A Study of AT132 in Young Children With X-Linked Myotubular Myopathy (XLMTM)

Phase 2

Active, not recruiting

Conditions: X-Linked Myotubular Myopathy

Interventions: Genetic: Resamirigene bilparvovec

Registration Number: NCT03199469

Lead Sponsor: Astellas Gene Therapies

Brief Summary: X-linked myotubular myopathy (XLMTM) is a rare and serious condition present at birth where the muscles do not work properly. There are currently no therapies for this serious condition.

The protein myotubularin is needed for muscle development and movement. A gene called MTM1 tells the body to make myotubularin. XLMTM is caused by changes, or mutations, in the MTM1 gene. Changes in the MTM1 gene causes low levels of myotubularin to be made, so the muscles do not work properly. XLMTM may also affect the liver, and in some cases, this can be dangerous and threaten the patient´s life.

Gene therapy is a way of getting a healthy copy of a gene into the body. This allows the body's cells to make a normal protein that may reduce disease symptoms. AT132 is a gene therapy that gets a healthy MTM1 gene into the body to help improve muscle development and function in young children with the disease. AT132 does not treat liver disease, and because of the way the treatment works, it may make liver problems worse.

AT132 was the gene therapy treatment given to children who participated in this study and is not available to the public. In this study, AT132 was given to children for the first time. Due to the occurrence of severe complications and fatalities associated with administration of AT132, the study has been stopped and no further participants will be enrolled.

The main aim of the study is to check how long young children need machines to support breathing (ventilation support) after AT132.

Due to the occurrence of severe complications and fatalities associated with administration of AT132, the study has been stopped and no further participants will be enrolled. This study included children with XLMTM under 5 years old who had breathing problems caused by XLMTM. They couldn't take part if they were born prematurely, recently had surgery, had liver disease or other condition or disease the study doctor thought was medically important. The study did enroll participants with medically significant liver disease.

This is an open-label study. This means that young children and their caregivers, and clinic staff know that young children received AT132. This study was designed with 2 parts and is now in a long-term follow-up phase to collect information on the safety and improvements in muscle function in the children who received AT132.

In Part 1, small groups of young children were given different doses of AT132, with one group receiving a lower dose and one group receiving a higher dose of AT132. The purpose of giving the two doses was to determine which dose was best for treating the muscle disease. After receiving AT132, a medical panel of experts reviewed each child for safety and for how their muscles responded. AT132 did not demonstrate appropriate safety at either dose. Administration of AT132 was stopped. Children who received AT132 are being monitored for 10 years for safety and to understand how their muscles function over time.

Detailed Description: This study evaluated safety and efficacy of gene transfer in X-Linked Myotubular Myopathy. Participants received a single dose of resamirigene bilparvovec delivered intravenously.

ASPIRO was being conducted in two parts. Part 1 was a dose escalation phase that was evaluating the preliminary safety and efficacy of Resamirigene bilparvovec at doses of 1.3x10\^14 vg/kg and 3.5x10\^14 vg/kg. Part 2 of ASPIRO was a pivotal expansion cohort designed to confirm the safety and efficacy of resamirigene bilparvovec at a dose of 3.5x10\^14 vg/kg. The pivotal expansion cohort enrolled eight participants, consisting of four age-matched pairs (within +/- 6 months of age). One participant from each pair was randomized to receive a single dose of resamirigene bilparvovec at 3.5x10\^14 vg/kg, and the other served as a delayed treatment control. Eligible delayed treatment control participants administered resamirigene bilparvovec after that individual participant completed the Week 24 visit as a delayed treatment control.

The primary efficacy endpoint measures assessed at Week 24. Participants were followed for a total of 10 years after administration of resamirigene bilparvovec. Only Part 1 of the study was reported.

This study utilized an independent Data Monitoring Committee (DMC) that monitored participant safety and provided recommendations to Astellas regarding dose escalation, dose expansion, and safety matters.

Recruitment & Eligibility

Status: ACTIVE_NOT_RECRUITING

Sex: Male

Target Recruitment: 27

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 dosing
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.
UNIQUE to France: Subject's weight is ≥ 4.8 kg.

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 previous scoliosis repair surgery/procedure, or planned/expected scoliosis repair surgery/procedure in the 12 months following Day 1 (Part 2 including any subjects enrolled under protocol v8 and beyond).
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 including any subjects enrolled under protocol V8 and beyond).
Subject is able to sit without assistance for at least 30 seconds at screening, in the opinion of the investigator (Part 2 including any subjects enrolled under protocol V8 and beyond).
Subject has a clinically important condition, including CTCAE v4.03 Grade ≥ 2 anemia (< 10 g/dL hemoglobin).
Subject has a contraindication to ursodiol (ursodeoxycholic acid).
UNIQUE to France: Subject has a prior diagnosis or history of cardiac arrhythmias, myocarditis, or any other cardiac disease.
UNIQUE to France: Subject has a contraindication to general anesthesia and to muscle biopsy procedures.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
1.3 × 10^14 vg/kg (Low dose)	Resamirigene bilparvovec	Participants received 1.3 x 10\^14 viral genomes per kilogram (vg/kg) of body weight resamirigene bilparvovec as a single dose intravenously on Day 1. A sentinel dose was given to first participant and if there were no safety concerns, subsequent participants received either resamirigene bilparvovec at the same dose or control with delayed treatment after at least 4 weeks of post-dose data from the sentinel participant.
3.5 × 10^14 vg/kg (High dose)	Resamirigene bilparvovec	Participants received 3.5 × 10\^14 vg/kg of body weight resamirigene bilparvovec as a single dose intravenously on Day 1. A sentinel dose was given to first participant and if there were no safety concerns, subsequent participants received either resamirigene bilparvovec at the same dose or control with delayed treatment after at least 4 weeks of post-dose data from the sentinel participant.

Primary Outcome Measures

Name	Time	Method
Change From Baseline in Hours of Ventilation Support at Week 24	Baseline, week 24	The hours of ventilation support were based on diary data from participants for whom diary data was collected at baseline and by assessment of time off ventilator questionnaire for all other participants. Weekly scores were the average of ventilation hours needed for at least 5 out of the 7 days leading up to and including the analysis visit day (e.g., Day 168 for Week 24). For cases where the diary or the ventilator assessment indicated the ventilator type = "None", then zero was imputed for the number of hours on ventilator.

Secondary Outcome Measures

Name	Time	Method
Time to Reduction in Required Ventilator Support to ≤ 16 Hours a Day From Dosing to Week 24	Baseline up to week 24	The reduced ventilator time was obtained directly from the daily diary or assessment of the time off ventilator questionnaire. The first instance of time reduction reported as ≤ 16 hours per day was considered as an event. Kaplan- Meier estimate was used for analysis.
Percentage of Participants Achieving Full Ventilator Independence at Week 24	Week 24	"Full ventilator independence" is defined as: the date of removal from ventilator field on the "Assessment of Ventilator Parameters" eCRF is not blank or "Is subject on a ventilator" = "No" on the same eCRF.
Percentage of Participants Achieving Functionally Independent Sitting for At Least 30 Seconds by Week 24	Week 24	Independence to sit is defined as a participant who sits for at least 30 seconds without assistance from another person or object. Data was determined from the motor milestone electronic case report form (eCRF) or the Bayley Scales of Infant and Toddler Development (BSID) subtest performance criteria number 26, used to determine whether the participant achieves (Yes) or doesn't achieve (No) the milestone. If data was not available then they would be included as "missing".
Change From Baseline in Maximal Inspiratory Pressure (MIP) at Week 24	Baseline, week 24	MIP is a quick and non-invasive test to measure strength of inspiratory muscles, primarily diaphragm, and allows for assessment of ventilatory failure, restrictive lung disease and respiratory muscle strength. MIP refers to how much air pressure force an individual creates by inhaling through the mouth as hard as possible.
Change From Baseline in Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) Total Score at Week 24	Baseline, week 24	The CHOP INTEND is an assessment scale that was originally designed to quantify motor abilities in infants aged 1.4 to 37.9 months, with spinal muscular atrophy type I (SMA-I) and has been validated for X-linked myotubular myopathy (XLMTM). The scale contains 16 questions, each of which is scored on a scale of 0 to 4, with 0 being no response/ability to perform the movement and 4 highest abilities to perform the task, per CHOP INTEND item instructions. The score used for analysis is the total sum of all 16 questions, which will range from 0 to 64. Higher score indicates better neuromuscular function. If an item is missing or scored as "Could Not Test (CNT)" then 0 will be imputed for the item score.
Change From Baseline in Quantitative Analysis of Myotubularin Expression in the Muscle Biopsy at Week 24	Baseline, week 24	Myotubularin is a protein, a highly conserved, dual-specific lipid phosphatase that is involved in the development, maturation, and maintenance of skeletal muscle cells. Myotubularin is encoded by an MTM1 gene. The concentration of the sample was normalized such that the equivalent amount of protein was tested per sample.
Change From Baseline in Quality of Life Assessment of Caregiver Experience With Neuromuscular Disease (ACEND) Total Score at Week 24	Baseline, week 24	ACEND was developed to measure impact on lives of parents/legally authorized representatives /caregivers caring for children with severe neuromuscular disorders. ACEND has 41 items which reflected 2 domains (physical impact \[feeding/grooming/dressing {6 items}, sitting/play {5 items}, transfers {5 items} and mobility {7 items}\] and general caregiver impact \[time {4 items}, emotion {9 items}, and finance {5 items}\]). Score for each item was based on 6- or 5-point ordinal scale, and scores for each domain and subdomain were scored on 0 - 100 scale. Higher scores reflected caregivers experiencing less intense care-giving impact. Raw scores for each subdomain was created by computing algebraic mean of items for those respondents who completed one item or more; setting missing for those items with no responses. Then, arithmetic mean of responded items was standardized to 0 to 100 score and transformed scores were from 0 to 100 for each subdomain. Higher score indicated a better outcome.
Change From Baseline in Pediatric Quality of Life Inventory (PedsQL) Assessment Total Score at Week 24	Baseline, week 24	PedsQL is a tool designed to measure health-related quality of life in healthy children and adolescents and those with acute and chronic health conditions. PedsQL measures the core dimensions of health as delineated by the World Health Organization, as well as role (school) functioning. This questionnaire has different modules that are administered depending on the age and condition of the child. Each item of the questionnaire is measured on a 5-point likert scale from - 0 (Never) to 4 (Almost always). The module is composed of 25 items comprising 3 dimensions: About My Neuromuscular Disease (17 items), Communication (3 items), About Our Family Resources (5 items). Items are reversed scored and linearly transformed to a total score of 0-100 scale. Higher scales/scores indicate lower problems.
Duration of Overall Survival	Baseline up to 5 years	Survival status was assessed at each visit until the participant withdraws consent or completes the study. If the participant missed a visit or withdraws for a reason other than withdrawal of consent or death, the site contacted the parent(s)/legally authorized representatives to ascertain if the participant was alive. For participants who withdrew from the study, the participant was contacted every 6 months for 5 years after administration and to assess for survival. Kaplan- Meier estimate was used for analysis.
Number of Participants With Treatment Emergent Adverse Events (TEAEs)	From first dose to 5 years	An AE is any untoward medical occurrence in a participant administered a study drug not necessarily having a causal relationship with this treatment. An AE can therefore be any unfavorable \& unintended sign, symptom, or disease temporally associated with the use of medicinal product (MP) whether or not considered related to MP. A TEAE is any AEs, regardless of relationship to study drug, that begins or worsens on or after baseline (dosing) visit date.
Mean Percent of Age-appropriate Clinically Relevant Gross Motor Function Milestones Attained Through Week 24	Baseline, weeks 4, 12, 16 and 24	Motor Developmental Milestones included: head control (holds head erect for at least 15 seconds without support), rolls from back to sides (turns from back to both sides), sits without support (sits alone without support for at least 10 seconds), stands with assistance (supports own weight for at least 2 seconds), crawls (makes forward progress of at least 5 feet by crawling on hands and knees), pulls to stand (raises self to standing position using chair or other convenient object for support), walks with assistance (child walks by making coordinated, alternating stepping movements. May hold on with 1 or 2 hands for support), stands alone (stands alone for at least 3 seconds after you release hands), walks alone (takes at least 3 steps without support, even if gait is stiff-legged and wobbly). Mean percentage of gross motor function milestones attained was reported.

Trial Locations

Locations (6): UCLA Medical Center
🇺🇸
Los Angeles, California, United States
Ann & Robert H Lurie Children's Hospital of Chicago
🇺🇸
Chicago, Illinois, United States
National Institute of Neurological Disorders and Stroke/NIH Porter
🇺🇸
Bethesda, Maryland, United States
Hospital for Sick Children
🇨🇦
Toronto, Ontario, Canada
Hopital Armad Trousseau
🇫🇷
Paris, France
Kinderklinik und Kinderpoliklinik im Dr. Von Haunerschen Kinderspital Klinikum der Universitat Munchen
🇩🇪
München, Germany