Gene Therapy For Children With Variant Late Infantile Neuronal Ceroid Lipofuscinosis 6 (vLINCL6) Disease

Study Overview
=================
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 participants with mild to moderate variant late infantile neuronal ceroid lipofuscinosis associated with mutation(s) in the CLN6 gene (vLINCL6 disease).

Detailed Description
-----------------
This is an open-label, single-dose study of AT-GTX-501 administered by a single intrathecal injection. Safety and efficacy are evaluated over a 2 year period. The efficacy assessments in this study are to evaluate motor, language, visual, and cognitive function, as well as survival and other outcome measures. Participants are tested at baseline, receive AT-GTX-501 on Day 0, and return for visits on Days 7, 14, 21, and 30, and then every 3 months until Month 24. Following completion of this study, there is a long-term follow up study in which data will continue to be collected (Study AT-GTX-501-02 / NCT04273243). For more information about this study, please contact Amicus Therapeutics Patient Advocacy at clinicaltrials@amicusrx.com or +1 609-662-2000.

Official Title
-----------------
Phase I/IIa Gene Transfer Clinical Trial for Variant Late Infantile Neuronal Ceroid Lipofuscinosis, Delivering the CLN6 Gene by Self-Complementary AAV9

Conditions
-----------------
Variant Late-Infantile Neuronal Ceroid Lipofuscinosis

Intervention / Treatment
-----------------
* Genetic: AT-GTX-501


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Diagnosis of vLINCL6 disease determined by genotype available at screening A score of ≥ 3 on the quantitative clinical assessment of the Hamburg motor-language aggregate scale at screening Aged ≥ 1 year Ambulatory or able to walk with assistance Exclusion Criteria: Presence of another inherited neurologic disease, for example, other forms of Batten disease (also known as NCL) or seizures unrelated to vLINCL6 disease (participants with febrile seizures may be eligible at discretion of the investigator.) Presence of another neurological illness that may have caused cognitive decline (for example, trauma, meningitis, hemorrhage) before screening Active viral infection (includes human immunodeficiency virus or serology positive for hepatitis B or C) Has received stem cell or bone marrow transplantation for vLINCL6 disease Contraindications for intrathecal administration of the product or lumbar puncture, such as bleeding disorders or other medical conditions (for example, spina bifida, meningitis, or clotting abnormalities) Contraindications for magnetic resonance imaging scans (for example, 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 (for example, 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 (Visit 2) Anti-AAV9 antibody titers > 1:50 as determined by enzyme-linked immunosorbent assay Has a medical condition or extenuating circumstance that, in the opinion of the investigator, might compromise the participant's ability to comply with the protocol-required testing or procedures or compromise the participant's wellbeing, safety, or clinical interpretability Pregnancy any time during the study (Any female participant judged by the investigator to be of childbearing potential will be tested for pregnancy.) Abnormal laboratory values from screening considered clinically significant (gamma glutamyl transferase > 3 times the upper limit of normal, bilirubin ≥ 3.0 mg/dL, creatinine ≥ 1.8 mg/dL, hemoglobin < 8 or > 18 g/dL, white blood cells > 15,000 per cmm) Family does not want to disclose participant's study participation with primary care physician and other medical providers. History of or current chemotherapy, radiotherapy, or other immunosuppression therapy within the 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.

Ages Eligible for Study
-----------------
Minimum Age: 1 Year

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Open Label<br>Participants with diagnosis of vLINCL6 Batten disease will receive a single intrathecal injection of AT-GTX-501 into the lumbar spinal cord region. | Genetic: AT-GTX-501<br>* CLN6 Gene delivered by Self-Complementary AAV9<br>* Other names: scAAV9.CB.CLN6;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence And Severity Of Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | An adverse event (AE) is defined as any untoward medical occurrence in a participant administered a pharmaceutical product, biologic, or medical device (medicinal products). An SAE is an AE occurring during any study phase (for example, baseline, treatment, or follow-up) that fulfils any of the following: results in death; is life-threatening; requires inpatient hospitalization or prolongs existing hospitalization; results in persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions; and results in a congenital anomaly/birth defect. All AEs that occurred after receipt of AT-GTX-501 are classified as TEAEs. A summary of serious and all other non-SAEs, regardless of causality, is located in the Reported Adverse Events module. | Up to 38.7 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline In Hamburg Motor And Language Scores at Month 24 | The Hamburg scale is an established tool to capture the rate of decline or regression. This tool was developed to document by rating motor, language, and visual functions in participants with late infantile neuronal ceroid lipofuscinosis type 2 (CLN2) Batten disease, and to collect their incidence of grand mal seizures. To assess disease progression and evaluate efficacy, the combined score of the motor and language domains of the Hamburg scale was used. Each domain was scored from 0 (no function) to 3 (normal function) for a maximal possible score of 6 for the combined score, referred to as the Hamburg Motor + Language aggregate score. The rate of decline in Hamburg Motor + Language aggregate, Motor, and Language scores were summarized using descriptive statistics. | Screening (Day -30 up to -2) up to Month 24 | 
| Change From Baseline In Unified Batten Disease Rating Scale (UBDRS) Scores At Month 24 | The Unified Batten Disease Rating Scale (UBDRS) was developed to monitor rate of progression. This scale includes assessment of extrapyramidal movement abnormalities and seizures, behavioral and capability assessments (Actual Vision), as well as history relevant to variant late infantile neuronal ceroid lipofuscinosis associated with mutation(s) in the CLN6 gene (vLINCL6) disease and scoring for global impression of symptom severity. A higher UBDRS subscale score indicated greater physical impairment, with zero indicating a better outcome. Subscales included Physical Assessment (range 0-84), Seizure Assessment (range 0-54), Behavioral Assessment (range 0-55) and Capability Assessment of Actual Vision and Normal Vision (range 0-14). A positive change from baseline score indicates increased impairment and a negative score indicates decreased impairment. | Screening (Day -30 up to -2) and Day 30 up to Month 24 | 
| Change From Baseline In Mullen (Age-Equivalent) Scales Of Early Learning At Month 24 | The Mullen Scales of Early Learning were utilized to assess cognitive and motor ability in 4 areas (visual reception, fine motor, expressive language, and receptive language) in infants and children. Raw scores range from 0-50 for visual reception, 0-49 for fine motor, 0-50 for expressive language, and 0-48 for receptive language. Lower scores from baseline indicated increased developmental delay and higher scores from baseline indicated decreased developmental delay. A positive change from baseline score indicates decreased developmental delay and a negative score indicates increased developmental delay. | Screening (Day -30 up to -2) and Month 24 | 
| Change From Baseline In Preschool Language Scales-5th Edition (PLS-5) (Age-Equivalent) At Month 24 | The Preschool Language Scales-5th Edition (PLS-5) (Age-Equivalent) was a comprehensive developmental language assessment. Standard scores from each domain (auditory comprehension, expressive communication, and total language) range from 50-150. Standard scores between 85 and 115 are considered to be within normal limits. Total scores are the sum of standard scores for auditory comprehension and expressive communication, which is then converted to a total standard score using PLS-5 Appendix B. Age-equivalent scores in each area were summarized by study visit with descriptive statistics. Higher scores represent better language development and lower scores reflect a possible language delay or disorder. A positive change from baseline score indicates better language development. | Screening (Day -30 up to -2) and Month 24 | 
| Change From Baseline In Development Profile-3 At Month 24 | The Development Profile-3 was used to screen for developmental delays in 5 areas (physical [score range 0-35], adaptive behavior [0-37], social-emotional [0-36], cognitive [0-38], communication [0-34]), where lower scores indicated increased developmental delay. The General Development Score is obtained by adding the sum of standard scores for the five scales together (range 0-180). Standard Score ranges are <70 Delayed, 70-84 Below Average, 85-115 Average, 116-130 Above Average, and >130 Well Above Average. A positive change from baseline score indicates decreased developmental delay and a negative score indicates increased developmental delay. | Screening (Day -30 up to -2) and Month 24 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Neuronal ceroid lipofuscinosis (NCL), CLN6, vLINCL6, Gene Transfer, CLN6 Batten Disease, Batten Disease