Restoring Dystrophin Expression in Duchenne Muscular Dystrophy: A Phase I/II Clinical Trial Using AVI-4658

• Register: EUCTR
• Last refreshed on: 31 October 2016
• Main ID: EUCTR2006-003833-33-GB
• Date of registration: 09/01/2009
• Prospective Registration: No
• Primary sponsor: Imperial College, London
• Public title: Restoring Dystrophin Expression in Duchenne Muscular Dystrophy: A Phase I/II Clinical Trial Using AVI-4658
• Scientific title: Restoring Dystrophin Expression in Duchenne Muscular Dystrophy: A Phase I/II Clinical Trial Using AVI-4658
• Date of first enrolment: 13/06/2007
• Target sample size: 9
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2006-003833-33
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: no Open: no Single blind: yes Double blind: no Parallel group: no Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no
• Phase: Human pharmacology (Phase I): yes Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

United Kingdom

Key inclusion & exclusion criteria

Inclusion criteria:
1. Subject is male = 12 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).
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 (Mercuri et al., 2002; Hawley et al., 1984).
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.

Are the trial subjects under 18? yes
Number of subjects for this age range:
F.1.2 Adults (18-64 years) no
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range

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.



Age minimum:
Age maximum:
Gender:
Female: no
Male: yes

Health Condition(s) or Problem(s) studied

Duchenne Muscular Dystrophy
MedDRA version: 9.1 Level: LLT Classification code 10013801 Term: Duchenne muscular dystrophy

Intervention(s)

Product Name: AVI-4658
Product Code: AVI-4658
Pharmaceutical Form: Solution for injection
Current Sponsor code: AVI-4658
Other descriptive name: Phosphorodiamidate Morpholino Oligomer
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 5-
Pharmaceutical form of the placebo: Solution for injection
Route of administration of the placebo: Intramuscular use

Primary Outcome(s)

Primary end point(s): The primary endpoint of the trial is the safety and tolerability of AVI-4658 compared to the contralateral sham (placebo) injected muscle (EDB).
Safety will be assessed by a series of examinations and comparison to the control injection site, and assessment of adverse reactions, either localised or generalised.
The Safety Monitoring committee (SMC) will receive safety data on a regular basis for their review. Any unexpected and serious responses will be promptly provided to the SMC for an unscheduled safety review and assessment.

Main Objective: The purpose of this trial is to evaluate the safety and tolerability of a single intramuscular (IM) dose of AVI-4658, a phosphorodiamidate Morpholino oligomer (PMO) at increasing dosages compared to placebo in up to 9 DMD subjects divided into three groups.

Secondary Objective: To determine if AVI-4658 restores some level of truncated dystrophin production at the local level.

Should this approach be safe and effective in restoring dystrophin production, a trial to assess systemic delivery of AVI-4658 in restoring dystrophin production would be undertaken.

Secondary ID(s)

CRO490