Clinical trial NCT01913405: Phase 3 Efficacy and Safety Study of BAX 855 in Severe Hemophilia A Patients Undergoing Surgical Procedures
Official title: A Phase 3, Multi-Center, Open Label Study of Efficacy and Safety of PEGylated rFVIII (BAX 855) in Previously Treated Patients With Severe Hemophilia A Undergoing Surgical or Other Invasive Procedures
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Hemophilia A
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2013-08-01
Enrollment: 30
Sex: MALE
Minimum age (years): 12
Maximum age (years): 65
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.


Eligibility criteria: 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.

Primary outcomes:
measure: Global Hemostatic Efficacy Assessment Score (GHEA) - Composed of 3 Individual Ratings
timeFrame: 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).
Secondary outcomes:
measure: Intraoperative Blood Loss
timeFrame: From initiation of surgery until end of surgery.
measure: Postoperative Blood Loss
timeFrame: From completion of surgery until 24 hours after surgery.
measure: Overall Perioperative Blood Loss
timeFrame: From start of surgery until discharge or day 14, whichever occurred first.
measure: Transfusion Requirements
timeFrame: From initiation of the surgery to 24 hours after completion of the surgery.
measure: Occurrence of Bleeding Episodes and Additional Need for Surgical Intervention
timeFrame: Intra- and post-operative period, until the last intensified treatment after hospital discharge (minor surgery 1-3 days, major surgery average approximately 2 weeks)
measure: Consumption of BAX855
timeFrame: 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.
measure: Pharmacokinetics (PK) - Area Under the Plasma Concentration/Time Curve From Time 0 to Infinity (AUC0-∞)
timeFrame: 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.
measure: Pharmacokinetics (PK) - Area Under the Plasma Concentration/Time Curve From Time 0 to 96 Hours Post-infusion (AUC0-96h)
timeFrame: 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.
measure: Pharmacokinetics (PK) - Terminal Half-life (T1/2)
timeFrame: 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.
measure: Pharmacokinetics (PK) - Mean Residence Time (MRT)
timeFrame: 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.
measure: Pharmacokinetics (PK) - Clearance (CL)
timeFrame: 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.
measure: Pharmacokinetics (PK) - Apparent Volume of Distribution at Steady State (Vss)
timeFrame: 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.
measure: Pharmacokinetics (PK) - Incremental Recovery(IR)
timeFrame: 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.
measure: Development of Inhibitory Antibodies to Factor VIII (FVIII)
timeFrame: 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).
measure: 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)
timeFrame: 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).
measure: Development of Treatment Emerging Anti-chinese Hamster Ovary (CHO) Antibodies
timeFrame: 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).
measure: Occurrence of Thrombotic Events
timeFrame: 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).
measure: Incidence of Severe Allergic Reactions (e.g. Anaphylaxis)
timeFrame: 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).
measure: Other Investigational Product (IP) - Related Adverse Events
timeFrame: 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).
measure: Clinically Significant Changes in Vital Signs - Body Temperature
timeFrame: Vital signs measurement prior to the PK/IR infusion and 15 minutes post-infusion.
measure: Clinically Significant Changes in Vital Signs - Systolic and Diastolic Blood Pressure (BP)
timeFrame: Vital signs measurement prior to the PK/IR infusion and 15 minutes post-infusion.
measure: Clinically Significant Changes in Vital Signs - Respiratory Rate
timeFrame: Vital signs measurement prior to the PK/IR infusion and 15 minutes post-infusion.
measure: Clinically Significant Changes in Vital Signs - Pulse Rate
timeFrame: Vital signs measurement prior to the PK/IR infusion and 15 minutes post-infusion.
measure: Clinically Significant Changes in Routine Laboratory Parameters- Hematology and Chemistry
timeFrame: 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).
Other outcomes:
Locations:
city: Gainesville
country: United States
facility: University of Florida College of Medicine
state: Florida
city: Peoria
country: United States
facility: Bleeding and Clotting Disorders Institute
state: Illinois
city: Louisville
country: United States
facility: University of Louisville
state: Kentucky
city: Kansas City
country: United States
facility: Children's Mercy Hospitals & Clinics
state: Missouri
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Hershey
country: United States
facility: Penn State Milton S. Hershey Medical Center
state: Pennsylvania
city: Salt Lake City
country: United States
facility: University of Utah Health Sciences Center
state: Utah
city: Seattle
country: United States
facility: University of Washington
state: Washington
city: Sofia
country: Bulgaria
facility: SHAT of Oncohaematology Diseases
city: Varna
country: Bulgaria
facility: MHAT 'Sv. Marina', EAD
city: Vilnius
country: Lithuania
facility: Vilnius University Hospital Santariskiu Clinics, Public Institution
city: Amsterdam
country: Netherlands
facility: Academisch Medisch Centrum
city: Kirov
country: Russian Federation
facility: FSHI "Kirov SR Institute of Hematology and Blood Transfusion FMBA"
city: Palma de Mallorca
country: Spain
facility: Hospital Universitari Son Espases
state: Baleares
city: A Coruña
country: Spain
facility: Complejo Hospitalario Universitario A Coruña
state: La Coruña
city: Malaga
country: Spain
facility: Hospital Regional Universitario de Malaga
state: Málaga
city: Valencia
country: Spain
facility: Hospital Universitari i Politecnic La Fe
city: Zuerich
country: Switzerland
facility: Universitaetsspital Zuerich
city: Lviv
country: Ukraine
facility: SI Institute of Blood Pathology and Transfusion Medicine of AMSU
city: London
country: United Kingdom
facility: Royal Free Hospital
state: Greater London
city: London
country: United Kingdom
facility: Great Ormond Street Hospital for Children
state: Greater London
city: Manchester
country: United Kingdom
facility: Royal Manchester Children's Hospital
state: Greater Manchester
Study officials:
affiliation: Takeda
name: Study Director
role: STUDY_DIRECTOR
References:
citation: Brand B, Gruppo R, Wynn TT, Griskevicius L, Lopez Fernandez MF, Chapman M, Dvorak T, Pavlova BG, Abbuehl BE. Efficacy and safety of pegylated full-length recombinant factor VIII with extended half-life for perioperative haemostasis in haemophilia A patients. Haemophilia. 2016 Jul;22(4):e251-8. doi: 10.1111/hae.12963. Epub 2016 Jun 21.