A Study to Assess Vamorolone in Boys Ages 2 to <4 Years and 7 to <18 Years With Duchenne Muscular Dystrophy (DMD)

Study Overview
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Brief Summary
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This Phase II study is an open-label, multiple dose study to evaluate the safety, tolerability, PK, PD, clinical efficacy, behavior and neuropsychology, and physical functioning vamorolone over a treatment period of 12 weeks in steroid-naïve boys ages 2 to <4 years, and glucocorticoid-treated and currently untreated boys ages 7 to <18 years with DMD.

Detailed Description
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This Phase II study is an open-label, multiple dose study to evaluate the safety, tolerability, PK, PD, clinical efficacy, behavior and neuropsychology, and physical functioning of vamorolone administered orally at daily doses of 2.0 mg/kg and 6.0 mg/kg over a treatment period of 3 months in steroid-naïve boys ages 2 to <4, and glucocorticoid-treated and currently untreated boys ages 7 to <18 years with DMD. The study is comprised of a 5-week Pretreatment Screening Period; a 1-day Pretreatment Baseline Period; a 3-month open-label Treatment Period (Weeks 1-12); and a 4-week open-label Dose-tapering Period (Weeks 13-16) for subjects who will not transition directly to further vamorolone or standard of care (SoC) glucocorticoid treatment at the end of the study. Subjects will be enrolled into the study at the Screening Visit, at the time written informed consent is obtained. Within the 2 to <4 years age group, the initial 10 eligible subjects will be assigned to the 2.0 mg/kg/day treatment group at the Baseline Day -1 Visit. The subsequent 10 eligible subjects will be assigned to the 6.0 mg/kg/day treatment group at the Baseline Day -1 Visit. Within the 7 to <18 years age group, both corticosteroid-treated and untreated, the initial 12 eligible subjects will be assigned to the 2.0 mg/kg/day treatment group at the Baseline Day -1 Visit. The subsequent 12 eligible subjects will be assigned to the 6.0 mg/kg/day treatment group at the Baseline Day -1 Visit. The first 6 subjects in each age group at 2 mg/kg will serve as the PK/safety run-in cohorts. PK assessments will be performed at week 2 and together with the safety assessment during the first 4 weeks of treatment this will be the basis to confirm whether 2 and 6 mg/kg/day will be used in the subsequent patients or if a dose adjustment is needed to avoid over or under-exposure in patients for any of the two age groups. Glucocorticoid-treated subjects in the 7 to <18 years age group will take their final dose of SoC glucocorticoid therapy for DMD on Baseline Day -1, within 24 hours prior to administration of the first dose of vamorolone study medication. All subjects in both age groups will begin their assigned vamorolone treatment on Treatment Period Day 1, and will continue to receive their assigned vamorolone treatment throughout the duration of the 3 month Treatment Period (Weeks 1-12). At the end of the 3-month Treatment Period (Week 12), subjects will be given the option to receive vamorolone in an expanded access or compassionate use program, if possible, or to transition to SoC treatment for DMD (may include glucocorticoids). Subjects completing VBP15-006 and enrolling directly into the expanded access or compassionate use program or transitioning directly to SoC glucocorticoid treatment will not need to taper their vamorolone dose prior to participation in the expanded access or compassionate use program or initiation of SoC glucocorticoid treatment. All subjects who will not transition directly to further vamorolone or SoC glucocorticoid treatment will begin a 4 week open label Dose tapering Period during which the dose of study medication will be progressively reduced and discontinued.

Official Title
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A Phase II Open-Label, Multiple Dose Study to Assess the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Exploratory Efficacy of Vamorolone in Boys Ages 2 to <4 Years and 7 to <18 Years With Duchenne Muscular Dystrophy (DMD)

Conditions
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Duchenne Muscular Dystrophy

Intervention / Treatment
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* Drug: Vamorolone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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; participants will be asked to give written or verbal assent according to local requirements; Subject has a centrally confirmed (by TRiNDS central genetic counselor[s]) diagnosis of DMD, 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 clinical picture consistent with typical DMD; Subject is male, 2 to <4 years or 7 to <18 years of age at time of enrollment in the study; If 7 to <18 years of age and currently taking standard of care glucocorticoids for treatment of DMD, subject has been taking standard of care glucocorticoids at stable dose for at least 3 months prior to enrollment in the study, and will continue the same stable dose regimen through the date of the Baseline Day -1 Visit. [Note: Inhaled and/or topical glucocorticoids are permitted if last use is at least 4 weeks prior to enrollment or if administered at stable dose beginning at least 4 weeks prior to enrollment and anticipated to be used at the stable dose regimen for the duration of the study]; If 7 to <18 years of age, and not currently glucocorticoid-treated, subject has not received oral glucocorticoids or other oral immunosuppressive agents for at least 3 months prior to enrollment. [Note: Inhaled and/or topical glucocorticoids are permitted if last use is at least 4 weeks prior to enrollment or if administered at stable dose beginning at least 4 weeks prior to enrollment and anticipated to be used at the stable dose regimen for the duration of the study]; 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. [Notes: Serum gamma glutamyl transferase (GGT), creatinine, and total bilirubin all must be ≤ upper limit of the normal range at the Screening Visit. An abnormal vitamin D level that is considered clinically significant will not exclude a subject from participating]; 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 had 2 doses of varicella vaccine, with or without serologic evidence of immunity; the second of the 2 immunizations must have been given at least 14 days prior to assignment to a dose group; Subject and parent(s)/guardian(s) 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 used mineralocorticoid receptor agents, such as spironolactone, eplerenone, canrenone (canrenoate potassium), prorenone (prorenoate potassium), or mexrenone (mexrenoate potassium) within 4 weeks prior to enrollment; Subject has a history of primary hyperaldosteronism; Subject has evidence of symptomatic cardiomyopathy [Note: Asymptomatic cardiac abnormality on investigation would not be exclusionary]; If 2 to <4 years of age, 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 1 month cumulative, with last use at least 3 months prior to enrollment, will be considered for eligibility on a case-by-case basis, unless discontinued for intolerance. Inhaled and/or topical glucocorticoids are permitted if last use is at least 4 weeks prior to enrollment or if administered at stable dose beginning at least 4 weeks prior to enrollment and anticipated to be used at the stable dose regimen for the duration of the study]; Subject has an allergy or hypersensitivity to the study medication or to any of its constituents; Subject has used idebenone within 4 weeks prior to enrollment; 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 enrollment) herbal remedies and supplements which can impact muscle strength and function (e.g., Co-enzyme Q10, creatine, etc); Subject is taking (or has taken within 3 months prior to enrollment) any medication indicated for DMD, including Exondys51, Exondys53, Exondys45, Viltepso and Translarna; 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 enrollment; Subject has previously been enrolled in the VBP15-006 study or any other vamorolone study.

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 17 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: Treatment Group 1<br>Patients in Treatment Group 1 must be ages 2-<4 years and will receive Vamorolone at 2.0 mg/kg/day for the duration of the study. Treatment Group 1 will be enrolled prior to Treatment Group 2. | Drug: Vamorolone<br>* Oral administration of vamorolone for 12 weeks.<br>* Other names: VBP15;|
| Experimental: Treatment Group 2<br>Patients in Treatment Group 2 must be ages 2-<4 years and will receive Vamorolone at 6.0 mg/kg/day for the duration of the study. Treatment Group 2 will be enrolled after Treatment Group 1. | Drug: Vamorolone<br>* Oral administration of vamorolone for 12 weeks.<br>* Other names: VBP15;|
| Experimental: Treatment Group 3<br>Patients in Treatment Group 3 must be ages 7-<18 years and must be steroid untreated at entry. Treatment Group 3 will receive Vamorolone at 2.0 mg/kg/day for the duration of the study. | Drug: Vamorolone<br>* Oral administration of vamorolone for 12 weeks.<br>* Other names: VBP15;|
| Experimental: Treatment Group 4<br>Patients in Treatment Group 4 must be ages 7-<18 years and must be on a stable dose of steroid for 3 months prior to entry. Treatment Group 4 will receive Vamorolone at 2.0 mg/kg/day for the duration of the study. | Drug: Vamorolone<br>* Oral administration of vamorolone for 12 weeks.<br>* Other names: VBP15;|
| Experimental: Treatment Group 5<br>Patients in Treatment Group 5 must be ages 7-<18 years and must be steroid untreated at entry. Treatment Group 5 will receive Vamorolone at 6.0 mg/kg/day for the duration of the study. | Drug: Vamorolone<br>* Oral administration of vamorolone for 12 weeks.<br>* Other names: VBP15;|
| Experimental: Treatment Group 6<br>Patients in Treatment Group 6 must be ages 7-<18 years and must be on a stable dose of steroid for 3 months prior to entry. Treatment Group 6 will receive Vamorolone at 6.0 mg/kg/day for the duration of the study. | Drug: Vamorolone<br>* Oral administration of vamorolone for 12 weeks.<br>* Other names: VBP15;|
| Experimental: Treatment Group 7<br>Patients in Treatment Group 7 must be ages 12-<18 years and must be on a stable dose of steroid for 3 months prior to entry. Treatment Group 7 will receive Vamorolone at 6.0 mg/kg/day for the duration of the study. | Drug: Vamorolone<br>* Oral administration of vamorolone for 12 weeks.<br>* Other names: VBP15;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Body Mass Index (BMI) from baseline to Week 12 | Body Mass Index is a measure of weight adjusted for height. | 12 weeks | 
| Change in Body Mass Index (BMI) z-score from baseline to Week 12 | Body Mass Index z-scores is a measure of relative weight adjusted for child age and sex. | 12 weeks | 
| Change in Weight from baseline to each of the scheduled on treatment and post-treatment assessment time points | Body weight will be assessed at each of the scheduled time points. | Week 2, Week 6, Week 12, Week 16 | 
| Change in Height from baseline to Week 12 | Standing height will be assessed for subjects ages 2-<4 years; height calculated from ulnar length in subjects ages 7-<18. | Week 12 | 
| Change in Height z score from baseline to Week 12 | Standing height will be assessed for subjects ages 2-<4 years; height calculated from ulnar length in subjects ages 7-<18. | Week 12 | 
| Change in sitting blood pressure from baseline to each of the scheduled on-treatment and post-treatment assessment time points | Sitting blood pressure will be assessed at scheduled on-treatment and post-treatment time points. | Day 1, Week 2, Week 6, Week 12, Week 16 | 
| Change in heart rate from baseline to each of the scheduled on-treatment and post-treatment assessment time points | Heart rate will be assessed at scheduled on-treatment and post-treatment time points. | Day 1, Week 2, Week 6, Week 12, Week 16 | 
| Change in respiratory rate from baseline to each of the scheduled on-treatment and post-treatment assessment time points | Respiratory rate will be assessed at scheduled on-treatment and post-treatment time points. | Day 1, Week 2, Week 6, Week 12, Week 16 | 
| Change in body temperature from baseline to each of the scheduled on-treatment and post-treatment assessment time points | Body temperature will be assessed at scheduled on-treatment and post-treatment time points. | Day 1, Week 2, Week 6, Week 12, Week 16 | 
| Number of participants with Cushingoid features | Cushingoid features measured by the presence of buffalo hump obesity, striations, adiposity, hypertension, diabetes, or osteoporosis. Change from baseline to each of the scheduled on-treatment and post-treatment assessment time points. | Week 6, Week 12, Week 16 | 
| Number of participants with abnormal blood laboratory test results | Blood samples will be collected from subjects for the analysis of clinical chemistry parameters, including White Blood cells (WBCs), Red Blood Cells, (RBCs), hemoglobin, Platelets, Sodium, Potassium, Chloride, Calcium, Inorganic Phosphorus, Blood Urea Nitrogen (BUN), Creatinine, Total Protein, Albumin, Bicarbonate, Lactate Dehydrogenase (LDH), Cystatin C, Total Bilirubin, Uric Acid, Glucose, Alkaline Phosphatase (ALP), Gamma Glutamyl Transferase (GGT), Aspartate aminotransferase (AST), Alanine aminotransferase (ALT), Creatine kinase (CK), Lipase, Amylase, Vitamin D, 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. | Day 1, Week 6, Week 12, Week 16 | 
| Number of participants with abnormal urine laboratory test results | Urine biomarkers will include protein, glucose, ketones, leukocyte esterase, White Blood Cells (WBCs), Red Blood Cells, (RBCs) and bacteria and will be assessed by dipstick and microscopic analysis. Change from baseline to each of the scheduled on treatment and post-treatment time points will be assessed. | Day 1, Week 6, Week 12, Week 16 | 
| Number of participants with abnormal ECGs | 12-lead 1electrocardiogram (ECG) as recorded after subject has rested quietly in a supine position for at least 5 minutes. ECG components are QRS duration, PR [PQ] interval, RR interval, QT interval and QTc. Change from baseline to Week 12 | Week 12 | 
| Number of participants with Glaucoma | Glaucoma as by measured by ocular pressure.Week 12 assessments compared to baseline. | 12 weeks | 
| Number of participants with Cataracts | Cataracts as measured by the presence of partial or complete opacity of the crystalline lens of one or both eyes. Week 12 assessments compared to baseline. | 12 weeks | 
| Number of Participants with Adverse Events as Assessed by Common Terminology Criteria for Adverse Events version 4.03 (CTCAE v4.03) | An Adverse Event is any untoward medical occurrence in a subject and does not necessarily have to have a causal relationship with the intervention. Pre-existing conditions that worsen during the study are to be reported as AEs. | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the Curve infinity (AUCinf) following oral administration | The pre-dose and post-dose plasma concentration measurements of vamorolone at Day 1 and Week 2 will be used for comparison of drug exposures by age group, dose level, and glucocorticoid treatment at entry (7 to <18 years only). | Day 1, Week 2 | 
| Change in morning cortisol concentration from baseline to Week 12 | Adrenal suppression is directly associated with risk of adrenal crisis, delay of puberty and stunting of growth. Measurement of morning cortisol concentrations will reflect the degree of adrenal suppression. Cortisol measures falling below 3.6 µg/dL (or 100 nM) will be considered to be indicative of the development of adrenal suppression. | Week 12 | 
| Change in fasting serum concentration of glucose from baseline to Week 12 | Glucocorticoids cause both acute and chronic insulin resistance, with serum elevations of both insulin and glucose. Measures of hyperinsulinemia and hyperglycemia are accepted measures of insulin resistance. Fasting glucose will be measured at baseline and Week 12. | Week 12 | 
| Change in fasting serum concentration of insulin from baseline to Week 12 | Glucocorticoids cause both acute and chronic insulin resistance, with serum elevations of both insulin and glucose. Measures of hyperinsulinemia and hyperglycemia are accepted measures of insulin resistance. Fasting insulin will be measured at baseline and Week 12. | Week 12 | 
| Change in serum concentration of hemoglobin A1c (HbA1c) from baseline to Week 12 | Glucocorticoids cause both acute and chronic insulin resistance, with serum elevations of both insulin and glucose. Measures of hyperinsulinemia and hyperglycemia are accepted measures of insulin resistance. Hemoglobin A1c (HbA1c) will be measured at baseline and Week 12. | Week 12 | 

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