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出境医 / 临床实验 / Study of the Efficacy and Safety PF-06741086 in Adult and Teenage Patients With Severe Hemophilia A or B

Study of the Efficacy and Safety PF-06741086 in Adult and Teenage Patients With Severe Hemophilia A or B

Study Description
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.

Condition or disease Intervention/treatment Phase
Hemophilia A Hemophilia B Drug: PF-06741086 Phase 3

Study Design
Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 145 participants
Allocation: N/A
Intervention Model: Crossover Assignment
Intervention Model Description: This is a one way Cross-Over Prevention study with 1 Arm that has No masking.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: An Open-Label Study in Adolescent and Adult Severe (Coagulation Factor Activity <1%) Hemophilia A or B Patients With or Without Inhibitors Comparing Standard Treatment to PF-06741086 Prophylaxis
Actual Study Start Date : March 9, 2020
Estimated Primary Completion Date : August 12, 2023
Estimated Study Completion Date : August 12, 2023
Arms and Interventions
Arm Intervention/treatment
Experimental: PF-06741086
Participants will be assigned to treatment with PF-06741086 after a 6 month Observation Phase on their current hemophilia regimen.
 Drug: PF-06741086
300 milligrams(mg) subcutaneous (sc) loading dose followed by 150 mg sq once weekly (qw). 300 mg sc qw is prescribed for participants who meet dose escalation criteria.
Outcome Measures
Primary Outcome Measures :
  1. Annualized bleeding rate (ABR) of treated bleeding events [ Time Frame: Through Observational Phase (6months) and Active Treatment Phase (12 months) for total of approximately 18 months ]
    Derived for each subject for each treatment period by using the following formula: ABR = number of bleeds requiring treatments/ (days on treatment period / 365.25)

  2. Incidence and severity of thrombotic events [ Time Frame: Through Observational Phase (6 months) and Active Treatment Phase (12 months) for total of approximately 18 months ]
  3. Incidence of anti drug antibody [ADA] against PF-06741086 [ Time Frame: Throughout Active Treatment Phase (12 months) ]
  4. Incidence of clinically significant persistent neutralizing antibody [NAb] against PF-06741086 [ Time Frame: Throughout Active Treatment Phase (12 months) ]
  5. Incidence and severity of injection site reaction [ Time Frame: Throughout Active Treatment Phase (12 months) ]
  6. Number of participants with clinically significant changes from baseline in physical exam [ Time Frame: From Baseline through Observation and Active Treatment (approximately 18 months) ]
  7. Incidence of clinically significant laboratory value abnormalities [ Time Frame: From Screening through Observation and Active Treatment (approximately 18 months) ]
  8. Incidence of severe hypersensitivity and anaphylactic reactions [ Time Frame: From Screening through Observational and Active Treatment (approximately 18 months) ]
  9. Incidence of adverse events and serious adverse events [ Time Frame: From screening through Observation and Active treatment (approximately 18 months) ]
  10. Number of participants with clinically significant changes from baseline in vital signs [ Time Frame: From Baseline through Observation and Active Treatment (approximately 18 months) ]
  11. Incidence and severity of thromboticangiopathy [ Time Frame: Throughout Active Treatment Phase (12 months) ]
  12. Incidence of intravascular coagulation/consumption coagulopathy [ Time Frame: Throughout Active Treatment Phase (12 months) ]

Secondary Outcome Measures :
  1. Total coagulation factor and/or bypass product consumption [ Time Frame: Through Observational Phase (6 months) and Active Treatment Phase (12 months) for total of approximately 18 months ]
    The Total Factor/bypass product consumed per participant as measured in total IU and IU/kg per month and per year

  2. Incidence of joint bleeds [ Time Frame: Through Observational Phase (6 months) and Active Treatment Phase (12 months) for total of approximately 18 months ]
  3. Incidence of spontaneous bleeds [ Time Frame: Through Observational Phase (6 months) and Active Treatment Phase (12 months) for total of approximately 18 months ]
  4. Incidence of target joint bleeds [ Time Frame: Through Observational Phase (6 months) and Active Treatment Phase (12 months) for total of approximately 18 months ]
  5. Incidence of total bleeds (treated and untreated) [ Time Frame: Through Observational and Active Treatment Phases (18 Months) ]
  6. Percentage of participants with no bleeding episodes [ Time Frame: Through Observational Phase (6 months) and Active Treatment Phase (12 months) for total of approximately 18 months ]
  7. Change from baseline in the Hemophilia Joint Health Score (HJHS) [ Time Frame: Through Observational Phase (6 months) and Active Treatment Phase (12 months) for total of approximately 18 months ]
  8. Change from baseline in (Haemophilia Adult Quality of Life Questionnaire (Haem-A-QoL) [ Time Frame: Through Observational Phase (6 months) and Active Treatment Phase (12 months) for total of approximately 18 months ]
  9. Change from baseline in Haemophilia Quality of Life Questionnaire for Children (Haemo-QoL) [ Time Frame: Through Observational Phase (6 months) and Active Treatment Phase (12 months) for total of approximately 18 months ]
  10. Change from baseline in Hemophilia Adult Activities List (HAL) [ Time Frame: Through Observational Phase (6 months) and Active Treatment Phase (12 months) for total of approximately 18 months ]
  11. Change from baseline in Hemophilia Pediatric Activities List (PedHAL) [ Time Frame: Through Observational Phase (6 months) and Active Treatment Phase (12 months) for total of approximately 18 months ]
  12. Patient Global Impression of Change - Hemophilia (PGIC-H) [ Time Frame: Through Observational Phase (6 months) and Active Treatment Phase (12 months) for total of approximately 18 months ]
  13. Change from baseline in EuroQol 5 Dimensions 5 Level (EQ-5D-5L) [ Time Frame: Through Observational Phase (6 months) and Active Treatment Phase (12 months) for total of approximately 18 months ]

Eligibility Criteria
Layout table for eligibility information
Ages Eligible for Study:   12 Years to 74 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   Male
Gender Based Eligibility:   Yes
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria

  • Participants with a diagnosis of severe hemophilia A or 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
  • Participants with on-demand treatment regimen with ≥6 bleeding episodes (spontaneous and/or traumatic) necessitating treatment with bypass factor during the 6 months prior to enrollment in the Observation Phase and willing to continue to receive on-demand treatment during this 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 approval 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.
  • Regular, concomitant therapy with immunomodulatory drugs
  • Ongoing or planned use of immune tolerance induction or prophylaxis with FVIII or FIX replacement during the Active Treatment Phase.
  • Previous exposure to PF 06741086 during to participation in studies B7841002 and B7841003.
  • Participation in other studies involving investigational drug(s) 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.
Contacts and Locations

Contacts
Layout table for location contacts
Contact: Pfizer CT.gov Call Center 1-800-718-1021 ClinicalTrials.gov_Inquiries@pfizer.com

Locations
Show Show 68 study locations
Sponsors and Collaborators
Pfizer
Investigators
Layout table for investigator information
Study Director: Pfizer CT.gov Call Center Pfizer
Tracking Information
First Submitted Date  ICMJE May 2, 2019
First Posted Date  ICMJE May 6, 2019
Last Update Posted Date May 13, 2021
Actual Study Start Date  ICMJE March 9, 2020
Estimated Primary Completion Date August 12, 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 19, 2019)
  • Annualized bleeding rate (ABR) of treated bleeding events [ Time Frame: Through Observational Phase (6months) and Active Treatment Phase (12 months) for total of approximately 18 months ]
    Derived for each subject for each treatment period by using the following formula: ABR = number of bleeds requiring treatments/ (days on treatment period / 365.25)
  • Incidence and severity of thrombotic events [ Time Frame: Through Observational Phase (6 months) and Active Treatment Phase (12 months) for total of approximately 18 months ]
  • Incidence of anti drug antibody [ADA] against PF-06741086 [ Time Frame: Throughout Active Treatment Phase (12 months) ]
  • Incidence of clinically significant persistent neutralizing antibody [NAb] against PF-06741086 [ Time Frame: Throughout Active Treatment Phase (12 months) ]
  • Incidence and severity of injection site reaction [ Time Frame: Throughout Active Treatment Phase (12 months) ]
  • Number of participants with clinically significant changes from baseline in physical exam [ Time Frame: From Baseline through Observation and Active Treatment (approximately 18 months) ]
  • Incidence of clinically significant laboratory value abnormalities [ Time Frame: From Screening through Observation and Active Treatment (approximately 18 months) ]
  • Incidence of severe hypersensitivity and anaphylactic reactions [ Time Frame: From Screening through Observational and Active Treatment (approximately 18 months) ]
  • Incidence of adverse events and serious adverse events [ Time Frame: From screening through Observation and Active treatment (approximately 18 months) ]
  • Number of participants with clinically significant changes from baseline in vital signs [ Time Frame: From Baseline through Observation and Active Treatment (approximately 18 months) ]
  • Incidence and severity of thromboticangiopathy [ Time Frame: Throughout Active Treatment Phase (12 months) ]
  • Incidence of intravascular coagulation/consumption coagulopathy [ Time Frame: Throughout Active Treatment Phase (12 months) ]
Original Primary Outcome Measures  ICMJE
 (submitted: May 2, 2019)
  • Annualized bleeding rate (ABR) of treated bleeding events [ Time Frame: Through Observational Phase (6months) and Active Treatment Phase (12 months) for total of approximately 18 months ]
    Derived for each subject for each treatment period by using the following formula: ABR = number of bleeds requiring treatments/ (days on treatment period / 365.25)
  • Incidence and severity of thrombotic events [ Time Frame: Through Observational Phase (6 months) and Active Treatment Phase (12 months) for total of approximately 18 months ]
  • Incidence of anti drug antibody [ADA] against PF-06741086 [ Time Frame: Throughout Active Treatment Phase (12 months) ]
  • Incidence of clinically significant persistent neutralizing antibody [NAb] against PF-06741086 [ Time Frame: Throughout Active Treatment Phase (12 months) ]
  • Incidence and severity of injection site reaction [ Time Frame: Throughout Active Treatment Phase (12 months) ]
  • Number of participants with clinically significant changes from baseline in physical exam [ Time Frame: From Baseline through Observation and Active Treatment (approximately 18 months) ]
  • Incidence of clinically significant laboratory value abnormalities [ Time Frame: From Screening through Observation and Active Treatment (approximately 18 months) ]
  • Incidence of severe hypersensitivity and anaphylactic reactions [ Time Frame: From Screening through Observational and Active Treatment (approximately 18 months) ]
  • Incidence of adverse events and serious adverse events [ Time Frame: From screening through Observation and Active treatment (approximately 18 months) ]
  • Number of participants with clinically significant changes from baseline in vital signs [ Time Frame: From Baseline through Observation and Active Treatment (approximately 18 months) ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 2, 2019)
  • Total coagulation factor and/or bypass product consumption [ Time Frame: Through Observational Phase (6 months) and Active Treatment Phase (12 months) for total of approximately 18 months ]
    The Total Factor/bypass product consumed per participant as measured in total IU and IU/kg per month and per year
  • Incidence of joint bleeds [ Time Frame: Through Observational Phase (6 months) and Active Treatment Phase (12 months) for total of approximately 18 months ]
  • Incidence of spontaneous bleeds [ Time Frame: Through Observational Phase (6 months) and Active Treatment Phase (12 months) for total of approximately 18 months ]
  • Incidence of target joint bleeds [ Time Frame: Through Observational Phase (6 months) and Active Treatment Phase (12 months) for total of approximately 18 months ]
  • Incidence of total bleeds (treated and untreated) [ Time Frame: Through Observational and Active Treatment Phases (18 Months) ]
  • Percentage of participants with no bleeding episodes [ Time Frame: Through Observational Phase (6 months) and Active Treatment Phase (12 months) for total of approximately 18 months ]
  • Change from baseline in the Hemophilia Joint Health Score (HJHS) [ Time Frame: Through Observational Phase (6 months) and Active Treatment Phase (12 months) for total of approximately 18 months ]
  • Change from baseline in (Haemophilia Adult Quality of Life Questionnaire (Haem-A-QoL) [ Time Frame: Through Observational Phase (6 months) and Active Treatment Phase (12 months) for total of approximately 18 months ]
  • Change from baseline in Haemophilia Quality of Life Questionnaire for Children (Haemo-QoL) [ Time Frame: Through Observational Phase (6 months) and Active Treatment Phase (12 months) for total of approximately 18 months ]
  • Change from baseline in Hemophilia Adult Activities List (HAL) [ Time Frame: Through Observational Phase (6 months) and Active Treatment Phase (12 months) for total of approximately 18 months ]
  • Change from baseline in Hemophilia Pediatric Activities List (PedHAL) [ Time Frame: Through Observational Phase (6 months) and Active Treatment Phase (12 months) for total of approximately 18 months ]
  • Patient Global Impression of Change - Hemophilia (PGIC-H) [ Time Frame: Through Observational Phase (6 months) and Active Treatment Phase (12 months) for total of approximately 18 months ]
  • Change from baseline in EuroQol 5 Dimensions 5 Level (EQ-5D-5L) [ Time Frame: Through Observational Phase (6 months) and Active Treatment Phase (12 months) for total of approximately 18 months ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Study of the Efficacy and Safety PF-06741086 in Adult and Teenage Patients With Severe Hemophilia A or B
Official Title  ICMJE An Open-Label Study in Adolescent and Adult Severe (Coagulation Factor Activity <1%) Hemophilia A or B Patients With or Without Inhibitors Comparing Standard Treatment to PF-06741086 Prophylaxis
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.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: N/A
Intervention Model: Crossover Assignment
Intervention Model Description:
This is a one way Cross-Over Prevention study with 1 Arm that has No masking.
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Hemophilia A
  • Hemophilia B
Intervention  ICMJE Drug: PF-06741086
300 milligrams(mg) subcutaneous (sc) loading dose followed by 150 mg sq once weekly (qw). 300 mg sc qw is prescribed for participants who meet dose escalation criteria.
Study Arms  ICMJE Experimental: PF-06741086
Participants will be assigned to treatment with PF-06741086 after a 6 month Observation Phase on their current hemophilia regimen.
Intervention: Drug: PF-06741086
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: May 2, 2019) 		145
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE August 12, 2023
Estimated Primary Completion Date August 12, 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria

  • Participants with a diagnosis of severe hemophilia A or 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
  • Participants with on-demand treatment regimen with ≥6 bleeding episodes (spontaneous and/or traumatic) necessitating treatment with bypass factor during the 6 months prior to enrollment in the Observation Phase and willing to continue to receive on-demand treatment during this 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 approval 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.
  • Regular, concomitant therapy with immunomodulatory drugs
  • Ongoing or planned use of immune tolerance induction or prophylaxis with FVIII or FIX replacement during the Active Treatment Phase.
  • Previous exposure to PF 06741086 during to participation in studies B7841002 and B7841003.
  • Participation in other studies involving investigational drug(s) 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.
Sex/Gender  ICMJE
Sexes Eligible for Study: Male
Gender Based Eligibility: Yes
Ages  ICMJE 12 Years to 74 Years   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Pfizer CT.gov Call Center 1-800-718-1021 ClinicalTrials.gov_Inquiries@pfizer.com
Listed Location Countries  ICMJE Australia,   Brazil,   Bulgaria,   Canada,   Croatia,   France,   Germany,   Hong Kong,   India,   Ireland,   Italy,   Japan,   Korea, Republic of,   Mexico,   Oman,   Russian Federation,   Serbia,   Spain,   Taiwan,   Turkey,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03938792
Other Study ID Numbers  ICMJE B7841005
2018-003660-31 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
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
Responsible Party Pfizer
Study Sponsor  ICMJE Pfizer
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Pfizer CT.gov Call Center Pfizer
PRS Account Pfizer
Verification Date May 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP

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