Gene Therapy for Children With CLN6 Batten Disease

• ClinicalTrials.gov Identifier: NCT02725580
• Recruitment Status: Active, not recruiting
• First Posted: April 1, 2016
• Last Update Posted: October 24, 2019
• Sponsor: Amicus Therapeutics
• Information provided by (Responsible Party): Amicus Therapeutics

Study Description

Brief Summary:

This is a phase 1/2, open-label, single dose study to evaluate the safety and efficacy of AT-GTX-501 delivered intrathecally into the lumbar spinal cord region of subjects with mild to moderate CLN6 Batten disease.

Condition or disease	Intervention/treatment	Phase
CLN6; Batten Disease	Genetic: AT-GTX-501	Phase 1; Phase 2

Detailed Description:

This is a phase 1/2, open-label, single-dose study of AT-GTX-501 administered intrathecally into the lumbar spinal cord region of patients with mild to moderate CLN6 Batten disease.

This study consists of a one-time injection of AT-GTX-501 with follow-up visits on Day 7, 14, 21, and 30, and every 3 months thereafter, ending at Month 24.

The primary outcome for this clinical study is safety evaluated based on the development of dose limiting toxicity (defined as any unanticipated AE that is considered related to AT-GTX-501 and is Common Terminology Criteria for Adverse Events Grade 3 or higher).

The secondary outcome measures include the modified Hamburg scale, Unified Batten Disease Rating Scale (UBDRS), brain magnetic resonance imaging (MRI), cognitive and language evaluations, Pediatric Quality of Life™ (PedsQL) inventory, ophthalmologic examinations, and long-term monitoring electroencephalograms.

A long-term follow-up safety and efficacy study in subjects with CLN6 Batten disease who received AT-GTX-501 in Study AT-GTX-501-01 is planned (Study AT-GTX-501-02).

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 13 participants
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase I/IIa Gene Transfer Clinical Trial for Variant Late Infantile Neuronal Ceroid Lipofuscinosis, Delivering the CLN6 Gene by Self-Complementary AAV9
• Actual Study Start Date: March 2016
• Estimated Primary Completion Date: October 2021
• Estimated Study Completion Date: December 2021

Arms and Interventions

Arm	Intervention/treatment
Experimental: Open Label; Batten CLN6 subjects will receive a single injection of AT-GTX-501 (scAAV9.CB.CLN6) via intrathecal delivery.	Genetic: AT-GTX-501; Subjects with diagnosis of CLN6 Batten disease will receive a single dose of AT-GTX-501 (scAAV9.CB.CLN6).

Outcome Measures

Primary Outcome Measures :

1. Safety evaluation based on the development of dose-limiting toxicity (DLT). [ Time Frame: 24 months ]
   The DLT is defined as any unanticipated AE that is considered related to AT-GTX-501 and is Common Terminology Criteria for Adverse Events Grade 3 or higher.

Secondary Outcome Measures :

1. Hamburg Scale [ Time Frame: 24 months ]
   The Hamburg scale is an established tool to capture the rate of decline or regression.
2. Unified Batten Disease Rating Scale (UBDRS) [ Time Frame: 24 months ]
   The UBDRS scale was developed to monitor rate of progression. This scale includes assessment of extrapyramidal movement behavior and seizures.
3. Brain MRI [ Time Frame: 24 months ]
   Brain MRI is utilized to capture the progression of atrophy.
4. The Development Profile (DP-3) [ Time Frame: Baseline, 6 months, 12 months, 24 months ]
   DP-3 allow you to quickly screen a child for development delays in five key areas. It consists of interview forms and parent/caregiver checklists. The DP-3 includes 180 provides a General Development score as well as the following scale scores including physical, adaptive behavior, social-emotional, cognitive and communication. Each scale has its own norms.
5. The Mullen Scale of Early Learning [ Time Frame: Baseline, 6 months, 12 months, 24 months ]
   An integrated system that assesses language, motor, perceptual abilities, measures cognitive ability and motor development. Mullen Scale of Early Learning includes five scales: Gross Motor, Visual Reception, Fine Motor, Expressive Language, and Receptive Language.
6. Preschool Language Scales - Fifth Edition (PLS-5) (birth to 7 years, 11 months of age) [ Time Frame: Baseline, 6 months, 12 months, 24 months ]
   The PLS-5 is a comprehensive developmental language assessment with items that range from pre-verbal, interaction-based skills to emerging language to early literacy. Auditory comprehension and expressive communication scales are assessed with hand scoring.
7. Pediatric Quality of Life (PedsQL) inventory [ Time Frame: Baseline, 6 months, 12 months, 24 months ]
   PedsQL has four Scales including Physical Functioning, Emotional Functioning, Social Functioning, and School Functioning. Items are reversed scored and linearly transformed to a 0-100 scale, so that higher scores indicate better Health-Related Quality of Life).
8. Visual acuity examination [ Time Frame: 24 months ]
   An visual acuity test that checks how well you see from a specific distance.
9. Visual refraction examination [ Time Frame: 24 months ]
   Assessment of high-resolution achromatic vision.
10. Confrontational visual field examination [ Time Frame: 24 months ]
    Assessment of peripheral achromatic vision.
11. Ocular motility examination [ Time Frame: 24 months ]
    Assessment of movements and alignment of eyes.
12. Pupil examination [ Time Frame: 24 months ]
    Measurement of size of pupils and their reaction to direct light stimulation.
13. Intraocular pressure examination [ Time Frame: 24 months ]
    Assessment of eye pressure.
14. Slit lamp examination [ Time Frame: 24 months ]
    As part of routine eye exam, the slit lamp examination is also called biomicroscopy.
15. Fundus examination [ Time Frame: 24 months ]
    Assessment of the fundus of the eye.
16. EEG video Monitoring [ Time Frame: 24 months ]
    24 hour EEG long term video monitoring to monitor progression of encephalopathy and epileptiform activity.

Eligibility Criteria

• Ages Eligible for Study: 1 Year and older (Child, Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Diagnosis of CLN6 disease determined by genotype available at Screening
• A score of ≥ 3 on the quantitative clinical assessment of the Hamburg motor-language aggregate score at Screening on CLN2 disease motor-language scale, as defined in the Ratings Assessment Guideline.
• Age ≥1 year
• Ambulatory or able to walk with assistance

Exclusion Criteria:

• Presence of another inherited neurologic disease, e.g., other forms of Batten disease (also known as NCL) or seizures unrelated to CLN6 Batten disease (subjects with febrile seizures may be eligible at discretion of the investigator)
• Presence of another neurological illness that may have caused cognitive decline (e.g., trauma, meningitis, hemorrhage) before screening
• Active viral infection (including HIV or serology positive for hepatitis B or C)
• Has received stem cell or bone marrow transplantation for CLN6 disease
• Contraindications for intrathecal administration of the product of lumbar puncture, such as bleeding disorders or other medical conditions (e.g., spina bifida, meningitis, or clotting abnormalities)
• Contraindications for magnetic resonance imaging (MRI) scans (e.g., cardiac pacemaker, metal fragment or chip in the eye, aneurysm clip in the brain)
• Episode of generalized motor status epilepticus within 4 weeks before the gene transfer visit (Visit 2)
• Severe infection (e.g., pneumonia, pyelonephritis, or meningitis) within 4 weeks before the gene transfer visit (Visit 2) (enrollment may be postponed)
• Has received any investigational medication within 30 days before the gene transfer visit
• Anti-AAV9 antibody titers ≥ 1:50 as determined by ELISA binding immunoassay
• 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
• Pregnancy any time during the study (Any female subject judged by the investigator to be of childbearing potential will be tested for pregnancy.)
• Abnormal laboratory values from screening considered clinically significant (GGT > 3XULN, Bilirubin ≥ 3.0 mg/dL , Creatinine ≥ 1.8 mg/dL, Hgb < 8 or > 18 g/dL; WBC > 15,000 per cmm)
• Family dose not want to disclose subject's study participation with primary care physician and other medical providers
• History of or current chemotherapy, radiotherapy, or other immunosuppression therapy within 30 days preceding screening (corticosteroid treatment may be permitted at the discretion of the investigator)
• Has 2 consecutive abnormal liver tests at screening (> 2 times the upper limit of normal). Liver enzymes will be re-tested once if abnormal upon initial screening.

Contacts and Locations

Locations

United States, Ohio

Nationwide Children's Hosptial

Columbus, Ohio, United States, 43205

Sponsors and Collaborators

Amicus Therapeutics

Investigators

• Study Director: Clinical Research; Amicus Therapeutics

More Information

• Responsible Party: Amicus Therapeutics
• ClinicalTrials.gov Identifier: NCT02725580
• Other Study ID Numbers: AT-GTX-501-01
• First Posted: April 1, 2016
• Last Update Posted: October 24, 2019
• Last Verified: October 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Amicus Therapeutics:

Neuronal ceroid lipofuscinosis; NCL; Gene Transfer

Additional relevant MeSH terms:

Neuronal Ceroid-Lipofuscinoses; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Nervous System Diseases; Genetic Diseases, Inborn; Lipidoses; Lipid Metabolism, Inborn Errors; Metabolism, Inborn Errors; Lipid Metabolism Disorders; Metabolic Diseases