Dose-ranging study of AVI-4658 to induce dystrophin expression in selected duchenne muscular dystrophy (DMD) patients

ISRCTN ISRCTN28347032
DOI https://doi.org/10.1186/ISRCTN28347032
ClinicalTrials.gov number NCT00844597
Secondary identifying numbers 6420
Submission date
23/04/2010
Registration date
23/04/2010
Last edited
10/09/2019
Recruitment status
No longer recruiting
Overall study status
Completed
Condition category
Nervous System Diseases
Prospectively registered
Protocol
Statistical analysis plan
Results
Individual participant data

Plain English summary of protocol

Not provided at time of registration

Study website

Contact information

Dr Kanagasabai Ganeshaguru
Scientific

Institute of Child Health
30 Guilford Street
London
WC1N 1EH
United Kingdom

Study information

Study designNon-randomised interventional screening treatment trial
Primary study designInterventional
Secondary study designNon randomised controlled trial
Study setting(s)GP practice
Study typeScreening
Participant information sheet Not available in web format, please use the contact details below to request a patient information sheet
Scientific titleDose-ranging study of AVI-4658 to induce dystrophin expression in selected duchenne muscular dystrophy (DMD) patients : a non-randomised interventional screening treatment trial
Study acronymAVI-4658
Study objectivesAVI BioPharma is developing AVI-4658, a phosphorodiamidate morpholino oligomer (PMO), for administration to patients with duchenne muscular dystrophy (DMD). It is believed that treatment with AVI-4658 will increase production of a truncated form of dystrophin, such as seen in patients with Becker muscular dystrophy (BMD), and consequently result in improved muscle function and overall quality of life for patients with DMD.
Ethics approval(s)Gene Therapy Advisory Committee (GTAC) approved on the 5th December 2008 (ref: GTAC157)
Health condition(s) or problem(s) studiedTopic: Medicines for Children Research Network; Subtopic: All Diagnoses; Disease: All Diseases
Intervention1. Muscle biopsy: dystrophin production will be determined by comparing results of immunohistological staining and Western blots of muscle homogenates between baseline and after the completion of 12 weekly doses of AVI-4658 (at week 14)
2. Quantitive Muscle Testing (QMT) (i.e., myometry assessments): obtain isometric strength assessments using a hand held myometer. This assessment entails measure of force of right and left knee extension, right and left knee flexion, right and left elbow flexion

Follow up length: 3 months.
Intervention typeDrug
Pharmaceutical study type(s)
PhasePhase I/II
Drug / device / biological / vaccine name(s)AVI-4658
Primary outcome measureSafety of escalating doses of AVI-4658, measured throughout the trial
Secondary outcome measures1. Pharmacokinetics, measured at 1st, 6th and 12th dosing
2. Efficacy (dystrophin expression) of AVI-4658 at week 14
Overall study start date01/02/2009
Completion date30/06/2010

Eligibility

Participant type(s)Patient
Age groupChild
SexMale
Target number of participantsPlanned sample size: 18; UK sample size: 18
Total final enrolment19
Key inclusion criteriaCandidates will be included in the study only if all of the following conditions are met:
1. Has provided written informed assent (as required by IRB) and parents/guardians have provided written informed consent
2. Has an out of frame deletion(s) that could be corrected by skipping exon 51 (45 - 50; 47 - 50; 48 - 50; 49 - 50; 50; 52), based on DNA sequencing data
3. Is male and between the ages of greater than or equal to 5 years and less than or equal to 15 years
4. Has a muscle biopsy analysis showing less than 5% revertant fibers present
5. DNA sequencing of exon 51 confirms that no DNA polymorphisms occur 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
8. Has a forced vital capacity (FVC) greater than or equal to 50% of predicted and does not require night time ventilatory support or supplemental oxygen
9. Receives the standard of care for DMD as recommended by the Muscular Dystrophy Association or the United Kingdom Board of Paediatrics
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
Key exclusion criteriaCandidates will be excluded from the study if any of the following conditions are present:
1. A DNA polymorphism within exon 51 that may compromise PMO duplex formation
2. 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 Cockroft and Gault Formula (See the Clinical Study Operations Manual)
5. A left ventricular ejection fraction (LVEF) of less than 35% and/or fractional shortening less than 30% based on echocardiography (ECHO) prior to or during screening
6. A history of respiratory insufficiency as defined by a need for intermittent, night time, or continuous supplemental oxygen
7. A severe cognitive dysfunction rendering the potential Subject unable to understand and comply with the study protocol
8. Any 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, and/or creatine protein supplementation)
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 completion or compliance
14. Use of any experimental treatments or has participated in any DMD interventional clinical trial within 4 weeks of study entry
Date of first enrolment01/02/2009
Date of final enrolment30/06/2010

Locations

Countries of recruitment

  • England
  • United Kingdom

Study participating centre

Institute of Child Health
London
WC1N 1EH
United Kingdom

Sponsor information

AVI Biopharma, Inc (USA)
Industry

3450 Monte Villa Parkway Suite 101
Bothell
WA 98021
United States of America

Website http://www.avibio.com/
ROR logo "ROR" https://ror.org/054f2wp19

Funders

Funder type

Research organisation

MRC Clinical Sciences Centre (UK)

No information available

AVI Biopharma, Inc (USA)

No information available

Results and Publications

Intention to publish date
Individual participant data (IPD) Intention to shareNo
IPD sharing plan summaryNot provided at time of registration
Publication and dissemination planNot provided at time of registration
IPD sharing plan

Study outputs

Output type Details Date created Date added Peer reviewed? Patient-facing?
Results article results 13/08/2011 Yes No
Basic results 10/09/2019 No No

Editorial Notes

10/09/2019: The following changes were made to the trial record:
1. ClinicalTrials.gov number added.
2. The total final enrolment was added.
3. A link to basic results was added to basic results (scientific)