E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
X-linked Myotubular Myopathy (XLMTM) |
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E.1.1.1 | Medical condition in easily understood language |
X-linked Myotubular Myopathy (XLMTM) |
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E.1.1.2 | Therapeutic area | Diseases [C] - Musculoskeletal Diseases [C05] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | HLGT |
E.1.2 | Classification code | 10029317 |
E.1.2 | Term | Neuromuscular disorders |
E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
OBJECTIVES: The objectives of the study are as follows: • To determine the optimal dose of AT132 • To confirm the safety and efficacy of an optimal dose of AT132 |
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E.2.2 | Secondary objectives of the trial |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Subject has a diagnosis of XLMTM resulting from a genetically confirmed mutation in the MTM1 gene as assessed by a Sponsor-approved testing facility.* 2. Subject is male.* 3. Subject is aged less than 5 years old at dosing* 4. 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 to 24 hours per day at screening (confirmed by daytime polysomnographic study). 5. Subject requiring invasive mechanical ventilator support is fitted with or willing to be fitted with a cuffed tracheostomy tube for some respiratory assessments.* 6. Subject has ventilator maximum positive end-expiratory pressure (PEEP) < 8 cm H2O at screening.* 7. Signed informed consent by the parent(s) or legally authorized representative(s) (LAR) (when applicable).* 8. Subject and parent(s)/LAR(s) are willing and able to comply with study visits and study procedures.* 9. Subject's weight is ≥ 4.8 kg (UNIQUE to France).
*Inclusion/exclusion criteria for delayed treatment control subjects before receiving AT132. |
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E.4 | Principal exclusion criteria |
1. Subject is participating in an interventional study designed to treat XLMTM.* 2. Subject born <35 weeks gestation who is still not term as per corrected age. 3. Subject tests positive for AAV8 neutralizing antibody with titers > 1:20 (subjects under the age of 18 months may be retested in cases where antibodies may have been maternally acquired and titers may decline in the first months of life).* 4. 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. 5. Subject has a clinically important condition or life-threatening disease, other than XLMTM, in the opinion of the investigator.* 6. Subject has a clinically significant underlying liver disease, defined as: ≥ Grade 3 aspartate aminotransferase (AST) (> 5.0 x upper limit of normal [ULN]; Common Terminology Criteria for Adverse Events [CTCAE] v. 4.03)* ≥ Grade 3 alanine aminotransferase (ALT) (> 5.0 x ULN; CTCAE v. 4.03)* Hepatic peliosis or any other clinically significant structural abnormality detected by ultrasound* 7. Subject is currently experiencing a clinically important respiratory infection or other active infection.* 8. Subject has received pyridostigmine or any medication to treat XLMTM within 3 months before Day 1.* 9. 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.* 10. Subject has a contraindication to prednisolone.* 11. Subject has a contraindication to study drug or ingredients.* 12. 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). 13. 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). 14. 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). 15. Subject has a clinically important condition, including CTCAE v4.03 Grade ≥ 2 anemia (< 10 g/dL hemoglobin).* 16. Subject has a contraindication to ursodiol (ursodeoxycholic acid).* 17. Subject has a prior diagnosis or history of cardiac arrhythmias, myocarditis, or any other cardiac disease (UNIQUE to France). 18. Subject has a contraindication to general anesthesia and to muscle biopsy procedures (UNIQUE to France).
* If a subject is a delayed-treatment control, this inclusion/exclusion criterion must be met before receiving AT132.
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E.5 End points |
E.5.1 | Primary end point(s) |
ENDPOINTS AND SAFETY ASSESSMENTS: The study consists of 2 parts. Part 1 will establish the optimal dose. Part 2 will confirm the safety and efficacy of AT132 at the optimal dose level in a controlled, randomized dose expansion.
Safety Assessments: • Adverse events (AEs), serious AEs (SAEs), and findings from safety laboratory tests, 12-lead ECG, echocardiograms (ECHOs), vital signs, growth parameters, physical examinations, liver ultrasounds, antibody formation (anti AAV8, anti MTM1), viral shredding, annualized hospitalization rate, annualized respiratory and non-respiratory SAE rate, and length of stay per hospitalization Primary Efficacy Endpoints: • Change from baseline in hours of ventilation support over time at Week 24
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
Key Secondary Efficacy Endpoints: Percentage of subjects achieving functionally independent sitting for at least 30 seconds by Week 24 as assessed by an independent blinded Physical Therapy Adjudication Committee Other Secondary Efficacy Endpoints: • Time to reduction in required ventilator support to ≤ 16 hours a day (only in subjects who require invasive ventilation) at Week 24 as assessed by independent blinded Pulmonary Adjudication Committee • Change from baseline in Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) at Week 24 • Change from baseline in maximal inspiratory pressure (MIP) at Week 24 • Change from baseline in quantitative analysis of myotubularin expression in the muscle biopsy at Week 24 • Change from baseline in quality of life assessments at Week 24 (ie, the Assessment of Caregiver Experience with Neuromuscular Disease [ACEND] and Pediatric Quality of Life Inventory [PedsQL]) • Number (%) of age-appropriate clinically relevant gross motor function milestones attained through Week 24, as assessed by independent blinded Physical Therapy Adjudication Committee • Percentage of subjects achieving full ventilator independence in the absence of acute illness and perioperatively at Week 24, as assessed by independent blinded Pulmonary Adjudication Committee • Change from baseline in the health profiles and overall health status as assessed by the EQ-5D-Y Proxy and the EQ-5D-5L versions at Week 24 • Survival
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | Yes |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
Delayed-treatment concurrent control group |
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E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 2 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Canada |
United States |
France |
Germany |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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Last visit of the last subject |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 12 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 12 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |