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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Astellas Gene Therapies Inc.

Participant type

Pediatric, Patients

Age range

0-17 years

Gender

Male

Therapeutic area

Diseases [C] - Musculoskeletal Diseases [C05]

Trial duration

21 Aug 2018 → ongoing

Decision date (initial)

2024-05-14

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Astellas Gene Therapies Inc.

External identifiers

EU CT number

2024-512637-32-00

EudraCT number

2017-000876-27

ClinicalTrials.gov

NCT03199469

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Dose response, Therapy, Safety, Efficacy

* To determine the therapeutic dose of AT132

* To confirm the safety and efficacy of the therapeutic dose of AT132

Conditions and MedDRA coding

X-linked Myotubular Myopathy (XLMTM)

Regulatory references

EMA paediatric investigation plan (PIP)

EMEA-002571-PIP01-19

Plan to share IPD

No

IPD plan description

Access to anonymized individual participant level data will not be provided for this trial as it meets one or more of the exceptions described on www.clinicalstudydatarequest.com under "Sponsor Specific Details for Astellas"

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

1. 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.* * = Inclusion/exclusion criteria for delayed treatment control subjects before receiving AT132.
2. 2. Subject is male.*
3. 3. Subject is aged less than 5 years old at dosing*
4. 4. Subject requires mechanical ventilatory support: Part 1: Subject requires some mechanical ventilatory support (eg., 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. 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. 6. Subject has ventilator maximum positive end-expiratory pressure (PEEP) < 8 cm H2O at screening.*
7. 7. Signed informed consent by the parent(s) or legally authorized representative(s) (LAR) (when applicable).*
8. 8. Subject and parent(s)/LAR(s) are willing and able to comply with study visits and study procedures.*
9. 9. Subject's range is ≥ 4.8 kg (UNIQUE to France)

Exclusion criteria 18

1. 1. Subject is participating in an interventional study designed to treat XLMTM.* * = If a subject is a delayed-treatment control, this inclusion/exclusion criterion must be met before receiving AT132.
2. 2. Subject born < 35 weeks gestation who is still not term as per corrected age.
3. 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. 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. 5. Subject has a clinically important condition or life-threatening disease, other than XLMTM, in the opinion of the Investigator.*
6. 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. 7. Subject is currently experiencing a clinically important respiratory infection or other active infection.*
8. 8.Subject has received pyridostigmine or any medication to treat XLMTM within 3 months before Day 1.*
9. 9.Other than as required per protocol, subject has received immunemodulating 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 beenstable for at least 4 weeks before dosing.*
10. 10.Subject has a contraindication to prednisolone.*
11. 11.Subject has a contraindication to study drug or ingredients.*
12. 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 enrolles under protocol v8 and beyond ).
13. 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 enrolles under protocol v8 and beyond ).
14. 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 enrolles under protocol v8 and beyond ).
15. 15. Subject has a clinically important condition, including CTCAE v4.03 Grade ≥ 2 anemia (< 10 g/dL hemoglobin).*
16. 16. Subject has a contraindication to ursodiol (ursodeoxycholic acid).*
17. 17. Subject has a prior diagnosis or history of cardiac arrhytmias, myocarditis, or any other cardiac disease (UNIQUE to FRANCE).
18. 18. Subject has a contradiction to general anesthesia and to muscle biopsy procedure (UNIQUE to France).

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Primary Efficacy Endpoint: • Change from baseline in hours of ventilation support at Week 24

Secondary endpoints 10

1. Key Secondary Efficacy Endpoint: Percentage of subjects achieving functionally independent sitting for at least 30 seconds at Week 24
2. 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
3. • Change from baseline in Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) at Week 24
4. • Change from baseline in maximal inspiratory pressure (MIP) at Week 24
5. • Change from baseline in quantitative analysis of myotubularin expression in the muscle biopsy at Week 24
6. • 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])
7. • Number (%) of age-appropriate clinically relevant gross motor function milestones attained through Week 24
8. • Percentage of subjects achieving full ventilator independence at Week 24
9. •Survival
10. 10 Safety Endpoints: • 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 shedding , annualized hospitalization rate , annualized respiratory and non-respiratory SAE rate, and length of stay per hospitalization

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Astellas Gene Therapies Inc.

Sponsor organisation

Astellas Gene Therapies Inc.

Address

600 California Street Floor 17th

City

San Francisco

Postcode

94108-2725

Country

United States

Scientific contact point

Organisation

Astellas Gene Therapies Inc.

Contact name

Head of Clinical Trial Unit Regulatory Affairs

Public contact point

Organisation

Astellas Gene Therapies Inc.

Contact name

Head of Clinical Trial Unit Regulatory Affairs

Third parties 18

Locations

2 EU/EEA countries · 2 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 35 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

8 submissions — initial application plus substantial / non-substantial modifications