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 disease, muscle weakness |
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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 | 18.1 |
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 |
• To investigate the efficacy of drisapersen sodium administered for 24 weeks compared to a placebo control group in ambulant subjects with DMD. |
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E.2.2 | Secondary objectives of the trial |
Secondary objectives
• To investigate the safety of drisapersen sodium administered for 24 weeks compared to placebo control group in ambulant subjects with DMD.
• To investigate the efficacy of drisapersen sodium administered to ambulant subjects with DMD for 96 weeks compared to a natural history control cohort.
• To compare the efficacy of drisapersen treatment from the start of the study to delayed drisapersen treatment (placebo subjects who have crossed over to drisapersen treatment post-24 weeks) at 48 and 96 weeks.
• To investigate the safety and tolerability of drisapersen sodium administered to ambulant subjects with DMD for 96 weeks.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Ambulant subjects with DMD resulting from a mutation/deletion within the dystrophin gene, confirmed by a Deoxyribonucleic acid (DNA) diagnostic technique covering all dystrophin gene exons (e.g. MLPA, CGH, SCAIP, H-RMCA) and correctable by drisapersen sodium-induced exon 51 skipping.
2. Male subjects aged ≥5 years at Screening.
3. Able to Rise from Floor in ≤ 7 seconds on at least 2 of the 3 pre-treatment visits (screening 1, screening 2, and baseline).
4. Able to walk at least 300m on the 6MWD on at least 2 of the 3 pre-treatment visits (screening 1, screening 2, and baseline).
5. Glucocorticosteroid use which is stable for at least 3 months prior to the first screening visit. Subjects must have been receiving glucocorticosteroids for at least 6 months prior to the first screening visit.
6. Willing and able to adhere to the study visit schedule and other protocol requirements.
7. Written informed consent signed (by parent(s)/legal guardian and/or the subject, according to the local regulations).
8. In France, a subject will be eligible for inclusion in this study only if either affiliated to, or a beneficiary of, a social security category. |
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E.4 | Principal exclusion criteria |
1. More than a 30º (degree) flexion of either ankle, measure by goniometry.
2. Any additional mutations for DMD that cannot be treated by drisapersen sodium.
3. Current or history of liver or renal disease or impairment.
4. Screening platelet count below the lower limit of normal (LLN).
5. Acute illness within 4 weeks prior to first study drug administration which may interfere with the study assessments.
6. History of significant medical disorder which may confound the interpretation of efficacy or safety data (e.g. inflammatory disease, severe mental retardation and/or behavioral problems).
7. Severe cardiomyopathy which, in the opinion of the Investigator prohibits participation in this study. If a subject has a left ventricular ejection fraction <45% at screening, the Investigator should discuss inclusion of the subject with the Medical Monitor.
8. Chronic use of anti-coagulants, anti-thrombotics or anti-platelet agents within 1 month of the first administration of study drug.
9. Use of idebenone or other forms of coenzyme Q10 within 1 month prior to the start of the screening for the study.
10. Use of any investigational product or participation in another trial with an investigational product, within the half-life of that investigational product or a minimum of 6 months prior to the start of screening for the study.
11. Previous use of drisapersen sodium or eteplirsen.
12. NOTE: Subjects who fail on an entry criterion (apart from those subjects deemed to be ineligible for safety reasons) may be allowed to be re-screened at a later date, following discussion with the Medical Monitor. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Efficacy
• Change from Baseline at Week 24 in the 6MWD drisapersen sodium group compared to the placebo control group. |
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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) |
Efficacy:
Change from Baseline, drisapersen sodium group compared to the placebo control group in:
• Percent predicted 6MWD
• North Star Ambulatory Assessment (NSAA)
• Rise from floor (assessed as part of NSAA)
• 10m walk/run (assessed as part of NSAA)
• 4-Stair Climb (ascent and descent)
• Pathological changes in skeletal muscle identified by Magnetic Resonance Imaging (MRI)/Magnetic Resonance Spectroscopy (MRS)
• Creatine kinase
• Pulmonary function
2. Change from Baseline, drisapersen sodium group compared to the natural history control group in:
• Absolute 6MWD
• Percent predicted 6MWD
• NSAA
• Rise from floor (assessed as part of NSAA)
• 10m walk/run (assessed as part of NSAA)
• 4-Stair Climb (ascent and descent)
• Pathological changes in skeletal muscle identified by Magnetic Resonance Imaging (MRI)/Magnetic Resonance Spectroscopy (MRS)
• Creatine kinase
• Pulmonary function
• Time to major disease milestones (e.g. loss of ambulation)
3. Change from Baseline, drisapersen sodium group compared to placebo/delayed drisapersen sodium group :
• Absolute 6MWD
• Percent predicted 6MWD
• NSAA
• Rise from floor (assessed as part of NSAA)
• 10m walk/run (assessed as part of NSAA)
• 4-Stair Climb (ascent and descent)
• Pathological changes in skeletal muscle identified by Magnetic Resonance Imaging (MRI)/Magnetic Resonance Spectroscopy (MRS)
• Creatine kinase
• Pulmonary function
• Time to major disease milestones (e.g. loss of ambulation)
Exploratory Endpoints:
1. Change from Baseline, drisapersen sodium group compared to a historical matched placebo population (from the drisapersen sodium PCTs) in:
• Absolute 6MWD
• Percent predicted 6MWD
• NSAA
• Rise from floor (assessed as part of NSAA)
• 10m walk/run (assessed as part of NSAA)
• 4-Stair Climb (ascent and descent)
• Creatine kinase
• Pulmonary function
• Biomarkers of disease progression (based on ongoing work)
Change from Baseline in:
• Quality of life – PODCI, NeuroQoL (physical domains), EQ5D-5L
2. Change from Baseline and compared to a natural history cohort:
• Exploratory biomarkers of disease progression (e.g., proteins from muscle, LDH, 6 phosphogluconate dehydrogenase, vascular endothelium E-cadkerin, miRNA-1, miRNA-133, triglycerides) (based on ongoing work) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Efficacy Endpoints:
1. at Week 24
2. at Week 96 and other time points
3. 48 weeks and 96 weeks
Exploratory Endpoints:
1. at Week 48
2. over 96 weeks |
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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 | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
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 | Yes |
E.6.13.1 | Other scope of the trial description |
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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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
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 | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
The initial 24-week double-blind study is followed by 72-week open-label extension study. |
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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 | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
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 | 20 |
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 |
France |
Germany |
Israel |
Italy |
Japan |
Poland |
Russian Federation |
Spain |
Sweden |
Turkey |
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 | 20 |
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 | 10 |