Back to resultsGene Transfer Clinical Study in Crigler-Najjar Syndrome (VALENS)
Primary Purpose
Crigler-Najjar Syndrome
Status
Terminated
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
AT342
Sponsored by
About this trial
This is an interventional treatment trial for Crigler-Najjar Syndrome focused on measuring Crigler-Najjar, CN, AAV8 Delivered Gene Transfer, Adeno Associated Virus
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.
Sites / Locations
- Children's Hospital at Montefiore
- Clinic for Special Children
- Shaare Zedek Medical Center
- King's College Hospital NHS Foundation Trust
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Arm Type
Experimental
Experimental
Experimental
No Intervention
Arm Label
Cohort 1
Cohort 2
Cohort 3
Delayed-Treatment Control
Arm Description
1.5 x 10^12 vg/kg of AT342 delivered intravenously one time
6.0 x 10^12 vg/kg of AT342 delivered intravenously one time
1.5 x 10^13 vg/kg of AT342 delivered intravenously one time
Control subjects will generally have the same assessments as treated subjects. Once the optimal dose is selected, control subjects will undergo pre-treatment baseline procedures to confirm that they are eligible to receive treatment with AT342. Once eligible control subjects are dosed with AT342, they will initiate the same post-dose procedures as subjects who received AT342.
Outcomes
Primary Outcome Measures
Treatment-emergent adverse events (safety and tolerability)
Adverse events, serious adverse events, and laboratory abnormalities (including immunological parameters)
Total serum bilirubin
Change in total serum bilirubin
Hours of Phototherapy
Change in number of hours of daily phototherapy (daily illumination time)
Secondary Outcome Measures
Phototherapy
Proportion of subjects with successful weaning off of phototherapy
UGT Protein
Change in Liver UGT protein expression, DNA, and RNA levels
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT03223194
Brief Title
Gene Transfer Clinical Study in Crigler-Najjar Syndrome
Acronym
VALENS
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
2. Study Status
Record Verification Date
May 2022
Overall Recruitment Status
Terminated
Why Stopped
Sponsor Decision
Study Start Date
September 8, 2017 (Actual)
Primary Completion Date
February 11, 2021 (Actual)
Study Completion Date
February 11, 2021 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Audentes Therapeutics
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Crigler-Najjar Syndrome
Keywords
Crigler-Najjar, CN, AAV8 Delivered Gene Transfer, Adeno Associated Virus
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Sequential Assignment
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.
Masking
None (Open Label)
Allocation
Randomized
Enrollment
1 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Cohort 1
Arm Type
Experimental
Arm Description
1.5 x 10^12 vg/kg of AT342 delivered intravenously one time
Arm Title
Cohort 2
Arm Type
Experimental
Arm Description
6.0 x 10^12 vg/kg of AT342 delivered intravenously one time
Arm Title
Cohort 3
Arm Type
Experimental
Arm Description
1.5 x 10^13 vg/kg of AT342 delivered intravenously one time
Arm Title
Delayed-Treatment Control
Arm Type
No Intervention
Arm Description
Control subjects will generally have the same assessments as treated subjects. Once the optimal dose is selected, control subjects will undergo pre-treatment baseline procedures to confirm that they are eligible to receive treatment with AT342. Once eligible control subjects are dosed with AT342, they will initiate the same post-dose procedures as subjects who received AT342.
Intervention Type
Genetic
Intervention Name(s)
AT342
Intervention Description
AT342 is an AAV8 vector containing a functional copy of the UGT1A1 gene.
Primary Outcome Measure Information:
Title
Treatment-emergent adverse events (safety and tolerability)
Description
Adverse events, serious adverse events, and laboratory abnormalities (including immunological parameters)
Time Frame
Baseline to Week 24
Title
Total serum bilirubin
Description
Change in total serum bilirubin
Time Frame
Baseline to Week 12 (on phototherapy) and Baseline to Week 18 (off phototherapy)
Title
Hours of Phototherapy
Description
Change in number of hours of daily phototherapy (daily illumination time)
Time Frame
Baseline to Week 18
Secondary Outcome Measure Information:
Title
Phototherapy
Description
Proportion of subjects with successful weaning off of phototherapy
Time Frame
Baseline to Week 18
Title
UGT Protein
Description
Change in Liver UGT protein expression, DNA, and RNA levels
Time Frame
24 Weeks
Other Pre-specified Outcome Measures:
Title
Quality of Life Assessment: Pediatric Quality of Life Inventory (PedsQL)
Description
Change in quality of life assessment
Time Frame
Baseline to Week 18
Title
Caregiver Burden Assessment: Family Impact Module Scores
Description
Change in Burden of Disease score
Time Frame
Baseline to Week 18
Title
Clinical Global Impression of Severity and of Improvement
Description
Change in Investigator assessment of disease severity and improvement
Time Frame
Baseline to Week 18
10. Eligibility
Sex
All
Minimum Age & Unit of Time
1 Year
Accepts Healthy Volunteers
No
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Suyash Prasad, M.D.
Organizational Affiliation
Audentes Therapeutics
Official's Role
Study Director
Facility Information:
Facility Name
Children's Hospital at Montefiore
City
Bronx
State/Province
New York
ZIP/Postal Code
10467
Country
United States
Facility Name
Clinic for Special Children
City
Strasburg
State/Province
Pennsylvania
ZIP/Postal Code
17579
Country
United States
Facility Name
Shaare Zedek Medical Center
City
Jerusalem
ZIP/Postal Code
9103102
Country
Israel
Facility Name
King's College Hospital NHS Foundation Trust
City
London
ZIP/Postal Code
SE9 9RS
Country
United Kingdom
12. IPD Sharing Statement
Plan to Share IPD
No
Learn more about this trial
Gene Transfer Clinical Study in Crigler-Najjar Syndrome
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