X-Linked Myotubular Myopathy
Conditions
Keywords
AAV8-Delivered Gene Therapy, XLMTM, Adeno Associated Virus
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.
Interventions
GENETICResamirigene bilparvovec
Resamirigene bilparvovec is an AAV8 vector containing a functional copy of the human MTM1 (hMTM1) gene.
Sponsors
Astellas Gene Therapies
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
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 subjects, consisting of four age-matched pairs (within +/- 6 months of age). One subject 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 subjects administered resamirigene bilparvovec after that individual subject completed the Week 24 visit as a delayed treatment control.
Eligibility
Sex/Gender
MALE
Age
No minimum to 5 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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". |
| 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. |
| 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 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 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. |
| 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. |
| 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. |
| 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. |
Countries
Canada, France, Germany, United States
Contacts
STUDY_DIRECTORMedical Director
Astellas Pharma Global Development, Inc.
Participant flow
Recruitment details
Participants diagnosed with X-linked myotubular myopathy (XLMTM) resulting from a genetically confirmed mutation in the myotubular myopathy (MTM) 1 gene as assessed by a Sponsor-approved testing facility were enrolled in this study.
Pre-assignment details
Participants who met all inclusion criteria and none of the exclusion criteria were enrolled in the study. The study is ongoing, and data for efficacy is reported for Part 1 (week 24) of the study only with mortality and safety data being reported up to data cut-off date 30 June 2023 (up to 5 years).
Participants by arm
| Arm | Count |
|---|---|
| 1.3 x 10^14 vg/kg (Low Dose) Participants received 1.3 x 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. | 7 |
| 3.5 x 10^14 vg/kg (High Dose) 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. | 20 |
| Total | 27 |
Baseline characteristics
| Characteristic | 1.3 x 10^14 vg/kg (Low Dose) | Total | 3.5 x 10^14 vg/kg (High Dose) |
|---|---|---|---|
| Age, Continuous | 21.78 Months STANDARD_DEVIATION 15.47 | 33.54 Months STANDARD_DEVIATION 23.37 | 37.66 Months STANDARD_DEVIATION 24.55 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 9 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants | 17 Participants | 13 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 4 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 7 Participants | 21 Participants | 14 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 7 Participants | 27 Participants | 20 Participants |
| Ventilation Support | 21 hours STANDARD_DEVIATION 4.69 | 22.89 hours STANDARD_DEVIATION 2.8 | 23.71 hours STANDARD_DEVIATION 0.52 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 7 | 3 / 17 |
| other Total, other adverse events | 7 / 7 | 17 / 17 |
| serious Total, serious adverse events | 5 / 7 | 13 / 17 |
Outcome results
Primary
Change From Baseline in Hours of Ventilation Support at 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.
Time frame: Baseline, week 24
Population: FAS population. Participants with available data were reported.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 1.3 × 10^14 vg/kg (Low Dose) | Change From Baseline in Hours of Ventilation Support at Week 24 | -8.92 hours | Standard Deviation 9.31 |
| 3.5 × 10^14 vg/kg (High Dose) | Change From Baseline in Hours of Ventilation Support at Week 24 | -5.84 hours | Standard Deviation 5.45 |
Secondary
Change From Baseline in Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) Total Score at 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.
Time frame: Baseline, week 24
Population: FAS population. Participants with available data were reported.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 1.3 × 10^14 vg/kg (Low Dose) | Change From Baseline in Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) Total Score at Week 24 | 11.86 Score on scale | Standard Deviation 15.12 |
| 3.5 × 10^14 vg/kg (High Dose) | Change From Baseline in Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) Total Score at Week 24 | 13.25 Score on scale | Standard Deviation 13.35 |
Secondary
Change From Baseline in Maximal Inspiratory Pressure (MIP) at 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.
Time frame: Baseline, week 24
Population: FAS population. Participants with available data were reported.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 1.3 × 10^14 vg/kg (Low Dose) | Change From Baseline in Maximal Inspiratory Pressure (MIP) at Week 24 | 41.07 centimeter of water (cmH2O) | Standard Deviation 35.03 |
| 3.5 × 10^14 vg/kg (High Dose) | Change From Baseline in Maximal Inspiratory Pressure (MIP) at Week 24 | 26.72 centimeter of water (cmH2O) | Standard Deviation 28.35 |
Secondary
Change From Baseline in Pediatric Quality of Life Inventory (PedsQL) Assessment Total Score at 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.
Time frame: Baseline, week 24
Population: FAS population. Participants with available data were reported.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 1.3 × 10^14 vg/kg (Low Dose) | Change From Baseline in Pediatric Quality of Life Inventory (PedsQL) Assessment Total Score at Week 24 | 9.39 Score on scale | Standard Deviation 15.51 |
| 3.5 × 10^14 vg/kg (High Dose) | Change From Baseline in Pediatric Quality of Life Inventory (PedsQL) Assessment Total Score at Week 24 | 12.06 Score on scale | Standard Deviation 19.23 |
Secondary
Change From Baseline in Quality of Life Assessment of Caregiver Experience With Neuromuscular Disease (ACEND) Total Score at 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.
Time frame: Baseline, week 24
Population: FAS population. Participants with available data were reported.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 1.3 × 10^14 vg/kg (Low Dose) | Change From Baseline in Quality of Life Assessment of Caregiver Experience With Neuromuscular Disease (ACEND) Total Score at Week 24 | 20.12 Score on scale | Standard Deviation 18.81 |
| 3.5 × 10^14 vg/kg (High Dose) | Change From Baseline in Quality of Life Assessment of Caregiver Experience With Neuromuscular Disease (ACEND) Total Score at Week 24 | 13.82 Score on scale | Standard Deviation 12.33 |
Secondary
Change From Baseline in Quantitative Analysis of Myotubularin Expression in the Muscle Biopsy at 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.
Time frame: Baseline, week 24
Population: FAS population. Participants with available data were reported.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 1.3 × 10^14 vg/kg (Low Dose) | Change From Baseline in Quantitative Analysis of Myotubularin Expression in the Muscle Biopsy at Week 24 | 923.69 picograms (pg)/15 microgram(µg) protein | Standard Deviation 816.09 |
| 3.5 × 10^14 vg/kg (High Dose) | Change From Baseline in Quantitative Analysis of Myotubularin Expression in the Muscle Biopsy at Week 24 | 2848.40 picograms (pg)/15 microgram(µg) protein | Standard Deviation 2903.83 |
Secondary
Duration of Overall Survival
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.
Time frame: Baseline up to 5 years
Population: FAS population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 1.3 × 10^14 vg/kg (Low Dose) | Duration of Overall Survival | NA Months |
| 3.5 × 10^14 vg/kg (High Dose) | Duration of Overall Survival | NA Months |
Secondary
Mean Percent of Age-appropriate Clinically Relevant Gross Motor Function Milestones Attained Through Week 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.
Time frame: Baseline, weeks 4, 12, 16 and 24
Population: FAS population. Participants with available data were reported.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 1.3 × 10^14 vg/kg (Low Dose) | Mean Percent of Age-appropriate Clinically Relevant Gross Motor Function Milestones Attained Through Week 24 | Baseline | 0.0 Percentage of gross motor function | — |
| 1.3 × 10^14 vg/kg (Low Dose) | Mean Percent of Age-appropriate Clinically Relevant Gross Motor Function Milestones Attained Through Week 24 | Week 4 | 30.00 Percentage of gross motor function | Standard Deviation 28.28 |
| 1.3 × 10^14 vg/kg (Low Dose) | Mean Percent of Age-appropriate Clinically Relevant Gross Motor Function Milestones Attained Through Week 24 | Week 12 | 0.0 Percentage of gross motor function | — |
| 1.3 × 10^14 vg/kg (Low Dose) | Mean Percent of Age-appropriate Clinically Relevant Gross Motor Function Milestones Attained Through Week 24 | Week 16 | 0.0 Percentage of gross motor function | — |
| 1.3 × 10^14 vg/kg (Low Dose) | Mean Percent of Age-appropriate Clinically Relevant Gross Motor Function Milestones Attained Through Week 24 | Week 24 | 0.0 Percentage of gross motor function | — |
| 3.5 × 10^14 vg/kg (High Dose) | Mean Percent of Age-appropriate Clinically Relevant Gross Motor Function Milestones Attained Through Week 24 | Week 24 | 26.67 Percentage of gross motor function | Standard Deviation 19.36 |
| 3.5 × 10^14 vg/kg (High Dose) | Mean Percent of Age-appropriate Clinically Relevant Gross Motor Function Milestones Attained Through Week 24 | Baseline | 12.50 Percentage of gross motor function | Standard Deviation 15.81 |
| 3.5 × 10^14 vg/kg (High Dose) | Mean Percent of Age-appropriate Clinically Relevant Gross Motor Function Milestones Attained Through Week 24 | Week 16 | 25.25 Percentage of gross motor function | Standard Deviation 16.26 |
| 3.5 × 10^14 vg/kg (High Dose) | Mean Percent of Age-appropriate Clinically Relevant Gross Motor Function Milestones Attained Through Week 24 | Week 4 | 23.33 Percentage of gross motor function | Standard Deviation 19.66 |
| 3.5 × 10^14 vg/kg (High Dose) | Mean Percent of Age-appropriate Clinically Relevant Gross Motor Function Milestones Attained Through Week 24 | Week 12 | 26.85 Percentage of gross motor function | Standard Deviation 15.06 |
Secondary
Number of Participants With Treatment Emergent Adverse Events (TEAEs)
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.
Time frame: From first dose to 5 years
Population: Safety Analysis Set (SAF) consisted of all randomized participants who received resamirigene bilparvovec.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 1.3 × 10^14 vg/kg (Low Dose) | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | 7 Participants |
| 3.5 × 10^14 vg/kg (High Dose) | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | 17 Participants |
Secondary
Percentage of Participants Achieving Full Ventilator Independence at 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.
Time frame: Week 24
Population: FAS population. Participants with available data were reported.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 1.3 × 10^14 vg/kg (Low Dose) | Percentage of Participants Achieving Full Ventilator Independence at Week 24 | Achieved | 28.6 Percentage of participants |
| 1.3 × 10^14 vg/kg (Low Dose) | Percentage of Participants Achieving Full Ventilator Independence at Week 24 | Not Achieved | 71.4 Percentage of participants |
| 3.5 × 10^14 vg/kg (High Dose) | Percentage of Participants Achieving Full Ventilator Independence at Week 24 | Achieved | 0 Percentage of participants |
| 3.5 × 10^14 vg/kg (High Dose) | Percentage of Participants Achieving Full Ventilator Independence at Week 24 | Not Achieved | 100 Percentage of participants |
Secondary
Percentage of Participants Achieving Functionally Independent Sitting for At Least 30 Seconds by 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.
Time frame: Week 24
Population: FAS population. Participants with available data were reported.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 1.3 × 10^14 vg/kg (Low Dose) | Percentage of Participants Achieving Functionally Independent Sitting for At Least 30 Seconds by Week 24 | Achieved | 83.3 Percentage of participants |
| 1.3 × 10^14 vg/kg (Low Dose) | Percentage of Participants Achieving Functionally Independent Sitting for At Least 30 Seconds by Week 24 | Not Achieved | 16.7 Percentage of participants |
| 3.5 × 10^14 vg/kg (High Dose) | Percentage of Participants Achieving Functionally Independent Sitting for At Least 30 Seconds by Week 24 | Not Achieved | 38.5 Percentage of participants |
| 3.5 × 10^14 vg/kg (High Dose) | Percentage of Participants Achieving Functionally Independent Sitting for At Least 30 Seconds by Week 24 | Achieved | 61.5 Percentage of participants |
Secondary
Time to Reduction in Required Ventilator Support to ≤ 16 Hours a Day From Dosing 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.
Time frame: Baseline up to week 24
Population: FAS population. Participants with available data were reported.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 1.3 × 10^14 vg/kg (Low Dose) | Time to Reduction in Required Ventilator Support to ≤ 16 Hours a Day From Dosing to Week 24 | 12.1 Weeks |
| 3.5 × 10^14 vg/kg (High Dose) | Time to Reduction in Required Ventilator Support to ≤ 16 Hours a Day From Dosing to Week 24 | NA Weeks |