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)

• ClinicalTrials.gov Identifier: NCT06003387
• Recruitment Status: Recruiting
• First Posted: August 22, 2023
• Sponsor: CSL Behring
• Information provided by (Responsible Party): CSL Behring

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Hemophilia B	Genetic: CSL222 (AAV5-hFIXco-Padua)	Phase 3

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 35 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Prevention
• 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
• Actual Study Start Date: January 30, 2024
• Estimated Primary Completion Date: October 2028
• Estimated Study Completion Date: October 2028

Arms and Interventions

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 D.	Genetic: CSL222 (AAV5-hFIXco-Padua); Administered as a single IV infusion.; Other Name: Etranacogene dezaparvovec

Outcome Measures

Primary Outcome Measures :

1. Annualized Bleeding Rate (ABR) [ Time Frame: Post-dose: Months 7 to 18 ]
   The total, spontaneous, joint, and Factor IX (FIX)-treated bleeding episodes will be analyzed. ABR is calculated as the total bleeding episodes divided by the total time at risk.

Secondary Outcome Measures :

1. Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs (TESAEs), and TEAEs of Special Interest (TEAESIs) [ Time Frame: Post-dose: At Months 6,12, and 18 ]
2. Percentage of Participants With TEAEs, TESAEs, and TEAESIs [ Time Frame: Post-dose: At Months 6,12, and 18 ]
3. Number of TEAEs, TESAEs, and TEAESIs [ Time Frame: Post-dose: At Months 6,12, and 18 ]
4. Number of Participants with Change From Baseline in Abdominal Ultrasound [ Time Frame: Baseline up to 18 months post dose ]
5. Number of Participants Who Develop Factor IX (FIX) Inhibitors [ Time Frame: Up to 18 months post dose ]
6. Percentage of Participants who Develop FIX Inhibitors [ Time Frame: Up to 18 months post dose ]
7. Number of Participants with Clinically Significant Hematology and Serum Chemistry Parameters [ Time Frame: Up to 18 months post dose ]
8. Percentage of Participants With Clinically Significant Hematology and Serum Chemistry Parameters [ Time Frame: Up to 18 months post dose ]
9. Number of Participants with Clinically Significant Change in Alanine Aminotransferase (ALT) or Aspartate Aminotransferase (AST) [ Time Frame: Up to 18 months post dose ]
10. Percentage of Participants With Clinically Significant Change in ALT or AST [ Time Frame: Up to 18 months post dose ]
11. Number of Participants Treated With Corticosteroids For Change in ALT or AST [ Time Frame: Up to 18 months post dose ]
12. Percentage of Participants Treated With Corticosteroids For Change in ALT or AST [ Time Frame: Up to 18 months post dose ]
13. Number of Participants With Clinically Significant Alpha-fetoprotein (AFP) [ Time Frame: Up to 18 months post dose ]
14. Percentage of Participants With Clinically Significant AFP [ Time Frame: Up to 18 months post dose ]
15. Number of Participants with Infusion Related Reactions or Hypersensitivity Reactions [ Time Frame: Up to 18 months post dose ]
16. Percentage of Participants With Infusion Related Reactions or Hypersensitivity Reactions [ Time Frame: Up to 18 months post dose ]
17. Number of Participants With the Endogenous FIX Activity [ Time Frame: Post-dose: At Months 6, 12, and 18 ]
18. Change From Baseline in the Endogenous FIX Activity [ Time Frame: Baseline up to Months 6, 12, and 18 post dose ]
19. Annualized Consumption of FIX Replacement Therapy [ Time Frame: Post-dose: Months 7 to 18 ]
20. Annualized Infusion Rate of FIX Replacement Therapy [ Time Frame: Post-dose: Months 7 to 18 ]
21. Percentage of Participants Remaining Free of Previous Continuous Routine FIX Prophylaxis [ Time Frame: Post-dose: Months 7 to 18 ]
22. ABR for Spontaneous Bleeding Episodes, Joint Bleeding Episodes, and FIX-treated Bleeding Episodes Separately [ Time Frame: Post-dose: Months 7 to 18 ]
23. Correlation Analysis of FIX Activity Levels [ Time Frame: Post-dose: Months 6 to 18 ]
24. Number of Participants With New Target Joints and Resolved New or Preexisting Target Joints [ Time Frame: Post-dose: Months 7 to 18 ]
    Target joint is defined as 3 or more spontaneous bleeding episodes into a single joint.
25. Number of Participants With Zero Bleeds Following Stable FIX Expression [ Time Frame: Post-dose: Months 7 to 18 ]
26. Percentage of Participants With Zero Bleeds Following Stable FIX Expression [ Time Frame: Post-dose: Months 7 to 18 ]
27. Hemophilia Quality of Life Questionnaire (Hem-A-QoL) Total Score and Treatment Domain Score [ Time Frame: Post-dose: Months 6 to 18 ]
    The Hem-A-QoL (Hemophilia Quality of Life Questionnaire for Adults) consists of 46 items comprising 10 domains: physical health, feelings, treatment, work and school, dealing with hemophilia, family planning, future, partnerships and sexuality, sports and leisure, and view of yourself for which responses will be recorded from 5 options (never, seldom, sometimes, often, and always; for some items, there is also a "not applicable" option). The Hem-A-QoL Total Score and Treatment Domain Score range from 0 to 100, with lower scores reflecting a better quality of life.
28. Change From Baseline in the Hem-A-QoL Total Score and Treatment Domain Score [ Time Frame: Baseline, Months 6 to 18 post dose ]
    The Hem-A-QoL consists of 46 items comprising 10 domains: physical health, feelings, treatment, work and school, dealing with hemophilia, family planning, future, partnerships and sexuality, sports and leisure, and view of yourself for which responses will be recorded from 5 options (never, seldom, sometimes, often, and always; for some items, there is also a "not applicable" option). The Hem-A-QoL Total Score and Treatment Domain Score range from 0 to 100, with lower scores reflecting a better quality of life. The change from baseline in the Hem-A-QoL Total Score and Treatment Domain Score will be determined.
29. EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) Visual Analogue Scale (VAS) Overall Score [ Time Frame: Post-dose: Months 6 to 18 ]
    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.
30. EQ-5D-5L Index Scores [ Time Frame: Post-dose: Months 6 to 18 ]
    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.
31. Change from Baseline in the EQ-5D-5L VAS Score [ Time Frame: Baseline, Months 6 to 18 post dose ]
    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.
32. Change From Baseline in the EQ-5D-5L Index Scores [ Time Frame: Baseline, Months 6 to 18 post dose ]
    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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• 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 Screening or Visit L (lead-in period)-Final (based on central laboratory results)
• Screening and 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 upper limit of normal (ULN) at Screening and Visit L-Final (based on central laboratory results)
• Any condition other than hemophilia B resulting in an increased bleeding tendency
• Any uncontrolled or untreated infection (human immunodeficiency virus [HIV], hepatitis C, etc.) or any other significant concurrent, uncontrolled medical condition evaluated by the investigator to interfere with adherence to the clinical study protocol or with the degree of tolerance to CSL222.
• Thrombocytopenia, defined as a platelet count below 50 × 10^9/L, at Screening and Visit L-Final (based on central laboratory results)
• Known history of allergy to corticosteroids or known medical condition that would require chronic administration of steroids.
• Known uncontrolled allergic conditions or allergy / hypersensitivity to any component of the CSL222 excipients
• Previous gene therapy treatment
• Receipt of an experimental agent or device within 60 days before Screening until the end of the study.
• Note: Other protocol pre-specified exclusion criteria may apply.

Contacts and Locations

Contacts

Contact: Trial Registration Coordinator; 1-610-878-4000; clinicaltrials@cslbehring.com

Locations

United States, Michigan

University of Michigan - 84000285; Recruiting

Ann Arbor, Michigan, United States, 48109

Contact: Use Central Contact

Canada, Ontario

McMaster University - Hamilton - 12400017; Recruiting

Hamilton, Ontario, Canada, L8N 3Z5

Contact: Use Central Contact

Israel

Sheba Medical Center - 37600004; Recruiting

Tel Hashomer, Israel, 5265601

Contact: Use Central Contact

Sponsors and Collaborators

CSL Behring

Investigators

• Study Director: Study Director; CSL Behring LLC

More Information

• Responsible Party: CSL Behring
• ClinicalTrials.gov Identifier: NCT06003387
• Other Study ID Numbers: CSL222_3005
• First Posted: August 22, 2023
• Last Update Posted: May 16, 2024
• Last Verified: May 2024

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes

Plan Description

CSL will consider requests to share Individual Patient Data (IPD) from systematic review groups or bona-fide researchers. For information on the process and requirements for submitting a voluntary data sharing request for IPD, please contact CSL at clinicaltrials@cslbehring.com.

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.

• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP)
• Time Frame: IPD requests may be submitted to CSL no earlier than 12 months after publication of the results of this study via an article made available on a public website.

Access Criteria

Requests may only be made by systematic review groups or bona-fide researchers whose proposed use of the IPD is non-commercial in nature and has been approved by an internal review committee.

An IPD request will not be considered by CSL unless the proposed research question seeks to answer a significant and unknown medical science or patient care question as determined by CSL's internal review committee.

The requesting party must execute an appropriate data sharing agreement before IPD will be made available.

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Hemophilia A; Hemophilia B; Blood Coagulation Disorders, Inherited; Blood Coagulation Disorders; Hematologic Diseases; Coagulation Protein Disorders; Hemorrhagic Disorders; Genetic Diseases, Inborn; Genetic Diseases, X-Linked