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A Phase I/II, Open Label, Escalating Dose, Pilot Study to Assess Effect, Safety, Tolerability and PK of Multiple SC Doses of Drisapersen in Patients With Duchenne Muscular Dystrophy and to Assess the Potential for IV Dosing as an Alternative Route of Administration

Primary Purpose

Muscular Dystrophies

Status
Terminated
Phase
Phase 2
Locations
Study Type
Interventional
Intervention
Drisapersen
Sponsored by
BioMarin Pharmaceutical
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Muscular Dystrophies focused on measuring drisapersen

Eligibility Criteria

5 Years - 16 Years (Child)MaleDoes not accept healthy volunteers

Inclusion Criteria:

  • Boys aged between 5 and 16 years inclusive.
  • Duchenne muscular dystrophy resulting from a mutation correctable by treatment with PRO051.
  • Not ventilator dependent.
  • Life expectancy of at least six months.
  • No previous treatment with investigational medicinal treatment within six months prior to the study.
  • Willing and able to adhere to the study visit schedule and other protocol requirements.

Exclusion Criteria:

  • Aberrant RNA splicing and/or aberrant response to PRO051, detected by in vitro PRO051 assay during screening.
  • Known presence of dystrophin in 5% of fibers in a pre-study diagnostic muscle biopsy.
  • Severe muscle abnormalities defined as increased signal intensity in >50% of the tibialis anterior muscle at MRI.
  • FEV1 and/or FVC <60% of predicted.
  • Current or history of liver or renal disease.
  • Acute illness within 4 weeks prior to treatment (Day 1) which may interfere with the measurements.
  • Severe mental retardation which in the opinion of the investigator prohibits participation in this study.
  • Severe cardiac myopathy which in the opinion of the investigator prohibits participation in this study.
  • Need for mechanical ventilation.
  • Creatinine concentration above 1.5 times the upper limit of normal (age corrected).
  • Serum ASAT and/or ALAT concentration(s) which suggest hepatic impairment.
  • Use of anticoagulants, antithrombotics or antiplatelet agents.
  • Subject has donated blood less than 90 days before the start of the study.
  • Current or history of drug and/or alcohol abuse.
  • Participation in another trial with an investigational product.

Sites / Locations

    Arms of the Study

    Arm 1

    Arm Type

    Experimental

    Arm Label

    Drisapersen

    Arm Description

    Extension phase of treatment. Intravenous dosing of drisapersen will be investigated as an alternative route of administration

    Outcomes

    Primary Outcome Measures

    Acute phase: Safety data
    Summarized per dose group
    Acute phase and Continued Treatment Phase : Pharmacokinetics measured by T1/2, Cmax, Ctrough, 7d, tmax, and volume of distribution and clearance
    Plasma concentration versus time profiles of PRO051 (GSK2402968)
    Acute phase and Continued Treatment Phase : Safety as assessed by the collection of adverse events (AEs)
    Change from baseline and summarized values
    Continued Treatment Phase :Safety as assessed by laboratory parameters
    Change from baseline and summarized values

    Secondary Outcome Measures

    Acute phase: Production of exon skip 51 messenger Ribonucleic acid (mRNA)
    Acute phase: Presence of dystrophin expression
    Acute phase: Muscle function
    Timed tests and 6-minutes walk
    Acute phase: Muscle strength
    Quantitative Muscle Testing [QMT]- Cooperative International Neuromuscular Research Group (CINRG) and Manual Muscle Testing [MMT]
    Continued Treatment Phase: Exon skip efficiency
    Continued Treatment Phase Dystrophin expression in muscle biopsy
    Continued Treatment Phase: Muscle function
    Timed tests and 6-minutes walk
    Continued Treatment Phase: Muscle strength
    Handheld myometry and spirometry

    Full Information

    First Posted
    August 2, 2012
    Last Updated
    November 4, 2016
    Sponsor
    BioMarin Pharmaceutical
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    1. Study Identification

    Unique Protocol Identification Number
    NCT01910649
    Brief Title
    A Phase I/II, Open Label, Escalating Dose, Pilot Study to Assess Effect, Safety, Tolerability and PK of Multiple SC Doses of Drisapersen in Patients With Duchenne Muscular Dystrophy and to Assess the Potential for IV Dosing as an Alternative Route of Administration
    Official Title
    A Phase I/II, Open Label, Escalating Dose, Pilot Study to Assess the Effect, Safety, Tolerability and Pharmacokinetics of Multiple Subcutaneous Doses of Drisapersen in Patients With Duchenne Muscular Dystrophy and to Assess the Potential for Intravenous Dosing as an Alternative Route of Administration
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    November 2016
    Overall Recruitment Status
    Terminated
    Why Stopped
    Regulatory approval was not obtained for drisapersen, hence BioMarin is stopping the development of all exon skipping oligonucleotides in DMD.
    Study Start Date
    March 2008 (undefined)
    Primary Completion Date
    September 2016 (Actual)
    Study Completion Date
    September 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 extension phase of this study is to determine whether Drisapersen is effective in the treatment of boys with Duchenne muscular dystrophy resulting from a mutation thought to be corrected by exon 51 skipping.

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Muscular Dystrophies
    Keywords
    drisapersen

    7. Study Design

    Primary Purpose
    Treatment
    Study Phase
    Phase 2
    Interventional Study Model
    Single Group Assignment
    Masking
    None (Open Label)
    Allocation
    N/A
    Enrollment
    12 (Actual)

    8. Arms, Groups, and Interventions

    Arm Title
    Drisapersen
    Arm Type
    Experimental
    Arm Description
    Extension phase of treatment. Intravenous dosing of drisapersen will be investigated as an alternative route of administration
    Intervention Type
    Drug
    Intervention Name(s)
    Drisapersen
    Other Intervention Name(s)
    PRO051
    Intervention Description
    Subcutaneous and Intravenous
    Primary Outcome Measure Information:
    Title
    Acute phase: Safety data
    Description
    Summarized per dose group
    Time Frame
    18 weeks
    Title
    Acute phase and Continued Treatment Phase : Pharmacokinetics measured by T1/2, Cmax, Ctrough, 7d, tmax, and volume of distribution and clearance
    Description
    Plasma concentration versus time profiles of PRO051 (GSK2402968)
    Time Frame
    18 weeks
    Title
    Acute phase and Continued Treatment Phase : Safety as assessed by the collection of adverse events (AEs)
    Description
    Change from baseline and summarized values
    Time Frame
    72 weeks
    Title
    Continued Treatment Phase :Safety as assessed by laboratory parameters
    Description
    Change from baseline and summarized values
    Time Frame
    72 weeks
    Secondary Outcome Measure Information:
    Title
    Acute phase: Production of exon skip 51 messenger Ribonucleic acid (mRNA)
    Time Frame
    18 weeks
    Title
    Acute phase: Presence of dystrophin expression
    Time Frame
    18 weeks
    Title
    Acute phase: Muscle function
    Description
    Timed tests and 6-minutes walk
    Time Frame
    18 weeks
    Title
    Acute phase: Muscle strength
    Description
    Quantitative Muscle Testing [QMT]- Cooperative International Neuromuscular Research Group (CINRG) and Manual Muscle Testing [MMT]
    Time Frame
    18 weeks
    Title
    Continued Treatment Phase: Exon skip efficiency
    Time Frame
    72 weeks
    Title
    Continued Treatment Phase Dystrophin expression in muscle biopsy
    Time Frame
    72 weeks
    Title
    Continued Treatment Phase: Muscle function
    Description
    Timed tests and 6-minutes walk
    Time Frame
    300 weeks
    Title
    Continued Treatment Phase: Muscle strength
    Description
    Handheld myometry and spirometry
    Time Frame
    300 weeks

    10. Eligibility

    Sex
    Male
    Minimum Age & Unit of Time
    5 Years
    Maximum Age & Unit of Time
    16 Years
    Accepts Healthy Volunteers
    No
    Eligibility Criteria
    Inclusion Criteria: Boys aged between 5 and 16 years inclusive. Duchenne muscular dystrophy resulting from a mutation correctable by treatment with PRO051. Not ventilator dependent. Life expectancy of at least six months. No previous treatment with investigational medicinal treatment within six months prior to the study. Willing and able to adhere to the study visit schedule and other protocol requirements. Exclusion Criteria: Aberrant RNA splicing and/or aberrant response to PRO051, detected by in vitro PRO051 assay during screening. Known presence of dystrophin in 5% of fibers in a pre-study diagnostic muscle biopsy. Severe muscle abnormalities defined as increased signal intensity in >50% of the tibialis anterior muscle at MRI. FEV1 and/or FVC <60% of predicted. Current or history of liver or renal disease. Acute illness within 4 weeks prior to treatment (Day 1) which may interfere with the measurements. Severe mental retardation which in the opinion of the investigator prohibits participation in this study. Severe cardiac myopathy which in the opinion of the investigator prohibits participation in this study. Need for mechanical ventilation. Creatinine concentration above 1.5 times the upper limit of normal (age corrected). Serum ASAT and/or ALAT concentration(s) which suggest hepatic impairment. Use of anticoagulants, antithrombotics or antiplatelet agents. Subject has donated blood less than 90 days before the start of the study. Current or history of drug and/or alcohol abuse. Participation in another trial with an investigational product.
    Overall Study Officials:
    First Name & Middle Initial & Last Name & Degree
    N Goemans, Dr.
    Organizational Affiliation
    UZ Leuven
    Official's Role
    Principal Investigator

    12. IPD Sharing Statement

    Citations:
    PubMed Identifier
    21428760
    Citation
    Goemans NM, Tulinius M, van den Akker JT, Burm BE, Ekhart PF, Heuvelmans N, Holling T, Janson AA, Platenburg GJ, Sipkens JA, Sitsen JM, Aartsma-Rus A, van Ommen GJ, Buyse G, Darin N, Verschuuren JJ, Campion GV, de Kimpe SJ, van Deutekom JC. Systemic administration of PRO051 in Duchenne's muscular dystrophy. N Engl J Med. 2011 Apr 21;364(16):1513-22. doi: 10.1056/NEJMoa1011367. Epub 2011 Mar 23. Erratum In: N Engl J Med. 2011 Oct 6;365(14):1361.
    Results Reference
    result
    PubMed Identifier
    27588424
    Citation
    Goemans NM, Tulinius M, van den Hauwe M, Kroksmark AK, Buyse G, Wilson RJ, van Deutekom JC, de Kimpe SJ, Lourbakos A, Campion G. Long-Term Efficacy, Safety, and Pharmacokinetics of Drisapersen in Duchenne Muscular Dystrophy: Results from an Open-Label Extension Study. PLoS One. 2016 Sep 2;11(9):e0161955. doi: 10.1371/journal.pone.0161955. eCollection 2016.
    Results Reference
    derived

    Learn more about this trial

    A Phase I/II, Open Label, Escalating Dose, Pilot Study to Assess Effect, Safety, Tolerability and PK of Multiple SC Doses of Drisapersen in Patients With Duchenne Muscular Dystrophy and to Assess the Potential for IV Dosing as an Alternative Route of Administration

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