Dose Confirmation Trial of AAV5-hFIXco-Padua
- Conditions
- Hemophilia B
- Interventions
- Genetic: AAV5-hFIXco-Padua (AMT-061)
- Registration Number
- NCT03489291
- Lead Sponsor
- CSL Behring
- Brief Summary
This is an open-label, single-dose, single-arm, multi-center trial, with a screening, a treatment + post-treatment follow-up phase, and a long-term follow-up phase.
The IMP AMT-061 is a recombinant adeno-associated viral vector of serotype 5 (AAV5) containing the Padua variant of a codon-optimized human FIX complementary deoxyribonucleic acid (cDNA) under the control of a liver-specific promoter. The IMP is identified as AAV5-hFIXco-Padua (AMT- 061). The pharmaceutical form of AMT-061 is a solution for intravenous infusion.
The administered dose of AMT-061 will be 2 x 10\^13 gc/kg.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- Male
- Target Recruitment
- 3
- Male
- Age ≥18 years
- Subjects with congenital hemophilia B classified as severe or moderately severe
- >20 previous exposure days of treatment with FIX protein
- History of FIX inhibitors
- Positive FIX inhibitor test at screening
- Select screening laboratory values > 2 times upper normal limit:
- Positive human immunodeficiency virus (HIV) at screening, not controlled with anti-viral therapy
- Active infection with Hepatitis B or C virus at screening
- History of Hepatitis B or C exposure, currently controlled by antiviral therapy
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Single infusion of AMT-061 AAV5-hFIXco-Padua (AMT-061) Subjects will receive a single infusion of AAV5-hFIXco-Padua (AMT- 061) at baseline. After IMP administration (post IMP), subjects will be monitored for tolerance to the IMP and detection of potential immediate AEs at the clinical trial site for 24 hours (overnight stay).
- Primary Outcome Measures
Name Time Method Factor IX Activity Levels 6 weeks post-dose To confirm that a single dose of 2x10\^13 gc/kg AMT-061 (CSL222) resulted in factor IX activity levels of ≥5% at 6 weeks after dosing measured by the one-stage (activated partial thromboplastin \[aPTT\]-based) assay.
- Secondary Outcome Measures
Name Time Method Annualized Bleeding Rate (ABR) 5 years post-dose ABR was calculated as the ratio of the number of bleeds to the number of days in the time interval multiplied by 365.25.
Number of Participants Remaining Free of Continuous Prophylaxis 1 year post-dose Participants with no usage of continuous factor IX prophylaxis after AMT-061 (CSL222) treatment were considered free from continuous factor IX prophylaxis use.
Annualized Exogenous Factor IX Usage Post-Continuous Prophylaxis Up to 5 years post-dose The post-continuous-prophylaxis period began on the day after the end of continuous (routine) prophylaxis.Therapy administered included the total dosage of FIX given as prophylaxis and on-demand. Use for invasive procedures was not included.
Annualized Exogenous Factor IX Usage 52 weeks post-dose Annualized use was calculated as the normalized amount of therapy administered per baseline weight, extrapolated where necessary from any time period less or greater than 1 year. Therapy administered included the total dosage of FIX given as prophylaxis and on-demand. Use for invasive procedures was not included.
Factor IX Activity Levels 52 weeks post-dose Measured by the one-stage (aPTT-based) assay.
Number of Participants With Treatment Emergent (TE): Adverse Events (AE), Mild, Moderate, and Severe AEs, AEs Related and Unrelated to the Study Treatment, and Serious AEs Up to 5 years post-dose Number of Participants With Clinically Meaningful Findings in Hematology and Serum Chemistry Parameters Up to 5 years post-dose Clinically meaningful findings were defined as values which were outside the standard normal reference ranges for hematology and serum chemistry parameters.
Number of Participants Receiving Corticosteroids for AST and ALT Elevations Up to 5 years post-dose Number of Participants With AAV5 Capsid-specific T Cell Response Up to Week 52 Time to First Negative Results for Vector Deoxyribonucleic Acid (DNA) From Semen and Blood Up to 5 years post-dose Time in weeks until the first negative result confirmed by negative result in 3 consecutive timepoints. A participant was considered to no longer be shedding vector DNA if they had a negative laboratory result for 3 or more consecutive timepoints.
Number of Participants Positive With AAV5 and Factor IX Neutralising Antibodies in Serum Baseline and at 5 years post-dose Number of Participants With Newly Occurring or Worsening Potentially Clinically Significant Changes in Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) Levels From baseline and up to 5 years post-dose Post-baseline newly occurring or worsening potentially clinically significant ALT and AST levels were defined as values greater than twice the baseline value.
Number of Participants With Inflammatory Marker Levels Outside Normal Ranges Baseline, Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 16, 18, 20, 22, 24, 26, 31, 36, 40, 44, 48 and 52 Inflammatory markers included interleukin (IL)-1β, IL-2, IL-6, interferon gamma (IFNγ), and monocyte chemotactic protein-1 (MCP-1). Only those biomarkers for which the data were higher than the normal range at the specified timepoints have been presented.
Number of Participants With Abnormal Values in Alpha-fetoprotein (AFP) Levels Up to 5 years post-dose Participants who were outside the normal limit range were to be reported.
Number of Participants With Abnormal Results in Abdominal Ultrasound At Months 36, 42, 48, 54, and 60 post-dose Ultrasounds were evaluated by qualified personnel and abnormalities were assessed by the Investigator.
Trial Locations
- Locations (4)
Phoenix Childrens Hospital
🇺🇸Phoenix, Arizona, United States
University of Michigan
🇺🇸Ann Arbor, Michigan, United States
University of California, Davis
🇺🇸Sacramento, California, United States
University of California, San Diego
🇺🇸San Diego, California, United States