A Study to Assess Vamorolone in Boys With Duchenne Muscular Dystrophy (DMD)

• ClinicalTrials.gov Identifier: NCT02760264
• Recruitment Status: Completed
• First Posted: May 3, 2016
• Results First Posted: January 2, 2019
• Last Update Posted: January 2, 2019
• Sponsor: ReveraGen BioPharma, Inc.
• Collaborators: University of Pittsburgh; National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS); National Institute of Neurological Disorders and Stroke (NINDS); Cooperative International Neuromuscular Research Group
• Information provided by (Responsible Party): ReveraGen BioPharma, Inc.

Tracking Information

• First Submitted Date: April 28, 2016
• First Posted Date: May 3, 2016
• Results First Submitted Date: September 28, 2018
• Results First Posted Date: January 2, 2019
• Last Update Posted Date: January 2, 2019
• Study Start Date: June 2016
• Actual Primary Completion Date: May 1, 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 11, 2018)

Overall Summary of Adverse Events as Assessed by CTCAE Version 4.03 [ Time Frame: Adverse events will be recorded from the date of informed consent and through the time of the subject's last study visit. Serious adverse events will be recorded from the date of informed consent and for up to 30 days after final drug administration. ]

Treatment-emergent adverse events (TEAEs) are defined as any adverse event or worsening of an existing conditions after initiation of the investigational product and through the subject's last study visit (study completion or early termination). Serious adverse events were recorded for up to 30 days after the final administration of study drug. Note: Total Number of Treatment Emergent Adverse Events: The total incidences of TEAEs experienced in study; Any Treatment Emergent Adverse Event: TEAEs reported at least once per dose group

• Original Primary Outcome Measures (submitted: April 30, 2016): Number of participants with treatment-related adverse events as assessed by CTCAE Version 4.03. [ Time Frame: 4 weeks ]

Current Secondary Outcome Measures (submitted: December 11, 2018)

• Serum Pharmacodynamic Biomarkers (Insulin Resistance)- Fasting Glucose [ Time Frame: Baseline, Week 2 ]
  Pharmacodynamic biomarkers were measured to investigate the effects of single and multiple oral doses of vamorolone on serum PD biomarkers in ambulant boys ages 4-< 7 years with DMD.
• Serum Pharmacodynamic Biomarkers (Insulin Resistance) -Fasting Glucose [ Time Frame: Baseline, Week 2 ]
  Pharmacodynamic biomarkers were measured to investigate the effects of single and multiple oral doses of vamorolone on serum PD biomarkers in ambulant boys ages 4-< 7 years with DMD.
• Serum Pharmacodynamic Biomarkers (Insulin Resistance)- Insulin [ Time Frame: Baseline , Week 2 ]
  Pharmacodynamic biomarkers were measured to investigate the effects of single and multiple oral doses of vamorolone on serum PD biomarkers in ambulant boys ages 4-< 7 years with DMD.
• Serum Pharmacodynamic Biomarkers (Insulin Resistance)- Insulin [ Time Frame: Baseline, Week 2 ]
  Pharmacodynamic biomarkers were measured to investigate the effects of single and multiple oral doses of vamorolone on serum PD biomarkers in ambulant boys ages 4-< 7 years with DMD.
• Serum Pharmacodynamic Biomarkers (Adrenal Axis Suppression)- First in Morning Cortisol [ Time Frame: Week 2 (pre-dose) ]
  Pharmacodynamic biomarkers were measured to investigate the effects of single and multiple oral doses of vamorolone on serum PD biomarkers in ambulant boys ages 4-< 7 years with DMD.
• Serum Pharmacodynamics Biomarkers (Bone Turnover) -Osteocalcin [ Time Frame: Baseline, Day 1, Week 2, Week 4 ]
  Pharmacodynamic biomarkers were measured to investigate the effects of single and multiple oral doses of vamorolone on serum PD biomarkers in ambulant boys ages 4-< 7 years with DMD.
• Serum Pharmacodynamic Biomarkers (Bone Turnover)- Procollagen 1 N-Terminal Propeptide [ Time Frame: Baseline Day 1 Week 2 Week 4 ]
  Pharmacodynamic biomarkers were measured to investigate the effects of single and multiple oral doses of vamorolone on serum PD biomarkers in ambulant boys ages 4-< 7 years with DMD.
• Serum Pharmacodynamic Biomarkers (Bone Turnover)- Procollagen 1 N-Terminal Propeptide [ Time Frame: Baseline, Day 1, Week 2, Week 4 ]
  Pharmacodynamic biomarkers were measured to investigate the effects of single and multiple oral doses of vamorolone on serum PD biomarkers in ambulant boys ages 4-< 7 years with DMD.
• Serum Pharmacodynamic Biomarkers (Bone Turnover)-Type I Collagen C-Telopeptides [ Time Frame: Baseline, Day 1, Week 4 ]
  Pharmacodynamic biomarkers were measured to investigate the effects of single and multiple oral doses of vamorolone on serum PD biomarkers in ambulant boys ages 4-< 7 years with DMD.
• Pharmacokinetic (PK) Assessments (Tmax) [ Time Frame: Day 1, Week 2 ]
  Plasma concentrations of vamorolone were measured using a specific and validated liquid chromatography tandem mass spectrometry (LC-MS) assay. tmax= time when plasma concentration is at maximum.
• Pharmacokinetic (PK) Assessments (AUC Inf) [ Time Frame: Day 1, Week 2 ]
  Plasma concentrations of vamorolone were measured using a specific and validated liquid chromatography tandem mass spectrometry (LC-MS) assay. AUC inf= Area under the concentration vs. time curve to time infinity.
• Pharmacokinetic (PK) Assessments CL (ml/hr/kg) [ Time Frame: Day 1, Week 2 ]
  Plasma concentrations of vamorolone were measured using a specific and validated liquid chromatography tandem mass spectrometry (LC-MS) assay
• Pharmacokinetic (PK) Assessments t(1/2) [ Time Frame: Day 1, Week 2 ]
  Plasma concentrations of vamorolone were measured using a specific and validated liquid chromatography tandem mass spectrometry (LC-MS) assay. t1/2= elimination half life.
• Pharmacokinetic (PK) Assessments (Cmax) [ Time Frame: Day 1, Week 2 ]
  Plasma concentrations of vamorolone were measured using a specific and validated liquid chromatography tandem mass spectrometry (LC-MS) assay
• Metabolites in Safety Testing (MIST) Assessment [ Time Frame: Week 2 (Day 14) ]
  A portion of each blood sample of the Week 2 (Day 14) pharmacokinetic assessment time points for the subjects receiving vamorolone 2 mg/kg/day was used for analysis of vamorolone metabolites.

Original Secondary Outcome Measures (submitted: April 30, 2016)

• Peak plasma concentration (Cmax) of vamorolone [ Time Frame: Day 1 ]
• Peak plasma concentration (Cmax) of vamorolone [ Time Frame: Week 2 ]
• Serum pharmacodynamics biomarkers measured by levels of cortisol, ACTH, PINP, osteocalcin, CTX, 17-hydroxyprogesterone, testosterone, corticosterone, 11-deoxycortisol, glucose and insulin [ Time Frame: Week 2 ]
• Serum metabolites of vamorolone [ Time Frame: Week 2 ]
  Metabolites in Safety Testing (MIST)

• Current Other Pre-specified Outcome Measures: Not Provided

Original Other Pre-specified Outcome Measures (submitted: April 30, 2016)

• Muscle strength measured by Quantitative Muscle Testing (QMT) [ Time Frame: 4 weeks ]
• Muscle function measured by Time to Stand Test (TTSTAND) [ Time Frame: 4 weeks ]
• Muscle function measured by Time to Climb Test (TTCLIMB) [ Time Frame: 4 weeks ]
• Muscle function measured by Time to Run/Walk 10 Meters Test (TTRW) [ Time Frame: 4 weeks ]
• Muscle function measured by North Star Ambulatory Assessment (NSAA) [ Time Frame: 4 weeks ]
• Muscle function measured by Six-minute Walk Test (6MWT) [ Time Frame: 4 weeks ]

Descriptive Information

• Brief Title: A Study to Assess Vamorolone in Boys With Duchenne Muscular Dystrophy (DMD)
• Official Title: A Phase IIa Open-Label, Multiple Ascending Dose Study to Assess the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Exploratory Efficacy of Vamorolone in Boys With Duchenne Muscular Dystrophy (DMD)
• Brief Summary: The purpose of this study is to determine whether a new medication called vamorolone is safe and well-tolerated by boys with Duchenne muscular dystrophy (DMD) ages ≥ 4 and < 7 years old.
• Detailed Description: This study will evaluate the safety and tolerability of a new steroid-like medication called vamorolone in boys with DMD ages ≥ 4 years and < 7 years. Enrolled participants will take the study medication for 14 days followed by a 14 day follow-up period. The potential effectiveness of vamorolone in treating DMD will also be explored.
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Sequential Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Duchenne Muscular Dystrophy

Intervention

• Drug: Vamorolone 0.25 mg/kg/day
  Oral administration of 0.25 mg/kg/day daily for 14 days.
  Other Name: VBP15
• Drug: Vamorolone 0.75 mg/kg/day
  Oral administration of 0.75 mg/kg/day daily for 14 days.
  Other Name: VBP15
• Drug: Vamorolone 2.0 mg/kg/day
  Oral administration of 2.0 mg/kg/day daily for 14 days.
  Other Name: VBP15
• Drug: Vamorolone 6.0 mg/kg/day
  Oral administration of 6 mg/kg/day daily for 14 days.
  Other Name: VBP15

Study Arms

• Experimental: Dose Level Group 1
  Participants enrolled in Dose Level Group 1 will receive vamorolone 0.25 mg/kg/day.
  Intervention: Drug: Vamorolone 0.25 mg/kg/day
• Experimental: Dose Level Group 2
  Participants enrolled in Dose Level Group 2 will receive vamorolone 0.75 mg/kg/day.
  Intervention: Drug: Vamorolone 0.75 mg/kg/day
• Experimental: Dose Level Group 3
  Participants enrolled in Dose Level Group 3 will receive vamorolone 2.0 mg/kg/day.
  Intervention: Drug: Vamorolone 2.0 mg/kg/day
• Experimental: Dose Level Group 4
  Participants enrolled in Dose Level Group 4 will receive vamorolone 6.0 mg/kg/day.
  Intervention: Drug: Vamorolone 6.0 mg/kg/day

Publications *

• Smith EC, Conklin LS, Hoffman EP, Clemens PR, Mah JK, Finkel RS, Guglieri M, Tulinius M, Nevo Y, Ryan MM, Webster R, Castro D, Kuntz NL, Kerchner L, Morgenroth LP, Arrieta A, Shimony M, Jaros M, Shale P, Gordish-Dressman H, Hagerty L, Dang UJ, Damsker JM, Schwartz BD, Mengle-Gaw LJ, McDonald CM; CINRG VBP15 and DNHS Investigators. Efficacy and safety of vamorolone in Duchenne muscular dystrophy: An 18-month interim analysis of a non-randomized open-label extension study. PLoS Med. 2020 Sep 21;17(9):e1003222. doi: 10.1371/journal.pmed.1003222. eCollection 2020 Sep.
• Li X, Conklin LS, van den Anker J, Hoffman EP, Clemens PR, Jusko WJ. Exposure-Response Analysis of Vamorolone (VBP15) in Boys With Duchenne Muscular Dystrophy. J Clin Pharmacol. 2020 Oct;60(10):1385-1396. doi: 10.1002/jcph.1632. Epub 2020 May 20.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: June 7, 2016): 48
• Original Estimated Enrollment (submitted: April 30, 2016): 30
• Actual Study Completion Date: May 1, 2018
• Actual Primary Completion Date: May 1, 2018 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Subject's parent or legal guardian has provided written informed consent/Health Insurance Portability and Accountability Act (HIPAA) authorization prior to any study-related procedures;

2. Subject has a confirmed (by Central Genetic Counselor) diagnosis of DMD as defined as:

   1. Dystrophin immunofluorescence and/or immunoblot showing complete dystrophin deficiency, and clinical picture consistent with typical DMD, OR
   2. 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
   3. 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 typical clinical picture of DMD;
3. Subject is ≥ 4 years and < 7 years of age at time of enrollment in the study;
4. Subject is able to complete the Time to Stand Test (TTSTAND) without assistance, as assessed at the Screening and Baseline Visits;
5. 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. (Note: Serum gamma glutamyl transferase [GGT], creatinine, and total bilirubin all must be ≤ upper limit of the normal range at the Screening Visit);
6. 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 testing laboratory at the Screening Visit; and
7. Subject and parent/guardian 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 evidence of symptomatic cardiomyopathy. [Note: Asymptomatic cardiac abnormality on investigation would not be exclusionary];
6. 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 3 months 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. Inhaled and/or topical corticosteroids prescribed for an indication other than DMD are permitted but must be administered at stable dose for at least 3 months prior to study drug administration];
7. Subject has used idebenone within 4 weeks prior to the first dose of study medication;
8. Subject has an allergy or hypersensitivity to the study medication or to any of its constituents;
9. Subject has severe behavioral or cognitive problems that preclude participation in the study, in the opinion of the Investigator;
10. 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;
11. Subject is taking any other investigational drug currently or has taken any other investigational drug within 3 months prior to the start of study treatment; or
12. Subject has previously been enrolled in the study.

Sex/Gender

• Sexes Eligible for Study: Male
• Gender Based Eligibility: Yes

• Ages: 4 Years to 6 Years (Child)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Canada, Israel, Sweden, United Kingdom, United States

Administrative Information

• NCT Number: NCT02760264
• Other Study ID Numbers: VBP15-002; 1R44NS095423-01 ( U.S. NIH Grant/Contract ); 1U34AR068616-01 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: Undecided

• Responsible Party: ReveraGen BioPharma, Inc.
• Study Sponsor: ReveraGen BioPharma, Inc.

Collaborators

• University of Pittsburgh
• National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
• National Institute of Neurological Disorders and Stroke (NINDS)
• Cooperative International Neuromuscular Research Group

Investigators

• Study Chair: Paula R Clemens, MD; University of Pittsburgh

• PRS Account: ReveraGen BioPharma, Inc.
• Verification Date: December 2018