| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Duchenne Muscular Dystrophy (DMD) |
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| E.1.1.1 | Medical condition in easily understood language |
| Duchenne Muscular Dystrophy (DMD) |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Musculoskeletal Diseases [C05] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10013801 |
| E.1.2 | Term | Duchenne muscular dystrophy |
| E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
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| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
The primary objectives:
1. To evaluate the long-term safety and tolerability of vamorolone, administered orally at daily doses up to 6.0 mg/kg over a 24-week Treatment Period, in boys ages 4-7 years with DMD;
2. To compare the efficacy, as measured by the Time to Stand Test (TTSTAND), of vamorolone administered orally at daily doses up to 6.0 mg/kg over a 24-week Treatment Period vs. untreated DMD historical controls in boys ages 4-7 years with DMD; and
3. To compare the safety, as measured by body mass index (BMI) z-score, of vamorolone administered orally at daily doses up to 6.0 mg/kg over a 24-week Treatment Period vs. prednisone-treated historical controls in boys ages 4-7 years with DMD. |
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| E.2.2 | Secondary objectives of the trial |
To investigate the effects of vamorolone, administered orally at daily doses up to 6.0 mg/kg over a 24-week Treatment Period:
- vs. prednisone-treated historical controls, on serum pharmacodynamic (PD) biomarkers of safety (insulin resistance, adrenal axis suppression, and bone turnover);
- vs. untreated historical controls, on serum PD biomarkers of efficacy (inflammatory protein suppression); and
- on muscle strength, mobility and functional exercise capacity vs. historical controls as measured by Quantitative Muscle Testing (QMT), Time to Run/Walk Test (TTRW), North Star Ambulatory Assessment (NSAA), Time to Climb Test (TTCLIMB), and 6-minute Walk Test (6MWT) in boys ages 4-7 years with DMD.
Exploratory Objective: To investigate the effects of vamorolone administered orally at daily doses up to 6.0 mg/kg over a 24-week Treatment Period on an extended panel of PD biomarkers using SomaScan aptamer arrays, and proteomic profiling. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Subject’s parent or legal guardian has provided written informed consent/HIPAA authorization prior to any extension study-specific procedures;
2. Subject has previously completed study VBP15-002 up to and including the Week 4 Follow-up assessments within 8 weeks prior to enrollment; and
3. Subject and parent/guardian are willing and able to comply with scheduled visits, study drug administration plan, and study procedures. |
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| E.4 | Principal exclusion criteria |
1. Subject had a serious or severe adverse event in study VBP15-002 that, in the opinion of the Investigator, was probably or definitely related to vamorolone use and precludes safe use of vamorolone for the subject in this study;
2. Subject has current or history of major renal or hepatic impairment, diabetes mellitus or immunosuppression;
3. Subject has current or history of chronic systemic fungal or viral infections;
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; or
11. Subject is currently taking any investigational drug, or has taken any investigational drug other than vamorolone within 3 months prior to the start of study treatment.
Note: Subjects may be re-evaluated if ineligible due to a transient condition which would prevent the subject from participating.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Safety Endpoint
- BMI z-score: Comparison with a prednisone-treated historical control group for change from Baseline to Week 24.
Clinical Efficacy Endpoint
- Time to Stand Test (TTSTAND) velocity (rise/second): Comparison with a historical natural history (untreated) control group for change from Baseline to Week 24. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Safety Endpoints
1. BMI z-score: Change from Baseline to each of the scheduled on-treatment and post treatment assessment time points.
2. Treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) by system organ class (SOC): Overall by treatment, by treatment and relationship, and by treatment and intensity.;
3. Vital signs [blood pressure, heart rate, respiratory rate, body temperature]: Change from Baseline to each of the scheduled on-treatment and post-treatment assessment time points;
4. Body weight: Change from Baseline to each of the scheduled on-treatment and post-treatment assessment time points;
5. Clinical laboratory values (hematology and biochemistry): Change from Baseline to each of the scheduled on-treatment and post-treatment assessment time points;
6. Lipid profile (triglycerides, total cholesterol, low density lipoprotein [LDL], high density lipoprotein [HDL]): Change from Baseline to each of the scheduled on-treatment and post-treatment assessment time points;
7. Urinalysis by dipstick and microscopic analysis: Change from Baseline to each of the scheduled on-treatment and post-treatment assessment time points;
8. 12-lead electrocardiogram (ECG): Change from Baseline to each of the scheduled on-treatment and post-treatment assessment time points
Efficacy Endpoints
1. Time to Stand Test (TTSTAND) velocity (rise/second): Change from Baseline to each of the scheduled on-treatment and post-treatment assessment time points;
2. Time to Climb (4 Steps) Test (TTCLIMB): Change from Baseline to each of the scheduled on-treatment and post-treatment assessment time points;
3. North Star Ambulatory Assessment (NSAA): Change in timed assessments and total score from Baseline to each of the scheduled on-treatment and post-treatment assessment time points;
4. Quantitative Muscle Testing (QMT): Change from Baseline to each of the scheduled on-treatment and post-treatment assessment time points;
5. Total distance traveled, in meters, in completing the Six-minute Walk Test (6MWT): Change from Baseline to each of the scheduled on-treatment and post-treatment assessment time points; and
6. Time to Run/Walk Test (TTRW): Change from Baseline to each of the scheduled on-treatment and post-treatment assessment time points.
Pharmacodynamic Endpoints
1. Concentrations of serum PD biomarkers: osteocalcin, ACTH, insulin, glucose, 17 hydroxyprogesterone, carboxy-terminal telopeptide (CTX), serum aminoterminal propeptide of type I collagen (P1NP), cortisol, testosterone, corticosterone, 11-deoxycortisol, and hemoglobin A1c (HbA1c).
Exploratory Endpoints
- Levels of an extended panel of PD biomarkers using SomaScan aptamer arrays and proteomic profiling.
Acceptability of vamorolone by a 5-point hedonic scale at the Week 12 and Week 24 Visits.
Quality of life assessment by Pediatric Outcomes Data Collection Instrument at Baseline Day -1, Week 12, and Week 24 Visits.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
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| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 2 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Canada |
| Israel |
| United Kingdom |
| United States |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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