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

September 3, 2015 updated by: Sarepta Therapeutics, Inc.

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

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

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

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
19

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 2
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

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

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

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

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
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

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Safety and Tolerability
Time Frame: Baseline to 6 months
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
Time Frame: from Baseline to Follow up (27 weeks)
Number of Patients with Treatment Emergent Adverse Events
from Baseline to Follow up (27 weeks)

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Pharmacokinetics - Mean Peak Plasma Concentration of AVI-4658 After Administration
Time Frame: 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.
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
Time Frame: 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.
Biopsies were taken at Baseline and Week 14

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Sarepta Therapeutics, Inc.

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
British Medical Research Council

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Study Director: Austen Eddy, MSM, AVI BioPharma, Director, Clinical Operations

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
January 1, 2009

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
June 1, 2010

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
December 1, 2010

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
December 24, 2008

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
February 12, 2009

First Posted (Estimate)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
February 16, 2009

Study Record Updates

Last Update Posted (Estimate)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
October 6, 2015

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
September 3, 2015

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
September 1, 2015

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • AVI-4658-28

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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