A Study to Assess the Efficacy and Safety of Vamorolone in Boys With Duchenne Muscular Dystrophy (DMD)

• ClinicalTrials.gov Identifier: NCT03439670
• Recruitment Status: Completed
• First Posted: February 20, 2018
• Results First Posted: July 13, 2022
• Last Update Posted: March 9, 2023
• Sponsor: ReveraGen BioPharma, Inc.
• Collaborators: European Union; Cooperative International Neuromuscular Research Group; Newcastle University; University of Pittsburgh
• Information provided by (Responsible Party): ReveraGen BioPharma, Inc.

Tracking Information

• First Submitted Date: January 9, 2018
• First Posted Date: February 20, 2018
• Results First Submitted Date: February 28, 2022
• Results First Posted Date: July 13, 2022
• Last Update Posted Date: March 9, 2023
• Actual Study Start Date: June 29, 2018
• Actual Primary Completion Date: February 23, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 28, 2022)

Efficacy Measured by Time to Stand Test (TTSTAND) Velocity in Rises/Second Change From Baseline [ Time Frame: 24 weeks ]

Vamorolone at 6.0mg/kg/day vs. placebo group in change from baseline to the Week 24 assessment

Original Primary Outcome Measures (submitted: February 13, 2018)

• Muscle function measured by Time to Stand Test (TTSTAND) [ Time Frame: 24 weeks ]
  (vamorolone at 2.0mg/kg/day and 6.0mg/kg/day vs. placebo)
• Body Size as measured by body mass index (BMI) z-score [ Time Frame: 24 weeks ]
  (vamorolone at 2.0mg/kg/day and 6.0mg/kg/day vs. prednisone at 0.75 mg/kg/day)

• Current Secondary Outcome Measures: Not Provided

Original Secondary Outcome Measures (submitted: February 13, 2018)

• Safety measure by Treatment emergent adverse events (TRAEs) and serious adverse events (SAEs) by organ system class (SOC). [ Time Frame: 48 weeks ]
  Overall by treatment, by treatment and relationship, and by treatment and intensity.
• Safety measure assessed by sitting blood pressure. [ Time Frame: Day 1, Week 2, Week 6, Week 12,Week 18, Week 24, Week 28, Week 30, Week 34, Week 40, Week 48. ]
  Change from baseline to each of the scheduled on-treatment and post-treatment assessment time points.
• Safety measure assessed by heart rate. [ Time Frame: Day 1, Week 2, Week 6, Week 12,Week 18, Week 24, Week 28, Week 30, Week 34, Week 40, Week 48. ]
  Change from baseline to each of the scheduled on-treatment and post-treatment assessment time points.
• Safety measured assessed by respiratory rate. [ Time Frame: Day 1, Week 2, Week 6, Week 12,Week 18, Week 24, Week 28, Week 30, Week 34, Week 40, Week 48. ]
  Change from baseline to each of the scheduled on-treatment and post-treatment assessment time points.
• Safety measure assesed by body temperature. [ Time Frame: Day 1, Week 2, Week 6, Week 12,Week 18, Week 24, Week 28, Week 30, Week 34, Week 40, Week 48. ]
  Change from baseline to each of the scheduled on-treatment and post-treatment assessment time points.
• Safety measure assessed by body weight. [ Time Frame: Week 2, Week 6, Week 12, Week 18, Week 24, Week 28, Week 30, Week 34, Week 40, Week 48. ]
  Change from baseline to each of the scheduled on-treatment and post-treatment assessment time points.
• Safety measure assessed by height [ Time Frame: Week 12, Week 24, Week 34, Week 48. ]
  Change from baseline to each of the scheduled on-treatment and post-treatment assessment time points.
• Cushingoid features measured by the presence of buffalo hump obesity, striations, adiposity, hypertension, diabetes, or osteoporosis [ Time Frame: Week 6, Week 12, Week 18, Week 24, Week 28, Week 34, Week 40, Week 48. ]
  Change from baseline to each of the scheduled on-treatment and post-treatment assessment time points.
• Safety measure assessed by blood laboratory measures. [ Time Frame: Day 1, Week 2, Week 6, Week 12, Week 18, Week 24, Week 28, Week 30, Week 34, Week 40, Week 48. ]
  Change from baseline to each of the scheduled on-treatment and post-treatment assessment time points.
• Safety measure assessed by urine laboratory measures. [ Time Frame: Day 1, Week 2, Week 6, Week 12, Week 18, Week 24, Week 28, Week 30, Week 34, Week 40, Week 48 ]
  Change from baseline to each of the scheduled on-treatment and post-treatment assessment time points.
• Cardiac function measured by 12 lead electrocardiogram (ECG) [ Time Frame: Week 12, Week 24, Week 40, Week 48. ]
  Change from baseline to each of the scheduled on-treatment and post-treatment assessment time points.
• Cardiac function measured by 2-D echocardiogram. [ Time Frame: Week 24, Week 48. ]
  Change from baseline to each of the scheduled on-treatment and post-treatment assessment time points.
• Safety measure based on dual-energy x-ray absorptiometry (DXA) scan. [ Time Frame: Week 24, Week 48. ]
  Change from baseline to Week 24 and Week 48 in BMD Z-score.
• Spine Fracture measured by spine X-ray [ Time Frame: 24 weeks ]
  Change from baseline to Week 24 assessment.
• Cataracts measured by the presence of partial or complete opacity of the crystalline lens of one or both eyes. [ Time Frame: Week 24, Week 48 ]
  Week 24 and Week 48 assessments compared to baseline
• Glaucoma measured by measured by ocular pressure. [ Time Frame: Week 24, Week 48 ]
  Week 24 and Week 48 assessments compared to baseline
• Safety measured assessed by Synacthen (ACTH) test [ Time Frame: 24, 48 weeks ]
• Efficacy measured by Time to Stand Test (TTSTAND) [ Time Frame: 48 weeks ]
  (Change from baseline to each of the scheduled study assessment time points for each treatment group up to Week 48)
• Efficacy measured by Time to Climb (TTCLIMB). [ Time Frame: 24, 48 weeks ]
  (vamorolone at 2.0mg/kg/day and vamorolone at 6.0 mg/kg/day vs. placebo)- 24 weeks ; (Change from baseline to each of the scheduled study assessment time points for each treatment group up to Week 48)
• Efficacy as measured by Time to Run/Walk Test (TTRW). [ Time Frame: 24, 48 weeks ]
  (vamorolone at 2.0mg/kg/day and vamorolone at 6.0 mg/kg/day vs. placebo)- 24 weeks ; (Change from baseline to each of the scheduled study assessment time points for each treatment group up to Week 48)
• Efficacy as measured by total distance traveled in meters, in completing the Six-minute Walk Test (6MWT) [ Time Frame: 24, 48 weeks ]
  (vamorolone at 2.0mg/kg/day and vamorolone at 6.0 mg/kg/day vs. placebo)- 24 weeks ; (Change from baseline to each of the scheduled study assessment time points for each treatment group up to Week 48)
• Efficacy as measured by the North Star Ambulatory Assessment (NSAA) [ Time Frame: 24, 48 weeks ]
  (vamorolone at 2.0mg/kg/day and vamorolone at 6.0 mg/kg/day vs. placebo)- 24 weeks ; (Change from baseline to each of the scheduled study assessment time points for each treatment group up to Week 48)
• Efficacy as measured by hand-held myometry (elbow flexors and knee extensors) [ Time Frame: 24, 48 weeks ]
  (vamorolone at 2.0mg/kg/day and vamorolone at 6.0 mg/kg/day vs. placebo)- 24 weeks ; (Change from baseline to each of the scheduled study assessment time points for each treatment group up to Week 48)
• Efficacy as measured by range of motion in the ankles (ROM) [ Time Frame: 24, 48 weeks ]
  (vamorolone at 2.0mg/kg/day and vamorolone at 6.0 mg/kg/day vs. placebo)- 24 weeks ; (Change from baseline to each of the scheduled study assessment time points for each treatment group up to Week 48)
• Safety as measured by serum pharmacodynamic biomarkers by morning cortisol. [ Time Frame: 48 weeks ]
• Safety as measured by serum pharmacodynamic biomarkers by levels of fasting glucose. [ Time Frame: 48 weeks ]
• Safety as measured by serum pharmacodynamic biomarkers by levels of fasting insulin. [ Time Frame: 48 weeks ]
• Safety as measured by serum pharmacodynamic biomarkers by levels of osteocalcin. [ Time Frame: 48 weeks ]
• Safety as measured by serum pharmacodynamic biomarkers by levels of CTX1. [ Time Frame: 48 weeks ]
• Safety as measured by serum pharmacodynamic biomarkers by levels of P1NP. [ Time Frame: 48 weeks ]
• Safety as measured by serum pharmacodynamic biomarkers by levels of differential lymphocyte percentage. [ Time Frame: 48 weeks ]
• Extremity Fracture Questionnaire [ Time Frame: 24, 48 weeks ]
• Physical examination findings at each of the pretreatment, on treatment, and post treatment assessment time points determined by change from baseline in physical examination findings, with assessment of clinical significance [ Time Frame: 48 weeks ]

• Current Other Pre-specified Outcome Measures: Not Provided

Original Other Pre-specified Outcome Measures (submitted: February 13, 2018)

• Parent satisfaction with treatment of vamorolone as measured by the Treatment Satisfaction Questionnaire (TSQM) [ Time Frame: 48 weeks ]
• Pediatric Outcome Data Collection Instrument (PODCI) [ Time Frame: 48 weeks ]
• Child Behavior Checklist [ Time Frame: 48 weeks ]
• PARS III Questionnaire [ Time Frame: 48 weeks ]
• Ease of administration of study medication administration questionnaire. [ Time Frame: 48 weeks ]
• Blindedness questionnaire. [ Time Frame: 24 weeks ]
  Asks each evaluator to predict the identity of the study medication (vamorolone, prednisone, or placebo) the subject was taking during Treatment Period #1, and to rate on a 4-point scale his/her level of certainty and the reason for the chosen level of certainty.
• Exploratory biomarker values for aspects of safety and efficacy [ Time Frame: 24 weeks ]
  Serum biomarkers that have been shown to be gluglucocorticoid-responsive in DMD patients, but not yet bridged to clinical outcomes will be assessed. Specific exploratory biomarkers include: MMP-3, leptin, insulin, IGFBP-5, angiotensinogen, afamin, GHBP, CD23, MDC (CCL22), IL-22BP, lymphotoxin a1/b2, IGFBP-2, Integrin a1b1 (CD49a), MMP-12, Protein C, ANGPT2, FGG, LY9 (vamorolone at 2.0mg/kg/day and 6.0 mg/kg/day vs. placebo) (vamorolone at 2.0mg/kg/day and 6.0mg/kg/day vs. 0.75 mg/kg/day prednisone)

Descriptive Information

• Brief Title: A Study to Assess the Efficacy and Safety of Vamorolone in Boys With Duchenne Muscular Dystrophy (DMD)
• Official Title: A Phase IIb Randomized, Double-blind, Parallel Group, Placebo- and Active-controlled Study With Double-Blind Extension to Assess the Efficacy and Safety of Vamorolone in Ambulant Boys With Duchenne Muscular Dystrophy (DMD)
• Brief 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.

Detailed Description

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.

The study is comprised of a 5-week Pretreatment Screening Period, a 1-day Pretreatment Baseline Period, a 24-week Treatment Period #1 (Weeks 1-24), a 4-week Transition Period (Weeks 25-28), a 20-week Treatment Period #2 (Weeks 28 + 1 day to 48), and a 4-week Dose-tapering Period (Weeks 49-52).

Subjects will be randomized to one of six treatment groups in a 2:2:1:1:1:1 ratio, where the two prednisone groups in Treatment Period #1 (Groups 3 and 4) will be combined and the two placebo groups in Treatment Period #1 (Groups 5 and 6) will be combined, effectively resulting in a 1:1:1:1 randomization (vamorolone 2.0 mg/kg/day : vamorolone 6.0 mg/kg/day : prednisone 0.75 mg/kg/day : placebo) for Treatment Period #1.

Subjects will be stratified based on age at study entry (<6 vs. ≥ 6 years). During the 4-week Transition Period between Treatment Period #1 and Treatment Period #2, all subjects will continue on the same oral suspension (vamorolone 2.0 mg/kg or 6.0 mg/kg, or matching placebo) they received during Treatment Period #1 and all subjects will have their tablet dose tapered to zero. Thus, subjects randomized to receive vamorolone during Treatment Period #1 (Groups 1 and 2) will continue to receive vamorolone at the same dose, while subjects randomized to receive prednisone will have their dose tapered to zero, and subjects randomized to placebo will continue to receive placebo.

The prednisone group will be used as an active control comparison for safety and efficacy endpoints as requested by the European Medicines Agency (EMA). The placebo group will be used as comparator for efficacy endpoints (superiority model) as requested by the EMA and Food and Drug Administration (FDA) protocol advisory board. Although glucocorticoids are part of the care recommendations for DMD, their adverse effect profile has limited their use. The age at which glucocorticoids should be started in DMD boys is uncertain, ranging from 4 to 7 years, based on a balance between benefits and side effects. In view of the age inclusion criteria and duration of the placebo-controlled study period (6 months), the use of a placebo group has been considered acceptable as in clinical practice it will not cause a real delay in prescription of an accepted treatment for this condition. Any exposure of placebo longer than 6 months was considered unethical.

At the end of the Treatment Period #2, subjects may be given access to vamorolone through an additional study or general access program, or given the option to transition to standard of care treatment for DMD (may include glucocorticoids). Subjects completing VBP15-004 and enrolling directly into an additional vamorolone study or general access program to receive vamorolone will not need to taper their vamorolone dose prior to enrollment. All other subjects will begin a 4-week double-blind Dose-tapering Period during which the dose of study medication will be progressively reduced and discontinued.

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Duchenne Muscular Dystrophy

Intervention

• Drug: Vamorolone
  Oral administration of 2.0 mg/kg/day for the duration of the study.
  Other Name: VBP15
• Drug: Prednisone
  Oral administration of 0.75 mg/kg/day for 24 weeks.
• Other: Placebo
  Oral administration of placebo daily for 24 weeks.
• Drug: Vamorolone
  Oral administration of 6.0 mg/kg/day for the duration of the study.
  Other Name: VBP15
• Drug: Vamorolone
  Oral administration of 2.0 mg/kg/day for 20 weeks.
  Other Name: VBP15
• Drug: Vamorolone
  Oral administration of 6.0 mg/kg/day for 20 weeks.
  Other Name: VBP15

Study Arms

• Experimental: Treatment Group 1
  Patients enrolled in Treatment Group 1 (experimental group) will receive vamorolone 2.0 mg/kg/day for the duration of the study.
  Intervention: Drug: Vamorolone
• Experimental: Treatment Group 2
  Patients enrolled in Treatment Group 2 (experimental group) will receive vamorolone at 6.0 mg/kg/day for the duration of the study.
  Intervention: Drug: Vamorolone
• Active Comparator: Treatment Group 3
  Patients enrolled in Treatment Group 3 (active comparator group) will receive prednisone 0.75 mg/kg/day for 24 weeks followed by 20 weeks of treatment with 2.0 mg/kg/day vamorolone.
  Interventions:

  • Drug: Prednisone
  • Drug: Vamorolone
• Active Comparator: Treatment Group 4
  Patients enrolled in Treatment Group 4 (active comparator group) will receive prednisone 0.75 mg/kg/day for 24 weeks followed by 20 weeks treatment with 6.0 mg/kg/day vamorolone.
  Interventions:

  • Drug: Prednisone
  • Drug: Vamorolone
• Placebo Comparator: Treatment Group 5
  Patients enrolled in Treatment Group 5 (placebo comparator group) will receive placebo daily for 24 weeks followed by 20 weeks treatment with 2.0 mg/kg/day vamorolone.
  Interventions:

  • Other: Placebo
  • Drug: Vamorolone
• Placebo Comparator: Treatment Group 6
  Patients enrolled in Treatment Group 6 (placebo comparator group) will receive placebo daily for 24 weeks followed by 20 weeks treatment with 6.0 mg/kg/day vamorolone.
  Interventions:

  • Other: Placebo
  • Drug: Vamorolone

Publications *

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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. Erratum In: Bioorg Med Chem. 2015 Apr 1;23(7):1664.
• 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.
• 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. Erratum In: PLoS One. 2015;10(3):e0121882. PLoS One. 2015;10(12):e0144079.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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. Erratum In: Lancet Neurol. 2015 Feb;14(2):135.
• Avioli LV. Glucocorticoid effects on statural growth. Br J Rheumatol. 1993 May;32 Suppl 2:27-30. doi: 10.1093/rheumatology/32.suppl_2.27.
• Wolthers OD, Pedersen S. Short term linear growth in asthmatic children during treatment with prednisolone. BMJ. 1990 Jul 21;301(6744):145-8. doi: 10.1136/bmj.301.6744.145.
• Bircan Z, Soran M, Yildirim I, Dogan M, Sahin A, Bilici A, Danaci M. The effect of alternate-day low dose prednisolone on bone age in children with steroid dependent nephrotic syndrome. Int Urol Nephrol. 1997;29(3):357-61. doi: 10.1007/BF02550936.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• van Staa TP, Leufkens HG, Abenhaim L, Zhang B, Cooper C. Oral corticosteroids and fracture risk: relationship to daily and cumulative doses. Rheumatology (Oxford). 2000 Dec;39(12):1383-9. doi: 10.1093/rheumatology/39.12.1383.
• FDA Draft Guidance for Industry: Duchenne muscular dystrophy and related dystrophinopathies: developing drugs for treatment. June 2015.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: September 3, 2020): 121
• Original Estimated Enrollment (submitted: February 13, 2018): 120
• Actual Study Completion Date: August 19, 2021
• Actual Primary Completion Date: February 23, 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Subject's parent(s) or legal guardian(s) has (have) provided written informed consent and Health Insurance Portability and Accountability Act (HIPAA) authorization, where applicable, prior to any study-related procedures; participants will be asked to give written or verbal assent according to local requirements

2. Subject has a centrally confirmed (by TRiNDS central genetic counselor[s]) diagnosis of DMD as defined as:

   • Dystrophin immunofluorescence and/or immunoblot showing complete dystrophin deficiency, and clinical picture consistent with typical DMD, OR
   • Identifiable mutation within the DMD gene (deletion/duplication of one or more exons), where reading frame can be predicted as 'out-of-frame,' and clinical picture consistent with typical DMD, OR
   • Complete dystrophin gene sequencing showing an alteration (point mutation, duplication, other) that is expected to preclude production of the dystrophin protein (i.e., nonsense mutation, deletion/duplication leading to a downstream stop codon), with a clinical picture consistent with typical DMD;
3. Subject is ≥ 4 years and <7 years of age at time of enrollment in the study;
4. Subject weighs >13.0 kg and ≤ 39.9 kg at the Screening Visit;
5. Subject is able to walk independently without assistive devices;
6. Subject is able to complete the Time to Stand Test (TTSTAND) without assistance in <10 seconds, as assessed at the Screening Visit;
7. Clinical laboratory test results are within the normal range at the Screening Visit, or if abnormal, are not clinically significant, in the opinion of the Investigator. [Notes: Serum gamma glutamyl transferase (GGT), creatinine, and total bilirubin all must be ≤ upper limit of the normal range at the Screening Visit. An abnormal vitamin D level that is considered clinically significant will not exclude a subject from randomization];

8. Subject has evidence of chicken pox immunity as determined by:

   • Presence of IgG antibodies to varicella, as documented by a positive test result from the local laboratory from blood collected during the Screening Period, OR
   • Documentation, provided at the Screening Visit, that the subject has had 2 doses of varicella vaccine, with or without serologic evidence of immunity; the second of the 2 immunizations must have been given at least 14 days prior to randomization.
9. Subject is able to swallow tablets, as confirmed by successful test swallowing of placebo tablets during the Screening Period; and
10. Subject and parent(s)/guardian(s) are willing and able to comply with scheduled visits, study drug administration plan, and study procedures.

Exclusion Criteria:

1. Subject has current or history of major renal or hepatic impairment, diabetes mellitus or immunosuppression;
2. Subject has current or history of chronic systemic fungal or viral infections;
3. Subject has had an acute illness within 4 weeks prior to the first dose of study medication;
4. Subject has used mineralocorticoid receptor agents, such as spironolactone, eplerenone, canrenone (canrenoate potassium), prorenone (prorenoate potassium), mexrenone (mexrenoate potassium) within 4 weeks prior to the first dose of study medication;
5. Subject has a history of primary hyperaldosteronism;
6. Subject has evidence of symptomatic cardiomyopathy [Note: Asymptomatic cardiac abnormality on investigation would not be exclusionary];
7. Subject is currently being treated or has received previous treatment with oral glucocorticoids or other immunosuppressive agents [Notes: Past transient use of oral glucocorticoids or other oral immunosuppressive agents for no longer than 1 month cumulative, with last use at least 3 months prior to first dose of study medication, will be considered for eligibility on a case-by-case basis, unless discontinued for intolerance. Inhaled and/or topical glucocorticoids are permitted if last use is at least 4 weeks prior to first dose of study medication or if administered at stable dose beginning at least 4 weeks prior to first dose of study medication and anticipated to be used at the stable dose regimen for the duration of the study];
8. Subject has an allergy or hypersensitivity to the study medication or to any of its constituents;
9. Subject has used idebenone within 4 weeks prior to the first dose of study medication;
10. Subject has severe behavioral or cognitive problems that preclude participation in the study, in the opinion of the Investigator;
11. Subject has previous or ongoing medical condition, medical history, physical findings or laboratory abnormalities that could affect safety, make it unlikely that treatment and follow-up will be correctly completed or impair the assessment of study results, in the opinion of the Investigator;
12. Subject is taking (or has taken within 4 weeks prior to the first dose of study medication) herbal remedies and supplements which can impact muscle strength and function (e.g., Co-enzyme Q10, creatine, etc);
13. Subject is taking (or has taken within 3 months prior to the first dose of study medication) any medication indicated for DMD, including Exondys51 and Translarna;
14. Subject has been administered a live attenuated vaccine within 14 days prior to the first dose of study medication;
15. Subject is currently taking any other investigational drug or has taken any other investigational drug within 3 months prior to the first dose of study medication;
16. Subject has a sibling who is currently enrolled in any vamorolone study or Expanded Access Program, or who intends to enroll in any vamorolone study or Expanded Access Program during the subject's participation in the VBP15-004 study; or
17. Subject has previously been enrolled in the study. Note: Any parameter/test may be repeated at the Investigator's discretion during Screening to determine reproducibility. In addition, subjects may be rescreened if ineligible due to a transient condition which would prevent the subject from participating, such as an upper respiratory tract infection or injury, or if ineligible due to negative anti-varicella IgG antibody test result.

Sex/Gender

• Sexes Eligible for Study: Male

• Ages: 4 Years to 7 Years (Child)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Belgium, Canada, Czechia, Greece, Israel, Netherlands, Spain, Sweden, United Kingdom, United States
• Removed Location Countries: Germany, Italy

Administrative Information

• NCT Number: NCT03439670
• Other Study ID Numbers: VBP15-004
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: ReveraGen BioPharma, Inc.
• Original Responsible Party: Same as current
• Current Study Sponsor: ReveraGen BioPharma, Inc.
• Original Study Sponsor: Same as current

Collaborators

• European Union
• Cooperative International Neuromuscular Research Group
• Newcastle University
• University of Pittsburgh

Investigators

• Study Chair: Michela Guglieri, M.D.; John Walton Muscular Dystrophy Research Centre
• Study Chair: Paula Clemens, M.D.; University of Pittsburgh

• PRS Account: ReveraGen BioPharma, Inc.
• Verification Date: March 2023