Dose-Ranging Study of AVI-4658 to Induce Dystrophin Expression in Selected Duchenne Muscular Dystrophy (DMD) Patients

Phase 1

Completed

• Conditions: Duchenne Muscular Dystrophy
• Interventions: Drug: AVI-4658 for Injection

• Registration Number: NCT00844597
• Lead Sponsor: Sarepta Therapeutics, Inc.

Brief Summary

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).

Detailed Description

Primary outcome is safety, tolerability and dose selection for future studies.

Study Timeline

• Study First Submitted: 2008-12-24
• Study Start: 2009-01
• Study First Submitted QC: 2009-02-12
• Study First Posted: 2009-02-16
• Primary Completion: 2010-06
• Study Completion: 2010-12
• Results First Submitted: 2015-06-08
• Status Verified: 2015-09
• Results First Submitted QC: 2015-09-03
• Last Update Submitted: 2015-09-03
• Results First Posted: 2015-10-06
• Last Update Posted: 2015-10-06

Recruitment & Eligibility

• Status: COMPLETED
• Sex: Male
• Target Recruitment: 19

Inclusion Criteria

1. Has provided written informed assent (as required by EC) and parents/guardians have provided written informed consent.
2. Has an out-of-frame deletion(s) that could be corrected by skipping exon 51 based on DNA sequencing data from the candidate.
3. Is male and between the ages of ≥ 5 years and ≤ 15 years.
4. Has a muscle biopsy analysis showing < 5% revertant fibres present at baseline.
5. 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.
6. Intact right and left bicep muscles or alternative arm muscle group.
7. Is able to walk independently at least 25 meters.
8. Has a forced vital capacity (FVC) ≥ 50% of predicted and does not require ventilatory support or supplemental oxygen.
9. Receives the standard of care for DMD as recommended by the DMD care recommendations from the North Star UK and TREAT-NMD.
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.

Exclusion Criteria

1. A DNA polymorphism within exon 51 that may compromise PMO duplex formation.
2. Known 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 Cockcroft and Gault Formula.
5. A left ventricular ejection fraction (EF) of < 35% and/or fractional shortening of <25% based on echocardiography (ECHO)during screening.
6. A history of respiratory insufficiency as defined by need for intermittent or continuous supplemental oxygen.
7. A severe cognitive dysfunction rendering the potential subject unable to understand and comply with the study protocol.
8. Any known 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).
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 compliance.
14. 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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Cohort 1 - 0.5 mg/kg/wk	AVI-4658 for Injection	Subjects in this group will receive a 0.5 mg/kg/wk dose of AVI-4658 over 12 weekly IV infusions in 50 mL of normal saline solution over a 60-minute period
Cohort 6 - 20.0 mg/kg/wk	AVI-4658 for Injection	Subjects in this group will receive a 20.0 mg/kg/wk dose of AVI-4658 over 12 weekly IV infusions in 50 mL of normal saline solution over a 60-minute period
Cohort 4 - 4.0 mg/kg/wk	AVI-4658 for Injection	Subjects in this group will receive a 4.0 mg/kg/wk dose of AVI-4658 over 12 weekly IV infusions in 50 mL of normal saline solution over a 60-minute period
Cohort 5 - 10.0 mg/kg/wk	AVI-4658 for Injection	Subjects in this group will receive a 10.0 mg/kg/wk dose of AVI-4658 over 12 weekly IV infusions in 50 mL of normal saline solution over a 60-minute period
Cohort 2 - 1.0 mg/kg/wk	AVI-4658 for Injection	Subjects in this group will receive a 1.0 mg/kg/wk dose of AVI-4658 over 12 weekly IV infusions in 50 mL of normal saline solution over a 60-minute period
Cohort 3 - 2.0 mg/kg/wk	AVI-4658 for Injection	Subjects in this group will receive a 2.0 mg/kg/wk dose of AVI-4658 over 12 weekly IV infusions in 50 mL of normal saline solution over a 60-minute period

Primary Outcome Measures

Name	Time	Method
Treatment Emergent Adverse Events	from Baseline to Follow up (27 weeks)	Number of Patients with Treatment Emergent Adverse Events
Safety and Tolerability	Baseline to 6 months	Number of subjects with 1 or more Treatment Emergent Adverse Event that are possibly related to the investigational drug

Secondary Outcome Measures

Name	Time	Method
Efficacy of Eteplirsen Over 12 Weeks of Dosing	Biopsies were taken at Baseline and Week 14	Efficacy was defined as an estimated change in the percentage of dystrophin positive fibers (assessed by IHC) at Week 14 from Baseline after 12 weekly doses of eterplirsen. This outcome measure represents the number of patients to show an increase in the percentage of dystrophin-positive fibers.
Pharmacokinetics - Mean Peak Plasma Concentration of AVI-4658 After Administration	Samples were taken: 30 minutes pre dose; and at 5 (±1), 15 (±2), 30 (±5), 60 (±5), and 90 (±5) minutes; and 2, 4, 6, 8, 12, and 24 hours (all ± 15 minutes) post dose at Weeks 1, 6, and 12	Standard Pharmacokinetic parameters estimated using non-compartmental modeling of plasma concentration data.

Trial Locations

Locations (2)

Great Ormond Street Hospital; 🇬🇧 London, England, United Kingdom

Royal Victoria Infirmary; 🇬🇧 Newcastle Upon Tyne, England, United Kingdom