Phase 3/4 Study of a Recombinant Protein-Free Factor VIII (rAHF-PFM): Comparison of Continuous Infusion Versus Intermittent Bolus Infusion in Hemophilia A Subjects Undergoing Major Orthopedic Surgery

• Sponsor: Baxalta now part of Shire (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00357656
• Collaborator: Baxalta Innovations GmbH, now part of Shire (Industry)
• Enrollment: 85
• Locations: 36
• Arms: 2
• Actual Duration (Months): 114.4
• Patients Per Site: 2.4
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

The purpose of this study is to compare the hemostatic efficacy and safety of continuous infusion versus intermittent bolus infusion in the peri- and post-operative setting, employing rAHF-PFM, a recombinant antihemophilic factor manufactured without added human or animal proteins, in previously treated patients with severe or moderately severe hemophilia A (baseline factor VIII level <= 2% of normal) who are undergoing unilateral major orthopedic surgery that requires drain placement. The total study period per subject (from consent to study completion) will vary from approximately 9 to 26 weeks and will involve clinical and laboratory assessments.

Condition or Disease	Intervention/Treatment	Phase
Hemophilia A	Drug: Recombinant Protein-Free Factor VIII (rAHF-PFM); Drug: Recombinant Protein-Free Factor VIII (rAHF-PFM)	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 85 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Antihemophilic Factor (Recombinant) Plasma/Albumin-Free Method (rAHF PFM): A Phase 3/4, Prospective, Controlled, Randomized, Multi-Center Study to Compare the Efficacy and Safety of Continuous Infusion (CI) Versus Intermittent Bolus Infusion (BI) in Subjects With Severe or Moderately Severe Hemophilia A Undergoing Major Orthopedic Surgery
• Actual Study Start Date: May 29, 2006
• Actual Primary Completion Date: Oct 1, 2015
• Actual Study Completion Date: Dec 9, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: BI Bolus infusion of rAHF-PFM	Drug: Recombinant Protein-Free Factor VIII (rAHF-PFM); The treatment schedule for intermittent BI of rAHF-PFM will begin with the administration of the loading dose according to the dose recommendations provided by the sponsor. If required by the hemostatic challenge, additional boluses may be administered after a blood sample for FVIII determination has been drawn. All infusions of rAHF PFM will be given over a period <= 5 minutes (maximum infusion rate, 10 mL/min).
Experimental: CI Continuous infusion of rAHF-PFM	Drug: Recombinant Protein-Free Factor VIII (rAHF-PFM); An initial loading dose will be administered intravenously over a period <= 5 minutes (maximum of infusion rate of 10 mL/minute) within 60 minutes prior to surgery dose in order to maintain a minimum target FVIII level of at least 80% of normal. CI will start prior to surgery as soon as the loading dose has been administered, at a rate calculated according to a formula provided by the sponsor. All study product must be administered with a syringe pump running at an infusion rate according to the dosing regimen, but always >= 0.4 mL/h.

Outcome Measures

Primary Outcome Measures

1. Cumulative Packed Red Blood Cell (PRBC) Volume in the Drainage Fluid During the First 24 Hours Following Surgery in Subjects Receiving ADVATE (rAHF-PFM) by Bolus (BI) or Continuous Infusion (CI) [During the first postoperative 24 hours every 8 hours ± 30 minutes the drainage fluid was to be recorded..]

   Drainage fluid volume was to be measured cumulatively and recorded every 8 hours ± 30 minutes during the first 24 hours following surgery. Unit of measure: Tera per Liter is the PRBC concentration in 10^12 units per 1 liter of drainage fluid.

Secondary Outcome Measures

1. Actual Postoperative Blood Loss During the First 24 Hours Compared With the Average Blood Loss as Predicted Preoperatively by the Operating Surgeon [During the first 24 postoperative hours blood loss was measured every 8 hours ± 30 minutes]

   Drainage fluid volume was to be measured cumulatively and recorded every 8 hours ± 30 minutes during the first 24 hours following surgery. Prior to surgery, the operating surgeon was to predict the estimated duration of surgery and the volume (mL) of the estimated expected blood loss for the surgery in a hemostatically normal individual of the same sex, age, and stature as the study subject 1) for the intraoperative procedure (defined as the time period from incision to application of compressive dressing and release of tourniquet, if applicable), 2) for the first 24 hours postoperatively, and 3) for the postoperative period until drain removal, if drainage continued beyond 24 hours. Units: Milliliter of blood

2. Actual Postoperative Blood Loss Compared to the Expected Average Blood Loss Until Drain Removal as Predicted Preoperatively by the Surgeon [From end of surgery (application of compressive dressing and release of tourniquet, if applicable) until drain removal (up to postoperative day 7).]

   The total blood loss for the postoperative period (from end of surgery until drain removal) was adjusted for the expected blood loss by applying a log-transformation of the blood loss data. The drainage volume was measured every 8 hours +/- 30 minutes during the first 24 hours. If the drainage continued beyond 24 hours, the PRBC volume and hemoglobin was to be measured cumulatively every 24 hours or whenever the drainage bottle was emptied and at the time of drain removal. Prior to surgery, the operating surgeon was to predict the estimated duration of surgery and the volume (mL) of the estimated expected blood loss for the surgery in a hemostatically normal individual of the same sex, age, and stature as the study subject for the first 24 hours postoperatively, and for the postoperative period until drain removal, if drainage continued beyond 24 hours. Units: Milliliter of blood

3. Number of Bleeding Episodes During Treatment With Continuous or Bolus Infusion [Through Postoperative Day 7]

   To simplify the results below: Bleeding episodes were reported for 4 subjects (3 subjects on bolus infusion: 2 in Stratum A and 1 in Stratum B, and 1 subject on continuous infusion/Stratum B). The 4 subjects had 1 bleeding episode each. No bleeding episodes were reported for Stratum C.

4. Number of Units of Packed Red Blood Cells Transfused [During the first postoperative 24 hours]

5. Number of Adverse Events Related to the Administration of the Study Product. [From first study drug exposure until study completion/discontinuation (approximately 9-26 weeks per subject)]

   All AEs from the first study drug exposure until the study completion/discontinuation date were to be recorded. Each AE was to be evaluated by the investigator for causal relationship (i.e., unrelated, possibly related or probably related) to the study product.

6. Incidence of Factor VIII Inhibitory Antibody (≥0.4 Bethesda Units Using the Nijmegen Modification of the Bethesda Assay Formation) [Throughout the study period of approximately 9-26 weeks per participant]

   Number of participants that developed Factor VIII inhibitory antibody during the study.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• The subject or the subject's legally authorized representative has provided signed informed consent.

• The subject is within 18 to 70 years of age.

• The subject has severe or moderately severe hemophilia A, defined by a baseline factor VIII level <= 2% of normal, as tested at screening. A subset of 15 subjects per group must have baseline factor VIII levels < 1% of normal.

• The aPTT must be within the range of normal after administration of FVIII concentrate, as determined in the preoperative pharmacokinetic evaluation, or as documented in the medical history, if available.

• The subject is scheduled to undergo an elective unilateral major orthopedic surgery that requires drain placement.

• The subject was previously treated with factor VIII concentrate(s) for a minimum of at least 150 exposure days (as estimated by the investigator) prior to study entry.

• Human immunodeficiency virus (HIV) positive subjects must be immunocompetent as determined with a CD4 count >= 200 cells/mm³ (CD4 count at screening), but HIV negative subjects with a CD4 count < 200 cells/mm³ qualify, if immunocompetency is documented.

• The subject has a life expectancy of at least 28 days from the day of surgery.

Exclusion Criteria:

• The subject has a detectable factor VIII inhibitor at screening, with a titer >= 0.4 BU (Nijmegen modification of the Bethesda assay) in the central laboratory.

• The subject has a history of factor VIII inhibitors with a titer >= 0.4 BU (by Nijmegen assay) or >= 0.5 BU (by Bethesda assay) at any time prior to screening.

• 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.

• Excluding hemophilia-related physical impairments, the subject is assigned to NYHA class >= III according to the New York Heart Association (NYHA).

• The subject has an abnormal renal function (serum creatinine > 1.5 mg/dL).

• The subject has active hepatic disease (alanine aminotransferase [ALT] or aspartate aminotransferase [AST] levels > 5 times the upper limit of normal).

• 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.

• 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 thrombocytopenia purpura).

• 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., alpha-interferon, corticosteroid agents at a dose equivalent to hydrocortisone greater than 10 mg/day).

• The subject has a known hypersensitivity to mouse or hamster proteins.

• The subject has received another investigational drug study 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 study.

• The subject is identified by the investigator as being unable or unwilling to cooperate with study procedures.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Los Angeles Orthopaedic Hospital	Los Angeles	California	United States	90007
2	Georgetown University	Washington	District of Columbia	United States	20057
3	Rush Presbyterian St. Lukes	Chicago	Illinois	United States	60612
4	James Graham Brown Cancer Center	Louisville	Kentucky	United States	40202
5	Tulane University	New Orleans	Louisiana	United States	70112-2699
6	Johns Hopkins Medical Institutions	Baltimore	Maryland	United States	21205
7	Brigham and Women´s Hospital	Boston	Massachusetts	United States	02115
8	University Hospitals of Cleveland	Cleveland	Ohio	United States	44106-6010
9	Penn State Milton S. Hershey Medical Center	Hershey	Pennsylvania	United States	17033
10	The University of Texas Health Science Center at Houston Medical School	Houston	Texas	United States	77030
11	University Hospital for Internal Medicine I (Hematology/Hemostaseology)	Vienna		Austria	1090
12	Cliniques Universitaires St. Luc, Haematology Department	Brussels		Belgium	1200
13	University Hospital Gasthuisberg	Leuven		Belgium	3000
14	Hôpital Edouard Herriot	Lyon		France	69437
15	State Health Centre, National Hemophilia Centre	Budapest		Hungary	1134
16	University of Debrecen, 2nd Dept of Internal Medicine	Debrecen		Hungary	4012
17	PTE ÁOK I. Internal Medical Clinic, Dept of Hematology	Pécs		Hungary	7624
18	Centro Emofilia e Trombosi "Angelo Bianchi Bonomi"	Milano		Italy	20122
19	Department of Clinical & Experimental Medecine, AOU Federico II	Naples		Italy	80129
20	AMC Medical Research BV, Department of Vascular Medicine	Amsterdam		Netherlands	1100
21	University Medical Centre Groningen	Groningen		Netherlands	9713
22	Academic Hospital Maastricht	Maastricht		Netherlands	6229
23	Rikshospitalet	Oslo		Norway	0027
24	Krakowskie Centrum Rehabilitacji	Krakow		Poland	30-224
25	Instytut Hematologii i Transfuzjologii, Klinika Zaburzeń Hemostazy i Chorób Wewnętrznych	Warsaw		Poland	02-776
26	Centro Hospitalar de Coimbra	Coimbra		Portugal	3040-316
27	Hospital Santo António	Porto		Portugal	4900-001
28	Fundeni Clinical Institute, Clinical Laboratory "St. Berceanu" Hematology and Bone Marrow Transplantation Department	Bucharest		Romania	022328
29	National Blood Transfusion Institute	Bucharest		Romania	11156
30	"Louis Turcanu" Emergency Clinical Children´s Hospital, 3rd Pediatrics Department, Hemophilia Center	Timisoara		Romania	022328
31	Regional Hemophilia Center	Kirov		Russian Federation	610027
32	Hematology Research Center under Russian Academy of Medical Sciences, Department of Reconstructive Orthopedic Surgery for Hemophilia Patients	Moscow		Russian Federation	125167
33	Russian Research Institute of Hematology and Transfusiology, Department of Surgical Hematology and Angiology	St. Petersburg		Russian Federation	191024
34	Hospital Vall d´Hebron, Servei d´Hemofilia	Barcelona		Spain	08035
35	Hospital Universitario La Fe	Valencia		Spain	46990
36	University Hospital MAS, Department for Coagulation Disorders	Malmo		Sweden	20502

Sponsors and Collaborators

• Baxalta now part of Shire
• Baxalta Innovations GmbH, now part of Shire

Investigators

• Study Director: Study Director, Takeda

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Baxalta now part of Shire
• ClinicalTrials.gov Identifier: NCT00357656
• Other Study ID Numbers: 060402; 2005-005697-71
• First Posted: Jul 27, 2006
• Last Update Posted: May 19, 2021
• Last Verified: Apr 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by Baxalta now part of Shire: Hemophilia A (severe or moderately severe)
• Additional relevant MeSH terms: Hemophilia A; Factor VIII

Study Results

Participant Flow

Recruitment Details	Enrollment was conducted at 22 clinical sites in 12 countries (US, Austria, Norway, France, Portugal, Netherlands, Spain, Russia, Romania, Hungary, Italy, Poland). Of 85 participants enrolled, 72 participants participated in a PK study in the preoperative period; 63 participants were then randomized to treatment by continuous or bolus infusion.
Pre-assignment Detail	Of 85 participants enrolled,15 were screen failures (2 after PK), 4 discontinued on the basis of the PK study in the preoperative period, 1 died, 1 was discontinued by physician decision (imprisonment), and 1 was discontinued per sponsor decision. Eventually, 63 participants were randomized to treatment by continuous (n=32) or bolus infusion (n=31)

Arm/Group Title	Bolus Infusion	Continuous Infusion
Arm/Group Description	Bolus infusion of ADVATE (rAHF-PFM)	Continuous infusion of ADVATE (rAHF-PFM)
Period Title: Overall Study
STARTED	31	32
COMPLETED	31	29
NOT COMPLETED	0	3

Baseline Characteristics

Arm/Group Title	Bolus Infusion	Continuous Infusion	Total
Arm/Group Description	Bolus infusion of ADVATE (rAHF-PFM)	Continuous infusion of ADVATE (rAHF-PFM)	Total of all reporting groups
Overall Participants	31	32	63
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	31 100%	32 100%	63 100%
>=65 years	0 0%	0 0%	0 0%
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	38.6 (9.76)	39.0 (11.52)	38.8 (10.61)
Sex: Female, Male (Count of Participants)
Female	0 0%	0 0%	0 0%
Male	31 100%	32 100%	63 100%

Outcome Measures

1. Primary Outcome

Title	Cumulative Packed Red Blood Cell (PRBC) Volume in the Drainage Fluid During the First 24 Hours Following Surgery in Subjects Receiving ADVATE (rAHF-PFM) by Bolus (BI) or Continuous Infusion (CI)
Description	Drainage fluid volume was to be measured cumulatively and recorded every 8 hours ± 30 minutes during the first 24 hours following surgery. Unit of measure: Tera per Liter is the PRBC concentration in 10^12 units per 1 liter of drainage fluid.
Time Frame	During the first postoperative 24 hours every 8 hours ± 30 minutes the drainage fluid was to be recorded..

Outcome Measure Data

Analysis Population Description

All subjects who were randomized to receive BI or CI and have observed drainage volumes up to 24 hours including hematocrit results for these drainage fluids. The overall number of participants treated by BI and CI comprises the number of participants in Stratum A, B and C for BI and CI.

Arm/Group Title	Bolus Infusion	Continuous Infusion	BI Stratum A	BI Stratum B	BI Stratum C	CI Stratum A	CI Stratum B	CI Stratum C
Arm/Group Description	Bolus infusion of ADVATE (rAHF-PFM)	Continuous infusion of ADVATE (rAHF-PFM)	Participants who underwent unilateral knee replacement and were treated by bolus infusion	Participants who underwent hip surgery and were treated by bolus infusion	Participants who underwent shoulder/elbow/ankle/knee (except knee replacement) surgery and were treated by bolus infusion	Participants who underwent unilateral knee replacement and were treated by continuous infusion	Participants who underwent hip surgery and were treated by continuous infusion	Participants who underwent shoulder/elbow/ankle/knee (except knee replacement) surgery and were treated by continuous infusion
Measure Participants	28	26	22	2	4	23	1	2
Mean (Standard Deviation) [Tera per Liter]	3.632 (0.971)	3.383 (0.632)	3.718 (0.978)	2.855 (1.732)	3.548 (0.577)	3.345 (0.616)	3.400 (NA)	3.820 (1.103)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bolus Infusion, Continuous Infusion, BI Stratum A, BI Stratum B, BI Stratum C, CI Stratum A, CI Stratum B, CI Stratum C
	Comments	The main analysis used a point estimate and a two-sided 95% confidence interval for ratio of the primary outcome measure of CI over BI combined over the three strata: stratum A: unilateral knee replacement, stratum B: hip surgery, stratum C: shoulder/elbow/ankle/knee (except knee replacement) surgery.
	Type of Statistical Test	Non-Inferiority or Equivalence (legacy)
	Comments	Non-inferiority by the 200% margin of non-inferiority was demonstrated if the upper confidence limit of a 95% 2-sided confidence interval for the ratio of means did not exceed 200%.
Statistical Test of Hypothesis	p-Value	0.001
	Comments	one-sided p-value against the null hypothesis of ration >=200%
	Method	Hypothesis test
	Comments
Method of Estimation	Estimation Parameter	Mean ratio CI/BI
	Estimated Value	0.924
	Confidence Interval	(2-Sided) 95%; 0.816 to 1.046
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Actual Postoperative Blood Loss During the First 24 Hours Compared With the Average Blood Loss as Predicted Preoperatively by the Operating Surgeon
Description	Drainage fluid volume was to be measured cumulatively and recorded every 8 hours ± 30 minutes during the first 24 hours following surgery. Prior to surgery, the operating surgeon was to predict the estimated duration of surgery and the volume (mL) of the estimated expected blood loss for the surgery in a hemostatically normal individual of the same sex, age, and stature as the study subject 1) for the intraoperative procedure (defined as the time period from incision to application of compressive dressing and release of tourniquet, if applicable), 2) for the first 24 hours postoperatively, and 3) for the postoperative period until drain removal, if drainage continued beyond 24 hours. Units: Milliliter of blood
Time Frame	During the first 24 postoperative hours blood loss was measured every 8 hours ± 30 minutes

Outcome Measure Data

Analysis Population Description

All subjects who were randomized to receive BI or CI and have observed drainage volumes up to 24 hours. The overall number of participants treated by BI and CI comprises the number of participants in Stratum A, B and C for BI and CI.

Arm/Group Title	Bolus Infusion	Contiuous Infusion	BI Stratum A	BI Stratum B	BI Stratum C	CI Stratum A	CI Stratum B	CI Stratum C
Arm/Group Description	Bolus infusion of ADVATE (rAHF-PFM)	Continuous infusion of ADVATE (rAHF-PFM)	Participants who underwent unilateral knee replacement and were treated by bolus infusion	Participants who underwent hip surgery and were treated by bolus infusion	Participants who underwent shoulder/elbow/ankle/knee (except knee replacement) surgery and were treated by bolus infusion	Participants who underwent unilateral knee replacement and were treated by continuous infusion	Participants who underwent hip surgery and were treated by continuous infusion	Participants who underwent shoulder/elbow/ankle/knee (except knee replacement) surgery and were treated by continuous infusion
Measure Participants	31	29	24	2	5	24	2	3
Mean (Standard Deviation) [Milliliter]	709.28 (150.103)	811.11 (79.511)	724.48 (66.367)	265 (49.497)	814.03 (171.019)	819.22 (66.992)	713.49 (0)	811.25 (163.027)

3. Secondary Outcome

Title	Actual Postoperative Blood Loss Compared to the Expected Average Blood Loss Until Drain Removal as Predicted Preoperatively by the Surgeon
Description	The total blood loss for the postoperative period (from end of surgery until drain removal) was adjusted for the expected blood loss by applying a log-transformation of the blood loss data. The drainage volume was measured every 8 hours +/- 30 minutes during the first 24 hours. If the drainage continued beyond 24 hours, the PRBC volume and hemoglobin was to be measured cumulatively every 24 hours or whenever the drainage bottle was emptied and at the time of drain removal. Prior to surgery, the operating surgeon was to predict the estimated duration of surgery and the volume (mL) of the estimated expected blood loss for the surgery in a hemostatically normal individual of the same sex, age, and stature as the study subject for the first 24 hours postoperatively, and for the postoperative period until drain removal, if drainage continued beyond 24 hours. Units: Milliliter of blood
Time Frame	From end of surgery (application of compressive dressing and release of tourniquet, if applicable) until drain removal (up to postoperative day 7).

Outcome Measure Data

Analysis Population Description

All subjects who were randomized to receive BI or CI and have observed drainage volumes up to 24 hours including hematocrit results for these drainage fluids. The overall number of participants treated by BI and CI comprises the number of participants in Stratum A, B and C for BI and CI.

Arm/Group Title	Bolus Infusion	Continuous Infusion	BI Stratum A	BI Stratum B	BI Stratum C	CI Stratum A	CI Stratum B	CI Stratum C
Arm/Group Description	Bolus infusion of ADVATE (rAHF-PFM)	Continuous infusion of ADVATE (rAHF-PFM)	Participants who underwent unilateral knee replacement and were treated by bolus infusion	Participants who underwent hip surgery and were treated by bolus infusion	Participants who underwent shoulder/elbow/ankle/knee (except knee replacement) surgery and were treated by bolus infusion	Participants who underwent unilateral knee replacement and were treated by continuous infusion	Participants who underwent hip surgery and were treated by continuous infusion	Participants who underwent shoulder/elbow/ankle/knee (except knee replacement) surgery and were treated by continuous infusion
Measure Participants	30	28	23	2	5	23	2	3
Mean (Standard Deviation) [Milliliter]	766.73 (182.463)	929.49 (167.662)	752.91 (42.343)	341.5 (135.075)	1000.37 (259.239)	899.83 (45.459)	921.1 (42.906)	1162.48 (514.033)

4. Secondary Outcome

Title	Number of Bleeding Episodes During Treatment With Continuous or Bolus Infusion
Description	To simplify the results below: Bleeding episodes were reported for 4 subjects (3 subjects on bolus infusion: 2 in Stratum A and 1 in Stratum B, and 1 subject on continuous infusion/Stratum B). The 4 subjects had 1 bleeding episode each. No bleeding episodes were reported for Stratum C.
Time Frame	Through Postoperative Day 7

Outcome Measure Data

Analysis Population Description

All subjects who were randomized to receive BI or CI and have observed drainage volumes up to 24 hours including hematocrit results for these drainage fluids. The overall number of participants treated by BI and CI comprises the number of participants in Stratum A, B and C for BI and CI.

Arm/Group Title	Bolus Infusion	Continuous Infusion	BI Stratum A	BI Stratum B	BI Stratum C	CI Stratum A	CI Stratum B	CI Stratum C
Arm/Group Description	Bolus infusion of rAHF-PFM	Continuous infusion of rAHF-PFM	Participants who underwent unilateral knee replacement and were treated by bolus infusion	Participants who underwent hip surgery and were treated by bolus infusion	Participants who underwent shoulder/elbow/ankle/knee (except knee replacement) surgery and were treated by bolus infusion	Participants who underwent unilateral knee replacement and were treated by continuous infusion	Participants who underwent hip surgery and were treated by continuous infusion	Participants who underwent shoulder/elbow/ankle/knee (except knee replacement) surgery and were treated by continuous infusion
Measure Participants	31	29	24	2	5	24	2	3
Mean (Standard Deviation) [Bleeding Episodes]	0.10 (0.301)	0.03 (0.186)	0.08 (0.282)	0.50 (0.707)	0.00 (0.000)	0.00 (0.000)	0.50 (0.707)	0.00 (0.000)

5. Secondary Outcome

Title	Number of Units of Packed Red Blood Cells Transfused
Time Frame	During the first postoperative 24 hours

Outcome Measure Data

Analysis Population Description

All subjects who were randomized to receive BI or CI and have observed drainage volumes up to 24 hours including hematocrit results for these drainage fluids. The overall number of participants treated by BI and CI comprises the number of participants in Stratum A, B and C for BI and CI.

Arm/Group Title	Bolus Infusion	Continuous Infusion	BI Stratum A	BI Stratum B	BI Stratum C	CI Stratum A	CI Stratum B	CI Stratum C
Arm/Group Description	Bolus infusion of ADVATE (rAHF-PFM)	Continuous infusion of ADVATE (rAHF-PFM)	Participants who underwent unilateral knee replacement and were treated by bolus infusion	Participants who underwent hip surgery and were treated by bolus infusion	Participants who underwent shoulder/elbow/ankle/knee (except knee replacement) surgery and were treated by bolus infusion	Participants who underwent unilateral knee replacement and were treated by continuous infusion	Participants who underwent hip surgery and were treated by continuous infusion	Participants who underwent shoulder/elbow/ankle/knee (except knee replacement) surgery and were treated by continuous infusion
Measure Participants	31	29	24	2	5	24	2	3
Mean (Standard Deviation) [PRBC Units]	0.9 (1.2)	1.3 (1.4)	1.0 (1.3)	1.5 (2.1)	0.2 (0.4)	1.2 (1.3)	3.5 (2.1)	0.7 (1.2)

6. Secondary Outcome

Title	Number of Adverse Events Related to the Administration of the Study Product.
Description	All AEs from the first study drug exposure until the study completion/discontinuation date were to be recorded. Each AE was to be evaluated by the investigator for causal relationship (i.e., unrelated, possibly related or probably related) to the study product.
Time Frame	From first study drug exposure until study completion/discontinuation (approximately 9-26 weeks per subject)

Outcome Measure Data

Analysis Population Description

Participants in the Safety Analysis Set treated with at least one ADVATE infusion.

Arm/Group Title	Bolus Infusion	Continuous Infusion	Safety Analysis Set
Arm/Group Description	Bolus infusion of ADVATE (rAHF-PFM)	Continuous infusion of ADVATE (rAHF-PFM)	All participants treated with at least one ADVATE (rAHF-PFM) dose.
Measure Participants	31	32	72
Number [Adverse Events]	6	8	14

7. Secondary Outcome

Title	Incidence of Factor VIII Inhibitory Antibody (≥0.4 Bethesda Units Using the Nijmegen Modification of the Bethesda Assay Formation)
Description	Number of participants that developed Factor VIII inhibitory antibody during the study.
Time Frame	Throughout the study period of approximately 9-26 weeks per participant

Outcome Measure Data

Analysis Population Description

Participants in the Safety Analysis Set treated with at least one ADVATE infusion.

Arm/Group Title	Bolus Infusion	Continuous Infusion	Safety Analysis Set
Arm/Group Description	Bolus infusion of ADVATE (rAHF-PFM)	Continuous infusion of ADVATE (rAHF-PFM)	All participants treated with at least one ADVATE (rAHF-PFM) dose
Measure Participants	31	32	72
Number [Participants]	2 6.5%	2 6.3%	4 6.3%

Adverse Events

Time Frame	Throughout the study period. Overall: 9 years and 6 months. Per participant: 9-26 weeks.
Arm/Group Title	Bolus Infusion		Continuous Infusion		Not Assigned Participants
Arm/Group Description	All participants who were randomized to receive bolus infusion (BI) of ADVATE (rAHF-PFM). At total of 31 participants were randomized and received at least one ADVATE (rAHF-PFM) dose.		All participants who were randomized to receive continuous infusion (CI) of ADVATE (rAHF-PFM). At total of 32 participants were randomized and received at least one ADVATE (rAHF-PFM) dose.		All participants who were not assigned to either bolus infusion or continuous infusion but received at least one ADVATE (rAHF-PFM) dose during pharmacokinetic evaluation. A total of 9 participants received only the pharmacokinetic infusion and were not randomized.
All Cause Mortality
	Bolus Infusion		Continuous Infusion		Not Assigned Participants
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Bolus Infusion		Continuous Infusion		Not Assigned Participants
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/31 (9.7%)		6/32 (18.8%)		1/9 (11.1%)
Blood and lymphatic system disorders
Factor VIII inhibition	2/31 (6.5%)	2	2/32 (6.3%)	2	0/9 (0%)	0
General disorders
Multi-organ failure	0/31 (0%)	0	0/32 (0%)	0	1/9 (11.1%)	1
Infections and infestations
Febrile infection	0/31 (0%)	0	1/32 (3.1%)	1	0/9 (0%)	0
Pseudomembranous colitis	0/31 (0%)	0	1/32 (3.1%)	1	0/9 (0%)	0
Musculoskeletal and connective tissue disorders
Hemarthrosis	1/31 (3.2%)	1	0/32 (0%)	0	0/9 (0%)	0
Joint swelling	0/31 (0%)	0	1/32 (3.1%)	1	0/9 (0%)	0
Muscle hemorrhage	0/31 (0%)	0	1/32 (3.1%)	1	0/9 (0%)	0
Other (Not Including Serious) Adverse Events
	Bolus Infusion		Continuous Infusion		Not Assigned Participants
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	22/31 (71%)		20/32 (62.5%)		2/9 (22.2%)
Blood and lymphatic system disorders
Anemia	10/31 (32.3%)	10	7/32 (21.9%)	7	1/9 (11.1%)	1
Thrombocytosis	3/31 (9.7%)	3	1/32 (3.1%)	1	0/9 (0%)	0
Cardiac disorders
Tachycardia	2/31 (6.5%)	2	2/32 (6.3%)	2	0/9 (0%)	0
Gastrointestinal disorders
Constipation	1/31 (3.2%)	1	4/32 (12.5%)	4	0/9 (0%)	0
Nausea	3/31 (9.7%)	3	0/32 (0%)	0	0/9 (0%)	0
Vomiting	2/31 (6.5%)	2	1/32 (3.1%)	1	0/9 (0%)	0
General disorders
Pyrexia	10/31 (32.3%)	10	5/32 (15.6%)	5	0/9 (0%)	0
Pain	5/31 (16.1%)	5	3/32 (9.4%)	3	0/9 (0%)	0
Infections and infestations
Tooth Infection	0/31 (0%)	0	0/32 (0%)	0	1/9 (11.1%)	1
Influenza	0/31 (0%)	0	2/32 (6.3%)	2	0/9 (0%)	0
Urinary tract infection	2/31 (6.5%)	2	1/32 (3.1%)	1	0/9 (0%)	0
Injury, poisoning and procedural complications
Procedural pain	10/31 (32.3%)	10	16/32 (50%)	16	0/9 (0%)	0
Anaemia postoperative	0/31 (0%)	0	2/32 (6.3%)	2	0/9 (0%)	0
Musculoskeletal and connective tissue disorders
Arthralgia	5/31 (16.1%)	5	2/32 (6.3%)	2	0/9 (0%)	0
Muscle Hemorrhage	0/31 (0%)	0	0/32 (0%)	0	1/9 (11.1%)	1
Haemarthrosis	2/31 (6.5%)	2	1/32 (3.1%)	1	0/9 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenoma benign	0/31 (0%)	0	0/32 (0%)	0	1/9 (11.1%)	1
Nervous system disorders
Headache	1/31 (3.2%)	1	3/32 (9.4%)	3	0/9 (0%)	0
Psychiatric disorders
Insomnia	1/31 (3.2%)	1	3/32 (9.4%)	3	0/9 (0%)	0
Anxiety	2/31 (6.5%)	2	0/32 (0%)	0	0/9 (0%)	0
Skin and subcutaneous tissue disorders
Erythema	0/31 (0%)	0	0/32 (0%)	0	1/9 (11.1%)	1

Limitations/Caveats

[Not Specified]

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Agreements with PIs may vary per requirements of individual PI, but contain common elements. For this study, PIs are restricted from independently publishing results until the earlier of the primary multicenter publication. Baxalta requires a review of results communication (e.g. for confidential information) >= 30 days prior to submission. Baxalta may request an additional delay of <=120 days (e.g. for intellectual property protection).