Duchenne Muscular DystrophyPhase 1/2NCT00844597

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

A Phase 1/2 study testing AVI-4658 for Injection in people with Duchenne Muscular Dystrophy, run by Sarepta Therapeutics, Inc. at 2 sites in United Kingdom.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial 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). Read more about this study

Who is it for?: Ages 5 to 15 years, men only
Conditions the study is for: Duchenne Muscular Dystrophy
What is being tested?: AVI-4658 for Injection
Type of treatment: Injection or infusion
Could I receive a placebo?: No, everyone receives an active treatment
How many people: 19 participants
Where: 2 sitesUnited Kingdom
Study dates: Jan 2009to Dec 2010
Phase: Phase 1/2
Are there results?: Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 5 to 15 years
Men only
No healthy volunteers
Child

Who may be able to join

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.

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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.

Who cannot join

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.

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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.

Trial locations and contacts

2 sites in 1 country.

United Kingdom2 sites

Great Ormond Street Hospital
London, England, WC1N 3JH
Royal Victoria Infirmary
Newcastle upon Tyne, England, NE2 4LP

Other trials in United Kingdom

About this study

Official title: 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).

Read the detailed description

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

Conditions: Duchenne Muscular Dystrophy
Being tested: AVI-4658 for Injection
Medical subject headings: Muscular Dystrophy, Duchenne

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

AVI-4658 for InjectionDrug
Also called Eteplirsen
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.

Study groups in NCT00844597
Study group	Role	What they receive
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 Receives: 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 Receives: 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 Receives: 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 Receives: 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 Receives: 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 Receives: Drug: AVI-4658 for Injection

What is being measured

The primary outcome is the main question the study is designed to answer.

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

Secondary outcomes (2)

Pharmacokinetics - Mean Peak Plasma Concentration of AVI-4658 After Administration
Standard Pharmacokinetic parameters estimated using non-compartmental modeling of plasma concentration data.
Measured: 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.
Measured: Biopsies were taken at Baseline and Week 14

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

Jan 2009Dec 2010

First posted16 Feb 2009 (estimated)
Study startJan 2009
Primary completionJun 2010
Study completionDec 2010

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
Publications (1)Papers the sponsor has linked to this study.
Other trials for Duchenne Muscular DystrophyStudies of the same condition, open and under way.
More trials run by Sarepta Therapeutics, Inc.The sponsor's other registered studies.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 1/2
Primary purpose: Treatment
Allocation: Non-randomised
Intervention model: Single group
Masking: None (open label)
Enrolment: 19 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT00844597
Sponsor's protocol ID: AVI-4658-28
Status last verified: Sep 2015
First submitted: 24 Dec 2008
Last updated: 6 Oct 2015
Results posted: Yes, on ClinicalTrials.gov
Data monitoring committee: Yes

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.
PubMed 21784508

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

See locations

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Safety and Dystrophin Expression of SPOT-03 in Duchenne Muscular Dystrophy (DMD) Patients
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All Duchenne Muscular Dystrophy trials

Study at a glance

From the registry record, last updated by the sponsor on 6 Oct 2015. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: 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.
ClinicalTrials.gov ID: NCT00844597
Acronym / sponsor ID: AVI-4658-28
Conditions: Duchenne Muscular Dystrophy
Phase: Phase 1/2
Study type: Interventional
Recruitment status: Completed
Enrolment: 19 participants (actual)
Lead sponsor: Sarepta Therapeutics, Inc.Industry (pharma, biotech, devices)
Collaborators: British Medical Research Council
Study start: Jan 2009
Primary completion: Jun 2010 (actual)
Study completion: Dec 2010 (actual)
First posted: 16 Feb 2009 (estimated)
Results: Posted 6 Oct 2015

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

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 design

Primary purpose: Treatment
Allocation: Non-randomised
Intervention model: Single group
Masking: None (open label)
Number of arms: 6

Arm	Type	Receives
Cohort 1 - 0.5 mg/kg/wk	Experimental	Drug: AVI-4658 for InjectionSubjects 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 2 - 1.0 mg/kg/wk	Experimental	Drug: AVI-4658 for InjectionSubjects 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	Experimental	Drug: AVI-4658 for InjectionSubjects 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
Cohort 4 - 4.0 mg/kg/wk	Experimental	Drug: AVI-4658 for InjectionSubjects 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	Experimental	Drug: AVI-4658 for InjectionSubjects 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 6 - 20.0 mg/kg/wk	Experimental	Drug: AVI-4658 for InjectionSubjects 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

Who may qualify

Ages: 5 to 15 years
Sex: Male only
Healthy volunteers: Not accepted
Age groups: Child

Key inclusion criteria (11 listed)

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.

Key exclusion criteria (14 listed)

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.

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
AVI-4658 for InjectionAlso: EteplirsenAVI-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.	Drug	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

Primary outcome

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
Treatment Emergent Adverse Events
Time frame: from Baseline to Follow up (27 weeks)
Number of Patients with Treatment Emergent Adverse Events

2 secondary outcomes

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
Efficacy of Eteplirsen Over 12 Weeks of Dosing
Time frame: Biopsies were taken at Baseline and Week 14

Results and safety

Results posted to the registry on 6 Oct 2015, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

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

Primary outcome: Safety and Tolerability

Time frame: Baseline to 6 months. Number. Unit: participants

Measure	Open Label Treatment Arm n = 19
Value	14

Population analysed: Safety Population - Any patient who received at least one dose of the study drug.

Primary outcome: Treatment Emergent Adverse Events

Time frame: from Baseline to Follow up (27 weeks). Number. Unit: participants

Measure	Open Label Treatment Arm n = 19
Value	19

Population analysed: Safety Population

2 secondary outcomes are reported in the full results.

Adverse events

Time frame: Adverse Event data for this study was collected from Baseline to Follow-up (27 Weeks). Other adverse events reported at 5% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
Cohort 1 - 0.5 mg/kg/wk	0 of 4 (0%)	4 of 4 (100%)	Not reported
Cohort 2 - 1.0 mg/kg/wk	0 of 2 (0%)	2 of 2 (100%)	Not reported
Cohort 3 - 2.0 mg/kg/wk	1 of 2 (50%)	2 of 2 (100%)	Not reported
Cohort 4 - 4.0 mg/kg/wk	1 of 3 (33.3%)	3 of 3 (100%)	Not reported
Cohort 5 - 10.0 mg/kg/wk	0 of 4 (0%)	4 of 4 (100%)	Not reported
Cohort 6 - 20.0 mg/kg/wk	0 of 4 (0%)	4 of 4 (100%)	Not reported

Limitations and caveats (from the sponsor): 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.

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 6 Oct 2015.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Results publication: PubMed 21784508Cirak 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.

Related trials for Duchenne Muscular Dystrophy

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Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

Austen Eddy, MSM study director

AVI BioPharma, Director, Clinical Operations

2 sites in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing AVI-4658 for Injection in people with Duchenne Muscular Dystrophy, run by Sarepta Therapeutics, Inc. at 2 sites in United Kingdom.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 11 inclusion and 14 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 6 Oct 2015. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 2 sites in United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 6 Oct 2015). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Safety and Tolerability (time frame: Baseline to 6 months). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00844597, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 6 Oct 2015.