Phase 3 Efficacy and Safety Study of BAX 855 in Severe Hemophilia A Patients Undergoing Surgical Procedures

Phase 3

Completed

Conditions: Hemophilia A

Interventions: Biological: PEGylated Recombinant factor VIII (rFVIII)

Registration Number: NCT01913405

Lead Sponsor: Baxalta now part of Shire

Brief Summary: The purpose of the study is to evaluate the efficacy and safety of BAX 855 in severe hemophilia A previously treated (PTP) males, 12 to 65 years of age who are undergoing elective surgical or other invasive procedures.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: Male

Target Recruitment: 30

Inclusion Criteria

Participant requires an elective major or minor surgical, dental or other invasive procedure (e.g. biopsy, endoscopy).
Participant and/or legal representative has/have provided signed informed consent.
Participant has severe hemophilia A (Factor VIII (FVIII) level <1%) as confirmed by the central lab at screening or a documented FVIII activity level <1%.
Participant was previously treated with FVIII concentrates with ≥150 documented exposure days (EDs).
Participant is currently receiving prophylaxis or on-demand therapy with FVIII concentrate.
Participant has a Karnofsky performance score of ≥60 at screening.
Participant is human immunodeficiency virus negative (HIV-); or HIV+ with stable disease and CD4+ count ≥200 cells/mm^3, as confirmed by central laboratory at screening.
Participant is Hepatitis C virus negative (HCV-) by antibody or PCR testing (if positive, antibody titer will be confirmed by PCR), as confirmed by central laboratory at screening; or HCV+ with chronic stable hepatitis as assessed by the investigator.
Participant is willing and able to comply with the requirements of the study protocol.

Exclusion Criteria

Participant has detectable FVIII inhibitory antibodies (≥0.4 Bethesda Unit (BU) using the Nijmegen modification of the Bethesda assay) at screening as determined by the central laboratory or at any timepoint prior to screening (≥0.4 BU using the Nijmegen modification of the Bethesda assay or ≥0.6 BU using the Bethesda assay).
History of ongoing or recent thrombotic disease, fibrinolysis or disseminated intravascular coagulation (DIC).
Participant has a platelet count <100 x 10^9/L, as confirmed by central laboratory at screening.
Participant has severe renal impairment (serum creatinine > 2.0 mg/dL), as confirmed by central laboratory at screening.
Participant has severe chronic hepatic dysfunction (eg ≥5 X upper limit of normal alanine aminotransferase (ALT), as confirmed by the central laboratory at screening, or a documented International Normalized Ratio (INR) > 1.5).
Participant has a known hypersensitivity towards mouse or hamster proteins, polysorbate 80 or to PEG.
Participant is currently using or has recently (< 30 days) used pegylated drugs (other than BAX 855) prior to study participation or is scheduled to use such drugs during trial participation.
Participant is currently participating in another clinical drug (other than BAX 855) or device study or use of another investigational product or device within 30 days prior to study entry.
Participant has a diagnosis of an inherited or acquired hemostatic defect other than hemophilia A.
Participant is currently receiving, or scheduled to receive during the course of the study, an immunomodulating drug (eg, systemic corticosteroid agent at a dose equivalent to hydrocortisone >10 mg/day, or alpha interferon) other than anti-retroviral chemotherapy.
Participant has a clinically significant medical, psychiatric, or cognitive illness, or recreational drug/alcohol use that, in the opinion of the investigator, would affect participant safety or compliance.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
BAX855	PEGylated Recombinant factor VIII (rFVIII)	Pre-operative loading dose: Single loading dose, pre-surgery administered based on each study participant's individual PK results as well as target trough level for type and character of surgery, dental or invasive procedure being performed. In general, major surgery will target an 80-150% FVIII trough level, and minor surgery will target an initial 30-100% FVIII trough level. Intra-operative and post-operative dosing of BAX855 must be based on pre-dosage measurements of FVIII and the type and character of the surgery performed.

Primary Outcome Measures

Name	Time	Method
Global Hemostatic Efficacy Assessment Score (GHEA) - Composed of 3 Individual Ratings	Hemostatic efficacy assessments were performed intraoperatively, postoperatively on day 1 (approximately 24 hours after surgery) and perioperatively at day 14 or discharge (whichever was first).	GHEA=Sum of 1-3 ratings: Excellent: 7-9 (no category \<2), Good: 5-7 (no category \<1), Fair: 3-4 (no category \<1) 1. Intraoperative and 2. Postoperative (postoperative day 1) hemostatic efficacy assessments: Excellent=3: Blood Loss (BL) ≤ than expected for procedure type in non-hemophilic population (NHP) (≤100%), Good=2: BL ≤50% more than expect. for procedure type in NHP (101-150%), Fair=1: BL \>50% more than expect. for procedure type in NHP (\>150%), None=0: Significant bleeding-requiring rescue therapy (RT) 3. Perioperative hemostatic efficacy assessment (day 14 or discharge, whatever is first): Excellent=3: BL and required blood transfusions (BT) less than or similar (≤100%) to that expected for procedure type in NHP, Good=2: BL ≤50% more (101-150%) and BT less than or similar to that expected for procedure type in NHP, Fair=1: BL \>50% more (\>150%) and BT greater than expected in NHP, None=0: Significant bleeding-requiring RT, BT substantially greater than expected in NHP

Secondary Outcome Measures

Name	Time	Method
Intraoperative Blood Loss	From initiation of surgery until end of surgery.	Actual intraoperative blood loss was assessed at the end of surgery and was compared to the estimated volume of expected average and maximum blood loss in a hemostatically normal individual of the same sex, age and stature as the study participant. Expected intraoperative blood loss was predicted preoperatively by the investigator/surgeon.
Postoperative Blood Loss	From completion of surgery until 24 hours after surgery.	Actual post-operative blood loss assessed at postoperative day 1 was compared to the estimated volume of expected average and maximum blood loss in a hemostatically normal individual of the same sex, age and stature as the study participant. Expected postoperative blood loss was predicted pre-operatively by the investigator/surgeon.
Consumption of BAX855	From initial loading dose until discharge for daily weight-adjusted dose and from first infusion (PK/IR) until end of study for total weight-adjusted dose.	Daily and total weight-adjusted consumption of BAX855 per subject.
Pharmacokinetics (PK) - Mean Residence Time (MRT)	PK measurements were done within 30 minutes pre-infusion, and post infusion at 15 (± 5) minutes, 3 hours (± 30 minutes), 9 hours (± 30 minutes), 32 (± 2) hours, 56 (± 4) hours and 96 (± 4) hours.	Following at least a 72 hour washout period a single dose of BAX855 will be administered. The PK profiles will be used to guide dosing and dosing frequency during the perioperative time period. Mean residence time (MRT) was calculated as total area under the moment curve divided by the total area under the curve. Main analysis was done on the one-stage clotting assay results, supportive analysis was done on the chromogenic assay results.
Overall Perioperative Blood Loss	From start of surgery until discharge or day 14, whichever occurred first.	Actual overall perioperative blood loss (assessed at the end of surgery, at postoperative day 1 and until discharge or day 14 - whichever is first) was compared to the estimated volume of expected average and maximum blood loss in a hemostatically normal individual of the same sex, age and stature as the study participant. Expected perioperative blood loss was predicted pre-operatively by the investigator/surgeon.
Pharmacokinetics (PK) - Area Under the Plasma Concentration/Time Curve From Time 0 to 96 Hours Post-infusion (AUC0-96h)	PK measurements were done within 30 minutes pre-infusion, and post infusion at 15 (± 5) minutes, 3 hours (± 30 minutes), 9 hours (± 30 minutes), 32 (± 2) hours, 56 (± 4) hours and 96 (± 4) hours.	Following at least a 72 hour (h) washout period a single dose of BAX855 will be administered. The PK profiles was used to guide dosing and dosing frequency during the perioperative time period. The area under the plasma concentration/time curve from time 0 to 96 hours postinfusion (AUC 0-96h) was computed using the linear trapezoidal rule. For the calculation of AUC 0-96h the levels at 96 hours were linearly interpolated/extrapolated from the 2 nearest sampling time points. Main analysis was done on the one-stage clotting assay results, supportive analysis was done on the chromogenic assay results.
Development of Treatment Emerging Binding Antibodies to Factor VIII (FVIII), Treatment Emergent Binding Antibodies to PEGylated Recombinant FVIII (BX855), and Treatment Emerging Binding Antibodies to Polyethylene Glycol (PEG)	Up to 105 days prior to surgery (Screening visit); and End of Study Visit (variable for each participant and depends on the nature of the invasive procedure (treatment period ranged from 43 days to 162 days).	A 72-hour washout period is required prior to immunogenicity tests.
Pharmacokinetics (PK) - Area Under the Plasma Concentration/Time Curve From Time 0 to Infinity (AUC0-∞)	PK measurements were done within 30 minutes pre-infusion, and post infusion at 15 (± 5) minutes, 3 hours (± 30 minutes), 9 hours (± 30 minutes), 32 (± 2) hours, 56 (± 4) hours and 96 (± 4) hours.	Following at least a 72 hour washout period a single dose of BAX855 was administered. The PK profiles was used to guide dosing and dosing frequency during the perioperative time period. The area under the plasma concentration/time curve from time 0 to infinity (AUC 0-inf) and the area under the first movement curve from time 0 to infinity (AUMC 0-inf) was calculated as the sum of AUC and AUMC from time 0 to the time of the last quantifiable concentration plus a tail area correction calculated as Ct/λz and Ct/λz(t+1/λz), respectively, where Ct is the last quantifiable concentration, t is the time of last quantifiable concentration and λz is the terminal or disposition rate constant. Main analysis was done on the one-stage clotting assay results, supportive analysis was done on the chromogenic assay results.
Pharmacokinetics (PK) - Clearance (CL)	PK measurements were done within 30 minutes pre-infusion, and post infusion at 15 (± 5) minutes, 3 hours (± 30 minutes), 9 hours (± 30 minutes), 32 (± 2) hours, 56 (± 4) hours and 96 (± 4) hours.	Following a 72 hour washout period a single dose of BAX855 will be administered. The PK profiles will be used to guide dosing and dosing frequency during the perioperative time period. Systemic clearance (CL) was calculated as the dose in IU/kg divided by the total AUC. Main analysis was done on the one-stage clotting assay results, supportive analysis was done on the chromogenic assay results. h = hours
Transfusion Requirements	From initiation of the surgery to 24 hours after completion of the surgery.	Volume of blood, red blood cells, platelets, and other blood products transfused. Only packed red blood cells were transfused in this study.
Occurrence of Bleeding Episodes and Additional Need for Surgical Intervention	Intra- and post-operative period, until the last intensified treatment after hospital discharge (minor surgery 1-3 days, major surgery average approximately 2 weeks)	Any clinically relevant bleeding episodes (as assessed by the investigator) as well as the need for any further surgical interventions were recorded. If the subject had not resumed his previous treatment after discharge, the occurrence and treatment of bleeding episodes were recorded in the subject's diary.
Pharmacokinetics (PK) - Terminal Half-life (T1/2)	PK measurements were done within 30 minutes pre-infusion, and post infusion at 15 (± 5) minutes, 3 hours (± 30 minutes), 9 hours (± 30 minutes), 32 (± 2) hours, 56 (± 4) hours and 96 (± 4) hours.	Following at least a 72 hour washout period a single dose of BAX855 will be administered. The PK profiles will be used to guide dosing and dosing frequency during the perioperative time period. Terminal or disposition half-life (HL) was calculated as log e(2)/λz where the terminal or disposition rate constant (λz) was estimated as the slope of a log-linear least squares regression model. Main analysis was done on the one-stage clotting assay results, supportive analysis was done on the chromogenic assay results. Terminal half life is the time it takes for the plasma concentration or the amount of drug in the body to be reduced by 50%.
Pharmacokinetics (PK) - Incremental Recovery(IR)	PK measurements were done within 30 minutes pre-infusion, and post infusion at 15 (± 5) minutes, 3 hours (± 30 minutes), 9 hours (± 30 minutes), 32 (± 2) hours, 56 (± 4) hours and 96 (± 4) hours.	Following at least a 72 hour washout period a single dose of BAX855 will be administered. The PK profiles will be used to guide dosing and dosing frequency during the perioperative time period. Incremental recovery (IR) was calculated as C post infusion minus C pre-infusion divided by the dose. Main analysis was done on the one-stage clotting assay results, supportive analysis was done on the chromogenic assay results.
Development of Treatment Emerging Anti-chinese Hamster Ovary (CHO) Antibodies	Up to 105 days prior to surgery (Screening visit); and End of Study Visit (variable for each participant and depends on the nature of the invasive procedure (treatment period ranged from 43 days to 162 days).	A 72-hour washout period is required prior to immunogenicity tests.
Occurrence of Thrombotic Events	Throughout the entire study period from screening to completion/termination. For each participant the duration of treatment and the entire study period depended on the nature of the invasive procedure (ranged from 43 days to 162 days).
Clinically Significant Changes in Vital Signs - Systolic and Diastolic Blood Pressure (BP)	Vital signs measurement prior to the PK/IR infusion and 15 minutes post-infusion.	Changes in systolic and diastolic blood pressure (mmHg) were assessed 15 minutes after the PK/IR infusion and compared to the pre-infusion values.
Clinically Significant Changes in Vital Signs - Respiratory Rate	Vital signs measurement prior to the PK/IR infusion and 15 minutes post-infusion.	Changes in Respiratory rate were assessed 15 minutes after the PK/IR infusion and compared to the pre-infusion values.
Clinically Significant Changes in Vital Signs - Pulse Rate	Vital signs measurement prior to the PK/IR infusion and 15 minutes post-infusion.	Changes in the pulse rate (beats/minute) were assessed 15 minutes after the PK/IR infusion and compared to the pre-infusion values.
Clinically Significant Changes in Routine Laboratory Parameters- Hematology and Chemistry	Throughout the entire study period from screening to completion/termination (variable for each participant and depends on the nature of the invasive procedure (treatment period ranged from 43 days to 162 days).	Changes in clinical chemistry and hematology parameters from a normal or abnormal not clinically significant (ncs) result at screening to an abnormal and clinically significant (cs) result at the end of study assessment (EOS) are listed. Changes did occur in the following laboratory parameters: Alanine Aminotransferase (ALT) (U/L), Hemoglobin (g/L), Hematocrit, Erythrocytes(TI/L), Eosinophils/Leucocytes.
Pharmacokinetics (PK) - Apparent Volume of Distribution at Steady State (Vss)	PK measurements were done within 30 minutes pre-infusion, and post infusion at 15 (± 5) minutes, 3 hours (± 30 minutes), 9 hours (± 30 minutes), 32 (± 2) hours, 56 (± 4) hours and 96 (± 4) hours.	Following at least a 72 hour washout period a single dose of BAX855 will be administered. The PK profiles will be used to guide dosing and dosing frequency during the perioperative time period. Apparent steady state volume of distribution (Vss) was calculated as dose multiplied with AUMC(0-inf) divided by AUC(0-inf) to square. Main analysis was done on the one-stage clotting assay results, supportive analysis was done on the chromogenic assay results.
Development of Inhibitory Antibodies to Factor VIII (FVIII)	Up to 105 days prior to surgery (Screening visit); and End of Study Visit (variable for each participant and depends on the nature of the invasive procedure (treatment period ranged from 43 days to 162 days).	Immunogenicity assessment using FVIII inhibitor by Nijmegen method. A 72-hour washout period is required prior to immunogenicity tests.
Clinically Significant Changes in Vital Signs - Body Temperature	Vital signs measurement prior to the PK/IR infusion and 15 minutes post-infusion.	Changes in body temperature were assessed 15 minutes after the PK/IR infusion and compared to the pre-infusion values.
Incidence of Severe Allergic Reactions (e.g. Anaphylaxis)	Throughout the entire study period from screening to completion/termination. For each participant the duration of treatment and the entire study period depended on the nature of the invasive procedure (ranged from 43 days to 162 days).
Other Investigational Product (IP) - Related Adverse Events	Throughout the entire study period from screening to completion/termination. For each participant the duration of treatment and the entire study period depended on the nature of the invasive procedure (ranged from 43 days to 162 days).

Trial Locations

Locations (22): University of Florida College of Medicine
🇺🇸
Gainesville, Florida, United States
Bleeding and Clotting Disorders Institute
🇺🇸
Peoria, Illinois, United States
University of Louisville
🇺🇸
Louisville, Kentucky, United States
Children's Mercy Hospitals & Clinics
🇺🇸
Kansas City, Missouri, United States
Cincinnati Children's Hospital Medical Center
🇺🇸
Cincinnati, Ohio, United States
Penn State Milton S. Hershey Medical Center
🇺🇸
Hershey, Pennsylvania, United States
University of Utah Health Sciences Center
🇺🇸
Salt Lake City, Utah, United States
Vilnius University Hospital Santariskiu Clinics, Public Institution
🇱🇹
Vilnius, Lithuania
SHAT of Oncohaematology Diseases
🇧🇬
Sofia, Bulgaria
MHAT 'Sv. Marina', EAD
🇧🇬
Varna, Bulgaria
Academisch Medisch Centrum
🇳🇱
Amsterdam, Netherlands
Hospital Universitari i Politecnic La Fe
🇪🇸
Valencia, Spain
Hospital Regional Universitario de Malaga
🇪🇸
Malaga, Málaga, Spain
Hospital Universitari Son Espases
🇪🇸
Palma de Mallorca, Baleares, Spain
Complejo Hospitalario Universitario A Coruña
🇪🇸
A Coruña, La Coruña, Spain
SI Institute of Blood Pathology and Transfusion Medicine of AMSU
🇺🇦
Lviv, Ukraine
Royal Free Hospital
🇬🇧
London, Greater London, United Kingdom
Great Ormond Street Hospital for Children
🇬🇧
London, Greater London, United Kingdom
Royal Manchester Children's Hospital
🇬🇧
Manchester, Greater Manchester, United Kingdom
University of Washington
🇺🇸
Seattle, Washington, United States
FSHI "Kirov SR Institute of Hematology and Blood Transfusion FMBA"
🇷🇺
Kirov, Russian Federation
Universitaetsspital Zuerich
🇨🇭
Zuerich, Switzerland