A Single Center Dose Ranging Pilot Study of (+)-Epicatechin in Non-ambulatory Adolescents With Duchenne Muscular Dystrophy and Pre-symptomatic Cardiac Dysfunction
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 15
- 试验地点
- 1
- 主要终点
- Laboratory Outcome: Absolute Values of Follistatin (AU) Measured by ELISA
研究概览
简要总结
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 8 Years 至 17 Years（Child）
- 性别
- Male
- 接受健康志愿者
- 否
入选标准
- •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).
排除标准
- •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.
研究组 & 干预措施
Cohort 1
8-weeks open-label (+)- Epicatechin at 25mg/day twice per day,
干预措施: (+)- Epicatechin (Drug)
Cohort 2
8-weeks open-label (+)- Epicatechin at 25mg/day three times per day
干预措施: (+)- Epicatechin (Drug)
Cohort 3
8-weeks open-label (+)- Epicatechin at 75mg/day at two times per day
干预措施: (+)- Epicatechin (Drug)
结局指标
主要结局
Laboratory Outcome: Absolute Values of Follistatin (AU) Measured by ELISA
时间窗: 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
时间窗: Baseline, Week 4 and Week 8
Evaluation of follistatin:myostatin ratio from plasma samples.
Pharmacokinetics Outcome: Absolute Values of (+)-Epicatechin Serum Concentration, Pre-dose (Trough) and 2 Hours Post-dose (Peak)
时间窗: Week 4
Pharmacokinetic evaluation for dose-response evaluation.
Safety: Number of Participants Who Experienced Treatment-Related Laboratory Abnormalities
时间窗: 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.
Clinical Outcome: Mean Percent of Baseline Cardiac Ejection Fraction by MRI
时间窗: 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.
Laboratory Outcome: Absolute Values of Nitric Oxide (AU) Measured by ELISA
时间窗: 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
时间窗: 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 Myostatin (AU) Measured by ELISA
时间窗: Baseline, Week 4, Week 8
Proteomics evaluation of plasma biomarkers to confirm intervention-responsive pathophysiological pathways, using enzyme-linked immunosorbent assay (ELISA).
次要结局
- Clinical Outcome: Total Score Using Performance of the Upper Limb Assessment(Baseline, Week 4, 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)
- Clinical Outcome: Percent of Normalized Upper Extremity Reachable Surface Area at Week 4 and Week 8(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)
研究者
Craig McDonald, MD
Professor and Chair of Department of Physical Rehabilitation
University of California, Davis