BAX 326 Surgery Study in Hemophilia B Patients
- Conditions
- Hemophilia B
- Interventions
- Biological: Recombinant factor IX
- Registration Number
- NCT01507896
- Lead Sponsor
- Baxalta now part of Shire
- Brief Summary
The purpose of the study is to assess the hemostatic efficacy and safety of BAX 326 in subjects with severe (FIX level \< 1%) or moderately severe (FIX level 1-2%) hemophilia B undergoing major or minor elective or emergency surgical, dental or other invasive procedures.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 30
- Participant and/or legal representative has/have voluntarily provided signed informed consent.
- Participant has severe (FIX level < 1%) or moderately severe (FIX level 1-2%) hemophilia B (based on the one stage activated partial thromboplastin time (aPTT) assay), as tested at screening at the central laboratory.
- Participant requires surgery
- Participant has previously been treated with plasma-derived and/or recombinant FIX concentrate(s) for a minimum of 150 exposure days
- Participant has no evidence of a history of FIX inhibitors
- Participant is immunocompetent as evidenced by a CD4 count ≥ 200 cells/mm3.
- Participant is human immunodeficiency (HIV) negative or is HIV+ with a viral load < 200 particles/μL ~ < 400,000 copies/mL.
Main
- Participant has a history of FIX inhibitors with a titer ≥ 0.6 Bethesda Units (BU) (as determined by the Nijmegen modification of the Bethesda assay or the assay employed in the respective local laboratory) at any time prior to screening.
- Participant has a detectable FIX inhibitor at screening, with a titer ≥0.6 Bethesda Units (BU) as determined by the Nijmegen modification of the Bethesda assay in the central laboratory.
- Participant has a history of allergic reaction or evidence of an ongoing or recent thrombotic disease, fibrinolysis or disseminated intravascular coagulation (DIC).
- Known hypersensitivity to hamster proteins or recombinant furin.
- Evidence of an ongoing or recent thrombotic disease, fibrinolysis or disseminated intravascular coagulation (DIC).
- Abnormal renal function
- Severe chronic liver disease
- Active hepatic disease with ALT or AST levels > 5 times the upper limit of normal.
- Diagnosis of an iherited or acquired hemostatic defect other than hemophilia B.
- Platelet count < 100,000/mL.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description BAX326 in Surgery Recombinant factor IX BAX 326 (recombinant factor IX) in Surgery
- Primary Outcome Measures
Name Time Method Pre-Surgical Pharmacokinetics (PK): Factor IX (FIX) Clearance (CL) Within 30 mins pre-infusion and post-infusion timepoints of 30 minutes, 6 hr, 24 hr, 48 hr and 72 hr CL is the volume of plasma which is completely cleared of study product per unit time and is calculated as the dose divided by the total area under the curve from 0 to infinity (AUC0-inf).
Intraoperative Hemostatic Efficacy On day of surgery Assessment by the operating surgeon on a 4 point ordinal scale (according to the definitions provided below): - Excellent: Intraoperative blood loss was less than or equal to that expected for the type of procedure performed in a hemostatically normal participant (≤ 100% ) - Good: Intraoperative blood loss was up to 50% more than expected for the type of procedure performed in a hemostatically normal participant (101 - 150%) - Fair: Intraoperative blood loss was more than 50% of that expected for the type of procedure performed in a hemostatically normal participant (\> 150%) - None: Uncontrolled hemorrhage that was the result of inadequate therapeutic response despite proper dosing, necessitating a change of Factor IX concentrate
Postoperative Hemostatic Efficacy at Drain Removal At drain removal (from 1-3 days postoperatively) The postoperative hemostatic efficacy was to be assessed by the operating surgeon according to the following criteria (4-point ordinal scale): - Excellent: Volume in drain was less than or equal than that expected for the type of procedure performed in a hemostatically normal participant (≤ 100% ) - Good: Volume in drain was up to 50% more than expected for the type of procedure performed in a hemostatically normal participant (101% - 150%) - Fair: Volume in drain was more than 50% of that expected for the type of procedure performed in a hemostatically normal participant (\> 150%) - None: Uncontrolled bleeding that was the result of inadequate therapeutic response despite proper dosing, necessitating a change of Factor IX concentrate
Actual Postoperative Blood Loss At drain removal (from 1-3 days postoperatively) Postoperative blood loss was based on the drainage fluid and was only assessed for participants who had a drain placed during surgery.
Volume of Blood Product Transfused From initiation of surgery until discharge from hospital (from 1-3 days postoperatively for minor surgery and approximately 2 weeks postoperatively for major surgery) Blood product transfusions consisted of packed red blood cells (PRBC) or fresh frozen plasma (FFP) or both.
Postoperative Hemostatic Efficacy on Day of Discharge At discharge from hospital (from 1-3 days postoperatively for minor surgery and approximately 2 weeks postoperatively for major surgery) Assessment by the operating surgeon on a 4 point ordinal scale: - Excellent: Postoperative hemostasis achieved with BAX326 was as good or better than that expected for the type of surgical procedure performed in a hemostatically normal participant - Good: Postoperative hemostasis achieved with BAX326 was probably as good as that expected for the type of surgical procedure performed in a hemostatically normal participant - Fair: Postoperative hemostasis with BAX326 was clearly less than optimal for the type of procedure performed but was maintained without the need to change the Factor IX concentrate - None: Participant experienced uncontrolled bleeding that was the result of inadequate therapeutic response despite proper dosing, necessitating a change of Factor IX concentrate
Actual Postoperative Blood Loss Compared to Average and Maximum Blood Loss Predicated Preoperatively by the Operating Surgeon At postoperative day 3 (approximately 72 hours postoperatively) Predicted average/maximum blood loss minus actual blood loss for participants who had a drain placed during surgery. Prior to the surgery, the surgeon will predict the estimated volume (mL) of the expected average and maximum blood loss for the planned surgical intervention in a hemostatically normal individual of the same sex, age, and stature as the study subject for the postoperative period until drain removal.
Daily Weight-Adjusted Dose of BAX326 Per Participant From initiation of surgery until discharge from hospital (from 1-3 days postoperatively for minor surgery and approximately 2 weeks postoperatively for major surgery) Daily weight-adjusted doses of BAX326 per participant were recorded from the day of surgery until postoperative Days 11+. Each category in outcome measure includes number of all, major and minor surgeries, respectively, if different from the totals.
Total Weight-Adjusted Dose of BAX326 Per Participant From initiation of surgery until discharge from hospital (from 1-3 days postoperatively for minor surgery and approximately 2 weeks postoperatively for major surgery) Assessed for the intra- and postoperative periods.
Actual Intraoperative Blood Loss On day of surgery Actual intraoperative blood loss was determined by the drainage volume, if a drain was placed, and the estimated blood loss into swabs and towels during the procedure.
Actual Intraoperative Blood Loss Compared to Average and Maximum Blood Loss Predicted Preoperatively by the Operating Surgeon On day of surgery Predicted average/maximum blood loss minus actual blood loss. Prior to the surgery, the surgeon predicted the estimated volume (mL) of the expected average and maximum blood loss for the planned surgical intervention in a hemostatically normal individual of the same sex, age, and stature as the study participant for the intraoperative period.
Postoperative Hemostatic Efficacy at Postoperative Day 3 At postoperative day 3 (approximately 72 hours postoperatively) Assessment by the operating surgeon on a 4 point ordinal scale: - Excellent: Postoperative hemostasis achieved with BAX326 was as good or better than that expected for the type of surgical procedure performed in a hemostatically normal participant - Good: Postoperative hemostasis achieved with BAX326 was probably as good as that expected for the type of surgical procedure performed in a hemostatically normal participant - Fair: Postoperative hemostasis with BAX326 was clearly less than optimal for the type of procedure performed but was maintained without the need to change the Factor IX concentrate - None: Participant experienced uncontrolled bleeding that was the result of inadequate therapeutic response despite proper dosing, necessitating a change of Factor IX concentrate
Safety: Number of Participants Who Developed Inhibitory Antibodies to Factor IX (FIX) Throughout the study period (approximately 2 years 5 months) Safety: Occurence of a Thrombotic Event Throughout the study period (approximately 2 years 5 months) Pre-Surgical Pharmacokinetics (PK): Area Under the Plasma Concentration Versus Time Curve (AUC) From 0 to 72 Hours Post-infusion Per Dose Within 30 mins pre-infusion and post-infusion timepoints of 30 minutes, 6 hr, 24 hr, 48 hr and 72 hr AUC0-72h (area under the plasma concentration/time curve from time 0 to 72 hours) was computed using the linear trapezoidal method. The concentration at 72 hours was interpolated from the two nearest sampling time points or extrapolated using the last quantifiable concentration and the terminal rate constant λz. λz was estimated from the slope of natural log-linear fitting to latter quantifiable concentrations, with largest adjusted R2.
Pre-Surgical Pharmacokinetics (PK): Incremental Recovery (IR) at 30 Min Within 30 mins pre-infusion and post-infusion at 30 minutes IR was defined as (C post-infusion - C pre-infusion) / Dose, where C post-infusion is the measured concentration achieved at 30±5 minutes for pre-surgical PK.
Incremental Recovery (IR) at 15±5 Minutes Following Loading Dose Prior to Surgery Within 60 minutes prior to surgery and 15 ± 5 minutes after loading dose/rebolus, if applicable. IR was defined as (C post-infusion - C pre-infusion) / Dose, where C post-infusion is the measured concentration achieved at 15±5 minutes for the loading dose.
Number of Units of Blood Product Transfused From initiation of surgery until discharge from hospital (from 1-3 days postoperatively for minor surgery and approximately 2 weeks postoperatively for major surgery) Blood product transfusions consisted of packed red blood cells (PRBC) or fresh frozen plasma (FFP) or both.
Safety: Number of Participants Who Developed Total Binding Antibodies to Factor IX (FIX) Throughout the study period (approximately 2 years 5 months) If there was more than 2-dilution increase as compared to pre-study level at screening.
Pre-Surgical Pharmacokinetics (PK): Mean Residence Time (MRT) Within 30 mins pre-infusion and post-infusion timepoints of 30 minutes, 6 hr, 24 hr, 48 hr and 72 hr The MRT is the average time that the study product stays in the body (or plasma) and is calculated as: AUMC 0-inf / AUC 0-inf, where AUMC 0-inf was determined in a similar manner as AUC 0-inf.
Pre-Surgical Pharmacokinetics (PK): Volume of Distribution at Steady State (Vss) Within 30 mins pre-infusion and post-infusion timepoints of 30 minutes, 6 hr, 24 hr, 48 hr and 72 hr Vss was computed as CL·MRT.
Safety: Number of Adverse Events Related to BAX326 Throughout the study period (approximately 2 years 5 months) Pre-Surgical Pharmacokinetics (PK): Total Area Under the Plasma Concentration Versus Time Curve Per Dose (Total AUC/Dose) Within 30 mins pre-infusion and post-infusion timepoints of 30 minutes, 6 hr, 24 hr, 48 hr and 72 hr Total AUC/Dose is also AUC0-inf (area under the plasma concentration/time curve from time 0 to infinity) and was defined as AUC0-t + Ct / λz, where t is the time of last quantifiable concentration, Ct is the last quantifiable concentration and λz is the terminal rate constant.
Pre-Surgical Pharmacokinetics (PK): Elimination Phase Half-life (T 1/2) Within 30 mins pre-infusion and post-infusion timepoints of 30 minutes, 6 hr, 24 hr, 48 hr and 72 hr T1/2 was determined as ln2 / λz.
- Secondary Outcome Measures
Name Time Method
Trial Locations
- Locations (14)
Hospital Dr. Sotero del Rio
🇨🇱Santiago, Chile
Klinika detska hematologie a onkologie, Fakultni Nemocnice Motol
🇨🇿Prague, Czechia
Medical University Lodz, Copernicus Hospital, Department of Hematology
🇵🇱Lodz, Poland
Independent Public Pediatric Teaching Hospital, Clinical Department of Hematology and Pediatrics
🇵🇱Warsaw, Poland
Institute of Haematology and Transfusion Medicine
🇵🇱Warsaw, Poland
Louis Turcanu Emergency Clinical Children´s Hospital
🇷🇴Timisoara, Romania
Hematology Research Center RAMS
🇷🇺Moscow, Russian Federation
Royal Manchester Children's Hospital, Department of Hematology
🇬🇧Manchester, United Kingdom
State Institution "Institute of Blood Pathology and Transfusion Medicine under the Academy of Medical Sciences of Ukraine"
🇺🇦Lviv, Ukraine
Centro Medico Imbanaco
🇨🇴Cali, Colombia
Specialized Haematological Hospital "Joan Pavel"
🇧🇬Sofia, Bulgaria
Instituto de Hematología y Medicina Clínica Rubén Dávoli
🇦🇷Rosario, Argentina
Federal State Institution Kirov, Hematology and Blood Transfusion Research Institute under the Federal Agency for High-Tech Medical Care
🇷🇺Kirov, Russian Federation
Children's Territorial Clinical Hospital
🇷🇺Krasnodar, Russian Federation