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
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 发起方
- Pfizer
- 入组人数
- 188
- 试验地点
- 105
- 主要终点
- Annualized bleeding rate (ABR) of treated bleeding events
研究概览
简要总结
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Crossover
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 12 Years 至 74 Years（Child, Adult, Older Adult）
- 性别
- Male
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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 B
- •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.
研究组 & 干预措施
PF-06741086
Participants will be assigned to treatment with PF-06741086 after a 6 month Observation Phase on their current hemophilia regimen.
干预措施: PF-06741086 (Drug)
结局指标
主要结局
Annualized bleeding rate (ABR) of treated bleeding events
时间窗: 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
时间窗: 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
时间窗: Throughout Active Treatment Phase (12 months)
Incidence of clinically significant persistent neutralizing antibody [NAb] against PF-06741086
时间窗: Throughout Active Treatment Phase (12 months)
Incidence and severity of injection site reaction
时间窗: Throughout Active Treatment Phase (12 months)
Number of participants with clinically significant changes from baseline in physical exam
时间窗: From Baseline through Observation and Active Treatment (approximately 18 months)
Incidence of clinically significant laboratory value abnormalities
时间窗: From Screening through Observation and Active Treatment (approximately 18 months)
Incidence of severe hypersensitivity and anaphylactic reactions
时间窗: From Screening through Observational and Active Treatment (approximately 18 months)
Incidence of adverse events and serious adverse events
时间窗: From screening through Observation and Active treatment (approximately 18 months)
Number of participants with clinically significant changes from baseline in vital signs
时间窗: From Baseline through Observation and Active Treatment (approximately 18 months)
Incidence and severity of thromboticangiopathy
时间窗: Throughout Active Treatment Phase (12 months)
Incidence of intravascular coagulation/consumption coagulopathy
时间窗: Throughout Active Treatment Phase (12 months)
Model-Based Annualized Bleeding Rate (ABR) of Treated Bleeding Events: Inhibitor Cohort (Participants With Prior OD Therapy at OP)
时间窗: OP reporting group: Up to 6 months; ATP reporting group: up to 12 months
ABR is defined as number of bleeding episodes per year. ABR was calculated as number of bleeds requiring treatments/ (days on treatment period/365.25). If a participant did not complete a treatment period, days on treatment ended at last dosing date + 6 days. Treated bleed: If a bleed was treated with factor replacement or bypass agents within 48 hours of start of bleeding, regardless of the type of treatment (preventive, prophylaxis or OD medication). A model-based ABR using a repeated measures negative binomial model is reported for this outcome measure.
Number of Participants With Thrombotic Events: Inhibitor and Non-Inhibitor Cohort
时间窗: OP reporting group: Up to 6 months; ATP reporting group: up to 13 months (includes 28-35 days of safety follow-up post last dose of study drug)
Thrombotic events are when a blood clot (thrombus) forms in a blood vessel in the arm, leg, lung, or head and can be life-threatening. A thrombus can occur in veins (venous thrombosis) or arteries (arterial thrombosis).
Model-Based ABR of Treated Bleeding Events: Non-Inhibitor Cohort (Participants With Prior OD Therapy at OP)
时间窗: OP reporting group: Up to 6 months; ATP reporting group: up to 12 months
ABR is defined as number of bleeding episodes per year. ABR was calculated as number of bleeds requiring treatments/ (days on treatment period/365.25). If a participant did not complete a treatment period, days on treatment ended at last dosing date + 6 days. Treated bleed: If a bleed was treated with factor replacement or bypass agents within 48 hours of start of bleeding, regardless of the type of treatment (preventive, prophylaxis or OD medication). A model-based ABR using a repeated measures negative binomial model is reported for this outcome measure.
Model-Based ABR of Treated Bleeding Events: Non-Inhibitor Cohort (Participants With RP at OP)
时间窗: OP reporting group: Up to 6 months; ATP reporting group: up to 12 months
ABR is defined as number of bleeding episodes per year. ABR was calculated as number of bleeds requiring treatments/ (days on treatment period/365.25). If a participant did not complete a treatment period, days on treatment ended at last dosing date + 6 days. Treated bleed: If a bleed was treated with factor replacement or bypass agents within 48 hours of start of bleeding, regardless of the type of treatment (preventive, prophylaxis or OD medication). A model-based ABR using a repeated measures negative binomial model is reported for this outcome measure.
Number of Participants With Adverse Events (AEs): Inhibitor and Non-Inhibitor Cohort
时间窗: OP reporting group: Up to 6 months; ATP reporting group: up to 13 months (includes 28-35 days of safety follow-up post last dose of study drug)
An AE was any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. AEs included both serious AEs and all other AEs.
Number of Participants With Serious Adverse Events (SAEs): Inhibitor and Non-Inhibitor Cohort
时间窗: OP reporting group: Up to 6 months; ATP reporting group: up to 13 months (includes 28-35 days of safety follow-up post last dose of study drug)
AE: any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. SAE: any untoward medical occurrence at any dose that resulted in any of the following outcomes: death; life-threatening; required inpatient hospitalization or prolongation of existing hospitalization; persistent or significant disability/incapacity; congenital anomaly/birth defect; or that was considered as an important medical event.
Number of Participants With Thrombotic Microangiopathy: Inhibitor and Non-Inhibitor Cohort
时间窗: OP reporting group: Up to 6 months; ATP reporting group: up to 13 months (includes 28-35 days of safety follow-up post last dose of study drug)
Thrombotic microangiopathy: pathological state where micro-vessels are occluded by platelet rich thrombi leading to thrombocytopenia (low platelets) and microangiopathic haemolytic anaemia (red blood cell destruction) and potential end organ damage.
Number of Participants With Disseminated Intravascular Coagulation/ Consumption Coagulopathy: Inhibitor and Non-Inhibitor Cohort
时间窗: OP reporting group: Up to 6 months; ATP reporting group: up to 13 months (includes 28-35 days of safety follow-up post last dose of study drug)
Disseminated intravascular coagulation is characterized by widespread clotting in small blood vessels, and consumption of platelets and clotting factors by the clots, leading to bleeding.
Number of Participants With Anti-drug Antibodies (ADA) and Neutralizing Antibodies (NAb) Against PF- 06741086: Inhibitor and Non-Inhibitor Cohort
时间窗: During prophylaxis treatment in ATP (12 months)
ADA positive: A participant with \>=1 treatment induced or treatment-boosted ADA response. NAb positive: An ADA positive participant with \>=1 treatment induced or treatment boosted NAb response.
Number of Participants With Transient and Persistent ADA and NAb Against PF-06741086: Inhibitor and Non-Inhibitor Cohort
时间窗: During prophylaxis treatment in ATP (12 months)
Persistent ADA: participant with treatment-induced or treatment-boosted ADA detected at 2 or more times during treatment including any follow-up, where first and last ADA positive samples separated by \>=16 weeks. Transient ADA: treatment-induced or treatment-boosted ADA detected at only 1 time during treatment or follow-up. Persistent NAb: NAb-positive participant with first and last positive NAb samples detected \>=16 weeks posttreatment, irrespective of any negative samples in between. Transient NAb: NAb-positive participant with (1) treatment-induced/treatment-boosted NAb sample detected at only 1 time posttreatment or (2) treatment-induced/treatment-boosted NAb samples detected at 2 or more times where first and last positive samples separated by \<16 weeks, and participant's last sample was NAb or ADA negative.
Number of Participants With Injection Site Reactions (ISRs): Inhibitor and Non-Inhibitor Cohort
时间窗: During prophylaxis treatment in ATP (12 months)
ISR included: injection site haematoma, injection site pain, injection site bruising, injection site erythema, injection site induration, injection site oedema, Injection site pruritus and Injection site swelling. ISR graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 where grade 1: tenderness with or without associated symptoms (warmth, erythema, itching), grade 2: pain, lipodystrophy, edema, phlebitis, grade 3: ulceration or necrosis, severe tissue damage, operative intervention indicated, grade 4: life-threatening consequences, urgent intervention indicated and grade 5: death. In this outcome measure only categories with non-zero values reported.
Number of Participants With Clinically Significant Changes in Physical Examinations: Inhibitor and Non-Inhibitor Cohort
时间窗: OP reporting group: Up to 6 months; ATP reporting group: up to 13 months (includes 28-35 days of safety follow-up post last dose of study drug)
Physical examination included assessments of the head, ears, eyes, nose, mouth, skin, heart and lung examinations, lymph nodes, gastrointestinal, musculoskeletal, and neurological systems. Height and weight were also measured and recorded. Clinical significance in physical examinations was determined by investigator.
Number of Participants With Clinically Significant Changes in Vital Signs: Inhibitor and Non-Inhibitor Cohort
时间窗: OP reporting group: Up to 6 months; ATP reporting group: up to 13 months (includes 28-35 days of safety follow-up post last dose of study drug)
Vital signs included temperature, pulse rate, respiratory rate, and blood pressure. Blood pressure and pulse rate were measured in a supine position using completely automated device after at least 5 minutes of rest for the participant in a quiet setting without distractions. Respiratory rate was measured by observing and counting the respirations of the participant for 30 seconds and multiplied by 2. Clinical significance of vital signs was determined by investigator.
Number of Participants With Clinically Significant Abnormalities in Laboratory Parameters: Inhibitor and Non-Inhibitor Cohort
时间窗: OP reporting group: Up to 6 months; ATP reporting group: up to 13 months (includes 28-35 days of safety follow-up post last dose of study drug)
Hematology included: hemoglobin; leukocytes; neutrophils; and platelets. Chemistry included: potassium; aspartate aminotransferase; creatinine; alkaline phosphatase; total bilirubin; albumin; calcium corrected, estimated decreased; sodium; and calcium. Clinical significance of laboratory parameters was determined by investigator.
Number of Participants With Severe/ Systematic Hypersensitivity and Anaphylactic Reactions: Inhibitor and Non-Inhibitor Cohort
时间窗: During prophylaxis treatment in ATP (12 months)
Systemic hypersensitivity is a complex immune response where the immune system reacts excessively to an antigen, often leading to severe allergic reactions, including widespread symptoms (which may affect multiple organs), such as rash, swelling of your face, lips, mouth, or tongue, trouble breathing, wheezing, dizziness, fainting, fast heartbeat, pounding in your chest or sweating. Anaphylaxis is a severe, potentially fatal, systemic allergic reaction that occurs suddenly after contact with an allergy causing substance.
次要结局
- Incidence of joint bleeds(Through Observational Phase (6 months) and Active Treatment Phase (12 months) for total of approximately 18 months)
- Incidence of spontaneous bleeds(Through Observational Phase (6 months) and Active Treatment Phase (12 months) for total of approximately 18 months)
- Incidence of target joint bleeds(Through Observational Phase (6 months) and Active Treatment Phase (12 months) for total of approximately 18 months)
- Incidence of total bleeds (treated and untreated)(Through Observational and Active Treatment Phases (18 Months))
- Change from baseline in the Hemophilia Joint Health Score (HJHS)(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)(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)(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)(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)(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)(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)(Through Observational Phase (6 months) and Active Treatment Phase (12 months) for total of approximately 18 months)
- Model-Based ABR of Joint Bleeds: Inhibitor and Non-Inhibitor Cohort(OP reporting group: Up to 6 months; ATP reporting group: up to 12 months)
- Model-Based ABR of Spontaneous Bleeds: Inhibitor and Non-Inhibitor Cohort(OP reporting group: Up to 6 months; ATP reporting group: up to 12 months)
- Model-Based ABR of Target Joint Bleeds: Inhibitor and Non-Inhibitor Cohort(OP reporting group: Up to 6 months; ATP reporting group: up to 12 months)
- Model-Based ABR of Total Bleeds: Inhibitor and Non-Inhibitor Cohort(OP reporting group: Up to 6 months; ATP reporting group: up to 12 months)
- Change From Baseline in Hemophilia Joint Health Score (HJHS) at Month 6: Non-Inhibitor Cohort(OP reporting group: Baseline (Day 1, day of study enrollment), Month 6; ATP reporting group: Baseline (before dose on Day 1 of ATP), Month 6)
- Change From Baseline in HJHS at Month 6: Inhibitor Cohort(OP reporting group: Baseline (Day 1, day of study enrollment), Month 6; ATP reporting group: Baseline (before dose on Day 1 of ATP), Month 6)
- Change From Baseline in Hemophilia Quality of Life Questionnaire for Adults (Haem-A-QoL) Total Score and Physical Health Domain at Month 6: Non-Inhibitor Cohort, Participants >=17 Years(OP reporting group: Baseline (Day 1, day of study enrollment), Month 6; ATP reporting group: Baseline (before dose on Day 1 of ATP), Month 6)
- Change From Baseline in Haem-A-QoL Total Score and Physical Health Domain at Month 6: Inhibitor Cohort, Participants >=17 Years(OP reporting group: Baseline (Day 1, day of study enrollment), Month 6; ATP reporting group: Baseline (before dose on Day 1 of ATP), Month 6)
- Change From Baseline in Hemophilia Quality of Life Questionnaire for Children (Haemo-QoL) Total Score at Month 6: Non-Inhibitor Cohort, Participants 12 to <17 Years(OP reporting group: Baseline (Day 1, day of study enrollment), Month 6; ATP reporting group: Baseline (before dose on Day 1 of ATP), Month 6)
- Change From Baseline in Haemo-QoL Total Score at Month 6: Inhibitor Cohort, Participants 12 to <17 Years(OP reporting group: Baseline (Day 1, day of study enrollment), Month 6; ATP reporting group: Baseline (before dose on Day 1 of ATP), Month 6)
- Change From Baseline in Hemophilia Activities List (HAL) Total Score at Month 6: Non-Inhibitor Cohort, Participants >=17 Years(OP reporting group: Baseline (Day 1, day of study enrollment), Month 6; ATP reporting group: Baseline (before dose on Day 1 of ATP), Month 6)
- Change From Baseline in HAL Total Score at Month 6: Inhibitor Cohort, Participants >=17 Years(OP reporting group: Baseline (Day 1, day of study enrollment), Month 6; ATP reporting group: Baseline (before dose on Day 1 of ATP), Month 6)
- Change From Baseline in Pediatric Hemophilia Activities List (pedHAL) Total Score at Month 6: Non-Inhibitor Cohort, Participants 12 to <17 Years(OP reporting group: Baseline (Day 1, day of study enrollment), Month 6; ATP reporting group: Baseline (before dose on Day 1 of ATP), Month 6)
- Change From Baseline in pedHAL Total Score at Month 6: Inhibitor Cohort, Participants 12 to <17 Years(OP reporting group: Baseline (Day 1, day of study enrollment), Month 6; ATP reporting group: Baseline (before dose on Day 1 of ATP), Month 6)
- Patient Global Impression of Change-Hemophilia (PGIC-H) at Month 6: Non-Inhibitor Cohort(Month 6)
- PGIC-H at Month 6: Inhibitor Cohort(Month 6)
- Change From Baseline in EuroQol 5 Dimensions 5 Level (EQ-5D-5L) Index and VAS Scores at Month 6: Non-Inhibitor Cohort(OP reporting group: Baseline (Day 1, day of study enrollment), Month 6; ATP reporting group: Baseline (before dose on Day 1 of ATP), Month 6)
- Change From Baseline in EQ-5D-5L Index and VAS Scores at Month 6: Inhibitor Cohort(OP reporting group: Baseline (Day 1, day of study enrollment), Month 6; ATP reporting group: Baseline (before dose on Day 1 of ATP), Month 6)