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

NCT00844597 | Completed Phase 1 Results DMC

• 1 other identifier: AVI-4658-28
• Study Type: interventional
• Target: 19
• Locations: 1 country
• Sites: 2

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).

Conditions

Duchenne Muscular Dystrophy

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (2)

• 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

• Efficacy of Eteplirsen Over 12 Weeks of Dosing

  Biopsies were taken at Baseline and Week 14

Study Arms (6)

Cohort 1 - 0.5 mg/kg/wk

EXPERIMENTAL

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

Cohort 2 - 1.0 mg/kg/wk

EXPERIMENTAL

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

Cohort 3 - 2.0 mg/kg/wk

EXPERIMENTAL

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

Cohort 4 - 4.0 mg/kg/wk

EXPERIMENTAL

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

Cohort 5 - 10.0 mg/kg/wk

EXPERIMENTAL

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

Cohort 6 - 20.0 mg/kg/wk

EXPERIMENTAL

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

Interventions

AVI-4658 for Injection DRUG

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.

Also known as: Eteplirsen

Cohort 1 - 0.5 mg/kg/wk; Cohort 2 - 1.0 mg/kg/wk; Cohort 3 - 2.0 mg/kg/wk; Cohort 4 - 4.0 mg/kg/wk; Cohort 5 - 10.0 mg/kg/wk; Cohort 6 - 20.0 mg/kg/wk

Eligibility Criteria

• Age: 5 Years - 15 Years
• Sex: male
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Sarepta Therapeutics, Inc.: lead
• British Medical Research Council: collaborator

Study Sites (2)

Great Ormond Street Hospital

London, England, WC1N 3JH, United Kingdom

Location

Royal Victoria Infirmary

Newcastle upon Tyne, England, NE2 4LP, United Kingdom

Location

Related Publications (1)

• 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.

  PMID: 21784508 RESULT

MeSH Terms

Conditions

Muscular Dystrophy, Duchenne

Interventions

eteplirsen; Injections

Condition Hierarchy (Ancestors)

Muscular Dystrophies; Muscular Disorders, Atrophic; Muscular Diseases; Musculoskeletal Diseases; Neuromuscular Diseases; Nervous System Diseases; Genetic Diseases, X-Linked; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Drug Administration Routes; Drug Therapy; Therapeutics

Limitations and Caveats

Due to the small number of study participants, a single adverse event (AE) in 1 patient exceeds the reporting threshold of 5%. Refer to the "Post-Hoc Outcome Measures" #5 for a summary of frequent and related AEs.

Results Point of Contact

• Title: Edward M. Kaye, MD, Interim CEO, SVP & Chief Medical Officer
• Organization: Sarepta Therapeutics

EKaye@Sarepta.com

617-274-4003

Study Officials

• Austen Eddy, MSM

  AVI BioPharma, Director, Clinical Operations

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 24, 2008
• First Posted: February 16, 2009
• Study Start: January 1, 2009
• Primary Completion: June 1, 2010
• Study Completion: December 1, 2010
• Last Updated: October 6, 2015
• Results First Posted: October 6, 2015

Record last verified: 2015-09

Locations

GB (2)