Clinical trial NCT06003387: Efficacy and Safety of CSL222 (Etranacogene Dezaparvovec) Gene Therapy in Adults With Hemophilia B With Pretreatment Adeno-associated Virus Serotype 5 (AAV5) Neutralizing Antibodies (Nabs)
Official title: Phase 3b, Open-label, Multicenter, Single-dose Study Investigating Efficacy and Safety of CSL222 (Etranacogene Dezaparvovec) Gene Therapy Administered to Adult Subjects With Severe or Moderately Severe Hemophilia B With Detectable Pretreatment AAV5 Neutralizing Antibodies
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Hemophilia B
Lead sponsor: CSL Behring
Sponsor class: INDUSTRY
First posted: 2023-08-22
Enrollment: 35
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to assess the risk of bleeding due to failure of expected pharmacological action of CSL222 in adults with severe or moderately severe hemophilia B with detectable pretreatment AAV5 Nabs.


Eligibility criteria: Inclusion Criteria:

* Age ≥ 18 years and considered legally an adult, as defined by country regulations.
* Has congenital hemophilia B with known severe or moderately severe FIX deficiency (≤ 2% of normal circulating FIX) for which the participant is on continuous routine FIX prophylaxis
* Has 2 consecutive detectable AAV5 NAb titer results between Screening and Visit L-Final using a validated AAV5 NAb assay (based on central laboratory results)
* Has \> 150 previous exposure days to FIX replacement therapy
* Has been on stable FIX prophylaxis for at least 2 months before Screening
* Has demonstrated capability to independently, accurately, and in a timely manner complete the eDiary during the Lead-in Period, as judged by the investigator
* Acceptance to barrier contraception protection for 1 year starting the day of CSL222 treatment.
* Able to provide informed consent after receipt of verbal and written information about the study
* Investigator believes that the participant (or the participant's legally acceptable representative\[s\]) understands the nature, scope, and possible consequences of the study and is able to adhere to the study procedures.

Exclusion Criteria:

* History of FIX inhibitors or positive FIX inhibitor test at Prescreening, Screening or Visit L Final (based on central laboratory results).
* Screening or Visit L-Final laboratory values that meet the definition of Severe Hepatic Impairment per Common Terminology Criteria for Adverse Events (CTCAE) (based on central laboratory results)
* ALT \> 2 × the ULN at Screening or Visit L-Final laboratory values (based on central laboratory results).
* Any condition other than hemophilia B resulting in an increased bleeding tendency.
* Thrombocytopenia, defined as a platelet count below 50 × 10\^9/L, at Screening or Visit L Final (based on central laboratory results).
* Any uncontrolled or untreated infection (human immunodeficiency virus \[HIV\], hepatitis B virus \[HBV\] and hepatitis C virus \[HCV\], 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 clinical study protocol procedures or with the degree of tolerance to CSL222.
* Known history of allergy to corticosteroids or known medical condition that would require chronic administration of oral corticosteroids.
* Known uncontrolled allergic conditions or allergy / hypersensitivity to any component of the CSL222 excipients (ie, sucrose, potassium chloride, potassium dihydrogen phosphate, sodium chloride, and disodium hydrogen phosphate).
* Previous gene therapy treatment.
* Receipt of an experimental agent or device within 60 days before Screening until the end of the study.

Primary outcomes:
measure: Annualized Bleeding Rate (ABR)
timeFrame: Months 7 to 18 after CSL222 treatment
Secondary outcomes:
measure: Number of participants with Treatment Emergent Adverse Events (TEAEs)
timeFrame: Up to 18 months after CSL222 treatment
measure: Percentage of participants with TEAEs
timeFrame: Up to 18 months after CSL222 treatment
measure: Number of TEAEs
timeFrame: Up to 18 months after CSL222 treatment
measure: Change in Liver ultrasound
timeFrame: Baseline and up to 18 months after CSL222 treatment
measure: Number of participants who develop Factor IX (FIX) Inhibitors
timeFrame: Up to 18 months after CSL222 treatment
measure: Percentage of participants who develop FIX Inhibitors
timeFrame: Up to 18 months after CSL222 treatment
measure: Change in hematology and biochemistry parameters
timeFrame: Baseline and up to 18 months after CSL222 treatment
measure: Number of participants with clinically significant increase in Alanine Aminotransferase (ALT) or Aspartate Aminotransferase (AST)
timeFrame: Up to 18 months after CSL222 treatment
measure: Percentage of participants with clinically significant increase in ALT or AST
timeFrame: Up to 18 months after CSL222 Treatment
measure: Corticosteroid use for ALT or AST increases after CSL222 treatment
timeFrame: Up to 18 months after CSL222 treatment
measure: Number of participants with clinically significant Alpha-fetoprotein (AFP)
timeFrame: Baseline and up to 18 months after CSL222 treatment
measure: Percentage of participants with clinically significant AFP
timeFrame: Baseline and up to 18 months after CSL222 treatment
measure: Number of participants with infusion related reactions or hypersensitivity reactions
timeFrame: Throughout CSL222 infusion period and up to 18 months after CSL222 treatment
measure: Percentage of participants with infusion related reactions or hypersensitivity reactions
timeFrame: Throughout CSL222 infusion period and up to 18 months after CSL222 treatment
measure: Change in the Endogenous FIX activity
timeFrame: Baseline and up to Months 6, 12, and 18 after CSL222 treatment
measure: Annualized consumption of FIX replacement therapy
timeFrame: Months 7 to 18 after CSL222 treatment
measure: Annualized infusion rate of FIX replacement therapy
timeFrame: Months 7 to 18 after CSL222 treatment
measure: Number of participants remaining free of continuous routine FIX prophylaxis
timeFrame: Months 7 to 18 after CSL222 treatment
measure: Percentage of participants remaining free of continuous routine FIX prophylaxis
timeFrame: Months 7 to 18 after CSL222 treatment
measure: ABR for spontaneous bleeding episodes
timeFrame: Months 7 to 18 after CSL222 treatment
measure: ABR for joint bleeding episodes
timeFrame: Months 7 to 18 after CSL222 treatment
measure: ABR for FIX-treated bleeding episodes
timeFrame: Months 7 to 18 after CSL222 treatment
measure: Correlation analysis of FIX activity levels with baseline AAV5 NAb titers
timeFrame: Months 7 to 18 after CSL222 treatment
measure: Number of participants with new target joints and resolved preexisting target joints
timeFrame: Months 7 to 18 after CSL222 treatment
measure: Number of participants with zero bleeds and zero FIX-treated bleeds
timeFrame: Months 7 to 18 after CSL222 treatment
measure: Percentage of participants with zero bleeds and zero FIX-treated bleeds
timeFrame: Months 7 to 18 after CSL222 treatment
measure: Change in the EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) Visual Analogue Scale (VAS) Overall Score
timeFrame: Baseline and up to 18 months after CSL222 treatment
measure: Change in the EQ-5D-5L Index Scores
timeFrame: Baseline and up to 18 months after CSL222 treatment
Other outcomes:
Locations:
city: Ann Arbor
country: United States
facility: University of Michigan - 84000285
state: Michigan
city: Camperdown
country: Australia
facility: Royal Prince Alfred Hospital - 03600044
state: New South Wales
city: Herston
country: Australia
facility: Royal Brisbane Hospital - 03600045
state: Queensland
city: Melbourne
country: Australia
facility: The Alfred Hospital - 03600043
state: Victoria
city: Hamilton
country: Canada
facility: McMaster University - Hamilton - 12400017
state: Ontario
city: Hong Kong
country: Hong Kong
facility: Queen Mary Hospital - 34400001
city: Sha Tin
country: Hong Kong
facility: Prince of Wales Hospital Chinese University of Hong Kong - 34400002
city: Tel Hashomer
country: Israel
facility: Sheba Medical Center - 37600004
city: Daegu
country: Korea, Republic of
facility: Kyungpook National University Hospital - 41000014
city: Seoul
country: Korea, Republic of
facility: Kyung Hee University Hospital at Gangdong - 41000015
city: Seoul
country: Korea, Republic of
facility: Severance Hospital, Yonsei University Health System - 41000013
city: Ciudad de México
country: Mexico
facility: Centro de Investigacion Clinica GRAMEL S.C. - 48400003
state: Distrito Federal
city: Riyadh
country: Saudi Arabia
facility: King Faisal Specialist Hospital and Research Center - 68200001
city: Singapore
country: Singapore
facility: National University Hospital - 70200002
city: Johannesburg
country: South Africa
facility: Haemophilia Comprehensive Care Centre - 71000001
city: Taipei City
country: Taiwan
facility: Tri-Service General Hospital - 15800012
state: Neihu District
city: Bornova
country: Turkey
facility: Ege University Medical Faculty - 79200002
city: Gaziantep
country: Turkey
facility: Gaziantep University Sahinbey Research and Practice Hospital - 79200004
Study officials:
affiliation: CSL Behring
name: Study Director
role: STUDY_DIRECTOR
References: