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.
Brief Title
Gene Transfer Clinical Study in Crigler-Najjar Syndrome
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.
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.
Categories
Completion Date
Completion Date Type
Actual
Conditions
Crigler-Najjar Syndrome
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.
* 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.
Inclusion Criteria
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).
* 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).
Gender
All
Gender Based
false
Keywords
Crigler-Najjar
CN
AAV8 Delivered Gene Transfer
Adeno Associated Virus
Healthy Volunteers
No
Last Update Post Date
Last Update Post Date Type
Actual
Last Update Submit Date
Minimum Age
1 Year
NCT Id
NCT03223194
Org Class
Industry
Org Full Name
Audentes Therapeutics
Org Study Id
AT342-02
Overall Status
Terminated
Phases
Phase 1
Primary Completion Date
Primary Completion Date Type
Actual
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
Primary Outcomes
Outcome Description
Adverse events, serious adverse events, and laboratory abnormalities (including immunological parameters)
Outcome Measure
Treatment-emergent adverse events (safety and tolerability)
Outcome Time Frame
Baseline to Week 24
Outcome Description
Change in total serum bilirubin
Outcome Measure
Total serum bilirubin
Outcome Time Frame
Baseline to Week 12 (on phototherapy) and Baseline to Week 18 (off phototherapy)
Outcome Description
Change in number of hours of daily phototherapy (daily illumination time)
Outcome Measure
Hours of Phototherapy
Outcome Time Frame
Baseline to Week 18
Secondary Outcomes
Outcome Description
Proportion of subjects with successful weaning off of phototherapy
Outcome Time Frame
Baseline to Week 18
Outcome Measure
Phototherapy
Outcome Description
Change in Liver UGT protein expression, DNA, and RNA levels
Outcome Time Frame
24 Weeks
Outcome Measure
UGT Protein
Start Date
Start Date Type
Actual
Status Verified Date
First Post Date
First Post Date Type
Actual
First Submit Date
First Submit QC Date
Std Ages
Child
Adult
Older Adult
Maximum Age Number (converted to Years and rounded down)
999
Minimum Age Number (converted to Years and rounded down)
1
Investigators
Investigator Type
Principal Investigator
Investigator Name
Nadia Ovchinsky
Investigator Email
NOVCHINS@montefiore.org
Investigator Phone