E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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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 | 10010331 - Congenital, familial and genetic disorders |
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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 |
To demonstrate the non-inferiority of CSL222 (formerly AMT-061 [2 × 10^13 gc/kg]) during the 52 weeks following establishment of stable factor IX expression (months 6 to 18) 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 annualized bleeding rate (ABR).
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E.2.2 | Secondary objectives of the trial |
The secondary objective is to demonstrate additional efficacy and safety aspects of systemic administration of CSL222 (formerly AMT-061) on: - Endogenous factor IX activity 6 months, 12 months, and 18 months - Bleeding prevention - Trough FIX activity - Discontinuation of previous continuous routine prophylaxis - Consumption of FIX replacement therapy - Occurrence & resolution of target joints - Estimated ABR during the 52 weeks following stable factor IX expression - Correlation of pre-IMP anti-AAV5 antibody titers - Exploratory efficacy objectives Safety objectives include: - monitoring of AEs - changes in abdominal ultrasound - formation of anti-AAV5 antibodies (total IgM & IgG neutralizing antibodies) - AAV5 capsid-specific T cell response - anti-FIX antibodies - FIX inhibitors and recovery - hematology & serum chemistry - shedding of vector DNA (blood & semen) - inflammatory markers - AST/ALT increase and alpha-fetoprotein (AFP) |
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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 subjects. - 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. If it is not possible to obtain the musculoskeletal ultrasound at screening (Visit S), it is allowed to obtain this first musculoskeletal ultrasound at a later time point (preferably as soon as possible during one of the lead-in visits). Additional ultrasounds may be collected at the investigator's discretion. |
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E.3 | Principal inclusion criteria |
- Male - Age ≥18 years - 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 (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 factor IX 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 3 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. |
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E.4 | Principal exclusion criteria |
- History of factor IX inhibitors - Positive factor IX 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 (except if this is caused by Gilbert disease) 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 (based on central laboratory results) - Hepatitis B or C infection with the following criteria present at Screening: i. Currently receiving antiviral therapy for this/these infection(s) and/or ii. Positive for any of the following (based on central laboratory results): • 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 • Hepatitis B extracellular antigen (HBeAg), • Hepatitis B virus deoxyribonucleic acid (HBV DNA) • Hepatitis C virus ribonucleic acid (HCV RNA) - 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, including but not limited to: • Disseminated intravascular coagulation • Accelerated fibrinolysis • Advanced liver fibrosis (suggestive of or equal to METAVIR Stage 3 disease; e.g. a FibroScan™ score of ≥9 kPa is considered equivalent) - Known history of an allergic reaction or anaphylaxis to factor IX products - Known uncontrolled allergic conditions or allergy/hypersensitivity to any component of the IMP excipients - Known history of allergy to corticosteroids - 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. |
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E.5 End points |
E.5.1 | Primary end point(s) |
ABR comparison between CSL222 (formerly: AMT-061) and prophylaxis for non-inferiority between the lead-in phase and the 52 weeks following stable factor IX expression (months 6-18 post treatment) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Comparison between 52-week post-treatment follow-up and the lead-in phase |
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E.5.2 | Secondary end point(s) |
Secondary efficacy endpoints - Endogenous factor IX activity at 6 months after CSL222 dosing - Endogenous factor IX activity at 12 months after CSL222 dosing - Endogenous factor IX activity at 18 months after CSL222 dosing - Annualized consumption of factor IX replacement therapy during the 52 weeks following stable factor IX expression (months 6-18 post-treatment), excluding factor IX replacement for invasive procedures, compared to the lead-in phase - Annualized infusion rate of factor IX replacement therapy during the 52 weeks following stable factor IX expression (months 6-18 posttreatment), 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 weeks following stable factor IX expression (months 6-18 post-treatment) - Comparison of the percentage of subjects with trough factor IX activity <12% of normal between the lead in phase and after treatment with CSL222 over the 52 weeks following stable factor IX expression (months 6-18 post-treatment) - ABR comparison between CSL222 and prophylaxis for superiority between the lead-in phase and the 52 weeks following stable factor IX expression (months 6-18 post-treatment) - Rate of spontaneous bleeding events during the 52 weeks following stable factor IX expression (months 6-18 post-treatment) compared to the lead in phase - Rate of joint bleeding events during the 52 weeks following stable factor IX expression (months 6-18 post treatment) compared to the lead-in phase - Estimated ABR – during the 52 weeks following stable factor IX expression (months 6-18 post-treatment) – as a function of pre-IMP anti-AAV5 antibody titers using the luciferase based NAB assay (as a "correlation" analysis) - Correlation of factor IX activity levels during the 52 weeks following stable factor IX expression (months 6-18 post-treatment) with pre-IMP anti-AAV5 antibody titers using the luciferase based NAB assay - Occurrence of (and resolution of) new target joints during the 52 weeks following stable factor IX expression (months 6-18 posttreatment) and resolution of pre-existing target joints following CSL222 dosing - Proportion of subjects with zero bleeds during the 52 weeks following stable factor IX expression (months 6-18 post-treatment) - PRO questionnaire scores from the international Physical Activity Questionnaire (iPAQ; total physical activity score) during the 12 months following CSL222 dosing compared with the lead-in phase - PRO questionnaire scores from the EuroQol-5 dimensions-5 levels (EQ 5D 5L) visual analogue scale (VAS) score during the 12 months following CSL222 dosing compared with the lead-in phase
Secondary safety endpoints - Adverse events - Changes in abdominal ultrasound - Anti-AAV5 antibodies (total [IgM and IgG], neutralizing antibodies) - AAV5 capsid-specific T cells - 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 - Alpha-fetoprotein (AFP)
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary efficacy endpoints - 6, 12, 18 months after CSL222 dosing - Months 6-18 compared to the lead-in phase - Months 6-18 compared to the lead-in phase - Months 6-18 compared to the lead-in phase - Months 6-18 compared to the lead-in phase - Months 6-18 compared to the lead-in phase - Months 6-18 compared to the lead-in phase - Months 6-18 compared to the lead-in phase - Months 6-18 compared to the lead-in phase - Months 6-18 compared to the lead-in phase - Months 6-18 compared to the lead-in phase - Months 6-18 compared to the lead-in phase - During the 12 months following CSL222 dosing compared with the lead-in phase - During the 12 months following CSL222 dosing compared with the lead-in phase
Secondary safety endpoints For the duration of the trial. |
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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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 26 |
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 |
United Kingdom |
United States |
Belgium |
Denmark |
Germany |
Ireland |
Italy |
Netherlands |
Sweden |
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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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 6 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
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 |