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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)

Primary Purpose

Hemophilia B

Status
Recruiting
Phase
Phase 3
Locations
United States
Study Type
Interventional
Intervention
CSL222 (AAV5-hFIXco-Padua)
Sponsored by
CSL Behring
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Hemophilia B

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • University of Michigan - 84000285Recruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

CSL222

Arm Description

Participants will receive CSL222 as a single intravenous (IV) infusion of 2 × 10^13 genome copies per kilogram (gc/kg) on Day D.

Outcomes

Primary Outcome Measures

Annualized Bleeding Rate (ABR)
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

Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs (TESAEs), and TEAEs of Special Interest (TEAESIs)
Percentage of Participants With TEAEs, TESAEs, and TEAESIs
Number of TEAEs, TESAEs, and TEAESIs
Number of Participants with Change From Baseline in Abdominal Ultrasound
Number of Participants Who Develop Factor IX (FIX) Inhibitors
Percentage of Participants who Develop FIX Inhibitors
Number of Participants with Clinically Significant Hematology and Serum Chemistry Parameters
Percentage of Participants With Clinically Significant Hematology and Serum Chemistry Parameters
Number of Participants with Clinically Significant Change in Alanine Aminotransferase (ALT) or Aspartate Aminotransferase (AST)
Percentage of Participants With Clinically Significant Change in ALT or AST
Number of Participants Treated With Corticosteroids For Change in ALT or AST
Percentage of Participants Treated With Corticosteroids For Change in ALT or AST
Number of Participants With Clinically Significant Alpha-fetoprotein (AFP)
Percentage of Participants With Clinically Significant AFP
Number of Participants with Infusion Related Reactions or Hypersensitivity Reactions
Percentage of Participants With Infusion Related Reactions or Hypersensitivity Reactions
Number of Participants With the Endogenous FIX Activity
Change From Baseline in the Endogenous FIX Activity
Annualized Consumption of FIX Replacement Therapy
Annualized Infusion Rate of FIX Replacement Therapy
Percentage of Participants Remaining Free of Previous Continuous Routine FIX Prophylaxis
ABR for Spontaneous Bleeding Episodes, Joint Bleeding Episodes, and FIX-treated Bleeding Episodes Separately
Correlation Analysis of FIX Activity Levels
Number of Participants With New Target Joints and Resolved New or Preexisting Target Joints
Target joint is defined as 3 or more spontaneous bleeding episodes into a single joint.
Number of Participants With Zero Bleeds Following Stable FIX Expression
Percentage of Participants With Zero Bleeds Following Stable FIX Expression
Hemophilia Quality of Life Questionnaire (Hem-A-QoL) Total Score and Treatment Domain Score
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.
Change From Baseline in the Hem-A-QoL Total Score and Treatment Domain Score
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.
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.
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.
Change from Baseline in the EQ-5D-5L VAS 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.
Change From Baseline 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.

Full Information

First Posted
August 1, 2023
Last Updated
October 24, 2023
Sponsor
CSL Behring
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1. Study Identification

Unique Protocol Identification Number
NCT06003387
Brief Title
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

2. Study Status

Record Verification Date
October 2023
Overall Recruitment Status
Recruiting
Study Start Date
October 2, 2023 (Actual)
Primary Completion Date
October 2028 (Anticipated)
Study Completion Date
October 2028 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
CSL Behring

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hemophilia B

7. Study Design

Primary Purpose
Prevention
Study Phase
Phase 3
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
35 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
CSL222
Arm Type
Experimental
Arm Description
Participants will receive CSL222 as a single intravenous (IV) infusion of 2 × 10^13 genome copies per kilogram (gc/kg) on Day D.
Intervention Type
Genetic
Intervention Name(s)
CSL222 (AAV5-hFIXco-Padua)
Other Intervention Name(s)
Etranacogene dezaparvovec
Intervention Description
Administered as a single IV infusion.
Primary Outcome Measure Information:
Title
Annualized Bleeding Rate (ABR)
Description
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.
Time Frame
Post-dose: Months 7 to 18
Secondary Outcome Measure Information:
Title
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
Title
Percentage of Participants With TEAEs, TESAEs, and TEAESIs
Time Frame
Post-dose: At Months 6,12, and 18
Title
Number of TEAEs, TESAEs, and TEAESIs
Time Frame
Post-dose: At Months 6,12, and 18
Title
Number of Participants with Change From Baseline in Abdominal Ultrasound
Time Frame
Baseline up to 18 months post dose
Title
Number of Participants Who Develop Factor IX (FIX) Inhibitors
Time Frame
Up to 18 months post dose
Title
Percentage of Participants who Develop FIX Inhibitors
Time Frame
Up to 18 months post dose
Title
Number of Participants with Clinically Significant Hematology and Serum Chemistry Parameters
Time Frame
Up to 18 months post dose
Title
Percentage of Participants With Clinically Significant Hematology and Serum Chemistry Parameters
Time Frame
Up to 18 months post dose
Title
Number of Participants with Clinically Significant Change in Alanine Aminotransferase (ALT) or Aspartate Aminotransferase (AST)
Time Frame
Up to 18 months post dose
Title
Percentage of Participants With Clinically Significant Change in ALT or AST
Time Frame
Up to 18 months post dose
Title
Number of Participants Treated With Corticosteroids For Change in ALT or AST
Time Frame
Up to 18 months post dose
Title
Percentage of Participants Treated With Corticosteroids For Change in ALT or AST
Time Frame
Up to 18 months post dose
Title
Number of Participants With Clinically Significant Alpha-fetoprotein (AFP)
Time Frame
Up to 18 months post dose
Title
Percentage of Participants With Clinically Significant AFP
Time Frame
Up to 18 months post dose
Title
Number of Participants with Infusion Related Reactions or Hypersensitivity Reactions
Time Frame
Up to 18 months post dose
Title
Percentage of Participants With Infusion Related Reactions or Hypersensitivity Reactions
Time Frame
Up to 18 months post dose
Title
Number of Participants With the Endogenous FIX Activity
Time Frame
Post-dose: At Months 6, 12, and 18
Title
Change From Baseline in the Endogenous FIX Activity
Time Frame
Baseline up to Months 6, 12, and 18 post dose
Title
Annualized Consumption of FIX Replacement Therapy
Time Frame
Post-dose: Months 7 to 18
Title
Annualized Infusion Rate of FIX Replacement Therapy
Time Frame
Post-dose: Months 7 to 18
Title
Percentage of Participants Remaining Free of Previous Continuous Routine FIX Prophylaxis
Time Frame
Post-dose: Months 7 to 18
Title
ABR for Spontaneous Bleeding Episodes, Joint Bleeding Episodes, and FIX-treated Bleeding Episodes Separately
Time Frame
Post-dose: Months 7 to 18
Title
Correlation Analysis of FIX Activity Levels
Time Frame
Post-dose: Months 6 to 18
Title
Number of Participants With New Target Joints and Resolved New or Preexisting Target Joints
Description
Target joint is defined as 3 or more spontaneous bleeding episodes into a single joint.
Time Frame
Post-dose: Months 7 to 18
Title
Number of Participants With Zero Bleeds Following Stable FIX Expression
Time Frame
Post-dose: Months 7 to 18
Title
Percentage of Participants With Zero Bleeds Following Stable FIX Expression
Time Frame
Post-dose: Months 7 to 18
Title
Hemophilia Quality of Life Questionnaire (Hem-A-QoL) Total Score and Treatment Domain Score
Description
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.
Time Frame
Post-dose: Months 6 to 18
Title
Change From Baseline in the Hem-A-QoL Total Score and Treatment Domain Score
Description
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.
Time Frame
Baseline, Months 6 to 18 post dose
Title
EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) Visual Analogue Scale (VAS) Overall Score
Description
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.
Time Frame
Post-dose: Months 6 to 18
Title
EQ-5D-5L Index Scores
Description
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.
Time Frame
Post-dose: Months 6 to 18
Title
Change from Baseline in the EQ-5D-5L VAS Score
Description
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.
Time Frame
Baseline, Months 6 to 18 post dose
Title
Change From Baseline in the EQ-5D-5L Index Scores
Description
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.
Time Frame
Baseline, Months 6 to 18 post dose

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility 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.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Trial Registration Coordinator
Phone
1-610-878-4000
Email
clinicaltrials@cslbehring.com
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Study Director
Organizational Affiliation
CSL Behring LLC
Official's Role
Study Director
Facility Information:
Facility Name
University of Michigan - 84000285
City
Ann Arbor
State/Province
Michigan
ZIP/Postal Code
48109
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Use Central Contact

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing 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.
IPD Sharing 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.
IPD Sharing 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.

Learn more about this trial

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)

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