An Ascending Single Dose Study To Evaluate The Safety, Tolerability And Pharmacokinetics/Pharmacodynamics Of Pf-05280602, A Recombinant Factor Viia Variant (813d), In Adult Hemophilia A And B Subjects With Or Without Inhibitors
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 29
- 试验地点
- 23
- 主要终点
- Number of Participants With Treatment-Emergent Hemophilia AEs and Withdrawals Due to Hemophilia AEs
研究概览
简要总结
This study hypothesizes that the study drug, PF-05280602 (at the selected doses) will be safe to administer to subjects with severe Hemophilia A or B with or without inhibitors and will demonstrate evidence of hemostatic activity. This is supported by the preclinical findings in hemophilic animal models.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Basic Science
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 64 Years（Adult）
- 性别
- Male
- 接受健康志愿者
- 否
入选标准
- •Male subjects 18 to <65 years old with severe hemophilia A or B with or without inhibitors to FVIII or FIX.
- •Subjects is willing and able to comply with the mandatory washout periods prior to screening and prior to dosing and through 48 hours post dosing. At screening this includes a washout of FIX for 96 hours and FVIII for 72 houts. At dosing this includes a washout of FIX for 96 hours and FVIII and other hemostatic agents for 72 hours through 48 hours post dosing.
- •Subjects must agree and commit to using a a highly effective method of birth control from the time of screening through four weeks after study drug administration.
排除标准
- •Presence of a bleeding disorder in addition to hemophilia A or B.
- •Regular, concomitant therapy with immunomodulating drugs (eg, intravenous immunoglobulin, and routine systemic corticosteroids).
- •History of coronary artery disease, thrombolic disease or diagnosis of prothrombic disorder.
研究组 & 干预措施
2
干预措施: PF-05280602 (Biological)
5
干预措施: PF-05280602 (Biological)
4
干预措施: PF-05280602 (Biological)
3
干预措施: PF-05280602 (Biological)
1
干预措施: PF-05280602 (Biological)
结局指标
主要结局
Number of Participants With Treatment-Emergent Hemophilia AEs and Withdrawals Due to Hemophilia AEs
时间窗: Baseline through Day 60
Hemophilia AEs included spontaneous (no known contributing factor) and traumatic (known or presumed contributing factor/reason) bleeding episodes.
Change From Baseline in Body Temperature
时间窗: Baseline, Day 2, Day 3, and Day 15
Body temperature was measured by mouth (oral) or ear (tympanic). A temperature greater than 38.5 degree Celsius was considered a fever.
Number of Participants With Treatment-Emergent Adverse Events (AEs), Serious Adverse Events (SAEs), and Withdrawals Due to AEs (Except Hemophilia AEs)
时间窗: Baseline through Day 60
An AE was any untoward medical occurrence in a participant who received study drug. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent are events between first dose of study drug and up to Day 15 that were absent before treatment or that worsened relative to pre-treatment state. AEs included both SAEs and non-SAEs.
Number of Treatment-Emergent AEs and SAEs by Severity (Except Hemophilia AEs)
时间窗: Baseline through Day 60
AE severity were graded as mild, moderate, or severe. Mild severity AEs do not interfere with the participant's usual function. Moderate AEs interfere to some extent with the participant's usual function. Severe AEs interfere significantly with the participant's usual function.
Number of Treatment-Emergent Hemophilia AEs by Severity
时间窗: Baseline through Day 60
Mild severity AEs do not interfere with the participant's usual function. Moderate AEs interfere to some extent with the participant's usual function. Severe AEs interfere significantly with the participant's usual function.
Number of Participants With Treatment-Emergent Abnormal Anti-Thrombin III (ATIII) Levels by Magnitude
时间窗: Baseline through Day 3
ATIII is a protein in the blood that blocks abnormal blood clots from forming. Low levels of ATIII can cause abnormal blood clots. ATIII levels of potential clinical concern are values \<1X LLN and \>1X ULN.
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)
时间窗: Baseline, Day 2, Day 3, and Day 15
Supine blood pressure (BP) was measured with the participant's arm supported at the level of the heart, and recorded to the nearest millimeters of mercury (mmHg) after 5 minutes of rest. The same arm (preferably the dominant arm) was to be used throughout the study.
Change From Baseline in Respiration Rate
时间窗: Baseline, Day 2, Day 3, and Day 15
Respiration rate measured as respirations per minute (resp/min).
Change From Baseline in Supine Pulse Rate
时间窗: Baseline, Day 2, Day 3, and Day 15
Change from baseline is the vital sign value at Day 2, Day 3, and Day 15 minus vital sign value at baseline.
Change From Baseline in Body Weight
时间窗: Baseline, Day 2, Day 3, and Day 15
Number of Participants With Changes Since Previous Physical Examination
时间窗: Baseline (Day 0), Day 1, Day 2, Day 3, Day 15
Physical examinations were conducted by a physician, trained physician's assistant, or nurse practitioner. A complete physical examination included head, ears, eyes, nose, mouth, skin, heart and lung examinations, lymph nodes, genitourinary, gastrointestinal, musculoskeletal, and neurological systems. The limited or abbreviated physical examination focused on general appearance, the respiratory and cardiovascular systems, as well as towards participant reported symptoms.
Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings
时间窗: Baseline through Day 15
ECG findings of potential clinical concern were: PR interval greater than or equal to (\>=)300 milliseconds (msec), \>=25% increase from baseline for baseline values \>200 msec, \>=50% increase from baseline for baseline values less than or equal to (\<=)200 msec; QRS complex \>=140 msec or \>=50% increase from baseline; QTcF interval (Fridericia's correction) \>=450 msec or \>=30 msec increase from baseline.
Number of Participants With Treatment-Emergent Abnormal Troponin-T Levels by Magnitude
时间窗: Baseline through Day 15
Troponin-T is a cardiac marker for the evaluation of possible cardiovascular injury. Troponin-T levels of potential clinical concern are values \>1.5 times the upper limit of normal (1.5X ULN) or \>=2.5X ULN.
Number of Participants With Treatment-Emergent Abnormal Tissue Factor Pathway Inhibitor (TFPI) Levels by Magnitude
时间窗: Baseline through Day 3
TFPI is a polypeptide that can regulate blood coagulation. TFPI levels of potential clinical concern are values \<1X LLN and \>1X ULN.
Number of Participants With Positive Immune Response (Anti-Drug Antibodies [ADA], PF-05280602 Inhibitor, Factor VIIa Inhibitor, Factor VII Inhibitor, and Depletion of Factor VII Activity)
时间窗: Baseline through Day 60
Assays for the determination of a positive immune response was performed. An antibody immune response was defined as a confirmed post-treatment positive ELISA result in combination with a negative baseline sample ELISA result. Positive antibody immune responses to PF-05280602 by ELISA was evaluated for cross reactivity to NovoSeven RT and to Factor VII.
Number of Participants With Treatment-Emergent Laboratory Test Abnormalities (Normal Baseline)
时间窗: Baseline through Day 15
The following laboratory parameters were analyzed: hematology (hemoglobin, hematocrit, red blood cell \[RBC\] count, platelets, leukocytes, total neutrophils, eosinophils, basophils, lymphocytes, monocytes); chemistry (total bilirubin, direct bilirubin, indirect bilirubin, aspartate aminotransferase \[AST\], alanine aminotransferase \[ALT\], alkaline phosphatase, creatinine, blood urea nitrogen \[BUN\], glucose, uric acid, sodium, potassium, chloride, bicarbonate, calcium, albumin, total protein, creatine kinase); urinalysis (urine white blood cell \[WBC\], urine RBC); other (troponin T).
Number of Participants With Clinically Significant Laboratory Abnormalities Meeting Stopping Criteria
时间窗: Baseline through Day 15
Clinically significant findings for stopping rules are: hemoglobin \<8 grams/deciliter (g/dL) or \>20% decrease from normal baseline; WBC \>20,000 cells/mm\^3 or \<1,500 decrease with normal baseline; platelets \<100,000/mm\^3 or \>33% decrease from baseline; total bilirubin \>1.5X ULN; AST or ALT \>2.5X ULN; alkaline phosphatase \>3X ULN; creatinine \>1.5X baseline; BUN \>31.0 mg/dL; glucose \<0.6 or \>1.5X reference range; uric acid \> ULN; sodium \>150 or \<130 mEq/L; potassium \>5.5 or \<3.0 mEq/L; calcium \>11.5 or \<8.0 mg/dL; albumin \<2.0 g/L; total protein \<5.0 g/L; positive D-dimer at Day 15; PT prolonged by 3 seconds above baseline; ATIII \< LLN and \>20% decrease from baseline; troponin-T values above the reference range; fibrinogen \<0.75X LLN or \>25% decrease from baseline.
次要结局
- Incremental Recovery (IncRec)(Day 1 (pre-dose and 5 min, 10 min, 20 min, 30 min, 1 hr, 3 hr, 6 hr, 9 hr, and 12 hrs post-dose), Day 2 (24 hrs post-dose), Day 3 (48 hrs post-dose))
- Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUCinf)(Day 1 (pre-dose and 5 min, 10 min, 20 min, 30 min, 1 hr, 3 hr, 6 hr, 9 hr, and 12 hrs post-dose), Day 2 (24 hrs post-dose), Day 3 (48 hrs post-dose))
- Mean Residence Time (MRT)(Day 1 (pre-dose and 5 min, 10 min, 20 min, 30 min, 1 hr, 3 hr, 6 hr, 9 hr, and 12 hrs post-dose), Day 2 (24 hrs post-dose), Day 3 (48 hrs post-dose))
- Maximum Mean Increase From Baseline in Prothrombin Fragments 1+2(Baseline through Day 3)
- Maximum Observed Plasma Concentration (Cmax)(Day 1 (pre-dose and 5 min, 10 min, 20 min, 30 min, 1 hr, 3 hr, 6 hr, 9 hr, and 12 hrs post-dose), Day 2 (24 hrs post-dose), Day 3 (48 hrs post-dose))
- Terminal Elimination Half-Life (t1/2)(Day 1 (pre-dose and 5 min, 10 min, 20 min, 30 min, 1 hr, 3 hr, 6 hr, 9 hr, and 12 hrs post-dose), Day 2 (24 hrs post-dose), Day 3 (48 hrs post-dose))
- Maximum Mean Increase From Baseline in Peak Thrombin Generation(Baseline through Day 3)
- Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast)(Day 1 (pre-dose and 5 min, 10 min, 20 min, 30 min, 1 hr, 3 hr, 6 hr, 9 hr, and 12 hrs post-dose), Day 2 (24 hrs post-dose), Day 3 (48 hrs post-dose))
- Volume of Distribution at Steady State (Vss)(Day 1 (pre-dose and 5 min, 10 min, 20 min, 30 min, 1 hr, 3 hr, 6 hr, 9 hr, and 12 hrs post-dose), Day 2 (24 hrs post-dose), Day 3 (48 hrs post-dose))
- Clearance (CL)(Day 1 (pre-dose and 5 min, 10 min, 20 min, 30 min, 1 hr, 3 hr, 6 hr, 9 hr, and 12 hrs post-dose), Day 2 (24 hrs post-dose), Day 3 (48 hrs post-dose))
- Time to Reach Maximum Observed Plasma Concentration (Tmax)(Day 1 (pre-dose and 5 min, 10 min, 20 min, 30 min, 1 hr, 3 hr, 6 hr, 9 hr, and 12 hrs post-dose), Day 2 (24 hrs post-dose), Day 3 (48 hrs post-dose))
- Maximum Mean Decrease From Baseline in Activated Partial Thromboplastin Time (aPTT)(Baseline through Day 15)
- Maximum Mean Decrease From Baseline in Thrombin Generation Lag Time(Baseline through Day 3)
- Maximum Mean Decrease From Baseline in Prothrombin Time (PT)(Baseline through Day 15)
- Maximum Mean Increase From Baseline in Thrombin Anti-Thrombin (TAT) Complexes(Baseline through Day 3)
- Maximum Mean Increase From Baseline in D-Dimers(Baseline through Day 15)
- Maximum Mean Increase From Baseline in Endogenous Thrombin Potential (ETP)(Baseline through Day 3)