E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
|
E.1.1.1 | Medical condition in easily understood language |
Hemophilia B - Bleeding disorder |
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E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10018939 |
E.1.2 | Term | Haemophilia B (Factor IX) |
E.1.2 | System Organ Class | 100000004850 |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective is to demonstrate the effect of AMT-061 on endogenous FIX activity 6 months after a single AMT-061 treatment. |
|
E.2.2 | Secondary objectives of the trial |
1. Demonstrate non-inferiority of AMT-061 as compared to standard of care continuous routine (CR) FIX prophylaxis in terms of bleeding prevention
Investigating effect of 2 x 10^13 gc/kg AMT-061 on
- Bleeding prevention
- Trough FIX activity
- Discontinuation of previous CR prophylaxis
- Consumption of FIX replacement therapy
- Occurrence & resolution of target joints
- Correlation of FIX activity levels after dosing & pre-IMP anti-AAV5 antibody titers
- Endogenous FIX activity 52 weeks after dosing.
- Exploratory efficacy objectives
2. Demonstrate additional efficacy and safety aspects of systemic administration of AMT-061.
- monitoring of AEs
- formation of anti-AAV5 antibodies (total IgM & IgG neutralizing antibodies)
- AAV5 capsid-specific T cell response
- anti-FIX antibodies
- FIX inhibitors
- hematology & serum chemistry
- shedding of vector DNA (blood & semen)
- inflammatory markers
- AST/ALT increase (corticosteroids use required to preserve FIX activity) |
|
E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
1. Patient Reported Outcomes, Burdens, and Experiences (PROBE) Questionnaire (optional):
- PROBE Questionnaire is a novel, patient-developed, patient-reported outcome tool specific to hemophilia and intended to capture clinical outcomes that are considered relevant by patients.
- The objective of this sub-study is to provide data complementary to the compendium of established PRO tools regarding the impact of gene therapy on patient relevant outcomes and quality of life over time.
2. Musculoskeletal Ultrasound (optional)
- This sub-study will provide objective assessment of the effects of receiving gene therapy on the progression of physiological joint damage over time.
- 8 Musculoskeletal ultrasounds to take place starting at screening. Additional ultrasounds may be collected at the investigator’s discretion. |
|
E.3 | Principal inclusion criteria |
- Male
- Age ≥18 years
- Subjects with congenital hemophilia B with known severe or moderately severe FIX deficiency (≤2% of normal circulating FIX) for which the subject is on continuous routine Factor IX prophylaxis (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).
- >150 previous exposure days of treatment with FIX protein
- Have been on stable prophylaxis for at least 2 months prior to screening
- Have demonstrated capability to independently, accurately and in a timely manner complete the diary during the lead-in phase as judged by the investigator
- 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)
- Able to provide informed consent following receipt of verbal and written information about the trial. |
|
E.4 | Principal exclusion criteria |
- History of FIX inhibitors
- Positive FIX inhibitor test at screening and Visit L-Final (based on local laboratory results)
- Screening and Visit L-Final laboratory values (based on central laboratory results):
a. ALT >2 times upper normal limit
b. Aspartate aminotransferase (AST) >2 times upper normal limit
c. Total bilirubin >2 times upper normal limit
d. Alkaline phosphatase (ALP) >2 times upper normal limit
e. Creatinine >2 times upper normal limit
- 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)
- Active infection with Hepatitis B or C virus as reflected by hepatitis B surface antigen (HBsAg), hepatitis B extracellular antigen (HBeAg), hepatitis B virus deoxyribonucleic acid (HBV DNA) or hepatitis C virus ribonucleic acid (HCV RNA) positivity, respectively, at screening and Visit L-Final (based on central laboratory results)
- History of hepatitis B or C exposure, currently receiving antiviral therapy at Visit L-Final
- Known coagulation disorder other than hemophilia B
- Thrombocytopenia, defined as a platelet count below 50 × 109/L, at screening and Visit L-Final (based on central laboratory results)
- 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
- Known significant medical condition that may significantly impact the intended transduction of the vector and/or expression and activity of the protein, such as disseminated intravascular coagulation, accelerated fibrinolysis, and profound liver fibrosis
- Known history of an allergic reaction or anaphylaxis to FIX products
- Known uncontrolled allergic conditions or allergy/hypersensitivity to any component of the IMP excipients
- Known medical condition that would require chronic administration of steroids
- Previous gene therapy treatment
- Receipt of an experimental agent within 60 days prior to screening
- Current participation or anticipated participation within one year after IMP administration in this trial in any other interventional clinical trial involving drugs or devices. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Endogenous FIX activity after AMT-061 dosing |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
26 weeks after AMT-061 dosing. |
|
E.5.2 | Secondary end point(s) |
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 FIX 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 FIX 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 FIX activity levels during the 52-week post-treatment follow-up and pre-IMP anti-AAV5 antibody titers using the luciferase based NAB assay
- Endogenous FIX activity at 52 weeks after AMT-061 dosing
Secondary safety endpoints
- Adverse events
- Anti-AAV5 antibodies (total [IgM and IgG], neutralizing antibodies)
- AAV5 capsid-specific T cells
- Anti-FIX antibodies
- FIX 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 |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary efficacy endpoints
- Comparison between 52-week post-treatment follow-up and the lead-in phase
- Comparison between the lead-in phase and after treatment with AMT-061 at 26 &52 weeks
- During the 52-week post-treatment follow-up
- 52-week post-treatment follow-up compared to the lead-in phase
- 52-week post-treatment follow-up compared to the lead-in phase
- 52-week post-treatment follow-up compared to the lead-in phase
- 52-week post-treatment follow-up compared to the lead-in phase
- During 52 weeks following AMT-061 dosing
- During the 52-week post-treatment follow-up and pre-IMP anti-AAV5 antibody titers using the luciferase based NAB assay
- At 52 weeks after AMT-061 dosing
Secondary safety endpoints
All will be monitored for the duration of the trial. |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 30 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Belgium |
Canada |
Denmark |
Finland |
France |
Germany |
Ireland |
Italy |
Netherlands |
South Africa |
Spain |
Sweden |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 7 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 7 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |