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

This study has been completed.
British Medical Research Council
Information provided by:
Sarepta Therapeutics Identifier:
First received: December 24, 2008
Last updated: April 22, 2011
Last verified: April 2011

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).

Condition Intervention Phase
Duchenne Muscular Dystrophy
Drug: AVI-4658 for Injection
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: 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.

Resource links provided by NLM:

Further study details as provided by Sarepta Therapeutics:

Primary Outcome Measures:
  • 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: 6 months ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Urine and plasma samples drawn for pharmacokinetics. Tolerability will be assessed relative to baseline observations. [ Time Frame: 6 months ] [ Designated as safety issue: No ]

Enrollment: 19
Study Start Date: January 2009
Study Completion Date: December 2010
Primary Completion Date: June 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 1 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 as follows:

Cohort 1: 0.5mg/kg once weekly for 12 weeks; Cohort 2: 1.0mg/kg once weekly for 12 weeks; Cohort 3: 2.0mg/kg once weekly for 12 weeks; Cohort 4: 4.0mg/kg once weekly for 12 weeks; Cohort 5: 10.0mg/kg once weekly for 12 weeks; Cohort 6: 20.0mg/kg once weekly for 12 weeks

Detailed Description:

Primary outcome is safety, tolerability and dose selection for future studies.


Ages Eligible for Study:   5 Years to 15 Years
Genders Eligible for Study:   Male
Accepts Healthy Volunteers:   No

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.
  Contacts and Locations
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Please refer to this study by its identifier: NCT00844597

United Kingdom
Great Ormond Street Hospital
London, England, United Kingdom, WC1N 3JH
Royal Victoria Infirmary
Newcastle Upon Tyne, England, United Kingdom, NE2 4LP
Sponsors and Collaborators
Sarepta Therapeutics
British Medical Research Council
Study Director: Austen Eddy, MSM AVI BioPharma, Director, Clinical Operations
  More Information

No publications provided by Sarepta Therapeutics

Additional publications automatically indexed to this study by Identifier (NCT Number):
Responsible Party: Professor Francesco Muntoni, University College of London Institute of Child Health Identifier: NCT00844597     History of Changes
Other Study ID Numbers: AVI-4658-28
Study First Received: December 24, 2008
Last Updated: April 22, 2011
Health Authority: United Kingdom: Medicines and Healthcare Products Regulatory Agency

Additional relevant MeSH terms:
Muscular Dystrophies
Muscular Dystrophy, Duchenne
Genetic Diseases, Inborn
Genetic Diseases, X-Linked
Muscular Diseases
Muscular Disorders, Atrophic
Musculoskeletal Diseases
Nervous System Diseases
Neuromuscular Diseases processed this record on October 02, 2015