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

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.

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).

Study Overview

• Status: Completed
• Conditions: Duchenne Muscular Dystrophy
• Intervention / Treatment: Drug: AVI-4658 for Injection

Detailed Description

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

• Study Type: Interventional
• Enrollment (Actual): 19
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United Kingdom
  • England
    • London, England, United Kingdom, WC1N 3JH
      • Great Ormond Street Hospital
    • Newcastle Upon Tyne, England, United Kingdom, NE2 4LP
      • Royal Victoria Infirmary

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 5 years to 15 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort 1 - 0.5 mg/kg/wk; 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	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 in 6 dose cohorts.; Other Names: Eteplirsen
Experimental: Cohort 2 - 1.0 mg/kg/wk; 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	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 in 6 dose cohorts.; Other Names: Eteplirsen
Experimental: Cohort 3 - 2.0 mg/kg/wk; 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	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 in 6 dose cohorts.; Other Names: Eteplirsen
Experimental: Cohort 4 - 4.0 mg/kg/wk; 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	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 in 6 dose cohorts.; Other Names: Eteplirsen
Experimental: Cohort 5 - 10.0 mg/kg/wk; 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	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 in 6 dose cohorts.; Other Names: Eteplirsen
Experimental: Cohort 6 - 20.0 mg/kg/wk; 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	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 in 6 dose cohorts.; Other Names: Eteplirsen

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetics - Mean Peak Plasma Concentration of AVI-4658 After Administration	Standard Pharmacokinetic parameters estimated using non-compartmental modeling of plasma concentration data.	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
Efficacy of Eteplirsen Over 12 Weeks of Dosing	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.	Biopsies were taken at Baseline and Week 14

Collaborators and Investigators

• Sponsor: Sarepta Therapeutics, Inc.
• Collaborators: British Medical Research Council
• Investigators: Study Director: Austen Eddy, MSM, AVI BioPharma, Director, Clinical Operations

Publications and helpful links

General Publications

• 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. doi: 10.1016/S0140-6736(11)60756-3. Epub 2011 Jul 23.

Study record dates

Study Major Dates

• Study Start: January 1, 2009
• Primary Completion (Actual): June 1, 2010
• Study Completion (Actual): December 1, 2010

Study Registration Dates

• First Submitted: December 24, 2008
• First Submitted That Met QC Criteria: February 12, 2009
• First Posted (Estimate): February 16, 2009

Study Record Updates

• Last Update Posted (Estimate): October 6, 2015
• Last Update Submitted That Met QC Criteria: September 3, 2015
• Last Verified: September 1, 2015

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Nervous System Diseases; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; Musculoskeletal Diseases; Muscular Diseases; Neuromuscular Diseases; Muscular Disorders, Atrophic; Muscular Dystrophies; Muscular Dystrophy, Duchenne
• Other Study ID Numbers: AVI-4658-28