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    Summary
    EudraCT Number:2017-000876-27
    Sponsor's Protocol Code Number:ATX-MTM-002
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:GB - no longer in EU/EEA
    Date on which this record was first entered in the EudraCT database:2017-07-31
    Trial 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 number2017-000876-27
    A.3Full title of the trial
    ASPIRO: A Phase 1/2, Randomized, Open-Label, Ascending-Dose, Delayed-Treatment Concurrent Control Clinical Study to Evaluate the Safety and Efficacy of AT132, an AAV8-Delivered Gene Therapy in X-Linked Myotubular Myopathy (XLMTM) Patients
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    First-in-human study of AT132 in X-Linked Myotubular Myopathy (XLMTM) Patients
    A.3.2Name or abbreviated title of the trial where available
    ASPIRO
    A.4.1Sponsor's protocol code numberATX-MTM-002
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03199469
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorAudentes Therapeutics Inc.
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportAudentes Therapeutics Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAudentes Therapeutics Inc.
    B.5.2Functional name of contact pointClinical Trials Information
    B.5.3 Address:
    B.5.3.1Street Address600 California Street, 17th Floor
    B.5.3.2Town/ citySan Francisco, CA
    B.5.3.3Post code94108
    B.5.3.4CountryUnited States
    B.5.6E-mailtrials@audentestx.com
    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 Yes
    D.2.5.1Orphan drug designation numberEMA/OD/074/15
    D.3 Description of the IMP
    D.3.1Product namerAAV8-Des-hMTM1
    D.3.2Product code AT132
    D.3.4Pharmaceutical form Solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    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) Yes
    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 No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Yes
    D.3.11.3.5.1CAT classification and reference numberThe EMA/CAT considers that product AT132 falls within the definition of gene therapy medicinal product as provided in Article 2(1) of Regulation (EC) No 1394/2007. Product Reference: H0004719
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    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 No
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    X-linked Myotubular Myopathy (XLMTM)
    E.1.1.1Medical condition in easily understood language
    X-linked Myotubular Myopathy (XLMTM)
    E.1.1.2Therapeutic area Diseases [C] - Musculoskeletal Diseases [C05]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The objectives of the study are as follows:
    • To determine the optimal dose of AT132 based on safety and preliminary efficacy in subjects with XLMTM.
    • To confirm the safety and efficacy of an optimal dose of AT132 in subjects with XLMTM.
    E.2.2Secondary objectives of the trial
    Not applicable
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Subject has a diagnosis of XLMTM resulting from a genetically confirmed mutation in the MTM1 gene as assessed by a Sponsor-approved testing facility.
    2. Subject is male.
    3. Subject is aged less than 5 years old at Day 1 and/or participated in the ATX MTM 009 (INCEPTUS) study.
    4. Subject requires mechanical ventilatory support:
    • Part 1: Subject requires some mechanical ventilatory support (e.g., ranging from 24 hours per day full time mechanical ventilation, to noninvasive support such as continuous positive airway pressure (CPAP) or bilevel positive airway pressure (BiPAP) during sleeping hours).
    • Part 2: Subject requires invasive mechanical ventilatory support ranging from 20 - 24 hours per day at screening (confirmed by daytime polysomnographic study).
    5. Subject requiring invasive mechanical ventilator support is fitted with or willing to be fitted with a cuffed tracheostomy tube for some respiratory assessments.
    6. Subject has ventilator maximum positive end-expiratory pressure (PEEP) < 8 cm H2O at screening.
    7. Signed informed consent by the parent(s) or legally authorized representative(s) (LAR) (when applicable).
    8. Subject and parent(s)/LAR(s) are willing and able to comply with study visits and study procedures.
    E.4Principal exclusion criteria
    1. Subject is participating in an interventional study designed to treat XLMTM.
    2. Subject born <35 weeks gestation who is still not term as per corrected age.
    3. Subject tests positive for AAV8 neutralizing antibody with titers > 1:20 (subjects under the age of 18 months may be retested in cases where antibodies may have been maternally acquired and titers may decline in the first months of life).
    4. Subject had recent surgery (< 3 months before Day 1) or has planned surgery that may confound data collection during the first 48 weeks of the study.
    5. Subject has a clinically important condition or life-threatening disease, other than XLMTM, in the opinion of the investigator.
    6. Subject has a clinically significant underlying liver disease, defined as:
    ≥ Grade 3 Aspartate aminotransferase (> 5.0 x upper limit of normal
    [ULN]) [CTCAE v. 4.03]
    ≥ Grade 3 Alanine aminotransferase (> 5.0 x ULN) [CTCAE v. 4.03] Hepatic peliosis or any other clinically significant structural abnormality detected by ultrasound
    7. Subject is currently experiencing a clinically important respiratory infection or other active infection.
    8. Subject has received pyridostigmine or any medication to treat XLMTM within 3 months before Day 1.
    9. Other than as required per protocol, subject has received immune-modulating agents within 3 months before Day 1 (use of inhaled corticosteroids to manage chronic respiratory conditions is allowed); use of other concomitant medications to manage chronic conditions must have been stable for at least 4 weeks before dosing.
    10. Subject has a contraindication to prednisolone.
    11. Subject has a contraindication to study drug or ingredients.
    12. Subject has previous scoliosis repair surgery/procedure, or planned/expected scoliosis repair surgery/procedure in the 12 months following Day 1 (Part 2 only).
    13. Subject has contractures, scoliosis, or other medical condition that would limit the potential to achieve unassisted sitting, in the opinion of the investigator (Part 2 only).
    14. Subject is able to sit without assistance for at least 30 seconds at screening, in the opinion of the investigator (Part 2 only).
    15. Subject has a clinically important condition, including Common Terminology Criteria for Adverse Events (CTCAE) v4.03 Grade ≥ 2 anemia (< 10g/dL hemoglobin)
    E.5 End points
    E.5.1Primary end point(s)
    ENDPOINTS AND SAFETY ASSESSMENTS: The study consists of 2 parts. Part 1 will establish the optimal dose. Part 2 will confirm the safety and efficacy of the optimal dose in a controlled, randomized dose expansion. Safety Assessments:
    - Adverse events (AEs), serious AEs (SAEs), and findings from safety laboratory tests, 12-lead ECG, echocardiograms (ECHOs), vital signs, growth parameters, physical examinations, liver ultrasounds, antibody formation (anti AAV8, anti MTM1), viral shedding, annualized hospitalization rate, annualized respiratory and non-respiratory SAE rate, and length of stay per hospitalization
    Primary Efficacy Endpoints:
    - Change from baseline in hours of ventilation support over time through Week 24
    E.5.1.1Timepoint(s) of evaluation of this end point
    Baseline to Week 24
    E.5.2Secondary end point(s)
    • Percentage of subjects achieving functionally independent sitting for at least 30 seconds by Week 24 as assessed by an independent blinded Physical Therapy Adjudication Panel
    • Time to reduction in required ventilator support to ≤ 16 hours a day (only in subjects who require invasive ventilation) by Week 24 as assessed by independent blinded Pulmonary Adjudication Panel
    • Change from baseline in Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) by Week 24
    • Change from baseline in maximal inspiratory pressure (PImax) by Week 24
    • Change from baseline in quantitative analysis of myotubularin expression in the muscle biopsy at Week 24
    • Change from baseline in quality of life assessments at Week 24 (ie, the Assessment of Caregiver Experience with Neuromuscular Disease [ACEND] and Pediatric Quality of Life Inventory [PedsQL])
    • Number (%) of age-appropriate clinically relevant gross motor function milestones attained through Week 24, as assessed by independent blinded Physical Therapy Adjudication Panel
    • Percentage of subjects achieving full ventilator independence in the absence of acute illness and perioperatively at Week 24, as assessed by independent blinded Pulmonary Adjudication Panel
    • Change from baseline in the health profiles and overall health status as assessed by the EQ-5D-Y Proxy and the EQ-5D-5L versions at Week 24
    • Survival
    E.5.2.1Timepoint(s) of evaluation of this end point
    Baseline to Week 24
    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 Yes
    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 Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group Yes
    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 No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    Delayed-treatment concurrent control group
    E.8.2.4Number of treatment arms in the trial2
    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.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA3
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    France
    Germany
    United Kingdom
    United States
    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
    Last visit of the last subject
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years7
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years7
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 20
    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) Yes
    F.1.1.4.1Number of subjects for this age range: 5
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 15
    F.1.1.6Adolescents (12-17 years) No
    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 Yes
    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 Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Subjects under the age of 17 years old
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state2
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 10
    F.4.2.2In the whole clinical trial 20
    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)
    Expected normal treatment of that condition
    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 Decision2017-09-25
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-12-06
    P. End of Trial
    P.End of Trial StatusGB - no longer in EU/EEA
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