Gene Transfer Clinical Study in X-Linked Myotubular Myopathy (ASPIRO)

Study Description

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Brief Summary:

This is a Phase 1/2, multinational, open-label, ascending-dose, delayed-treatment concurrent control clinical study to evaluate the safety and preliminary efficacy of AT132 in subjects with X-Linked Myotubular Myopathy aged less than 5 years old. Subjects will receive a single dose of AT132 and will be followed for safety and efficacy for 5 years

Condition or disease	Intervention/treatment	Phase
X-Linked Myotubular Myopathy	Genetic: AT132	Phase 1; Phase 2

Detailed Description:

This study will evaluate safety and preliminary efficacy of gene transfer in X-Linked Myotubular Myopathy. Subjects will receive a single dose of AT132 delivered intravenously. A maximum of 3 dose levels of AT132 are planned for evaluation in this study. Four subjects will be enrolled at each dose level, including 1 subject at each dose level randomized to control with delayed administration of the investigational medicinal product. Dose escalation to the next dose level will be considered after evaluation of at least 4 weeks of data from all subjects dosed at the current dose level. One of the dose levels will be chosen for dose expansion, and the chosen dose will be administered to all delayed-treatment control subjects.

The primary efficacy endpoint measures will be assessed at Week 48. Subjects will be followed for a total of 5 years after administration of AT132.

This study will utilize an independent Data Monitoring Committee (DMC) that will monitor subject safety and provide recommendations to Audentes regarding dose escalation, dose expansion, and safety matters.

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	12 participants
Allocation:	Randomized
Intervention Model:	Sequential Assignment
Intervention Model Description:	Four subjects will be enrolled at each dose level including 1 subject at each dose level randomized to control with delayed initiation of treatment. One of the dose levels will be chosen for dose expansion and all control subjects will then be treated at the chosen dose level.
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	ASPIRO: A Phase 1/2, Randomized, Open-Label, Ascending-Dose, Delayed-Treatment Concurrent Control Clinical Study to Evaluate the Safety and Preliminary Efficacy of AT132, an AAV8-Delivered Gene Therapy in X-Linked Myotubular Myopathy (XLMTM) Patients
Actual Study Start Date :	August 2, 2017
Estimated Primary Completion Date :	March 2019
Estimated Study Completion Date :	March 2025

Arms and Interventions

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Arm	Intervention/treatment
Experimental: Cohort 1; 1.0 x 10^14 vg/kg of AT132 delivered intravenously one time	Genetic: AT132; AT132 is an AAV8 vector containing a functional copy of the human MTM1 (hMTM1) gene.
Experimental: Cohort 2; 3.0 x 10^14 vg/kg of AT132 delivered intravenously one time	Genetic: AT132; AT132 is an AAV8 vector containing a functional copy of the human MTM1 (hMTM1) gene.
Experimental: Cohort 3; 5.0 x 10^14 vg/kg of AT132 delivered intravenously one time	Genetic: AT132; AT132 is an AAV8 vector containing a functional copy of the human MTM1 (hMTM1) gene.
No Intervention: Delayed-Treatment Control; Delayed-Treatment Control subjects will generally have the same assessments as treated subjects. Once the optimal AT132 dose is selected, delayed-treatment control subjects will undergo pre-treatment baseline procedures to confirm that they remain eligible to receive treatment with AT132. Once eligible, delayed-treatment control subjects are dosed with AT132, they will initiate the same post-dose procedures as subjects who received AT132

Outcome Measures

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Primary Outcome Measures :

1. Treatment-emergent adverse events (safety and tolerability) [ Time Frame: Baseline through Week 48 ]
   Adverse events, serious adverse events, and laboratory abnormalities (including immunological parameters)
2. Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) [ Time Frame: Baseline to Week 48 ]
   Change in CHOP-INTEND
3. Maximal Inspiratory Pressure (PImax) [ Time Frame: Baseline to Week 48 ]
   Change in PImax

Secondary Outcome Measures :

1. Motor Function Measure Scale (MFM-20) [ Time Frame: Baseline to Week 48 ]
   Change in MFM-20
2. Bayley III (motor domain) [ Time Frame: Baseline to Week 48 ]
   Change in Bayley III motor domain
3. Muscle Biopsy [ Time Frame: Baseline to Week 48 ]
   Change in quantitative analysis of muscle biopsy
4. Respiratory Endurance (Sprinting) [ Time Frame: Baseline to Week 48 ]
   Change in respiratory endurance
5. Time Off Ventilator [ Time Frame: Baseline to Week 48 ]
   Change in Time Off Ventilator
6. Survival [ Time Frame: Baseline to Week 48 ]

Other Outcome Measures:

1. Quality of Life Assessment: Assessment of Caregiver Experience with Neuromuscular Disease (ACEND) [ Time Frame: Baseline to Week 48 ]
   Change in Quality of Life Assessments
2. Quality of Life Assessment: Pediatric Quality of Life Inventory (PedsQL) - Neuromuscular Module [ Time Frame: Baseline to Week 48 ]
3. Incidence of adverse events, serious adverse events, and laboratory abnormalities (including immunological parameters) [ Time Frame: Baseline to Year 5 ]

Eligibility Criteria

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Ages Eligible for Study:	up to 5 Years (Child)
Sexes Eligible for Study:	Male
Accepts Healthy Volunteers:	No

Criteria

Key Inclusion Criteria:

• Subject has a diagnosis of XLMTM resulting from a genetically confirmed mutation in the MTM1 gene as assessed by a Sponsor-approved testing facility.
• Subject is male.
• Subject is aged less than 5 years old at Day 1 and/or participated in the ATX-MTM-009 (INCEPTUS) study.
• Subject requires some mechanical ventilator support (eg, 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).
• Subject requiring invasive mechanical ventilator support is fitted with or willing to be fitted with a cuffed tracheostomy tube for some respiratory assessments.
• Subject has ventilator maximum positive end-expiratory pressure (PEEP) <8 cm H2O at screening.

Key Exclusion Criteria:

• Subject is participating in an interventional study designed to treat XLMTM.
• Subject born <35 weeks gestation who is still not term as per corrected age.
• Subject tests positive for AAV8 neutralizing antibody with titers above protocol specified threshold.
• 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.
• Subject has a clinically important condition other than XLMTM in the opinion of the investigator.
• Subject has a clinically significant underlying liver disease.
• Subject is currently experiencing a clinically important respiratory infection or other active infection.
• Subject has received pyridostigmine or any medication to treat XLMTM within 3 months before Day 1.
• 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.
• Subject has a contraindication to prednisolone.
• Subject has a contraindication to study drug or ingredients.

Contacts and Locations

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Contacts

Contact: Kim Trant, Director of Patient Advocacy	+1 415 805 1049	trials@audentestx.com

Locations

United States, California
UCLA Medical Center	Recruiting
Los Angeles, California, United States, 90095
United States, Florida
Powell Center for Rare Disease Research, Univ. of Florida	Recruiting
Gainesville, Florida, United States, 32610
United States, Illinois
Ann & Robert H Lurie Children's Hospital of Chicago	Recruiting
Chicago, Illinois, United States, 60611
United States, Maryland
National Institute of Neurological Disorders and Stroke/NIH Porter	Recruiting
Bethesda, Maryland, United States, 208892
Canada, Ontario
Hospital for Sick Children	Recruiting
Toronto, Ontario, Canada, M5G0A4
France
Hopital Armad Trousseau	Recruiting
Paris, France, 75012

Sponsors and Collaborators

Audentes Therapeutics

Investigators

Study Director:	Salvador Rico, MD, PhD	Audentes Therapeutics

More Information

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Responsible Party:	Audentes Therapeutics
ClinicalTrials.gov Identifier:	NCT03199469 History of Changes
Other Study ID Numbers:	ATX-MTM-002
First Posted:	June 27, 2017
Last Update Posted:	September 11, 2018
Last Verified:	September 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	No

Studies a U.S. FDA-regulated Drug Product:		Yes
Studies a U.S. FDA-regulated Device Product:		No

Keywords provided by Audentes Therapeutics:

AAV8-Delivered Gene Therapy; XLMTM; Adeno Associated Virus

Additional relevant MeSH terms:

Muscular Diseases; Myopathies, Structural, Congenital; Musculoskeletal Diseases; Neuromuscular Diseases; Nervous System Diseases