E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Duchenne muscular dystrophy resulting from a mutation correctable by PRO053-induced DMD exon 53 skipping |
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E.1.1.1 | Medical condition in easily understood language |
Duchenne muscular dystrophy |
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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 assess the efficacy of PRO053 at recommended dosing regimen after 48 weeks treatment in ambulant subjects with Duchenne muscular dystrophy. |
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E.2.2 | Secondary objectives of the trial |
To assess the safety and tolerability of PRO053 after single intravenous (IV) and subcutaneous (SC) dose and after 48 weeks of treatment in subjects with Duchenne muscular dystrophy.
To investigate the pharmacokinetics PRO053 at different dosing regimens in subjects with Duchenne muscular dystrophy.
To assess the safety and tolerability at different dosing regimens in subjects with Duchenne muscular dystrophy.
To assess the pharmacodynamics of PRO053 at different dosing regimens in subjects with Duchenne muscular dystrophy.
To assess efficacy trends and safety of PRO053 in subjects with Duchenne Muscular Dystrophy not included in the primary analysis after 48 weeks of dosing and/or dosing extension. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Duchenne muscular dystrophy resulting from a mutation correctable by treatment with PRO053 confirmed by a state-of-the-art DNA diagnostic technique covering all DMD gene exons, including but not limited to MLPA (Multiplex Ligation-dependent Probe Amplification), CGH (Comparative Genomic Hybridisation), SCAIP (Single Condition Amplification/Internal Primer) or HRMCA (High-Resolution Melting Curve Analysis).
2. Ambulant boys aged at least 5 years on the day of first dosing able to walk for at least 300 metres in the 6 minute walking distance (6MWD) test at the first screeining visit and also at the baseline visit. In addition, results of 2 of any of the 3 pretreatment 6MWD test (assessed screen 1, screen 2, baseline) must be within ±30 metres of each other prior to first PRO053 administration. Subjects must also be able to rise from the floor in ≤ 7 seconds at the first screening visit and also at the baseline visit.
3. Adequate quality for biopsy (confirmed with MRI) of the lateral head of the gastrocnemius muscle. Only under exceptional circumstances will an alternative muscle (preferably brachii) be considered for biopsy and only following discussion between the Principal Investigator and the BioMarin Medical Monitor.
4. Life expectancy of at least 3 years after inclusion in the study.
5. Glucocorticosteroid use which is stable for at least 3 months prior to first PRO053 administration. Subjects must have been receiving glucocorticosteroids for at least 6 months prior to the first PRO053 administration.
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.
9. Anticipated adequate vein access for intravenous (IV) infusion. |
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E.4 | Principal exclusion criteria |
1. Current or history of liver disease or impairment.
2. Current or history of renal disease or impairment.
3. Screening aPTT above upper limit of normal (ULN).
4. Screening platelet count below the lower limit of normal (LLN).
5. Acute illness within 4 weeks prior to first dose of PRO053 which may interfere with the study assessments.
6. Severe mental retardation and/or behavioural problems which, in the opinion of the Investigator, prohibit participation in this study.
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. Expected need for daytime mechanical ventilation within the next year.
9. Use of anticoagulants, antithrombotics or antiplatelet agents.
10. Use of idebenone or other forms of coenzyme Q10 within 1 month prior to the start of the screening for the study.
11. Use of nutritional or herbal supplements which, in the opinion of the Investigator, may influence muscle performance within 1 month prior to first dose of PRO053.
12. Use of any other investigational product or participation in another trial with an investigational product, within 6 months prior to the start of the screening for the study. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Change from baseline in 6MWD after 48 weeks of treatment phase for primary evaluation at recommended regimen |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
At screening, baseline, at weeks 13, 25, 37 and 49 |
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E.5.2 | Secondary end point(s) |
Efficacy:
• Muscle function (North Star Ambulatory Assessment, Timed tests, 6MWD)
• Muscle strength (handheld myometry)
• Pulmonary function (spirometry)
• Performance of upper limb (PUL)
• DMD Functional Outcomes Questionnaire (DMD-FOS)
• Exploratory efficacy endpoints:
- Accelerometry
- Myotools (grip strength, key pinch, moviplate)
Safety parameters:
• Adverse events
• Local tolerability
• Laboratory assessments including:
- Routine biochemistry and haematology
- Urinalysis (routine parameters plus 1-microglobulin, microscopy) and 24-hour urine (additionally including protein electrophoresis, urine cystatin and KIM-1 and exploratory measurement of specific DMD protein biomarkers and micro RNAs)
- Coagulation parameters (aPTT, PTT [INR], fibrinogen)
- Complement C3 and split products (C3a, SC5b-9, Bb)
- Pro-inflammatory markers (cytokines IL-6, TNF- and chemokine MCP-1)
• Anti-dystrophin antibodies
• ECG parameters
• Vital signs (temperature, blood pressure, pulse rate, respiration rate)
• Echocardiography
• Physical examination
• DEXA
• Standard renal ultrasound
Pharmacokinetic parameters:
• t ½ (if reliable)
• AUC: 0-24h, 0-72h, 0-7d, 0- (where applicable)
• Cmax, Ctrough, 7d
• tmax
• Vd (for IV) or Vd/F (for SC)
• CL (for IV) or CL/F (for SC)
• PRO053 concentrations in urine
• PRO053 concentrations in muscle tissue
Pharmacodynamic parameters:
• Presence of (BMD-like) dystrophin expression after treatment (in muscle biopsy)
• Histological and immunological staining on cross-sections of muscle tissue
• Production of exon skip 53 mRNA (in muscle biopsy)
• Exploratory PD endpoints:
- Nuclear Magnetic Resonance imaging and spectroscopy (MRI and MRS)
- Exploratory biomarkers(e.g. MMP-9, miR-1, miR-133) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Efficacy: at all available study visits
Safety: at all time points
Pharmacokinetic parameters: per protocol
Pharmacodynamic parameters: per protocol |
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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 | Yes |
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) | Yes |
E.7.1.1 | First administration to humans | Yes |
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 | Information not present in EudraCT |
E.8.1.2 | Open | Information not present in EudraCT |
E.8.1.3 | Single blind | Information not present in EudraCT |
E.8.1.4 | Double blind | Information not present in EudraCT |
E.8.1.5 | Parallel group | Information not present in EudraCT |
E.8.1.6 | Cross over | Information not present in EudraCT |
E.8.1.7 | Other | Information not present in EudraCT |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
E.8.2.2 | Placebo | Information not present in EudraCT |
E.8.2.3 | Other | Information not present in EudraCT |
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 | 15 |
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 |
Argentina |
Australia |
Belgium |
Brazil |
Bulgaria |
Chile |
France |
Germany |
Hungary |
Israel |
Italy |
Japan |
Netherlands |
Poland |
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 | 2 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |