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

• ClinicalTrials.gov Identifier: NCT03199469
• Recruitment Status: Active, not recruiting
• First Posted: June 27, 2017
• Last Update Posted: November 17, 2020
• Sponsor: Audentes Therapeutics
• Information provided by (Responsible Party): Audentes Therapeutics

Tracking Information

• First Submitted Date: June 21, 2017
• First Posted Date: June 27, 2017
• Last Update Posted Date: November 17, 2020
• Actual Study Start Date: August 2, 2017
• Estimated Primary Completion Date: March 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 3, 2019)

• Treatment-emergent adverse events (safety and tolerability) [ Time Frame: Baseline through Week 24 ]
  Adverse events, serious adverse events, and laboratory abnormalities (including immunological parameters)
• Change from baseline in hours of ventilation support over time through Week 24 [ Time Frame: Baseline to Week 24 ]
  Change in hours of ventilation

Original Primary Outcome Measures (submitted: June 23, 2017)

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

Current Secondary Outcome Measures (submitted: September 3, 2019)

• 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 Frame: Baseline to Week 24 ]
  Achieve functionally independent sitting for at least 30 seconds
• 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 [ Time Frame: Baseline to Week 24 ]
  Reduction in required ventilator support
• Change from baseline in Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) by Week 24 [ Time Frame: Baseline to Week 24 ]
  Change in CHOP-INTEND
• Change from baseline in maximal inspiratory pressure (PImax) by Week 24 [ Time Frame: Baseline to Week 24 ]
  Change in respiratory endurance
• Change from baseline in quantitative analysis of myotubularin expression in the muscle biopsy at Week 24 [ Time Frame: Baseline to Week 24 ]
  Change in myotubularin expression

Original Secondary Outcome Measures (submitted: June 23, 2017)

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

• Current Other Pre-specified Outcome Measures: Not Provided

Original Other Pre-specified Outcome Measures (submitted: June 23, 2017)

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

Descriptive Information

• Brief Title: Gene Transfer Clinical Study in X-Linked Myotubular Myopathy
• Official Title: 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
• Brief Summary: This is a multinational, open-label, ascending-dose, delayed-treatment concurrent control clinical study to evaluate the safety and 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

Detailed Description

This study will evaluate safety and efficacy of gene transfer in X-Linked Myotubular Myopathy. Subjects will receive a single dose of AT132 delivered intravenously.

ASPIRO is being conducted in two parts. Part 1 is a dose escalation phase that is evaluating the preliminary safety and efficacy of AT132 at doses of 1x1014 vg/kg and 3x1014 vg/kg. Part 2 of ASPIRO is a pivotal expansion cohort designed to confirm the safety and efficacy of AT132 at a dose of 3x1014 vg/kg. The pivotal expansion cohort will enroll eight subjects, consisting of four age-matched pairs (within +/- 6 months of age). One subject from each pair will be randomized to receive a single dose of AT132 at 3x1014 vg/kg, and the other will serve as a delayed treatment control. Eligible delayed treatment control subjects will be administered AT132 after that individual subject has completed the Week 24 visit as a delayed treatment control.

The primary efficacy endpoint measures will be assessed at Week 24. Subjects will be followed for a total of 5 years after administration of AT132.

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

• Study Type: Interventional
• Study Phase: Phase 1; Phase 2

Study Design

Allocation: Randomized
Intervention Model: Sequential Assignment
Intervention Model Description:

ASPIRO is being conducted in two parts. Part 1 is a dose escalation phase that is evaluating the preliminary safety and efficacy of AT132 at doses of 1x1014 vg/kg and 3x1014 vg/kg. Part 2 of ASPIRO is a pivotal expansion cohort designed to confirm the safety and efficacy of AT132 at a dose of 3x1014 vg/kg. The pivotal expansion cohort will enroll eight subjects, consisting of four age-matched pairs (within +/- 6 months of age). One subject from each pair will be randomized to receive a single dose of AT132 at 3x1014 vg/kg, and the other will serve as a delayed treatment control. Eligible delayed treatment control subjects will be administered AT132 after that individual subject has completed the Week 24 visit as a delayed treatment control.

Masking: None (Open Label)
Primary Purpose: Treatment

• Condition: X-Linked Myotubular Myopathy

Intervention

Genetic: AT132

AT132 is an AAV8 vector containing a functional copy of the human MTM1 (hMTM1) gene.

Study Arms

• Experimental: 1.0 x 10^14 vg/kg
  1.0 x 10^14 vg/kg of AT132 delivered intravenously one time
  Intervention: Genetic: AT132
• Experimental: 3.0 x 10^14 vg/kg
  3.0 x 10^14 vg/kg of AT132 delivered intravenously one time
  Intervention: Genetic: AT132
• No Intervention: Delayed-Treatment Control
  Delayed-Treatment Control subjects will generally have the same assessments as treated subjects. After the follow up period, eligible delayed-treatment control subjects will be dosed with AT132 and initiate the same post-dose procedures as subjects who received AT132.

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Estimated Enrollment (submitted: September 3, 2019): 24
• Original Estimated Enrollment (submitted: June 23, 2017): 12
• Estimated Study Completion Date: March 2024
• Estimated Primary Completion Date: March 2024 (Final data collection date for primary outcome measure)

Eligibility 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 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).

• 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.
• 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).
• Subject is able to sit without assistance for at least 30 seconds at screening, in the opinion of the investigator (Part 2 only).

Sex/Gender

• Sexes Eligible for Study: Male

• Ages: up to 5 Years (Child)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Canada, France, Germany, United States

Administrative Information

• NCT Number: NCT03199469
• Other Study ID Numbers: ATX-MTM-002
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

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

IPD Sharing Statement

• Plan to Share IPD: No

• Responsible Party: Audentes Therapeutics
• Study Sponsor: Audentes Therapeutics
• Collaborators: Not Provided

Investigators

• Study Director: Nathan Bachtell, MD; Audentes Therapeutics

• PRS Account: Audentes Therapeutics
• Verification Date: February 2020