A Study to Evaluate the Efficacy and Safety of Factor IX Gene Therapy With PF-06838435 in Adult Males With Moderately Severe to Severe Hemophilia B (BENEGENE-2)

• ClinicalTrials.gov Identifier: NCT03861273
• Recruitment Status: Active, not recruiting
• First Posted: March 4, 2019
• Results First Posted: March 27, 2024
• Last Update Posted: May 3, 2024
• Sponsor: Pfizer
• Information provided by (Responsible Party): Pfizer

Study Description

Brief Summary:

This study will evaluate the efficacy and safety of PF-06838435 (a gene therapy drug) in adult male participants with moderately severe to severe hemophilia B (participants that have a Factor IX circulating activity of 2% or less). The gene therapy is designed to introduce genetic material into cells to compensate for missing or non-functioning Factor IX. Eligible study participants will have completed a minimum 6 months of routine Factor IX prophylaxis therapy during the lead in study (C0371004). Participants will be dosed once (intravenously) and will be evaluated over the course of 6 years. The main objective of the study will evaluate the annualized bleeding rate [ABR] for participants treated with gene therapy versus standard of care (SOC) therapy (FIX prophylaxis replacement regimen).

Condition or disease	Intervention/treatment	Phase
Hemophilia B	Biological: PF-06838435/ fidanacogene elaparvovec	Phase 3

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 51 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase 3, Open-label, Single-arm Study to Evaluate Efficacy and Safety of FIX Gene Transfer With PF-06838435 (rAAV-Spark100-hFIX-R338L) in Adult Male Participants With Moderately Severe to Severe Hemophilia B (FIX:C =2%) (BeneGene-2)
• Actual Study Start Date: July 29, 2019
• Actual Primary Completion Date: November 16, 2022
• Estimated Study Completion Date: September 5, 2030

Arms and Interventions

Arm	Intervention/treatment
Experimental: PF-06838435/ fidanacogene elaparvovec	Biological: PF-06838435/ fidanacogene elaparvovec; Gene Therapy

Outcome Measures

Primary Outcome Measures :

1. Annualized Bleeding Rate (ABR) for Total Bleeds (Treated and Untreated) From Week 12 to Month 15 [ Time Frame: Pre-infusion period: minimum of 6 months through first dose of current study, an average of 1.31 years (FIX Prophylaxis arm); Week 12 to Month 15 post infusion in current study (PF-06838435 arm) ]
   ABR = number of total bleeding episodes on study during the given time period) *365.25/ (Date of last day - date of first day +1) in that time period. Surgical procedures were excluded from summary/analyses. Treated Bleed: An event necessitating administration of coagulation factor within 72 hours of signs or symptoms of bleeding (protocol definition, unless specifically referring to untreated bleed). Untreated Bleed: A bleeding event not necessitating administration of coagulation factor within 72 hours of signs or symptoms of bleeding. This outcome measure compared data collected from lead-in study C0371004 and from current study C0371002. Pre-infusion period = at least 6 months of prospectively collected data while receiving FIX prophylaxis replacement therapy in lead-in study C0371004 up to dosing in current study C0371002.

Secondary Outcome Measures :

1. ABR for Treated Bleeds From Week 12 to Month 15 [ Time Frame: Pre-infusion period: minimum of 6 months through first dose of current study, an average of 1.31 years (FIX Prophylaxis arm); Week 12 to Month 15 post infusion in current study (PF-06838435 arm) ]
   ABR = number of total bleeding episodes on study during the given time period) *365.25/ (Date of last day - date of first day +1) in that time period. Surgical procedures were excluded from summary/analyses. Treated Bleed: An event necessitating administration of coagulation factor within 72 hours of signs or symptoms of bleeding (protocol definition, unless specifically referring to untreated bleed). This outcome measure compared data collected from lead-in study C0371004 and from current study C0371002. Pre-infusion period = at least 6 months of prospectively collected data while receiving FIX prophylaxis replacement therapy in lead-in study C0371004 up to dosing in current study C0371002.
2. Annualized Infusion Rate (AIR) of Exogenous FIX From Week 12 to Month 15 [ Time Frame: Pre-infusion period: minimum of 6 months through first dose of current study, an average of 1.31 years (FIX Prophylaxis arm); Week 12 to Month 15 post infusion in current study (PF-06838435 arm) ]
   AIR = number of exogenous infusions (for any reason) received during given time period *365.25/ (Date of last day - date of first day +1) in that time period. This outcome measure compared data collected from lead-in study C0371004 and from current study C0371002. Pre-infusion period = at least 6 months of prospectively collected data while receiving FIX prophylaxis replacement therapy in lead-in study C0371004 up to dosing in current study C0371002.
3. Steady State Circulating Factor IX (FIX:C) From Week 12 to Month 15 [ Time Frame: Week 12 to Month 15 ]
   The certified central clinical laboratory analyzed the sample by two one-stage assays and a chromogenic assay. The first one-stage assay was performed on BCSXP analyzer with Actin-FSL reagent. The second one-stage assay used the same analyzer but SynthAsil as reagent. Data reported in this Outcome Measure is the geometric mean of all assessments from week 12 to Month 15.
4. Circulating Factor IX (FIX:C) at Week 12, Week 24, Week 65 [ Time Frame: Week 12, Week 24, Week 65 ]
   The certified central clinical laboratory analyzed the sample by two one-stage assays and a chromogenic assay. The first one-stage assay was performed on BCSXP analyzer with Actin-FSL reagent. The second one-stage assay used the same analyzer but SynthAsil as reagent.
5. Annualized Factor IX (FIX) Consumption From Week 12 to Month 15 [ Time Frame: Pre-infusion period: minimum of 6 months through first dose of current study, an average of 1.31 years (FIX Prophylaxis arm); Week 12 to Month 15 post infusion in current study (PF-06838435 arm) ]
   Annualized FIX consumption was reported by International Units per kilogram (IU/kg). This outcome measure compared data collected from lead-in study C0371004 and from current study C0371002. Pre-infusion period = at least 6 months of prospectively collected data while receiving FIX prophylaxis replacement therapy in lead-in study C0371004 up to dosing in current study C0371002. Data reported in this Outcome Measure is average of all assessments from Week 12 to Month 15.
6. ABR for Spontaneous Bleeds From Week 12 to Month 15 [ Time Frame: Pre-infusion period: minimum of 6 months through first dose of current study, an average of 1.31 years (FIX Prophylaxis arm); Week 12 to Month 15 post infusion in current study (PF-06838435 arm) ]
   ABR = number of total bleeding episodes on study during the given time period) *365.25/ (Date of last day - date of first day +1) in that time period. Surgical procedures were excluded from summary/analyses. Surgical procedures were excluded from summary/analyses. Spontaneous Bleeds: Bleeding for no apparent/known reason particularly into the joints, muscles, and soft tissues. This outcome measure compared data collected from lead-in study C0371004 and from current study C0371002. Pre-infusion period = at least 6 months of prospectively collected data while receiving FIX prophylaxis replacement therapy in lead-in study C0371004 up to dosing in current study C0371002.
7. ABR for Traumatic Bleeds From Week 12 to Month 15 [ Time Frame: Pre-infusion period: minimum of 6 months through first dose of current study, an average of 1.31 years (FIX Prophylaxis arm); Week 12 to Month 15 post infusion in current study (PF-06838435 arm) ]
   ABR = number of total bleeding episodes on study during the given time period) *365.25/ (Date of last day - date of first day +1) in that time period. Surgical procedures were excluded from summary/analyses. Surgical procedures were excluded from summary/analyses. Traumatic Bleeds: Bleeding event occurring for an apparent/known reason. This outcome measure compared data collected from lead-in study C0371004 and from current study C0371002. Pre-infusion period = at least 6 months of prospectively collected data while receiving FIX prophylaxis replacement therapy in lead-in study C0371004 up to dosing in current study C0371002.
8. ABR for Untreated Bleeds From Week 12 to Month 15 [ Time Frame: Pre-infusion period: minimum of 6 months through first dose of current study, an average of 1.31 years (FIX Prophylaxis arm); Week 12 to Month 15 post infusion in current study (PF-06838435 arm) ]
   ABR = number of total bleeding episodes on study during the given time period) *365.25/ (Date of last day - date of first day +1) in that time period. Surgical procedures were excluded from summary/analyses. Surgical procedures were excluded from summary/analyses. Untreated Bleed: A bleeding event not necessitating administration of coagulation factor within 72 hours of signs or symptoms of bleeding. This outcome measure compared data collected from lead-in study C0371004 and from current study C0371002. Pre-infusion period = at least 6 months of prospectively collected data while receiving FIX prophylaxis replacement therapy in lead-in study C0371004 up to dosing in current study C0371002.
9. Number of Target Joint Bleeds From Week 12 to Month 15 [ Time Frame: Pre-infusion period: minimum of 6 months through first dose of current study, an average of 1.31 years (FIX Prophylaxis arm); Week 12 to Month 15 post infusion in current study (PF-06838435 arm) ]
   Target Joint: Defined as a major joint (e.g., hip, elbow, wrist, shoulder, knee, and ankle) into which repeated bleeds occurred (three or more spontaneous bleeds into a single joint within a consecutive 6-month period). A target joint was considered resolved when there were =<2 bleeds into the joint within a 12-month period. Joint Bleed: A bleeding episode characterized by rapid loss of range of motion as compared with baseline that was associated with any combination of the following: pain or an unusual sensation in the joint, palpable swelling, and warmth of the skin over the joint. This outcome measure compared data collected from lead-in study C0371004 and from current study C0371002. Pre-infusion period = at least 6 months of prospectively collected data while receiving FIX prophylaxis replacement therapy in lead-in study C0371004 up to dosing in current study C0371002.
10. Percentage of the Participants Without Bleeds From Week 12 to Month 15 [ Time Frame: Week 12 to Month 15 ]
    Percentage of participants without bleeds (total bleeds and treated bleeds) were summarized by type from Week 12 to Month 15.
11. Change From Baseline in Joint Health as Measured by the Hemophilia Joint Health Score (HJHS) Instrument at Month 12 [ Time Frame: Baseline, Month 12 ]
    A qualified healthcare professional assessed six joints (left ankle, right ankle, left elbow, right elbow, left knee, right knee) scored from 0 to 20 based on: duration of swelling, muscle atrophy, crepitus, flexion loss, extension loss, instability, joint pain, and strength. Gait was scored (0 to 4) based on walking, stairs, running, hopping on one leg. Total score = sum of scores from all joints + gait score ranged from 0 to 124, with the higher the number equating to more severe joint damage.
12. Change From Baseline in Hemophilia Quality of Life (Haem A QoL) Physical Health Domain at Month 12 [ Time Frame: Baseline, Month 12 ]
    The Haem-A-QoL questionnaire contained 46 items with ten domains that assessed health in the following areas: Physical Health; Feelings; View of Self; Sports and Leisure; Work and School; Dealing with Haemophilia; Treatment; Future; Family Planning; and Partnership and Sexuality. The physical health domain was considered as the primary domain in this questionnaire, had a transformed score range from 0 to 100, with lower scores representing higher quality of life. In this Outcome Measure Physical Health domain scores of Haem A QoL are reported.
13. Change From Baseline in Hemophilia Activities List (HAL) Complex Lower Extremity Activities Component Score at Month 12 [ Time Frame: Baseline, Month 12 ]
    The HAL was a multiple domain measure of the impact of hemophilia on functional abilities in adults. The 7 domains of this instrument contained 42 items in total, as follows: lying/sitting/kneeling/standing; lower (leg) functioning; upper (arm) functioning; transportation; self-care; household tasks; and sports/leisure. Selected items from five of the domains were used to create three components: upper extremity; basic lower extremity; and complex lower extremity activities. The component score of "complex lower extremity activities" was the most important in this questionnaire, had a transformed score range from 0 to 100, higher values indicated less functional limitations in performing tasks.
14. Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs [ Time Frame: Maximum up to 6 years (Week 312) after PF-06838435 infusion ]
    Results would be posted at secondary completion date.
15. Number of Participants With Adverse Events of Special Interest [ Time Frame: Maximum up to 6 years (Week 312) after PF-06838435 infusion ]
    Results would be posted at secondary completion date.
16. Number of Participants With Positive Neutralizing Antibody (nAb) to Adeno-associated Virus Vector (AAV) and Anti-Drug Antibody (ADA) [ Time Frame: Maximum up to 6 years (Week 312) after PF-06838435 infusion ]
    Results would be posted at secondary completion date.
17. ABR for Total Bleeds (Treated and Untreated) Through the Study [ Time Frame: Maximum up to 6 years (Week 312) after PF-06838435 infusion ]
    Results would be posted at secondary completion date.
18. ABR for Treated Bleeds Through the Study [ Time Frame: Maximum up to 6 years (Week 312) after PF-06838435 infusion ]
    Results would be posted at secondary completion date.
19. AIR of Exogenous Factor IX Through the Study [ Time Frame: Maximum up to 6 years (Week 312) after PF-06838435 infusion ]
    Results would be posted at secondary completion date.
20. FIX: C Level Through the Study [ Time Frame: Maximum up to 6 years (Week 312) after PF-06838435 infusion ]
    Results would be posted at secondary completion date.
21. Annualized Factor IX Consumption Through the Study [ Time Frame: Maximum up to 6 years (Week 312) after PF-06838435 infusion ]
    Results would be posted at secondary completion date.
22. ABR for Spontaneous and Traumatic, and Untreated Bleeds Through the Study [ Time Frame: Maximum up to 6 years (Week 312) after PF-06838435 infusion ]
    Results would be posted at secondary completion date.
23. Change From Baseline in Joint Health as Measured by the HJHS Instrument Through the Study [ Time Frame: Baseline, 6 years ]
    Results would be posted at secondary completion date.
24. Number of Target Joint Bleeds Through the Study [ Time Frame: Maximum up to 6 years (Week 312) after PF-06838435 infusion ]
    Results would be posted at secondary completion date.
25. Change From Baseline in Haem A QoL Physical Health Domain Through the Study [ Time Frame: Baseline, Maximum up to 6 years (Week 312) after PF-06838435 infusion ]
    Results would be posted at secondary completion date.
26. Change From Baseline in HAL Complex Lower Extremity Activities Component Score Through the Study [ Time Frame: Baseline, 6 years ]
    Results would be posted at secondary completion date.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 65 Years (Adult, Older Adult)
• Sexes Eligible for Study: Male
• Gender Based Eligibility: Yes
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria

• Males who completed 6 months of Factor IX prophylaxis therapy during the lead-in study (C0371004) prior to providing consent at the screening visit for this study.
• Documented moderately severe to severe hemophilia B (Factor IX activity < =2%)
• Previous experience with FIX therapy (=>50 documented exposure days to a FIX protein product)
• Suspension of prophylaxis therapy for hemophilia B after administration of the study drug
• Laboratory values (hemoglobin, platelets and creatinine) within study specified limits
• Agree to contraception until components of the drug are eliminated from their body
• Capable of giving signed informed consent

Exclusion Criteria

• Anti-AAVRh74var neutralizing antibodies (nAb) titer above the established threshold (ie, positive for nAb).
• History of inhibitor to Factor IX or inhibitor detected during screening. Clinical signs or symptoms of decreased response to Factor IX
• Hypersensitivity to Factor IX replacement product or IV immunoglobulin administration
• History of chronic infection or other chronic disease
• Any conditions associated with increased thromboembolic risk
• Concurrent clinically significant major disease or condition unsuitable for participation and/or may interfere with the interpretation of study results
• Laboratory values at screening visit that are abnormal or outside acceptable study limits
• Current unstable liver or biliary disease
• Currently on antiviral therapy for hepatitis B or C
• Planned surgical procedure requiring Factor IX surgical prophylactic factor treatment 15 months from screening visit
• Use of restricted therapies (e.g., blood products, acetylsalicylic acid [aspirin] or ibuprofen, other investigational therapy, and by-passing agents)
• Previously dosed in a gene therapy research trial at any time or in an interventional clinical study within 12 weeks of screening visit
• Active hepatitis B or C; hepatitis B surface antigen, hepatitis B virus deoxyribonucleic acid positivity, or hepatitis C virus ribonucleic acid positivity
• Significant liver disease
• Serological evidence of HIV1 or HIV2 infection with either CD4+ cell count <=200 mm3 and/or a viral load >20 copies/mL
• Study and sponsor staff involved in the conduct of the study and their families
• Unable to comply with study procedures
• Sensitivity to heparin or heparin induced thrombocytopenia
• Sensitivity to any of the study interventions, or components thereof, or drug or other allergy

Contacts and Locations

Locations

United States, California

University of California, San Francisco - Clinical Research Center

San Francisco, California, United States, 94143

University of California, San Francisco - Outpatient Hematology Clinic

San Francisco, California, United States, 94143

United States, Colorado

Hemophilia and Thrombosis Center at the University of Colorado Anschutz Medical Campus

Aurora, Colorado, United States, 80045

United States, Indiana

Indiana Hemophilia & Thrombosis Center, Inc.

Indianapolis, Indiana, United States, 46260

Indiana Hemophilia and Thrombosis Center, Inc

Indianapolis, Indiana, United States, 46260

St. Vincent Hospital & Health Care Center, Inc.

Indianapolis, Indiana, United States, 46260

United States, Mississippi

Madison Radiological Group

Madison, Mississippi, United States, 39110

Mississippi Center for Advanced Medicine

Madison, Mississippi, United States, 39110

United States, Pennsylvania

Center for Human Phenomic Science CHPS

Philadelphia, Pennsylvania, United States, 19104

Center for Human Phenomic Science

Philadelphia, Pennsylvania, United States, 19104

Investigational Drug Service

Philadelphia, Pennsylvania, United States, 19104

Penn Blood Disorder Center

Philadelphia, Pennsylvania, United States, 19104

Australia, New South Wales

Royal Prince Alfred Hospital

Camperdown, New South Wales, Australia, 2050

Australia, Queensland

Royal Brisbane and Women's Hospital

Brisbane, Queensland, Australia, 4029

Australia, South Australia

Royal Adelaide Hospital

Adelaide, South Australia, Australia, 5000

Australia, Victoria

The Alfred Hospital

Melbourne, Victoria, Australia, 3004

Australia, Western Australia

Fiona Stanley Hospital

Murdoch, Western Australia, Australia, 6150

Brazil

Centro Estadual de Hemoterapia e Hematologia Marcos Daniel Santos - Hemoes

Vitoria, Espirito Santo, Brazil, 29047-105

Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo

Sao Paulo, SP, Brazil, 05403-010

Centro de Hematologia e Hemoterapia - Hemocentro de Campinas - UNICAMP

Campinas, SÃO Paulo, Brazil, 13083-878

Instituto Estadual de Hematologia Arthur de Siqueira Cavalcanti - HEMORIO

Rio de Janeiro, Brazil, 20211-030

Instituto Estadual de Hematologia Arthur de Siqueira Cavalcanti- HEMORIO

Rio de Janeiro, Brazil, 20211-030

Canada, Ontario

McMaster University Medical Centre - Hamilton Health Sciences

Hamilton, Ontario, Canada, L8N 3Z5

Juravinski Hospital - Hamilton Health Sciences

Hamilton, Ontario, Canada, L8V 1C3

St. Michael's Hospital

Toronto, Ontario, Canada, M5B 1W8

France

Hopital Cardiologique Louis Pradel - CRTH

Bron, France, 69677

Hopital Necker

Paris, France, 75015

Germany

Vivantes Klinikum Friedrichshain

Berlin, Germany, 10249

Vivantes Klinikum im Friedrichshain

Berlin, Germany, 10249

Universitätsklinikum Bonn, Anstalt des öffentlichen Rechts

Bonn, Germany, 53127

Universitätsklinikum Bonn

Bonn, Germany, 53127

Universität und Universitätsklinikum des Saarlandes

Homburg/Saar, Germany, 66421

Greece

General Hospital of Athens "LAIKO", 2nd Regional Blood Transfusion Center

Athens, Greece, 11527

Japan

Sapporo Tokushukai Hospital

Sapporo, Hokkaido, Japan, 004-0041

Nara Medical University Hospital

Kashihara, Nara, Japan, 634-8522

Saitama Medical University Hospital

Iruma-gun, Saitama, Japan, 350-0495

National Center for Child Health and Development

Setagaya-ku, Tokyo, Japan, 157-8535

Korea, Republic of

Kyung Hee University Hospital at Gangdong

Seoul, Korea, Republic of, 05278

Saudi Arabia

King Faisal Specialist Hospital and Research Centre

Riyadh, Saudi Arabia

Sweden

Skåne University Hospital, Department of Hematology, Oncology and Radiation Physics

Malmö, Sweden, 205 02

ApoEx AB

Malmö, Sweden, 211 24

Taiwan

Changhua Christian Hospital

Changhua, Taiwan, 500

Kaohsiung Medical University Chung-Ho Memorial Hospital

Kaohsiung, Taiwan, 807

Chung Shan Medical University Hospital

Taichung City, Taiwan, 40201

Chung Shan Medical University

Taichung City, Taiwan, 40201

Taichung Veterans General Hospital

Taichung, Taiwan, 40705

National Taiwan University Hospital

Taipei, Taiwan, 10002

Turkey

Acibadem Adana Hospital

Adana, Turkey, 01130

Gaziantep University Sahinbey Training and Research Hospital

Gaziantep, Turkey, 27310

Istanbul University Oncology Institute

Istanbul, Turkey, 34093

Ege University Medical Faculty Hospital

Izmir, Turkey, 35040

United Kingdom

Newcastle upon Tyne Hospitals NHS FT

Newcastle Upon Tyne, Tyne & Wear, United Kingdom, NE1 4LP

Newcastle upon Tyne Hospitals NHS FT

Newcastle upon Tyne, Tyne & Wear, United Kingdom, NE2 4HH

Glasgow Royal Infirmary

Glasgow, United Kingdom, G4 0SF

Guy's and St. Thomas' NHS Foundation Trust

London, United Kingdom, SE1 7EH

Newcastle upon Tyne Hospitals NHS Foundation Trust

Newcastle upon Tyne, United Kingdom, NE2 4HH

Sponsors and Collaborators

Pfizer

Investigators

• Study Director: Pfizer CT.gov Call Center; Pfizer

  Study Documents (Full-Text)

Documents provided by Pfizer:

Study Protocol  [PDF] June 29, 2022

Statistical Analysis Plan  [PDF] July 7, 2022

More Information

Additional Information:

To obtain contact information for a study center near you, click here. 

• Responsible Party: Pfizer
• ClinicalTrials.gov Identifier: NCT03861273
• Other Study ID Numbers: C0371002; 2018-003086-33 ( EudraCT Number ); 2022-502844-11-00 ( Other Identifier: EU CT )
• First Posted: March 4, 2019
• Results First Posted: March 27, 2024
• Last Update Posted: May 3, 2024
• Last Verified: May 2024

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.
• URL: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes

Keywords provided by Pfizer:

PF 06838435; Hemophilia; Hemophilia B; Factor IX; FIX; Gene Therapy; Infusion; rAAV Spark100 hFIX Padua; rAAV Spark100-hFIX-R338L; R338L; BeneGene 2; Hematological Diseases; Annualized bleeding rate (ABR)

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