Back to resultsA Phase I/II Study of BMN053 in Subjects With Duchenne Muscular Dystrophy (DMD)
Primary Purpose
Duchenne Muscular Dystrophy
Status
Terminated
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
Regimen Selection Phase Group 2
Regimen Selection Phase Group 3
Treatment Phase Group 4
Regimen Selection Phase Group 1 (COMPLETED)
Dosing Extension
Sponsored by
About this trial
This is an interventional treatment trial for Duchenne Muscular Dystrophy focused on measuring DMD, Duchenne muscular dystrophy, Duchenne, BMN053, BioMarin
Eligibility Criteria
Inclusion Criteria:
- 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).
- 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.
- 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.
- 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 BMN053 administration. Subjects must have been receiving glucocorticosteroids for at least 6 months prior to the first BMN053 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.
- Anticipated adequate vein access for intravenous (IV) infusion.
Exclusion Criteria:
- Current or history of liver disease or impairment.
- Current or history of renal disease or impairment.
- At least two aPTT above upper limit of normal (ULN) within the last month prior to first dose of BMN053.
- Screening platelet count below the lower limit of normal (LLN).
- Acute illness within 4 weeks prior to first dose of BMN053 which may interfere with the study assessments.
- Severe mental retardation and/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 within 1 month prior to first dose of BMN053.
- 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.
Sites / Locations
- UZ Leuven, Campus Gasthuisberg
- Institut de Myologie
- Policlinico Universitario Agostino Gemelli
- Leids Universitair Medisch Centrum
- Great Ormond Street Hospital for Children
- Institute of Genetic Medicine International Centre for Life
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Arm Type
Experimental
Experimental
Experimental
Experimental
Arm Label
Dose escalation phase
Regimen selection
48-week Treatment Phase
Dosing extension
Arm Description
In the dose-escalation phase, following screening assessment, two cohorts of three subjects each receive two single doses of BMN 053 in two study periods (i.e., four single doses in total per subject). In each study period they will receive BMN 053 by IV infusion and by SC injection (separated by one week). The proposed doses are 1 mg/kg (Cohort 1, study period 1), 3 mg/kg (Cohort 2, study period 1), 6 mg/kg (Cohort 1, study period 2) and 9 mg/kg (Cohort 2, study period 2). The actual doses may be amended or repeated based on emerging data from previous doses.
After completion of the dose-escalation period of Cohort 1, the safety data of the subjects will be reviewed by a DSMB and if no safety concerns these subjects will continue to receive 6 mg/kg BMN053 weekly by SC injection for 48 weeks. 3 more treatment-naïve subjects will be entered into this Group. These 6 subjects will form Group 1 of the Regimen Selection phase who received 6 mg/kg SC. At the time of this amendment (4) this part of the study has been completed. Following completion of the dose-escalation study period of Cohort 2 (9 mg/kg), the planned review of the preliminary plasma PK data from the dose-escalation phase showed a relative bioavailability of 50% for BMN053 with SC dosing (50% lower plasma AUC after SC dosing compared to IV dosing). Taking into consideration the risk of injection site reactions noted with similar compounds when administered SC over longer term, the planned 9 mg/kg BMN053 weekly by SC injection will be discontinued to be replaced by an IV regimen.
Thirty additional treatment-naïve subjects will be recruited for the primary evaluation and will receive treatment at the recommended regimen for a total of 48 weeks. Subjects dosed initially in the dose escalation phase and/or the regimen selection phase of the study will not be included in the primary analysis. Following completion of the 2nd study period for Cohort 2, the safety data will be reviewed by the DSMB and in the absence of safety concerns the subjects may enter the 48 week treatment phase and receive 9 mg/kg PRO053 once weekly by SC injection. Three new subjects will enter cohort 2 (i.e. 6 subjects in total at this dose level). After the initial 12 subjects have completed 12 weeks of dosing the dose for the Treatment group (30 new subjects) will be selected based on the totality of the 12-week data from those initial 12 subjects. The initial 12 subjects will also be dosed on the selected dose (i.e. continue on their dose or [down-]titrate).
All subjects who have completed the dose escalation and regimen selection phase of the study (N=15), and subjects who have complete the treatment phase of the study who have tolerated the treatment will be offered to continue dosing in the dosing extension with ongoing assessment of efficacy, safety, and tolerability of BMN 053. Safety, efficacy, PK/PD and biomarker assessments will be performed at scheduled visits; adverse events (AEs) and concomitant medications and therapies will be continuously monitored. The dose extension phase will provide BMN 053 treatment for 48 weeks.
Outcomes
Primary Outcome Measures
Change from baseline in 6 minute walk test
Secondary Outcome Measures
Muscle function
Muscle strength
Pulmonary function
Functional outcomes questionnaire
Adverse Events
Safety Laboratory
Cardiac function
Pharmacokinetic parameters at different dose levels
Presence of (BMD-like) dystrophin expression in muscle biopsy
Production of exon skip 53 mRNA in muscle biopsy
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT01957059
Brief Title
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
2. Study Status
Record Verification Date
December 2017
Overall Recruitment Status
Terminated
Study Start Date
June 2013 (Actual)
Primary Completion Date
August 3, 2016 (Actual)
Study Completion Date
August 3, 2016 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
BioMarin Pharmaceutical
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
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
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Duchenne Muscular Dystrophy
Keywords
DMD, Duchenne muscular dystrophy, Duchenne, BMN053, BioMarin
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
9 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Dose escalation phase
Arm Type
Experimental
Arm Description
In the dose-escalation phase, following screening assessment, two cohorts of three subjects each receive two single doses of BMN 053 in two study periods (i.e., four single doses in total per subject). In each study period they will receive BMN 053 by IV infusion and by SC injection (separated by one week). The proposed doses are 1 mg/kg (Cohort 1, study period 1), 3 mg/kg (Cohort 2, study period 1), 6 mg/kg (Cohort 1, study period 2) and 9 mg/kg (Cohort 2, study period 2). The actual doses may be amended or repeated based on emerging data from previous doses.
Arm Title
Regimen selection
Arm Type
Experimental
Arm Description
After completion of the dose-escalation period of Cohort 1, the safety data of the subjects will be reviewed by a DSMB and if no safety concerns these subjects will continue to receive 6 mg/kg BMN053 weekly by SC injection for 48 weeks. 3 more treatment-naïve subjects will be entered into this Group. These 6 subjects will form Group 1 of the Regimen Selection phase who received 6 mg/kg SC. At the time of this amendment (4) this part of the study has been completed. Following completion of the dose-escalation study period of Cohort 2 (9 mg/kg), the planned review of the preliminary plasma PK data from the dose-escalation phase showed a relative bioavailability of 50% for BMN053 with SC dosing (50% lower plasma AUC after SC dosing compared to IV dosing). Taking into consideration the risk of injection site reactions noted with similar compounds when administered SC over longer term, the planned 9 mg/kg BMN053 weekly by SC injection will be discontinued to be replaced by an IV regimen.
Arm Title
48-week Treatment Phase
Arm Type
Experimental
Arm Description
Thirty additional treatment-naïve subjects will be recruited for the primary evaluation and will receive treatment at the recommended regimen for a total of 48 weeks. Subjects dosed initially in the dose escalation phase and/or the regimen selection phase of the study will not be included in the primary analysis.
Following completion of the 2nd study period for Cohort 2, the safety data will be reviewed by the DSMB and in the absence of safety concerns the subjects may enter the 48 week treatment phase and receive 9 mg/kg PRO053 once weekly by SC injection. Three new subjects will enter cohort 2 (i.e. 6 subjects in total at this dose level).
After the initial 12 subjects have completed 12 weeks of dosing the dose for the Treatment group (30 new subjects) will be selected based on the totality of the 12-week data from those initial 12 subjects. The initial 12 subjects will also be dosed on the selected dose (i.e. continue on their dose or [down-]titrate).
Arm Title
Dosing extension
Arm Type
Experimental
Arm Description
All subjects who have completed the dose escalation and regimen selection phase of the study (N=15), and subjects who have complete the treatment phase of the study who have tolerated the treatment will be offered to continue dosing in the dosing extension with ongoing assessment of efficacy, safety, and tolerability of BMN 053. Safety, efficacy, PK/PD and biomarker assessments will be performed at scheduled visits; adverse events (AEs) and concomitant medications and therapies will be continuously monitored. The dose extension phase will provide BMN 053 treatment for 48 weeks.
Intervention Type
Drug
Intervention Name(s)
Regimen Selection Phase Group 2
Intervention Description
All doses of BMN053 will be administered as IV infusions. The proposed doses are as follows:
• 3 mg/kg
Intervention Type
Drug
Intervention Name(s)
Regimen Selection Phase Group 3
Intervention Description
All doses of BMN053 will be administered as IV infusions. The proposed doses are as follows:
• 4-6 mg/kg
Intervention Type
Drug
Intervention Name(s)
Treatment Phase Group 4
Intervention Description
All doses of PRO053 will be administered as IV infusions. The proposed doses will be decided upon completion of the Regimen Selection Phase of Groups 2 and 3
Intervention Type
Drug
Intervention Name(s)
Regimen Selection Phase Group 1 (COMPLETED)
Intervention Description
All doses of BMN053 have been administered as subcutaneous injections.
Intervention Type
Drug
Intervention Name(s)
Dosing Extension
Intervention Description
All doses of PRO053 will be administered as IV infusions. The proposed doses will be decided upon completion of the Regimen Selection Phase of Groups 2 and 3 and the Treatment Phase Group 4.
Primary Outcome Measure Information:
Title
Change from baseline in 6 minute walk test
Time Frame
after 48 weeks of treatment phase
Secondary Outcome Measure Information:
Title
Muscle function
Time Frame
after 48 weeks treatment phase
Title
Muscle strength
Time Frame
after 48 weeks treatment phase
Title
Pulmonary function
Time Frame
after 48 weeks treatment phase
Title
Functional outcomes questionnaire
Time Frame
after 48 weeks treatment phase
Title
Adverse Events
Time Frame
after single intravenous and subcutaneous doses, and after 48 weeks of treatment phase
Title
Safety Laboratory
Time Frame
after single intravenous and subcutaneous doses, and after 48 weeks of treatment phase
Title
Cardiac function
Time Frame
after single intravenous and subcutaneous doses, and after 48 weeks of treatment phase
Title
Pharmacokinetic parameters at different dose levels
Time Frame
after single intravenous and subcutaneous doses, and after 48 weeks of treatment phase
Title
Presence of (BMD-like) dystrophin expression in muscle biopsy
Time Frame
after 48 weeks treatment phase
Title
Production of exon skip 53 mRNA in muscle biopsy
Time Frame
after 48 weeks treatment phase
10. Eligibility
Sex
Male
Minimum Age & Unit of Time
5 Years
Maximum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
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).
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.
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.
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 BMN053 administration. Subjects must have been receiving glucocorticosteroids for at least 6 months prior to the first BMN053 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.
Anticipated adequate vein access for intravenous (IV) infusion.
Exclusion Criteria:
Current or history of liver disease or impairment.
Current or history of renal disease or impairment.
At least two aPTT above upper limit of normal (ULN) within the last month prior to first dose of BMN053.
Screening platelet count below the lower limit of normal (LLN).
Acute illness within 4 weeks prior to first dose of BMN053 which may interfere with the study assessments.
Severe mental retardation and/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 within 1 month prior to first dose of BMN053.
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
V. Straub, Prof.
Organizational Affiliation
Institute of Genetic Medicine, Newcastle University, UK
Official's Role
Principal Investigator
Facility Information:
Facility Name
UZ Leuven, Campus Gasthuisberg
City
Leuven
ZIP/Postal Code
3000
Country
Belgium
Facility Name
Institut de Myologie
City
Paris
ZIP/Postal Code
75651
Country
France
Facility Name
Policlinico Universitario Agostino Gemelli
City
Rome
ZIP/Postal Code
00168
Country
Italy
Facility Name
Leids Universitair Medisch Centrum
City
Leiden
ZIP/Postal Code
2333ZA
Country
Netherlands
Facility Name
Great Ormond Street Hospital for Children
City
London
ZIP/Postal Code
WC1N 3JH
Country
United Kingdom
Facility Name
Institute of Genetic Medicine International Centre for Life
City
Newcastle
ZIP/Postal Code
NE1 3BZ
Country
United Kingdom
12. IPD Sharing Statement
Links:
URL
http://www.biomarin.com
Description
BioMarin website
Learn more about this trial
A Phase I/II Study of BMN053 in Subjects With Duchenne Muscular Dystrophy (DMD)
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