This is an open-label, single-dose, multi-center, multinational trial to demonstrate the efficacy of AMT-061 and to further describe its safety profile. The study drug is identified as AAV5-hFIXco-Padua (AMT- 061). 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 pharmaceutical form of AMT-061 is a solution for intravenous infusion administered at a dose of 2 x 10\^13 gc/kg.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
67
Single intravenous infusion of AAV5-hFIXco-Padua (AMT-061)
During the lead-in phase, which lasted for a minimum of 26 weeks (i.e., ≥6 months), subjects recorded their use of FIX replacement therapy and bleeding episodes in their dedicated e-diary.
Annualized Bleeding Rate (ABR) for All Bleeding Episodes
Adjusted ABR for Lead-in and Post-Treatment period was estimated from a repeated measures generalized estimating equations negative binomial regression model accounting for the paired design of the trial with an offset parameter to account for the differential collection periods. Treatment period was included as a categorical covariate.
Time frame: Lead-in period and months 7-18 post-treatment of AMT-061 (CSL222)
Factor IX Activity Levels After AMT-061 (CSL222) Dosing
One-stage activated partial thromboplastin time (aPTT) based endogenous FIX activity levels from central laboratory assay.
Time frame: At Baseline, 6, 12, and 18 months after AMT-061 (CSL222) dosing
Annualized Exogenous FIX Consumption
Annualized consumption of FIX replacement therapy.
Time frame: Lead-in period and months 0-6, 7-12, and 13-18 after AMT-061 (CSL222) dosing
Adjusted Annualized Infusion Rate of FIX Replacement Therapy
Time frame: Lead-in period and months 7-18 after AMT-061 (CSL222) dosing
Percent of Participants Who Discontinued FIX Prophylaxis and Remained Free of Routine FIX Prophylaxis After AMT-061 (CSL222) Dosing
Time frame: Months 7-18 after AMT-061 (CSL222) dosing
Percentage of Participants With Trough FIX Activity <12% of Normal
Time frame: Lead-in and 3, 12, and 18 months after AMT-061 (CSL222) dosing
ABR for FIX-treated Bleeding Episodes
Adjusted ABR for Lead-In and Post-Treatment period was estimated from a repeated measures generalized estimating equations negative binomial regression model accounting for the paired design of the trial with an offset parameter to account for the differential collection periods. Treatment period was included as a categorical covariate.
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Phoenix Children's Hospital
Phoenix, Arizona, United States
Arkansas Children's Hospital
Little Rock, Arkansas, United States
Los Angeles Orthopedic Hospital
Los Angeles, California, United States
Children's Hospital of Los Angeles
Los Angeles, California, United States
University of California, Davis
Sacramento, California, United States
University of California, San Diego
San Diego, California, United States
University of Colorado Denver
Aurora, Colorado, United States
Children's National Medical Center Hematology and Oncology
Washington D.C., District of Columbia, United States
University of South Florida
Tampa, Florida, United States
University of Michigan
Ann Arbor, Michigan, United States
...and 23 more locations
Time frame: Lead-in and Months 7-18 after AMT-061 (CSL222) dosing
Annualized Rate of Spontaneous Bleeding Episodes
Adjusted ABR for Lead-In and Post-Treatment period was estimated from a repeated measures generalized estimating equations negative binomial regression model accounting for the paired design of the trial with an offset parameter to account for the differential collection periods. Treatment period was included as a categorical covariate.
Time frame: Lead-in period and months 7-18 after AMT-061 (CSL222) dosing
Annualized Rate of Joint Bleeding Episodes
Adjusted ABR for Lead-In and Post-Treatment period was estimated from a repeated measures generalized estimating equations negative binomial regression model accounting for the paired design of the trial with an offset parameter to account for the differential collection periods. Treatment period was included as a categorical covariate.
Time frame: Lead-in period and months 7-18 after AMT-061 (CSL222) dosing
Mean FIX Activity (%) in Participants With Pre-Existing Neutralizing Antibodies to AAV5 After AMT-061 (CSL222) Dosing
One-stage aPTT-based endogenous FIX activity levels from central laboratory assay.
Time frame: At Baseline, 6, 12, and 18 months after AMT-061 (CSL222) dosing
Mean FIX Activity (%) in Participants Without Pre-Existing Neutralizing Antibodies to AAV5 After AMT-061 (CSL222) Dosing
One-stage aPTT-based endogenous FIX activity levels from central laboratory assay.
Time frame: At Baseline, 6, 12 and 18 months after AMT-061 (CSL222) dosing
Number of New Target Joints and the Number of New Target Joints Resolved
A target joint was defined as 3 or more spontaneous bleeding episodes into a single joint within a consecutive 6-month period prior to the dosing visit and which was not resolved by the time of dosing. An identified target joint with ≤2 spontaneous bleeding episodes within a consecutive 12-month period was considered resolved.
Time frame: Up to 18 months after AMT-061 (CSL222) dosing
Percent of Participants With Zero Bleeding Episodes During the 52 Weeks Following Stable FIX Expression (6 to 18 Months) After AMT-061 (CSL222) Dosing
Time frame: Lead-in period and months 7-18 post-treatment of AMT-061 (CSL222)
International Physical Activity Questionnaire (iPAQ) Overall Score
The iPAQ was designed to provide an evaluation of daily physical activities in metabolic equivalent of task (MET) minutes/week. To calculate MET minutes a week multiply the MET value given (walking = 3.3, moderate activity = 4, vigorous activity = 8) by the minutes the activity was carried out and again by the number of days the activity was undertaken. A higher score is considered to be more favorable.
Time frame: Lead-in period and up to 12 months after AMT-061 (CSL222) dosing
EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) VAS Overall Score
The EQ-5D-5L descriptive system of health-related QoL states consists of 5 dimensions (mobility, self-care, usual activities, pain/discomfort, anxiety/depression). The EQ-5D-5L VAS overall score ranges from 0 to 100. A higher score is considered to be more favorable.
Time frame: Lead-in period and up to 12 months after AMT-061 (CSL222) dosing
Number of Participants With Adverse Events
Time frame: Up to 5 years
Number of Participants With Change (Shift) in Abdominal Ultrasound Results From Normal, Abnormal and Missing to Abnormal Post Treatment
To monitor participants for liver fibrosis and potential occurrences of liver malignancies, abdominal ultrasounds were performed. Number of participants with change in abdominal ultrasound result from normal to abnormal, abnormal to abnormal (no change) and missing to abnormal are reported for this outcome measure.
Time frame: Up to 5 years
Number of Participants With Anti-AAV5 Antibodies
Number of participants who developed antibodies directed against AAV5 (including IgM, IgG and neutralizing antibodies) are reported for this outcome measure. A participant was reported as having an IgG and IgM anti-AAV5 antibody titer greater than or equal to (≥) the LOD if both the screening and confirmatory test results were positive and the titer value was ≥ 50.
Time frame: At Month 60
Number of Participants With AAV5 Capsid-specific T Cells
Time frame: At Month 12 after treatment
Number of Participants With Anti-FIX Antibodies
Time frame: At Month 60
Number of Participants With FIX Inhibitors and Recovery
Number of participants with \>LOD level of fix inhibitors up to Month 60 are reported for this outcome measure. Here, LOD = 0.415 Nijmegen-Bethesda Units per milliliter (NBU/mL).
Time frame: Up to Month 60
Number of Participants With Increased Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) Levels And Who Used Any Corticosteroids For Treatments
Number of participants with increased AST and ALT levels and who used corticosteroids to treat these elevations are reported for this outcome measure.
Time frame: Up to Month 60
Number of Participants With Newly Occurring or Worsening Potentially Clinically Significant Laboratory Values
Only parameters with post-baseline, newly occurring or worsening potentially clinically significant laboratory values are reported for this outcome measure. Criteria threshold: Hemoglobin: \< 80 grams per liter (g/L); Platelet Count: \< 50 10\^9 cells per liter; AST and ALT: \> 2 x Baseline value; Total Bilirubin: \> 2 x upper limit of normal (ULN).
Time frame: Up to Month 60
Number of Participants With Vector DNA Shedding
A participant was considered to no longer be shedding vector DNA if they had a negative laboratory result (\<LOD) for 3 or more consecutive timepoints.
Time frame: Up to 12 months after treatment
Number of Participants With Inflammatory Markers
Inflammatory markers assessed included Interleukin-1beta (IL-1β), Interleukin-2 (IL-2), Interleukin-6 (IL-6), Interferon gamma (IFNγ), and Monocyte chemotactic protein-1 (MCP-1). Lower limit of quantification (LLOQ): IFNγ = 2.86 nanograms per milliliter (ng/mL), IL-1β = 0.60 ng/mL, IL-2 = 0.72 ng/mL, IL-6 = 0.94 ng/mL, MCP-1 = 1.68 ng/mL. Number of participants with inflammatory markers \>= LLOQ are reported for this outcome measure.
Time frame: Up to 12 months after treatment
Number of Participants With Alpha-fetoprotein (AFP) Levels Above LLOQ at Month 60
Number of participants with AFP levels \>= LLOQ at Month 60 are reported for this outcome measure. LLOQ for AFP = 1.09 IU/mL.
Time frame: At Month 60