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: Recruiting

Contact Information

Tammi Lewis

Brief Summary

The primary aim of the trial is to demonstrate the effect of AMT-061 on endogenous Factor IX activity 6 months after a single AMT-061 treatment.

The non-inferiority of a single AMT-061 treatment as compared to Factor IX prophylaxis treatment, with respect to ABR, will be assessed as a secondary endpoint. Single treatment with AMT-061 will be claimed to be non-inferior to Factor IX prophylaxis treatment when the upper limit of the one-sided 97.5% confidence interval of the rate ratio in ABR between AMT-061 (post-treatment) and Factor IX prophylaxis (lead-in) is less than 1.8.

Other secondary endpoints of the trial will focus on investigating the effect of 2 x 1013 gc/kg AMT 061 on assessment of trough Factor IX activity, discontinuation of previous continuous routine prophylaxis, total consumption of Factor IX replacement therapy, bleeding events, occurrence and resolution of target joints, correlation of Factor IX activity levels and observed anti-AAV5 antibody titers using the luciferase based NAB assay after AMT-061 dosing, endogenous Factor IX activity 52 weeks after AMT-061 dosing, and safety. 

Exploratory endpoints in the trial will focus on the effect of AMT 061 on any bleeding events not requiring Factor IX replacement therapy, health care utilization, and quality of life.

Endpoints for the two sub-studies will be described in the Statistical Analysis Plan.

Analyses will be based on central laboratory measurements if results are available from both local and central

Primary efficacy endpoints
- Endogenous Factor IX activity at 26 weeks after AMT-061 dosing

Secondary efficacy endpoints
- ABR comparison between AMT-061 (during the 52-week post-treatment follow-up) and prophylaxis (during the lead-in phase)
- Comparison of the number of patients with trough Factor IX activity <12% of normal between the lead-in phase and after treatment with AMT-061 at 26 and 52 weeks
- Remaining free of previous continuous routine prophylaxis during the 52-week post-treatment follow-up
- Total consumption of Factor IX replacement therapy during the 52-week post-treatment follow-up, excluding ad hoc prophylaxis for invasive procedures compared to the lead-in phase
- Frequency and percentage of spontaneous (unprovoked) bleeding events during the 52-week post-treatment follow-up compared to the lead-in phase
- Frequency and percentage of joint bleeding during the 52-week post-treatment follow-up compared to the lead-in phase
- Frequency and percentage of traumatic (provoked) 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 weeks following AMT-061 dosing
- Correlation of Factor IX activity levels during the 52-week post-treatment follow-up and pre-IMP anti-AAV5 antibody titers using the luciferase based NAB assay
- Endogenous Factor IX activity at 52 weeks after AMT-061 dosing

Exploratory efficacy endpoints
- Any bleeding events not requiring Factor IX replacement therapy during the 52 weeks following AMT-061dosing
- HJHS scores during the 52 weeks following AMT-061 dosing
- PRO questionnaires: EuroQoL (EQ-5D-5L), international Physical Activity Questionnaire (iPAQ), 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).

Secondary safety endpoints
- Adverse events
- Anti-AAV5 antibodies (total [IgM and IgG], neutralizing antibodies)
- AAV5 capsid-specific T cells

- Anti-Factor IX antibodies
- Factor IX inhibitors
- 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
- Vital signs

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):                                                                                                                                            -  ALT >2 times upper normal limit

     - Aspartate aminotransferase (AST) >2 times upper normal limit

    - Total bilirubin >2 times upper normal limit

    - Alkaline phosphatase (ALP) >2 times upper normal limit

    - Creatinine >2 times upper normal limit

  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 Visit L-Final:
    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 extracellular antigen (HBeAg)
      3. Hepatitis B virus deoxyribonucleic acid (HBV DNA)
      4. 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: 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.