Duchenne muscular dystrophy Duchenne's disease
Conditions
Interventions
Doses with the IP, BMN 045, will be administered by subcutaneous (SC) injection
once per week.
Five groups of three subjects are planned in the dose-escalation phase. The
proposed starting doses in
Sponsors
BioMarin Parmaceutical Inc.
Eligibility
Age
2 Years to 11 Years
Inclusion criteria
Inclusion criteria: 1. Duchenne muscular dystrophy resulting from a mutation correctable by treatment with BMN 045 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 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 BMN 045 administration 3. Adequate quality for biopsy (confirmed with MRI) of the lateral head of the gastrocnemius muscle. 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 BMN 045 administration. Subjects must have been receiving glucocorticosteroids for at least 6 months prior to the first BMN 045 administration.
Exclusion criteria
Exclusion criteria: 1. 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). 2. Current or history of liver disease or impairment 3. Current, or history of, renal disease or impairment. 4. at least two aPTT above ULN within the last month 5. Screening platelet count below the lower limit of normal (LLN). 6. Acute illness within 4 weeks prior to first dose of BMN 045 which may interfere with the study assessments. 7. Severe mental retardation or behavioural problems which, in the opinion of the investigator, prohibit participation in this study 8.Severe cardiomyopathy which in the opinion of the investigator prohibits participation in this study. If a subject has a left ventricular ejection fraction
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Change from baseline in 6MWD after 48 weeks of treatment phase at selected dose. | — |
Secondary
| Measure | Time frame |
|---|---|
| Efficacy (at all available study visits): - 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: - Accelerometry - Myotools (grip strength, key pinch, moviplate) Safety parameters: - Adverse events - Local tolerability - Laboratory assessments including: - Routine biochemistry and haematology - Urinalysis (routine parameters plus a1-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-a and chemokine MCP-1) - Anti-dystrophin antibodies - ECG parameters - Vital signs (temperature, blood pressure, pulse rate, respiration rate) - Echocardiography - Physical examination and DEXA - Standard renal ultrasound Pharmacokinetic parameters - BMN 045 levels in urine - BMN 045 levels 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 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) | — |
Countries
Netherlands
Outcome results
None listed