| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Duchenne muscular dystrophy (DMD) |
| Μυϊκή δυστροφία Duchenne (DMD) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Duchenne muscular dystrophy (DMD) |
| Μυϊκή δυστροφία Duchenne (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 | 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 |
|
| 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 2.0 mg/kg and 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. |
|
| E.2.2 | Secondary objectives of the trial |
1. & 2. To compare the safety (secondary obj. 1.) and efficacy
(secondary obj. 2.) of vamorolone administered orally at daily doses of
2.0 mg/kg and 6.0 mg/kg over a 24-wk treatment period vs. daily
prednisone 0.75 mg/kg in ambulant boys ages 4 to <7 years with DMD;
3. To compare the efficacy of vamorolone administered orally at daily
doses of 2.0 mg/kg vs. vamorolone administered orally at daily doses of
6.0 mg/kg over a 24-wk treatm. period 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. |
|
| 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-offrame',
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. |
|
| 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 1 month cumulative, with last use at least 3 months prior to first
dose of study medication, will be considered for eligibility on a case-bycase
basis, unless discontinued for intolerence. 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 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 has been administered a live attenuated vaccine within 14
days prior to the first dose of study medication;
15. 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;
16.Subject has a sibling who is currently enrolled in any vamorolone
study or Expanded Access Program, or who intends to enroll in any
vamorolone study or Expanded Access Program during the subject's
participation in the VBP15-004 study; or
17. 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 antivaricella
IgG antibody test result. |
|
| 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
each vamorolone 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 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Secondary Efficacy Endpoints
1. Change from baseline to each of the scheduled study assessment time points for each treatment group up to Week 48, with comparison of each
vamorolone dose level group versus the placebo group at each of the
scheduled study assessment time points up to and including Week 24
for:
• Time to Stand Test (TTSTAND) velocity (rise/second) (other than
Week 24);
• 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).
2. Change from baseline with comparison of each vamorolone dose level
group versus the prednisone group at each of the scheduled study
assessment time points up to and including week 24 for:
- total distance traveled, in meters, in completing the Six-minute Walk
test (6MWT).
Safety Endpoints
1. BMI z-score: Comparison of each vamorolone dose level group with
the prednisone group in 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 (sitting blood pressure, heart rate, respiratory rate, and
body temperature): Change from baseline to each of the scheduled ontreatment
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, spine BMD Z-score, 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 insufficiency at Week 24
and Week 48. Adrenal suppression is likely if cortisol levels <18 μg/dL
(or 500 nM) 30 or 60 minutes after stimulation with Cosyntropin.
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
insufficiency.
b. Bone turnover. Measures of serum osteocalcin are reflective of bone
formation, and measures of serum CTX1 are reflective of bone
reabsorption. Ratios 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.
d. Immune suppression. Glucocorticoids can cause immunosuppression.
Measure of differential lymphocyte percentage can be a biomarker for
immune suppression.
2. Exploratory biomarkers for aspects of safety and efficacy. |
|
| 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 | 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 |
|
| 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 | 1 |
| 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 |
| Czech Republic |
| Germany |
| Greece |
| Israel |
| Italy |
| Netherlands |
| Spain |
| Sweden |
| United Kingdom |
|
| 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 | 1 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
Print
