Clinical trial NCT03938792: Study of the Efficacy and Safety PF-06741086 in Adult and Teenage Participants With Severe Hemophilia A or Moderately Severe to Severe Hemophilia B
Official title: An Open-Label Study in Adolescent and Adult Severe (Coagulation Factor Activity <1%) Hemophilia A Participants With or Without Inhibitors or Moderately Severe to Severe Hemophilia B Participants (Coagulation Factor Activity ≤2%) With or Without Inhibitors Comparing Standard Treatment to PF-06741086 Prophylaxis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Hemophilia A
Hemophilia B
Keywords: Factor VIII
Factor IX
Inhibitors
Anti-Tissue Factor Pathway Inhibitor (TFPI)
Subcutaneous (sc)
Prophylaxis
On-Demand
BASIS
Inhibitor
SC
Subcutaneous
Injection
On demand
aTFPI
Anti-TFPI
Severe hemophilia
Severe bleeding
Hemophilia
PF-06741086
PF 06741086
Marstacimab
Lead sponsor: Pfizer
Sponsor class: INDUSTRY
First posted: 2019-05-06
Enrollment: 189
Sex: MALE
Minimum age (years): 12
Maximum age (years): 74
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: CROSSOVER
Intervention model description: This is a one way Cross-Over Prevention study with 1 Arm that has No masking.
Primary purpose: TREATMENT

Brief summary: Treatment with PF-06741086 is anticipated to demonstrate a clinically relevant advantage and/or a major contribution to patient care in comparison to current methods of treatment for hemophilia A or B because it works differently than factor replacement products and will work in the presence of inhibitors. The potential for once weekly (QW) subcutaneous (SC) administration provides for treatment options in the absence of reliable vascular access, increased convenience and may enable better compliance. Combined, these qualities should result in a reduction of bleeding episodes.


Eligibility criteria: Inclusion Criteria

* Participants with a diagnosis of severe hemophilia A or moderately severe to severe hemophilia B with a minimum weight of 35 kg at screening.
* Participant or legally authorized representative, or participant's caregiver capable of giving signed informed consent (or minor assent, when applicable).

Participants who are enrolled into the Non-Inhibitor Cohort must also meet the following criteria:

* No detectable or documented history of inhibitors
* Participants on FVIII/FIX routine prophylaxis who have demonstrated at least 80% compliance with scheduled prophylaxis regimen during 6 months prior to enrollment and are willing to continue to receive routine prophylaxis treatment with FVIII/FIX replacement during the Observational Phase.
* Participants with on-demand treatment regimen with ≥6 acute bleeding episodes (spontaneous or traumatic) that required coagulation factor infusion during the 6 months period prior to enrollment and willing to continue to receive on demand treatment during the Observational Phase.

Participants who are enrolled into the Inhibitor Cohort must also meet the following criteria:

* Documentation of current high titer inhibitor (≥5 BU/mL) or current low titer inhibitor (\<5 BU/mL) refractory to FVIII or FIX replacement and with FVIII or FIX recovery \<60% of expected within previous 6 months prior to enrolment into the Observational Phase
* Hemophilia A participants with on-demand treatment regimen with ≥6 bleeding episodes or hemophilia B participants with ≥4 bleeding episodes (spontaneous or traumatic) necessitating treatment with bypass factor during the 6 months prior to Enrollment into Observational Phase and willing to continue to receive on-demand treatment during the Observational Phase.
* Participants who have documented inhibitors while on factor-replacement therapy but who do not meet the quantitative inhibitor criteria described in the prior bullet at the time of Screening (eg, participant with a previously documented high-titer inhibitor (≥5 BU/mL) and whose condition precludes re-challenge with FVIII or FIX replacement) may be considered for eligibility on a case-by-case basis with prior agreement from the Pfizer Medical Monitor
* Participants who meet the bleeding criteria noted above and who are on routine prophylaxis (defined as treatment by IV injection of bypass factor to prevent bleeding) and have demonstrated at least 80% compliance with scheduled prophylaxis regimen during the 6 months prior to enrollment, may be considered for eligibility on a case-by-case basis with discussion and agreement from the Pfizer medical monitor.

Exclusion Criteria

* Previous or current treatment for and/or history of coronary artery diseases, venous or arterial thrombosis or ischemic disease
* Known planned surgical procedure during the planned study period.
* Known hemostatic defect other than hemophilia A or B.
* Abnormal renal or hepatic function
* Current unstable liver or biliary disease
* Abnormal hematologic parameters
* Other acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator,
* Current routine prophylaxis with bypassing agent or non-coagulation non-factor- replacement therapy, or any previous treatment with a gene therapy product for treatment of hemophilia (participants treated with prophylaxis using bypassing agents or who had prior treatment with non-factor products may be considered on a case-by-case basis).
* Regular, concomitant therapy with immunomodulatory drugs

  - Ongoing or planned use of immune tolerance induction during the Observational Phase or Active Treatment Phase, or prophylaxis with FVIII or FIX replacement at any time after initiation of treatment with study intervention during the Active Treatment Phase
* Previous exposure to PF 06741086 during participation in studies B7841002 and B7841003.
* Participation in other studies involving investigational drug(s) or investigational vaccines within 30 days (or as determined by local requirements) or 5 half-lives prior to study entry and/or during study participation.
* CD4 cell count ≤200/uL if human immunodeficiency virus (HIV)-positive
* Screening ECG that demonstrates clinically relevant abnormalities that may affect participant safety or interpretation of study results.
* Individuals with hypersensitivity or an allergic reaction to hamster protein or other components of the study intervention.
* 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.

Primary outcomes:
measure: Annualized bleeding rate (ABR) of treated bleeding events
timeFrame: Through Observational Phase (6months) and Active Treatment Phase (12 months) for total of approximately 18 months
measure: Incidence and severity of thrombotic events
timeFrame: Through Observational Phase (6 months) and Active Treatment Phase (12 months) for total of approximately 18 months
measure: Incidence of anti drug antibody [ADA] against PF-06741086
timeFrame: Throughout Active Treatment Phase (12 months)
measure: Incidence of clinically significant persistent neutralizing antibody [NAb] against PF-06741086
timeFrame: Throughout Active Treatment Phase (12 months)
measure: Incidence and severity of injection site reaction
timeFrame: Throughout Active Treatment Phase (12 months)
measure: Number of participants with clinically significant changes from baseline in physical exam
timeFrame: From Baseline through Observation and Active Treatment (approximately 18 months)
measure: Incidence of clinically significant laboratory value abnormalities
timeFrame: From Screening through Observation and Active Treatment (approximately 18 months)
measure: Incidence of severe hypersensitivity and anaphylactic reactions
timeFrame: From Screening through Observational and Active Treatment (approximately 18 months)
measure: Incidence of adverse events and serious adverse events
timeFrame: From screening through Observation and Active treatment (approximately 18 months)
measure: Number of participants with clinically significant changes from baseline in vital signs
timeFrame: From Baseline through Observation and Active Treatment (approximately 18 months)
measure: Incidence and severity of thromboticangiopathy
timeFrame: Throughout Active Treatment Phase (12 months)
measure: Incidence of intravascular coagulation/consumption coagulopathy
timeFrame: Throughout Active Treatment Phase (12 months)
Secondary outcomes:
measure: Incidence of joint bleeds
timeFrame: Through Observational Phase (6 months) and Active Treatment Phase (12 months) for total of approximately 18 months
measure: Incidence of spontaneous bleeds
timeFrame: Through Observational Phase (6 months) and Active Treatment Phase (12 months) for total of approximately 18 months
measure: Incidence of target joint bleeds
timeFrame: Through Observational Phase (6 months) and Active Treatment Phase (12 months) for total of approximately 18 months
measure: Incidence of total bleeds (treated and untreated)
timeFrame: Through Observational and Active Treatment Phases (18 Months)
measure: Change from baseline in the Hemophilia Joint Health Score (HJHS)
timeFrame: Through Observational Phase (6 months) and Active Treatment Phase (12 months) for total of approximately 18 months
measure: Change from baseline in (Haemophilia Adult Quality of Life Questionnaire (Haem-A-QoL)
timeFrame: Through Observational Phase (6 months) and Active Treatment Phase (12 months) for total of approximately 18 months
measure: Change from baseline in Haemophilia Quality of Life Questionnaire for Children (Haemo-QoL)
timeFrame: Through Observational Phase (6 months) and Active Treatment Phase (12 months) for total of approximately 18 months
measure: Change from baseline in Hemophilia Adult Activities List (HAL)
timeFrame: Through Observational Phase (6 months) and Active Treatment Phase (12 months) for total of approximately 18 months
measure: Change from baseline in Hemophilia Pediatric Activities List (PedHAL)
timeFrame: Through Observational Phase (6 months) and Active Treatment Phase (12 months) for total of approximately 18 months
measure: Patient Global Impression of Change - Hemophilia (PGIC-H)
timeFrame: Through Observational Phase (6 months) and Active Treatment Phase (12 months) for total of approximately 18 months
measure: Change from baseline in EuroQol 5 Dimensions 5 Level (EQ-5D-5L)
timeFrame: Through Observational Phase (6 months) and Active Treatment Phase (12 months) for total of approximately 18 months
Other outcomes:
Locations:
city: Tampa
country: United States
facility: USF Health Morsani Center For Advanced Healthcare
state: Florida
city: Iowa City
country: United States
facility: University of Iowa
state: Iowa
city: New Hyde Park
country: United States
facility: Northwell Health HTC
state: New York
city: Seattle
country: United States
facility: Washington Institute for Coagulation
state: Washington
city: Sofia
country: Bulgaria
facility: National Specialized Hospital for the Active Treatment of Hematological Diseases - EAD, Sofia
city: Stara Zagora
country: Bulgaria
facility: UMHAT "Prof.Dr. Stoyan Kirkovich"
city: Hamilton
country: Canada
facility: McMaster University Medical Centre - Hamilton Health Sciences
state: Ontario
city: Hamilton
country: Canada
facility: McMaster Children's Hospital
state: Ontario
city: Hamilton
country: Canada
facility: McMaster University
state: Ontario
city: Toronto
country: Canada
facility: The Hospital For Sick Children
state: Ontario
city: Guangzhou
country: China
facility: Nanfang Hospital, Southern Medical University
state: Guangdong
city: Guiyang
country: China
facility: The Affiliated Hospital of Guizhou Medical University
state: Guizhou
city: Nanchang
country: China
facility: Jiangxi Provincial People's Hospital
state: Jiangxi
city: Tianjin
country: China
facility: Institute of Hematology, Chinese Academy of Medical Sciences
state: Tianjin
city: Beijing
country: China
facility: Beijing Children's Hospital, Capital Medical University
city: Zagreb
country: Croatia
facility: Klinicki bolnicki centar Zagreb
city: Paris
country: France
facility: Hôpital Necker Enfants Malades
city: Hong Kong
country: Hong Kong
facility: Prince of Wales Hospital
city: Hong Kong
country: Hong Kong
facility: Queen Mary Hospital
city: Surat
country: India
facility: Nirmal Hospital Pvt, Ltd
state: Gujarat
city: Pune
country: India
facility: Sahyadri Clinical Research and Development Center
state: Maharashtra
city: Pune
country: India
facility: Sahyadri Super Speciality Hospital
state: Maharashtra
city: Vellore
country: India
facility: Christian Medical College
state: Tamil Nadu
city: Milano
country: Italy
facility: Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico
state: Milan
city: Roma
country: Italy
facility: Università degli Studi di Roma "Sapienza"-Policlinico Umberto I
state: RM
city: Perugia
country: Italy
facility: Università degli Studi di Perugia, Azienda Ospedaliera di Perugia, Ospedale Santa Maria della
city: Nagoya
country: Japan
facility: Nagoya University Hospital - Transfusion Medicine
state: Aichi
city: Sapporo
country: Japan
facility: Sapporo Tokushukai Hospital
state: Hokkaido
city: Iruma-gun
country: Japan
facility: Saitama Medical University Hospital
state: Saitama
city: Hiroshima
country: Japan
facility: Hiroshima University Hospital
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: Monterrey
country: Mexico
facility: Hospital Universitario "Dr Jose Eleuterio Gonzalez"
state: Nuevo Leon
city: Mérida
country: Mexico
facility: Centro Multidisciplinario para el Desarrollo Especializado de la Inv. Clínica en Yucatán, S.C.P.
state: Yucatán
city: Muscat
country: Oman
facility: Sultan Qaboos University Hospital
city: Samara
country: Russian Federation
facility: FGBOU VO "Samara State Medical University" of MoH of Russia
city: Jeddah
country: Saudi Arabia
facility: King Abdulaziz University Hospital
city: Riyadh
country: Saudi Arabia
facility: King Faisal Specialist Hospital & Research Center
city: Belgrade
country: Serbia
facility: Clinical Center of Serbia
city: Belgrade
country: Serbia
facility: Institute for Mother and Child healthcare "Dr Vukan Cupic"
city: Kragujevac
country: Serbia
facility: Clinical Center Kragujevac
city: Nis
country: Serbia
facility: Clinical Center Nis
city: Johannesburg
country: South Africa
facility: Charlotte Maxeke Johannesburg Academic Hospital
state: Gauteng
city: A Coruna
country: Spain
facility: Hospital Universitario A Coruna
city: Barcelona
country: Spain
facility: Hospital Universitario Vall d´Hebron
city: Madrid
country: Spain
facility: Hospital Universitario La Paz
city: Salamanca
country: Spain
facility: Hospital Universitario de Salamanca
city: Zaragoza
country: Spain
facility: Hospital Universitario Miguel Servet
city: Changhua City
country: Taiwan
facility: ChangHua Christian Hospital
state: Changhua County
city: Taichung
country: Taiwan
facility: Taichung Veterans General Hospital
city: Adana
country: Turkey
facility: Acibadem Adana Hospital
city: Ankara
country: Turkey
facility: Hacettepe University Medical Faculty
city: Ankara
country: Turkey
facility: Gazi University Health Research and Practice Center Gazi Hospital
city: Antalya
country: Turkey
facility: Akdeniz University Medical Faculty
city: Gaziantep
country: Turkey
facility: Gaziantep University Sahinbey Research and Training Hospital
city: Istanbul
country: Turkey
facility: Istanbul University Oncology Institute
city: Izmir
country: Turkey
facility: Ege University Medical Faculty
city: Izmir
country: Turkey
facility: Dr. Behcet Uz Child Diseases Surgery Education and Research Hospital
city: Kayseri
country: Turkey
facility: Erciyes University Medical Faculty
city: Samsun
country: Turkey
facility: Ondokuz Mayıs University Medical Faculty
city: Trabzon
country: Turkey
facility: Karadeniz Technical University Medical Faculty
Study officials:
affiliation: Pfizer
name: Pfizer CT.gov Call Center
role: STUDY_DIRECTOR
References: