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.

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Duchenne Muscular Dystrophy	Drug: Vamorolone 0.25 mg/kg/day; Drug: Vamorolone 0.75 mg/kg/day; Drug: Vamorolone 2.0 mg/kg/day; Drug: Vamorolone 6.0 mg/kg/day	Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 48 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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)
• Study Start Date: June 2016
• Actual Primary Completion Date: May 1, 2018
• Actual Study Completion Date: May 1, 2018

Arms and Interventions

Arm	Intervention/treatment
Experimental: Dose Level Group 1; Participants enrolled in Dose Level Group 1 will receive vamorolone 0.25 mg/kg/day.	Drug: Vamorolone 0.25 mg/kg/day; Oral administration of 0.25 mg/kg/day daily for 14 days.; Other Name: VBP15
Experimental: Dose Level Group 2; Participants enrolled in Dose Level Group 2 will receive vamorolone 0.75 mg/kg/day.	Drug: Vamorolone 0.75 mg/kg/day; Oral administration of 0.75 mg/kg/day daily for 14 days.; Other Name: VBP15
Experimental: Dose Level Group 3; Participants enrolled in Dose Level Group 3 will receive vamorolone 2.0 mg/kg/day.	Drug: Vamorolone 2.0 mg/kg/day; Oral administration of 2.0 mg/kg/day daily for 14 days.; Other Name: VBP15
Experimental: Dose Level Group 4; Participants enrolled in Dose Level Group 4 will receive vamorolone 6.0 mg/kg/day.	Drug: Vamorolone 6.0 mg/kg/day; Oral administration of 6 mg/kg/day daily for 14 days.; Other Name: VBP15

Outcome Measures

Primary Outcome Measures :

1. 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

Secondary Outcome Measures :

1. 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.
2. 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.
3. 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.
4. 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.
5. 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.
6. 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.
7. 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.
8. 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.
9. 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.
10. 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.
11. 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.
12. 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
13. 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.
14. 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
15. 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.

Eligibility Criteria

• Ages Eligible for Study: 4 Years to 6 Years (Child)
• Sexes Eligible for Study: Male
• Gender Based Eligibility: Yes
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

United States, California

University of California Davis

Davis, California, United States, 95616

United States, Florida

University of Florida

Gainesville, Florida, United States, 32611

Nemours Children's Hospital

Orlando, Florida, United States, 32827

United States, Illinois

Ann & Robert H. Lurie Children's Hospital

Chicago, Illinois, United States, 60611

United States, North Carolina

Duke University

Durham, North Carolina, United States, 27710

United States, Texas

University of Texas Southwestern Medical Center

Dallas, Texas, United States, 75207

Australia

Royal Children's Hospital

Melbourne, Australia

Sydney Children's Hospital

Westmead, Australia

Canada, Alberta

Alberta Children's Hospital

Calgary, Alberta, Canada, T3B 6A8

Israel

Schneider Children's Medical Center

Petah Tikvah, Israel, 49202

Sweden

Queen Silvia Children's Hospital

Gothenburg, Sweden, 41685

United Kingdom

Newcastle upon Tyne Hospitals NHS Foundation Trust

Newcastle upon Tyne, United Kingdom, NE7 7DN

Sponsors and Collaborators

ReveraGen BioPharma, Inc.

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

  Study Documents (Full-Text)

Documents provided by ReveraGen BioPharma, Inc.:

Study Protocol  [PDF] January 20, 2017

Statistical Analysis Plan  [PDF] January 31, 2018

More Information

Additional Information:

Cooperative International Research Group 

ReveraGen BioPharma, Inc 

Phase IIa trial in Duchenne muscular dystrophy shows vamorolone is a first-in-class dissociative steroidal anti-inflammatory drug. 

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: ReveraGen BioPharma, Inc.
• ClinicalTrials.gov Identifier: NCT02760264
• Other Study ID Numbers: VBP15-002; 1R44NS095423-01 ( U.S. NIH Grant/Contract ); 1U34AR068616-01 ( U.S. NIH Grant/Contract )
• First Posted: May 3, 2016
• Results First Posted: January 2, 2019
• Last Update Posted: January 2, 2019
• Last Verified: December 2018

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

Keywords provided by ReveraGen BioPharma, Inc.:

Duchenne Muscular Dystrophy; vamorolone

Additional relevant MeSH terms:

Muscular Dystrophies; Muscular Dystrophy, Duchenne; Muscular Disorders, Atrophic; Muscular Diseases; Musculoskeletal Diseases; Neuromuscular Diseases; Nervous System Diseases; Genetic Diseases, Inborn; Genetic Diseases, X-Linked