| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated | | Duchenne muscular dystrophy | |
| E.1.1.1 | Medical condition in easily understood language | | Duchenne muscular dystrophy | |
| E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
| 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 | Double-blind Treatment Period
1. To evaluate the efficacy of WVE-210201 by assessing changes in dystrophin levels (United States/Other regions, as applicable)
2. To evaluate the efficacy of WVE-210201 by assessing changes in motor function by North Star Ambulatory Assessment (NSAA) (European Union [EU]/Japan)
Open-label Treatment Period
To evaluate the long-term efficacy, safety and PK of WVE-210201 | |
| E.2.2 | Secondary objectives of the trial | Double-blind Treatment Period
1. To evaluate the efficacy of WVE-210201 by assessing changes in upper limb proximal strength
2. To evaluate the efficacy of WVE-210201 by assessing changes in lower limb motor function
3. To evaluate the efficacy of WVE-210201 by assessing changes in respiratory function
4. To evaluate the efficacy of WVE-210201 by assessing changes in stride velocity
5. To evaluate the safety of WVE-210201 | |
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives | Magnetic Resonance Imaging (MRI) Sub-study
A subset of patients at selected sites may be asked to participate in an optional imaging sub-study that will assess cardiac and muscle parameters by MRI. The details will be provided via a separate protocol and patients participating in that study will be consented specifically for the imaging study.
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| E.3 | Principal inclusion criteria | 1. Patient and/or parent or legal guardian must have the ability and be willing to provide written informed consent prior to any study-related procedures.
2. Diagnosis of DMD based on clinical phenotype with increased serum creatine kinase.
3. Documented mutation in the Dystrophin gene associated with DMD that is amenable to exon 51 skipping.
4. Ambulatory male, able to walk independently for at least 10 meters in 10 seconds or less at the time of Screening visit (performed as part of the NSAA)
5. Age of ≥5 and ≤12 years at time of randomization
6. Willing and able to comply with scheduled visits, drug administration plan, laboratory tests, study restrictions, and all study procedures, including undergoing the biopsy procedures.
7. Stable pulmonary and cardiac function, as measured by:
a. Reproducible percent predicted forced vital capacity (FVC) ≥50%
b. Left ventricular ejection fraction (LVEF) >55% in patients <10 years of age and >45% in patients ≥10 years of age, as measured (and documented) by echocardiogram.
8. Currently on a stable corticosteroid therapy regimen, defined as: initiation of systemic corticosteroid therapy occurred ≥6 months prior to Screening, and no changes in dose ≤3 months prior to Screening visit.
9. Adequate deltoid muscle at Screening to perform open muscle biopsies
10. Sexually mature males must be willing to use contraception for the duration of the study, if the patient is sexually active.
11. Patient and caregivers must agree not to post any study-related information on social media.
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| E.4 | Principal exclusion criteria | 1. Clinically significant medical finding on the physical examination other than DMD that, in the judgment of the Investigator, will make the patient unsuitable for participation in, and/or completion of the study procedures.
2. Other prior or ongoing medical conditions including:
a. Acute illness within 4 weeks of the initial Screening visit;
b. Abnormal physical findings, other than those associated with musculoskeletal findings attributable to DMD
3. Laboratory abnormality, that, in the Investigator's opinion, could adversely affect the safety of the patient, make it unlikely that the course of treatment or follow-up would be completed, or impair the assessment of study results. These include, but are not limited to:
a. Renal insufficiency;
b. Impaired hepatic function glutamate dehydrogenase (GLDH) ≥ 2.5x upper limit of normal (ULN) and bilirubin ≥ 2x ULN (or International Normalized Ratio [INR] ≥ 1.5x ULN);
c. Activated partial thromboplastin time (aPTT) values above ULN;
d. Platelet count < lower limit of normal (LLN).
4. Documented positive hepatitis B surface antigen or hepatitis C antibody test.
5. Known to be positive for human immunodeficiency virus (HIV).
6. Severe mental retardation and/or behavioral problems that, in the opinion of the Investigator, could prohibit participation in this study.
7. Cardiac insufficiency:
a. Severe cardiomyopathy that, in the opinion of the Investigator, prohibits participation in this study; however, cardiomyopathy that is managed by ACE inhibitors or beta blockers is acceptable provided the patient meets the LVEF inclusion criterion
b. Any other evidence of clinically significant structural or functional heart abnormality
c. A cardiac troponin I value > 0.2 ng/mL on initial and repeat testing if initial test is elevated at screening.
8. Need for daytime mechanical or non-invasive ventilation OR anticipated need for daytime mechanical or non-invasive ventilation within the next year, in the opinion of the Investigator. Nighttime non-invasive ventilation is permitted.
9. Changes in nutritional or herbal supplements or concomitant medications within 1 month prior to Screening visit or plans to modify (dose or regimen) during the study.
10. Currently on anticoagulants or drugs that are known to significantly increase the risk of bleeding, such as NSAIDs and heparin.
11. Received prior treatment with drisapersen or with an investigational peptide-conjugated phosphorodiamidate morpholino oligomer (PPMO).
12. Received prior treatment with WVE-210201.
13. Received prior treatment with gene therapy for DMD
14. Received treatment with ataluren or eteplirsen within the 14 weeks prior to the planned Baseline biopsy collection.
15. Received any investigational drug within 3 months or 5 half-lives, whichever is longer prior to the planned baseline biopsy collection.
16. Known hypersensitivity to any oligonucleotide, as demonstrated by a systemic allergic reaction such as changes in pulse, blood pressure, breathing function, etc.
17. Parent or legal guardian is directly or indirectly involved in the conduct and administration of this study as an Investigator, sub-investigator, study coordinator, or other study staff member, or the patient is a first-degree family member, significant other, or relative residing with one of the above persons involved directly or indirectly in the study. | |
| E.5 End points |
| E.5.1 | Primary end point(s) | Double-blind Treatment Period
1. Change from baseline in dystrophin level (% normal dystrophin) assessed by Western blot of muscle tissue (United States/Other regions, as applicable)
2. Change from baseline in NSAA at 48 weeks (EU/Japan)
Open-label Treatment Period
1. Long-term efficacy, safety, and PK of WVE-210201
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| E.5.1.1 | Timepoint(s) of evaluation of this end point | Double-blind Treatment Period
1. 1 of 3 timepoints, week 12, week 22 or week 46
2. 48 weeks
Open-label Treatment Period
1. 48 weeks | |
| E.5.2 | Secondary end point(s) | Double-blind Treatment Period
1. Key secondary endpoint - Change from baseline in NSAA at 48 weeks (United States/Other regions as applicable)
2. Key secondary endpoint - Change from baseline dystrophin level (% normal dystrophin) assessed by Western blot of muscle tissue (EU/Japan)
3. Change from baseline in upper limb proximal strength assessed by hand held myometry at 48 weeks
4. Change from baseline in 4-stair climb (4SC) at 48 weeks
5. Change from baseline in the 10-meter walk/run test at 48 weeks
6. Change from baseline in FVC (% predicted) at 48 weeks
7. Change from baseline in the 95th percentile of stride velocity at 48 weeks | |
| E.5.2.1 | Timepoint(s) of evaluation of this end point | Double-blind Treatment Period
1. 48 weeks
2. 1 of 3 timepoints, week 12, week 22 or week 46
3. 48 weeks
4. 48 weeks
5. 48 weeks
6. 48 weeks
7. 48 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 | Yes |
| 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 | 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) | 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 | 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 | | A Randomized, Double-blind, Placebo-controlled Study with Open-label Extension | |
| 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 | 3 |
| 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 31 |
| 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 | | Ireland | | Italy | | Japan | | Netherlands | | Poland | | Spain | | Sweden | | Turkey | | 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 | 2 |
| E.8.9.1 | In the Member State concerned months | |
| 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 days | 0 |
