Hemophilia APhase 3NCT01913405
Phase 3 Efficacy and Safety Study of BAX 855 in Severe Hemophilia A Patients Undergoing Surgical Procedures
A Phase 3 study testing PEGylated Recombinant factor VIII (rFVIII) in people with Hemophilia A, run by Baxalta now part of Shire at 22 sites in 9 countries.
Trial 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. Read more about this study
- Who is it for?
- Ages 12 to 65 years, men only
- Conditions the study is for
- Hemophilia A
- What is being tested?
- PEGylated Recombinant factor VIII (rFVIII)
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 30 participants
- Where
- 22 sitesin 9 countries
- Study dates
- 20 Dec 2013to 23 Sep 2016
- Phase
- Phase 3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 12 to 65 years
- Men only
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- 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.
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- 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.
Who cannot join
- 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.
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- 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.
Trial locations and contacts
22 sites in 9 countries.
22 sites in 9 countries
United States8 sites
Cincinnati Children's Hospital Medical Center
Cincinnati, Ohio, 45229
University of Florida College of Medicine
Gainesville, Florida, 32610
Penn State Milton S. Hershey Medical Center
Hershey, Pennsylvania, 17033
Children's Mercy Hospitals & Clinics
Kansas City, Missouri, 64108
University of Louisville
Louisville, Kentucky, 40202
Bleeding and Clotting Disorders Institute
Peoria, Illinois, 61614
University of Utah Health Sciences Center
Salt Lake City, Utah, 84132
University of Washington
Seattle, Washington, 98104
Spain4 sites
Complejo Hospitalario Universitario A Coruña
A Coruña, La Coruña, 15006
Hospital Regional Universitario de Malaga
Málaga, Málaga, 29010
Hospital Universitari Son Espases
Palma de Mallorca, Balearic Islands, 07010
Hospital Universitari i Politecnic La Fe
Valencia, 46026
United Kingdom3 sites
Royal Free Hospital
London, Greater London, NW3 2QG
Great Ormond Street Hospital for Children
London, Greater London, WC1N 3JH
Royal Manchester Children's Hospital
Manchester, Greater Manchester, M13 9WL
Bulgaria2 sites
SHAT of Oncohaematology Diseases
Sofia, 1527
MHAT 'Sv. Marina', EAD
Varna, 9003
Lithuania1 site
Vilnius University Hospital Santariskiu Clinics, Public Institution
Vilnius, 08661
Russia1 site
FSHI "Kirov SR Institute of Hematology and Blood Transfusion FMBA"
Kirov, 610000
Ukraine1 site
SI Institute of Blood Pathology and Transfusion Medicine of AMSU
Lviv, 79044
About this study
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
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.
- Conditions
- Hemophilia A
- Being tested
- PEGylated Recombinant factor VIII (rFVIII)
- Medical subject headings
- Hemophilia A
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
PEGylated Recombinant factor VIII (rFVIII)Biological
Also called BAX 855, ADYNOVATE
Lyophilized powder and solvent for solution for injection
| Study group | Role | What they receive |
|---|---|---|
| BAX855 | Experimental | 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. Receives: Biological: PEGylated Recombinant factor VIII (rFVIII) |
What is being measured
The primary outcome is the main question the study is designed to answer.
Global Hemostatic Efficacy Assessment Score (GHEA) - Composed of 3 Individual Ratings
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
Measured: 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 (24)
Intraoperative Blood Loss
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.
Measured: From initiation of surgery until end of surgery.
Postoperative Blood Loss
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.
Measured: From completion of surgery until 24 hours after surgery.
Overall Perioperative Blood Loss
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.
Measured: From start of surgery until discharge or day 14, whichever occurred first.
Transfusion Requirements
Volume of blood, red blood cells, platelets, and other blood products transfused. Only packed red blood cells were transfused in this study.
Measured: From initiation of the surgery to 24 hours after completion of the surgery.
Occurrence of Bleeding Episodes and Additional Need for Surgical Intervention
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.
Measured: Intra- and post-operative period, until the last intensified treatment after hospital discharge (minor surgery 1-3 days, major surgery average approximately 2 weeks)
Consumption of BAX855
Daily and total weight-adjusted consumption of BAX855 per subject.
Measured: 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.
Pharmacokinetics (PK) - Area Under the Plasma Concentration/Time Curve From Time 0 to Infinity (AUC0-∞)
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.
Measured: 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.
Pharmacokinetics (PK) - Area Under the Plasma Concentration/Time Curve From Time 0 to 96 Hours Post-infusion (AUC0-96h)
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.
Measured: 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.
Pharmacokinetics (PK) - Terminal Half-life (T1/2)
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%.
Measured: 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.
Pharmacokinetics (PK) - Mean Residence Time (MRT)
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.
Measured: 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.
Pharmacokinetics (PK) - Clearance (CL)
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
Measured: 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.
Pharmacokinetics (PK) - Apparent Volume of Distribution at Steady State (Vss)
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.
Measured: 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.
Pharmacokinetics (PK) - Incremental Recovery(IR)
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.
Measured: 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.
Development of Inhibitory Antibodies to Factor VIII (FVIII)
Immunogenicity assessment using FVIII inhibitor by Nijmegen method. A 72-hour washout period is required prior to immunogenicity tests.
Measured: 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).
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)
A 72-hour washout period is required prior to immunogenicity tests.
Measured: 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).
Development of Treatment Emerging Anti-chinese Hamster Ovary (CHO) Antibodies
A 72-hour washout period is required prior to immunogenicity tests.
Measured: 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).
Occurrence of Thrombotic Events
Measured: 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).
Incidence of Severe Allergic Reactions (e.g. Anaphylaxis)
Measured: 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
Measured: 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 - Body Temperature
Changes in body temperature were assessed 15 minutes after the PK/IR infusion and compared to the pre-infusion values.
Measured: Vital signs measurement prior to the PK/IR infusion and 15 minutes post-infusion.
Clinically Significant Changes in Vital Signs - Systolic and Diastolic Blood Pressure (BP)
Changes in systolic and diastolic blood pressure (mmHg) were assessed 15 minutes after the PK/IR infusion and compared to the pre-infusion values.
Measured: Vital signs measurement prior to the PK/IR infusion and 15 minutes post-infusion.
Clinically Significant Changes in Vital Signs - Respiratory Rate
Changes in Respiratory rate were assessed 15 minutes after the PK/IR infusion and compared to the pre-infusion values.
Measured: Vital signs measurement prior to the PK/IR infusion and 15 minutes post-infusion.
Clinically Significant Changes in Vital Signs - Pulse Rate
Changes in the pulse rate (beats/minute) were assessed 15 minutes after the PK/IR infusion and compared to the pre-infusion values.
Measured: Vital signs measurement prior to the PK/IR infusion and 15 minutes post-infusion.
Clinically Significant Changes in Routine Laboratory Parameters- Hematology and Chemistry
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.
Measured: 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).
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted1 Aug 2013 (estimated)
- Study start20 Dec 2013
- Primary completion23 Sep 2016
- Study completion23 Sep 2016
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Hemophilia AStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 30 participants (actual)
Sponsor and investigators
- Lead sponsor
- Baxalta now part of Shire
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Study Director, Study director, Takeda
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01913405
- Sponsor's protocol ID
- 261204
- Other IDs
- 2013-001359-11
- Status last verified
- Apr 2021
- First submitted
- 27 Jun 2013
- Last updated
- 24 May 2021
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- Individual data sharing
- Yes: Takeda provides access to the de-identified individual participant data (IPD) for eligible studies to aid qualified researchers in addressing legitimate scientific objectives (Takeda's data sharing commitment is available on https://clinicaltrials.takeda.com/takedas-commitment?commitment=5). These IPDs will be provided in a secure research environment following approval of a data sharing request, and under the terms of a data sharing agreement.
Publications
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.
PubMed 27328112
Study at a glance
From the registry record, last updated by the sponsor on 24 May 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT01913405
- Acronym / sponsor ID
- 261204
- Conditions
- Hemophilia A
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 30 participants (actual)
- Lead sponsor
- Baxalta now part of ShireIndustry (pharma, biotech, devices)
- Study start
- 20 Dec 2013 (actual)
- Primary completion
- 23 Sep 2016 (actual)
- Study completion
- 23 Sep 2016 (actual)
- First posted
- 1 Aug 2013 (estimated)
- Results
- Posted 14 May 2018
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| BAX855 | Experimental | Biological: 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. |
Who may qualify
- Ages
- 12 to 65 years
- Sex
- Male only
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (9 listed)
- 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.
Key exclusion criteria (11 listed)
- 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).
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| PEGylated Recombinant factor VIII (rFVIII)Also: BAX 855, ADYNOVATELyophilized powder and solvent for solution for injection | Biological | BAX855 |
Primary outcome
Global Hemostatic Efficacy Assessment Score (GHEA) - Composed of 3 Individual Ratings
Time frame: 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
24 secondary outcomes
Intraoperative Blood Loss
Time frame: From initiation of surgery until end of surgery.
Postoperative Blood Loss
Time frame: From completion of surgery until 24 hours after surgery.
Overall Perioperative Blood Loss
Time frame: From start of surgery until discharge or day 14, whichever occurred first.
Transfusion Requirements
Time frame: From initiation of the surgery to 24 hours after completion of the surgery.
Occurrence of Bleeding Episodes and Additional Need for Surgical Intervention
Time frame: Intra- and post-operative period, until the last intensified treatment after hospital discharge (minor surgery 1-3 days, major surgery average approximately 2 weeks)
Consumption of BAX855
Time frame: 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.
Pharmacokinetics (PK) - Area Under the Plasma Concentration/Time Curve From Time 0 to Infinity (AUC0-∞)
Time frame: 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.
Pharmacokinetics (PK) - Area Under the Plasma Concentration/Time Curve From Time 0 to 96 Hours Post-infusion (AUC0-96h)
Time frame: 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.
Pharmacokinetics (PK) - Terminal Half-life (T1/2)
Time frame: 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.
Pharmacokinetics (PK) - Mean Residence Time (MRT)
Time frame: 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.
Pharmacokinetics (PK) - Clearance (CL)
Time frame: 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.
Pharmacokinetics (PK) - Apparent Volume of Distribution at Steady State (Vss)
Time frame: 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.
Pharmacokinetics (PK) - Incremental Recovery(IR)
Time frame: 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.
Development of Inhibitory Antibodies to Factor VIII (FVIII)
Time frame: 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).
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)
Time frame: 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).
Development of Treatment Emerging Anti-chinese Hamster Ovary (CHO) Antibodies
Time frame: 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).
Occurrence of Thrombotic Events
Time frame: 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).
Incidence of Severe Allergic Reactions (e.g. Anaphylaxis)
Time frame: 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
Time frame: 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 - Body Temperature
Time frame: Vital signs measurement prior to the PK/IR infusion and 15 minutes post-infusion.
Clinically Significant Changes in Vital Signs - Systolic and Diastolic Blood Pressure (BP)
Time frame: Vital signs measurement prior to the PK/IR infusion and 15 minutes post-infusion.
Clinically Significant Changes in Vital Signs - Respiratory Rate
Time frame: Vital signs measurement prior to the PK/IR infusion and 15 minutes post-infusion.
Clinically Significant Changes in Vital Signs - Pulse Rate
Time frame: Vital signs measurement prior to the PK/IR infusion and 15 minutes post-infusion.
Clinically Significant Changes in Routine Laboratory Parameters- Hematology and Chemistry
Time frame: 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).
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 24 May 2021.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Results publication: PubMed 27328112Brand 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.
- Individual participant dataSharing planned: Yes. Takeda provides access to the de-identified individual participant data (IPD) for eligible studies to aid qualified researchers in addressing legitimate scientific objectives (Takeda's data sharing commitment is available on https://clinicaltrials.takeda.com/takedas-commitment?commitment=5). These IPDs will be provided in a secure research environment following approval of a data sharing request, and under the terms of a data sharing agreement.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Study Director study director
Takeda
22 sites in 9 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing PEGylated Recombinant factor VIII (rFVIII) in people with Hemophilia A, run by Baxalta now part of Shire at 22 sites in 9 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 9 inclusion and 11 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 24 May 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 22 sites in United States, Spain, United Kingdom, Bulgaria, Lithuania and 4 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 14 May 2018). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Global Hemostatic Efficacy Assessment Score (GHEA) - Composed of 3 Individual Ratings (time frame: 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).). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01913405, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 24 May 2021.