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%)

Hemophilia A Clinical Trial

Official title:

AN OPEN-LABEL, NON-INVESTIGATIONAL PRODUCT, MULTI-CENTER, LEAD-IN STUDY TO EVALUATE PROSPECTIVE EFFICACY AND SAFETY DATA OF FACTOR IX OR FACTOR VIII 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 nAb TO AAV VECTOR-SPARK100 AND MODERATELY SEVERE TO SEVERE HEMOPHILIA A ADULT SUBJECTS (FVIII:C≤1%) WHO ARE NEGATIVE FOR nAb TO AAV VECTOR SB-525 CAPSID (AAV6), PRIOR TO THE RESPECTIVE THERAPEUTIC PH 3 GENE THERAPY STUDIES (See Detailed Description Section for Official Protocol Title)

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03587116
• Other study ID #: C0371004
• Secondary ID: 2017-001271-23NA
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: July 26, 2018
• Est. completion date: July 26, 2024

Study information

• Verified date: April 2024
• Source: Pfizer
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 213
• Est. completion date: July 26, 2024
• Est. primary completion date: July 26, 2024
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 18 Years to 64 Years

Eligibility

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.

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).

Related Conditions & MeSH terms

• Hemophilia A
• Hemophilia B

Intervention

Drug:
• Standard of Care FIX Replacement therapy
There is no investigational product being administered. Subjects will be administering their own standard of care FIX replacement therapy.
• Standard of Care FVIII Replacement therapy
There is no investigational product being administered. Subjects will be administering their own standard of care FVIII replacement therapy.

Locations

Country	Name	City	State
Australia	Royal Adelaide Hospital	Adelaide	South Australia
Australia	Royal Prince Alfred Hospital	Camperdown	New South Wales
Australia	Royal Brisbane and Women's Hospital	Herston	Queensland
Australia	The Alfred Hospital	Melbourne	Victoria
Australia	Fiona Stanley Hospital	Murdoch	Western Australia
Belgium	Cliniques universitaires Saint-Luc/Unité d'Hématology et Hémostase	Brussels
Brazil	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 Clínicas Da Faculdade de Medicina de Ribeirao Preto Da Universidade de Sao Paulo	Ribeirão Preto	SÃO Paulo
Brazil	lnstituto Estadual de Hematologia Arthur de Siqueira Cavalcanti - HEMORIO	Rio de Janeiro
Brazil	Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo	São Paulo
Brazil	Centro Estadual de Hemoterapia e Hematologia Marcos Daniel Santos - Hemoes	Vitoria	Espirito Santo
Canada	McMaster University Medical Centre - Hamilton Health Sciences	Hamilton	Ontario
Canada	St. Michael's Hospital	Toronto	Ontario
France	CHRU de Brest - Hôpital Morvan	Brest
France	CHU de Brest	Brest
France	Hôpital Cardiologique Louis Pradel	Bron
France	CHU Hôtel-Dieu	Nantes Cedex 1
France	Hopital Necker, Hematologie Adultes	Paris
Germany	Vivantes Klinikum Friedrichshain	Berlin
Germany	Universitatsklinikum Bonn. Anstalt des oeffentlichen Rechts	Bonn
Germany	Universitaetsklinikum Frankfurt, Goethe-Universitaet	Frankfurt/Main
Germany	Universitaetsklinikum Giessen	Giessen
Germany	Universität und Universitätsklinikum des Saarlandes	Homburg/Saar
Greece	General Hospital of Athens "Hippokration"	Athens	Attica
Greece	General Hospital of Athens "LAIKO", 2nd Regional Blood Transfusion Center	Athens	Attica
Israel	The Chaim Sheba Medical Center, The National Hemophilia Center	Tel-Hashomer
Italy	IRCCS - AOU di Bologna, Policlinico di Sant'Orsola	Bologna	BO
Italy	SODc. Malattie Emorragiche e della Coagulazione Centro di Riferimento Regionale per le	Firenze
Italy	Azienda Ospedaliera Universitaria Federico II	Napoli
Italy	Università degli studi di Roma "La Sapienza"- Policlinico Umberto I	Roma
Japan	Saitama Medical University Hospital	Iruma-gun	Saitama
Japan	Nara Medical University Hospital	Kashihara	Nara
Japan	Nagoya University Hospital - Transfusion Medicine	Nagoya	Aichi
Japan	Sapporo Tokushukai Hospital	Sapporo	Hokkaido
Japan	National Center for Child Health and Development	Setagaya-ku	Tokyo
Japan	Ogikubo Hospital	Suginami-ku	Tokyo
Korea, Republic of	Kyungpook National University Hospital	Daegu
Korea, Republic of	Kyung Hee University Hospital At Gangdong	Seoul
Korea, Republic of	Severance Hospital, Yonsei University Health System	Seoul
Saudi Arabia	King Abdulaziz Medical City	Riyadh
Saudi Arabia	King Faisal Specialist Hospital & Research Center	Riyadh
Spain	Hospital de la Santa Creu i Sant Pau	Barcelona
Spain	Hospital Universitari Vall d´Hebrón	Barcelona
Spain	Hospital Universitario Virgen de la Arrixaca	El Palmar	Murcia
Spain	H.U. La Paz.	Madrid
Spain	H.U. Rio Hortega	Valladolid
Sweden	Skåne University Hospital	Malmö
Taiwan	Changhua Christian Hospital	Changhua
Taiwan	Kaohsiung Medical University Chung-Ho Memorial Hospital	Kaohsiung
Taiwan	Taichung Veterans General Hospital	Taichung
Taiwan	Chung Shan Medical University Hospital	Taichung City
Taiwan	National Taiwan University Hospital	Taipei
Taiwan	Taipei Medical University Hospital	Taipei City
Turkey	Acibadem Adana Hospital, Department of Pediatric Hematology	Adana
Turkey	Akdeniz University Medical Faculty Hospital	Antalya
Turkey	Ege Universitesi Tip Fakultesi Cocuk Sagligi Ve Hastaliklari Anabilim Dali Pediatric Hematoloji	Bornova	I?zmir
Turkey	Ege Universitesi Tip Fakultesi Hematoloji BD	Bornova	I?zmir
Turkey	Gaziantep University Sahinbey Training and Research Hospital	Gaziantep
Turkey	Istanbul University Oncology Institute	Istanbul
United Kingdom	Clinical Research Facility	Glasgow
United Kingdom	Department of Haematology	Glasgow
United Kingdom	Guy's and St Thomas' NHS Foundation Trust	London
United Kingdom	Newcastle upon Tyne Hospitals NHS Foundation Trust	Newcastle upon Tyne	Tyne & Wear
United Kingdom	Non Malignant Haematology Research Unit	Newcastle upon Tyne	Tyne & Wear
United States	Emory University Hospital	Atlanta	Georgia
United States	Emory University Hospital Midtown	Atlanta	Georgia
United States	Investigational Drug Service	Atlanta	Georgia
United States	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	Alliance for Childhood Diseases	Las Vegas	Nevada
United States	Mississippi Center for Advanced Medicine	Madison	Mississippi
United States	Clinical and Translational Research Unit (CTRU)	Palo Alto	California
United States	Lucile Packard Childrens Hospital	Palo Alto	California
United States	Penn Blood Disorder Center	Philadelphia	Pennsylvania
United States	Penn Comprehensive Hemophilia & Thrombosis Program, Hospital of the University of Pennsylvania	Philadelphia	Pennsylvania
United States	University of California, San Francisco - Outpatient Hematology Clinic	San Francisco	California
United States	Bloodworks NW	Seattle	Washington
United States	Stanford Health Care	Stanford	California

Sponsors (1)

Lead Sponsor	Collaborator
Pfizer

Countries where clinical trial is conducted

United States,  Australia,  Belgium,  Brazil,  Canada,  France,  Germany,  Greece,  Israel,  Italy,  Japan,  Korea, Republic of,  Saudi Arabia,  Spain,  Sweden,  Taiwan,  Turkey,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Annualized bleeding rate (ABR)	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).	6 months
Primary	Incidence of serious adverse events	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.	6 months
Primary	Events of special interest (ESI):inhibitor against FIX or FVIII, thrombotic events, and FIX or FVIII hypersensitivity reactions	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.	6 months
Secondary	Annualized infusion rate (AIR)	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).	6 months
Secondary	Dose and total factor consumption	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.	6 months
Secondary	Number of bleeding events (spontaneous and/or traumatic)	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.	6 months

External Links

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