Clinical trial NCT03587116: 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%)
Official title: AN OPEN-LABEL, NON-INVESTIGATIONAL PRODUCT, LEAD-IN STUDY TO EVALUATE AT LEAST 6 MONTHS OF 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 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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Hemophilia B
Hemophilia A
Lead sponsor: Pfizer
Sponsor class: INDUSTRY
First posted: 2018-07-16
Enrollment: 213
Sex: MALE
Minimum age (years): 18
Maximum age (years): 64
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: The data obtained from this lead-in study will serve as the control group for the subsequent Phase 3 gene therapy study.
Primary purpose: OTHER

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

Eligibility criteria: 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).

Primary outcomes:
measure: Annualized bleeding rate (ABR)
timeFrame: 6 months
measure: Incidence of serious adverse events
timeFrame: 6 months
measure: Events of special interest (ESI):inhibitor against FIX or FVIII, thrombotic events, and FIX or FVIII hypersensitivity reactions
timeFrame: 6 months
Secondary outcomes:
measure: Annualized infusion rate (AIR)
timeFrame: 6 months
measure: Dose and total factor consumption
timeFrame: 6 months
measure: Number of bleeding events (spontaneous and/or traumatic)
timeFrame: 6 months
Other outcomes:
Locations:
city: Palo Alto
country: United States
facility: Clinical and Translational Research Unit (CTRU)
state: California
city: Palo Alto
country: United States
facility: Lucile Packard Childrens Hospital
state: California
city: San Francisco
country: United States
facility: University of California, San Francisco - Outpatient Hematology Clinic
state: California
city: Stanford
country: United States
facility: Stanford Health Care
state: California
city: Aurora
country: United States
facility: Hemophilia and Thrombosis Center at the University of Colorado Anschutz Medical Campus
state: Colorado
city: Atlanta
country: United States
facility: Emory University Hospital Midtown
state: Georgia
city: Atlanta
country: United States
facility: Emory University Hospital
state: Georgia
city: Atlanta
country: United States
facility: Investigational Drug Service
state: Georgia
city: Indianapolis
country: United States
facility: Indiana Hemophilia & Thrombosis Center, Inc.
state: Indiana
city: Madison
country: United States
facility: Mississippi Center for Advanced Medicine
state: Mississippi
city: Las Vegas
country: United States
facility: Alliance for Childhood Diseases
state: Nevada
city: Philadelphia
country: United States
facility: Penn Blood Disorder Center
state: Pennsylvania
city: Seattle
country: United States
facility: Bloodworks NW
state: Washington
city: Camperdown
country: Australia
facility: Royal Prince Alfred Hospital
state: New South Wales
city: Herston
country: Australia
facility: Royal Brisbane and Women's Hospital
state: Queensland
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital
state: South Australia
city: Melbourne
country: Australia
facility: The Alfred Hospital
state: Victoria
city: Murdoch
country: Australia
facility: Fiona Stanley Hospital
state: Western Australia
city: Brussels
country: Belgium
facility: Cliniques universitaires Saint-Luc/Unité d'Hématology et Hémostase
city: Vitoria
country: Brazil
facility: Centro Estadual de Hemoterapia e Hematologia Marcos Daniel Santos - Hemoes
state: Espirito Santo
city: Belem
country: Brazil
facility: Centro de Hemoterapia e Hematologia do Para - Fundação HEMOPA
state: Para
city: Campinas
country: Brazil
facility: Centro de Hematologia e Hemoterapia - Hemocentro de Campinas - UNICAMP
state: SAO Paulo
city: Ribeirão Preto
country: Brazil
facility: Hospital Das Clínicas Da Faculdade de Medicina de Ribeirao Preto Da Universidade de Sao Paulo
state: SÃO Paulo
city: Rio de Janeiro
country: Brazil
facility: lnstituto Estadual de Hematologia Arthur de Siqueira Cavalcanti - HEMORIO
city: São Paulo
country: Brazil
facility: Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo
city: Hamilton
country: Canada
facility: McMaster University Medical Centre - Hamilton Health Sciences
state: Ontario
city: Toronto
country: Canada
facility: St. Michael's Hospital
state: Ontario
city: Brest
country: France
facility: CHRU de Brest - La Cavale Blanche
city: Bron
country: France
facility: Hôpital Cardiologique Louis Pradel
city: Nantes Cedex 1
country: France
facility: CHU Hôtel-Dieu
city: Paris
country: France
facility: Hopital Necker, Hematologie Adultes
city: Berlin
country: Germany
facility: Vivantes Klinikum Friedrichshain
city: Bonn
country: Germany
facility: Universitatsklinikum Bonn. Anstalt des oeffentlichen Rechts
city: Giessen
country: Germany
facility: Universitaetsklinikum Giessen
city: Homburg/Saar
country: Germany
facility: Universität und Universitätsklinikum des Saarlandes
city: Athens
country: Greece
facility: General Hospital of Athens "Hippokration"
state: Attica
city: Athens
country: Greece
facility: General Hospital of Athens "LAIKO", 2nd Regional Blood Transfusion Center
state: Attica
city: Tel-Hashomer
country: Israel
facility: The Chaim Sheba Medical Center, The National Hemophilia Center
city: Bologna
country: Italy
facility: IRCCS - AOU di Bologna, Policlinico di Sant'Orsola
state: BO
city: Napoli
country: Italy
facility: UOC Medicina Interna - Malattie Emorragiche e Trombotiche
state: Naples
city: Firenze
country: Italy
facility: SODc. Malattie Emorragiche e della Coagulazione Centro di Riferimento Regionale per le
city: Roma
country: Italy
facility: Università degli studi di Roma "La Sapienza"- Policlinico Umberto I
city: Nagoya
country: Japan
facility: Nagoya University Hospital - Transfusion Medicine
state: Aichi
city: Sapporo
country: Japan
facility: Sapporo Tokushukai Hospital
state: Hokkaido
city: Kashihara
country: Japan
facility: Nara Medical University Hospital
state: Nara
city: Iruma-gun
country: Japan
facility: Saitama Medical University Hospital
state: Saitama
city: Setagaya-ku
country: Japan
facility: National Center for Child Health and Development
state: Tokyo
city: Suginami-ku
country: Japan
facility: Ogikubo Hospital
state: Tokyo
city: Daegu
country: Korea, Republic of
facility: Kyungpook National University Hospital
city: Seoul
country: Korea, Republic of
facility: Severance Hospital, Yonsei University Health System
city: Seoul
country: Korea, Republic of
facility: Kyung Hee University Hospital At Gangdong
city: Riyadh
country: Saudi Arabia
facility: King Abdulaziz Medical City
city: Riyadh
country: Saudi Arabia
facility: King Faisal Specialist Hospital & Research Center
city: El Palmar
country: Spain
facility: Hospital Universitario Virgen de la Arrixaca
state: Murcia
city: Barcelona
country: Spain
facility: Hospital de la Santa Creu i Sant Pau
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d´Hebrón
city: Madrid
country: Spain
facility: H.U. La Paz.
city: Valladolid
country: Spain
facility: H.U. Rio Hortega
city: Malmö
country: Sweden
facility: Skåne University Hospital
city: Changhua
country: Taiwan
facility: Changhua Christian Hospital
city: Kaohsiung
country: Taiwan
facility: Kaohsiung Medical University Chung-Ho Memorial Hospital
city: Taichung City
country: Taiwan
facility: Chung Shan Medical University Hospital
city: Taichung
country: Taiwan
facility: Taichung Veterans General Hospital
city: Taipei
country: Taiwan
facility: National Taiwan University Hospital
city: Bornova
country: Turkey
facility: Ege Universitesi Tip Fakultesi Cocuk Sagligi Ve Hastaliklari Anabilim Dali Pediatric Hematoloji
state: İ̇zmir
city: Bornova
country: Turkey
facility: Ege Universitesi Tip Fakultesi Hematoloji BD
state: İ̇zmir
city: Adana
country: Turkey
facility: Acibadem Adana Hospital, Department of Pediatric Hematology
city: Antalya
country: Turkey
facility: Akdeniz University Medical Faculty Hospital
city: Gaziantep
country: Turkey
facility: Gaziantep University Sahinbey Training and Research Hospital
city: Istanbul
country: Turkey
facility: Istanbul University Oncology Institute
city: Newcastle upon Tyne
country: United Kingdom
facility: Newcastle upon Tyne Hospitals NHS Foundation Trust
state: Tyne & Wear
city: Newcastle upon Tyne
country: United Kingdom
facility: Non Malignant Haematology Research Unit
state: Tyne & Wear
city: Glasgow
country: United Kingdom
facility: Clinical Research Facility
city: Glasgow
country: United Kingdom
facility: Department of Haematology
city: London
country: United Kingdom
facility: Guy's and St Thomas' NHS Foundation Trust
Study officials:
affiliation: Pfizer
name: Pfizer CT.gov Call Center
role: STUDY_DIRECTOR
References: