myostatin at 8 Weeks | Baseline | 0.79 AU | Standard Deviation 0.3 |
| Treatment With Epicatechin | Mean Change From Baseline in Muscle Tissue Myostatin at 8 Weeks | Week 8 | 0.51 AU | Standard Deviation 0.25 |
p-value: 0.0082t-test, 2 sided
Primary
Mean Change From Baseline in Muscle Tissue Utrophin at 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).
Time frame: 8 weeks
Population: One participant sustained a fall at home that resulted in a minor injury just prior to the 8 week evaluation and declined undergoing the 8 week biopsy. Thus, only 6 participants were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment With Epicatechin | Mean Change From Baseline in Muscle Tissue Utrophin at 8 Weeks | Baseline | 0.63 AU | Standard Deviation 0.27 |
| Treatment With Epicatechin | Mean Change From Baseline in Muscle Tissue Utrophin at 8 Weeks | Week 8 | 0.8 AU | Standard Deviation 0.19 |
p-value: 0.0257t-test, 2 sided
Secondary
Change From Baseline in 6-Minute Walk Distance at 8 Weeks
Muscle function will be assessed by measuring the 6-minute walk distance
Time frame: Baseline and 8 Weeks
Population: One participant did not complete 8 Week exercise testing due to unrelated injury.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment With Epicatechin | Change From Baseline in 6-Minute Walk Distance at 8 Weeks | 11.2 meters | Standard Error 16.6 |
p-value: 0.5Mixed Models Analysis
Secondary
Change From Baseline in Elbow Flexion at 8 Weeks
Elbow flexion will be assessed using an isokinetic dynamometer.
Time frame: Baseline and 8 Weeks
Population: One participant did not participate in the strength testing due to the advanced level of the disease.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment With Epicatechin | Change From Baseline in Elbow Flexion at 8 Weeks | Baseline | 27.7 pounds | Standard Error 11.1 |
| Treatment With Epicatechin | Change From Baseline in Elbow Flexion at 8 Weeks | Change from Baseline at 8 Weeks | 5.33 pounds | Standard Error 3.79 |
p-value: 0.159Mixed Models Analysis
Secondary
Change From Baseline in Knee Extension at 8 Weeks
Knee extension will be assessed using an isokinetic dynamometer.
Time frame: Baseline and 8 Weeks
Population: One participant did not participate in the strength testing due to the advanced level of the disease.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment With Epicatechin | Change From Baseline in Knee Extension at 8 Weeks | Baseline | 48.1 pounds | Standard Error 42.6 |
| Treatment With Epicatechin | Change From Baseline in Knee Extension at 8 Weeks | Change from Baseline at 8 Weeks | -1.82 pounds | Standard Error 2.51 |
p-value: 0.47Mixed Models Analysis
Secondary
Change From Baseline in Stand From Supine at 8 Weeks
Muscle burst function will be assessed by time function tests.
Time frame: Baseline and 8 Weeks
Population: 1 participant was unable to perform the assessment due to his advanced disease.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment With Epicatechin | Change From Baseline in Stand From Supine at 8 Weeks | Baseline | 9.621667 seconds | Standard Deviation 10.19124 |
| Treatment With Epicatechin | Change From Baseline in Stand From Supine at 8 Weeks | Week 8 | 12.145 seconds | Standard Deviation 10.12084 |
Secondary
-(-)Epicatechin Pharmacokinetics
Pharmacokinetics sequentially after dosing will be measured.
Time frame: 8 Weeks
Population: Sponsor did not perform PK analysis (samples were discarded) based on availability of other published data and switched to alternative enantiomer of epicatechin in subsequent studies.
Secondary
Participants With Abnormal Treatment-Related Laboratory Assessments
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.
Time frame: 8 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment With Epicatechin | Participants With Abnormal Treatment-Related Laboratory Assessments | 0 Participants |