drugset / Trial / NCT03439670
A Study to Assess the Efficacy and Safety of Vamorolone in Boys With Duchenne Muscular Dystrophy (DMD)
Phase 2
Completed
121 enrolled
ReveraGen BioPharma, Inc.
Cooperative International Neuromuscular Research Group · collabEuropean Union · collabNewcastle University · collabUniversity of Pittsburgh · collab
RandomizedParallel-groupQuadruple-blindTreatment
Summary
Brief Summary: This Phase IIb study is a randomized, double-blind, parallel group, placebo and active-controlled study to evaluate the efficacy, safety, PD, and population PK of vamorolone administered orally at daily doses of 2.0 mg/kg and 6.0 mg/kg versus prednisone 0.75 mg/kg/day and placebo over a Treatment Period of 24 weeks, and to evaluate persistence of effect over a Treatment Period of 48 weeks in ambulant boys ages 4 to \<7 years with DMD.
Timeline
- Start
- 2018-06-29
- Primary completion
- 2021-02-23
- Completion
- 2021-08-19
Publications
- Background Mah JK, Korngut L, Dykeman J, Day L, Pringsheim T, Jette N. A systematic review and meta-analysis on the epidemiology of Duchenne and Becker muscular dystrophy. Neuromuscul Disord. 2014 Jun;24(6):482-91. doi: 10.1016/j.nmd.2014.03.008. Epub 2014 Mar 22.
- Background Hoffman EP, Brown RH Jr, Kunkel LM. Dystrophin: the protein product of the Duchenne muscular dystrophy locus. Cell. 1987 Dec 24;51(6):919-28. doi: 10.1016/0092-8674(87)90579-4.
- Background Evans NP, Misyak SA, Robertson JL, Bassaganya-Riera J, Grange RW. Immune-mediated mechanisms potentially regulate the disease time-course of duchenne muscular dystrophy and provide targets for therapeutic intervention. PM R. 2009 Aug;1(8):755-68. doi: 10.1016/j.pmrj.2009.04.010.
- Background Kumar A, Boriek AM. Mechanical stress activates the nuclear factor-kappaB pathway in skeletal muscle fibers: a possible role in Duchenne muscular dystrophy. FASEB J. 2003 Mar;17(3):386-96. doi: 10.1096/fj.02-0542com.
- Background Acharyya S, Villalta SA, Bakkar N, Bupha-Intr T, Janssen PM, Carathers M, Li ZW, Beg AA, Ghosh S, Sahenk Z, Weinstein M, Gardner KL, Rafael-Fortney JA, Karin M, Tidball JG, Baldwin AS, Guttridge DC. Interplay of IKK/NF-kappaB signaling in macrophages and myofibers promotes muscle degeneration in Duchenne muscular dystrophy. J Clin Invest. 2007 Apr;117(4):889-901. doi: 10.1172/JCI30556. Epub 2007 Mar 22.
- Background Dogra C, Changotra H, Wergedal JE, Kumar A. Regulation of phosphatidylinositol 3-kinase (PI3K)/Akt and nuclear factor-kappa B signaling pathways in dystrophin-deficient skeletal muscle in response to mechanical stretch. J Cell Physiol. 2006 Sep;208(3):575-85. doi: 10.1002/jcp.20696.
- Background Pahl HL. Activators and target genes of Rel/NF-kappaB transcription factors. Oncogene. 1999 Nov 22;18(49):6853-66. doi: 10.1038/sj.onc.1203239.
- Background Spencer MJ, Montecino-Rodriguez E, Dorshkind K, Tidball JG. Helper (CD4(+)) and cytotoxic (CD8(+)) T cells promote the pathology of dystrophin-deficient muscle. Clin Immunol. 2001 Feb;98(2):235-43. doi: 10.1006/clim.2000.4966.
- Background Spencer MJ, Tidball JG. Do immune cells promote the pathology of dystrophin-deficient myopathies? Neuromuscul Disord. 2001 Sep;11(6-7):556-64. doi: 10.1016/s0960-8966(01)00198-5.
- Background Malik V, Rodino-Klapac LR, Mendell JR. Emerging drugs for Duchenne muscular dystrophy. Expert Opin Emerg Drugs. 2012 Jun;17(2):261-77. doi: 10.1517/14728214.2012.691965.
- Background Reeves EKM, Hoffman EP, Nagaraju K, Damsker JM, McCall JM. VBP15: preclinical characterization of a novel anti-inflammatory delta 9,11 steroid. Bioorg Med Chem. 2013 Apr 15;21(8):2241-2249. doi: 10.1016/j.bmc.2013.02.009. Epub 2013 Feb 18.
- Background Bushby K, Finkel R, Birnkrant DJ, Case LE, Clemens PR, Cripe L, Kaul A, Kinnett K, McDonald C, Pandya S, Poysky J, Shapiro F, Tomezsko J, Constantin C; DMD Care Considerations Working Group. Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and pharmacological and psychosocial management. Lancet Neurol. 2010 Jan;9(1):77-93. doi: 10.1016/S1474-4422(09)70271-6. Epub 2009 Nov 27.
- Background Pane M, Mazzone ES, Sivo S, Sormani MP, Messina S, D'Amico A, Carlesi A, Vita G, Fanelli L, Berardinelli A, Torrente Y, Lanzillotta V, Viggiano E, D Ambrosio P, Cavallaro F, Frosini S, Barp A, Bonfiglio S, Scalise R, De Sanctis R, Rolle E, Graziano A, Magri F, Palermo C, Rossi F, Donati MA, Sacchini M, Arnoldi MT, Baranello G, Mongini T, Pini A, Battini R, Pegoraro E, Previtali S, Bruno C, Politano L, Comi GP, Bertini E, Mercuri E. Long term natural history data in ambulant boys with Duchenne muscular dystrophy: 36-month changes. PLoS One. 2014 Oct 1;9(10):e108205. doi: 10.1371/journal.pone.0108205. eCollection 2014.
- Background Manzur AY, Kuntzer T, Pike M, Swan A. Glucocorticoid corticosteroids for Duchenne muscular dystrophy. Cochrane Database Syst Rev. 2008 Jan 23;(1):CD003725. doi: 10.1002/14651858.CD003725.pub3.
- Background Heier CR, Damsker JM, Yu Q, Dillingham BC, Huynh T, Van der Meulen JH, Sali A, Miller BK, Phadke A, Scheffer L, Quinn J, Tatem K, Jordan S, Dadgar S, Rodriguez OC, Albanese C, Calhoun M, Gordish-Dressman H, Jaiswal JK, Connor EM, McCall JM, Hoffman EP, Reeves EK, Nagaraju K. VBP15, a novel anti-inflammatory and membrane-stabilizer, improves muscular dystrophy without side effects. EMBO Mol Med. 2013 Oct;5(10):1569-85. doi: 10.1002/emmm.201302621. Epub 2013 Sep 9.
- Background Damsker JM, Dillingham BC, Rose MC, Balsley MA, Heier CR, Watson AM, Stemmy EJ, Jurjus RA, Huynh T, Tatem K, Uaesoontrachoon K, Berry DM, Benton AS, Freishtat RJ, Hoffman EP, McCall JM, Gordish-Dressman H, Constant SL, Reeves EK, Nagaraju K. VBP15, a glucocorticoid analogue, is effective at reducing allergic lung inflammation in mice. PLoS One. 2013 May 7;8(5):e63871. doi: 10.1371/journal.pone.0063871. Print 2013.
- Background Dillingham BC, Knoblach SM, Many GM, Harmon BT, Mullen AM, Heier CR, Bello L, McCall JM, Hoffman EP, Connor EM, Nagaraju K, Reeves EKM, Damsker JM. VBP15, a novel anti-inflammatory, is effective at reducing the severity of murine experimental autoimmune encephalomyelitis. Cell Mol Neurobiol. 2015 Apr;35(3):377-387. doi: 10.1007/s10571-014-0133-y. Epub 2014 Nov 13.
- Background Dadgar S, Wang Z, Johnston H, Kesari A, Nagaraju K, Chen YW, Hill DA, Partridge TA, Giri M, Freishtat RJ, Nazarian J, Xuan J, Wang Y, Hoffman EP. Asynchronous remodeling is a driver of failed regeneration in Duchenne muscular dystrophy. J Cell Biol. 2014 Oct 13;207(1):139-58. doi: 10.1083/jcb.201402079.
- Background Raman SV, Hor KN, Mazur W, Halnon NJ, Kissel JT, He X, Tran T, Smart S, McCarthy B, Taylor MD, Jefferies JL, Rafael-Fortney JA, Lowe J, Roble SL, Cripe LH. Eplerenone for early cardiomyopathy in Duchenne muscular dystrophy: a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2015 Feb;14(2):153-61. doi: 10.1016/S1474-4422(14)70318-7. Epub 2014 Dec 30.
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- Background Manolagas SC, Weinstein RS. New developments in the pathogenesis and treatment of steroid-induced osteoporosis. J Bone Miner Res. 1999 Jul;14(7):1061-6. doi: 10.1359/jbmr.1999.14.7.1061. No abstract available.
- Background Sali A, Guerron AD, Gordish-Dressman H, Spurney CF, Iantorno M, Hoffman EP, Nagaraju K. Glucocorticoid-treated mice are an inappropriate positive control for long-term preclinical studies in the mdx mouse. PLoS One. 2012;7(4):e34204. doi: 10.1371/journal.pone.0034204. Epub 2012 Apr 3.
- Background Kauh E, Mixson L, Malice MP, Mesens S, Ramael S, Burke J, Reynders T, Van Dyck K, Beals C, Rosenberg E, Ruddy M. Prednisone affects inflammation, glucose tolerance, and bone turnover within hours of treatment in healthy individuals. Eur J Endocrinol. 2012 Mar;166(3):459-67. doi: 10.1530/EJE-11-0751. Epub 2011 Dec 17.
- Background Wehling-Henricks M, Oltmann M, Rinaldi C, Myung KH, Tidball JG. Loss of positive allosteric interactions between neuronal nitric oxide synthase and phosphofructokinase contributes to defects in glycolysis and increased fatigability in muscular dystrophy. Hum Mol Genet. 2009 Sep 15;18(18):3439-51. doi: 10.1093/hmg/ddp288. Epub 2009 Jun 19.
- Background Younes M, Neffati F, Touzi M, Hassen-Zrour S, Fendri Y, Bejia I, Ben Amor A, Bergaoui N, Najjar MF. Systemic effects of epidural and intra-articular glucocorticoid injections in diabetic and non-diabetic patients. Joint Bone Spine. 2007 Oct;74(5):472-6. doi: 10.1016/j.jbspin.2006.10.009. Epub 2007 Jul 6.
- Background Moon HJ, Choi KH, Lee SI, Lee OJ, Shin JW, Kim TW. Changes in blood glucose and cortisol levels after epidural or shoulder intra-articular glucocorticoid injections in diabetic or nondiabetic patients. Am J Phys Med Rehabil. 2014 May;93(5):372-8. doi: 10.1097/PHM.0000000000000001.
- Background Investigator's Brochure, Version 4, Vamorolone (17α,21-dihydroxy-16α-methyl-pregna-1,4,9(11)-triene-3,20-dione) 4% Oral Suspension, ReveraGen BioPharma, Inc., January 10, 2017.
- Background Fleishaker DL, Mukherjee A, Whaley FS, Daniel S, Zeiher BG. Safety and pharmacodynamic dose response of short-term prednisone in healthy adult subjects: a dose ranging, randomized, placebo-controlled, crossover study. BMC Musculoskelet Disord. 2016 Jul 16;17:293. doi: 10.1186/s12891-016-1135-3.
- Background Hathout Y, Conklin LS, Seol H, Gordish-Dressman H, Brown KJ, Morgenroth LP, Nagaraju K, Heier CR, Damsker JM, van den Anker JN, Henricson E, Clemens PR, Mah JK, McDonald C, Hoffman EP. Serum pharmacodynamic biomarkers for chronic corticosteroid treatment of children. Sci Rep. 2016 Aug 17;6:31727. doi: 10.1038/srep31727.
- Background Agwu JC, Spoudeas H, Hindmarsh PC, Pringle PJ, Brook CG. Tests of adrenal insufficiency. Arch Dis Child. 1999 Apr;80(4):330-3. doi: 10.1136/adc.80.4.330.
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- Background McDonald C, Camino E, Escandon R, Finkel RS, Fischer R, Flanigan K, Furlong P, Juhasz R, Martin AS, Villa C, Sweeney HL. Draft Guidance for Industry Duchenne Muscular Dystrophy, Becker Muscular Dystrophy, and Related Dystrophinopathies - Developing Potential Treatments for the Entire Spectrum of Disease. J Neuromuscul Dis. 2024;11(2):499-523. doi: 10.3233/JND-230219.
- Background Brooke MH, Griggs RC, Mendell JR, Fenichel GM, Shumate JB, Pellegrino RJ. Clinical trial in Duchenne dystrophy. I. The design of the protocol. Muscle Nerve. 1981 May-Jun;4(3):186-97. doi: 10.1002/mus.880040304. No abstract available.
- Background Mazzone ES, Messina S, Vasco G, Main M, Eagle M, D'Amico A, Doglio L, Politano L, Cavallaro F, Frosini S, Bello L, Magri F, Corlatti A, Zucchini E, Brancalion B, Rossi F, Ferretti M, Motta MG, Cecio MR, Berardinelli A, Alfieri P, Mongini T, Pini A, Astrea G, Battini R, Comi G, Pegoraro E, Morandi L, Pane M, Angelini C, Bruno C, Villanova M, Vita G, Donati MA, Bertini E, Mercuri E. Reliability of the North Star Ambulatory Assessment in a multicentric setting. Neuromuscul Disord. 2009 Jul;19(7):458-61. doi: 10.1016/j.nmd.2009.06.368. Epub 2009 Jun 23.
- Background McDonald CM, Henricson EK, Han JJ, Abresch RT, Nicorici A, Elfring GL, Atkinson L, Reha A, Hirawat S, Miller LL. The 6-minute walk test as a new outcome measure in Duchenne muscular dystrophy. Muscle Nerve. 2010 Apr;41(4):500-10. doi: 10.1002/mus.21544.
- Background Bello L, Kesari A, Gordish-Dressman H, Cnaan A, Morgenroth LP, Punetha J, Duong T, Henricson EK, Pegoraro E, McDonald CM, Hoffman EP; Cooperative International Neuromuscular Research Group Investigators. Genetic modifiers of ambulation in the Cooperative International Neuromuscular Research Group Duchenne Natural History Study. Ann Neurol. 2015 Apr;77(4):684-96. doi: 10.1002/ana.24370. Epub 2015 Mar 13.
- Background Spurney C, Shimizu R, Morgenroth LP, Kolski H, Gordish-Dressman H, Clemens PR; CINRG Investigators. Cooperative International Neuromuscular Research Group Duchenne Natural History Study demonstrates insufficient diagnosis and treatment of cardiomyopathy in Duchenne muscular dystrophy. Muscle Nerve. 2014 Aug;50(2):250-6. doi: 10.1002/mus.24163. Epub 2014 May 14.
- Background McDonald CM, Henricson EK, Abresch RT, Han JJ, Escolar DM, Florence JM, Duong T, Arrieta A, Clemens PR, Hoffman EP, Cnaan A; Cinrg Investigators. The cooperative international neuromuscular research group Duchenne natural history study--a longitudinal investigation in the era of glucocorticoid therapy: design of protocol and the methods used. Muscle Nerve. 2013 Jul;48(1):32-54. doi: 10.1002/mus.23807. Epub 2013 May 16.
- Background Henricson EK, Abresch RT, Cnaan A, Hu F, Duong T, Arrieta A, Han J, Escolar DM, Florence JM, Clemens PR, Hoffman EP, McDonald CM; CINRG Investigators. The cooperative international neuromuscular research group Duchenne natural history study: glucocorticoid treatment preserves clinically meaningful functional milestones and reduces rate of disease progression as measured by manual muscle testing and other commonly used clinical trial outcome measures. Muscle Nerve. 2013 Jul;48(1):55-67. doi: 10.1002/mus.23808. Epub 2013 May 6.
- Background Escolar DM, Hache LP, Clemens PR, Cnaan A, McDonald CM, Viswanathan V, Kornberg AJ, Bertorini TE, Nevo Y, Lotze T, Pestronk A, Ryan MM, Monasterio E, Day JW, Zimmerman A, Arrieta A, Henricson E, Mayhew J, Florence J, Hu F, Connolly AM. Randomized, blinded trial of weekend vs daily prednisone in Duchenne muscular dystrophy. Neurology. 2011 Aug 2;77(5):444-52. doi: 10.1212/WNL.0b013e318227b164. Epub 2011 Jul 13.
- Results Guglieri M, Clemens PR, Perlman SJ, Smith EC, Horrocks I, Finkel RS, Mah JK, Deconinck N, Goemans N, Haberlova J, Straub V, Mengle-Gaw LJ, Schwartz BD, Harper AD, Shieh PB, De Waele L, Castro D, Yang ML, Ryan MM, McDonald CM, Tulinius M, Webster R, McMillan HJ, Kuntz NL, Rao VK, Baranello G, Spinty S, Childs AM, Sbrocchi AM, Selby KA, Monduy M, Nevo Y, Vilchez-Padilla JJ, Nascimento-Osorio A, Niks EH, de Groot IJM, Katsalouli M, James MK, van den Anker J, Damsker JM, Ahmet A, Ward LM, Jaros M, Shale P, Dang UJ, Hoffman EP. Efficacy and Safety of Vamorolone vs Placebo and Prednisone Among Boys With Duchenne Muscular Dystrophy: A Randomized Clinical Trial. JAMA Neurol. 2022 Oct 1;79(10):1005-1014. doi: 10.1001/jamaneurol.2022.2480.
- Clemens PR, Berglund A, Schiava M, James MK, McDermott MP, Bushby K, Lampa E, Rochford ETJ, Ward LM, Griggs RC, Hoffman EP, Guglieri M. Vamorolone for Duchenne Muscular Dystrophy: A Cross-Trial Efficacy Comparison With Classic Corticosteroids From the FOR-DMD Trial. Neurology. 2026 Jul 14;107(1):e214756. doi: 10.1212/WNL.0000000000214756. Epub 2026 May 27.
- de Vera A, Clemens PR, Dang UJ, Dutreix C, Gresko E, Guglieri M, Hagerty L, Hasham S, Damsker J, Hathout Y, Linden A, Berglund A, Tobin R, Wahbi K, Hoffman EP. Mineralocorticoid receptor antagonism of vamorolone: Evidence from LIONHEART and VISION-DMD clinical trials. Steroids. 2025 Nov;223:109689. doi: 10.1016/j.steroids.2025.109689. Epub 2025 Sep 14.
- Dang UJ, Damsker JM, Guglieri M, Clemens PR, Perlman SJ, Smith EC, Horrocks I, Finkel RS, Mah JK, Deconinck N, Goemans NM, Haberlova J, Straub V, Mengle-Gaw L, Schwartz BD, Harper A, Shieh PB, De Waele L, Castro D, Yang ML, Ryan MM, McDonald CM, Tulinius M, Webster RI, Mcmillan HJ, Kuntz N, Rao VK, Baranello G, Spinty S, Childs AM, Sbrocchi AM, Selby KA, Monduy M, Nevo Y, Vilchez JJ, Nascimento-Osorio A, Niks EH, De Groot IJM, Katsalouli M, Van Den Anker JN, Ward LM, Leinonen M, D'Alessandro AL, Hoffman EP. Efficacy and Safety of Vamorolone Over 48 Weeks in Boys With Duchenne Muscular Dystrophy: A Randomized Controlled Trial. Neurology. 2024 Mar 12;102(5):e208112. doi: 10.1212/WNL.0000000000208112. Epub 2024 Feb 9.
Drugs
| Evaluation | Drug | Modality | Dose | Route |
|---|---|---|---|---|
| Comparator | Prednisone | Other / unclassified | 0.75 mg/kg | Oral |
| Comparator | Vamorolone | Small molecule | 2 mg/kg | Oral |
| Comparator | Vamorolone | Small molecule | 6 mg/kg | Oral |