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Efficacy and Safety of Vamorolone vs Placebo and Prednisone Among Boys With Duchenne Muscular Dystrophy: A Randomized Clinical Trial
M. Guglieri, PR. Clemens, SJ. Perlman, EC. Smith, I. Horrocks, RS. Finkel, JK. Mah, N. Deconinck, N. Goemans, J. Haberlova, V. Straub, LJ. Mengle-Gaw, BD. Schwartz, AD. Harper, PB. Shieh, L. De Waele, D. Castro, ML. Yang, MM. Ryan, CM. McDonald,...
Language English Country United States
Document type Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't
- MeSH
- Adrenal Insufficiency * chemically induced drug therapy MeSH
- Adrenocorticotropic Hormone therapeutic use MeSH
- Anti-Inflammatory Agents adverse effects MeSH
- Biomarkers MeSH
- Muscular Dystrophy, Duchenne * drug therapy MeSH
- Double-Blind Method MeSH
- Adrenal Cortex Hormones MeSH
- Hydrocortisone therapeutic use MeSH
- Quality of Life MeSH
- Humans MeSH
- Prednisone therapeutic use MeSH
- Child, Preschool MeSH
- Treatment Outcome MeSH
- Check Tag
- Humans MeSH
- Male MeSH
- Child, Preschool MeSH
- Publication type
- Journal Article MeSH
- Multicenter Study MeSH
- Research Support, Non-U.S. Gov't MeSH
- Randomized Controlled Trial MeSH
- Research Support, N.I.H., Extramural MeSH
IMPORTANCE: Corticosteroidal anti-inflammatory drugs are widely prescribed but long-term use shows adverse effects that detract from patient quality of life. OBJECTIVE: To determine if vamorolone, a structurally unique dissociative steroidal anti-inflammatory drug, is able to retain efficacy while reducing safety concerns with use in Duchenne muscular dystrophy (DMD). DESIGN, SETTING, AND PARTICIPANTS: Randomized, double-blind, placebo- and prednisone-controlled 24-week clinical trial, conducted from June 29, 2018, to February 24, 2021, with 24 weeks of follow-up. This was a multicenter study (33 referral centers in 11 countries) and included boys 4 to younger than 7 years of age with genetically confirmed DMD not previously treated with corticosteroids. INTERVENTIONS: The study included 4 groups: placebo; prednisone, 0.75 mg/kg per day; vamorolone, 2 mg/kg per day; and vamorolone, 6 mg/kg per day. MAIN OUTCOMES AND MEASURES: Study outcomes monitored (1) efficacy, which included motor outcomes (primary: time to stand from supine velocity in the vamorolone, 6 mg/kg per day, group vs placebo; secondary: time to stand from supine velocity [vamorolone, 2 mg/kg per day], 6-minute walk distance, time to run/walk 10 m [vamorolone, 2 and 6 mg/kg per day]; exploratory: NorthStar Ambulatory Assessment, time to climb 4 stairs) and (2) safety, which included growth, bone biomarkers, and a corticotropin (ACTH)-challenge test. RESULTS: Among the 133 boys with DMD enrolled in the study (mean [SD] age, 5.4 [0.9] years), 121 were randomly assigned to treatment groups, and 114 completed the 24-week treatment period. The trial met the primary end point for change from baseline to week 24 time to stand velocity for vamorolone, 6 mg/kg per day (least-squares mean [SE] velocity, 0.05 [0.01] m/s vs placebo -0.01 [0.01] m/s; 95% CI, 0.02-0.10; P = .002) and the first 4 sequential secondary end points: time to stand velocity, vamorolone, 2 mg/kg per day, vs placebo; 6-minute walk test, vamorolone, 6 mg/kg per day, vs placebo; 6-minute walk test, vamorolone, 2 mg/kg per day, vs placebo; and time to run/walk 10 m velocity, vamorolone, 6 mg/kg per day, vs placebo. Height percentile declined in prednisone-treated (not vamorolone-treated) participants (change from baseline [SD]: prednisone, -1.88 [8.81] percentile vs vamorolone, 6 mg/kg per day, +3.86 [6.16] percentile; P = .02). Bone turnover markers declined with prednisone but not with vamorolone. Boys with DMD at baseline showed low ACTH-stimulated cortisol and high incidence of adrenal insufficiency. All 3 treatment groups led to increased adrenal insufficiency. CONCLUSIONS AND RELEVANCE: In this pivotal randomized clinical trial, vamorolone was shown to be effective and safe in the treatment of boys with DMD over a 24-week treatment period. Vamorolone may be a safer alternative than prednisone in this disease, in which long-term corticosteroid use is the standard of care. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03439670.
A Kyriakou Children's Hospital Athens Greece
Alberta Children's Hospital Research Institute University of Calgary Calgary Alberta Canada
Alder Hey Children's NHS Foundation Trust Liverpool United Kingdom
BC Children's Hospital Research Institute Vancouver British Columbia Canada
Carleton University Ottawa Ontario Canada
Children's Hospital of Eastern Ontario Research Institute Ottawa Ontario Canada
Children's National Medical Center Washington DC
Department of Development and Regeneration KU Leuven Leuven Belgium
Department of Paediatric Neurology University Hospitals Leuven Leuven Belgium
Duke University School of Medicine Durham North Carolina
Hospital Quirónsalud Valencia Valencia Spain
Kids Neuroscience Centre The Children's Hospital at Westmead Westmead Australia
Leeds Teaching Hospitals Trust Leeds United Kingdom
Leiden University Medical Center Leiden the Netherlands
Montreal Children's Hospital Montreal Quebec Canada
Murdoch Children's Research Institute Melbourne Australia
Nemours Children's Hospital Orlando Florida
Neuromuscular Reference Center UZ Ghent Ghent Belgium
Neuropaediatrics Department Institut de Recerca Pediàtrica Hospital Sant Joan de Déu Barcelona Spain
Queen Silvia Children's Hospital Gothenburg Sweden
ReveraGen BioPharma Rockville Maryland
Richmond Children's Hospital Richmond Virginia
Robert H Lurie Children's Hospital Chicago Illinois
Royal Hospital for Children Glasgow United Kingdom
Schneider Children's Medical Center Tel Aviv University Tel Aviv Israel
St Jude Children's Research Hospital Memphis Tennessee
Summit Analytical Denver Colorado
The Camden Group St Louis Missouri
The Royal Children's Hospital Melbourne Australia
UCLA Medical School Los Angeles California
UMC St Radboud Nijmegen the Netherlands
University of California Davis Sacramento
University of Colorado School of Medicine Children's Hospital Colorado Aurora
University of Ottawa Ottawa Ontario Canada
University of Pittsburgh School of Medicine Pittsburgh Pennsylvania
References provided by Crossref.org
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