First-in-human study of AT132 in X-Linked Myotubular Myopathy (XLMTM) Patients

• Register: EUCTR
• Last refreshed on: 21 August 2023
• Main ID: EUCTR2017-000876-27-DE
• Date of registration: 22/09/2017
• Prospective Registration: Yes
• Primary sponsor: Audentes Therapeutics Inc., an Astellas Company
• Public title: First-in-human study of AT132 in X-Linked Myotubular Myopathy (XLMTM) Patients
• Scientific title: 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 - ASPIRO
• Date of first enrolment: 22/05/2018
• Target sample size: 26
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2017-000876-27
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: yes Single blind: no Double blind: no Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: no Other: yes Other specify the comparator: Delayed-treatment concurrent control group Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): yes Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Canada, France, Germany, United Kingdom, United States

Contacts

• Name: Clinical Trials Information
• Affiliation: Audentes Therapeutics, Inc., an Astellas Company

• Name: Clinical Trials Information
• Affiliation: Audentes Therapeutics, Inc., an Astellas Company

Key inclusion & exclusion criteria

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.*

*Inclusion/exclusion criteria for delayed treatment control subjects before receiving AT132.
Are the trial subjects under 18? yes
Number of subjects for this age range: 26
F.1.2 Adults (18-64 years) no
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range

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).*
* If a subject is a delayed-treatment control, this inclusion/exclusion criterion must be met before receiving AT132.



Age minimum:
Age maximum:
Gender:
Female: no
Male: yes

Health Condition(s) or Problem(s) studied

X-linked Myotubular Myopathy (XLMTM)
MedDRA version: 20.0 Level: HLGT Classification code 10029317 Term: Neuromuscular disorders System Organ Class: 10029205 - Nervous system disorders

Therapeutic area: Diseases [C] - Musculoskeletal Diseases [C05]

Intervention(s)

Product Name: rAAV8-Des-hMTM1
Product Code: AT132
Pharmaceutical Form: Solution for infusion

Primary Outcome(s)

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

Timepoint(s) of evaluation of this end point: Baseline to Week 24

Secondary Objective: Not applicable

Main Objective: 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

Secondary Outcome(s)

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 (PImax) 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

Timepoint(s) of evaluation of this end point: Baseline to Week 24

Secondary ID(s)

ATX-MTM-002

NCT03199469

2017-000876-27-GB

Source(s) of Monetary Support

Audentes Therapeutics, Inc., an Astellas Company

Ethics review

Status: Approved
Approval date: 02/05/2018
Contact: