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Dose-Ranging Study of AVI-4658 to Induce Dystrophin Expression in Selected Duchenne Muscular Dystrophy (DMD) Patients

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ClinicalTrials.gov Identifier: NCT00844597
Recruitment Status : Completed
First Posted : February 16, 2009
Results First Posted : October 6, 2015
Last Update Posted : October 6, 2015
Sponsor:
Collaborator:
British Medical Research Council
Information provided by (Responsible Party):
Sarepta Therapeutics, Inc.

Tracking Information
First Submitted Date  ICMJE December 24, 2008
First Posted Date  ICMJE February 16, 2009
Results First Submitted Date  ICMJE June 8, 2015
Results First Posted Date  ICMJE October 6, 2015
Last Update Posted Date October 6, 2015
Study Start Date  ICMJE January 2009
Actual Primary Completion Date June 2010   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 3, 2015)
  • Safety and Tolerability [ Time Frame: Baseline to 6 months ]
    Number of subjects with 1 or more Treatment Emergent Adverse Event that are possibly related to the investigational drug
  • Treatment Emergent Adverse Events [ Time Frame: from Baseline to Follow up (27 weeks) ]
    Number of Patients with Treatment Emergent Adverse Events
Original Primary Outcome Measures  ICMJE
 (submitted: February 12, 2009)
Safety will be assessed in a comprehensive series of conventional safety laboratory tests,throughout the course of the study. Furthermore, careful evaluations will be made during scheduled physical exams. [ Time Frame: 9 months ]
Change History Complete list of historical versions of study NCT00844597 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: September 3, 2015)
  • Pharmacokinetics - Mean Peak Plasma Concentration of AVI-4658 After Administration [ Time Frame: Samples were taken: 30 minutes pre dose; and at 5 (±1), 15 (±2), 30 (±5), 60 (±5), and 90 (±5) minutes; and 2, 4, 6, 8, 12, and 24 hours (all ± 15 minutes) post dose at Weeks 1, 6, and 12 ]
    Standard Pharmacokinetic parameters estimated using non-compartmental modeling of plasma concentration data.
  • Efficacy of Eteplirsen Over 12 Weeks of Dosing [ Time Frame: Biopsies were taken at Baseline and Week 14 ]
    Efficacy was defined as an estimated change in the percentage of dystrophin positive fibers (assessed by IHC) at Week 14 from Baseline after 12 weekly doses of eterplirsen. This outcome measure represents the number of patients to show an increase in the percentage of dystrophin-positive fibers.
Original Secondary Outcome Measures  ICMJE
 (submitted: February 12, 2009)
Urine samples drawn for pharmacokinetics. Tolerability will be assessed relative to baseline observations. [ Time Frame: 9 months ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Dose-Ranging Study of AVI-4658 to Induce Dystrophin Expression in Selected Duchenne Muscular Dystrophy (DMD) Patients
Official Title  ICMJE Clinical Study to Assess the Safety fo AVI-4658 in Subjects With Duchenne Muscular Dystrophy Due to a Frame-shift Mutation Amenable to Correction by Skipping Exon 51.
Brief Summary The specific aim of this Phase I/II study is to assess the safety of intravenous administered Morpholino oligomer directed against exon 51 (AVI-4658 PMO).
Detailed Description Primary outcome is safety, tolerability and dose selection for future studies.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Duchenne Muscular Dystrophy
Intervention  ICMJE Drug: AVI-4658 for Injection
AVI-4658 for Injection, is packaged as 100 mg/mL in phosphate buffered saline with 1 mL per vial. Study dosages will be infused over a 1 hour period with Normal saline in 6 dose cohorts.
Other Name: Eteplirsen
Study Arms  ICMJE
  • Experimental: Cohort 1 - 0.5 mg/kg/wk
    Subjects in this group will receive a 0.5 mg/kg/wk dose of AVI-4658 over 12 weekly IV infusions in 50 mL of normal saline solution over a 60-minute period
    Intervention: Drug: AVI-4658 for Injection
  • Experimental: Cohort 2 - 1.0 mg/kg/wk
    Subjects in this group will receive a 1.0 mg/kg/wk dose of AVI-4658 over 12 weekly IV infusions in 50 mL of normal saline solution over a 60-minute period
    Intervention: Drug: AVI-4658 for Injection
  • Experimental: Cohort 3 - 2.0 mg/kg/wk
    Subjects in this group will receive a 2.0 mg/kg/wk dose of AVI-4658 over 12 weekly IV infusions in 50 mL of normal saline solution over a 60-minute period
    Intervention: Drug: AVI-4658 for Injection
  • Experimental: Cohort 4 - 4.0 mg/kg/wk
    Subjects in this group will receive a 4.0 mg/kg/wk dose of AVI-4658 over 12 weekly IV infusions in 50 mL of normal saline solution over a 60-minute period
    Intervention: Drug: AVI-4658 for Injection
  • Experimental: Cohort 5 - 10.0 mg/kg/wk
    Subjects in this group will receive a 10.0 mg/kg/wk dose of AVI-4658 over 12 weekly IV infusions in 50 mL of normal saline solution over a 60-minute period
    Intervention: Drug: AVI-4658 for Injection
  • Experimental: Cohort 6 - 20.0 mg/kg/wk
    Subjects in this group will receive a 20.0 mg/kg/wk dose of AVI-4658 over 12 weekly IV infusions in 50 mL of normal saline solution over a 60-minute period
    Intervention: Drug: AVI-4658 for Injection
Publications * Cirak S, Arechavala-Gomeza V, Guglieri M, Feng L, Torelli S, Anthony K, Abbs S, Garralda ME, Bourke J, Wells DJ, Dickson G, Wood MJ, Wilton SD, Straub V, Kole R, Shrewsbury SB, Sewry C, Morgan JE, Bushby K, Muntoni F. Exon skipping and dystrophin restoration in patients with Duchenne muscular dystrophy after systemic phosphorodiamidate morpholino oligomer treatment: an open-label, phase 2, dose-escalation study. Lancet. 2011 Aug 13;378(9791):595-605. doi: 10.1016/S0140-6736(11)60756-3. Epub 2011 Jul 23.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: April 22, 2011)
19
Original Estimated Enrollment  ICMJE
 (submitted: February 12, 2009)
16
Actual Study Completion Date  ICMJE December 2010
Actual Primary Completion Date June 2010   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Has provided written informed assent (as required by EC) and parents/guardians have provided written informed consent.
  2. Has an out-of-frame deletion(s) that could be corrected by skipping exon 51 based on DNA sequencing data from the candidate.
  3. Is male and between the ages of ≥ 5 years and ≤ 15 years.
  4. Has a muscle biopsy analysis showing < 5% revertant fibres present at baseline.
  5. DNA sequencing of the candidate's dystrophin exon 51 confirms that no DNA polymorphisms are present that could compromise PMO duplex formation or there is confirmation of in vitro dystrophin production after AVI-4658 exposure to fibroblast or myoblast in vitro cultures.
  6. Intact right and left bicep muscles or alternative arm muscle group.
  7. Is able to walk independently at least 25 meters.
  8. Has a forced vital capacity (FVC) ≥ 50% of predicted and does not require ventilatory support or supplemental oxygen.
  9. Receives the standard of care for DMD as recommended by the DMD care recommendations from the North Star UK and TREAT-NMD.
  10. The parent(s) or legal guardian and Subject have undergone counselling about the expectations of this protocol and agree to participate.
  11. The parent(s) or legal guardian and Subject intend to comply with all study evaluations and return for all study activities.

Exclusion Criteria:

  1. A DNA polymorphism within exon 51 that may compromise PMO duplex formation.
  2. Known antibodies to dystrophin.
  3. Lacks intact right and left bicep muscles or alternative arm muscle group.
  4. A calculated creatinine clearance less than 70% of predicted normal for age based on the Cockcroft and Gault Formula.
  5. A left ventricular ejection fraction (EF) of < 35% and/or fractional shortening of <25% based on echocardiography (ECHO)during screening.
  6. A history of respiratory insufficiency as defined by need for intermittent or continuous supplemental oxygen.
  7. A severe cognitive dysfunction rendering the potential subject unable to understand and comply with the study protocol.
  8. Any known immune deficiency or autoimmune disease.
  9. A known bleeding disorder or has received chronic anticoagulant treatment within three months of study entry.
  10. Receipt of pharmacologic treatment, apart from corticosteroids, that might affect muscle strength or function within 8 weeks of study entry (viz., growth hormone, anabolic steroids).
  11. Surgery within 3 months of study entry or planned for anytime during the duration of the study.
  12. Another clinically significant illness at time of study entry.
  13. Subject or parent has active psychiatric disorder, has adverse psychosocial circumstances,recent significant emotional loss, and/or history of depressive or anxiety disorder that might interfere with protocol compliance.
  14. Use of any experimental treatments, has participated in any DMD interventional clinical trial within 4 weeks of study entry or participated in the AVI-4658-33 intramuscular (i.m.) trial.
Sex/Gender  ICMJE
Sexes Eligible for Study: Male
Ages  ICMJE 5 Years to 15 Years   (Child)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United Kingdom
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00844597
Other Study ID Numbers  ICMJE AVI-4658-28
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Sarepta Therapeutics, Inc.
Study Sponsor  ICMJE Sarepta Therapeutics, Inc.
Collaborators  ICMJE British Medical Research Council
Investigators  ICMJE
Study Director: Austen Eddy, MSM AVI BioPharma, Director, Clinical Operations
PRS Account Sarepta Therapeutics, Inc.
Verification Date September 2015

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP