ASPIRO: A Phase 1/2/3, 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
试验速览
- 阶段
- 2 期
- 状态
- 进行中（未招募）
- 发起方
- 入组人数
- 27
- 试验地点
- 11
- 主要终点
- Change From Baseline in Hours of Ventilation Support at Week 24
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- — 至 5 Years（Child）
- 性别
- Male
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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
- •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.
研究组 & 干预措施
1.3 × 10^14 vg/kg (Low dose)
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.
干预措施: Resamirigene bilparvovec (Genetic)
3.5 × 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.
干预措施: Resamirigene bilparvovec (Genetic)
结局指标
主要结局
Change From Baseline in Hours of Ventilation Support at Week 24
时间窗: 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.
次要结局
- Time to Reduction in Required Ventilator Support to ≤ 16 Hours a Day From Dosing to Week 24(Baseline up to week 24)
- Percentage of Participants Achieving Full Ventilator Independence at Week 24(Week 24)
- Percentage of Participants Achieving Functionally Independent Sitting for At Least 30 Seconds by Week 24(Week 24)
- Change From Baseline in Maximal Inspiratory Pressure (MIP) at Week 24(Baseline, week 24)
- Change From Baseline in Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) Total Score at Week 24(Baseline, week 24)
- Change From Baseline in Quantitative Analysis of Myotubularin Expression in the Muscle Biopsy at Week 24(Baseline, week 24)
- Change From Baseline in Quality of Life Assessment of Caregiver Experience With Neuromuscular Disease (ACEND) Total Score at Week 24(Baseline, week 24)
- Change From Baseline in Pediatric Quality of Life Inventory (PedsQL) Assessment Total Score at Week 24(Baseline, week 24)
- Duration of Overall Survival(Baseline up to 5 years)
- Number of Participants With Treatment Emergent Adverse Events (TEAEs)(From first dose to 5 years)
- Mean Percent of Age-appropriate Clinically Relevant Gross Motor Function Milestones Attained Through Week 24(Baseline, weeks 4, 12, 16 and 24)