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)

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

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.

Study Overview

• Status: Recruiting
• Conditions: Hemophilia B
• Intervention / Treatment: Genetic: CSL222 (AAV5-hFIXco-Padua)

• Study Type: Interventional
• Enrollment (Estimated): 35
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Trial Registration Coordinator; Phone Number: 1-610-878-4697; Email: clinicaltrials@cslbehring.com

Study Locations

• Australia
  • New South Wales
    • Camperdown, New South Wales, Australia, 2050
      • Recruiting
      • Royal Prince Alfred Hospital
      • Contact: Use Central Contact
  • Queensland
    • Herston, Queensland, Australia, 4029
      • Recruiting
      • Royal Brisbane Hospital
      • Contact: Use Central Contact
  • South Australia
    • Adelaide, South Australia, Australia, 5000
      • Recruiting
      • Royal Adelaide Hospital
  • Victoria
    • Melbourne, Victoria, Australia, 3004
      • Recruiting
      • The Alfred Hospital
      • Contact: Use Central Contact
• Canada
  • Ontario
    • Hamilton, Ontario, Canada, L8N 3Z5
      • Recruiting
      • McMaster University - Hamilton
      • Contact: Use Central Contact
• Hong Kong
  • Hong Kong, Hong Kong, 999077
    • Recruiting
    • Queen Mary Hospital
    • Contact: Use Central Contact
  • Shatin, Hong Kong, 999077
    • Recruiting
    • Prince of Wales Hospital Chinese University of Hong Kong
    • Contact: Use Central Contact
• Israel
  • Tel Litwinsky, Israel, 5265601
    • Recruiting
    • Sheba Medical Center
    • Contact: Use Central Contact
• Mexico
  • Mexico City
    • Mexico City, Mexico City, Mexico, 3720
      • Recruiting
      • Centro de Investigación Clínica Gramel S.C.
      • Contact: Use Central Contact
• Saudi Arabia
  • Riyadh, Saudi Arabia, 11471
    • Recruiting
    • King Faisal Specialist Hospital and Research Center
    • Contact: Use Central Contact
• Singapore
  • Singapore, Singapore, 169608
    • Recruiting
    • Singapore General Hospital
  • Singapore, Singapore, 110974
    • Recruiting
    • National University Hospital
    • Contact: Use Central Contact
• South Africa
  • Johannesburg, South Africa, 2193
    • Recruiting
    • Haemophilia Comprehensive Care Centre
    • Contact: Use Central Contact
• South Korea
  • Daegu, South Korea, 41944
    • Recruiting
    • Kyungpook National University Hospital
    • Contact: Use Central Contact
  • Seoul, South Korea, 3722
    • Recruiting
    • Severance Hospital, Yonsei University Health System
    • Contact: Use Central Contact
  • Seoul, South Korea, 05278
    • Recruiting
    • Kyung Hee University Hospital at Gangdong
    • Contact: Use Central Contact
• Taiwan
  • Chang-hua, Taiwan, 500
    • Recruiting
    • Changhua Christian Hospital (CCH)
    • Contact: Use Central Contact
  • Taichung, Taiwan, 40705
    • Recruiting
    • Taichung Veterans General Hospital -
    • Contact: Use Central Contact
  • Taipei, Taiwan, 100225
    • Recruiting
    • National Taiwan University Hospital
  • Neihu District
    • Taipei, Neihu District, Taiwan, 114
      • Recruiting
      • Tri-Service General Hospital
      • Contact: Use Central Contact
  • Sanmin District
    • Kaohsiung City, Sanmin District, Taiwan, 80756
      • Recruiting
      • Kaohsiung Medical University Chung-Ho Memorial Hospital (KMUH)
      • Contact: Use Central Contact
• Turkey (Türkiye)
  • Bornova, Turkey (Türkiye), 35100
    • Recruiting
    • Ege University Medical Faculty
    • Contact: Use Central Contact
  • Gaziantep, Turkey (Türkiye), 27310
    • Recruiting
    • Gaziantep University Şahinbey Research and Practice Hospital
    • Contact: Use Central Contact
  • Seyhan, Turkey (Türkiye), 01130
    • Recruiting
    • Özel Acibadem Adana Hastanesi
    • Contact: Use Central Contact
• United States
  • California
    • San Diego, California, United States, 92121
      • Recruiting
      • University of California, San Diego (UCSD)
      • Contact: Use Central Contact
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • Recruiting
      • University of Michigan
      • Contact: Use Central Contact

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Considered legally an adult, as defined by country regulations.
• Has congenital hemophilia B with known severe or moderately severe FIX deficiency (less than or equal to [<=] 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 greater than (>) 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 adhere to contraception guidelines.
• 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 (based on central laboratory results) of total bilirubin > 2 × the upper limit of normal (ULN) (except if caused by Gilbert's syndrome).
• Screening or Visit L-Final laboratory values (based on central laboratory results) of any of the following laboratory abnormalities:
• a) ALT > 2 × the ULN
• b) AST > 2 × the ULN
• c) Alkaline phosphatase > 2 × the ULN
• d) Serum creatinine > 2 × the ULN
• e) Hemoglobin less than (<) 8 g/dL
• Any condition other than hemophilia B resulting in an increased bleeding tendency.
• Thrombocytopenia, defined as a platelet count <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 AAV5 gene therapy treatment.
• Receipt of an experimental agent or device within 60 days before Screening until the end of the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: CSL222; Participants will receive CSL222 as a single intravenous (IV) infusion of 2 × 10^13 genome copies per kilogram (gc/kg) on Day 1.	Genetic: CSL222 (AAV5-hFIXco-Padua); Administered as a single IV infusion.; Other Names: Etranacogene dezaparvovec

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Annualized Bleeding Rate (ABR)	The total bleeding episodes will be analyzed. ABR is calculated as the total bleeding episodes divided by the total time at risk.	Months 7 to 18 after CSL222 treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Annualized consumption of FIX replacement therapy		Months 7 to 18 after CSL222 treatment
Annualized infusion rate of FIX replacement therapy		Months 7 to 18 after CSL222 treatment
ABR for spontaneous bleeding episodes		Months 7 to 18 after CSL222 treatment
ABR for joint bleeding episodes		Months 7 to 18 after CSL222 treatment
ABR for FIX-treated bleeding episodes		Months 7 to 18 after CSL222 treatment
Correlation analysis of FIX activity levels with baseline AAV5 NAb titers		Months 7 to 18 after CSL222 treatment
Change in the EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) Visual Analogue Scale (VAS) Overall Score	The EQ-5D-5L questionnaire visual analogue scale (VAS) measures overall health status on a vertical VAS ranging from 0 to 100. A higher score indicates better quality of life. The change from baseline in the EQ-5D-5L VAS score will be determined.	Baseline and up to 18 months after CSL222 treatment
Change in the EQ-5D-5L Index Scores	The EQ-5D-5L questionnaire descriptive system of health-related quality of life consists of 5 dimensions (mobility, self-care, usual activities, pain/discomfort, anxiety/depression) for which responses will be recorded on 5 levels of severity (no problems, slight problems, moderate problems, severe problems, and extreme problems). The responses will be converted into a single index utility score (typically between -0.6 and 1). A higher score indicates better quality of life. The change from baseline in the EQ-5D-5L index score will be determined.	Baseline and up to 18 months after CSL222 treatment
Number of participants with Treatment Emergent Adverse Events (TEAEs)		Up to 60 months after CSL222 treatment
Percentage of participants with TEAEs		Up to 60 months after CSL222 treatment
Number of TEAEs		Up to 60 months after CSL222 treatment
Change in Liver ultrasound		Up to 60 months after CSL222 treatment
Number of participants who develop Factor IX (FIX) Inhibitors		Up to 60 months after CSL222 treatment
Percentage of participants who develop FIX Inhibitors		Up to 60 months after CSL222 treatment
Change in hematology and biochemistry parameters		Up to 60 months after CSL222 treatment
Number of participants with clinically significant increase in Alanine Aminotransferase (ALT) or Aspartate Aminotransferase (AST)		Up to 60 months after CSL222 treatment
Percentage of participants with clinically significant increase in ALT or AST		Up to 60 months after CSL222 treatment
Corticosteroid use for ALT or AST increases after CSL222 treatment		Up to 60 months after CSL222 treatment
Number of participants with clinically significant Alpha-fetoprotein (AFP)		Baseline and up to 60 months after CSL222 treatment
Percentage of participants with clinically significant AFP		Baseline and up to 60 months after CSL222 treatment
Number of participants with infusion related reactions or hypersensitivity reactions		Throughout CSL222 infusion period and up to 60 months after CSL222 treatment
Percentage of participants with infusion related reactions or hypersensitivity reactions		Throughout CSL222 infusion period and up to 60 months after CSL222 treatment
Change in the Uncontaminated Endogenous FIX activity		Baseline and up to Months 6, 12, and 18 after CSL222 treatment
Number of participants remaining free of continuous FIX prophylaxis		Months 7 to 18 after CSL222 treatment
Percentage of participants remaining free of continuous FIX prophylaxis		Months 7 to 18 after CSL222 treatment
Number of participants with new target joints and resolved pre-existing target joints	Target joint is defined as 3 or more spontaneous bleeding episodes into a single joint.	Months 7 to 18 after CSL222 treatment
Number of participants with zero bleeding episodes and zero FIX-treated bleeding episodes		Months 7 to 18 after CSL222 treatment
Percentage of participants with zero bleeding episodes and zero FIX-treated bleeding episodes		Months 7 to 18 after CSL222 treatment
Number of Participants with Uncontaminated Endogenous FIX Activity of Greater than or Equal to (>=) 5%		Months 7 to 18 after CSL222 treatment
Percentage of Participants with Uncontaminated Endogenous FIX Activity of >= 5%		Months 7 to 18 after CSL222 treatment

Collaborators and Investigators

• Sponsor: CSL Behring
• Investigators: Study Director: Study Director, CSL Behring

Study record dates

Study Major Dates

• Study Start (Actual): January 30, 2024
• Primary Completion (Estimated): October 4, 2028
• Study Completion (Estimated): April 2, 2032

Study Registration Dates

• First Submitted: August 1, 2023
• First Submitted That Met QC Criteria: August 14, 2023
• First Posted (Actual): August 22, 2023

Study Record Updates

• Last Update Posted (Actual): March 17, 2026
• Last Update Submitted That Met QC Criteria: March 16, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Genetic Diseases, Inborn; Hematologic Diseases; Blood Coagulation Disorders; Hemorrhagic Disorders; Genetic Diseases, X-Linked; Blood Coagulation Disorders, Inherited; Coagulation Protein Disorders; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Hemic and Lymphatic Diseases; Hemophilia B
• Other Study ID Numbers: CSL222_3005; 2023-509590-23-00 (Ctis)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: CSL will consider on a case-by-case basis requests to share Individual Patient Data (IPD) with external bona-fide, qualified scientific and medical researchers. For information on the process and requirements for submitting a voluntary data sharing request for IPD, please contact CSL at clinicaltrials@cslbehring.com.
• IPD Sharing Time Frame: Requests for IPD will generally be considered once review by major regulatory authorities (ie FDA, EMA) is complete and the primary publication is available.

IPD Sharing Access Criteria

Proposed research should seek to answer a previously unanswered important medical or scientific question.

Applicable country specific privacy and other laws and regulations will be considered and may prevent sharing of IPD.

If the request is approved and the researcher has executed an appropriate data sharing agreement, IPD that has been appropriately anonymized will be available.

• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No