E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Duchenne Muscular Dystrophy (DMD) |
|
E.1.1.1 | Medical condition in easily understood language |
Duchenne Muscular Dystrophy (DMD) |
|
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 |
|
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 |
To evaluate the safety and tolerability of multiple ascending oral doses of vamorolone in ambulant boys ages 4-< 7 years with DMD. |
|
E.2.2 | Secondary objectives of the trial |
- To investigate the single-dose and multiple-dose PK of oral vamorolone at multiple dose levels in ambulant boys ages 4-< 7 years with DMD;
- 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;
- To evaluate metabolites of vamorolone in Metabolites in Safety Testing (MIST) assessments following administration of multiple ascending oral doses.
|
|
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/Health Insurance Portability and Accountability Act (HIPAA) authorization prior to any study-related procedures;
2. Subject has a confirmed (by Central Genetic Counselor) diagnosis of DMD as defined as:
a. Dystrophin immunofluorescence and/or immunoblot showing complete dystrophin deficiency, and clinical picture consistent with typical DMD, OR
b. 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
c. 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;
3. Subject is ≥ 4 years and < 7 years of age at time of enrollment in the study;
4. Subject is able to complete the Time to Stand Test (TTSTAND) without assistance, as assessed at the Screening and Baseline Visits;
5. 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);
6. 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
7. Subject and parent/guardian are willing and able to comply with scheduled visits, study drug administration plan, and study procedures. |
|
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 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;
11. 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
12. Subject has previously been enrolled in the study.
Note: Any parameter/test may be repeated at the Investigator’s discretion during Screening and/or Day 1 to determine sustainability and 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 if ineligible due to negative anti-varicella IgG antibody test result.
|
|
E.5 End points |
E.5.1 | Primary end point(s) |
Safety Endpoints
1. Treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs), by system organ class (SOC): overall by treatment, by treatment and relationship, by treatment and outcome, and by treatment and intensity (Common Terminology Criteria for Adverse Events [CTCAE] grade);
2. Vital sign [supine blood pressure (BP), heart rate, respiratory rate, oral temperature] values: change from Pretreatment to each of the scheduled on-treatment and post-treatment assessment time points;
3. Body weight: change from Pretreatment to each of the scheduled on-treatment and post-treatment assessment time points;
4. Clinical laboratory values: change from Pretreatment to each of the scheduled on-treatment and post-treatment assessment time points in:
- Hematology and biochemistry
- Lipid profile (triglycerides, total cholesterol, low density lipoprotein [LDL], high density lipoprotein [HDL])
- Urinalysis (urine protein and glucose);
5. Concentrations of serum metabolites of vamorolone;
6. 12-lead electrocardiogram (ECG) results: change from Pretreatment to Day 14 and Day 28; and
7. Physical examination findings of abnormality.
|
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
E.5.2 | Secondary end point(s) |
Pharmacodynamic Endpoints
1. Concentration of acute and chronic serum PD biomarkers (change from Pretreatment to on-treatment and post-treatment time points): osteocalcin, serum aminoterminal propeptide of type I collagen (P1NP), carboxy-terminal telopeptide (CTX), cortisol, ACTH, 17-hydroxyprogesterone, testosterone, corticosterone, and 11-deoxycortisol, insulin, and glucose and SomaScan and proteomics profiling.
Exploratory Clinical Efficacy Endpoints
All exploratory clinical efficacy measures are assessed as change from Pretreatment to each of the scheduled on-treatment and post-treatment assessment time points:
1. Quantitative Muscle Testing (QMT): unilateral elbow and knee muscle flexion and extension;
2. Time to Stand Test (TTSTAND) from a supine position;
3. Time to Climb 4 Steps Test (TTCLIMB);
4. Time to Run/Walk 10 meters Test (TTRW);
5. North Star Ambulatory Assessment (NSAA); and
6. Six-minute Walk Test (6MWT).
Acceptability of vamorolone by a 5-point hedonic scale. Assessed on-treatment and post-treatment assessment time points
Pharmacokinetic Endpoints
Plasma PK parameters derived from serial blood samples collected 0.5 hour pre-dose and 1, 2, 4, 6, and 8 hours after the first and final doses of study drug on Day 1 and Day 14.
|
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
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 | 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 |
|
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 |
|
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
|
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 0 |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 5 |
E.8.9.2 | In all countries concerned by the trial days | 0 |