Safety and Efficacy Study of Antisense Oligonucleotides in Duchenne Muscular Dystrophy

NCT00159250 | Completed Phase 1 Results DMC

• 3 other identifiers: 05/MRE12/32AVI-4658-332006-003833-33
• Study Type: interventional
• Target: 7
• Locations: 1 country
• Sites: 1

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.

Conditions

Duchenne Muscular Dystrophy

Keywords

Duchenne muscular dystrophy;; antisense oligonucleotides;; gene restoration;; deletion

Outcome Measures

Primary Outcomes (3)

• Number of Participants With Adverse Events Related to AVI-4568

  Number of Subjects with Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs

  Baseline up to Day 120

• Number of Participants With Injection Site Reactions

  From the Day of Screening to Day 3

• Number of Subjects With Clinically Significant Change From Baseline in Laboratory Values

  Assessed by light microscopy and immunocytochemistry to detect the differences in inflammatory infiltrates between the AVI-4568 and placebo-treated EDB muscles

  From the Day of Screening up to Day 28

Secondary Outcomes (3)

• Number of Participants With Induced Skipping of Exon 51 in the Treated Extensor Digitorum Brevis (EDB) Muscle Determined by Reverse Transcription Polymerase Chain Reaction

  Day 14 to Day 28

• Number of Participants With Restoration of Dystrophin Protein Expression Measured by Immunocytochemistry

  Day 14 to Day 28

• Number of Participants With Restoration of Dystrophin Protein Expression Measured by Western Blot Analysis

  Day 14 to Day 28

Study Arms (2)

Low dose

EXPERIMENTAL

Low dose of AVI-4658

Drug: AVI-4658 (PMO)

High dose

EXPERIMENTAL

High dose of AVI-4658

Drug: AVI-4658 (PMO)

Interventions

AVI-4658 (PMO) DRUG

morpholino antisense oligonucleotide

High dose; Low dose

Eligibility Criteria

• Age: 10 Years - 17 Years
• Gender Eligibility Details: male
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• Subject is male ≥ 10 years and ≤ 17 years of age at the time of study drug administration.
• 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 \[45-50; 47-50; 48-50; 49-50; 50; 52; 52-63\].
• 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.
• Subject is unable to ambulate or stand independently.
• Subject has Stage 1 to 3 EDB muscle preservation determined by MRI.
• Subject has a forced vital capacity ≥ 25% confirmed within 3 months from Day One.
• Subject has mean oxygen saturation monitoring \> 94% in overnight domiciliary overnight sleep study within 3 months of Day One.
• Subject has the ability to comply with all study evaluations and return for all study.
• Subject and parent have psychiatric adjustments, adequately supportive psychosocial circumstances and a full understanding of study aims process and likely outcomes.

You may not qualify if:

• Subject has had external digitorum brevis (EDB) muscle removed.
• Subject has Stage 4 EDB muscle preservation determined by MRI.
• 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.
• 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.
• Subject has severe respiratory insufficiency defined by the need for invasive or non-invasive mechanical ventilation (does not include nocturnal ventilatory support).
• Subject has severe cognitive dysfunction rendering them unable to understand and collaborate with study protocol.
• Subject has immune deficiency or autoimmune disease.
• Subject has a known bleeding disorder or has received chronic anticoagulant treatment within three months of study entry.
• 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).
• Subject has had surgery within 3 months of study entry or planned for anytime during study.
• Subject has active significant illness at time of study entry.
• Subject has is unable to undergo MRI testing (viz., has metal implants).
• 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.
• Subject has any known allergies to products likely to be used in the study (viz.,antiseptics, anaesthetics).
• Subject has used any experimental treatments or has participated in any clinical trial within 4 weeks of study entry.

Sponsors & Collaborators

• Imperial College London: lead
• Department of Health, United Kingdom: collaborator
• Sarepta Therapeutics, Inc.: collaborator

Study Sites (1)

Dubowitz Neuromuscular Centre, Hammersmith Hospital and Clinical Trails Unit, St Mary's Hospital

London, W12 0HS, United Kingdom

Location

Related Publications (8)

• Lu QL, Morris GE, Wilton SD, Ly T, Artem'yeva OV, Strong P, Partridge TA. Massive idiosyncratic exon skipping corrects the nonsense mutation in dystrophic mouse muscle and produces functional revertant fibers by clonal expansion. J Cell Biol. 2000 Mar 6;148(5):985-96. doi: 10.1083/jcb.148.5.985.

  PMID: 10704448 BACKGROUND

• De Angelis FG, Sthandier O, Berarducci B, Toso S, Galluzzi G, Ricci E, Cossu G, Bozzoni I. Chimeric snRNA molecules carrying antisense sequences against the splice junctions of exon 51 of the dystrophin pre-mRNA induce exon skipping and restoration of a dystrophin synthesis in Delta 48-50 DMD cells. Proc Natl Acad Sci U S A. 2002 Jul 9;99(14):9456-61. doi: 10.1073/pnas.142302299. Epub 2002 Jun 20.

  PMID: 12077324 BACKGROUND

• Lu QL, Mann CJ, Lou F, Bou-Gharios G, Morris GE, Xue SA, Fletcher S, Partridge TA, Wilton SD. Functional amounts of dystrophin produced by skipping the mutated exon in the mdx dystrophic mouse. Nat Med. 2003 Aug;9(8):1009-14. doi: 10.1038/nm897. Epub 2003 Jul 6.

  PMID: 12847521 BACKGROUND

• Lu QL, Rabinowitz A, Chen YC, Yokota T, Yin H, Alter J, Jadoon A, Bou-Gharios G, Partridge T. Systemic delivery of antisense oligoribonucleotide restores dystrophin expression in body-wide skeletal muscles. Proc Natl Acad Sci U S A. 2005 Jan 4;102(1):198-203. doi: 10.1073/pnas.0406700102. Epub 2004 Dec 17.

  PMID: 15608067 BACKGROUND

• Gebski BL, Mann CJ, Fletcher S, Wilton SD. Morpholino antisense oligonucleotide induced dystrophin exon 23 skipping in mdx mouse muscle. Hum Mol Genet. 2003 Aug 1;12(15):1801-11. doi: 10.1093/hmg/ddg196.

  PMID: 12874101 BACKGROUND

• Fletcher S, Honeyman K, Fall AM, Harding PL, Johnsen RD, Wilton SD. Dystrophin expression in the mdx mouse after localised and systemic administration of a morpholino antisense oligonucleotide. J Gene Med. 2006 Feb;8(2):207-16. doi: 10.1002/jgm.838.

  PMID: 16285002 BACKGROUND

• Alter J, Lou F, Rabinowitz A, Yin H, Rosenfeld J, Wilton SD, Partridge TA, Lu QL. Systemic delivery of morpholino oligonucleotide restores dystrophin expression bodywide and improves dystrophic pathology. Nat Med. 2006 Feb;12(2):175-7. doi: 10.1038/nm1345. Epub 2006 Jan 29.

  PMID: 16444267 BACKGROUND

• Kinali M, Arechavala-Gomeza V, Feng L, Cirak S, Hunt D, Adkin C, Guglieri M, Ashton E, Abbs S, Nihoyannopoulos P, Garralda ME, Rutherford M, McCulley C, Popplewell L, Graham IR, Dickson G, Wood MJ, Wells DJ, Wilton SD, Kole R, Straub V, Bushby K, Sewry C, Morgan JE, Muntoni F. Local restoration of dystrophin expression with the morpholino oligomer AVI-4658 in Duchenne muscular dystrophy: a single-blind, placebo-controlled, dose-escalation, proof-of-concept study. Lancet Neurol. 2009 Oct;8(10):918-28. doi: 10.1016/S1474-4422(09)70211-X. Epub 2009 Aug 25.

  PMID: 19713152 RESULT

MeSH Terms

Conditions

Muscular Dystrophy, Duchenne

Interventions

eteplirsen

Condition Hierarchy (Ancestors)

Muscular Dystrophies; Muscular Disorders, Atrophic; Muscular Diseases; Musculoskeletal Diseases; Neuromuscular Diseases; Nervous System Diseases; Genetic Diseases, X-Linked; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Results Point of Contact

• Title: Francesco Muntoni
• Organization: Imperial College London

f.muntoni@ucl.ac.uk

+44 02075941872

Study Officials

• Francesco Muntoni, FRCPCH

  Dubowitz neuromuscular Centre, Imperial College, London

  PRINCIPAL INVESTIGATOR

• 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

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 8, 2005
• First Posted: September 12, 2005
• Study Start: October 26, 2007
• Primary Completion: December 1, 2008
• Study Completion: March 31, 2009
• Last Updated: December 5, 2019
• Results First Posted: December 5, 2019

Record last verified: 2019-11

Locations

GB (1)