Clinical trial NCT03223194: Gene Transfer Clinical Study in Crigler-Najjar Syndrome
Official title: VALENS: A Phase 1/2, Randomized, Open-Label, Ascending-Dose, Delayed-Treatment Concurrent Control Clinical Study to Evaluate the Safety and Preliminary Efficacy of AT342, an AAV8-Delivered Gene Transfer Therapy in Crigler-Najjar Syndrome Subjects Aged 1 Year and Older
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Crigler-Najjar Syndrome
Keywords: Crigler-Najjar
CN
AAV8 Delivered Gene Transfer
Adeno Associated Virus
Lead sponsor: Audentes Therapeutics
Sponsor class: INDUSTRY
First posted: 2017-07-21
Enrollment: 1
Sex: ALL
Minimum age (years): 1
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: Up to four subjects will be enrolled at each dose level including up to1 subject at each dose level randomized to control with delayed initiation of treatment. One of the dose levels will be chosen for dose expansion and all control subjects will then be treated at the chosen dose level.
Primary purpose: TREATMENT

Brief summary: This is a Phase 1/2, multinational, open-label, ascending-dose, delayed-treatment concurrent control clinical study to evaluate the safety and preliminary efficacy of AT342 in subjects with Crigler-Najjar aged ≥1 year. Subjects will receive a single dose of AT342 and will be followed for safety and efficacy for 5 years.

Detailed description: This study will evaluate safety and preliminary efficacy of gene transfer in Crigler Najjar Syndrome. Subjects will receive a single dose of AT342 delivered intravenously. A maximum of 3 dose levels of AT342 are planned for evaluation in this study. Up to four subjects will be enrolled at each dose level including up to 1 subject at each dose level randomized to control with delayed administration of the investigational product. Dose escalation to the next dose level will be considered after evaluation of at least 4 weeks of data from subjects dosed at the current dose level. One of the dose levels will be chosen for dose expansion, and the chosen dose will be administered to all delayed-treatment control subjects.

The primary efficacy endpoint measure of change in total serum bilirubin will be assessed at weeks 12 (whilst still on phototherapy) and week 18 (after phototherapy has been weaned) after administration of AT342; and the primary efficacy endpoint measure of change in number of hours of phototherapy will be assessed at week 18

This study will utilize an independent Data Monitoring Committee that will monitor subject safety and provide recommendations to Audentes regarding dose escalation, dose expansion, and safety matters.

At study termination, only one (1) pediatric participant was enrolled. This study was intended to be a Phase 1/2 trial but the study never moved forward to Phase 2.

Eligibility criteria: Key Inclusion Criteria:

* Subject has a diagnosis of Crigler-Najjar syndrome resulting from a confirmed mutation in the UGT1A1 gene as assessed by a Sponsor-approved testing facility.
* Subject is aged ≥1 year.
* Subject is prescribed daily phototherapy for a minimum of 6 hours within a 24-hour period (daily illumination time).

Key Exclusion Criteria:

* Subject is currently participating in an interventional study or has received gene or cell therapy.
* Subject has received a whole liver, partial liver, or hepatocyte transplant; or subject has a liver transplant scheduled within the treatment period of this study.
* Subject has significant cholestatic disease at screening.
* Subject is receiving phenobarbital or other known inducer of UGT1A1 within 30 days of screening.
* Subject tests positive for AAV8 neutralizing antibodies with titers above protocol specified threshold.
* Other than as required per protocol, subject has received immune-modulating agents within 3 months before dosing (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.
* Subject has any clinically significant laboratory values, in the opinion of the investigator.
* Subject has clinically significant underlying liver disease (other than CN) at screening.
* Subject has a history of, or currently has, a clinically important condition other than CN, in the opinion of the investigator.

Primary outcomes:
measure: Treatment-emergent adverse events (safety and tolerability)
timeFrame: Baseline to Week 24
measure: Total serum bilirubin
timeFrame: Baseline to Week 12 (on phototherapy) and Baseline to Week 18 (off phototherapy)
measure: Hours of Phototherapy
timeFrame: Baseline to Week 18
Secondary outcomes:
measure: Phototherapy
timeFrame: Baseline to Week 18
measure: UGT Protein
timeFrame: 24 Weeks
Other outcomes:
measure: Quality of Life Assessment: Pediatric Quality of Life Inventory (PedsQL)
timeFrame: Baseline to Week 18
measure: Caregiver Burden Assessment: Family Impact Module Scores
timeFrame: Baseline to Week 18
measure: Clinical Global Impression of Severity and of Improvement
timeFrame: Baseline to Week 18
Locations:
city: Bronx
country: United States
facility: Children's Hospital at Montefiore
state: New York
city: Strasburg
country: United States
facility: Clinic for Special Children
state: Pennsylvania
city: Jerusalem
country: Israel
facility: Shaare Zedek Medical Center
city: London
country: United Kingdom
facility: King's College Hospital NHS Foundation Trust
Study officials:
affiliation: Audentes Therapeutics
name: Suyash Prasad, M.D.
role: STUDY_DIRECTOR
References: