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Protocol Details

ASPIRO: A Phase 1/2, Randomized, Open-Label, Ascending-Dose, Delayed-Treatment Concurrent Control Clinical Study to Evaluate the Safety and Preliminary Efficacy of AT132, an AAV8-Delivered Gene Therapy in X-Linked Myotubular Myopathy (XLMTM) Patients

This study is currently recruiting participants.

Summary | Eligibility | Citations | Contacts

Summary

Number

18-N-0083

Sponsoring Institute

National Institute of Neurological Disorders and Stroke (NINDS)

Recruitment Detail

Type: Enrolling by Invitation
Gender: Male & Female
Min Age: N/A
Max Age: 5

Referral Letter Required

Yes

Population Exclusion(s)

None

Special Instructions

Currently Not Provided

Keywords

Pediatric;
Neuromuscular

Recruitment Keyword(s)

None

Condition(s)

Muscle Myopathies;
Muscular Disease

Investigational Drug(s)

AT132

Investigational Device(s)

None

Intervention(s)

Biological/Vaccine: AT132

Supporting Site

National Institute of Neurological Disorders and Stroke

Background:

X-Linked Myotubular Myopathy (XLMTM) is caused by a mutation in the MTM1 gene, which helps the body make the protein myotubularin. This causes severe muscle weakness in children. AT132 therapy gives the normal MTM1 gene to a child with XLMTM. This could help XLMTM symptoms.

Objective:

To see if AT132 is safe, increases myotubularin production, and helps symptoms in children with XLMTM.

Eligibility:

Boys under age 5 who:

Have XLMTM and a MTM1 mutation

Require mechanical breathing support

Design:

Participants will be screened with:

Physical exam

Blood, urine, and heart tests

Abdomen ultrasound

Medical history

Participants will join either the early treatment or delayed treatment group.

Participants will be admitted to the hospital. The next day they will get AT132 by IV infusion. They will stay in the hospital 1 or 2 nights. Two days after the infusion they will have the screening procedures, plus:

Performing simple tasks while being videotaped

Breathing tests: Participants will wear a facemask, breathing tube, or ventilator. Their airflow will be temporarily blocked.

Muscle biopsy. A small piece of muscle is taken from the participant s arm or leg under general anesthesia.

Wrist X-ray

Starting the day before their infusion, participants will take the drug prednisolone for 16 weeks.

Participants will have many visits over several years in this order:

Weekly for 2 months after the infusion

1 month later

Every 3 months for 1 year

Every 6 months for 5 years

Delayed treatment group participants will have visits 1 and 3 months after screening, then every 3 months for up to 1 year before receiving AT132.

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Eligibility

INCLUSION CRITERIA:

Subjects must meet all of the following inclusion criteria to be eligible for participation in this study.

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 Day 1 and/or participated in the ATX-MTM- 009 (INCEPTUS) study.

4. 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).

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) less than 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 must be willing and able to stay off of exclusionary medications for 12 months, including pyridostigmine, and any other experimental therapies for XLMTM.

EXCLUSION CRITERIA:

Subjects who meet any of the following exclusion criteria are not to be enrolled in this study.

1. Subject is participating in an interventional study designed to treatXLMTM.

2. Subject born less than 35 weeks gestation who is still not term as per correctedage.

3. Subject tests positive for AAV8 neutralizing antibody with titers greater than 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 (less than 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, including Common Terminology Criteria for

Adverse Events (CTCAE) v4.03 Grade greater than or equal to 2 anemia (less than 10g/dL hemoglobin), or life threatening disease other than XLMTM, in the opinion of the investigator.

6. Subject has a clinically significant underlying liver disease, defined as:

-- greater than or equal to Grade 3 Aspartate aminotransferase (greater than 5.0 x upper limit of normal [ULN]) [CTCAE v. 4.03]

-- greater than or equal to Grade 3 Alanine aminotransferase (greater than 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 at the time of screening.

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 (e.g., uncontrolled hyperglycemia, high cholesterol, increased ocular pressure, high blood pressure).

11. Subject has a contraindication to study drug or ingredients (i.e., an allergy to lactated ringers or poloxamer 188).


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Citations:

Not Provided

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Contacts:

Principal Investigator

Referral Contact

For more information:

Carsten G. Bonnemann, M.D.
National Institute of Neurological Disorders and Stroke (NINDS)



Gilberto V. Averion
National Institute of Neurological Disorders and Stroke (NINDS)
National Institutes of Health
Building 10
Room 12N210
10 Center Drive
Bethesda, Maryland 20892
(301) 594-2760
gilbertoav@mail.nih.gov

Office of Patient Recruitment
National Institutes of Health Clinical Center (CC)
Building 61, 10 Cloister Court
Bethesda, Maryland 20892
Toll Free: 1-800-411-1222
Local Phone: 301-451-4383
TTY: 1-866-411-1010
PRPL@cc.nih.gov

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