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Safety and Efficacy Study of Antisense Oligonucleotides in Duchenne Muscular Dystrophy

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ClinicalTrials.gov Identifier: NCT00159250
Recruitment Status : Completed
First Posted : September 12, 2005
Results First Posted : December 5, 2019
Last Update Posted : December 5, 2019
Department of Health, United Kingdom
Sarepta Therapeutics, Inc.
Information provided by (Responsible Party):
Imperial College London

Brief Summary:

Duchenne muscular dystrophy (DMD), a fatal muscle degenerative disorder, arises from mutations in the dystrophin gene. Antisense therapy with the use of antisense oligonucleotides (AON) has the potential to restore effectively the production of dystrophin, the defective protein, in >70% of DMD. This could result in increased life expectancy through improved muscle survival and function. Recent scientific research has demonstrated the potential of this technique to skip mutated dystrophin exons, restore the reading frame and generate functional dystrophin protein. Having demonstrated proof-of-principle in human cell culture and animal model studies, we now intend to determine efficacy and safety of this approach to induce dystrophin exon skipping in children with DMD.

The specific aim of this phase I/II study is to assess efficacy (dystrophin production) and safety of intramuscular administered morpholino oligomer directed against exon 51 (AVI-4658 PMO). We are performing parallel preclinical studies to develop methods of systemic delivery that will be necessary for future phase II/III clinical studies.

Condition or disease Intervention/treatment Phase
Duchenne Muscular Dystrophy Drug: AVI-4658 (PMO) Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 7 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: Single (Participant)
Primary Purpose: Treatment
Official Title: Restoring Dystrophin Expression in Duchenne Muscular Dystrophy: A Phase I/II Clinical Trial Using AVI-4658
Actual Study Start Date : October 26, 2007
Actual Primary Completion Date : December 2008
Actual Study Completion Date : March 31, 2009

Arm Intervention/treatment
Experimental: Low dose
Low dose of AVI-4658
Drug: AVI-4658 (PMO)
morpholino antisense oligonucleotide

Experimental: High dose
High dose of AVI-4658
Drug: AVI-4658 (PMO)
morpholino antisense oligonucleotide

Primary Outcome Measures :
  1. Number of Participants With Adverse Events Related to AVI-4568 [ Time Frame: Baseline up to Day 120 ]
    Number of Subjects with Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs

  2. Number of Participants With Injection Site Reactions [ Time Frame: From the Day of Screening to Day 3 ]
  3. Number of Subjects With Clinically Significant Change From Baseline in Laboratory Values [ Time Frame: From the Day of Screening up to Day 28 ]
    Assessed by light microscopy and immunocytochemistry to detect the differences in inflammatory infiltrates between the AVI-4568 and placebo-treated EDB muscles

Secondary Outcome Measures :
  1. Number of Participants With Induced Skipping of Exon 51 in the Treated Extensor Digitorum Brevis (EDB) Muscle Determined by Reverse Transcription Polymerase Chain Reaction [ Time Frame: Day 14 to Day 28 ]
    Induced Skipping of Exon 51 in the Treated Extensor Digitorum Brevis (EDB) Muscle Determined by Reverse Transcription Polymerase Chain Reaction was assessed by Sequencing of the RT-PCR products

  2. Number of Participants With Restoration of Dystrophin Protein Expression Measured by Immunocytochemistry [ Time Frame: Day 14 to Day 28 ]
  3. Number of Participants With Restoration of Dystrophin Protein Expression Measured by Western Blot Analysis [ Time Frame: Day 14 to Day 28 ]

Information from the National Library of Medicine

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Ages Eligible for Study:   10 Years to 17 Years   (Child)
Sexes Eligible for Study:   Male
Gender Based Eligibility:   Yes
Gender Eligibility Description:   male
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  1. Subject is male ≥ 10 years and ≤ 17 years of age at the time of study drug administration.
  2. Subject has clinical diagnosis compatible with Duchenne's Muscular Dystrophy (DMD) and evidence of mutational and dystrophin defects from muscle biopsy consistent with DMD (out-of frame deletions, absent dystrophin).Eligible deletions are those that can be rescued by the skipping of exon 51 [45-50; 47-50; 48-50; 49-50; 50; 52; 52-63].
  3. Subject has had a muscle biopsy analysed, showing <5% revertant fibres present. Biopsy may be collected at the time of DMD diagnosis or as part of protocol screening procedures.
  4. Subject is unable to ambulate or stand independently.
  5. Subject has Stage 1 to 3 EDB muscle preservation determined by MRI.
  6. Subject has a forced vital capacity ≥ 25% confirmed within 3 months from Day One.
  7. Subject has mean oxygen saturation monitoring > 94% in overnight domiciliary overnight sleep study within 3 months of Day One.
  8. Subject has the ability to comply with all study evaluations and return for all study.
  9. Subject and parent have psychiatric adjustments, adequately supportive psychosocial circumstances and a full understanding of study aims process and likely outcomes.

Exclusion Criteria:

  1. Subject has had external digitorum brevis (EDB) muscle removed.
  2. Subject has Stage 4 EDB muscle preservation determined by MRI.
  3. Subject has a left ventricular shortening fraction of < 25% and/or an ejection fraction of < 35% by echocardiography at visit one or within three months of visit one.
  4. Subject has evidence of nocturnal hypoventilation (mean oxygen saturation at night of ≤ 94%) confirmed via overnight sleep study at Visit One (as screening procedure) or within 3 months of Visit One by overnight sleep study.
  5. Subject has severe respiratory insufficiency defined by the need for invasive or non-invasive mechanical ventilation (does not include nocturnal ventilatory support).
  6. Subject has severe cognitive dysfunction rendering them unable to understand and collaborate with study protocol.
  7. Subject has immune deficiency or autoimmune disease.
  8. Subject has a known bleeding disorder or has received chronic anticoagulant treatment within three months of study entry.
  9. Subject has received pharmacologic treatment, apart from corticosteroids, that might affect muscle strength or function within 8 weeks of study entry (viz.,anabolic steroids, creatine protein supplementation, albuterol or other beta agonists).
  10. Subject has had surgery within 3 months of study entry or planned for anytime during study.
  11. Subject has active significant illness at time of study entry.
  12. Subject has is unable to undergo MRI testing (viz., has metal implants).
  13. Subject or parent has active psychiatric disorder, has adverse psychosocial circumstances, recent significant emotional loss, history of depressive or anxiety disorders that might interfere with protocol completion or compliance.
  14. Subject has any known allergies to products likely to be used in the study (viz.,antiseptics, anaesthetics).
  15. Subject has used any experimental treatments or has participated in any clinical trial within 4 weeks of study entry.
  16. Subject has used intranasal, inhaled or topical steroids for a condition other than muscular dystrophy within 1 weeks of study entry.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00159250

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United Kingdom
Dubowitz Neuromuscular Centre, Hammersmith Hospital and Clinical Trails Unit, St Mary's Hospital
London, United Kingdom, W12 0HS
Sponsors and Collaborators
Imperial College London
Department of Health, United Kingdom
Sarepta Therapeutics, Inc.
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Principal Investigator: Francesco Muntoni, FRCPCH Dubowitz neuromuscular Centre, Imperial College, London
Study Director: Kate Bushby, MRCP Institute of Human Genetics, University of Newcastle upon Tyne
Study Director: Volker Straub, FRCPCH Institute of Human Genetics, University of Newcastle upon Tyne
Additional Information:
Publications of Results:
Other Publications:

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Responsible Party: Imperial College London
ClinicalTrials.gov Identifier: NCT00159250    
Other Study ID Numbers: 05/MRE12/32
AVI-4658-33 ( Other Identifier: Sarepta )
2006-003833-33 ( EudraCT Number )
First Posted: September 12, 2005    Key Record Dates
Results First Posted: December 5, 2019
Last Update Posted: December 5, 2019
Last Verified: November 2019

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Imperial College London:
Duchenne muscular dystrophy;
antisense oligonucleotides;
gene restoration;
Additional relevant MeSH terms:
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Muscular Dystrophies
Muscular Dystrophy, Duchenne
Muscular Disorders, Atrophic
Muscular Diseases
Musculoskeletal Diseases
Neuromuscular Diseases
Nervous System Diseases
Genetic Diseases, Inborn
Genetic Diseases, X-Linked