Clinical trial NCT01957059: A Phase I/II Study of BMN053 in Subjects With Duchenne Muscular Dystrophy (DMD)
Official title: A Phase I/II, Open-label, Dose Escalating With 48 Week Treatment Study to Assess the Safety and Tolerability, Pharmacokinetics, Pharmacodynamics and Efficacy of BMN053 (Previously Known as PRO053) in Subjects With Duchenne Muscular Dystrophy.
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Duchenne Muscular Dystrophy
Keywords: DMD
Duchenne muscular dystrophy
Duchenne
BMN053
BioMarin
Lead sponsor: BioMarin Pharmaceutical
Sponsor class: INDUSTRY
First posted: 2013-10-08
Enrollment: 9
Sex: MALE
Minimum age (years): 5
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of the study is to see whether BMN053 is safe and effective to use as medication for Duchenne muscular dystrophy (DMD) patients with a mutation around location 53 in the DNA for the dystrophin protein.

Detailed description: A Phase I/II, open-label, dose escalating with 48-week treatment study to assess the safety and tolerability, pharmacokinetics, pharmacodynamics and efficacy of BMN 053 (previously known as PRO053) in subjects with Duchenne muscular dystrophy

Eligibility criteria: Inclusion Criteria:

1. Duchenne muscular dystrophy resulting from a mutation correctable by treatment with BMN053 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. In addition, results of the 6MWD test must be within ±30 metres of each other at 2 of 3 pre-treatment visits (screen 1, 2 and baseline) prior to first BMN053 administration.
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 BMN053 administration. Subjects must have been receiving glucocorticosteroids for at least 6 months prior to the first BMN053 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.

Exclusion Criteria:

1. Current or history of liver disease or impairment.
2. Current or history of renal disease or impairment.
3. At least two aPTT above upper limit of normal (ULN) within the last month prior to first dose of BMN053.
4. Screening platelet count below the lower limit of normal (LLN).
5. Acute illness within 4 weeks prior to first dose of BMN053 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 BMN053.
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.

Primary outcomes:
measure: Change from baseline in 6 minute walk test
timeFrame: after 48 weeks of treatment phase
Secondary outcomes:
measure: Muscle function
timeFrame: after 48 weeks treatment phase
measure: Muscle strength
timeFrame: after 48 weeks treatment phase
measure: Pulmonary function
timeFrame: after 48 weeks treatment phase
measure: Functional outcomes questionnaire
timeFrame: after 48 weeks treatment phase
measure: Adverse Events
timeFrame: after single intravenous and subcutaneous doses, and after 48 weeks of treatment phase
measure: Safety Laboratory
timeFrame: after single intravenous and subcutaneous doses, and after 48 weeks of treatment phase
measure: Cardiac function
timeFrame: after single intravenous and subcutaneous doses, and after 48 weeks of treatment phase
measure: Pharmacokinetic parameters at different dose levels
timeFrame: after single intravenous and subcutaneous doses, and after 48 weeks of treatment phase
measure: Presence of (BMD-like) dystrophin expression in muscle biopsy
timeFrame: after 48 weeks treatment phase
measure: Production of exon skip 53 mRNA in muscle biopsy
timeFrame: after 48 weeks treatment phase
Other outcomes:
Locations:
city: Leuven
country: Belgium
facility: UZ Leuven, Campus Gasthuisberg
city: Paris
country: France
facility: Institut de Myologie
city: Rome
country: Italy
facility: Policlinico Universitario Agostino Gemelli
city: Leiden
country: Netherlands
facility: Leids Universitair Medisch Centrum
city: London
country: United Kingdom
facility: Great Ormond Street Hospital for Children
city: Newcastle
country: United Kingdom
facility: Institute of Genetic Medicine International Centre for Life
Study officials:
affiliation: Institute of Genetic Medicine, Newcastle University, UK
name: V. Straub, Prof.
role: PRINCIPAL_INVESTIGATOR
References: