This study has been transitioned to CTIS with ID 2024-510738-42-00 check the CTIS register for the current data. The primary aim of the trial is to demonstrate the non-inferiority of CSL222 (formerly AMT-061) (2 × 1013 gc/kg) during the 52 weeks…
ID
Source
Brief title
Condition
- Coagulopathies and bleeding diatheses (excl thrombocytopenic)
- Blood and lymphatic system disorders congenital
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary efficacy endpoints
- 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)
Secondary outcome
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 post-treatment), 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 post-treatment) 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 (AE's)
- Changes in abdominal ultrasound
- Anti-AAV5 antibodies (total [IgM and IgG], neutralizing antibodies (NAB's))
- AAV5 capsid-specific T cells
- Anti-FIX antibodies
- FIX 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)
Background summary
Congenital hemophilia B is an inherited bleeding disorder characterized by an
increased bleeding tendency due to a partial or complete deficiency of the
essential blood coagulation Factor IX (FIX).
Approximately 1 in 20,000-50,000 live male newborns have hemophilia B. The
number of diagnosed hemophilia B patients globally is about 30,000.
Bleeding is the main symptom of the disease. Mild cases may go unnoticed until
later in life, when they occur because of surgery or trauma. In severe or
moderate hemophilia internal bleeding may occur anywhere, but bleeding into
joints is most common. Severe recurrent bleedings may result in chronic pain,
disability and reduced quality of life (QoL).
There is no cure for hemophilia B. The primary goals of hemophilia B therapy
are the prevention of bleeding episodes, treatment of bleeding episodes and
provision of acceptable hemostasis during surgery and emergencies. Currently,
these goals are met for hemophilia B subjects by intravenous (IV) injections.
The recent approvals of extended half-life FIX products allow for reduced
frequency of factor administration (once every 7 to 14 days) and maintaining a
higher FIX trough level.
Study objective
This study has been transitioned to CTIS with ID 2024-510738-42-00 check the CTIS register for the current data.
The primary aim of the trial is to demonstrate the non-inferiority of CSL222
(formerly AMT-061) (2 × 1013 gc/kg) during the 52 weeks following establishment
of stable factor IX expression (months 6 to 18) post-treatment (CSL222
(formerly 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).
Secondary: To demonstrate additional efficacy and safety aspects of systemic
administration of CSL222 (formerly AMT-061).
Study design
This is an open-label, single-dose, multi-center, multinational trial, with a
screening period, a lead-in phase, a treatment + post-treatment follow-up
phase, and a long-term follow-up phase.
Intervention
Subjects will receive a single infusion of CSL222 (formerly AMT-061). CSL222
(formerly AMT-061) will be administered at a dose of 2 x 10^13 gc/kg as a
one-time infusion in a peripheral vein, subjects will be monitored for
tolerance to the Investigational Medicinal Product and detection of immediate
Adverse Events for three hours after dosing.
Study burden and risks
Risks: possible side effects of the research medication and research procedures
Burden: blood samples, completion of questionnaires
First Avenue 1020
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First Avenue 1020
King of Prussia PA 19406-0901
US
Listed location countries
Age
Inclusion criteria
1. Male
2. Age >=18 years
3. 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*
4. >150 previous exposure days of treatment with FIX 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
1. History of FIX inhibitors
2. Positive FIX 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. Aspartate aminotransferase (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 limit
4. Positive human immunodeficiency virus (HIV) serological test at screening
and Visit L-Final, not controlled with anti-viral therapy as shown by CD4+
counts <= 200/µL (based on central laboratory results)
5. 5. 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 virus deoxyribonucleic acid (HBV DNA)
• 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:
• Disseminated intravascular coagulation
• Accelerated fibrinolysis
• 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.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EU-CTR | CTIS2024-510738-42-00 |
| EudraCT | EUCTR2017-004305-40-NL |
| ClinicalTrials.gov | NCT03569891 |
| CCMO | NL65714.000.18 |