Clinical trial NCT02760264: 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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Duchenne Muscular Dystrophy
Keywords: Duchenne Muscular Dystrophy
vamorolone
Lead sponsor: ReveraGen BioPharma, Inc.
Sponsor class: INDUSTRY
Collaborators: name: University of Pittsburgh
name: National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
name: National Institute of Neurological Disorders and Stroke (NINDS)
name: Cooperative International Neuromuscular Research Group
First posted: 2016-05-03
Enrollment: 48
Sex: MALE
Minimum age (years): 4
Maximum age (years): 6
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Overall Summary of Adverse Events as Assessed by CTCAE Version 4.03
timeFrame: 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.
Secondary outcomes:
measure: Serum Pharmacodynamic Biomarkers (Insulin Resistance)- Fasting Glucose
timeFrame: Baseline, Week 2
measure: Serum Pharmacodynamic Biomarkers (Insulin Resistance) -Fasting Glucose
timeFrame: Baseline, Week 2
measure: Serum Pharmacodynamic Biomarkers (Insulin Resistance)- Insulin
timeFrame: Baseline , Week 2
measure: Serum Pharmacodynamic Biomarkers (Insulin Resistance)- Insulin
timeFrame: Baseline, Week 2
measure: Serum Pharmacodynamic Biomarkers (Adrenal Axis Suppression)- First in Morning Cortisol
timeFrame: Week 2 (pre-dose)
measure: Serum Pharmacodynamics Biomarkers (Bone Turnover) -Osteocalcin
timeFrame: Baseline, Day 1, Week 2, Week 4
measure: Serum Pharmacodynamic Biomarkers (Bone Turnover)- Procollagen 1 N-Terminal Propeptide
timeFrame: Baseline Day 1 Week 2 Week 4
measure: Serum Pharmacodynamic Biomarkers (Bone Turnover)- Procollagen 1 N-Terminal Propeptide
timeFrame: Baseline, Day 1, Week 2, Week 4
measure: Serum Pharmacodynamic Biomarkers (Bone Turnover)-Type I Collagen C-Telopeptides
timeFrame: Baseline, Day 1, Week 4
measure: Pharmacokinetic (PK) Assessments (Tmax)
timeFrame: Day 1, Week 2
measure: Pharmacokinetic (PK) Assessments (AUC Inf)
timeFrame: Day 1, Week 2
measure: Pharmacokinetic (PK) Assessments CL (ml/hr/kg)
timeFrame: Day 1, Week 2
measure: Pharmacokinetic (PK) Assessments t(1/2)
timeFrame: Day 1, Week 2
measure: Pharmacokinetic (PK) Assessments (Cmax)
timeFrame: Day 1, Week 2
measure: Metabolites in Safety Testing (MIST) Assessment
timeFrame: Week 2 (Day 14)
Other outcomes:
Locations:
city: Davis
country: United States
facility: University of California Davis
state: California
city: Gainesville
country: United States
facility: University of Florida
state: Florida
city: Orlando
country: United States
facility: Nemours Children's Hospital
state: Florida
city: Chicago
country: United States
facility: Ann & Robert H. Lurie Children's Hospital
state: Illinois
city: Durham
country: United States
facility: Duke University
state: North Carolina
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center
state: Texas
city: Melbourne
country: Australia
facility: Royal Children's Hospital
city: Westmead
country: Australia
facility: Sydney Children's Hospital
city: Calgary
country: Canada
facility: Alberta Children's Hospital
state: Alberta
city: Petah Tikvah
country: Israel
facility: Schneider Children's Medical Center
city: Gothenburg
country: Sweden
facility: Queen Silvia Children's Hospital
city: Newcastle upon Tyne
country: United Kingdom
facility: Newcastle upon Tyne Hospitals NHS Foundation Trust
Study officials:
affiliation: University of Pittsburgh
name: Paula R Clemens, MD
role: STUDY_CHAIR
References:
citation: 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.
citation: 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.