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.

Alberta Children's Hospital Research Institute University of Calgary Calgary Alberta Canada

Alder Hey Children's NHS Foundation Trust Liverpool United Kingdom

Ann and Robert H Lurie Children's Hospital Chicago Illinois

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

Department of Pharmaceutical Sciences School of Pharmacy and Pharmaceutical Sciences Binghamton University State University of New York Binghamton

Duke University School of Medicine Durham North Carolina

Hospital Quirónsalud Valencia Valencia Spain

John Walton Muscular Dystrophy Research Centre Newcastle Hospitals NHS Foundation Trust and Newcastle University Newcastle United Kingdom

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 Centre Department of Pediatric Neurology Motol University Hospital 2nd Medical School Charles University Prague Czech Republic

Neuromuscular Reference Center UZ Ghent Ghent Belgium

Neuropaediatrics Department Institut de Recerca Pediàtrica Hospital Sant Joan de Déu Barcelona Spain

P and A Kyriakou Children's Hospital Athens Greece

Queen Silvia Children's Hospital Gothenburg Sweden

ReveraGen BioPharma Rockville Maryland

Richmond Children's Hospital Richmond Virginia

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 Dubowitz Neuromuscular Centre National Institute for Health Research Great Ormond Street Hospital Biomedical Research Centre Great Ormond Street Institute of Child Health University College London London United Kingdom

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

University of Washington School of Medicine Seattle

UT Southwestern Medical Center Dallas Texas

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Efficacy and Safety of Vamorolone Over 48 Weeks in Boys With Duchenne Muscular Dystrophy: A Randomized Controlled Trial

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ClinicalTrials.gov
NCT03439670