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    Summary
    EudraCT Number:2006-003833-33
    Sponsor's Protocol Code Number:CRO490
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2009-01-09
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedUK - MHRA
    A.2EudraCT number2006-003833-33
    A.3Full title of the trial
    Restoring Dystrophin Expression in Duchenne Muscular Dystrophy: A Phase I/II Clinical Trial Using AVI-4658
    A.4.1Sponsor's protocol code numberCRO490
    A.7Trial is part of a Paediatric Investigation Plan Information not present in EudraCT
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorImperial College, London
    B.1.3.4CountryUnited Kingdom
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    B.5.2Functional name of contact point
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameAVI-4658
    D.3.2Product code AVI-4658
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    D.3.7Routes of administration for this IMPIntramuscular use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.2Current sponsor codeAVI-4658
    D.3.9.3Other descriptive namePhosphorodiamidate Morpholino Oligomer
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) Information not present in EudraCT
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product Yes
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Information not present in EudraCT
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Information not present in EudraCT
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for injection
    D.8.4Route of administration of the placeboIntramuscular use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Duchenne Muscular Dystrophy
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 9.1
    E.1.2Level LLT
    E.1.2Classification code 10013801
    E.1.2Term Duchenne muscular dystrophy
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The purpose of this trial is to evaluate the safety and tolerability of a single intramuscular (IM) dose of AVI-4658, a phosphorodiamidate Morpholino oligomer (PMO) at increasing dosages compared to placebo in up to 9 DMD subjects divided into three groups.
    E.2.2Secondary objectives of the trial
    To determine if AVI-4658 restores some level of truncated dystrophin production at the local level.

    Should this approach be safe and effective in restoring dystrophin production, a trial to assess systemic delivery of AVI-4658 in restoring dystrophin production would be undertaken.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Subject is male ≥ 12 years and ≤ 17 years of age at the time of study drug administration.
    2. Subject has clinical diagnosis compatible with Duchenne’s Muscular Dystrophy (DMD) and evidence of mutational and dystrophin defects from muscle biopsy consistent with DMD (out-of frame deletions, absent dystrophin).
    3. Subject has had a muscle biopsy analysed, showing <5% revertant fibres present. Biopsy may be collected at the time of DMD diagnosis or as part of protocol screening procedures.
    4. Subject is unable to ambulate or stand independently.
    5. Subject has Stage 1 to 3 EDB muscle preservation determined by MRI (Mercuri et al., 2002; Hawley et al., 1984).
    6. Subject has a forced vital capacity ≥ 25% confirmed within 3 months from Day One.
    7. Subject has mean oxygen saturation monitoring > 94% in overnight domiciliary overnight sleep study within 3 months of Day One.
    8. Subject has the ability to comply with all study evaluations and return for all study.
    9. Subject and parent have psychiatric adjustments, adequately supportive psychosocial circumstances and a full understanding of study aims process and likely outcomes.
    E.4Principal exclusion criteria
    1. Subject has had external digitorum brevis (EDB) muscle removed.
    2. Subject has Stage 4 EDB muscle preservation determined by MRI.
    3. Subject has a left ventricular shortening fraction of < 25% and/or an ejection fraction of < 35% by echocardiography at visit one or within three months of visit one.
    4. Subject has evidence of nocturnal hypoventilation (mean oxygen saturation at night of ≤ 94%) confirmed via overnight sleep study at Visit One (as screening procedure) or within 3 months of Visit One by overnight sleep study.
    5. Subject has severe respiratory insufficiency defined by the need for invasive or non-invasive mechanical ventilation (does not include nocturnal ventilatory support).
    6. Subject has severe cognitive dysfunction rendering them unable to understand and collaborate with study protocol.
    7. Subject has immune deficiency or autoimmune disease.
    8. Subject has a known bleeding disorder or has received chronic anticoagulant treatment within three months of study entry.
    9. Subject has received pharmacologic treatment, apart from corticosteroids, that might affect muscle strength or function within 8 weeks of study entry (viz., anabolic steroids, creatine protein supplementation, albuterol or other beta agonists).
    10. Subject has had surgery within 3 months of study entry or planned for anytime during study.
    11. Subject has active significant illness at time of study entry.
    12. Subject has is unable to undergo MRI testing (viz., has metal implants).
    13. Subject or parent has active psychiatric disorder, has adverse psychosocial circumstances, recent significant emotional loss, history of depressive or anxiety disorders that might interfere with protocol completion or compliance.
    14. Subject has any known allergies to products likely to be used in the study (viz., antiseptics, anaesthetics).
    15. Subject has used any experimental treatments or has participated in any clinical trial within 4 weeks of study entry.
    16. Subject has used intranasal, inhaled or topical steroids for a condition other than muscular dystrophy within 1 weeks of study entry.
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint of the trial is the safety and tolerability of AVI-4658 compared to the contralateral sham (placebo) injected muscle (EDB).
    Safety will be assessed by a series of examinations and comparison to the control injection site, and assessment of adverse reactions, either localised or generalised.
    The Safety Monitoring committee (SMC) will receive safety data on a regular basis for their review. Any unexpected and serious responses will be promptly provided to the SMC for an unscheduled safety review and assessment.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) Yes
    E.7.1.1First administration to humans Yes
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised No
    E.8.1.2Open No
    E.8.1.3Single blind Yes
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.4.1Number of sites anticipated in Member State concerned1
    E.8.5The trial involves multiple Member States No
    E.8.5.1Number of sites anticipated in the EEA1
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA Information not present in EudraCT
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months5
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial months5
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.2Adults (18-64 years) No
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female No
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Information not present in EudraCT
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others Yes
    F.3.3.7.1Details of other specific vulnerable populations
    Adolescent subjects with chronic progressive disease for which there is no cure
    F.4 Planned number of subjects to be included
    F.4.1In the member state9
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 9
    F.4.2.2In the whole clinical trial 9
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Treatment/care after participation in the trial will be no different from normal treatment.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2007-06-13
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2006-10-06
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2009-03-31
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