|E.1 Medical condition or disease under investigation
|Medical condition(s) being investigated
|Duchenne muscular dystrophy resulting from a mutation correctable by PRO045-induced DMD exon 45 skipping
|Medical condition in easily understood language
|Duchenne muscular dystrophy
|Diseases [C] - Musculoskeletal Diseases [C05]
|E.1.2 Medical condition or disease under investigation
|Duchenne muscular dystrophy
|System Organ Class
|10010331 - Congenital, familial and genetic disorders
|Condition being studied is a rare disease
|E.2 Objective of the trial
|Main objective of the trial
|To assess the efficacy of PRO045 after 48 weeks treatment in ambulant subjects with Duchenne muscular dystrophy.
|Secondary objectives of the trial
|To assess the safety and tolerability of PRO045 after 48 weeks of treatment in all study subjects with Duchenne muscular dystrophy including subjects from the dose-escalation phase of the study.
To determine the pharmacokinetics of PRO045 at different dose levels after subcutaneous administration in subjects with Duchenne muscular dystrophy.
To assess the pharmacokinetics, bioavailability and safety of PRO045 following single intravenous dose administration at different dose levels.
To assess the pharmacodynamics of PRO045 at different dose levels after subcutaneous administration in subjects with Duchenne muscular dystrophy.
To assess trend in efficacy in all subjects with Duchenne Muscular Dystrophy not included in the primary objective after 48 weeks of treatment.
|Trial contains a sub-study
|Principal inclusion criteria
|Duchenne muscular dystrophy resulting from a mutation correctable by treatment with PRO045 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).
Ambulant boys aged at least 5 years on the day of first dosing able to walk for at least 230 meters in the 6 minute walking distance (6MWD) at the first screening visit and also at the baseline visit. In addition, 2 of the 3 pre-treatment 6MWD tests (screen 1, screen 2, baseline) must be within ± 30 meters of each other prior to first PRO045 administration.
Adequate quality for biopsy (confirmed with MRI) of the lateral head of the gastrocnemius muscle. An alternative muscle may be considered for biopsy but only following discussion between the Principal Investigator and the Prosensa Medical Monitor.
Life expectancy of at least 3 years after inclusion in the study.
Glucocorticosteroid use which is stable for at least 3 months prior to first PRO045 administration. Subjects must have been receiving glucocorticosteroids for at least 6 months prior to the first PRO045 administration.
Willing and able to adhere to the study visit schedule and other protocol requirements.
Written informed consent signed (by parent(s)/legal guardian and/or the subject, according to the local regulations).
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.
|Principal exclusion criteria
|Known presence of dystrophin in ≥5% of fibres in a pre-study diagnostic muscle biopsy (i.e. historic muscle biopsy taken prior to written informed consent for this study).
Current or history of liver disease or impairment.
Current or history of renal disease or impairment.
At least two aPTT above ULN within the last month.
Screening platelet count below the lower limit of normal (LLN).
Acute illness within 4 weeks prior to first dose of PRO045 which may interfere with the study assessments.
Severe mental retardation or behavioural problems which, in the opinion of the investigator, prohibit participation in this study.
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.
Expected need for daytime mechanical ventilation within the next year.
Use of anticoagulants, antithrombotics or antiplatelet agents.
Use of idebenone or other forms of coenzyme Q10 within 1 month prior to the start of the screening for the study.
Use of nutritional or herbal supplements which, in the opinion of the investigator, may influence muscle performance, within1 month of the study
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.
|E.5 End points
|Primary end point(s)
|Change from baseline in 6MWD after 48 weeks of treatment phase at the selected dose
|Timepoint(s) of evaluation of this end point
|At 48 weeks of treatment phase .
|Secondary end point(s)
• Muscle function (North Star Ambulatory Assessment, Timed tests, 6MWD)
• Muscle strength (spirometry, handheld myometry)
• Performance of upper limb (PUL)
• DMD Functional Outcomes Questionnaire (DMD-FOS)
• Exploratory efficacy endpoints:
- Myotools (grip strength, key pinch, moviplate)
• Adverse events
• Local tolerability
• Laboratory assessments including:
- Routine biochemistry and haematology
- Urinalysis (routine parameters plus α1-microglobulin, microscopy) and 24-hour urine (additionally including protein electrophoresis, urine cystatin, KIM-1 and exploratory measurement of specific DMD protein biomarkers and micro RNAs)
- Coagulation parameters (aPTT, PTT [INR], fibrinogen)
- Complement split products (C3a, SC5b-9, Bb)
- Pro inflammatory markers (cytokines IL-6, TNF-α and chemokine MCP-1)
• Anti-dystrophin antibodies
• ECG parameters
• Vital signs (temperature, blood pressure, pulse rate, respiration rate)
• Physical examination and DEXA
• Standard renal ultrasound
• t ½
• AUC: 0-24h, 0-7d, 0-∞
• Cmax, Ctrough, 7d
• Vd/F (Volume of distribution)
• CL/F (clearance)
• PRO045 levels in urine
• PRO045 levels in muscle tissue
• 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 45 mRNA (in muscle biopsy)
• Exploratory PD endpoints:
- Nuclear Magnetic Resonance imaging and spectroscopy (MRI and MRS)
- Exploratory biomarkers(e.g. TIMP, MMP-9, miR-1, miR-133)
|Timepoint(s) of evaluation of this end point
|Efficacy: at all available study visits
Safety: at all time points
Pharmacokinetic parameters: at all available study visits
Pharmacodynamic parameters: at all available study visits
|E.6 and E.7 Scope of the trial
|Scope of the trial
|Trial type and phase
|Human pharmacology (Phase I)
|First administration to humans
|Other trial type description
|Therapeutic exploratory (Phase II)
|Therapeutic confirmatory (Phase III)
|Therapeutic use (Phase IV)
|E.8 Design of the trial
| Comparator of controlled trial
|Other medicinal product(s)
|Number of treatment arms in the trial
The trial involves single site in the Member State concerned
| The trial involves multiple sites in the Member State concerned
|The trial involves multiple Member States
|Number of sites anticipated in the EEA
|E.8.6 Trial involving sites outside the EEA
|Trial being conducted both within and outside the EEA
|Trial being conducted completely outside of the EEA
|Trial has a data monitoring committee
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
|In the Member State concerned years
|In the Member State concerned months
|In the Member State concerned days
|In all countries concerned by the trial years
|In all countries concerned by the trial months
|In all countries concerned by the trial days