Vasodilator and Exercise Study for DMD (VASO-REx)

Official title

Vasodilators and Exercise as Adjuvant Therapy for Duchenne Muscular Dystrophy (VASO-REx Study)

Overview

Examining two strategies as potential adjuvant therapies for Duchenne muscular dystrophy (DMD); aerobic exercise training (to induce adaptations in skeletal muscle and improve cardiovascular health) and tadalafil, an FDA-approved vasodilator (to optimize blood flow and muscle perfusion which is impaired and often overlooked in DMD). Target: improved muscle function, vascular health, and DMD treatment.

Detailed description

Duchenne muscular dystrophy (DMD) is characterized by rapid muscle deterioration, mitochondrial and vascular impairments, resulting in premature loss of ambulation and mortality. Disease-modifying therapeutics are emerging and although they are expected to improve muscle function and daily activity in boys with DMD, most are not designed to correct the vascular impairment. This impairment is due to the lack of restoration of neuronal nitric oxide synthase signaling, which is crucial for vasodilation during and after exercise. The investigators believe limitations in study design were responsible for the lack of efficacy. Therefore, this study combines tadalafil with aerobic exercise to necessitate increased blood flow and activate the drug.

This Exploratory Clinical Trial will assess two potential adjuvant therapies for ambulatory boys with DMD (6 years and older): 1) aerobic exercise training and 2) tadalafil, an FDA-approved vasodilator drug. Preclinical and clinical data, including recent findings from the principal investigator's lab, support the use of these strategies and their potential to benefit muscle perfusion, fatigue, and quality of life.

The study will first test for drug responsiveness (increase in muscle oxygenation) after a single dose. Drug-responsive boys with DMD will be randomized to a 6-month intervention of daily tadalafil or placebo, combined with structured cycle exercise training. Participants will receive exercise-related equipment for use at home and be monitored by the research team via video. The study will quantify the intervention's impact on vascular impairment, muscle pathophysiology (inflammation, fat accumulation, mitochondrial dysfunction), exertional fatigue, and cycling performance.

Our findings are expected to yield:

1. Criteria to identify DMD patients most likely to benefit from tadalafil as adjuvant therapy. 2. Evidence of a powerful synergy between drug impact and exercise training in DMD.

Interventions

• Drug Tadalafil
  Patients will be given either the intervention medication or a placebo (double-blinded, randomized trial) and will be asked to take the medication every day for 6 months in conjunction with weekly exercise sessions.
• Drug Placebo
  Patients will be given either the intervention medication or a placebo (double-blinded, randomized trial) and will be asked to take the medication every day for 6 months in conjunction with weekly exercise sessions.
• Other Exercise Training
  The home-based cycling exercise training program is designed to improve muscle strength and endurance. Participants will engage in individualized exercise sessions up to four times per week, lasting up to 40 minutes each. Live video and heart rate monitoring will ensure proper exercise performance and allow for adjustments to the program throughout the study. The participants will receive the exercise equipment for use at home.

Primary outcome measures

• Vascular responsiveness after muscle contraction to a single dose of tadalafil. [Time frame: up to 4 weeks after the completion of Visits 1 and 2 of Aim 1.]
• Cycling time to fatigue [Time frame: Baseline and 6 month follow-up visits of Aim 2.]

Secondary outcome measures (12)

• Quadriceps muscle Fat Fraction [Time frame: Aim 1 and Aim 2 (baseline and 6 month follow-up)]
• Metabolic recovery [Time frame: Through study completion, an average of 3 years.]
• cardiopulmonary exercise testing (CPET) - Peak aerobic capacity (VO2max) [Time frame: Through study completion, an average of 3 years.]
• cardiopulmonary exercise testing (CPET) - Minute Ventilation (VE) [Time frame: Through study completion, an average of 3 years.]
• cardiopulmonary exercise testing (CPET) - Ventilatory Equivalent for Oxygen (VE/VO2) [Time frame: Through study completion, an average of 3 years.]
• cardiopulmonary exercise testing (CPET) - Gas Exchange Threshold (GET) [Time frame: Through study completion, an average of 3 years.]
• cardiopulmonary exercise testing (CPET) - Workload at Anaerobic Threshold (W at AT) [Time frame: Through study completion, an average of 3 years.]
• The 100-meter timed test (100m) [Time frame: Through study completion, an average of 3 years.]
• the North Star Ambulatory Assessment (NSAA) [Time frame: Through study completion, an average of 3 years.]
• The 4-stair climb [Time frame: Through study completion, an average of 3 years.]
• The Physical activity questionnaire (PAQ-C) [Time frame: Through study completion, an average of 3 years.]
• Pulmonary function testing - vital capacity (FVC) [Time frame: Through study completion, an average of 3 years.]

Eligibility criteria

Inclusion criteria

• Diagnosis of DMD confirmed by genetic report
• Minimum entry age of 6.0 years old
• Ambulatory
• On stable glucocorticoid regimen (for > 3 months)

Exclusion criteria

• Contraindication to a Magnetic resonance Imaging examination (e.g. severe claustrophobia, magnetic implants, unable/unwilling to perform test)
• Presence of unstable medical problems, including severe cardiomyopathy, left ventricular ejection fraction <45%, cardiac conduction abnormalities as evidenced on ECG, uncontrolled seizure disorder, uncontrolled hypo or hypertension
• Presence of a secondary condition that impacts muscle function or muscle metabolism (e.g., myasthenia gravis, endocrine disorder, mitochondrial disease)
• Presence of a secondary condition leading to developmental delay or impaired motor control (e.g., cerebral palsy) or previous history of unprovoked rhabdomyolysis
• Contraindications to phosphodiesterase 5 inhibitors (use of nitrates, alpha-adrenergic blockers, other phosphodiesterase 5 inhibitors) or other medications known to modulate blood flow or muscle metabolism
• Participation in currently approved FDA trials or other investigational clinical trials during the period of the study

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

United States · 1 center

• University of Florida Clinical and Translational Research Building — Gainesville

Publications

• Lopez C, Taivassalo T, Berru MG, Saavedra A, Rasmussen HC, Batra A, Arora H, Roetzheim AM, Walter GA, Vandenborne K, Forbes SC. Postcontractile blood oxygenation level-dependent (BOLD) response in Duchenne muscular dystrophy. J Appl Physiol (1985). 2021 Jul 1;131(1):83-94. doi: 10.1152/japplphysiol.00634.2020. Epub 2021 May 20. PMID 34013753
• Mendell JR, Sahenk Z, Lehman K, Nease C, Lowes LP, Miller NF, Iammarino MA, Alfano LN, Nicholl A, Al-Zaidy S, Lewis S, Church K, Shell R, Cripe LH, Potter RA, Griffin DA, Pozsgai E, Dugar A, Hogan M, Rodino-Klapac LR. Assessment of Systemic Delivery of rAAVrh74.MHCK7.micro-dystrophin in Children With Duchenne Muscular Dystrophy: A Nonrandomized Controlled Trial. JAMA Neurol. 2020 Sep 1;77(9):1122- PMID 32539076
• Harper SQ. Molecular dissection of dystrophin identifies the docking site for nNOS. Proc Natl Acad Sci U S A. 2013 Jan 8;110(2):387-8. doi: 10.1073/pnas.1220256110. Epub 2012 Dec 31. No abstract available. PMID 23277550
• Duan D. Systemic AAV Micro-dystrophin Gene Therapy for Duchenne Muscular Dystrophy. Mol Ther. 2018 Oct 3;26(10):2337-2356. doi: 10.1016/j.ymthe.2018.07.011. Epub 2018 Jul 17. PMID 30093306
• Percival JM, Adamo CM, Beavo JA, Froehner SC. Evaluation of the therapeutic utility of phosphodiesterase 5A inhibition in the mdx mouse model of duchenne muscular dystrophy. Handb Exp Pharmacol. 2011;(204):323-44. doi: 10.1007/978-3-642-17969-3_14. PMID 21695647
• Thomas GD. Functional muscle ischemia in Duchenne and Becker muscular dystrophy. Front Physiol. 2013 Dec 18;4:381. doi: 10.3389/fphys.2013.00381. PMID 24391598
• Kobayashi YM, Rader EP, Crawford RW, Iyengar NK, Thedens DR, Faulkner JA, Parikh SV, Weiss RM, Chamberlain JS, Moore SA, Campbell KP. Sarcolemma-localized nNOS is required to maintain activity after mild exercise. Nature. 2008 Nov 27;456(7221):511-5. doi: 10.1038/nature07414. Epub 2008 Oct 26. PMID 18953332
• Sheffield-Moore M, Wiktorowicz JE, Soman KV, Danesi CP, Kinsky MP, Dillon EL, Randolph KM, Casperson SL, Gore DC, Horstman AM, Lynch JP, Doucet BM, Mettler JA, Ryder JW, Ploutz-Snyder LL, Hsu JW, Jahoor F, Jennings K, White GR, McCammon SD, Durham WJ. Sildenafil increases muscle protein synthesis and reduces muscle fatigue. Clin Transl Sci. 2013 Dec;6(6):463-8. doi: 10.1111/cts.12121. Epub 2013 Oc PMID 24330691

Identifiers

NCT: NCT06290713 · IRB202301491 · 1R21AR079755-01 · PRO00050023

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗