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:
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).
Duchenne Muscular Dystrophy
Drug: AVI-4658 for Injection
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
||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.
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 ]
| Study Start Date:
| Study Completion Date:
| Primary Completion Date:
||June 2010 (Final data collection date for primary outcome measure)
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
Primary outcome is safety, tolerability and dose selection for future studies.
|Ages Eligible for Study:
||5 Years to 15 Years
|Genders Eligible for Study:
|Accepts Healthy Volunteers:
- Has provided written informed assent (as required by EC) and parents/guardians have provided written informed consent.
- Has an out-of-frame deletion(s) that could be corrected by skipping exon 51 based on DNA sequencing data from the candidate.
- Is male and between the ages of ≥ 5 years and ≤ 15 years.
- Has a muscle biopsy analysis showing < 5% revertant fibres present at baseline.
- 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.
- Intact right and left bicep muscles or alternative arm muscle group.
- Is able to walk independently at least 25 meters.
- Has a forced vital capacity (FVC) ≥ 50% of predicted and does not require ventilatory support or supplemental oxygen.
- Receives the standard of care for DMD as recommended by the DMD care recommendations from the North Star UK and TREAT-NMD.
- The parent(s) or legal guardian and Subject have undergone counselling about the expectations of this protocol and agree to participate.
- The parent(s) or legal guardian and Subject intend to comply with all study evaluations and return for all study activities.
- A DNA polymorphism within exon 51 that may compromise PMO duplex formation.
- Known antibodies to dystrophin.
- Lacks intact right and left bicep muscles or alternative arm muscle group.
- A calculated creatinine clearance less than 70% of predicted normal for age based on the Cockcroft and Gault Formula.
- A left ventricular ejection fraction (EF) of < 35% and/or fractional shortening of <25% based on echocardiography (ECHO)during screening.
- A history of respiratory insufficiency as defined by need for intermittent or continuous supplemental oxygen.
- A severe cognitive dysfunction rendering the potential subject unable to understand and comply with the study protocol.
- Any known immune deficiency or autoimmune disease.
- A known bleeding disorder or has received chronic anticoagulant treatment within three months of study entry.
- 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).
- Surgery within 3 months of study entry or planned for anytime during the duration of the study.
- Another clinically significant illness at time of study entry.
- 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.
- 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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00844597
|Great Ormond Street Hospital
|London, England, United Kingdom, WC1N 3JH |
|Royal Victoria Infirmary
|Newcastle Upon Tyne, England, United Kingdom, NE2 4LP |
British Medical Research Council
||Austen Eddy, MSM
||AVI BioPharma, Director, Clinical Operations
No publications provided by Sarepta Therapeutics
Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Cirak S, Arechavala-Gomeza V, Guglieri M, Feng L, Torelli S, Anthony K, Abbs S, Garralda ME, Bourke J, Wells DJ, Dickson G, Wood MJ, Wilton SD, Straub V, Kole R, Shrewsbury SB, Sewry C, Morgan JE, Bushby K, Muntoni F. Exon skipping and dystrophin restoration in patients with Duchenne muscular dystrophy after systemic phosphorodiamidate morpholino oligomer treatment: an open-label, phase 2, dose-escalation study. Lancet. 2011 Aug 13;378(9791):595-605. Epub 2011 Jul 23.
||Professor Francesco Muntoni, University College of London Institute of Child Health
History of Changes
|Other Study ID Numbers:
|Study First Received:
||December 24, 2008
||April 22, 2011
||United Kingdom: Medicines and Healthcare Products Regulatory Agency
Additional relevant MeSH terms:
ClinicalTrials.gov processed this record on May 16, 2013
Muscular Dystrophy, Duchenne
Muscular Disorders, Atrophic
Nervous System Diseases
Genetic Diseases, X-Linked
Genetic Diseases, Inborn