A Study to Evaluate Prospective Efficacy and Safety Data of Current FIX Prophylaxis Replacement Therapy in Adult Hemophilia B Subjects (FIX:C≤2%) or Current FVIII Prophylaxis Replacement Therapy in Adult Hemophilia A Subjects (FVIII:C≤1%)

Phase 3

Active, not recruiting

• Conditions: Hemophilia B; Hemophilia A
• Interventions: Drug: Standard of Care FIX Replacement therapy; Drug: Standard of Care FVIII Replacement therapy

• Registration Number: NCT03587116
• Lead Sponsor: Pfizer

Brief Summary

To establish baseline prospective efficacy data of current FIX prophylaxis replacement therapy in the usual care setting of hemophilia B subjects, who are negative for nAb to AAV-Spark100, prior to the Phase 3 gene therapy study.

To establish baseline prospective efficacy data of current FVIII prophylaxis replacement therapy in the usual care setting of hemophilia A subjects, who are negative for nAb to AAV6, prior to the Phase 3 gene therapy study.

The enrollment for hemophilia A participants is completed. At this time participants are only being enrolled for hemophilia B cohort.

Detailed Description

AN OPEN-LABEL, NON-INVESTIGATIONAL PRODUCT, MULTI-CENTER, LEAD-IN STUDY TO EVALUATE PROSPECTIVE EFFICACY AND SELECTED SAFETY DATA OF CURRENT FACTOR IX (FIX) OR FACTOR VIII (FVIII) PROPHYLAXIS REPLACEMENT THERAPY IN THE USUAL CARE SETTING OF MODERATELY SEVERE TO SEVERE ADULT HEMOPHILIA B SUBJECTS (FIX:C≤2%) WHO ARE NEGATIVE FOR NEUTRALIZING ANTIBODIES TO ADENO-ASSOCIATED VIRUS VECTOR-SPARK100 (BENEGENE-1) AND MODERATELY SEVERE TO SEVERE HEMOPHILIA A ADULT SUBJECTS (FVIII:C≤1%) WHO ARE NEGATIVE FOR NEUTRALIZING ANTIBODIES TO ADENO-ASSOCIATED VIRUS VECTOR 6 (AAV6), PRIOR TO THE RESPECTIVE THERAPEUTIC PHASE 3 GENE THERAPY STUDIES

Study Timeline

• Study First Submitted: 2018-06-29
• Study First Submitted QC: 2018-07-02
• Study First Posted: 2018-07-16
• Study Start: 2018-07-26
• Status Verified: 2024-10
• Last Update Submitted: 2024-10-04
• Last Update Posted: 2024-10-08
• Primary Completion: 2024-10-25
• Study Completion: 2024-10-25

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: Male
• Target Recruitment: 213

Inclusion Criteria

Hemophilia B Population:

1. Evidence of a signed and dated informed consent document indicating that the participant has been informed of all pertinent aspects of the study.

2. Willing and able to comply with scheduled visits, FIX prophylaxis treatment plan, laboratory tests and other study procedures.

3. Males ≥ 18 and <65 years of age with moderately severe to severe hemophilia B and documented FIX activity (≤2%) prior to baseline visit.

4. Previous experience with FIX therapy (≥50 documented exposure days to a FIX protein product such as recombinant, plasma-derived or extended half-life FIX product).

5. Participants on FIX prophylaxis replacement therapy (recombinant, plasma-derived or extended half-life FIX product) must have the intention to remain on FIX prophylaxis replacement therapy for the duration of the study.

6. No known hypersensitivity to FIX replacement product.

7. No history of FIX inhibitor (clinical or laboratory-based assessment) defined as a titer

   • 0.6 BU/mL, regardless of the laboratory normal range, or any measured Bethesda inhibitor titer greater than the upper limit of normal for the laboratory performing the assay. Clinically, no signs or symptoms of decreased response to FIX administration. Participants will not be required to undergo diagnostic evaluation of inhibitor status to participate in the study.

Hemophilia A Population:

1. Evidence of a signed and dated informed consent document indicating that the participant has been informed of all pertinent aspects of the study.
2. Willing and able to comply with scheduled visits, FVIII prophylaxis treatment plan, laboratory tests and other study procedures.
3. Males ≥18 and <65 years of age with moderately severe to severe hemophilia A and documented FVIII activity (≤1%) prior to baseline visit.
4. Previous experience with FVIII therapy (≥150 documented exposure days to a FVIII protein product such as recombinant, plasma-derived or extended half-life FVIII product).
5. Participants must be on a stable FVIII prophylaxis replacement therapy (recombinant, plasma-derived or extended half-life FVIII product) at study entry and must have the intention to remain on FVIII prophylaxis replacement therapy for the duration of the study. This does not include nonfactor treatments, which are prohibited.
6. No known hypersensitivity to FVIII replacement product.
7. No history of FVIII inhibitor (clinical or laboratory-based assessment) defined as a titer ≥0.6 BU/mL, regardless of the laboratory normal range, or any measured Bethesda inhibitor titer greater than the upper limit of normal for the laboratory performing the assay. Clinically, no signs or symptoms of decreased response to FVIII administration. Participants will not be required to undergo diagnostic evaluation of inhibitor status to participate in the study.

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Exclusion Criteria

1. Anti-AAV-Spark100 neutralizing antibody titer above the established threshold performed by a central laboratory during screening in hemophilia B subjects or Anti-AAV6 neutralizing antibody titer above the established threshold performed by a central laboratory during screening in hemophilia A subjects.

2. Lack of participant compliance with documentation of bleeds and/or prophylaxis replacement therapy administration.

3. If there is no documentation regarding hepatitis status, as defined below, within the last 12 months prior to screening for hepatitis B and 6 months prior to screening for hepatitis C, then participants will be required to have the following hepatitis testing performed at screening:

   1. Hepatitis B screening (acute and chronic):

      HBsAg (also referred to as Hepatitis B surface antigen), HBV-DNA viral assay (also referred to as a nucleic acid test for Hepatitis B virus DNA), and Anti-HBc (also referred to as Total Hepatitis B core antibody).

      • A participant is not eligible if either HbsAg is positive or HBV-DNA is positive/detectable.
      • Anti-HBc must be obtained in all participants for determination of whether the participant had prior hepatitis B. If the anti-HBc is positive and both HBsAg and HBV DNA are negative this would be consistent with a prior infection and the subject would be eligible for the study. Anti-HBc must be obtained in all subjects to discriminate between those with no prior hepatitis B and those with prior infection in the event of reactivation. FDA has noted reactivation of hepatitis B virus exists.
      • One documented negative HBV-DNA viral load is sufficient to assess eligibility. A participant who is currently undergoing anti-viral therapy for hepatitis B is not eligible.

   2. Hepatitis C (acute or chronic):

      • A participant who is currently undergoing anti-viral therapy for chronic hepatitis C is not eligible.
      • Participants treated with anti-viral therapy for chronic hepatitis C, must have completed anti-viral therapy at least 6 months prior to screening and have a negative HCV-RNA at least 6 months prior to screening.
      • All participants (who are not currently undergoing anti-viral therapy for chronic hepatitis C) must have a single HCV-RNA load assay (also referred to as a nucleic acid test [NAT] for HCV RNA) obtained during the 6 months preceding screening. This includes participants with prior known chronic hepatitis C who have completed treatment with anti-viral therapy.
      • A participant is not eligible if his HCV-RNA load assay result is positive/detectable.

4. Currently on antiviral therapy for hepatitis B or C.

5. Significant liver disease, as defined by pre-existing diagnosis of portal hypertension, splenomegaly, or hepatic encephalopathy.

   All participants who do not have the listed pre existing diagnoses above must have the following assessments performed within the last 12 months prior to screening and if not will need to be tested for liver fibrosis status at screening: a serum albumin level below normal limits and/or significant liver fibrosis by any of the following diagnostic modalities: FibroScan median stiffness score >8 kPa units OR FibroTest/FibroSURE >0.48*.

   * NOTE: If there is concern regarding the validity of any of the liver fibrosis test results please contact the medical monitor to discuss whether any additional testing needs to be performed (ie, either repeating any test or performing another fibrosis test). Also, note, if a participant has a known history of Gilbert's syndrome, a FibroTest cannot be used for fibrosis testing.

6. Documented serological evidence of human immunodeficiency virus HIV-1 or HIV-2 with Cluster of Differentiation 4 positive (CD4+) cell count ≤200 mm3 within the last 12 months prior to screening. Participants who are HIV positive and stable, have an adequate CD4 count (>200/mm3) and undetectable viral load (<50 gc/mL) documented within the preceding 12 months, and are on an antiretroviral drug regimen are eligible to enroll. Participants who have not been tested within the prior 12 months of screening will need to be tested for HIV status at screening.

7. History of chronic infection or other chronic disease that the investigator deems an unacceptable risk. In addition, any participant with conditions associated with increased thromboembolic risk such as known inherited or acquired thrombophilia, or a history of thrombotic events including but not limited to stroke, myocardial infarction, and/or venous thromboembolism, is excluded.

8. Any concurrent clinically significant major disease or condition that the investigator deems unsuitable for participation or other acute or chronic medical or psychiatric condition including recent (within the past year) or active suicidal ideation or behavior or laboratory abnormality that may increase the risk associated with study participation or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the participant inappropriate for entry into this study. In addition, any participant with a history of a neoplasm (including hepatic malignancy) that required treatment (eg, chemotherapy, radiotherapy, immunotherapy), is excluded, except for adequately treated basal or squamous cell carcinoma of the skin or a surgically removed benign neoplasm not requiring chemotherapy, radiotherapy and/or immunotherapy. Any other neoplasm that has been cured by resection should be discussed between the investigator and sponsor.

9. Participation in other studies if involving administration of investigational product(s) within the last 3 months prior to study entry and/or during study participation or in a previous gene therapy clinical study within the last 12 months prior to screening.

   • Participants already enrolled in this lead-in study (C0371004) may be allowed to participate in the screening and baseline periods of either C0371002 or C3731003 protocols prior to their completion of the end of study visit in this lead-in study.

10. Any participant who previously received fidanacogene elaparvovec (hemophilia B) or giroctocogene fitelparvovec (hemophilia A) or any AAV gene-based therapy.

11. Participants using restricted therapies.

12. Any participant with a planned surgical procedure requiring FIX (hemophilia B) or FVIII (hemophilia A) surgical prophylactic factor treatment in the next 24 months.

13. Investigator site staff members directly involved in the conduct of the study and their family members, site staff members otherwise supervised by the investigator, or participants who are Pfizer employees, including their family members, directly involved in the conduct of the study.

NOTE: The sponsor's medical team should be contacted if there are any questions regarding any of the inclusion or exclusion criteria (Sections: 4.1 and 4.2).

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Standard of Care FIX replacement therapy	Standard of Care FIX Replacement therapy	-
Standard of Care FVIII replacement therapy	Standard of Care FVIII Replacement therapy	-

Primary Outcome Measures

Name	Time	Method
Events of special interest (ESI):inhibitor against FIX or FVIII, thrombotic events, and FIX or FVIII hypersensitivity reactions	6 months	Frequency and percentage of these ESI events will be summarized by event. In addition any events leading to discontinuation from the study will be described.
Annualized bleeding rate (ABR)	6 months	The annualized bleeding rate (ABR) per subject will be calculated as the number of bleeds over number of days subject received FIX prophylaxis replacement therapy from baseline visit (Day 1) to end of study x 365.25 days. ABR will be summarized using descriptive statistics (n, mean, standard deviation, median, Q1, Q3, minimum, maximum).; The annualized bleeding rate (ABR) per subject will be calculated as the number of bleeds over number of days subject received FVIII prophylaxis replacement therapy from baseline visit (Day 1) to end of study x 365.25 days. ABR will be summarized using descriptive statistics (n, mean, standard deviation, median, Q1, Q3, minimum, maximum).
Incidence of serious adverse events	6 months	The primary safety analysis will be performed on all subjects that sign the informed consent document and are subsequently identified as nAb negative and are enrolled (complete baseline visit) into the study.

Secondary Outcome Measures

Name	Time	Method
Dose and total factor consumption	6 months	The total factor IX replacement therapy consumption and the corresponding dose will be descriptively summarized by the categories of the replacement therapy, where appropriate. Infusion diary (electronic infusion diary) of the factor IX replacement therapy will be listed.; The total factor VIII replacement therapy consumption and the corresponding dose will be descriptively summarized by the categories of the replacement therapy, where appropriate. Infusion diary (electronic infusion diary) of the factor VIII replacement therapy will be listed.
Number of bleeding events (spontaneous and/or traumatic)	6 months	The number of bleeding episodes will be summed up by spontaneous, traumatic and overall as defined as any bleed occurring \>72 hours after stopping treatment from the original bleed for which treatment was initiated or a bleed occurring at a different site from the original bleed regardless of the time from last injection.
Annualized infusion rate (AIR)	6 months	The annualized infusion rate (AIR) per subject will be calculated as the number of infusions received over number of days subject received FIX prophylaxis replacement therapy from baseline visit (Day 1) to end of study x 365.25 days. AIR will be summarized using descriptive statistics (n, mean, standard deviation, median, Q1, Q3, minimum, maximum).; The annualized infusion rate (AIR) per subject will be calculated as the number of infusions received over number of days subject received FVIII prophylaxis replacement therapy from baseline visit (Day 1) to end of study x 365.25 days. AIR will be summarized using descriptive statistics (n, mean, standard deviation, median, Q1, Q3, minimum, maximum).

Trial Locations

Locations (80)

Hemophilia and Thrombosis Center at the University of Colorado Anschutz Medical Campus; 🇺🇸 Aurora, Colorado, United States

Indiana Hemophilia & Thrombosis Center, Inc.; 🇺🇸 Indianapolis, Indiana, United States

Penn Blood Disorder Center; 🇺🇸 Philadelphia, Pennsylvania, United States

Emory University Hospital; 🇺🇸 Atlanta, Georgia, United States

Investigational Drug Service; 🇺🇸 Atlanta, Georgia, United States

Royal Adelaide Hospital; 🇦🇺 Adelaide, South Australia, Australia

McMaster University Medical Centre - Hamilton Health Sciences; 🇨🇦 Hamilton, Ontario, Canada

Royal Brisbane and Women's Hospital; 🇦🇺 Herston, Queensland, Australia

Hospital Das Clínicas Da Faculdade de Medicina de Ribeirao Preto Da Universidade de Sao Paulo; 🇧🇷 Ribeirão Preto, SÃO Paulo, Brazil

CHRU de Brest - Hôpital Morvan; 🇫🇷 Brest, France

CHRU de Brest - La Cavale Blanche; 🇫🇷 Brest, France

Penn Comprehensive Hemophilia & Thrombosis Program, Hospital of the University of Pennsylvania; 🇺🇸 Philadelphia, Pennsylvania, United States

CHU de Brest; 🇫🇷 Brest, France

Bloodworks NW; 🇺🇸 Seattle, Washington, United States

Fiona Stanley Hospital; 🇦🇺 Murdoch, Western Australia, Australia

St. Michael's Hospital; 🇨🇦 Toronto, Ontario, Canada

Hôpital Cardiologique Louis Pradel; 🇫🇷 Bron, France

Centro Estadual de Hemoterapia e Hematologia Marcos Daniel Santos - Hemoes; 🇧🇷 Vitoria, Espirito Santo, Brazil

General Hospital of Athens "Hippokration"; 🇬🇷 Athens, Attica, Greece

Hopital Necker, Hematologie Adultes; 🇫🇷 Paris, France

Universitaetsklinikum Frankfurt, Goethe-Universitaet; 🇩🇪 Frankfurt/Main, Germany

Hospital de la Santa Creu i Sant Pau; 🇪🇸 Barcelona, Spain

Universitatsklinikum Bonn. Anstalt des oeffentlichen Rechts; 🇩🇪 Bonn, Germany

Universität und Universitätsklinikum des Saarlandes; 🇩🇪 Homburg/Saar, Germany

The Chaim Sheba Medical Center, The National Hemophilia Center; 🇮🇱 Tel-Hashomer, Israel

Università degli studi di Roma "La Sapienza"- Policlinico Umberto I; 🇮🇹 Roma, Italy

IRCCS - AOU di Bologna, Policlinico di Sant'Orsola; 🇮🇹 Bologna, BO, Italy

Saitama Medical University Hospital; 🇯🇵 Iruma-gun, Saitama, Japan

Ogikubo Hospital; 🇯🇵 Suginami-ku, Tokyo, Japan

King Abdulaziz Medical City; 🇸🇦 Riyadh, Saudi Arabia

Taichung Veterans General Hospital; 🇨🇳 Taichung, Taiwan

Taipei Medical University Hospital; 🇨🇳 Taipei City, Taiwan

Newcastle upon Tyne Hospitals NHS Foundation Trust; 🇬🇧 Newcastle upon Tyne, Tyne & Wear, United Kingdom

Skåne University Hospital; 🇸🇪 Malmö, Sweden

National Taiwan University Hospital; 🇨🇳 Taipei, Taiwan

Department of Haematology; 🇬🇧 Glasgow, United Kingdom

Ege Universitesi Tip Fakultesi Cocuk Sagligi Ve Hastaliklari Anabilim Dali Pediatric Hematoloji; 🇹🇷 Bornova, İ̇zmir, Turkey

Akdeniz University Medical Faculty Hospital; 🇹🇷 Antalya, Turkey

Acibadem Adana Hospital, Department of Pediatric Hematology; 🇹🇷 Adana, Turkey

Gaziantep University Sahinbey Training and Research Hospital; 🇹🇷 Gaziantep, Turkey

Non Malignant Haematology Research Unit; 🇬🇧 Newcastle upon Tyne, Tyne & Wear, United Kingdom

Clinical Research Facility; 🇬🇧 Glasgow, United Kingdom

Centro de Hemoterapia e Hematologia do Para - Fundação HEMOPA; 🇧🇷 Belem, Para, Brazil

Centro de Hematologia e Hemoterapia - Hemocentro de Campinas - UNICAMP; 🇧🇷 Campinas, SAO Paulo, Brazil

Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo; 🇧🇷 São Paulo, Brazil

Severance Hospital, Yonsei University Health System; 🇰🇷 Seoul, Korea, Republic of

Universitaetsklinikum Giessen; 🇩🇪 Giessen, Germany

Hospital Universitari Vall d´Hebrón; 🇪🇸 Barcelona, Spain

H.U. Rio Hortega; 🇪🇸 Valladolid, Spain

H.U. La Paz.; 🇪🇸 Madrid, Spain

Lucile Packard Childrens Hospital; 🇺🇸 Palo Alto, California, United States

Stanford Health Care; 🇺🇸 Stanford, California, United States

University of California, San Francisco - Outpatient Hematology Clinic; 🇺🇸 San Francisco, California, United States

Clinical and Translational Research Unit (CTRU); 🇺🇸 Palo Alto, California, United States

Emory University Hospital Midtown; 🇺🇸 Atlanta, Georgia, United States

Royal Prince Alfred Hospital; 🇦🇺 Camperdown, New South Wales, Australia

lnstituto Estadual de Hematologia Arthur de Siqueira Cavalcanti - HEMORIO; 🇧🇷 Rio de Janeiro, Brazil

CHU Hôtel-Dieu; 🇫🇷 Nantes Cedex 1, France

Vivantes Klinikum Friedrichshain; 🇩🇪 Berlin, Germany

General Hospital of Athens "LAIKO", 2nd Regional Blood Transfusion Center; 🇬🇷 Athens, Attica, Greece

SODc. Malattie Emorragiche e della Coagulazione Centro di Riferimento Regionale per le; 🇮🇹 Firenze, Italy

Azienda Ospedaliera Universitaria Federico II; 🇮🇹 Napoli, Italy

Nara Medical University Hospital; 🇯🇵 Kashihara, Nara, Japan

Kyungpook National University Hospital; 🇰🇷 Daegu, Korea, Republic of

Hospital Universitario Virgen de la Arrixaca; 🇪🇸 El Palmar, Murcia, Spain

Kyung Hee University Hospital At Gangdong; 🇰🇷 Seoul, Korea, Republic of

Alliance for Childhood Diseases; 🇺🇸 Las Vegas, Nevada, United States

Mississippi Center for Advanced Medicine; 🇺🇸 Madison, Mississippi, United States

Nagoya University Hospital - Transfusion Medicine; 🇯🇵 Nagoya, Aichi, Japan

Sapporo Tokushukai Hospital; 🇯🇵 Sapporo, Hokkaido, Japan

King Faisal Specialist Hospital & Research Center; 🇸🇦 Riyadh, Saudi Arabia

Changhua Christian Hospital; 🇨🇳 Changhua, Taiwan

Cliniques universitaires Saint-Luc/Unité d'Hématology et Hémostase; 🇧🇪 Brussels, Belgium

Kaohsiung Medical University Chung-Ho Memorial Hospital; 🇨🇳 Kaohsiung, Taiwan

Chung Shan Medical University Hospital; 🇨🇳 Taichung City, Taiwan

Ege Universitesi Tip Fakultesi Hematoloji BD; 🇹🇷 Bornova, İ̇zmir, Turkey

Istanbul University Oncology Institute; 🇹🇷 Istanbul, Turkey

The Alfred Hospital; 🇦🇺 Melbourne, Victoria, Australia

National Center for Child Health and Development; 🇯🇵 Setagaya-ku, Tokyo, Japan

Guy's and St Thomas' NHS Foundation Trust; 🇬🇧 London, United Kingdom