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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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)

Conditions
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Duchenne Muscular Dystrophy

Intervention / Treatment
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* 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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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; Subject has a confirmed (by Central Genetic Counselor) 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 typical clinical picture of DMD; Subject is ≥ 4 years and < 7 years of age at time of enrollment in the study; Subject is able to complete the Time to Stand Test (TTSTAND) without assistance, as assessed at the Screening and Baseline Visits; 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); 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 Subject and parent/guardian are willing and able to comply with scheduled visits, study drug administration plan, and study procedures. Exclusion Criteria: Subject has current or history of major renal or hepatic impairment, diabetes mellitus or immunosuppression; Subject has current or history of chronic systemic fungal or viral infections; Subject has had an acute illness within 4 weeks prior to the first dose of study medication; 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; Subject has evidence of symptomatic cardiomyopathy. [Note: Asymptomatic cardiac abnormality on investigation would not be exclusionary]; 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]; Subject has used idebenone within 4 weeks prior to the first dose of study medication; Subject has an allergy or hypersensitivity to the study medication or to any of its constituents; Subject has severe behavioral or cognitive problems that preclude participation in the study, in the opinion of the Investigator; 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; 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 Subject has previously been enrolled in the study.

Ages Eligible for Study
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Minimum Age: 4 Years
Maximum Age: 6 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Level Group 1<br>Participants enrolled in Dose Level Group 1 will receive vamorolone 0.25 mg/kg/day. | Drug: Vamorolone 0.25 mg/kg/day<br>* Oral administration of 0.25 mg/kg/day daily for 14 days.<br>* Other names: VBP15;|
| Experimental: Dose Level Group 2<br>Participants enrolled in Dose Level Group 2 will receive vamorolone 0.75 mg/kg/day. | Drug: Vamorolone 0.75 mg/kg/day<br>* Oral administration of 0.75 mg/kg/day daily for 14 days.<br>* Other names: VBP15;|
| Experimental: Dose Level Group 3<br>Participants enrolled in Dose Level Group 3 will receive vamorolone 2.0 mg/kg/day. | Drug: Vamorolone 2.0 mg/kg/day<br>* Oral administration of 2.0 mg/kg/day daily for 14 days.<br>* Other names: VBP15;|
| Experimental: Dose Level Group 4<br>Participants enrolled in Dose Level Group 4 will receive vamorolone 6.0 mg/kg/day. | Drug: Vamorolone 6.0 mg/kg/day<br>* Oral administration of 6 mg/kg/day daily for 14 days.<br>* Other names: VBP15;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Summary of Adverse Events as Assessed by CTCAE Version 4.03 | 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 | 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serum Pharmacodynamic Biomarkers (Insulin Resistance)- Fasting Glucose | 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. | Baseline, Week 2 | 
| Serum Pharmacodynamic Biomarkers (Insulin Resistance) -Fasting Glucose | 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. | Baseline, Week 2 | 
| Serum Pharmacodynamic Biomarkers (Insulin Resistance)- Insulin | 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. | Baseline , Week 2 | 
| Serum Pharmacodynamic Biomarkers (Insulin Resistance)- Insulin | 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. | Baseline, Week 2 | 
| Serum Pharmacodynamic Biomarkers (Adrenal Axis Suppression)- First in Morning Cortisol | 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. | Week 2 (pre-dose) | 
| Serum Pharmacodynamics Biomarkers (Bone Turnover) -Osteocalcin | 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. | Baseline, Day 1, Week 2, Week 4 | 
| Serum Pharmacodynamic Biomarkers (Bone Turnover)- Procollagen 1 N-Terminal Propeptide | 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. | Baseline Day 1 Week 2 Week 4 | 
| Serum Pharmacodynamic Biomarkers (Bone Turnover)- Procollagen 1 N-Terminal Propeptide | 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. | Baseline, Day 1, Week 2, Week 4 | 
| Serum Pharmacodynamic Biomarkers (Bone Turnover)-Type I Collagen C-Telopeptides | 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. | Baseline, Day 1, Week 4 | 
| Pharmacokinetic (PK) Assessments (Tmax) | 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. | Day 1, Week 2 | 
| Pharmacokinetic (PK) Assessments (AUC Inf) | 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. | Day 1, Week 2 | 
| Pharmacokinetic (PK) Assessments CL (ml/hr/kg) | Plasma concentrations of vamorolone were measured using a specific and validated liquid chromatography tandem mass spectrometry (LC-MS) assay | Day 1, Week 2 | 
| Pharmacokinetic (PK) Assessments t(1/2) | Plasma concentrations of vamorolone were measured using a specific and validated liquid chromatography tandem mass spectrometry (LC-MS) assay. t1/2= elimination half life. | Day 1, Week 2 | 
| Pharmacokinetic (PK) Assessments (Cmax) | Plasma concentrations of vamorolone were measured using a specific and validated liquid chromatography tandem mass spectrometry (LC-MS) assay | Day 1, Week 2 | 
| Metabolites in Safety Testing (MIST) Assessment | 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. | Week 2 (Day 14) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Duchenne Muscular Dystrophy, vamorolone