Gene Therapy for Children With CLN3 Batten Disease

Batten Disease Clinical Trial

Official title:

Phase I/IIa Gene Transfer Clinical Trial for Juvenile Neuronal Ceroid Lipofuscinosis, Delivering the CLN3 Gene by Self-Complementary AAV9

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03770572
• Other study ID #: AT-GTX-502-01
• Status: Active, not recruiting
• Phase: Phase 1/Phase 2
• Start date: November 13, 2018
• Est. completion date: September 30, 2024

Study information

• Verified date: August 2023
• Source: Amicus Therapeutics
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a phase 1/2, open-label, single dose, dose-escalation clinical trial to evaluate the safety and efficacy of AT-GTX-502 (previous NCH Code: scAAV9.P546.CLN3) delivered intrathecally into the lumbar spinal cord region of subjects with CLN3 Batten disease.

Description:

This is a phase 1/2, open-label, single-dose, dose-escalation study of AT-GTX-502 administered intrathecally into the lumbar spinal cord region of pediatric patients with CLN3 Batten disease.

This study consists of a one-time injection of AT-GTX-502 with follow-up visits on Day 7, 14, 21, and 30, followed by every 3 months through 1 year post-dose, and then every 6 months through the fifth year. There are two Cohorts with a low dose and a high dose.

The primary outcome for this clinical study is to evaluate safety. The co-primary objective is to determine the efficacy of AT-GTX-502 as measured by United Batten Disease Rating Scale (UBDRS) physical subscale.

The secondary outcome measures include Pediatric Quality of Life (PedsQL) inventory, seizure subscale of the UBDRS and global impression subscale of the UBDRS.

The exploratory outcome measures include visual impairment assessment, cognitive evaluations, Brain magnetic resonance imaging (MRI), electroencephalogram (EEG), electrocardiogram (ECG) and echocardiogram (ECHO).

For more information about this study, please contact Amicus Therapeutics Patient Advocacy at clinicaltrials@amicusrx.com or +1 609-662-2000.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 7
• Est. completion date: September 30, 2024
• Est. primary completion date: September 30, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 3 Years to 10 Years

Eligibility

Inclusion Criteria

1. Diagnosis of CLN3 Batten disease determined by genotype available at screening by a College of American Pathologists/Clinical Laboratory Improvement Amendments (CAP/CLIA)-certified laboratory (or a non-US laboratory with an equivalent national accreditation/certification)

2. Aged = 3 to < 11 years

3. UBDRS physical impairment score of = 7

4. Able to walk independently at least 50 feet

Exclusion Criteria

1. Presence of another inherited neurologic or metabolic disease, eg, other forms of Batten disease (also known as neuronal ceroid lipofuscinosis; NCL) or seizures unrelated to CLN3 Batten disease (subjects with febrile seizures may be eligible at the discretion of the investigator)

2. Presence of another neurological illness that may have caused cognitive decline (eg, trauma, meningitis, hemorrhage) before screening

3. Active viral infection (includes HIV or serology positive for hepatitis B or C)

4. Subjects with 2 consecutive aminotransaminase liver tests > 3 times the upper limit of normal or > 1.5 times the upper limit of normal if taking valproic acid at Visit 1 (screening/baseline)

5. Subjects with anti-AAV9 antibody titers > 1:400 as determined by ELISA (enzyme-linked immunosorbent assay) binding immunoassay

6. Abnormal laboratory values considered clinically significant

7. Presence of immunologic disease

8. Has received stem cell or bone marrow transplantation

9. Has received any form of organ transplant

10. History of or current chemotherapy, radiotherapy, or other immunosuppression therapy within the past 30 days (corticosteroid treatment may be permitted at the discretion of the investigator)

11. Current use of cannabinoids and any by-products

12. Contraindications for intrathecal administration of the product or lumbar puncture (for collection of CSF), such as bleeding disorders or other medical conditions (eg, spina bifida, meningitis, or clotting abnormalities)

13. Contraindications for MRI scans (eg, cardiac pacemaker, metal fragment or chip in the eye, aneurysm clip in the brain)

14. Poorly controlled seizures - intractable epilepsy

15. Episode of generalized motor status epilepticus within 4 weeks before the Gene Transfer visit

16. History of corneal or intraocular surgery

17. Severe infection (eg, upper respiratory tract infection, pneumonia, pyelonephritis, or meningitis) within 4 weeks before the Gene Transfer visit (Enrollment may be postponed.)

18. Has received any investigational medication within 30 days before the infusion of study drug

19. Has a medical condition or extenuating circumstance that, in the opinion of the investigator, might compromise the subject's ability to comply with the protocol required testing or procedures or compromise the subject's wellbeing, safety, or clinical interpretability

20. Pregnancy at screening or Day 0. Any female subject judged by the investigator to be of childbearing potential will be tested for pregnancy.

21. Family does not want to disclose subject's study participation with primary care physician and other medical providers

Related Conditions & MeSH terms

• Batten Disease
• CLN3
• Neuronal Ceroid-Lipofuscinoses

Intervention

Genetic:
• Low dose AT-GTX-502
Subjects with diagnosis of CLN3 Batten disease will receive a single dose of AT-GTX-502 at low dose
• High dose AT-GTX-502
Subjects with diagnosis of CLN3 Batten disease will receive a single dose of AT-GTX-502 at high dose

Locations

Country	Name	City	State
United States	Nationwide Children's Hospital	Columbus	Ohio

Sponsors (1)

Lead Sponsor	Collaborator
Amicus Therapeutics

Country where clinical trial is conducted

United States, 

References & Publications (8)

Adams HR, Mink JW; University of Rochester Batten Center Study Group. Neurobehavioral features and natural history of juvenile neuronal ceroid lipofuscinosis (Batten disease). J Child Neurol. 2013 Sep;28(9):1128-36. doi: 10.1177/0883073813494813. — View Citation

Cotman SL, Vrbanac V, Lebel LA, Lee RL, Johnson KA, Donahue LR, Teed AM, Antonellis K, Bronson RT, Lerner TJ, MacDonald ME. Cln3(Deltaex7/8) knock-in mice with the common JNCL mutation exhibit progressive neurologic disease that begins before birth. Hum Mol Genet. 2002 Oct 15;11(22):2709-21. doi: 10.1093/hmg/11.22.2709. — View Citation

Drack AV, Mullins RF, Pfeifer WL, Augustine EF, Stasheff SF, Hong SD. Immunosuppressive Treatment for Retinal Degeneration in Juvenile Neuronal Ceroid Lipofuscinosis (Juvenile Batten Disease). Ophthalmic Genet. 2015;36(4):359-64. doi: 10.3109/13816810.2014.886271. Epub 2014 Feb 19. — View Citation

Kwon JM, Adams H, Rothberg PG, Augustine EF, Marshall FJ, Deblieck EA, Vierhile A, Beck CA, Newhouse NJ, Cialone J, Levy E, Ramirez-Montealegre D, Dure LS, Rose KR, Mink JW. Quantifying physical decline in juvenile neuronal ceroid lipofuscinosis (Batten disease). Neurology. 2011 Nov 15;77(20):1801-7. doi: 10.1212/WNL.0b013e318237f649. Epub 2011 Oct 19. — View Citation

Munroe PB, Mitchison HM, O'Rawe AM, Anderson JW, Boustany RM, Lerner TJ, Taschner PE, de Vos N, Breuning MH, Gardiner RM, Mole SE. Spectrum of mutations in the Batten disease gene, CLN3. Am J Hum Genet. 1997 Aug;61(2):310-6. doi: 10.1086/514846. — View Citation

Ostergaard JR, Rasmussen TB, Molgaard H. Cardiac involvement in juvenile neuronal ceroid lipofuscinosis (Batten disease). Neurology. 2011 Apr 5;76(14):1245-51. doi: 10.1212/WNL.0b013e31821435bd. — View Citation

Phillips SN, Benedict JW, Weimer JM, Pearce DA. CLN3, the protein associated with batten disease: structure, function and localization. J Neurosci Res. 2005 Mar 1;79(5):573-83. doi: 10.1002/jnr.20367. — View Citation

Schulz A, Kohlschutter A, Mink J, Simonati A, Williams R. NCL diseases - clinical perspectives. Biochim Biophys Acta. 2013 Nov;1832(11):1801-6. doi: 10.1016/j.bbadis.2013.04.008. Epub 2013 Apr 17. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Safety evaluation based on the development of dose-limiting toxicity (DLT).	The DLT is defined as any unanticipated AE that is considered related to AT-GTX-502 and is Common Terminology Criteria for Adverse Events Grade 3 or higher.	36 Months
Primary	Efficacy: Change in rating as determined using the Unified Batten Disease Rating Scale (UBDRS) rating scale.	The UBDRS is a clinical ratings instrument used specifically to assess motor, seizure, behavioral and functional capabilities. The "Physical Assessment" is a 20 item subscale that measures vision, speech, motor strength, gait, abnormal involuntary movements and balance. Each item has a score range of 0 to 4. The minimum score is 0 and the maximum score is 112. The items are summed up to obtain a total score.The higher the score, the more severe the disability and worse the outcome.	36 months
Secondary	QOL: Change in Quality of Life (QOL) as determined using the Pediatric Quality of Life (PedsQL™) scale.	The PedsQL is used to assess physical, emotional, social, and school functioning of pediatric subjects in ranging from 2 years to 18 years of age.	36 months
Secondary	Seizures: Change is seizure subscore as determined using Seizure subscale of the UBDRS scale.	The UBDRS seizure subscale is used to assess seizure history, type, frequency, duration, and frequency of seizure-related injury.	36 months
Secondary	Global impression: Change in disease severity using the UBDRS clinical global impression (CGI) subscale.	The clinical global impression subscale includes assessment of motor, seizure, behavioral and cognitive function in NCL subjects.	36 months