A Study to Assess Vamorolone in Becker Muscular Dystrophy (BMD)

Study Overview
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Brief Summary
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This Phase II pilot study is a randomized, double-blind, placebo-controlled study to evaluate the safety, tolerability, PK, PD, and exploratory clinical efficacy of vamorolone 500mg (250mg for body weight <50 kg) daily administered orally compared to placebo over a treatment period of 24 weeks in males with BMD. Funding Source - FDA OOPD

Detailed Description
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This Phase II pilot study is a randomized, double-blind, placebo-controlled study to evaluate the safety, tolerability, PK, PD, and exploratory clinical efficacy of vamorolone 500mg (250mg for body weight <50 kg) daily administered orally compared to placebo over a treatment period of 24 weeks in males with BMD. The study is comprised of a Pretreatment Screening Period of up to 5 weeks duration (unless extended to accommodate varicella vaccination), a 1-day Pretreatment Baseline Period, a 24-week Treatment Period, and a 4-week Dose-tapering Period (for subjects not continuing directly with further vamorolone treatment). Subjects will be enrolled into this study at the time written informed consent is given, and administered study medication only after completion of all Pretreatment Screening assessments to confirm eligibility. Subjects will be assessed for safety, tolerability, PK, PD, and effect on physical functioning at scheduled visits throughout the study. Screening assessments will be performed prior to baseline assessments on Day -1 and first administration of study medication on Day 1. After completion of Screening and Baseline assessments, subjects will return to the study clinic on Day 1 for safety, PK and PD assessments prior to administration of the first dose of study medication. Additional on-site study visits will occur at Week 4, Week 12, and Week 24. Adverse events, including serious adverse events (SAEs), and concomitant medications will be recorded throughout the study. A Data and Safety Monitoring Board (DSMB) will review SAEs and other pertinent safety data at regular intervals during the study, and make recommendations to the Sponsor and Study Team regarding study conduct. Subject diaries will be dispensed at the Day 1, Week 12, and Week 24 (for subjects participating in the Dose-tapering Period) Visits to record AEs, changes to concomitant medications taken during the study, and any missed or incomplete doses of study medication. The scheduled Week 12 and Week 24 assessments may be performed over a 2-day period, if necessary, to facilitate scheduling. Subjects who complete the VBP15-BMD-001 study assessments through the Week 24 Visit may be given the opportunity to continue to receive vamorolone as part of an expanded access or compassionate use program. Subjects who complete the VBP15-BMD-001 study and will enroll directly into an expanded access or compassionate use program to continue vamorolone treatment will be discharged from the VBP15-BMD-001 study following completion of all Week 24 assessments. Subjects who will not continue vamorolone treatment in the expanded access or compassionate use program will have their study medication dose tapered during a 4-week Dose-tapering Period to taper study medication prior to discharge from the study. For these subjects, site study staff will contact the subject or parent(s)/guardian(s) by telephone at Week 26 to ensure that the dose tapering is proceeding according to protocol, to assess potential signs or symptoms of adrenal suppression, and to address any questions the subject or parent(s)/guardian(s) may have. In the event that any clinical or laboratory parameters remain abnormal at the time of discharge from the study, the subject will be followed medically, as clinically indicated. Any subject who discontinues the study prior to the Week 24 Visit should return to the study unit for scheduled Week 24 assessments at the time of early withdrawal and a Week 28 Visit following the taper, whenever possible, assuming the subject has not withdrawn consent. Any subject who withdraws early from the study after study medication dosing has begun should undergo dose-tapering following early completion of the Week 24 assessments and a Week 28 Visit following the taper.

Official Title
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A Phase II Pilot Trial of Vamorolone vs. Placebo for the Treatment of Becker Muscular Dystrophy

Conditions
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Becker Muscular Dystrophy

Intervention / Treatment
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* Drug: Vamorolone
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject or 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; Subject is a male and has a confirmed diagnosis of Becker dystrophy as defined as: Identifiable mutation within the DMD gene (deletion/duplication of one or more exons), where reading frame can be predicted as 'in-frame', and clinical picture consistent with Becker dystrophy, OR Complete dystrophin gene sequencing showing an alteration (small mutation, duplication, other) that is expected to allow production of an internally deleted dystrophin protein, with a typical clinical picture of Becker dystrophy; Subject is ≥ 18 years of age and <65 years of age at time of informed consent; Subject is able to perform the timed run/walk 10 meters assessment (TTRW) in ≤ 30 sec at screening; assistive devices, cane or walker, are allowed. Subject has an NSAA score ≤ 32 at screening. 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). While AST and ALT can be elevated due to disease of muscle or liver, the study PI will review any increases of AST or ALT. If above upper limit of normal (ULN), then study PI will assess whether the increases are likely of muscle origin to determine inclusion. Subject has not received oral glucocorticoids or other oral immunosuppressive agents for at least 3 months prior to first administration of study medication. [Note: Inhaled and/or topical glucocorticoids are permitted if last use is at least 4 weeks prior to first administration of study medication or if administered at stable dose beginning at least 4 weeks prior to first administration of study medication and anticipated to be used at the stable dose regimen for the duration of the study]; 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 received 2 doses of varicella vaccine, with or without serologic evidence of immunity, with the second of the 2 immunizations given at least 14 days prior to first administration of study medication; Subject is willing and able to comply with scheduled visits, study medication administration plan, and study procedures. Subject agrees to use barrier contraception methods during his participation in this study and for 30 days after the tapering dose is completed. Exclusion Criteria: Subject has current or history of major renal or hepatic impairment, uncontrolled diabetes mellitus (defined as a diagnosis of diabetes with random glucose more than 1.5x ULN at screening and the patient has symptoms of polyuria or polydipsia) 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), or mexrenone (mexrenoate potassium) within 4 weeks prior to administration of study medication; Subject has evidence of symptomatic cardiomyopathy [Note: Asymptomatic cardiac abnormality on investigation would not be exclusionary unless cardiac ejection fraction is less than 40%]; 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 (or has taken within 4 weeks prior to first dose of study medication) herbal remedies and supplements which can impact muscle strength and function (e.g., Co-enzyme Q10, creatine, etc); Subject has been administered a live attenuated vaccine within 14 days prior to the first dose of study medication; Subject is currently taking any other investigational drug or has taken any other investigational drug within 3 months prior to first dose of study medication; or Subject has previously been enrolled in the VBP15-BMD-001 study or any other vamorolone study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 64 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: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Vamorolone 500mg/day [250mg if <50kg body weight]<br>Subjects will be randomized to one of two treatment groups in a 1:2 ratio (placebo:vamorolone). | Drug: Vamorolone<br>* Vamorolone 4.0% wt/wt oral suspension will be administered for the duration of the study.<br>* Other names: VBP15;|
| Placebo Comparator: Placebo<br>Subjects will be randomized to one of two treatment groups in a 1:2 ratio (placebo:vamorolone). | Drug: Placebo<br>* Placebo to Vamorolone 4.0% wt/wt oral suspension will be administered for the duration of the study.<br>* Other names: Placebo to vamorolone;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety as measured by Treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) by system organ class (SOC and PT) | Clinical AEs and clinical laboratory AEs will be graded according to the Common Terminology Criteria for Adverse Events (CTCAE), version 4.03, dated June 14, 2010. Dose-limiting toxicities will be defined as follows: The presence of a CTCAE Grade ≥ 3 AE, considered to be probably or definitely related to study drug The presence of a CTCAE Grade ≥ 3 clinical laboratory AE considered to be probably or definitely related to study drug Deterioration of the muscle condition, unexpected for the natural course of BMD and without other clear cause | 24 weeks | 
| Safety as measured by Sitting Blood Pressure | Change in Sitting Blood Pressure from baseline to each of the scheduled on-treatment and post-treatment assessment time points for each treatment group. | Day 1, Week 4, Week 12, Week 24, Week 28 | 
| Safety as measured by Heart Rate | Change in Heart Rate from baseline to each of the scheduled on-treatment and post-treatment assessment time points for each treatment group. | Day 1, Week 4, Week 12, Week 24, Week 28 | 
| Safety as measured by Respiratory Rate | Change in Respiratory Rate from baseline to each of the scheduled on-treatment and post-treatment assessment time points for each treatment group. | Day 1, Week 4, Week 12, Week 24, Week 28 | 
| Safety as measured by Body Temperature | Change in Body Temperature from baseline to each of the scheduled on-treatment and post-treatment assessment time points for each treatment group. | Day 1, Week 4, Week 12, Week 24, Week 28 | 
| Safety as measured by Body Weight | Change in Body Weight from baseline to each of the scheduled on-treatment and post-treatment assessment time points for each treatment group. | Week 12, Week 24, Week 28 | 
| Safety as measured by Height | Change in Height from screening to each of the scheduled on-treatment and post-treatment assessment time points for each treatment group. | Week 12, Week 24, Week 28 | 
| Safety: concentration of blood laboratory biomarkers as assessed by standardized clinical laboratory reference ranges | Blood biomarkers are White Blood cells (WBCs), Red Blood Cells, (RBCs), hemoglobin, Platelets, Sodium, Potassium, Chloride, Calcium, Blood Urea Nitrogen (BUN), Creatinine, Total Protein, Albumin, Total Bilirubin, Glucose, Alkaline Phosphatase (ALP), Gamma Glutamyl Transferase (GGT), Glutamate Dehydrogenase (GLDH), Aspartate aminotransferase (AST), Alanine aminotransferase (ALT), Creatine kinase (CK), Bicarbonate, Triglycerides, Total cholesterol, Low Density Lipoprotein (LDL) and High density Lipoprotein (HDL). Change from baseline to each of the scheduled on treatment and post-treatment time points will be assessed. | Week 4, Week 12, Week 24 | 
| Safety: concentration of urine laboratory biomarkers as measured by dipstick and microscopic analysis | Urine biomarkers are protein, glucose, ketones, leukocyte esterase, White Blood Cells (WBCs), Red Blood Cells, (RBCs) and bacteria. Change from baseline to each of the scheduled on treatment and post-treatment time points will be assessed. | Week 4, Week 12, Week 24 | 
| Safety as measured by 12-lead ECG | 12-lead ECG as recorded after subject has rested quietly in a supine position for at least 5 minutes. ECG components are QRS duration, PR interval, QT interval and QTc interval. Change from baseline to each of the scheduled on-treatment and post-treatment assessment time points. | Week 12, Week 24 | 
| Tolerability as measured by incidence of Premature Discontinuation | Premature Discontinuation of study treatment due to adverse event. | 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics as measured by AUCinf | Blood will be collected from all subjects at the Day 1 Visit, at 1, 2 and 3 hours post-dose, for vamorolone PK analysis | Day 1 | 
| Safety as measured by serum concentration of osteocalcin | Change from baseline to Week 24 will be assessed for each treatment group. | Week 24 | 
| Safety as measured by serum concentration of hemoglobin A1c (HbA1c) | Change from baseline to Week 24 will be assessed for each treatment group. | Week 24 | 
| Safety as measured by fasting serum concentration of glucose | Change from baseline to each of the scheduled study assessment time points for each treatment group. | Week 12, Week 24 | 
| Safety as measured by fasting serum concentration of insulin | Change from baseline to each of the scheduled study assessment time points for each treatment group. | Week 12, Week 24 | 
| Efficacy as measured by concentration of serum pharmacodynamic biomarkers | CD23 (also known as Fc epsilon RII) and Macrophage Derived Chemokine (MDC) and concentration from baseline to Week 24. | Week 12, Week 24 | 
| Safety as measured by concentration of Salivary Cortisol | First-in-morning salivary cortisol levels will be measured. Cortisol measures falling below 3.6 µg/dL (or 100 nM) will be considered to be indicative of the development of adrenal suppression. Cortisol will be assessed for each treatment group. | Day 1, Week 12, Week 24 | 

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