Subjects with Severe or Moderately Severe Hemophilia A (baseline factor VIII (FVIII) level <= 2% of normal) hemophilia A undergoing major orthopedic surgery MedDRA version: 18.0 Level: LLT Classification code 10060612 Term: Hemophilia A System Organ Class: 100000004850
Conditions
Interventions
Trade Name: Advate (rAHF - PFM)
Product Name: ADVATE (rAHF-PFM)
Product Code: not applicable
Pharmaceutical Form: Powder and solvent for solution for injection
INN or Proposed INN: OCTOCOG ALFA
CAS Nu
Sponsors
Baxalta Innovations GmbH
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1.The subject or the subject’s legally authorized representative has provided signed informed consent. 2.The subject is within 18 to 70 years of age. 3.The subject has severe or moderately severe hemophilia A, defined by a baseline FVIII level = 2% of normal, as tested at screening. A subset of 15 subjects per group must have baseline FVIII levels =65 years) yes F.1.3.1 Number of subjects for this age range 6
Exclusion criteria
Exclusion criteria: 1. The subject has a detectable FVIII inhibitor at screening, with a titer = 0.4BU (Nijmegen modification of the Bethesda Assay) in the central laboratory. 2.The subject has a history of FVIII inhibitors with a titer = 0.4BU (by Nijmegen assay) or = 0.5 BU (by Bethesda assay) at any time prior to screening. 3.The subject is scheduled to undergo any other concurrent minor or major surgery during the course of the study. The placement of central venous lines and the performance of fine needle aspiration biopsies are permitted. 4. Excluding hemophilia-related physical impairments, the subject is assigned to NYHA class = III according to the New York Heart Association (NYHA). 5.The subject has an abnormal renal function (serum creatinine > 1.5 mg/dL). 6.The subject has active hepatic disease (alanine aminotransferase [ALT] or aspartate aminotransferase [AST] levels > 5 times the upper limit of normal). 7.The subject has severe chronic liver disease as evidenced by, but not limited to, any of the following: International Normalized Ratio (INR) > 1.4, hypoalbuminemia, portal vein hypertension including presence of otherwise unexplained splenomegaly and history of esophageal varices. 8.The subject has clinical and/or laboratory evidence of abnormal hemostasis from causes other than hemophilia A (e.g., late-stage chronic liver disease, immune thrombocytopenic purpura). 9.The subject is currently receiving, or is scheduled to receive during the course of the study, an immunomodulating drug other than anti-retroviral chemotherapy (e.g., a-interferon, corticosteroid agents at a dose equivalent to hydrocortisone greater than 10 mg/day). 10.The subject has a known hypersensitivity to mouse or hamster proteins. 11.The subject has received another investigational drug within 30 days prior to screening and/or is scheduled to receive additional investigational drug during the course of the trial in the context of another investigational drug study. 12.The subject is identified by the investigator as being unable or unwilling to cooperate with study procedures.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: The primary objective is to compare the hemostatic efficacy of CI versus intermittent BI in the peri- and post-operative setting employing rAHF-PFM in PTPs with severe or moderately severe hemophilia A (baseline FVIII level = 2% of normal) undergoing elective unilateral major orthopedic surgery that requires drain placement by assessing the cumulative packed red blood cell (PRBC) volume in the drainage fluid during the first 24 hours following surgery.;Secondary Objective: • Efficacy 1. To assess and compare the total amount of hemoglobin in the drainage fluid 2. To determine the blood loss compared with the predicted blood loss 3. To determine the blood loss compared with the predicted blood loss until removal of drain 4. To determine the number of bleeding episodes during treatment with CI or BI 5. To record the occurrence and dimensions of any clinically relevant postoperative hematomas 6. To assess the number of units of PRBCs transfused 7. To assess and compare the global hemostatic efficacy of rAHF-PFM using an exploratory score between subjects receiving CI versus BI. 8. To determine the total weight-adjusted dose of rAHF-PFM per subject 9. To calculate the total daily intra- and post-operative weight-adjusted dose of rAHF-PFM during administration of CI or BI • Safety 1. To record the number of adverse experiences (AEs) related to the administration of the study product 2. To identify the incidence of FVIII antibody formation;Primary end point(s): The primary endpoint will be a comparison of the cumulative PRBC volume in the drainage fluid during the first 24 hours following surgery in subjects receiving rAHF-PFM by BI or CI.;Timepoint(s) of evaluation of this end point: postoperative day 1 | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): 1. Efficacy 1. Actual postoperative blood loss during the first 24 hours compared with the average blood loss as predicted preoperatively by the operating surgeon 2. Actual postoperative blood loss compared to the expected average blood loss until drain removal as predicted preoperatively by the surgeon 3. Number of bleeding episodes during treatment with CI or BI through postoperative Day 7 4. Number of units of PRBCs transfused 2. Safety 1. Number of AEs related to the administration of the study product 2. Incidence of FVIII inhibitory antibody (=0.4 BU using the Nijmegen modification of the Bethesda assay) formation. 3. Exploratory Outcome Measures 1. Total amount of hemoglobin in the cumulative drainage fluid during the first postoperative 24 hours and until time of drain removal, if drainage continues beyond 24 hours 2. Occurrence and dimensions of any clinically relevant postoperative hematomas 3. Determination of an exploratory global hemostatic efficacy assessment score (GHEA), which is composed of 3 different categories: a. Assessment of intra-operative hemostatic efficacy of rAHF-PFM performed by the operating surgeon, and b. Assessment of blood loss in drains within the first 24 hours postoperatively performed by the operating surgeon, and c. Assessment of postoperative hemostatic efficacy of rAHF-PFM at postoperative Day 8 performed by the investigator. 4. Total weight-adjusted dose of rAHF-PFM per subject through postoperative Day 7 (IU/kg body weight/subject) 5. Total daily intra- and postoperative weight-adjusted dose of rAHF-PFM (IU/kg body weight/subject) 6. Pharmacokinetic parameters: AUC 0-48h, total AUC, AUMC, T 1/2, CL, MRT, Vss, Cmax and IR;Timepoint(s) of evaluation of this end point: 1. Efficacy 1.First postoperative 24 hours. 2.until time of drain removal, if drainage continues beyond 24 hours 3.Post-operative day 8 4.Post-operative day 8 2. Safety 1.End-of-study visit. 2.End-of-study | — |
Countries
Austria, Belgium, France, Hungary, Italy, Netherlands, Norway, Poland, Portugal, Spain, Sweden, United Kingdom, United States
Contacts
Public ContactJudit Koranyi, MD - ClinOps
Baxalta Innovations GmbH
Outcome results
None listed