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Gene Transfer Clinical Study in Crigler-Najjar Syndrome (VALENS)

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ClinicalTrials.gov Identifier: NCT03223194
Recruitment Status : Recruiting
First Posted : July 21, 2017
Last Update Posted : August 15, 2018
Sponsor:
Information provided by (Responsible Party):
Audentes Therapeutics

Study Description
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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.

Condition or disease Intervention/treatment Phase
Crigler-Najjar Syndrome Genetic: AT342 Phase 1 Phase 2

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.


Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 12 participants
Allocation: Randomized
Intervention Model: Sequential Assignment
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.
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : September 8, 2017
Estimated Primary Completion Date : February 2019
Estimated Study Completion Date : September 2024

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: Cohort 1
1.5 x 10^12 vg/kg of AT342 delivered intravenously one time
 Genetic: AT342
AT342 is an AAV8 vector containing a functional copy of the UGT1A1 gene.
Experimental: Cohort 2
6.0 x 10^12 vg/kg of AT342 delivered intravenously one time
 Genetic: AT342
AT342 is an AAV8 vector containing a functional copy of the UGT1A1 gene.
Experimental: Cohort 3
1.5 x 10^13 vg/kg of AT342 delivered intravenously one time
 Genetic: AT342
AT342 is an AAV8 vector containing a functional copy of the UGT1A1 gene.
No Intervention: Delayed-Treatment Control
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.


Outcome Measures
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Primary Outcome Measures :
  1. Treatment-emergent adverse events (safety and tolerability) [ Time Frame: Baseline to Week 24 ]
    Adverse events, serious adverse events, and laboratory abnormalities (including immunological parameters)

  2. Total serum bilirubin [ Time Frame: Baseline to Week 12 (on phototherapy) and Baseline to Week 18 (off phototherapy) ]
    Change in total serum bilirubin

  3. Hours of Phototherapy [ Time Frame: Baseline to Week 18 ]
    Change in number of hours of daily phototherapy (daily illumination time)


Secondary Outcome Measures :
  1. Phototherapy [ Time Frame: Baseline to Week 18 ]
    Proportion of subjects with successful weaning off of phototherapy

  2. UGT Protein [ Time Frame: 24 Weeks ]
    Change in Liver UGT protein expression, DNA, and RNA levels


Other Outcome Measures:
  1. Quality of Life Assessment: Pediatric Quality of Life Inventory (PedsQL) [ Time Frame: Baseline to Week 18 ]
    Change in quality of life assessment

  2. Caregiver Burden Assessment: Family Impact Module Scores [ Time Frame: Baseline to Week 18 ]
    Change in Burden of Disease score

  3. Clinical Global Impression of Severity and of Improvement [ Time Frame: Baseline to Week 18 ]
    Change in Investigator assessment of disease severity and improvement


Eligibility Criteria
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Ages Eligible for Study:   1 Year and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03223194


Contacts
Contact: Kim Trant, Director of Patient Advocacy +1 (415) 805-1049 trials@audentestx.com

Locations
United States, New York
Children's Hospital at Montefiore Recruiting
Bronx, New York, United States, 10467
United States, Pennsylvania
Clinic for Special Children Recruiting
Strasburg, Pennsylvania, United States, 17579
Israel
Shaare Zedek Medical Center Not yet recruiting
Jerusalem, Israel, 9103102
United Kingdom
King's College Hospital NHS Foundation Trust Recruiting
London, United Kingdom, SE9 9RS
Sponsors and Collaborators
Audentes Therapeutics
Investigators
Study Director: Suyash Prasad, M.D. Audentes Therapeutics
More Information
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Responsible Party: Audentes Therapeutics
ClinicalTrials.gov Identifier: NCT03223194     History of Changes
Other Study ID Numbers: AT342-02
First Posted: July 21, 2017    Key Record Dates
Last Update Posted: August 15, 2018
Last Verified: August 2018
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 Audentes Therapeutics:
Crigler-Najjar
CN
AAV8 Delivered Gene Transfer
Adeno Associated Virus

Additional relevant MeSH terms:
Syndrome
Crigler-Najjar Syndrome
Cardiomyopathies
Disease
Pathologic Processes
Hyperbilirubinemia, Hereditary
 Metabolism, Inborn Errors
Genetic Diseases, Inborn
Metabolic Diseases
Heart Diseases
Cardiovascular Diseases