| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Duchenne muscular dystrophy (DMD) |
| Duchenne spierdystrofie |
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| E.1.1.1 | Medical condition in easily understood language |
| Duchenne muscular dystrophy (DMD) |
| Duchenne spierdystrofie |
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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 | 20.0 |
| 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 |
1. To compare the efficacy of vamorolone administered orally at daily doses of 6.0 mg/kg over a 24-week treatment period vs. placebo in ambulant boys ages 4 to <7 years with DMD; and
2. To evaluate the safety and tolerability of vamorolone administered orally at daily doses of 2.0 mg/kg and 6.0 mg/kg in ambulant boys ages 4 to <7 years with DMD. |
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| E.2.2 | Secondary objectives of the trial |
1. To compare the efficacy of vamorolone administered orally at daily doses of
2.0 mg/kg over a 24-week treatment period vs. placebo in ambulant boys ages 4 to <7 years with DMD
2. & 3. To compare the safety (secondary obj. 2) and the safety (secondary obj. 3) of vamorolone administered orally at daily doses of 2.0 mg/kg and 6.0 mg/kg over a 24-week treatment period vs. daily prednisone
0.75 mg/kg in ambulant boys ages 4 to <7 years with DMD;
4. & 5. To compare the efficacy (secondary obj. 4.) and the safety (secondary obj. 5.) of vamorolone administered orally at daily doses of 2.0 mg/kg and 6.0 mg/kg over a 48-wk treatm. period in ambulant boys ages 4 to <7 years with DMD vs. respectively untreated DMD historical controls and prednisone-treated DMD historical controls;
6. To evaluate the population pharmacokinetics of vamorolone administered orally at daily doses of 2.0 mg/kg and 6.0 mg/kg in ambulant boys ages 4 to <7 years with DMD. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. 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
2. Subject has a centrally confirmed (by TRiNDS central genetic counselor[s]) 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 clinical picture consistent with typical DMD;
3. Subject is ≥4 years and <7 years of age at time of enrollment in the study;
4. Subject weighs >13.0 kg and ≤39.9 kg at the Screening Visit;
5. Subject is able to walk independently without assistive devices;
6. Subject is able to complete the Time to Stand Test (TTSTAND) without assistance in <10 seconds, as assessed at the Screening Visit;
7. 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];
8. 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 at the Screening Visit;
9. Subject is able to swallow tablets, as confirmed by successful test aswallowing of placebo tablets during the Screening Period; and
10. Subject and parent(s)/guardian(s) 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 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 a history of primary hyperaldosteronism;
6. Subject has evidence of symptomatic cardiomyopathy [Note: Asymptomatic cardiac abnormality on investigation would not be exclusionary];
7. 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 indication other than DMD 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 glucocorticoids prescribed for an indication other than DMD are permitted if last use is at least 4 weeks prior to first dose of study medication or are administered at stable dose beginning at least 4 weeks prior to first dose of study medication, and are anticipated to be used at the stable dose regimen for the duration of the study];
8. Subject has an allergy or hypersensitivity to the study medication or to any of its constituents;
9. Subject has used idebenone within 4 weeks prior to the first dose of study medication;
10. Subject has severe behavioural or cognitive problems that preclude participation in the study, in the opinion of the Investigator;
11. 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;
12. Subject is taking (or has taken within 4 weeks prior to the first dose of study medication) herbal remedies and supplements which can impact muscle strength and function (e.g. Co-enzyme Q10, Creatine, Proglandine etc);
13. Subject is taking (or has taken within 3 months prior to the first dose of study medication) any medication indicated for DMD, including Exondys51 and Translarna;
14. Subject is currently taking any other investigational drug or has taken any other investigational drug within 3 months prior to the first dose of study medication; or
15. Subject has previously been enrolled in the study.
Note: Any parameter/test may be repeated at the Investigator’s discretion during Screening to determine reproducibility. In addition, subjects may be rescreened if ineligible due to a transient condition which would prevent the subject from participating, such as an upper respiratory tract infection or injury, or if ineligible due to negative anti-varicella IgG antibody test result.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary Clinical Efficacy Endpoint
1. Time to Stand Test (TTSTAND) velocity (rise/second): Comparison of vamorolone 6.0 mg/kg/day dose level group versus the placebo group in change from baseline to the Week 24 assessment.
For safety endpoints and pharmacodynamic endpoints see E.5.2 |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
Secondary Efficacy Endpoints
1. Change from baseline to Week 24 for the following comparisons:
• TTSTAND velocity, vamorolone 2.0 mg/kg/day vs placebo
• 6 Minute Walk Test (6MWT) meters walked, vamorolone 6.0 mg/kg/day vs. placebo
• 6 Minute Walk Test (6MWT) meters walked, vamorolone 2.0 mg/kg/day vs. placebo
• Time to Run/Walk (TTRW) 10 meters velocity, vamorolone 6.0 mg/kg/day vs. placebo
• Time to Run/Walk (TTRW) 10 meters velocity, vamorolone 2.0 mg/kg/day vs. placebo
• 6MWT meters walked, vamorolone 6.0 mg/kg/day vs. prednisone
• 6MWT meters walked, vamorolone 2.0 mg/kg/day vs. prednisone
2. Change from baseline to each of the scheduled study assessment time points for each treatment group up to Week 48 for:
• Time to Stand Test (TTSTAND) velocity (rise/second);
• Time to Climb (4 Steps) Test (TTCLIMB) velocity (tasks/second);
• Time to Run/Walk Test (TTRW) velocity (meters/second) to complete 10 meters of a 14 meter course;
• Total distance traveled, in meters, in completing the Six-minute Walk Test (6MWT);
• North Star Ambulatory Assessment (NSAA);
• Hand-held myometry (elbow flexors and knee extensors); and
• Range of motion in the ankles (ROM)
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 (see Section 7.5);
3. Vital signs (sitting blood pressure, heart rate, respiratory rate, and body temperature): Change from baseline to each of the scheduled on-treatment and post-treatment assessment time points;
4. Body weight and height: Change from baseline to each of the scheduled on-treatment and post-treatment assessment time points;
5. Cushingoid features: Change from baseline to each of the scheduled on-treatment and post-treatment assessment time points (changes from baseline will be recorded as AEs);
6. Clinical laboratory values: Change from baseline to each of the scheduled on-treatment and post-treatment assessment time points in:
• Hematology and clinical chemistry
• Lipid profile (triglycerides, total cholesterol, low density lipoprotein [LDL],
high density lipoprotein [HDL])
• Vitamin D level
• Urinalysis;
7. 12-lead electrocardiogram (ECG): Change from baseline to each of the scheduled on-treatment and post-treatment assessment time points;
8. 2D-echocardiogram: Change from baseline to Week 24 and Week 48;
9. Dual-energy x-ray absorptiometry (DXA) scan: Change from baseline to Week 24 and Week 48 in spine BMD, total body BMD, spine and total body bone mass, and total body composition (lean mass, fat mass, fat-free mass, Lean Mass Index, and Fat Mass Index);
10. Spine x-rays: Change from baseline to Week 24 assessment;
11. Eye examination for detection of clinically significant abnormalities (cataracts and/or glaucoma) at Week 24 and Week 48 assessments compared to baseline;
12. ACTH Stimulation Test: measure of adrenal suppression at Week 24 and Week 48. Percentage of subjects in each treatment group with cortisol levels <18 µg/dL (or 500 nM) 30 or 60 minutes after stimulation with Cosyntropin;
13. Linear growth velocity: Change from baseline to each of the scheduled on-treatment and post-treatment assessment time points in height percentile for age.
Pharmacodynamic Endpoints
1. The following pharmacodynamic biomarkers are considered secondary outcome measures focusing on safety outcomes. In each case, the biomarkers studied reflect safety concerns of glucocorticoids:
a. Adrenal suppression. First-in-morning serum 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.
ACTH Stimulation Test will be performed at the Screening Visit and at the Week 24 Follow-up Visit (48 ± 3 hours after the final dose of Treatment Period #1 study medication) and at the Week 48 Follow-up Visit (48 ± 3 hours after the final dose of Treatment Period #2 study medication): cortisol levels <18 µg/dL (or 500 nM) 30 or 60 minutes after stimulation with Cosyntropin (250 µg) will be considered to be indicative of adrenal suppression.
b. Bone turnover. Measures of serum osteocalcin are reflective of bone formation, and measures of serum CTX1 are reflective of bone reabsorption. Levels of osteocalcin and CTX1 predict later clinical safety concerns of osteopenia and bone fragility.
c. Insulin resistance. 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.
2. Exploratory biomarkers for aspects of safety and efficacy |
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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 | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| 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 | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| At week 28, subjects in prednisone or placebo arm switch to VBP15 (2 or 6 mg/kg) daily for 20 weeks |
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| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 6 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 18 |
| 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 |
| Belgium |
| Canada |
| Czechia |
| Germany |
| Greece |
| Israel |
| Italy |
| Netherlands |
| Spain |
| Sweden |
| 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 | 7 |
| 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 | 8 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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