TY - JOUR
T1 - Efficacy and Safety of Vamorolone vs Placebo and Prednisone among Boys with Duchenne Muscular Dystrophy
T2 - A Randomized Clinical Trial
AU - Guglieri, Michela
AU - Clemens, Paula R.
AU - Perlman, Seth J.
AU - Smith, Edward C.
AU - Horrocks, Iain
AU - Finkel, Richard S.
AU - Mah, Jean K.
AU - Deconinck, Nicolas
AU - Goemans, Nathalie
AU - Haberlova, Jana
AU - Straub, Volker
AU - Mengle-Gaw, Laurel J.
AU - Schwartz, Benjamin D.
AU - Harper, Amy D.
AU - Shieh, Perry B.
AU - De Waele, Liesbeth
AU - Castro, Diana
AU - Yang, Michelle L.
AU - Ryan, Monique M.
AU - McDonald, Craig M.
AU - Tulinius, Mar
AU - Webster, Richard
AU - McMillan, Hugh J.
AU - Kuntz, Nancy L.
AU - Rao, Vashmi K.
AU - Baranello, Giovanni
AU - Spinty, Stefan
AU - Childs, Anne Marie
AU - Sbrocchi, Annie M.
AU - Selby, Kathryn A.
AU - Monduy, Migvis
AU - Nevo, Yoram
AU - Vilchez-Padilla, Juan J.
AU - Nascimento-Osorio, Andres
AU - Niks, Erik H.
AU - De Groot, Imelda J.M.
AU - Katsalouli, Marina
AU - James, Meredith K.
AU - Van Den Anker, Johannes
AU - Damsker, Jesse M.
AU - Ahmet, Alexandra
AU - Ward, Leanne M.
AU - Jaros, Mark
AU - Shale, Phil
AU - Dang, Utkarsh J.
AU - Hoffman, Eric P.
N1 - Funding Information:
reported receiving clinical trial and grant support from ReveraGen; grants from the European Commission and the National Institutes of Health; speaker honoraria from Sarepta Therapeutics; serving as principal investigator of a clinical trial of Duchenne muscular dystrophy from Sarepta Therapeutics, Pfizer, Santhera, and Italfarmaco; serving on the advisory board for Pfizer (honoraria
Funding Information:
Funding/Support: This work was funded by the
Funding Information:
ReveraGen and AGADA Biosciences; grants from the National Institutes of Health and the European Commission; being a board member of TRiNDS outside the submitted work; and having a patent for ES2744879T3 owned by ReveraGen. No other disclosures were reported.
Publisher Copyright:
© 2022 American Medical Association. All rights reserved.
PY - 2022/10
Y1 - 2022/10
N2 - 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.
AB - 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.
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U2 - 10.1001/jamaneurol.2022.2480
DO - 10.1001/jamaneurol.2022.2480
M3 - Article
C2 - 36036925
AN - SCOPUS:85137319255
SN - 2168-6149
VL - 79
SP - 1005
EP - 1014
JO - JAMA Neurology
JF - JAMA Neurology
IS - 10
ER -