Principal Investigator: Richard Lemons
Keywords: Clinical Trial , Hemophilia , Phase III , Bleeding Disorders , Factor IX Department: Pediatric Administration
IRB Number: 00113507
Specialty: Pediatric Hematology and Oncology, Hematology/BMT, Pediatrics, General, Pediatric Hematology and Oncology, Pediatric Genetics, Pediatric Hematology and Oncology, Pediatrics, General, Pediatric Genetics
Sub Specialties: Hemophilia, Adolescent Medicine, Blood and Marrow Transplantation, Medical Genetics
Recruitment Status: Active, not recruiting

Contact Information

Elias Rios
elias.rios@hsc.utah.edu
801-213-4128

Brief Summary

Primary Objective
The primary objectives are to demonstrate the effect of AMT-061 on endogenous factor IX activity 6 months (26 weeks) and 12 months (52 weeks) after a single AMT-061 treatment, and to demonstrate the non-inferiority of AMT-061 during the 52-week post-treatment (AMT-061) follow-up compared to standard of care continuous routine factor IX prophylaxis during the lead-in phase, as measured by the ABR.

Secondary and Exploratory Objectives
The secondary objective is to demonstrate additional efficacy and safety aspects of systemic administration of AMT-061.

Secondary efficacy objectives are focused on investigating the effect of 2 × 1013 gc/kg AMT-061 on prevention of bleedings, assessment of trough factor IX activity, discontinuation of previous continuous routine prophylaxis, consumption of factor IX replacement therapy, occurrence and resolution of target joints, correlation of factor IX activity levels after AMT-061 dosing and pre- IMP anti-AAV5 antibody titers using the luciferase based NAB assay, EuroQol (EQ-5D-5L), and international Physical Activity Questionnaire (iPAQ).

Exploratory efficacy objectives will investigate the effect of AMT-061 on factor IX protein levels, Hemophilia Joint Health Score (HJHS) scores, Work Productivity and Activity Impairment Questionnaire (WPAI), Brief Pain Inventory (BPI), Hemophilia Activities List (HAL), and Hemophilia Quality of Life Questionnaire for Adults (Hem-A-Qol), subgroup analyses, and will estimate ABR as a function of mean factor IX activity (as a “correlation” analysis).

Safety Objectives
The safety objectives include monitoring of AEs, changes in abdominal ultrasound, formation of anti-AAV5 antibodies (total immunoglobulin M and immunoglobulin G [IgM and IgG], NABs), AAV5 capsid-specific T cell response, formation of anti-factor IX antibodies, formation of factor IX inhibitors and recovery, hematology and serum chemistry, shedding of vector DNA in blood and semen, inflammatory markers, AST/ALT increase, use of corticosteroids required to preserve factor IX activity in the context of AST/ALT increases, and alpha-fetoprotein (AFP).

The primary efficacy endpoints are as follows:

  • Endogenous factor IX activity at 26 weeks after AMT-061 dosing
  • Endogenous factor IX activity at 52 weeks after AMT-061 dosing
  • ABR comparison between AMT-061 and prophylaxis for non-inferiority between the 52-week post treatment (AMT-061) follow-up and the lead-in phase

Secondary efficacy endpoints

  • Annualized consumption of factor IX replacement therapy during the 52-week post-treatment follow-up, excluding factor IX replacement for invasive procedures, compared to the lead-in phase
  • Annualized infusion rate of factor IX replacement therapy during the 52-week post-treatment follow-up, excluding factor IX replacement for invasive procedures, compared to the lead-in phase
  • Proportion of subjects remaining free of previous continuous routine prophylaxis during the 52-week post-treatment follow-up
  • Comparison of the percentage of subjects with trough factor IX activity <12% of normal between the lead-in phase and after treatment with AMT-061 at Week 52
  • ABR comparison between AMT-061 and prophylaxis for superiority between the lead-in and the 52-week post-treatment (AMT-061) follow-up
  • Rate of spontaneous bleeding events during the 52-week post-treatment follow-up compared to the lead-in phase
  • Rate of spontaneous bleeding events during the 52-week post-treatment follow-up compared to the lead-in phase
  • Rate of joint bleeding events during the 52-week post-treatment follow-up compared to the lead-in phase
  • Occurrence and resolution of target joints during the 52-week post-treatment follow-up
  • Correlation of factor IX activity levels at Week 52 post-AMT-061 treatment with pre-IMP anti-AAV5 antibody titers using the luciferase based NAB assay
  • Proportion of subjects with zero bleeds in the 52-week post-treatment follow-up
  • Patient reported outcome (PRO) questionnaire scores from the iPAQ during the 52 weeks following AMT-061 dosing compared with the lead-in phase
  • PRO questionnaire scores from the EQ-5D-5L during the 52 weeks following AMT-061 dosing compared with the lead-in phase

Exploratory efficacy endpoints

  • Factor IX protein levels during the 52 weeks following AMT-061 dosing
  • HJHS scores during the lead-in phase (prophylaxis) and during the 52 weeks following AMT-061 dosing
  • Other PRO questionnaires: WPAI, BPI, HAL, and Hem-A-Qol questionnaires during the lead-in phase (prophylaxis) and during the 52 weeks following AMT-061 dosing
  • Estimated ABRs over time as a function of mean factor IX activity (as a “correlation” analysis) over the 52 week post-AMT-061 treatment follow-up
  • Rate of traumatic bleeding events during the 52-week post-treatment follow-up compared to the lead-in phase
  • Subgroup analyses will be carried out for the following endpoints (the subgroups will be identified in the Statistical Analysis Plan [SAP]):
    • o Endogenous factor IX activity at Week 26
    • o Annualized consumption of factor IX replacement therapy during the 52-week post-treatment follow-up, excluding replacement for invasive procedures, compared to the lead-in phase
    • o Annualized infusion rate of factor IX replacement therapy during the 52-week post-treatment follow-up, excluding replacement for invasive procedures, compared to the lead-in phase
    • o Endogenous factor IX activity at Week 52
    • o ABR comparison between AMT-061 (during the 52-week post-treatment follow-up) and factor IX prophylaxis (during the lead-in phase)
    • o Comparison of the percentage of subjects with trough factor IX activity <12% of normal between the lead-in phase and after treatment with AMT-061 at Week 52
    • o Proportion of subjects remaining free of previous prescribed continuous routine prophylaxis during the 52-week post-treatment follow-up

All efficacy endpoints will be analyzed as exploratory endpoints as part of the CSR addendum written at the end of the trial:

  • Endogenous factor IX activity at 2, 3, 4, and 5 years after AMT-061 dosing
  • ABR comparison between AMT-061 and prophylaxis for non-inferiority between the 2-year, 3-year, 4-year, and 5-year post treatment (AMT-061) follow-up and the lead-in phase
  • Annualized consumption of factor IX replacement therapy during the 2-year, 3-year, 4-year, and 5-year post-treatment follow-up, excluding factor IX replacement for invasive procedures, compared to the lead-in phase
  •  Annualized infusion rate of factor IX replacement therapy during the 2-year, 3-year, 4-year, and 5-year post-treatment follow-up, excluding factor IX replacement for invasive procedures, compared to the lead-in phase
  • Proportion of subjects remaining free of previous continuous routine prophylaxis during the 2-year, 3-year, 4-year, and 5-year post-treatment follow-up
  • Comparison of the percentage of subjects with trough factor IX activity <12% of normal between the lead-in phase and after treatment with AMT-061 at 2, 3, 4, and 5 years after AMT-061 dosing
  •  ABR comparison between AMT-061 and prophylaxis for superiority between the lead-in phase and the 2-year, 3-year, 4-year, and 5-year post-treatment (AMT-061) follow-up
  •  Rate of spontaneous bleeding events during the 2-year, 3-year, 4-year, and 5-year post-treatment (AMT-061) follow-up compared to the lead-in phase
  •  Rate of joint bleeding events during the 2-year, 3-year, 4-year, and 5-year post-treatment (AMT-061) post-treatment follow-up compared to the lead-in phase
  •  Occurrence and resolution of target joints during the 2 years, 3 years, 4 years, and 5 years following AMT-061 dosing
  •  Correlation of factor IX activity levels at 2 years, 3 years, 4 years, and 5 years post-AMT-061 treatment with pre-IMP anti-AAV5 antibody titers using the luciferase based NAB assay
  •  Proportion of subjects with zero bleeds in the 2 years, 3 years, 4 years, and 5 years post-treatment (AMT-061) follow-up
  •  PRO questionnaire scores from the iPAQ at 2 years, 3 years, 4 years, and 5 years post-AMT-061 treatment compared to the lead-in phase
  •  PRO questionnaire scores from the EQ-5D-5L at 2 years, 3 years, 4 years, and 5 years post-AMT-061 treatment compared to the lead-in phase
  • Factor IX protein levels during the 2 years, 3 years, 4 years, and 5 years following AMT-061 dosing
  •  HJHS scores during the lead-in phase (prophylaxis) and during the 2 years, 3 years, 4 years, and 5 years following AMT-061 dosing
  •  Other PRO questionnaires: WPAI, BPI, HAL, and Hem-A-Qol questionnaires during the lead-in phase (prophylaxis) and during the 2 years, 3 years, 4 years, and 5 years following AMT-061 dosing
  •  Estimated ABRs over time as a function of mean factor IX activity (as a “correlation” analysis) over the 2 years, 3 years, 4 years, and 5 years post-AMT-061 treatment follow-up
  •  Rate of traumatic bleeding events during the 2 years, 3 years, 4 years, and 5 years post-treatment follow-up compared to the lead-in phase

Exploratory analysis
All exploratory endpoints will be presented using descriptive statistics, where applicable. No formal statistical testing will be required. Continuous endpoints will be summarized descriptively by visit (and by subset for the subset analyses). Analysis will be based on the FAS and the PP population. A full description of the exploratory analyses will be included in the SAP.

Optional Sub-study endpoints

  • PROBE summary scores and individual item responses.
  • MSKUS sub-study endpoints
    • Joint Tissue Activity and Damage Exam (J.A.D.E.) scores

The analysis for the optional PROBE Questionnaire sub-study will be described in the SAP. There will be a separate SAP document for the statistical analysis of the optional MSKUS substudy results.

Analysis will be based on the FAS population for the set of subjects participating in the respective sub-study. Any subject with at least one assessment of the sub-study endpoint will be considered to be participating in the respective sub-study.

Safety Analyses
Safety endpoints to be analyzed are:

  • AEs
  • Changes in abdominal ultrasound
  •  Anti-AAV5 antibodies (total [IgM and IgG], NABs)
  • AAV5 capsid-specific T cell response
  •  Anti-factor IX antibodies 
  •  Factor IX inhibitors and recovery
  •  Hematology and serum chemistry parameters
  •  ALT/AST levels and corticosteroid use for ALT/AST increases
  •  Vector DNA in blood and semen
  •  Inflammatory markers: IL-1β, IL-2, IL-6, IFNγ, MCP-1
  •  AFP

Inclusion Criteria

The subject cannot be enrolled in the trial before all of the following inclusion criteria are met:

  1. Male
  2. Age ≥18 years
  3. Subjects with congenital hemophilia B with known severe or moderately severe factor IX deficiency (≤2% of normal circulating factor IX) for which the subject is on continuous routine factor IX prophylaxis*
  4. >150 previous exposure days of treatment with factor IX protein
  5. Have been on stable prophylaxis for at least 2 months prior to screening
  6. Have demonstrated capability to independently, accurately and in a timely manner complete the diary during the lead-in phase as judged by the investigator
  7. Acceptance to use a condom during sexual intercourse in the period from IMP administration until AAV5 has been cleared from semen, as evidenced by the central laboratory from negative analysis results for at least three consecutively collected semen samples (this criterion is applicable also for subjects who are surgically sterilized)
  8. Able to provide informed consent following receipt of verbal and written information about the trial.

* Continuous routine prophylaxis is defined as the intent of treating with an a priori defined frequency of infusions (e.g., twice weekly, once every two weeks, etc.) as documented in the medical records.

Exclusion Criteria

Subjects are excluded from the trial if any of the following exclusion criteria (including local and
central laboratory test results, as specified) are met:

  1. History of factor IX inhibitors
  2. Positive factor IX inhibitor test at screening and Visit L-Final (based on local laboratory results)
  3. Screening and Visit L-Final laboratory values (based on central laboratory results):                                                                                                                                     

    a. ALT >2 times ULN
    b. AST >2 times ULN
    c. Total bilirubin >2 times ULN (except if this is caused by Gilbert disease)
    d. Alkaline phosphatase (ALP) >2 times ULN
    e. Creatinine >2 times ULN

  4. Positive human immunodeficiency virus (HIV) serological test at screening and Visit LFinal, not controlled with anti-viral therapy as shown by CD4+ counts ≤ 200/μL or by a viral load of > 200 copies/mL (based on central laboratory results)
  5. Hepatitis B or C infection with the following criteria present at screening:
    1. Currently receiving antiviral therapy for this/these infection(s) and/or
    2. Positive for any of the following (based on central laboratory results):
      1. Hepatitis B surface antigen (HBsAg), except if in the opinion of the investigator this is due to a previous Hepatitis B vaccination rather than active Hepatitis B infection.
      2. Hepatitis B virus deoxyribonucleic acid (HBV DNA)
      3. Hepatitis C virus ribonucleic acid (HCV RNA)
  6. Known coagulation disorder other than hemophilia B
  7. Thrombocytopenia, defined as a platelet count below 50 × 109/L, at screening and Visit L-Final (based on central laboratory results)
  8. Known severe infection or any other significant concurrent, uncontrolled medical condition including, but not limited to, renal, hepatic, cardiovascular, hematological, gastrointestinal, endocrine, pulmonary, neurological, cerebral or psychiatric disease, alcoholism, drug dependency or any other psychological disorder evaluated by the Investigator to interfere with adherence to the protocol procedures or with the degree of tolerance to the IMP
  9. Known significant medical condition that may significantly impact the intended transduction of the vector and/or expression and activity of the protein, including but not limited to:
    1. Disseminated intravascular coagulation
    2. Accelerate fibrinolysis
    3. Advanced liver fibrosis (suggestive of or equal to METAVIR Stage 3 disease: e.g., a FibroScan score of >9 kPa is considered equivalent)
  10. Known history of an allergic reaction or anaphylaxis to factor IX products
  11. Known history of allergy to corticosteroids
  12. Known uncontrolled allergic conditions or allergy/hypersensitivity to any component of the IMP excipients
  13. Known medical condition that would require chronic administration of steroids
  14. Previous gene therapy treatment
  15. Receipt of an experimental agent within 60 days prior to screening
  16. Current participation or anticipated participation within one year after IMP administration in this trial in any other interventional clinical trial involving drugs or devices.