A study to test if BMN 053 is safe and effective in people who suffer from Duchenne muscular dystrophy

• Register: EUCTR
• Last refreshed on: 30 June 2019
• Main ID: EUCTR2011-005042-35-GB
• Date of registration: 18/03/2013
• Prospective Registration: Yes
• Primary sponsor: BioMarin Pharmaceutical Inc.
• Public title: A study to test if BMN 053 is safe and effective in people who suffer from Duchenne muscular dystrophy
• Scientific 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 BMN 053 (previously known as PRO053) in subjects with Duchenne muscular dystrophy
• Date of first enrolment: 23/08/2013
• Target sample size: 45
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2011-005042-35
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: no; Randomised: Open: Single blind: Double blind: Parallel group: Cross over: Other: If controlled, specify comparator, Other Medicinial Product: Placebo: Other:
• Phase: Human pharmacology (Phase I): yes Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Argentina, Australia, Belgium, Brazil, Bulgaria, Chile, France, Germany, Hungary, Israel, Italy, Japan, Netherlands, Poland, Turkey, United Kingdom, United States

Contacts

• Name: Clinical department
• Affiliation: BioMarin Pharmaceutical Inc.

• Name: Clinical department
• Affiliation: BioMarin Pharmaceutical Inc.

Key inclusion & exclusion criteria

Inclusion criteria:
1. Duchenne muscular dystrophy resulting from a mutation correctable by treatment with BMN 053 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 screening visit and also at the baseline visit. In addition, results of 2 of any of the 3 pretreatment 6MWD tests (assessed screen 1, screen 2, baseline) must be within ±30 metres of each other prior to first BMN 053 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 BMN 053 administration. Subjects must have been receiving glucocorticosteroids for at least 6 months prior to the first BMN 053 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.
Are the trial subjects under 18? yes
Number of subjects for this age range: 45
F.1.2 Adults (18-64 years) no
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range

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) within the last month prior to first dose of BMN 053.
4. Screening platelet count below the lower limit of normal (LLN).
5. Acute illness within 4 weeks prior to first dose of BMN 053 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 BMN 053.
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.


Age minimum:
Age maximum:
Gender:
Female: no
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Musculoskeletal Diseases [C05]

Duchenne muscular dystrophy resulting from a mutation correctable by BMN 053-induced DMD exon 53 skipping
MedDRA version: 18.1 Level: PT Classification code 10013801 Term: Duchenne muscular dystrophy System Organ Class: 10010331 - Congenital, familial and genetic disorders

Intervention(s)

Product Name: BMN 053
Product Code: BMN 053
Pharmaceutical Form: Solution for injection/infusion
INN or Proposed INN: PS524
Current Sponsor code: PS524
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 200-

Primary Outcome(s)

Timepoint(s) of evaluation of this end point: At screening, baseline, at weeks 13, 25, 37 and 49

Secondary Objective: To assess the safety and tolerability of BMN 053 after single intravenous (IV) and subcutaneous (SC) dose in subjects with Duchenne muscular dystrophy.

To investigate the pharmacokinetics BMN 053 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 BMN 053 at different dosing regimens levels in subjects with Duchenne muscular dystrophy.

To assess efficacy and safety of BMN 053 in subjects with Duchenne Muscular Dystrophy not included in the primary analysis after 48 weeks of dosing and/or dosing extension

Main Objective: To assess the efficacy of BMN 053 at recommended dosing regimen after 48 weeks treatment in ambulant subjects with Duchenne muscular dystrophy.

Primary end point(s): Change from baseline in 6MWD after 48 weeks of treatment phase for primary evaluation at recommended regimen

Secondary Outcome(s)

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

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
- 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)
• BMN 053 concentrations in urine
• BMN 053 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)

Secondary ID(s)

PRO053-CLIN-01

Source(s) of Monetary Support

BioMarin Pharmaceutical Inc.

Ethics review

Status: Approved
Approval date:
Contact:

Results

• Results available: Yes
• Date Posted: 23/03/2017
• Date Completed: 31/08/2016
• URL: https://www.clinicaltrialsregister.eu/ctr-search/trial/2011-005042-35/results