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

This study has been completed.
Sponsor:
Collaborator:
British Medical Research Council
Information provided by (Responsible Party):
Sarepta Therapeutics
ClinicalTrials.gov Identifier:
NCT00844597
First received: December 24, 2008
Last updated: September 3, 2015
Last verified: September 2015

December 24, 2008
September 3, 2015
January 2009
June 2010   (final data collection date for primary outcome measure)
  • Safety and Tolerability [ Time Frame: Baseline to 6 months ] [ Designated as safety issue: Yes ]
    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) ] [ Designated as safety issue: Yes ]
    Number of Patients with Treatment Emergent Adverse Events
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 ] [ Designated as safety issue: Yes ]
Complete list of historical versions of study NCT00844597 on ClinicalTrials.gov Archive Site
  • 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 ] [ Designated as safety issue: Yes ]
    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 ] [ Designated as safety issue: No ]
    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.
Urine samples drawn for pharmacokinetics. Tolerability will be assessed relative to baseline observations. [ Time Frame: 9 months ] [ Designated as safety issue: No ]
Not Provided
Not Provided
 
Dose-Ranging Study of AVI-4658 to Induce Dystrophin Expression in Selected Duchenne Muscular Dystrophy (DMD) Patients
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.
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).
Primary outcome is safety, tolerability and dose selection for future studies.
Interventional
Phase 1
Phase 2
Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Duchenne Muscular Dystrophy
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
  • 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
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.
 
Completed
19
December 2010
June 2010   (final data collection date for primary outcome measure)

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.
Male
5 Years to 15 Years   (Child)
No
Contact information is only displayed when the study is recruiting subjects
United Kingdom
 
NCT00844597
AVI-4658-28
Yes
Not Provided
Not Provided
Sarepta Therapeutics
Sarepta Therapeutics
British Medical Research Council
Study Director: Austen Eddy, MSM AVI BioPharma, Director, Clinical Operations
Sarepta Therapeutics
September 2015

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