PROPEL: BAX 855 PK-guided Dosing

• Sponsor: Baxalta now part of Shire (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02585960
• Collaborator: Baxalta Innovations GmbH, now part of Shire (Industry)
• Enrollment: 135
• Locations: 83
• Arms: 3
• Actual Duration (Months): 32.4
• Patients Per Site: 1.6
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

1. To compare the efficacy and safety of pharmacokinetic (PK)-guided treatment with BAX 855 targeting FVIII trough levels of 1-3% and approximately 10% (8-12%)

2. To further characterize pharmacokinetic (PK) and pharmacodynamic (PD) parameters of BAX 855

Condition or Disease	Intervention/Treatment	Phase
Hemophilia A	Biological: PEGylated Recombinant Factor VIII; Biological: PEGylated Recombinant Factor VIII; Biological: PEGylated Recombinant Factor VIII	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 135 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Prevention
• Official Title: Phase 3, Prospective, Randomized, Multi-center Clinical Study Comparing the Safety and Efficacy of BAX 855 Following PK-guided Prophylaxis Targeting Two Different FVIII Trough Levels in Subjects With Severe Hemophilia A
• Actual Study Start Date: Nov 23, 2015
• Actual Primary Completion Date: Aug 5, 2018
• Actual Study Completion Date: Aug 5, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Pharmacokinetic (PK) evaluation of BAX 855 Participants will first undergo an initial pharmacokinetic (PK) assessment. Following the PK assessment participants will be randomized to one of 2 dosing regimens.	Biological: PEGylated Recombinant Factor VIII; Pharmacokinetic (PK) evaluation; Other Names: BAX855 BAX 855
Experimental: FVIII trough target 1-3% Standard treatment arm - PK-guided dosing schedule to achieve a Factor VIII (FVIII) trough of 1-3%	Biological: PEGylated Recombinant Factor VIII; Standard treatment; Other Names: BAX 855 BAX855
Experimental: FVIII trough target 8-12% Intensified treatment arm - PK-guided dosing schedule to achieve a Factor VIII (FVIII) trough of 8-12%	Biological: PEGylated Recombinant Factor VIII; Intensified treatment; Other Names: BAX855 BAX 855

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With a Total Annualized Bleeding Rate (ABR) of Zero for Second Six Months [Day 183 to Day 364 (6 months)]

   Annualized bleeding rate was determined by dividing the number of bleeds by observation period in years.

Secondary Outcome Measures

1. Total Annualized Bleeding Rate for Second Six Months [Day 183 to Day 364 (6 months)]

   Annualized bleeding rate was determined by dividing the number of bleeds by observation period in years.

2. Annualized Spontaneous Bleeding Rate for Second Six Months [Day 183 to Day 364 (6 months)]

   Annualized spontaneous bleeding rate was determined by dividing the number of spontaneous bleeds by observation period in years. A bleed was defined as spontaneous if it was not related to injury/trauma.

3. Annualized Traumatic Bleeding Rate for Second Six Months [Day 183 to Day 364 (6 months)]

   Annualized traumatic bleeding rate was determined by dividing the number of traumatic bleeds by observation period in years. A bleed was defined as traumatic if it was related to injury/trauma.

4. Annualized Joint Bleeding Rate (AJBR) for Second Six Months [Day 183 to Day 364 (6 months)]

   Annualized joint bleeding rate was determined by dividing the number of joint bleeds by observation period in years. An acute joint bleed include some or all of the following: 'aura', pain, swelling, warmth of the skin over the joint, decreased range of motion and difficulty in using the limb compared with baseline or loss of function.

5. Total Weight-adjusted Consumption of BAX 855 [From start of study treatment up to 12 months (completion or termination)]

   Total weight-adjusted consumption of BAX 855 were reported.

6. Number of Bleeding Episodes: Overall Hemostatic Efficacy Rating at Number of Infusions [8 hours after study drug administration]

   The participant or caregiver rated the overall treatment response using a 4-point efficacy rating scale as Excellent: Full relief of pain and cessation of objective signs of bleeding after a single infusion and no additional infusion is required for the control of bleeding; Good: Definite pain relief and/or improvement in signs of bleeding after a single infusion and possibly requires more than 1 infusion for complete resolution; Fair: Probable and/or slight relief of pain and slight improvement in signs of bleeding after a single infusion and required more than 1 infusion for complete resolution and None: No improvement or condition worsens.

7. Number of Bleeding Episodes: Overall Hemostatic Efficacy Rating at Bleed Resolution [From start of study treatment up to bleed resolution (up to 12 months)]

   The participant or caregiver rated the overall treatment response using a 4-point efficacy rating scale as Excellent: Full relief of pain and cessation of objective signs of bleeding after a single infusion and no additional infusion is required for the control of bleeding; Good: Definite pain relief and/or improvement in signs of bleeding after a single infusion and possibly requires more than 1 infusion for complete resolution; Fair: Probable and/or slight relief of pain and slight improvement in signs of bleeding after a single infusion and required more than 1 infusion for complete resolution and None: No improvement or condition worsens.

8. Treatment of Bleeding Episodes: Number of BAX 855 Infusions Per Bleeding Episode Required Until Bleed Resolution [From start of study treatment up to 12 months (completion or termination)]

   Infusions of BAX 855 that were required until bleed resolution were reported.

9. Change From Baseline in Hemophilia Joint Health Score (HJHS)- Total Score [Baseline, Month 12]

   HJHS was assessed based on the following components of the elbow, knee, and ankle joints: swelling, duration of swelling, muscle atrophy, crepitus on motion, flexion loss, extension loss, joint pain, and strength, together with an assessment of the global gait. The HJHS is a validated 11-item scoring tool based on radiologic and clinical evaluation, sensitive to detect early signs and minor changes. HJHS ranges from 0 to 124. Higher values in the HJHS represent worse situation for the participant.

10. Number of Participants With Hemostatic Efficacy Ratings for BAX 855 Treatment of Operative Bleeds [Day 0 through discharge or 14 days post-surgery]

    The participant or caregiver rated the overall treatment response using a 4-point efficacy rating scale as Excellent: Full relief of pain and cessation of objective signs of bleeding after a single infusion and no additional infusion is required for the control of bleeding; Good: Definite pain relief and/or improvement in signs of bleeding after a single infusion and possibly requires more than 1 infusion for complete resolution; Fair: Probable and/or slight relief of pain and slight improvement in signs of bleeding after a single infusion and required more than 1 infusion for complete resolution and None: No improvement or condition worsens. Hemostatic efficacy was evaluated intra-operatively (from start to end of the procedure), post-operatively (from the end of procedure up to 24 h post procedure), and perioperatively (from the start of procedure to participant discharge from hospital or 14 days after completion of procedure; whichever was first).

11. Blood Loss Per Participant in Case of Surgery [Day 0 through discharge or 14 days post-surgery]

    The intraoperative blood loss was measured by determining the volume of blood and fluid removal through suction into the collection container (waste box and/or cell saver) and the estimated blood loss into swabs and towels during the procedure, per the anesthesiologist's record. Postoperatively, blood loss was determined by the drainage volume collected, which mainly consisted of drainage fluid via vacuum or gravity drain, as applicable. In cases where no drain was present, blood loss was determined by the surgeon's clinical judgment, as applicable or entered as "not available". Blood loss was evaluated intra-operatively (from start to end of the procedure), post-operatively (from the end of procedure up to 24 h post procedure), and perioperatively (from the start of procedure to participant discharge from hospital or 14 days after completion of procedure; whichever was first).

12. Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) [From start of study treatment up to 12 months (completion or termination)]

    An AE was any unfavorable and unintended sign (an abnormal laboratory finding), symptom (rash, pain, discomfort, fever, dizziness, etc.), disease (peritonitis, bacteremia, etc.), or outcome of death temporally associated with the use of an investigational product (IP), whether or not considered causally related to the IP. A SAE was defined as an untoward medical occurrence that at any dose met one or more of the following criteria: outcome was fatal/results in death, life-threatening, required in-patient hospitalization or resulted in prolongation of an existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, was a medically important event that was not immediately life-threatening or resulted in death or required hospitalization but jeopardize the participant or required medical or surgical intervention to prevent any of the above outcomes.

13. Number of Participants With Clinically Significant Changes in Vital Signs Reported as Treatment Related Adverse Events [From start of study treatment up to 12 months (completion or termination)]

    Vital signs included systolic and diastolic blood pressure, pulse rate, respiratory rate, body temperature.

14. Number of Participants With Clinically Significant Changes in Clinical Laboratory Parameters Reported as Treatment Related Adverse Events [From start of study treatment up to 12 months (completion or termination)]

    Clinical laboratory assessments included clinical chemistry, hematology, lipid panel, genetics, T-cell, B-cell and NK cell (TBNK) and viral serology.

15. Number of Participants With Positive Inhibitory Antibodies and Binding Antibodies to Factor VIII (FVIII), BAX 855, Polyethylene Glycol (PEG), and Chinese Hamster Ovary (CHO) Protein [From start of study treatment up to 12 months (completion or termination)]

    Positive Inhibitory Antibodies and Binding Antibodies to Factor VIII (FVIII), BAX 855, Polyethylene Glycol (PEG), and Chinese Hamster Ovary (CHO) Protein were reported here.

16. Change From Baseline in Physical Component Scores (PCS) of the Short Form-36 (SF-36) Health Survey [Baseline, Month 12 (completion or termination)]

    Short Form (36) Health Survey (SF-36) is a 36-item validated, generic health related quality of life (HR QoL) instrument. PCS is a summary scale of the dimensions physical functioning, role physical, bodily pain, and general health. The component score is normalized to a standard population. Scores range from 0 to 100 with higher scores representing better health. There is no total overall score; scoring is done for both sub-scores and summary scores.

17. Area Under the Plasma Concentration of BAX 855 From Zero to Infinity (AUC0-inf) [Pre-infusion, 15 - 30 minutes, 3, 8, 24, 48, 72 and 96 hours post-infusion]

    Area under the plasma concentration versus time curve from time 0 to infinity of BAX 855 were reported.

18. Incremental Recovery (IR) at Maximum Plasma Concentration (Cmax) of BAX 855 [Pre-infusion, 15 - 30 minutes, 3, 8, 24, 48, 72 and 96 hours post-infusion]

    IR at Cmax of BAX 855 were reported.

19. Plasma Half-life (T1/2) of BAX 855 [Pre-infusion, 15 - 30 minutes, 3, 8, 24, 48, 72 and 96 hours post-infusion]

    T1/2 of BAX 855 in plasma were reported.

20. Mean Residence Time (MRT) of BAX 855 [Pre-infusion, 15 - 30 minutes, 3, 8, 24, 48, 72 and 96 hours post-infusion]

    MRT of BAX 855 were reported.

21. Maximum Plasma Concentration (Cmax) of BAX 855 [Pre-infusion, 15 - 30 minutes, 3, 8, 24, 48, 72 and 96 hours post-infusion]

    Cmax of BAX 855 were reported.

22. Time to Maximum Concentration of BAX 855 in Plasma (Tmax) [Pre-infusion, 15 - 30 minutes, 3, 8, 24, 48, 72 and 96 hours post-infusion]

    Tmax of BAX 855 were reported.

23. Total Body Clearance (CL) of BAX 855 [Pre-infusion, 15 - 30 minutes, 3, 8, 24, 48, 72 and 96 hours post-infusion]

    Total body clearance of BAX 855 from blood by the kidney were reported.

24. Volume of Distribution at Steady State (Vss) [Pre-infusion, 15 - 30 minutes, 3, 8, 24, 48, 72 and 96 hours post-infusion]

    Volume of distribution was defined as the theoretical volume in which the total amount of drug was uniformly distributed to produce the desired blood concentration of a drug. Vss is the apparent volume of distribution at steadystate.

25. Incremental Recovery (IR) Over Time [Baseline, Month 3, 6, 7.5, 9, 10.5, 12 (Completion or termination)]

    Incremental recovery was calculated by BAX 855 increment (IU/dL) / BAX 855 dose (IU/kg).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 12 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

INCLUSION CRITERIA:

• Participants transitioning from another BAX 855 study who meet ALL of the following criteria are eligible for this study:

1. Participant has completed the end of study visit of a BAX 855 study or is transitioning from the ongoing Baxalta Continuation Study 261302.

2. Participant is either receiving on-demand treatment or prophylactic treatment with BAX 855 and had an Annual Bleed Rate (ABR) of ≥ 2 documented and treated during the past 12 months.

3. Participant is human immunodeficiency virus negative (HIV-); or HIV+ with stable disease and CD4+ count ≥ 200 cells/mm^3, as confirmed by central laboratory.

4. Participant is willing and able to comply with the requirements of the protocol.

• Newly recruited participants (ie not transitioning from another BAX 855 study) including BAX855 naïve participants who meet ALL of the following criteria are eligible for this study:

1. Participant has severe hemophilia A (FVIII clotting activity < 1%) as confirmed by central laboratory OR by historically documented FVIII clotting activity performed by a certified clinical laboratory, optionally supported by a FVIII gene mutation consistent with severe hemophilia A

2. Participant has been previously treated with plasma-derived FVIII concentrates or recombinant FVIII for ≥ 150 documented exposure days (EDs)

3. Participant is either receiving on-demand treatment or prophylactic treatment and had an annual bleeding rate of ≥ 2 documented and treated during the past 12 months.

4. Participant has a Karnofsky performance score of ≥ 60 at screening

5. Participant is HIV-; or HIV+ with stable disease and CD4+ count ≥ 200 cells/mm^3, as confirmed by central laboratory at screening

6. Participant is hepatitis C virus negative (HCV-) by antibody (if positive, additional PCR testing will be performed), as confirmed by central laboratory at screening; or HCV+ with chronic stable hepatitis

7. If female of childbearing potential, participant presents with a negative urine pregnancy test and agrees to employ adequate birth control measures for the duration of the study

8. Participant is willing and able to comply with the requirements of the protocol.

EXCLUSION CRITERIA:

• Participants transitioning from another BAX 855 study who meet ANY of the following criteria are not eligible for this study:

1. Participant has developed a confirmed inhibitory antibody to FVIII with a titer of ≥ 0.6 BU using the Nijmegen modification of the Bethesda assay as determined at the central laboratory during the course of the previous BAX 855 study.

2. Participant has been diagnosed with an acquired hemostatic defect other than hemophilia A.

3. The participant's weight is < 35 kg or > 100 kg.

4. Participant's platelet count is < 100,000/mL.

5. Participant has an abnormal renal function (serum creatinine > 1.5 times the upper limit of normal).

6. Participant has active hepatic disease with alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) levels ≥ 5 times the upper limit of normal.

7. Participant is scheduled to receive a systemic immunomodulating drug (e.g. corticosteroid agents at a dose equivalent to hydrocortisone greater than 10 mg/day, or α-interferon) other than anti-retroviral chemotherapy during the study.

8. 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's safety or compliance.

9. Participant is planning to take part in any other clinical study during the course of the study.

10. Participant is a member of the team conducting this study or is in a dependent relationship with one of the study team members. Dependent relationships include close relatives (ie, children, partner/spouse, siblings, parents) as well as employees of the investigator or site personnel conducting the study.

Newly recruited participants (ie not transitioning from another BAX 855 study) who meet ANY of the following criteria are not eligible for this study:

1. Participant has detectable FVIII inhibitory antibodies (≥ 0.6 BU using the Nijmegen modification of the Bethesda assay) as confirmed by central laboratory at screening.

2. Participant has a history of confirmed FVIII inhibitors with a titer ≥ 0.6 Bethesda Units (BU) (as determined by the Nijmegen modification of the Bethesda assay or the assay employed with the respective cut-off in the local laboratory) at any time prior to screening.

3. Participant has been diagnosed with an inherited or acquired hemostatic defect other than hemophilia A (eg, qualitative platelet defect or von Willebrand's disease).

4. The participant's weight is < 35 kg or > 100 kg.

5. Participant's platelet count is < 100,000/mL.

6. Participant has known hypersensitivity towards mouse or hamster proteins, PEG or Tween

8. Participant has severe chronic hepatic dysfunction [eg, ≥ 5 times upper limit of normal alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST), as confirmed by central laboratory at screening, or a documented INR > 1.5].

9. Participant has severe renal impairment (serum creatinine > 1.5 times the upper limit of normal).

10. Participant has current or recent (< 30 days) use of other pegylated drugs prior to study participation or is scheduled to use such drugs during study participation.

11. Participant is scheduled to receive during the course of the study, a systemic immunomodulating drug (e.g. corticosteroid agents at a dose equivalent to hydrocortisone greater than 10 mg/day, or α-interferon) other than anti-retroviral chemotherapy.

12. Participant has participated in another clinical study involving an IP or investigational device within 30 days prior to enrollment or is scheduled to participate in another clinical study involving an IP or investigational device during the course of this study.

13. Participant has a medical, psychiatric, or cognitive illness or recreational drug/alcohol use that, in the opinion of the investigator, would affect participant safety or compliance.

14. Participant is a member of the team conducting this study or is in a dependent relationship with one of the study team members. Dependent relationships include close relatives (ie, children, partner/spouse, siblings, parents) as well as employees of the investigator or site personnel conducting the study.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Phoenix Childrens Hospital	Phoenix	Arizona	United States	85016-7710
2	Arizona Hemophilia & Thrombosis Center, located within The University of Arizona Cancer Center	Tucson	Arizona	United States	85724
3	Children's Hospital Los Angeles	Los Angeles	California	United States	90027
4	University of Colorado	Aurora	Colorado	United States	80045
5	University of Florida College of Medicine	Gainesville	Florida	United States	32610
6	Emory University-ECC	Atlanta	Georgia	United States	30322
7	University of Kentucky Medical Center	Lexington	Kentucky	United States	40504
8	University of Louisville KCPCRU	Louisville	Kentucky	United States	40202
9	Tulane University	New Orleans	Louisiana	United States	70112
10	Boston Children's Hospital	Boston	Massachusetts	United States	02115
11	University of Nebraska Medical Center	Omaha	Nebraska	United States	68198-5456
12	Gulf States Hemophilia Centre	Houston	Texas	United States	77030
13	University of Utah	Salt Lake City	Utah	United States	84132
14	University of Washington	Seattle	Washington	United States	98104
15	Royal Brisbane Women's Hospital	Herston	Queensland	Australia	4006
16	The Perth Blood Institute	Nedlands	Western Australia	Australia	6009
17	AKH - Medizinische Universität Wien	Vienna		Austria	1090
18	UMHAT "Sv. Georgi", EAD	Plovdiv		Bulgaria	4002
19	UMHAT 'Tsaritsa Yoanna - ISUL', EAD	Sofia		Bulgaria	1527
20	MHAT 'Sv. Marina', EAD, Clinic of Clinical Hematology	Varna		Bulgaria	9010
21	CHU Nice- Service hematologie	Nice	Alpes Maritimes	France	06200
22	Hôpital Morvan	Brest Cedex	Finistere	France	29609
23	CHU Rennes - Hopital Pontchaillou	Rennes cedex 09	Ille Et Vilaine	France	35033
24	CHU de Caen - Hôpital Côte de Nacre	Caen		France	14003
25	CHU Charles Nicolle	Rouen		France	76031
26	HZRM Hamophilie Zentrum Rhein Main GmbH	Mörfelden-Walldorf	Hessen	Germany	65446
27	Inst. f. Experimentelle Hamatologie u. Transfusionsmedizin	Bonn	Nordrhein Westfalen	Germany	53127
28	COAGULATION RESEARCH CENTRE GmbH	Duisburg	Nordrhein Westfalen	Germany	47051
29	Hamophiliezentrum/Gerinnungssprechstunde	Berlin		Germany	10249
30	MVZ Labor Dr. Reising-Ackermann	Leipzig		Germany	04289
31	University of Hong Kong	Hong Kong		Hong Kong
32	Prince of Wales Hospital	Shatin		Hong Kong	00000
33	Magyar Honvedseg EK	Budapest		Hungary	1134
34	DE OEC Belgyógyászati Int	Debrecen		Hungary	4032
35	PTE ÁOK	Pecs		Hungary	7624
36	Chaim Sheba Medical Center	Tel-Hashomer		Israel	5262000
37	UOC Ematologia, Azienda ULSS 8 Asolo, Regione Veneto	Castelfranco Veneto	Treviso	Italy	31033
38	Presidio Osped. Ferrarotto	Catania		Italy	90124
39	Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico	Milano		Italy	20122
40	Umberto I Pol. di Roma-Università di Roma La Sapienza	Roma		Italy	00144
41	Fondazione Policlinico Universitario A. Gemelli	Roma		Italy	00168
42	AOU Citta della Salute e della Scienza - Presidio Molinette	Torino		Italy	10126
43	ULSS n. 6 "Vicenza"	Vicenza		Italy	36100
44	Hospital Ampang	Ampang	Kuala Lumpur	Malaysia	68000
45	Hospital Queen Elizabeth	Kota Kinabalu	Sabah	Malaysia	88586
46	Hospital Kuala Lumpur	Kuala Lumpur		Malaysia	50586
47	Hospital Melaka	Melaka		Malaysia	75400
48	Hospital Pulau Pinang	Pulau Pinang		Malaysia	10450
49	Oslo Universitetssykehus HF	Oslo		Norway	0372
50	Wojewodzki Szpital Specjalistyczny im. Mikolaja Kopernika, Klinika Hematologii	Lodz		Poland	93-510
51	Alvamed	Poznań		Poland	61-828
52	Instytut Hematologii Ii Transfuzjologii	Warszawa		Poland	02-776
53	SP Szpital Kliniczny Nr 1 we Wroclawiu	Wroclaw		Poland	50-367
54	Spitalul Clinic Judetean de Urgenta Brasov	Brasov		Romania	500365
55	Institutul Oncologic ClNa.	Cluj Napoca		Romania	400124
56	National University Hospital	Singapore		Singapore	119074
57	Singapore General Hospital- Parent	Singapore		Singapore	169608
58	KK Women's And Children's Hospital	Singapore		Singapore	229899
59	Hospital Universitari Son Espases	Palma de Mallorca	Baleares	Spain	07010
60	Complejo Hospitalario Universitario A Coruña	A Coruña	La Coruña	Spain	15006
61	Hospital Regional Universitario de Malaga	Malaga	Málaga	Spain	29010
62	Hospital Universitario La Paz	Madrid		Spain	28046
63	Sahlgrenska Universitetssjukhuset	Gothenburg		Sweden	S-41345
64	Karolinska Universitetssjukhuset	Stockholm		Sweden	17176
65	Universitätsspital Zürich	Zürich		Switzerland	8091
66	China Medical University Hospital	Taichung		Taiwan	40447
67	Taichung Veterans General Hospital	Taichung		Taiwan	40705
68	Tri-Service General Hospital	Taipei		Taiwan	11490
69	Acibadem Hastanesi	Adana		Turkey	01130
70	Akdeniz University	Antalya		Turkey	07070
71	Istanbul University	Istanbul		Turkey	34098
72	Ege University	Izmir		Turkey	35040
73	NChSH Okhmatdyt of MoHU Center of Children Oncohematology and Bone Marrow Transplantation	Kyiv		Ukraine	1135
74	Kyiv CCH #9 Dept of Surgery City SPC of Diagnostics & Treatment of Patients with HP	Kyiv		Ukraine	4112
75	SI Institute of Blood Pathology and Transfusion Medicine of NAMSU	Lviv		Ukraine	79044
76	M.V. Sklifosovskyi Poltava RCH Dept of Gematology HSEIU Ukrainian Medical Stomatological Academy	Poltava		Ukraine	36011
77	Bristol Royal Hospital for Children	Bristol	Avon	United Kingdom	BS2 8BJ
78	Royal Free Hospital	London	Greater London	United Kingdom	NW3 2QG
79	Royal Manchester Children's Hospital	Manchester	Greater Manchester	United Kingdom	M13 9WL
80	Southampton General Hospital	Southampton	Hampshire	United Kingdom	SO16 6YD
81	Leicester Royal Infirmary	Leicester	Leicestershire	United Kingdom	LE1 5WW
82	Churchill Hospital	Oxford	Oxfordshire	United Kingdom	OX3 7LJ
83	University Hospital of Wales	Cardiff	West Glamorgan	United Kingdom	CF14 4XN

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)

• Study Protocol: Protocol - Jan 13, 2015
• Study Protocol: Amendment 1 - Mar 20, 2015
• Study Protocol: Amendment 2 - May 12, 2015
• Study Protocol: Amendment 3 - Sep 4, 2015
• Study Protocol: Amendment 5 - Oct 18, 2016
• Statistical Analysis Plan - Sep 19, 2018

More Information

Publications

None provided.

• Responsible Party: Baxalta now part of Shire
• ClinicalTrials.gov Identifier: NCT02585960
• Other Study ID Numbers: 261303; 2014-005477-37
• First Posted: Oct 26, 2015
• Last Update Posted: May 25, 2021
• Last Verified: May 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Additional relevant MeSH terms: Hemophilia A; Factor VIII; BAX 855

Study Results

Participant Flow

Recruitment Details	The study was conducted at 62 study centers in 19 countries between 23 November 2015 (first participant first visit) and 05 August 2018 (last participant last visit).
Pre-assignment Detail	A total of 135 participants were enrolled in the study. Of them,14 participants were dropped out and did not receive any treatment 121 participants underwent initial pharmacokinetic(PK) assessment with a single administration of BAX 855 and based on their individual PK values, 115 participants were randomized to any one of the prophylactic regimen.

Arm/Group Title	BAX 855-Low Level	BAX 855-High Level	BAX 855-Non-randomized
Arm/Group Description	Participants with severe hemophilia A received a single BAX 855 dose of 60 +/- 5 international units per kilogram (IU/kg) intravenous (IV) infusion (PK assessment) followed by a PK-guided dose of BAX 855 twice weekly (Alternating 3 and 4-day infusion intervals or an infusion every 3.5 days), targeting factor VIII (FVIII) trough levels of 1-3%. Depending on participant's individual PK, more frequent dosing was considered if single doses of greater than (>) 80 IU/kg were required or regular FVIII peak levels of 200% were reached.	Participants with severe hemophilia A received a single BAX 855 dose of 60 +/- 5 IU/kg IV infusion (PK assessment) followed by a PK-guided dose of BAX 855 every other day, targeting FVIII trough levels of 8-12%. Depending on participant's individual PK, a different dosing interval was considered to prevent regular high FVIII peak levels.	Participants with severe hemophilia A received a single BAX 855 dose of 60 +/- 5 IU/kg IV infusion (PK assessment) and were not randomized to any treatments.
Period Title: PK/Safety Assessment Period
STARTED	57	58	6
Completed 1st 6 Month Period	57	53	0
Completed 2nd 6 Month Period	52	48	0
COMPLETED	52	48	0
NOT COMPLETED	5	10	6
Period Title: PK/Safety Assessment Period
STARTED	52	48	0
COMPLETED	52	43	0
NOT COMPLETED	0	5	0

Baseline Characteristics

Arm/Group Title	BAX 855-Low Level	BAX 855-High Level	BAX 855-Non-randomized	Total
Arm/Group Description	Participants with severe hemophilia A received a single BAX 855 dose of 60 +/- 5 IU/kg IV infusion (PK assessment) followed by a PK-guided dose of BAX 855 twice weekly (Alternating 3 and 4-day infusion intervals or an infusion every 3.5 days), targeting FVIII trough levels of 1-3%. Depending on participant's individual PK, more frequent dosing was considered if single doses of > 80 IU/kg were required or regular FVIII peak levels of 200% were reached.	Participants with severe hemophilia A received a single BAX 855 dose of 60 +/- 5 IU/kg IV infusion (PK assessment) followed by a PK-guided dose of BAX 855 every other day, targeting FVIII trough levels of 8-12%. Depending on participant's individual PK, a different dosing interval was considered to prevent regular high FVIII peak levels.	Participants with severe hemophilia A received a single BAX 855 dose of 60 +/- 5 IU/kg IV infusion (PK assessment) and were not randomized to any treatments.	Total of all reporting groups
Overall Participants	57	58	6	121
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	31.1 (13.76)	31.2 (12.22)	25.8 (10.03)	30.9 (12.84)
Sex: Female, Male (Count of Participants)
Female	0 0%	0 0%	0 0%	0 0%
Male	57 100%	58 100%	6 100%	121 100%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	2 3.5%	5 8.6%	2 33.3%	9 7.4%
Not Hispanic or Latino	53 93%	53 91.4%	4 66.7%	110 90.9%
Unknown or Not Reported	2 3.5%	0 0%	0 0%	2 1.7%
Race/Ethnicity, Customized (Count of Participants)
Asian	14 24.6%	18 31%	2 33.3%	34 28.1%
White	40 70.2%	36 62.1%	4 66.7%	80 66.1%
Native Latin American	1 1.8%	1 1.7%	0 0%	2 1.7%
Mestizo	0 0%	1 1.7%	0 0%	1 0.8%
Other	2 3.5%	2 3.4%	0 0%	4 3.3%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With a Total Annualized Bleeding Rate (ABR) of Zero for Second Six Months
Description	Annualized bleeding rate was determined by dividing the number of bleeds by observation period in years.
Time Frame	Day 183 to Day 364 (6 months)

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) included all participants who were randomized to one of the two prophylactic arms and treated prophylactically for any period of time.

Arm/Group Title	BAX 855-Low Level	BAX 855-High Level
Arm/Group Description	Participants with severe hemophilia A received a single BAX 855 dose of 60 +/- 5 IU/kg IV infusion (PK assessment) followed by a PK-guided dose of BAX 855 twice weekly (Alternating 3 and 4-day infusion intervals or an infusion every 3.5 days), targeting FVIII trough levels of 1-3%. Depending on participant's individual PK, more frequent dosing was considered if single doses of > 80 IU/kg were required or regular FVIII peak levels of 200% were reached.	Participants with severe hemophilia A received a single BAX 855 dose of 60 +/- 5 IU/kg IV infusion (PK assessment) followed by a PK-guided dose of BAX 855 every other day, targeting FVIII trough levels of 8-12%. Depending on participant's individual PK, a different dosing interval was considered to prevent regular high FVIII peak levels.
Measure Participants	57	58
Number [Percentage of participants]	42.1 73.9%	62.1 107.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	BAX 855-Low Level, BAX 855-High Level
	Comments	The proportion of participants with an ABR of 0 during the second 6-month period on BAX 855 prophylaxis, was compared between the 2 prophylaxis arms using a chi-square test with continuity correction at a 2-sided 5% level of significance.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0545
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Gaussian Statistic estimate
	Estimated Value	1.960
	Confidence Interval	(2-Sided) 95%; -0.038 to 3.958
	Parameter Dispersion	Type: Value:
	Estimation Comments	Approximately Gaussian Statistic is obtained by taking the square root of the Chi-squared test with continuity adjustment.

2. Secondary Outcome

Title	Total Annualized Bleeding Rate for Second Six Months
Description	Annualized bleeding rate was determined by dividing the number of bleeds by observation period in years.
Time Frame	Day 183 to Day 364 (6 months)

Outcome Measure Data

Analysis Population Description

FAS included all participants who were randomized to one of the two prophylactic arms and treated prophylactically for any period of time. Here "Number of participants analyzed" refer to number of participants evaluable for this outcome at specified time point.

Arm/Group Title	BAX 855-Low Level	BAX 855-High Level
Arm/Group Description	Participants with severe hemophilia A received a single BAX 855 dose of 60 +/- 5 IU/kg IV infusion (PK assessment) followed by a PK-guided dose of BAX 855 twice weekly (Alternating 3 and 4-day infusion intervals or an infusion every 3.5 days), targeting FVIII trough levels of 1-3%. Depending on participant's individual PK, more frequent dosing was considered if single doses of > 80 IU/kg were required or regular FVIII peak levels of 200% were reached.	Participants with severe hemophilia A received a single BAX 855 dose of 60 +/- 5 IU/kg IV infusion (PK assessment) followed by a PK-guided dose of BAX 855 every other day, targeting FVIII trough levels of 8-12%. Depending on participant's individual PK, a different dosing interval was considered to prevent regular high FVIII peak levels.
Measure Participants	57	53
Mean (Standard Deviation) [Bleeds per year]	3.603 (7.512)	1.649 (3.433)

3. Secondary Outcome

Title	Annualized Spontaneous Bleeding Rate for Second Six Months
Description	Annualized spontaneous bleeding rate was determined by dividing the number of spontaneous bleeds by observation period in years. A bleed was defined as spontaneous if it was not related to injury/trauma.
Time Frame	Day 183 to Day 364 (6 months)

Outcome Measure Data

Analysis Population Description

FAS included all participants who were randomized to one of the two prophylactic arms and treated prophylactically for any period of time. Here "Number of participants analyzed" refer to number of participants evaluable for this outcome at specified time point.

Arm/Group Title	BAX 855 - Low Level	BAX 855 - High Level
Arm/Group Description	Participants with severe hemophilia A received a single BAX 855 dose of 60 +/- 5 IU/kg IV infusion (PK assessment) followed by a PK-guided dose of BAX 855 twice weekly (Alternating 3 and 4-day infusion intervals or an infusion every 3.5 days), targeting FVIII trough levels of 1-3%. Depending on participant's individual PK, more frequent dosing was considered if single doses of > 80 IU/kg were required or regular FVIII peak levels of 200% were reached.	Participants with severe hemophilia A received a single BAX 855 dose of 60 +/- 5 IU/kg IV infusion (PK assessment) followed by a PK-guided dose of BAX 855 every other day, targeting FVIII trough levels of 8-12%. Depending on participant's individual PK, a different dosing interval was considered to prevent regular high FVIII peak levels.
Measure Participants	57	53
Mean (Standard Deviation) [Bleeds per year]	2.489 (6.554)	0.737 (1.738)

4. Secondary Outcome

Title	Annualized Traumatic Bleeding Rate for Second Six Months
Description	Annualized traumatic bleeding rate was determined by dividing the number of traumatic bleeds by observation period in years. A bleed was defined as traumatic if it was related to injury/trauma.
Time Frame	Day 183 to Day 364 (6 months)

Outcome Measure Data

Analysis Population Description

FAS included all participants who were randomized to one of the two prophylactic arms and treated prophylactically for any period of time. Here "Number of participants analyzed" refer to number of participants evaluable for this outcome at specified time points.

Arm/Group Title	BAX 855-Low Level	BAX 855-High Level
Arm/Group Description	Participants with severe hemophilia A received a single BAX 855 dose of 60 +/- 5 IU/kg IV infusion (PK assessment) followed by a PK-guided dose of BAX 855 twice weekly (Alternating 3 and 4-day infusion intervals or an infusion every 3.5 days), targeting FVIII trough levels of 1-3%. Depending on participant's individual PK, more frequent dosing was considered if single doses of > 80 IU/kg were required or regular FVIII peak levels of 200% were reached.	Participants with severe hemophilia A received a single BAX 855 dose of 60 +/- 5 IU/kg IV infusion (PK assessment) followed by a PK-guided dose of BAX 855 every other day, targeting FVIII trough levels of 8-12%. Depending on participant's individual PK, a different dosing interval was considered to prevent regular high FVIII peak levels.
Measure Participants	57	53
Mean (Standard Deviation) [Bleeds per year]	1.114 (2.037)	0.912 (2.647)

5. Secondary Outcome

Title	Annualized Joint Bleeding Rate (AJBR) for Second Six Months
Description	Annualized joint bleeding rate was determined by dividing the number of joint bleeds by observation period in years. An acute joint bleed include some or all of the following: 'aura', pain, swelling, warmth of the skin over the joint, decreased range of motion and difficulty in using the limb compared with baseline or loss of function.
Time Frame	Day 183 to Day 364 (6 months)

Outcome Measure Data

Analysis Population Description

FAS included all participants who were randomized to one of the two prophylactic arms and treated prophylactically for any period of time. Here "Number of participants analyzed" refer to number of participants evaluable for this outcome at specified time points.

Arm/Group Title	BAX 855-Low Level	BAX 855-High Level
Arm/Group Description	Participants with severe hemophilia A received a single BAX 855 dose of 60 +/- 5 IU/kg IV infusion (PK assessment) followed by a PK-guided dose of BAX 855 twice weekly (Alternating 3 and 4-day infusion intervals or an infusion every 3.5 days), targeting FVIII trough levels of 1-3%. Depending on participant's individual PK, more frequent dosing was considered if single doses of > 80 IU/kg were required or regular FVIII peak levels of 200% were reached.	Participants with severe hemophilia A received a single BAX 855 dose of 60 +/- 5 IU/kg IV infusion (PK assessment) followed by a PK-guided dose of BAX 855 every other day, targeting FVIII trough levels of 8-12%. Depending on participant's individual PK, a different dosing interval was considered to prevent regular high FVIII peak levels.
Measure Participants	57	53
Mean (Standard Deviation) [Bleeds per year]	2.617 (7.361)	1.079 (2.553)

6. Secondary Outcome

Title	Total Weight-adjusted Consumption of BAX 855
Description	Total weight-adjusted consumption of BAX 855 were reported.
Time Frame	From start of study treatment up to 12 months (completion or termination)

Outcome Measure Data

Analysis Population Description

FAS included all participants who were randomized to one of the two prophylactic arms and treated prophylactically for any period of time.

Arm/Group Title	BAX 855-Low Level	BAX 855-High Level
Arm/Group Description	Participants with severe hemophilia A received a single BAX 855 dose of 60 +/- 5 IU/kg IV infusion (PK assessment) followed by a PK-guided dose of BAX 855 twice weekly (Alternating 3 and 4-day infusion intervals or an infusion every 3.5 days), targeting FVIII trough levels of 1-3%. Depending on participant's individual PK, more frequent dosing was considered if single doses of > 80 IU/kg were required or regular FVIII peak levels of 200% were reached.	Participants with severe hemophilia A received a single BAX 855 dose of 60 +/- 5 IU/kg IV infusion (PK assessment) followed by a PK-guided dose of BAX 855 every other day, targeting FVIII trough levels of 8-12%. Depending on participant's individual PK, a different dosing interval was considered to prevent regular high FVIII peak levels.
Measure Participants	57	58
Mean (Standard Deviation) [International units per kilogram (IU/kg)]	3984.593 (1678.461)	7030.714 (3208.049)

7. Secondary Outcome

Title	Number of Bleeding Episodes: Overall Hemostatic Efficacy Rating at Number of Infusions
Description	The participant or caregiver rated the overall treatment response using a 4-point efficacy rating scale as Excellent: Full relief of pain and cessation of objective signs of bleeding after a single infusion and no additional infusion is required for the control of bleeding; Good: Definite pain relief and/or improvement in signs of bleeding after a single infusion and possibly requires more than 1 infusion for complete resolution; Fair: Probable and/or slight relief of pain and slight improvement in signs of bleeding after a single infusion and required more than 1 infusion for complete resolution and None: No improvement or condition worsens.
Time Frame	8 hours after study drug administration

Outcome Measure Data

Analysis Population Description

FAS included all participants who were randomized to one of the two prophylactic arms and treated prophylactically for any period of time. Here "Number of participants analyzed" refer to number of participants evaluable for this outcome at specified time points.

Arm/Group Title	BAX 855-Low Level	BAX 855-High Level
Arm/Group Description	Participants with severe hemophilia A received a single BAX 855 dose of 60 +/- 5 IU/kg IV infusion (PK assessment) followed by a PK-guided dose of BAX 855 twice weekly (Alternating 3 and 4-day infusion intervals or an infusion every 3.5 days), targeting FVIII trough levels of 1-3%. Depending on participant's individual PK, more frequent dosing was considered if single doses of > 80 IU/kg were required or regular FVIII peak levels of 200% were reached.	Participants with severe hemophilia A received a single BAX 855 dose of 60 +/- 5 IU/kg IV infusion (PK assessment) followed by a PK-guided dose of BAX 855 every other day, targeting FVIII trough levels of 8-12%. Depending on participant's individual PK, a different dosing interval was considered to prevent regular high FVIII peak levels.
Measure Participants	28	19
Measure Bleeds	97	46
Excellent: Bleeds treated with 1 infusion	19	17
Excellent: Bleeds treated with 2 infusions	3	1
Excellent: Bleeds treated with 3 infusions	0	1
Excellent: Bleeds treated with >= 4 infusions	0	0
Good: Bleeds treated with 1 infusion	36	16
Good: Bleeds treated with 2 infusions	16	6
Good: Bleeds treated with 3 infusions	5	1
Good: Bleeds treated with >= 4 infusion	2	2
Fair: Bleeds treated with 1 infusion	2	0
Fair: Bleeds treated with 2 infusions	7	0
Fair: Bleeds treated with 3 infusions	4	0
Fair: Bleeds treated with >= 4 infusions	1	0
None: Bleeds treated with 1 infusion	1	0
None: Bleeds treated with 2 infusions	1	0
None: Bleeds treated with 3 infusions	0	1
None: Bleeds treated with >= 4 infusions	0	1

8. Secondary Outcome

Title	Number of Bleeding Episodes: Overall Hemostatic Efficacy Rating at Bleed Resolution
Description	The participant or caregiver rated the overall treatment response using a 4-point efficacy rating scale as Excellent: Full relief of pain and cessation of objective signs of bleeding after a single infusion and no additional infusion is required for the control of bleeding; Good: Definite pain relief and/or improvement in signs of bleeding after a single infusion and possibly requires more than 1 infusion for complete resolution; Fair: Probable and/or slight relief of pain and slight improvement in signs of bleeding after a single infusion and required more than 1 infusion for complete resolution and None: No improvement or condition worsens.
Time Frame	From start of study treatment up to bleed resolution (up to 12 months)

Outcome Measure Data

Analysis Population Description

FAS included all participants who were randomized to one of the two prophylactic arms and treated prophylactically for any period of time. Here "Number of participants analyzed" refer to number of participants evaluable for this outcome at specified time points.

Arm/Group Title	BAX 855-Low Level	BAX 855-High Level
Arm/Group Description	Participants with severe hemophilia A received a single BAX 855 dose of 60 +/- 5 IU/kg IV infusion (PK assessment) followed by a PK-guided dose of BAX 855 twice weekly (Alternating 3 and 4-day infusion intervals or an infusion every 3.5 days), targeting FVIII trough levels of 1-3%. Depending on participant's individual PK, more frequent dosing was considered if single doses of > 80 IU/kg were required or regular FVIII peak levels of 200% were reached.	Participants with severe hemophilia A received a single BAX 855 dose of 60 +/- 5 IU/kg IV infusion (PK assessment) followed by a PK-guided dose of BAX 855 every other day, targeting FVIII trough levels of 8-12%. Depending on participant's individual PK, a different dosing interval was considered to prevent regular high FVIII peak levels.
Measure Participants	39	26
Measure Bleeds	148	78
Excellent: Bleeds treated with 1 infusion	50	34
Excellent: Bleeds treated with 2 infusions	4	2
Good:Bleeds treated with 1 infusion	47	24
Good:Bleeds treated with 2 infusions	19	7
Good:Bleeds treated with 3 infusions	6	3
Good:Bleeds treated with >= 4 infusions	3	6
Fair:Bleeds treated with 1 infusion	3	0
Fair:Bleeds treated with 2 infusions	5	1
Fair:Bleeds treated with 3 infusions	7	0
Fair:Bleeds treated with >= 4 infusions	3	0
None:Bleeds treated with 2 infusions	1	0
None:Bleeds treated with 3 infusions	0	1

9. Secondary Outcome

Title	Treatment of Bleeding Episodes: Number of BAX 855 Infusions Per Bleeding Episode Required Until Bleed Resolution
Description	Infusions of BAX 855 that were required until bleed resolution were reported.
Time Frame	From start of study treatment up to 12 months (completion or termination)

Outcome Measure Data

Analysis Population Description

FAS included all participants who were randomized to one of the two prophylactic arms and treated prophylactically for any period of time. Here "Number of participants analyzed" refer to number of participants with treated bleeds.

Arm/Group Title	BAX 855-Low Level	BAX 855-High Level
Arm/Group Description	Participants with severe hemophilia A received a single BAX 855 dose of 60 +/- 5 IU/kg IV infusion (PK assessment) followed by a PK-guided dose of BAX 855 twice weekly (Alternating 3 and 4-day infusion intervals or an infusion every 3.5 days), targeting FVIII trough levels of 1-3%. Depending on participant's individual PK, more frequent dosing was considered if single doses of > 80 IU/kg were required or regular FVIII peak levels of 200% were reached.	Participants with severe hemophilia A received a single BAX 855 dose of 60 +/- 5 IU/kg IV infusion (PK assessment) followed by a PK-guided dose of BAX 855 every other day, targeting FVIII trough levels of 8-12%. Depending on participant's individual PK, a different dosing interval was considered to prevent regular high FVIII peak levels.
Measure Participants	41	26
Mean (Standard Deviation) [Infusions]	1.6 (1.19)	1.6 (1.36)

10. Secondary Outcome

Title	Change From Baseline in Hemophilia Joint Health Score (HJHS)- Total Score
Description	HJHS was assessed based on the following components of the elbow, knee, and ankle joints: swelling, duration of swelling, muscle atrophy, crepitus on motion, flexion loss, extension loss, joint pain, and strength, together with an assessment of the global gait. The HJHS is a validated 11-item scoring tool based on radiologic and clinical evaluation, sensitive to detect early signs and minor changes. HJHS ranges from 0 to 124. Higher values in the HJHS represent worse situation for the participant.
Time Frame	Baseline, Month 12

Outcome Measure Data

Analysis Population Description

FAS included all participants who were randomized to one of the two prophylactic arms and treated prophylactically for any period of time. Here "Number of participants analyzed" refer to number of participants evaluable for this outcome at specified time points.

Arm/Group Title	BAX 855-Low Level	BAX 855-High Level
Arm/Group Description	Participants with severe hemophilia A received a single BAX 855 dose of 60 +/- 5 IU/kg IV infusion (PK assessment) followed by a PK-guided dose of BAX 855 twice weekly (Alternating 3 and 4-day infusion intervals or an infusion every 3.5 days), targeting FVIII trough levels of 1-3%. Depending on participant's individual PK, more frequent dosing was considered if single doses of > 80 IU/kg were required or regular FVIII peak levels of 200% were reached.	Participants with severe hemophilia A received a single BAX 855 dose of 60 +/- 5 IU/kg IV infusion (PK assessment) followed by a PK-guided dose of BAX 855 every other day, targeting FVIII trough levels of 8-12%. Depending on participant's individual PK, a different dosing interval was considered to prevent regular high FVIII peak levels.
Measure Participants	57	54
Mean (Standard Deviation) [Score on a scale]	-1.9 (5.25)	-1.1 (7.77)

11. Secondary Outcome

Title	Number of Participants With Hemostatic Efficacy Ratings for BAX 855 Treatment of Operative Bleeds
Description	The participant or caregiver rated the overall treatment response using a 4-point efficacy rating scale as Excellent: Full relief of pain and cessation of objective signs of bleeding after a single infusion and no additional infusion is required for the control of bleeding; Good: Definite pain relief and/or improvement in signs of bleeding after a single infusion and possibly requires more than 1 infusion for complete resolution; Fair: Probable and/or slight relief of pain and slight improvement in signs of bleeding after a single infusion and required more than 1 infusion for complete resolution and None: No improvement or condition worsens. Hemostatic efficacy was evaluated intra-operatively (from start to end of the procedure), post-operatively (from the end of procedure up to 24 h post procedure), and perioperatively (from the start of procedure to participant discharge from hospital or 14 days after completion of procedure; whichever was first).
Time Frame	Day 0 through discharge or 14 days post-surgery

Outcome Measure Data

Analysis Population Description

Surgery analysis set included all participants in the FAS (randomized to one of the two prophylactic arms and treated prophylactically for any period of time) who underwent some form of surgery (including dental) during the course of study participation.

Arm/Group Title	BAX 855-Low Level	BAX 855-High Level
Arm/Group Description	Participants with severe hemophilia A received a single BAX 855 dose of 60 +/- 5 IU/kg IV infusion (PK assessment) followed by a PK-guided dose of BAX 855 twice weekly (Alternating 3 and 4-day infusion intervals or an infusion every 3.5 days), targeting FVIII trough levels of 1-3%. Depending on participant's individual PK, more frequent dosing was considered if single doses of > 80 IU/kg were required or regular FVIII peak levels of 200% were reached.	Participants with severe hemophilia A received a single BAX 855 dose of 60 +/- 5 IU/kg IV infusion (PK assessment) followed by a PK-guided dose of BAX 855 every other day, targeting FVIII trough levels of 8-12%. Depending on participant's individual PK, a different dosing interval was considered to prevent regular high FVIII peak levels.
Measure Participants	3	4
Excellent: Intra-operative	1 1.8%	3 5.2%
Excellent: Post-operative	3 5.3%	4 6.9%
Excellent: Peri-operative	2 3.5%	4 6.9%
Good: Intra-operative	0 0%	0 0%
Good: Post-operative	0 0%	0 0%
Good: Peri-operative	0 0%	0 0%
Fair: Intra-operative	0 0%	1 1.7%
Fair: Post-operative	0 0%	0 0%
Fair: Peri-operative	0 0%	0 0%
None: Intra-operative	0 0%	0 0%
None: Post-operative	0 0%	0 0%
None: Peri-operative	0 0%	0 0%
Unknown: Intra-operative	2 3.5%	0 0%
Unknown: Post-operative	0 0%	0 0%
Unknown: Peri-operative	1 1.8%	0 0%

12. Secondary Outcome

Title	Blood Loss Per Participant in Case of Surgery
Description	The intraoperative blood loss was measured by determining the volume of blood and fluid removal through suction into the collection container (waste box and/or cell saver) and the estimated blood loss into swabs and towels during the procedure, per the anesthesiologist's record. Postoperatively, blood loss was determined by the drainage volume collected, which mainly consisted of drainage fluid via vacuum or gravity drain, as applicable. In cases where no drain was present, blood loss was determined by the surgeon's clinical judgment, as applicable or entered as "not available". Blood loss was evaluated intra-operatively (from start to end of the procedure), post-operatively (from the end of procedure up to 24 h post procedure), and perioperatively (from the start of procedure to participant discharge from hospital or 14 days after completion of procedure; whichever was first).
Time Frame	Day 0 through discharge or 14 days post-surgery

Outcome Measure Data

Analysis Population Description

Surgery analysis set included all participants in the FAS (randomized to one of the two prophylactic arms and treated prophylactically for any period of time) who underwent some form of surgery (including dental) during the course of study participation.

Arm/Group Title	BAX 855-Low Level	BAX 855-High Level
Arm/Group Description	Participants with severe hemophilia A received a single BAX 855 dose of 60 +/- 5 IU/kg IV infusion (PK assessment) followed by a PK-guided dose of BAX 855 twice weekly (Alternating 3 and 4-day infusion intervals or an infusion every 3.5 days), targeting FVIII trough levels of 1-3%. Depending on participant's individual PK, more frequent dosing was considered if single doses of > 80 IU/kg were required or regular FVIII peak levels of 200% were reached.	Participants with severe hemophilia A received a single BAX 855 dose of 60 +/- 5 IU/kg IV infusion (PK assessment) followed by a PK-guided dose of BAX 855 every other day, targeting FVIII trough levels of 8-12%. Depending on participant's individual PK, a different dosing interval was considered to prevent regular high FVIII peak levels.
Measure Participants	3	4
Intra-operative: Observed	4.400 (4.017)	72.000 (160.741)
Intra-operative: Predicted Average	10.600 (9.227)	65.833 (139.290)
Intra-operative: Predicted Maximum	20.800 (18.089)	128.333 (231.790)
Post-operative: Observed	820.000 (NA)
Post-operative: Predicted Average	10.000 (9.129)	145.000 (320.967)
Post-operative: Predicted Maximum	20.200 (17.987)	230.000 (475.563)

13. Secondary Outcome

Title	Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
Description	An AE was any unfavorable and unintended sign (an abnormal laboratory finding), symptom (rash, pain, discomfort, fever, dizziness, etc.), disease (peritonitis, bacteremia, etc.), or outcome of death temporally associated with the use of an investigational product (IP), whether or not considered causally related to the IP. A SAE was defined as an untoward medical occurrence that at any dose met one or more of the following criteria: outcome was fatal/results in death, life-threatening, required in-patient hospitalization or resulted in prolongation of an existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, was a medically important event that was not immediately life-threatening or resulted in death or required hospitalization but jeopardize the participant or required medical or surgical intervention to prevent any of the above outcomes.
Time Frame	From start of study treatment up to 12 months (completion or termination)

Outcome Measure Data

Analysis Population Description

SAS included all participants enrolled who had at least one BAX 855 infusion.

Arm/Group Title	BAX 855-Low Level	BAX 855-High Level	BAX 855-Non-randomized
Arm/Group Description	Participants with severe hemophilia A received a single BAX 855 dose of 60 +/- 5 international units per kilogram (IU/kg) intravenous (IV) infusion (PK assessment) followed by a PK-guided dose of BAX 855 twice weekly (Alternating 3 and 4-day infusion intervals or an infusion every 3.5 days), targeting FVIII trough levels of 1-3%. Depending on participant's individual PK, more frequent dosing was considered if single doses of >80 IU/kg were required or regular FVIII peak levels of 200% were reached.	Participants with severe hemophilia A received a single BAX 855 dose of 60 +/- 5 IU/kg IV infusion (PK assessment) followed by a PK-guided dose of BAX 855 every other day, targeting FVIII trough levels of 8-12%. Depending on participant's individual PK, a different dosing interval was considered to prevent regular high FVIII peak levels.	Participants with severe hemophilia A received a single BAX 855 dose of 60 +/- 5 IU/kg IV infusion (PK assessment) and were not randomized to any treatments.
Measure Participants	57	58	6
Number of Participants with SAE	5 8.8%	5 8.6%	0 0%
Number of Participants with AE	35 61.4%	38 65.5%	0 0%

14. Secondary Outcome

Title	Number of Participants With Clinically Significant Changes in Vital Signs Reported as Treatment Related Adverse Events
Description	Vital signs included systolic and diastolic blood pressure, pulse rate, respiratory rate, body temperature.
Time Frame	From start of study treatment up to 12 months (completion or termination)

Outcome Measure Data

Analysis Population Description

SAS included all participants enrolled who had at least one BAX 855 infusion.

Arm/Group Title	BAX 855-Low Level	BAX 855-High Level	BAX 855-Non-randomized
Arm/Group Description	Participants with severe hemophilia A received a single BAX 855 dose of 60 +/- 5 IU/kg IV infusion (PK assessment) followed by a PK-guided dose of BAX 855 twice weekly (Alternating 3 and 4-day infusion intervals or an infusion every 3.5 days), targeting FVIII trough levels of 1-3%. Depending on participant's individual PK, more frequent dosing was considered if single doses of > 80 IU/kg were required or regular FVIII peak levels of 200% were reached.	Participants with severe hemophilia A received a single BAX 855 dose of 60 +/- 5 IU/kg IV infusion (PK assessment) followed by a PK-guided dose of BAX 855 every other day, targeting FVIII trough levels of 8-12%. Depending on participant's individual PK, a different dosing interval was considered to prevent regular high FVIII peak levels.	Participants with severe hemophilia A received a single BAX 855 dose of 60 +/- 5 IU/kg IV infusion (PK assessment) and were not randomized to any treatments.
Measure Participants	57	58	6
Count of Participants [Participants]	0 0%	0 0%	0 0%

15. Secondary Outcome

Title	Number of Participants With Clinically Significant Changes in Clinical Laboratory Parameters Reported as Treatment Related Adverse Events
Description	Clinical laboratory assessments included clinical chemistry, hematology, lipid panel, genetics, T-cell, B-cell and NK cell (TBNK) and viral serology.
Time Frame	From start of study treatment up to 12 months (completion or termination)

Outcome Measure Data

Analysis Population Description

SAS included all participants enrolled who had at least one BAX 855 infusion.

Arm/Group Title	BAX 855-Low Level	BAX 855-High Level	BAX 855-Non-randomized
Arm/Group Description	Participants with severe hemophilia A received a single BAX 855 dose of 60 +/- 5 IU/kg IV infusion (PK assessment) followed by a PK-guided dose of BAX 855 twice weekly (Alternating 3 and 4-day infusion intervals or an infusion every 3.5 days), targeting FVIII trough levels of 1-3%. Depending on participant's individual PK, more frequent dosing was considered if single doses of > 80 IU/kg were required or regular FVIII peak levels of 200% were reached.	Participants with severe hemophilia A received a single BAX 855 dose of 60 +/- 5 IU/kg IV infusion (PK assessment) followed by a PK-guided dose of BAX 855 every other day, targeting FVIII trough levels of 8-12%. Depending on participant's individual PK, a different dosing interval was considered to prevent regular high FVIII peak levels.	Participants with severe hemophilia A received a single BAX 855 dose of 60 +/- 5 IU/kg IV infusion (PK assessment) and were not randomized to any treatments.
Measure Participants	57	58	6
Count of Participants [Participants]	2 3.5%	1 1.7%	0 0%

16. Secondary Outcome

Title	Number of Participants With Positive Inhibitory Antibodies and Binding Antibodies to Factor VIII (FVIII), BAX 855, Polyethylene Glycol (PEG), and Chinese Hamster Ovary (CHO) Protein
Description	Positive Inhibitory Antibodies and Binding Antibodies to Factor VIII (FVIII), BAX 855, Polyethylene Glycol (PEG), and Chinese Hamster Ovary (CHO) Protein were reported here.
Time Frame	From start of study treatment up to 12 months (completion or termination)

Outcome Measure Data

Analysis Population Description

SAS included all participants enrolled who had at least one BAX 855 infusion.

Arm/Group Title	BAX 855-Low Level	BAX 855-High Level
Arm/Group Description	Participants with severe hemophilia A received a single BAX 855 dose of 60 +/- 5 international units per kilogram (IU/kg) intravenous (IV) infusion (PK assessment) followed by a PK-guided dose of BAX 855 twice weekly (Alternating 3 and 4-day infusion intervals or an infusion every 3.5 days), targeting FVIII trough levels of 1-3%. Depending on participant's individual PK, more frequent dosing was considered if single doses of >80 IU/kg were required or regular FVIII peak levels of 200% were reached.	Participants with severe hemophilia A received a single BAX 855 dose of 60 +/- 5 IU/kg IV infusion (PK assessment) followed by a PK-guided dose of BAX 855 every other day, targeting FVIII trough levels of 8-12%. Depending on participant's individual PK, a different dosing interval was considered to prevent regular high FVIII peak levels.
Measure Participants	57	58
Binding IgG antibodies to FVIII	0 0%	3 5.2%
Binding IgM antibodies to FVIII	0 0%	0 0%
Binding IgG antibodies to PEG-FVIII	2 3.5%	7 12.1%
Binding IgM antibodies to PEG-FVIII	0 0%	1 1.7%
Binding IgG antibodies to PEG	0 0%	0 0%
Binding IgM antibodies to PEG	1 1.8%	3 5.2%
Binding Ig antibodies to CHO	0 0%	0 0%
Inhibitory antibodies to FVIII	0 0%	1 1.7%

17. Secondary Outcome

Title	Change From Baseline in Physical Component Scores (PCS) of the Short Form-36 (SF-36) Health Survey
Description	Short Form (36) Health Survey (SF-36) is a 36-item validated, generic health related quality of life (HR QoL) instrument. PCS is a summary scale of the dimensions physical functioning, role physical, bodily pain, and general health. The component score is normalized to a standard population. Scores range from 0 to 100 with higher scores representing better health. There is no total overall score; scoring is done for both sub-scores and summary scores.
Time Frame	Baseline, Month 12 (completion or termination)

Outcome Measure Data

Analysis Population Description

FAS included all participants who were randomized to one of the two prophylactic arms and treated prophylactically for any period of time. Here "Number of participants analyzed" refer to number of participants evaluable for this outcome at specified time points.

Arm/Group Title	BAX 855-Low Level	BAX 855-High Level
Arm/Group Description	Participants with severe hemophilia A received a single BAX 855 dose of 60 +/- 5 international units per kilogram (IU/kg) intravenous (IV) infusion (PK assessment) followed by a PK-guided dose of BAX 855 twice weekly (Alternating 3 and 4-day infusion intervals or an infusion every 3.5 days), targeting FVIII trough levels of 1-3%. Depending on participant's individual PK, more frequent dosing was considered if single doses of >80 IU/kg were required or regular FVIII peak levels of 200% were reached.	Participants with severe hemophilia A received a single BAX 855 dose of 60 +/- 5 IU/kg IV infusion (PK assessment) followed by a PK-guided dose of BAX 855 every other day, targeting FVIII trough levels of 8-12%. Depending on participant's individual PK, a different dosing interval was considered to prevent regular high FVIII peak levels.
Measure Participants	47	48
Mean (Standard Deviation) [Score on a scale]	3.551 (8.351)	2.846 (8.658)

18. Secondary Outcome

Title	Area Under the Plasma Concentration of BAX 855 From Zero to Infinity (AUC0-inf)
Description	Area under the plasma concentration versus time curve from time 0 to infinity of BAX 855 were reported.
Time Frame	Pre-infusion, 15 - 30 minutes, 3, 8, 24, 48, 72 and 96 hours post-infusion

Outcome Measure Data

Analysis Population Description

Pharmacokinetic analysis set (PKAS) included all participants in the SAS that had at least one quantifiable post-dose FVIII activity level without major protocol deviations or events with potential to affect the PK analysis. Here "Number of participants analyzed" refer to number of participants evaluable for this outcome at specified time points.

Arm/Group Title	BAX 855-Low Level	BAX 855-High Level	BAX 855-Non-randomized
Arm/Group Description	Participants with severe hemophilia A received a single BAX 855 dose of 60 +/- 5 international units per kilogram (IU/kg) intravenous (IV) infusion (PK assessment) followed by a PK-guided dose of BAX 855 twice weekly (Alternating 3 and 4-day infusion intervals or an infusion every 3.5 days), targeting FVIII trough levels of 1-3%. Depending on participant's individual PK, more frequent dosing was considered if single doses of >80 IU/kg were required or regular FVIII peak levels of 200% were reached.	Participants with severe hemophilia A received a single BAX 855 dose of 60 +/- 5 IU/kg IV infusion (PK assessment) followed by a PK-guided dose of BAX 855 every other day, targeting FVIII trough levels of 8-12%. Depending on participant's individual PK, a different dosing interval was considered to prevent regular high FVIII peak levels.	Participants with severe hemophilia A received a single BAX 855 dose of 60 +/- 5 IU/kg IV infusion (PK assessment) and were not randomized to any treatments.
Measure Participants	54	57	5
Mean (Standard Deviation) [International units*hour per deciliter]	2673 (877.3)	2659 (1041)	2214 (355.8)

19. Secondary Outcome

Title	Incremental Recovery (IR) at Maximum Plasma Concentration (Cmax) of BAX 855
Description	IR at Cmax of BAX 855 were reported.
Time Frame	Pre-infusion, 15 - 30 minutes, 3, 8, 24, 48, 72 and 96 hours post-infusion

Outcome Measure Data

Analysis Population Description

PKAS included all participants in the SAS that had at least one quantifiable post-dose FVIII activity level without major protocol deviations or events with potential to affect the PK analysis. Here "Number of participants analyzed" refer to number of participants evaluable for this outcome at specified time points.

Arm/Group Title	BAX 855-Low Level	BAX 855-High Level	BAX 855-Non-randomized
Arm/Group Description	Participants with severe hemophilia A received a single BAX 855 dose of 60 +/- 5 international units per kilogram (IU/kg) intravenous (IV) infusion (PK assessment) followed by a PK-guided dose of BAX 855 twice weekly (Alternating 3 and 4-day infusion intervals or an infusion every 3.5 days), targeting FVIII trough levels of 1-3%. Depending on participant's individual PK, more frequent dosing was considered if single doses of >80 IU/kg were required or regular FVIII peak levels of 200% were reached.	Participants with severe hemophilia A received a single BAX 855 dose of 60 +/- 5 IU/kg IV infusion (PK assessment) followed by a PK-guided dose of BAX 855 every other day, targeting FVIII trough levels of 8-12%. Depending on participant's individual PK, a different dosing interval was considered to prevent regular high FVIII peak levels.	Participants with severe hemophilia A received a single BAX 855 dose of 60 +/- 5 IU/kg IV infusion (PK assessment) and were not randomized to any treatments.
Measure Participants	57	58	5
Mean (Standard Deviation) [(IU/dL) / (IU/kg)]	2.227 (0.5201)	2.231 (0.5451)	2.478 (0.2016)

20. Secondary Outcome

Title	Plasma Half-life (T1/2) of BAX 855
Description	T1/2 of BAX 855 in plasma were reported.
Time Frame	Pre-infusion, 15 - 30 minutes, 3, 8, 24, 48, 72 and 96 hours post-infusion

Outcome Measure Data

Analysis Population Description

PKAS included all participants in the SAS that had at least one quantifiable post-dose FVIII activity level without major protocol deviations or events with potential to affect the PK analysis.

Arm/Group Title	BAX 855-Low Level	BAX 855-High Level	BAX 855-Non-randomized
Arm/Group Description	Participants with severe hemophilia A received a single BAX 855 dose of 60 +/- 5 international units per kilogram (IU/kg) intravenous (IV) infusion (PK assessment) followed by a PK-guided dose of BAX 855 twice weekly (Alternating 3 and 4-day infusion intervals or an infusion every 3.5 days), targeting FVIII trough levels of 1-3%. Depending on participant's individual PK, more frequent dosing was considered if single doses of >80 IU/kg were required or regular FVIII peak levels of 200% were reached.	Participants with severe hemophilia A received a single BAX 855 dose of 60 +/- 5 IU/kg IV infusion (PK assessment) followed by a PK-guided dose of BAX 855 every other day, targeting FVIII trough levels of 8-12%. Depending on participant's individual PK, a different dosing interval was considered to prevent regular high FVIII peak levels.	Participants with severe hemophilia A received a single BAX 855 dose of 60 +/- 5 IU/kg IV infusion (PK assessment) and were not randomized to any treatments.
Measure Participants	57	58	5
Median (Full Range) [hour (h)]	15.28	14.66	10.97

21. Secondary Outcome

Title	Mean Residence Time (MRT) of BAX 855
Description	MRT of BAX 855 were reported.
Time Frame	Pre-infusion, 15 - 30 minutes, 3, 8, 24, 48, 72 and 96 hours post-infusion

Outcome Measure Data

Analysis Population Description

Pharmacokinetic analysis set (PKAS) included all participants in the SAS (participants enrolled who had at least 1 BAX 855 infusion) that had at least one quantifiable post-dose FVIII activity level without major protocol deviations or events with potential to affect the PK analysis.

Arm/Group Title	BAX 855-Low Level	BAX 855-High Level	BAX 855-Non-randomized
Arm/Group Description	Participants with severe hemophilia A received a single BAX 855 dose of 60 +/- 5 international units per kilogram (IU/kg) intravenous (IV) infusion (PK assessment) followed by a PK-guided dose of BAX 855 twice weekly (Alternating 3 and 4-day infusion intervals or an infusion every 3.5 days), targeting FVIII trough levels of 1-3%. Depending on participant's individual PK, more frequent dosing was considered if single doses of >80 IU/kg were required or regular FVIII peak levels of 200% were reached.	Participants with severe hemophilia A received a single BAX 855 dose of 60 +/- 5 IU/kg IV infusion (PK assessment) followed by a PK-guided dose of BAX 855 every other day, targeting FVIII trough levels of 8-12%. Depending on participant's individual PK, a different dosing interval was considered to prevent regular high FVIII peak levels.	Participants with severe hemophilia A received a single BAX 855 dose of 60 +/- 5 IU/kg IV infusion (PK assessment) and were not randomized to any treatments.
Measure Participants	57	58	5
Median (Full Range) [hour (h)]	22.77	21.50	16.18

22. Secondary Outcome

Title	Maximum Plasma Concentration (Cmax) of BAX 855
Description	Cmax of BAX 855 were reported.
Time Frame	Pre-infusion, 15 - 30 minutes, 3, 8, 24, 48, 72 and 96 hours post-infusion

Outcome Measure Data

Analysis Population Description

PKAS included all participants in the SAS that had at least one quantifiable post-dose FVIII activity level without major protocol deviations or events with potential to affect the PK analysis. Here "Number of participants analyzed" refer to number of participants evaluable for this outcome at specified time points.

Arm/Group Title	BAX 855-Low Level	BAX 855-High Level	BAX 855-Non-randomized
Arm/Group Description	Participants with severe hemophilia A received a single BAX 855 dose of 60 +/- 5 international units per kilogram (IU/kg) intravenous (IV) infusion (PK assessment) followed by a PK-guided dose of BAX 855 twice weekly (Alternating 3 and 4-day infusion intervals or an infusion every 3.5 days), targeting FVIII trough levels of 1-3%. Depending on participant's individual PK, more frequent dosing was considered if single doses of >80 IU/kg were required or regular FVIII peak levels of 200% were reached.	Participants with severe hemophilia A received a single BAX 855 dose of 60 +/- 5 IU/kg IV infusion (PK assessment) followed by a PK-guided dose of BAX 855 every other day, targeting FVIII trough levels of 8-12%. Depending on participant's individual PK, a different dosing interval was considered to prevent regular high FVIII peak levels.	Participants with severe hemophilia A received a single BAX 855 dose of 60 +/- 5 IU/kg IV infusion (PK assessment) and were not randomized to any treatments.
Measure Participants	54	57	5
Mean (Standard Deviation) [International units per deciliter(IU/dL)]	132.54 (31.83)	135.65 (33.10)	149.18 (12.86)

23. Secondary Outcome

Title	Time to Maximum Concentration of BAX 855 in Plasma (Tmax)
Description	Tmax of BAX 855 were reported.
Time Frame	Pre-infusion, 15 - 30 minutes, 3, 8, 24, 48, 72 and 96 hours post-infusion

Outcome Measure Data

Analysis Population Description

PKAS included all participants in the SAS that had at least one quantifiable post-dose FVIII activity level without major protocol deviations or events with potential to affect the PK analysis.

Arm/Group Title	BAX 855-Low Level	BAX 855-High Level	BAX 855-Non-randomized
Arm/Group Description	Participants with severe hemophilia A received a single BAX 855 dose of 60 +/- 5 international units per kilogram (IU/kg) intravenous (IV) infusion (PK assessment) followed by a PK-guided dose of BAX 855 twice weekly (Alternating 3 and 4-day infusion intervals or an infusion every 3.5 days), targeting FVIII trough levels of 1-3%. Depending on participant's individual PK, more frequent dosing was considered if single doses of >80 IU/kg were required or regular FVIII peak levels of 200% were reached.	Participants with severe hemophilia A received a single BAX 855 dose of 60 +/- 5 IU/kg IV infusion (PK assessment) followed by a PK-guided dose of BAX 855 every other day, targeting FVIII trough levels of 8-12%. Depending on participant's individual PK, a different dosing interval was considered to prevent regular high FVIII peak levels.	Participants with severe hemophilia A received a single BAX 855 dose of 60 +/- 5 IU/kg IV infusion (PK assessment) and were not randomized to any treatments.
Measure Participants	57	58	5
Median (Full Range) [hour (h)]	0.467	0.475	0.417

24. Secondary Outcome

Title	Total Body Clearance (CL) of BAX 855
Description	Total body clearance of BAX 855 from blood by the kidney were reported.
Time Frame	Pre-infusion, 15 - 30 minutes, 3, 8, 24, 48, 72 and 96 hours post-infusion

Outcome Measure Data

Analysis Population Description

PKAS included all participants in the SAS that had at least one quantifiable post-dose FVIII activity level without major protocol deviations or events with potential to affect the PK analysis.

Arm/Group Title	BAX 855-Low Level	BAX 855-High Level	BAX 855-Non-randomized
Arm/Group Description	Participants with severe hemophilia A received a single BAX 855 dose of 60 +/- 5 international units per kilogram (IU/kg) intravenous (IV) infusion (PK assessment) followed by a PK-guided dose of BAX 855 twice weekly (Alternating 3 and 4-day infusion intervals or an infusion every 3.5 days), targeting FVIII trough levels of 1-3%. Depending on participant's individual PK, more frequent dosing was considered if single doses of >80 IU/kg were required or regular FVIII peak levels of 200% were reached.	Participants with severe hemophilia A received a single BAX 855 dose of 60 +/- 5 IU/kg IV infusion (PK assessment) followed by a PK-guided dose of BAX 855 every other day, targeting FVIII trough levels of 8-12%. Depending on participant's individual PK, a different dosing interval was considered to prevent regular high FVIII peak levels.	Participants with severe hemophilia A received a single BAX 855 dose of 60 +/- 5 IU/kg IV infusion (PK assessment) and were not randomized to any treatments.
Measure Participants	57	58	5
Mean (Standard Deviation) [Deciliters per kilogram * hour (dL/kg*h)]	0.02477 (0.009580)	0.02624 (0.009333)	0.02774 (0.004385)

25. Secondary Outcome

Title	Volume of Distribution at Steady State (Vss)
Description	Volume of distribution was defined as the theoretical volume in which the total amount of drug was uniformly distributed to produce the desired blood concentration of a drug. Vss is the apparent volume of distribution at steadystate.
Time Frame	Pre-infusion, 15 - 30 minutes, 3, 8, 24, 48, 72 and 96 hours post-infusion

Outcome Measure Data

Analysis Population Description

PKAS included all participants in the SAS that had at least one quantifiable post-dose FVIII activity level without major protocol deviations or events with potential to affect the PK analysis.

Arm/Group Title	BAX 855-Low Level	BAX 855-High Level	BAX 855-Non-randomized
Arm/Group Description	Participants with severe hemophilia A received a single BAX 855 dose of 60 +/- 5 international units per kilogram (IU/kg) intravenous (IV) infusion (PK assessment) followed by a PK-guided dose of BAX 855 twice weekly (Alternating 3 and 4-day infusion intervals or an infusion every 3.5 days), targeting FVIII trough levels of 1-3%. Depending on participant's individual PK, more frequent dosing was considered if single doses of >80 IU/kg were required or regular FVIII peak levels of 200% were reached.	Participants with severe hemophilia A received a single BAX 855 dose of 60 +/- 5 IU/kg IV infusion (PK assessment) followed by a PK-guided dose of BAX 855 every other day, targeting FVIII trough levels of 8-12%. Depending on participant's individual PK, a different dosing interval was considered to prevent regular high FVIII peak levels.	Participants with severe hemophilia A received a single BAX 855 dose of 60 +/- 5 IU/kg IV infusion (PK assessment) and were not randomized to any treatments.
Measure Participants	57	58	5
Mean (Standard Deviation) [Deciliters per kilogram (dL/kg)]	0.5147 (0.1209)	0.5158 (0.1062)	149.18 (12.86)

26. Secondary Outcome

Title	Incremental Recovery (IR) Over Time
Description	Incremental recovery was calculated by BAX 855 increment (IU/dL) / BAX 855 dose (IU/kg).
Time Frame	Baseline, Month 3, 6, 7.5, 9, 10.5, 12 (Completion or termination)

Outcome Measure Data

Analysis Population Description

PKAS included all participants in the SAS that had at least one quantifiable post-dose FVIII activity level without major protocol deviations or events with potential to affect the PK analysis. Here "Number of participants analyzed" refer to number of participants evaluable for this outcome at specified time points.

Arm/Group Title	BAX 855-Low Level	BAX 855-High Level
Arm/Group Description	Participants with severe hemophilia A received a single BAX 855 dose of 60 +/- 5 IU/kg IV infusion (PK assessment) followed by a PK-guided dose of BAX 855 twice weekly (Alternating 3 and 4-day infusion intervals or an infusion every 3.5 days), targeting FVIII trough levels of 1-3%. Depending on participant's individual PK, more frequent dosing was considered if single doses of > 80 IU/kg were required or regular FVIII peak levels of 200% were reached.	Participants with severe hemophilia A received a single BAX 855 dose of 60 +/- 5 IU/kg IV infusion (PK assessment) followed by a PK-guided dose of BAX 855 every other day, targeting FVIII trough levels of 8-12%. Depending on participant's individual PK, a different dosing interval was considered to prevent regular high FVIII peak levels.
Measure Participants	57	58
Baseline	2.68 (0.513)	2.70 (0.450)
Month 3	2.68 (0.515)	2.66 (0.459)
Month 6	2.62 (0.585)	2.76 (0.552)
Month 7.5	2.53 (0.360)	2.71 (0.545)
Month 9	2.65 (0.511)	2.68 (0.545)
Month 10.5	2.61 (0.467)	2.58 (0.584)
Completion/ Termination	2.71 (0.553)	2.73 (0.689)

Adverse Events

Time Frame	From start of study treatment up to 12 months (completion or termination)
Arm/Group Title	BAX 855-Low Level		BAX 855-High Level		BAX 855-Non-randomized
Arm/Group Description	Participants with severe hemophilia A received a single BAX 855 dose of 60 +/- 5 IU/kg IV infusion (PK assessment) followed by a PK-guided dose of BAX 855 twice weekly (Alternating 3 and 4-day infusion intervals or an infusion every 3.5 days), targeting FVIII trough levels of 1-3%. Depending on participant's individual PK, more frequent dosing was considered if single doses of > 80 IU/kg were required or regular FVIII peak levels of 200% were reached.		Participants with severe hemophilia A received a single BAX 855 dose of 60 +/- 5 IU/kg IV infusion (PK assessment) followed by a PK-guided dose of BAX 855 every other day, targeting FVIII trough levels of 8-12%. Depending on participant's individual PK, a different dosing interval was considered to prevent regular high FVIII peak levels.		Participants with severe hemophilia A received a single BAX 855 dose of 60 +/- 5 IU/kg IV infusion (PK assessment) and were not randomized to any treatments.
All Cause Mortality
	BAX 855-Low Level		BAX 855-High Level		BAX 855-Non-randomized
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/57 (0%)		0/58 (0%)		0/6 (0%)
Serious Adverse Events
	BAX 855-Low Level		BAX 855-High Level		BAX 855-Non-randomized
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/57 (8.8%)		5/58 (8.6%)		0/6 (0%)
Blood and lymphatic system disorders
Factor viii inhibition	0/57 (0%)	0	1/58 (1.7%)	1	0/6 (0%)	0
Infections and infestations
Abscess limb	1/57 (1.8%)	1	0/58 (0%)	0	0/6 (0%)	0
Appendicitis	1/57 (1.8%)	1	0/58 (0%)	0	0/6 (0%)	0
Cellulitis	1/57 (1.8%)	1	0/58 (0%)	0	0/6 (0%)	0
Injury, poisoning and procedural complications
Hand fracture	0/57 (0%)	0	1/58 (1.7%)	1	0/6 (0%)	0
Head injury	1/57 (1.8%)	1	1/58 (1.7%)	1	0/6 (0%)	0
Laceration	0/57 (0%)	0	1/58 (1.7%)	1	0/6 (0%)	0
Multiple injuries	0/57 (0%)	0	1/58 (1.7%)	1	0/6 (0%)	0
Radius fracture	1/57 (1.8%)	1	0/58 (0%)	0	0/6 (0%)	0
Musculoskeletal and connective tissue disorders
Synovitis	1/57 (1.8%)	1	0/58 (0%)	0	0/6 (0%)	0
Nervous system disorders
Cerebellar haematoma	0/57 (0%)	0	1/58 (1.7%)	1	0/6 (0%)	0
Other (Not Including Serious) Adverse Events
	BAX 855-Low Level		BAX 855-High Level		BAX 855-Non-randomized
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	25/57 (43.9%)		25/58 (43.1%)		0/6 (0%)
Gastrointestinal disorders
Diarrhoea	3/57 (5.3%)	3	2/58 (3.4%)	2	0/6 (0%)	0
General disorders
Pyrexia	2/57 (3.5%)	2	3/58 (5.2%)	3	0/6 (0%)	0
Infections and infestations
Nasopharyngitis	6/57 (10.5%)	8	5/58 (8.6%)	6	0/6 (0%)	0
Rhinitis	3/57 (5.3%)	3	3/58 (5.2%)	3	0/6 (0%)	0
Sinusitis	3/57 (5.3%)	3	0/58 (0%)	0	0/6 (0%)	0
Upper respiratory tract infection	6/57 (10.5%)	11	12/58 (20.7%)	16	0/6 (0%)	0
Musculoskeletal and connective tissue disorders
Arthralgia	6/57 (10.5%)	7	5/58 (8.6%)	5	0/6 (0%)	0
Back pain	1/57 (1.8%)	2	3/58 (5.2%)	3	0/6 (0%)	0
Nervous system disorders
Headache	5/57 (8.8%)	7	6/58 (10.3%)	7	0/6 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

If a multicenter publication is not submitted within twelve (12) months after conclusion, abandonment or termination of the Study at all sites, or after Sponsor confirms there shall be no multicenter Study publication, the Institution and/or such Principal Investigator may publish the results from the Institution site individually.