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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03199469
Recruitment Status : Active, not recruiting
First Posted : June 27, 2017
Last Update Posted : November 17, 2020
Sponsor:
Information provided by (Responsible Party):
Audentes Therapeutics

Tracking Information
First Submitted Date  ICMJE June 21, 2017
First Posted Date  ICMJE June 27, 2017
Last Update Posted Date November 17, 2020
Actual Study Start Date  ICMJE August 2, 2017
Estimated Primary Completion Date March 2024   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (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  ICMJE
 (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
Change History
Current Secondary Outcome Measures  ICMJE
 (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  ICMJE
 (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  ICMJE Gene Transfer Clinical Study in X-Linked Myotubular Myopathy
Official Title  ICMJE 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  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE 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  ICMJE X-Linked Myotubular Myopathy
Intervention  ICMJE Genetic: AT132
AT132 is an AAV8 vector containing a functional copy of the human MTM1 (hMTM1) gene.
Study Arms  ICMJE
  • 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

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Estimated Enrollment  ICMJE
 (submitted: September 3, 2019)
24
Original Estimated Enrollment  ICMJE
 (submitted: June 23, 2017)
12
Estimated Study Completion Date  ICMJE March 2024
Estimated Primary Completion Date March 2024   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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  ICMJE
Sexes Eligible for Study: Male
Ages  ICMJE up to 5 Years   (Child)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Canada,   France,   Germany,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03199469
Other Study ID Numbers  ICMJE 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  ICMJE
Plan to Share IPD: No
Responsible Party Audentes Therapeutics
Study Sponsor  ICMJE Audentes Therapeutics
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Nathan Bachtell, MD Audentes Therapeutics
PRS Account Audentes Therapeutics
Verification Date February 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP