Study Investigating a PEGylated Recombinant Factor VIII (BAX 855) for Hemophilia A (PROLONG-ATE Study)

• Sponsor: Baxalta now part of Shire (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01736475
• Collaborator: (none)
• Enrollment: 159
• Locations: 72
• Arms: 2
• Actual Duration (Months): 17.5
• Patients Per Site: 2.2
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

To assess efficacy and safety, including immunogenicity of BAX 855 administered as prophylaxis and as on-demand therapy in adult and adolescent (12-65 years) previously treated patients (PTPs) with severe hemophilia A To determine the pharmacokinetic (PK) parameters of BAX 855.

Condition or Disease	Intervention/Treatment	Phase
Hemophilia A	Biological: Antihemophilic Factor (Recombinant) - Plasma/Albumin Free Method; Biological: PEGylated Recombinant Factor VIII; Biological: PEGylated Recombinant Factor VIII; Biological: PEGylated Recombinant Factor VIII	Phase 2/Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 159 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Prevention
• Official Title: A Phase 2/3, Multi-Center, Open Label Study of Efficacy, Safety, and Pharmacokinetics of PEGylated Recombinant Factor VIII (BAX 855) Administered for Prophylaxis and Treatment of Bleeding in Previously Treated Patients With Severe Hemophilia A
• Actual Study Start Date: Jan 31, 2013
• Actual Primary Completion Date: Jul 17, 2014
• Actual Study Completion Date: Jul 17, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Prophylaxis	Biological: Antihemophilic Factor (Recombinant) - Plasma/Albumin Free Method; Pharmacokinetic (PK) evaluation of ADVATE; Other Names: ADVATE ; Biological: PEGylated Recombinant Factor VIII; Pharmacokinetic (PK) evaluation of BAX 855; Other Names: BAX 855 ; Biological: PEGylated Recombinant Factor VIII; Prophylaxis treatment; Other Names: BAX 855
Experimental: On-demand	Biological: PEGylated Recombinant Factor VIII; On-demand treatment; Other Names: BAX 855

Outcome Measures

Primary Outcome Measures

1. Annualized Bleeding Rate (ABR) [9 months]

   Comparisons between prophylactic and on-demand treatment were based on ABR estimates from a negative binomial regression model, taking into account the treatment regimen, target joints and age at screening, and duration of the observation period for efficacy.

Secondary Outcome Measures

1. Rate of Success of BAX 855 for Treatment of Bleeding Episodes [At least 50 exposure days or 6 months (±2 weeks), whichever occurs last, for the prophylaxis arm and 6 months (± 2 weeks) for the on-demand arm.]

   Success in the control of bleeding was defined as a rating of excellent or good using the Efficacy Rating Scale for Treatment of Bleeding Episodes measured 24 hours after initiation of treatment for the bleeding episode. EXCELLENT: Full relief of pain and cessation of objective signs of bleeding (eg, swelling, tenderness, and decreased range of motion in the case of musculoskeletal hemorrhage) after a single infusion. No additional infusion is required for the control of bleeding. Administration of further infusions to maintain hemostasis would not affect this scoring. GOOD: Definite pain relief and/or improvement in signs of bleeding after a single infusion. 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. Required more than 1 infusion for complete resolution. NONE: No improvement or condition worsens.

2. Average Number of BAX 855 Infusions Needed for the Treatment of Bleeding Episodes [From first exposure to BAX 855 until the end of the study, [at least 50 exposure days or 6 months (±2 weeks), whichever occurs last, for the prophylaxis arm; and 6 months (± 2 weeks) for the on-demand arm].]

3. Number of Participants With ≤1, 2, 3, 4, 5, 6, or >6 Month Time Intervals Between Bleeding Episodes or no Bleeding Episodes [From first exposure to BAX 855 until the end of the study, [at least 50 exposure days or 6 months (±2 weeks), whichever occurs last, for the prophylaxis arm; and 6 months (± 2 weeks) for the on-demand arm].]

   Interval between Bleeds in months was calculated as: Observation period for efficacy (in days)/(number of bleeds)*(12/365.2425)

4. Weight-adjusted Consumption of BAX 855 - Per Prophylactic Infusion and Pharmacokinetic (PK) Infusion [Prophylactic Infusion: ≥50 exposure days or 6 months (±2 weeks), whichever occurs last. PK Infusion: PK #1 Pre-infusion within 30 minutes; Post-infusion 10 min, and 0.5, 1, 3, 6, 24, 32, 48, 56 hours (h). PK #2 also at Post-infusion 96h]

5. Weight-adjusted Consumption of BAX 855 - Per Treatment of Bleeding Episode (BE) and Per BE for Maintenance of Hemostasis [Treatment of Bleeding Episode (BE): Minor/Moderate BE every 12 to 24 hours until bleeding is resolved; Major BE every 8 to 12 hours until bleeding is resolved. Per BE for Maintenance of Hemostasis: within 48 hours after bleeding episode resolution.]

   Infusions per bleeding episode for maintenance of hemostasis only includes infusions following the resolution of a bleed to maintain hemostasis.

6. Percentage of Participants With Adverse Events [From first exposure to BAX 855 until the end of the study, [at least 50 exposure days or 6 months (±2 weeks), whichever occurs last, for the prophylaxis arm; and 6 months (± 2 weeks) for the on-demand arm].]

   Adverse Events (AEs) and Serious Adverse Events (SAEs)

7. Immunogenicity - Number of Participants With Positive Inhibitory Antibodies to FVIII, Binding Antibodies to FVIII, PEG-VIII, PEG and Anti-CHO Antibodies at Study Completion/Termination [From first exposure to BAX 855 until the end of the study, [at least 50 exposure days or 6 months (±2 weeks), whichever occurs last, for the prophylaxis arm; and 6 months (± 2 weeks) for the on-demand arm].]

   Number of participants who received BAX855, with immunogenicity data from study completion/termination visit. FVIII = factor VIII; PEG-VIII = polyethylene glycol-factor VIII; Anti-CHO = Anti-Chinese hamster ovary

8. Patient Reported Outcomes: Haemo-SYM Questionnaire, Change in Score From Baseline to End of Study [Baseline; and end of study visit [at least 50 exposure days or 6 months (±2 weeks), whichever occurs last, for the prophylaxis arm and 6 months (± 2 weeks) for the on-demand arm].]

   The HAEMO-SYM has two subscales: pain and bleeds. HAEMO-SYM subscale scores are calculated by taking the mean of the items in each subscale and transforming them to a 0 (none or absent) to 100 (very severe) scale. Given that higher scores indicate more severe symptoms on the Haemo-SYM and that the change scores were calculated as the value at study completion minus the value at baseline, a negative change score indicates an improvement (reduction in symptoms). Conversely, a positive change score indicates worsening symptoms.

9. Patient Reported Outcomes - Short Form (SF)-36, Change From Baseline to End of Study [Baseline; and end of study visit [at least 50 exposure days or 6 months (±2 weeks), whichever occurs last, for the prophylaxis arm and 6 months (± 2 weeks) for the on-demand arm]]

   Change from Baseline to End of Study for SF-36 Questionnaire is provided. Scores for individual SF-36 categories range from 0 to 100 with higher scores representing better health. Given that higher scores indicate better health-related quality of life (HRQoL) and that the change scores were calculated as the value at study completion minus the value at baseline, a negative change score indicates a worsening of HRQoL.

10. Pharmacokinetics (Pk) - Plasma Half-life (One-stage Clotting Assay) [Within 30 minutes prior to start of infusion; and post-infusion at 10, 30 minutes, and 1, 3, 6, 9, 24, 32, 48, 56, 72 (PK2 and PK3 only), and 96 hours (PK2 and PK3 only).]

    Terminal half-life calculated as log_e2/λz where λz is the terminal elimination rate constant. Participants in the pharmacokinetic full analysis set (PKFAS) analysis set received an initial infusion of ADVATE for pharmacokinetic analysis (PK-1) followed by a washout period and an infusion of BAX 855 for a second pharmacokinetic analysis (PK-2). After at least 50 EDs of BAX 855, participants in the PK subgroup received another infusion of BAX 855 for pharmacokinetic analysis (PK-3).

11. Pharmacokinetics (Pk) - Mean Residence Time (One-stage Clotting Assay) [Within 30 minutes prior to start of infusion; and post-infusion at 10, 30 minutes, and 1, 3, 6, 9, 24, 32, 48, 56, 72 (PK2 and PK3 only), and 96 hours (PK2 and PK3 only).]

    The mean residence time (MRT) w as calculated as total area under the moment curve divided by the total area under the curve starting from the begin of infusion (or the end of infusion if start time is not available). Participants in the pharmacokinetic full analysis set (PKFAS) analysis set received an initial infusion of ADVATE for pharmacokinetic analysis (PK-1) followed by a washout period and an infusion of BAX 855 for a second pharmacokinetic analysis (PK-2). After at least 50 EDs of BAX 855, participants in the PK subgroup received another infusion of BAX 855 for pharmacokinetic analysis (PK-3).

12. Pharmacokinetics (Pk) - Total Body Clearance (One-stage Clotting Assay) [Within 30 minutes prior to start of infusion; and post-infusion at 10, 30 minutes, and 1, 3, 6, 9, 24, 32, 48, 56, 72 (PK2 and PK3 only), and 96 hours (PK2 and PK3 only).]

    Clearance in dL/(kg.h) will be calculated as the dose in IU/kg divided by the total area under the curve starting from the begin of infusion (or the end of infusion if start time is not available). Participants in the pharmacokinetic full analysis set (PKFAS) analysis set received an initial infusion of ADVATE for pharmacokinetic analysis (PK-1) followed by a washout period and an infusion of BAX 855 for a second pharmacokinetic analysis (PK-2). After at least 50 EDs of BAX 855, participants in the PK subgroup received another infusion of BAX 855 for pharmacokinetic analysis (PK-3).

13. Pharmacokinetics (Pk) - Incremental Recovery Over Time (One-stage Clotting Assay) [Within 30 minutes prior to start of infusion; and post-infusion at 10, 30 minutes, and 1, 3, 6, 9, 24, 32, 48, 56, 72 (PK2 and PK3 only), and 96 hours (PK2 and PK3 only).]

    Incremental recovery (IR) in (IU/dL)/ (IU/kg) calculated as: IR = (Cmax- (C pre-infusion)) / (Dose/kg), where C =concentration. Participants in the pharmacokinetic full analysis set (PKFAS) analysis set received an initial infusion of ADVATE for pharmacokinetic analysis (PK-1) followed by a washout period and an infusion of BAX 855 for a second pharmacokinetic analysis (PK-2). After at least 50 EDs of BAX 855, participants in the PK subgroup received another infusion of BAX 855 for pharmacokinetic analysis (PK-3).

14. Pharmacokinetics (Pk) - Area Under the Concentration Versus Time Curve From 0 to Infinity (AUC0-∞) (One-stage Clotting Assay) [Within 30 minutes prior to start of infusion; and post-infusion at 10, 30 minutes, and 1, 3, 6, 9, 24, 32, 48, 56, 72 (PK2 and PK3 only), and 96 hours (PK2 and PK3 only).]

    Calculated by WinNonlin NCA (Model 201, calculation method: Linear Trapezoidal Linear/Log Interpolation). Participants in the pharmacokinetic full analysis set (PKFAS) analysis set received an initial infusion of ADVATE for pharmacokinetic analysis (PK-1) followed by a washout period and an infusion of BAX 855 for a second pharmacokinetic analysis (PK-2). After at least 50 EDs of BAX 855, participants in the PK subgroup received another infusion of BAX 855 for pharmacokinetic analysis (PK-3).

15. Pharmacokinetics (Pk) - Apparent Volume of Distribution at Steady State (Vss) (One-stage Clotting Assay) [Within 30 minutes prior to start of infusion; and post-infusion at 10, 30 minutes, and 1, 3, 6, 9, 24, 32, 48, 56, 72 (PK2 and PK3 only), and 96 hours (PK2 and PK3 only).]

    The apparent volume of distribution at steady state (Vss) will be calculated as: Vss = Clearance * Mean Residence Time. Participants in the pharmacokinetic full analysis set (PKFAS) analysis set received an initial infusion of ADVATE for pharmacokinetic analysis (PK-1) followed by a washout period and an infusion of BAX 855 for a second pharmacokinetic analysis (PK-2). After at least 50 EDs of BAX 855, participants in the PK subgroup received another infusion of BAX 855 for pharmacokinetic analysis (PK-3).

16. Pharmacokinetics (Pk) - Maximum Plasma Concentration (Cmax) (One-stage Clotting Assay) [Within 30 minutes prior to start of infusion; and post-infusion at 10, 30 minutes, and 1, 3, 6, 9, 24, 32, 48, 56, 72 (PK2 and PK3 only), and 96 hours (PK2 and PK3 only).]

    Participants in the pharmacokinetic full analysis set (PKFAS) analysis set received an initial infusion of ADVATE for pharmacokinetic analysis (PK-1) followed by a washout period and an infusion of BAX 855 for a second pharmacokinetic analysis (PK-2). After at least 50 EDs of BAX 855, participants in the PK subgroup received another infusion of BAX 855 for pharmacokinetic analysis (PK-3).

17. Pharmacokinetics (Pk) -Time to Maximum Concentration in Plasma (Tmax) (One-stage Clotting Assay) [Within 30 minutes prior to start of infusion; and post-infusion at 10, 30 minutes, and 1, 3, 6, 9, 24, 32, 48, 56, 72 (PK2 and PK3 only), and 96 hours (PK2 and PK3 only).]

    Tmax in hours will be defined as the time to reach Cmax. Participants in the pharmacokinetic full analysis set (PKFAS) analysis set received an initial infusion of ADVATE for pharmacokinetic analysis (PK-1) followed by a washout period and an infusion of BAX 855 for a second pharmacokinetic analysis (PK-2). After at least 50 EDs of BAX 855, participants in the PK subgroup received another infusion of BAX 855 for pharmacokinetic analysis (PK-3).

18. Change in Vital Signs From Screening - Temperature [Screening, week 2, week 4, exposure day 10-15, month 3, study completion/termination]

19. Change in Vital Signs From Screening - Pulse Rate [Screening, week 2, week 4, exposure day 10-15, month 3, study completion/termination]

20. Change in Vital Signs From Screening - Respiratory Rate [Screening, week 2, week 4, exposure day 10-15, month 3, study completion/termination]

21. Changes in Vital Signs From Screening - Blood Pressure [Screening, week 2, week 4, exposure day 10-15, month 3, study completion/termination]

    Systolic Blood Pressure (SBP) Diastolic Blood Pressure (DBP)

22. Changes in Clinical Chemistry Laboratory Assessments From Screening - Albumin and Protein [Screening, week 2, week 4, month 3, study completion/termination]

23. Changes in Clinical Chemistry Laboratory Assessments From Screening - Alkaline Phosphatase, Alanine Aminotransferase, Aspartate Aminotransferase [Screening, week 2, week 4, month 3, study completion/termination]

    Alkaline Phosphatase (Alk Phos); Alanine Aminotransferase (Ala Amino); Aspartate Aminotransferase (Asp Amino)

24. Changes in Clinical Chemistry Laboratory Assessments From Screening - Bicarbonate, Chloride, Glucose, Potassium, Sodium, Blood Urea Nitrogen (BUN) [Screening, week 2, week 4, month 3, study completion/termination]

25. Changes in Clinical Chemistry Laboratory Assessments From Screening - Creatinine, and Bilirubin [Screening, week 2, week 4, month 3, study completion/termination]

26. Changes in Hematology Laboratory Assessments From Screening - Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, Platelets, and Leukocytes [Screening, week 2, week 4, month 3, study completion/termination]

27. Changes in Hematology Laboratory Assessments From Screening - Hematocrit [Screening, week 2, week 4, month 3, study completion/termination]

28. Changes in Hematology Laboratory Assessments From Screening - Hemoglobin [Screening, week 2, week 4, month 3, study completion/termination]

29. Changes in Hematology Laboratory Assessments From Screening - Erythrocytes [Screening, week 2, week 4, month 3, study completion/termination]

30. Changes in Lipid Panel Assessments From Screening - Cholesterol; High Density Lipoprotein (HDL); Low Density Lipoprotein (LDL); Triglycerides; and Very Low Density Lipoprotein (VLDL) [Screening, week 2, week 4, month 3, study completion/termination]

Eligibility Criteria

Criteria

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

Main Inclusion Criteria:

• Participant and/or legal representative has/have voluntarily provided signed informed consent

• Participant is 12 to 65 years old at the time of screening

• Participant is male with severe hemophilia A (Factor VIII (FVIII) clotting activity < 1%) as confirmed by central laboratory at screening after the appropriate washout period or a documented FVIII clotting activity <1%

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

• Participant is currently receiving prophylaxis or on-demand therapy with FVIII

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

Main Exclusion Criteria:

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

• Participant has history of FVIII inhibitory antibodies (≥ 0.4 BU using the Nijmegen modification of the Bethesda assay or ≥ 0.6 BU using the Bethesda assay) at any time prior to screening

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Colorado	Aurora	Colorado	United States	80045
2	University of Florida, College of Medicine	Gainesville	Florida	United States	32610
3	Children's Healthcare of Atlanta	Atlanta	Georgia	United States	30322
4	Bleeding and Clotting Disorders Institute	Peoria	Illinois	United States	61614
5	University of Kentucky Medical Center	Lexington	Kentucky	United States	40504
6	University of Louisville Hospital	Louisville	Kentucky	United States	40202
7	Tulane University Medical School	New Orleans	Louisiana	United States	70124
8	Children's Mercy Hospitals & Clinics	Kansas City	Missouri	United States	66211
9	Weill Cornell Medical College-New York Presbyterian Hospital	New York	New York	United States	10065
10	University of North Carolina Chapel Hill	Chapel Hill	North Carolina	United States	27599
11	Duke University Medical Center	Durham	North Carolina	United States	27710
12	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio	United States	45229
13	The Cleveland Clinic Foundation	Cleveland	Ohio	United States	44195
14	Penn State Milton S. Hershey Medical Center	Hershey	Pennsylvania	United States	17033
15	Palmetto Health	Columbia	South Carolina	United States	29203
16	University of Utah Health Sciences Center	Salt Lake City	Utah	United States	84132
17	Puget Sound Blood Group	Seattle	Washington	United States	98104
18	Royal Adelaide Hospital	Adelaide	South Australia	Australia	5000
19	The Alfred Hospital	Clayton	Victoria	Australia	3168
20	Fremantle Hospital	Fremantle	Western Australia	Australia	6160
21	Hollywood Specialist Centre	Nedlands	Western Australia	Australia	6009
22	Landes-Frauen-und Kinderklinik Linz	Linz		Austria	4020
23	AKH - Medizinische Universität Wien	Vienna		Austria	1090
24	SHAT of Oncohaematology Diseases	Sofia		Bulgaria	1527
25	Fakultni nemocnice Brno	Brno		Czechia	61300
26	Fakultni nemocnice Olomouc	Olomouc		Czechia	775 20
27	Fakultni nemocnice v Motole	Praha 5		Czechia	150 06
28	Gerinnungszentrum Rhein-Ruhr	Duisburg	Nordrhein Westfalen	Germany	47051
29	Vivantes Klinikum im Friedrichshain - Landsberger Allee	Berlin		Germany	10249
30	Universitaetsklinikum Hamburg-Eppendorf	Hamburg		Germany	20246
31	Werlhof-Institut MVZ	Hannover		Germany	30159
32	Rambam Health Care Campus	Haifa		Israel	3109601
33	Chaim Sheba Medical Center	Tel Aviv		Israel	64239
34	Nagoya University Hospital	Nagoya-shi	Aichi-Ken	Japan	466-8560
35	University of Occupational and Environmental Health Hospital	Kitakyushu-shi	Fukuoka-Ken	Japan	807-8556
36	Hiroshima University Hospital	Hiroshima-shi	Hiroshima-Ken	Japan	734-8551
37	Hyogo College of Medicine Hospital	Nishinomiya-shi	Hyogo-Ken	Japan	663-8501
38	St. Marianna University School of Medicine Hospital	Kawasaki-shi	Kanagawa-Ken	Japan	216-8511
39	Nara Medical University Hospital	Kashihara-shi	Nara-Ken	Japan	634-8522
40	Tokyo Medical University Hospital	Shinjuku-ku	Tokyo-To	Japan	160-0023
41	Ogikubo Hospital	Suginami-ku	Tokyo-To	Japan	167-8515
42	Chonnam National University Hwasun Hospital	Hwasun	Jeollanam-do	Korea, Republic of	519-763
43	Pusan National University Hospital	Busan		Korea, Republic of	602-739
44	Eulji University Hospital	Daejeon		Korea, Republic of	302-120
45	Kyung hee University Hospital at Gangdong	Seoul		Korea, Republic of	134-727
46	Ulsan University Hospital	Ulsan		Korea, Republic of	682-714
47	Vilnius University Hospital Santariskiu Clinics, Public Institution	Vilnius		Lithuania	08661
48	Children's Hospital, Affiliate of Vilnius University Hospital Santariskiu Klinikos	Vilnius		Lithuania	LT-08406
49	Hospital Pulau Pinang	George Town	Pulau Pinang	Malaysia	10990
50	Hospital Tengku Ampuan Rahimah	Klang	Selangor	Malaysia	41200
51	Pusat Darah Negara	Kuala Lumpur		Malaysia	50400
52	Academisch Medisch Centrum	Amsterdam		Netherlands	1105 AZ
53	Uniwersyteckie Centrum Kliniczne	Gdansk		Poland	80-952
54	Wojewodzki Szpital Specjalistyczny im.M.Kopernika w Lodzi	Lodz		Poland	93-510
55	Sanador SRL	Bucuresti		Romania	011026
56	Hospital Universitari Son Espases	Palma de Mallorca	Baleares	Spain	07010
57	Complejo Hospitalario Universitario A Coruña	A Coruña	La Coruña	Spain	15006
58	Hospital Regional Universitario de Malaga	Malaga	Málaga	Spain	29010
59	Hospital Universitari i Politecnic La Fe	Valencia		Spain	46026
60	Skånes Universitetssjukhus, Malmö	Malmö		Sweden	20502
61	Karolinska Universitetssjukhuset, Solna	Stockholm		Sweden	17176
62	Universitatsspital Zurich	Zurich		Switzerland	8091
63	Tri-Service General Hospital	Taipei		Taiwan	11490
64	SI V.K.Gusak Emergency and Reconstructive Surgery Institute of NAMSU Center of IT	Donetsk		Ukraine	83045
65	SI Institute of Blood Pathology and Transfusion Medicine of NAMSU	Lviv		Ukraine	79044
66	Bristol Royal Hospital for Children	Bristol	Avon	United Kingdom	BS2 8BJ
67	Royal Free Hospital	London	Greater London	United Kingdom	NW3 2QG
68	St Thomas' Hospital	London	Greater London	United Kingdom	SE1 7EH
69	Manchester Royal Infirmary	Manchester	Greater Manchester	United Kingdom	M13 9WL
70	Royal Manchester Children's Hospital	Manchester	Greater Manchester	United Kingdom	M13 9WL
71	Leicester Royal Infirmary	Leicester	Leicestershire	United Kingdom	LE1 5WW
72	Churchill Hospital	Oxford	Oxfordshire	United Kingdom	OX3 7LJ

Sponsors and Collaborators

• Baxalta 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: NCT01736475
• Other Study ID Numbers: 261201; 2012-003599-38
• First Posted: Nov 29, 2012
• Last Update Posted: May 20, 2021
• Last Verified: Apr 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	Participants were enrolled (signed informed consent) at 72 sites.
Pre-assignment Detail	A total of 159 participants provided informed consent and were screened for study participation, of which there were 21 screen failures. 138 participants were assigned to the prophylactic arm or the on-demand treatment regimen.

Arm/Group Title	Prophylaxis	On-demand
Arm/Group Description	Twice weekly at a dose of 45 ± 5 IU/kg	10 to 60 ± 5 IU/kg
Period Title: Overall Study
STARTED	121	17
COMPLETED	109	17
NOT COMPLETED	12	0

Baseline Characteristics

Arm/Group Title	Prophylaxis	On-demand	Total
Arm/Group Description	Total of all reporting groups
Overall Participants	121	17	138
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	29.8 (12.53)	31.5 (11.05)	30.0 (12.34)
Sex: Female, Male (Count of Participants)
Female	0 0%	0 0%	0 0%
Male	121 100%	17 100%	138 100%

Outcome Measures

1. Primary Outcome

Title	Annualized Bleeding Rate (ABR)
Description	Comparisons between prophylactic and on-demand treatment were based on ABR estimates from a negative binomial regression model, taking into account the treatment regimen, target joints and age at screening, and duration of the observation period for efficacy.
Time Frame	9 months

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	Prophylaxis	On-demand
Arm/Group Description
Measure Participants	120	17
Least Squares Mean (95% Confidence Interval) [Bleeds per year]	4.3	43.4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Prophylaxis, On-demand
	Comments	Ratio Annualized Bleeding Rate (ABR) Prophylaxis/On-demand: Prophylaxis treatment w ill be considered to be successful if the upper limit of the 95% CI for the ratio between treatment regimen does not exceed 0.5 (corresponding to a 50% reduction of the mean ABR compared to the on-demand treatment). H01: μ1 ≥0.5*μ2 Ha1: μ1<0.5*μ2 w here μ1 and μ2 are the mean ABRs in on prophylaxis and on-demand, respectively
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Regression, Negative binomial
	Comments
Method of Estimation	Estimation Parameter	Ratio of means
	Estimated Value	0.10
	Confidence Interval	(2-Sided) 95%; 0.06 to 0.19
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Rate of Success of BAX 855 for Treatment of Bleeding Episodes
Description	Success in the control of bleeding was defined as a rating of excellent or good using the Efficacy Rating Scale for Treatment of Bleeding Episodes measured 24 hours after initiation of treatment for the bleeding episode. EXCELLENT: Full relief of pain and cessation of objective signs of bleeding (eg, swelling, tenderness, and decreased range of motion in the case of musculoskeletal hemorrhage) after a single infusion. No additional infusion is required for the control of bleeding. Administration of further infusions to maintain hemostasis would not affect this scoring. GOOD: Definite pain relief and/or improvement in signs of bleeding after a single infusion. 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. Required more than 1 infusion for complete resolution. NONE: No improvement or condition worsens.
Time Frame	At least 50 exposure days or 6 months (±2 weeks), whichever occurs last, for the prophylaxis arm and 6 months (± 2 weeks) for the on-demand arm.

Outcome Measure Data

Analysis Population Description

Full Analysis Set - All bleeding episodes treated with BAX 855 in participants on on-demand and prophylaxis treatment regimens were analyzed as a single group.

Arm/Group Title	Participants With a Bleeding Episode
Arm/Group Description	All bleeding episodes treated with BAX 855 in participants on on-demand and prophylaxis treatment regimens.
Measure Participants	81
Measure Bleeding episodes	591
Number (95% Confidence Interval) [Bleeding episodes]	0.96

3. Secondary Outcome

Title	Average Number of BAX 855 Infusions Needed for the Treatment of Bleeding Episodes
Time Frame	From first exposure to BAX 855 until the end of the study, [at least 50 exposure days or 6 months (±2 weeks), whichever occurs last, for the prophylaxis arm; and 6 months (± 2 weeks) for the on-demand arm].

Outcome Measure Data

Analysis Population Description

Participants from the Full Analysis Set who experienced at least one bleeding episode.

Arm/Group Title	Prophylaxis	On-demand
Arm/Group Description	Break-through bleeds during prophylaxis
Measure Participants	65	17
Mean (Standard Deviation) [Infusions]	1.37 (0.80)	1.21 (0.35)

4. Secondary Outcome

Title	Number of Participants With ≤1, 2, 3, 4, 5, 6, or >6 Month Time Intervals Between Bleeding Episodes or no Bleeding Episodes
Description	Interval between Bleeds in months was calculated as: Observation period for efficacy (in days)/(number of bleeds)*(12/365.2425)
Time Frame	From first exposure to BAX 855 until the end of the study, [at least 50 exposure days or 6 months (±2 weeks), whichever occurs last, for the prophylaxis arm; and 6 months (± 2 weeks) for the on-demand arm].

Outcome Measure Data

Analysis Population Description

Study participants from the Full Analysis Set (FAS) who received BAX855 during the study period. Note: one participant was assigned to the prophylactic arm (thus was included in the FAS) and received only ADVATE during the screening period.

Arm/Group Title	Prophylaxis	On-demand
Arm/Group Description
Measure Participants	120	17
No bleed	45 37.2%	0 0%
>6 Months	5 4.1%	0 0%
6 Months	20 16.5%	0 0%
5 Months	3 2.5%	0 0%
4 Months	0 0%	0 0%
3 Months	11 9.1%	0 0%
2 Months	16 13.2%	0 0%
≤1 Month	20 16.5%	17 100%

5. Secondary Outcome

Title	Weight-adjusted Consumption of BAX 855 - Per Prophylactic Infusion and Pharmacokinetic (PK) Infusion
Time Frame	Prophylactic Infusion: ≥50 exposure days or 6 months (±2 weeks), whichever occurs last. PK Infusion: PK #1 Pre-infusion within 30 minutes; Post-infusion 10 min, and 0.5, 1, 3, 6, 24, 32, 48, 56 hours (h). PK #2 also at Post-infusion 96h

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) - Note: data analyzed by subsets of FAS (1) participants who received BAX855 prophylactic infusion or (2) BAX855 pharmacokinetic (PK) participants. - Subset of participants who received BAX855 prophylactic infusion: N= 120 - Subset of BAX855 pharmacokinetic (PK) participants: N=26

Arm/Group Title	All Study Participants
Arm/Group Description
Measure Participants	137
Measure Infusions	5941
Per Prophylactic Infusion (N= 5941 Infusions)	44.51 (4.556)
Per PK Infusion (N= 50 Infusions)	45.48 (2.592)

6. Secondary Outcome

Title	Weight-adjusted Consumption of BAX 855 - Per Treatment of Bleeding Episode (BE) and Per BE for Maintenance of Hemostasis
Description	Infusions per bleeding episode for maintenance of hemostasis only includes infusions following the resolution of a bleed to maintain hemostasis.
Time Frame	Treatment of Bleeding Episode (BE): Minor/Moderate BE every 12 to 24 hours until bleeding is resolved; Major BE every 8 to 12 hours until bleeding is resolved. Per BE for Maintenance of Hemostasis: within 48 hours after bleeding episode resolution.

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) - Note: data analyzed by subsets of FAS (1) participants who received BAX855 for treatment of BEs (2) BAX855 for Maintenance of Hemostasis. - Subset of participants who received BAX855 for treatment of BEs: N= 92 - Subset BAX855 for Maintenance of Hemostasis participants: N=16

Arm/Group Title	All Study Participants
Arm/Group Description	All Study Participants who received at least one infusion of BAX855.
Measure Participants	137
Measure Bleeds	592
Per Treatment of BE (N= 592 bleeds)	37.44 (28.105)
Per BE for Maintenance of Hemostasis (N=34 bleeds)	39.29 (34.206)

7. Secondary Outcome

Title	Percentage of Participants With Adverse Events
Description	Adverse Events (AEs) and Serious Adverse Events (SAEs)
Time Frame	From first exposure to BAX 855 until the end of the study, [at least 50 exposure days or 6 months (±2 weeks), whichever occurs last, for the prophylaxis arm; and 6 months (± 2 weeks) for the on-demand arm].

Outcome Measure Data

Analysis Population Description

Safety Analysis Set (SAS) - All participants treated with BAX 855 were analyzed as a single group (ie on-demand and prophylaxis treatment regimens were analyzed as a single group).

Arm/Group Title	All Study Participants
Arm/Group Description	All Study Participants who received at least one infusion of BAX855.
Measure Participants	137
SAE, Moderate, Unrelated	0.7 0.6%
SAE, Severe, Unrelated	2.9 2.4%
nSAE, Mild, Unrelated	40.1 33.1%
nSAE, Mild, Related	3.6 3%
nSAE, Moderate, Unrelated	19.0 15.7%
nSAE, Moderate, Related	1.5 1.2%
nSAE, Unknown Severity, Unrelated	0.7 0.6%
nSAE, Severe, Unrelated	1.5 1.2%

8. Secondary Outcome

Title	Immunogenicity - Number of Participants With Positive Inhibitory Antibodies to FVIII, Binding Antibodies to FVIII, PEG-VIII, PEG and Anti-CHO Antibodies at Study Completion/Termination
Description	Number of participants who received BAX855, with immunogenicity data from study completion/termination visit. FVIII = factor VIII; PEG-VIII = polyethylene glycol-factor VIII; Anti-CHO = Anti-Chinese hamster ovary
Time Frame	From first exposure to BAX 855 until the end of the study, [at least 50 exposure days or 6 months (±2 weeks), whichever occurs last, for the prophylaxis arm; and 6 months (± 2 weeks) for the on-demand arm].

Outcome Measure Data

Analysis Population Description

Safety Analysis Set (SAS) - who received BAX855 during the study period. Note: one participant was assigned to the prophylactic arm but did not receive BAX855 (only received ADVATE, during the screening period).

Arm/Group Title	Prophylaxis	On-demand
Arm/Group Description	Twice weekly at a dose of 45 ± 5 IU/kg	10 to 60 ± 5 IU/kg
Measure Participants	120	17
Inhibitory Antibodies to FVIII (N= 112, 14)	0 0%	0 0%
IgG: Binding Antibodies FVIII (N= 117, 15)	0 0%	0 0%
IgM: Binding Antibodies FVIII (N= 117, 15)	0 0%	0 0%
IgG: Binding Antibodies PEG (N= 117, 15)	0 0%	0 0%
IgM: Binding Antibodies PEG (N= 117, 15)	0 0%	0 0%
IgG: Binding Antibodies PEG-FVIII (N= 117, 15)	0 0%	1 5.9%
IgM: Binding Antibodies PEG-FVIII (N= 117, 15)	0 0%	0 0%
CHO-Protein Antibodies (N= 117, 15)	0 0%	0 0%

9. Secondary Outcome

Title	Patient Reported Outcomes: Haemo-SYM Questionnaire, Change in Score From Baseline to End of Study
Description	The HAEMO-SYM has two subscales: pain and bleeds. HAEMO-SYM subscale scores are calculated by taking the mean of the items in each subscale and transforming them to a 0 (none or absent) to 100 (very severe) scale. Given that higher scores indicate more severe symptoms on the Haemo-SYM and that the change scores were calculated as the value at study completion minus the value at baseline, a negative change score indicates an improvement (reduction in symptoms). Conversely, a positive change score indicates worsening symptoms.
Time Frame	Baseline; and end of study visit [at least 50 exposure days or 6 months (±2 weeks), whichever occurs last, for the prophylaxis arm and 6 months (± 2 weeks) for the on-demand arm].

Outcome Measure Data

Analysis Population Description

Full Analysis Set - Subset of participants with both baseline and study completion HAEMO-SYM scores

Arm/Group Title	Prophylaxis	On-demand
Arm/Group Description	Participants with both baseline and study completion HAEMO-SYM scores	Participants with both baseline and study completion HAEMO-SYM scores
Measure Participants	82	11
Bleed Severity Total Score	-4.17 (17.05)	-4.24 (15.71)
Pain Severity Total Score	-1.22 (12.50)	-0.17 (11.88)

10. Secondary Outcome

Title	Patient Reported Outcomes - Short Form (SF)-36, Change From Baseline to End of Study
Description	Change from Baseline to End of Study for SF-36 Questionnaire is provided. Scores for individual SF-36 categories range from 0 to 100 with higher scores representing better health. Given that higher scores indicate better health-related quality of life (HRQoL) and that the change scores were calculated as the value at study completion minus the value at baseline, a negative change score indicates a worsening of HRQoL.
Time Frame	Baseline; and end of study visit [at least 50 exposure days or 6 months (±2 weeks), whichever occurs last, for the prophylaxis arm and 6 months (± 2 weeks) for the on-demand arm]

Outcome Measure Data

Analysis Population Description

Full Analysis Set - Subset of participants with both baseline and study completion SF-36 scores

Arm/Group Title	Prophylaxis	On-demand
Arm/Group Description	Participants with both baseline and study completion SF-36 Scores	Participants with both baseline and study completion SF-36 Scores
Measure Participants	97	12
Physical Functioning (N= 97, 12)	0.49 (5.27)	-2.46 (4.29)
Role-physical (N= 97, 12)	1.31 (7.36)	-3.67 (9.01)
Bodily Pain (N= 97, 12)	2.08 (8.19)	0.60 (4.44)
General Health (N= 96, 12)	0.40 (6.43)	-0.28 (9.04)
Vitality (N= 96, 12)	-0.38 (7.43)	0.26 (9.36)
Social Functioning (N= 97, 12)	0.90 (7.54)	-3.18 (6.35)
Role Emotional (N= 97, 12)	-0.20 (8.46)	0.65 (7.92)
Mental Health (N= 96, 12)	0.09 (7.26)	-3.29 (7.95)
Physical Component Score (N= 96, 12)	1.36 (5.76)	-1.58 (4.97)
Mental Component Score (N= 96, 12)	-0.37 (7.38)	-1.14 (5.03)

11. Secondary Outcome

Title	Pharmacokinetics (Pk) - Plasma Half-life (One-stage Clotting Assay)
Description	Terminal half-life calculated as log_e2/λz where λz is the terminal elimination rate constant. Participants in the pharmacokinetic full analysis set (PKFAS) analysis set received an initial infusion of ADVATE for pharmacokinetic analysis (PK-1) followed by a washout period and an infusion of BAX 855 for a second pharmacokinetic analysis (PK-2). After at least 50 EDs of BAX 855, participants in the PK subgroup received another infusion of BAX 855 for pharmacokinetic analysis (PK-3).
Time Frame	Within 30 minutes prior to start of infusion; and post-infusion at 10, 30 minutes, and 1, 3, 6, 9, 24, 32, 48, 56, 72 (PK2 and PK3 only), and 96 hours (PK2 and PK3 only).

Outcome Measure Data

Analysis Population Description

Pharmacokinetic full analysis set (PKFAS)

Arm/Group Title	Pharmacokinetic Analysis Participants
Arm/Group Description
Measure Participants	26
PK-1: ADVATE	10.40 (2.244)
PK-2: BAX 855	14.30 (3.838)
PK-3: BAX 855, After ≥50 Exposure Days (N=22)	16.02 (4.922)

12. Secondary Outcome

Title	Pharmacokinetics (Pk) - Mean Residence Time (One-stage Clotting Assay)
Description	The mean residence time (MRT) w as calculated as total area under the moment curve divided by the total area under the curve starting from the begin of infusion (or the end of infusion if start time is not available). Participants in the pharmacokinetic full analysis set (PKFAS) analysis set received an initial infusion of ADVATE for pharmacokinetic analysis (PK-1) followed by a washout period and an infusion of BAX 855 for a second pharmacokinetic analysis (PK-2). After at least 50 EDs of BAX 855, participants in the PK subgroup received another infusion of BAX 855 for pharmacokinetic analysis (PK-3).
Time Frame	Within 30 minutes prior to start of infusion; and post-infusion at 10, 30 minutes, and 1, 3, 6, 9, 24, 32, 48, 56, 72 (PK2 and PK3 only), and 96 hours (PK2 and PK3 only).

Outcome Measure Data

Analysis Population Description

Pharmacokinetic full analysis set (PKFAS)

Arm/Group Title	Pharmacokinetic Analysis Participants
Arm/Group Description
Measure Participants	26
PK-1: ADVATE	12.86 (3.044)
PK-2: BAX 855	19.56 (5.315)
PK-3: BAX 855, After ≥50 Exposure Days (N=22)	20.65 (4.821)

13. Secondary Outcome

Title	Pharmacokinetics (Pk) - Total Body Clearance (One-stage Clotting Assay)
Description	Clearance in dL/(kg.h) will be calculated as the dose in IU/kg divided by the total area under the curve starting from the begin of infusion (or the end of infusion if start time is not available). Participants in the pharmacokinetic full analysis set (PKFAS) analysis set received an initial infusion of ADVATE for pharmacokinetic analysis (PK-1) followed by a washout period and an infusion of BAX 855 for a second pharmacokinetic analysis (PK-2). After at least 50 EDs of BAX 855, participants in the PK subgroup received another infusion of BAX 855 for pharmacokinetic analysis (PK-3).
Time Frame	Within 30 minutes prior to start of infusion; and post-infusion at 10, 30 minutes, and 1, 3, 6, 9, 24, 32, 48, 56, 72 (PK2 and PK3 only), and 96 hours (PK2 and PK3 only).

Outcome Measure Data

Analysis Population Description

Pharmacokinetic full analysis set (PKFAS)

Arm/Group Title	Pharmacokinetic Analysis Participants
Arm/Group Description
Measure Participants	26
PK-1: ADVATE	0.04551 (0.021725)
PK-2: BAX 855	0.02760 (0.020288)
PK-3: BAX 855, After ≥50 Exposure Days (N=22)	0.02474 (0.008225)

14. Secondary Outcome

Title	Pharmacokinetics (Pk) - Incremental Recovery Over Time (One-stage Clotting Assay)
Description	Incremental recovery (IR) in (IU/dL)/ (IU/kg) calculated as: IR = (Cmax- (C pre-infusion)) / (Dose/kg), where C =concentration. Participants in the pharmacokinetic full analysis set (PKFAS) analysis set received an initial infusion of ADVATE for pharmacokinetic analysis (PK-1) followed by a washout period and an infusion of BAX 855 for a second pharmacokinetic analysis (PK-2). After at least 50 EDs of BAX 855, participants in the PK subgroup received another infusion of BAX 855 for pharmacokinetic analysis (PK-3).
Time Frame	Within 30 minutes prior to start of infusion; and post-infusion at 10, 30 minutes, and 1, 3, 6, 9, 24, 32, 48, 56, 72 (PK2 and PK3 only), and 96 hours (PK2 and PK3 only).

Outcome Measure Data

Analysis Population Description

Pharmacokinetic full analysis set (PKFAS)

Arm/Group Title	Pharmacokinetic Analysis Participants
Arm/Group Description
Measure Participants	26
PK-1: ADVATE	2.372 (0.5357)
PK-2: BAX 855	2.493 (0.6944)
PK-3: BAX 855, After ≥50 Exposure Days (N=22)	2.297 (0.6377)

15. Secondary Outcome

Title	Pharmacokinetics (Pk) - Area Under the Concentration Versus Time Curve From 0 to Infinity (AUC0-∞) (One-stage Clotting Assay)
Description	Calculated by WinNonlin NCA (Model 201, calculation method: Linear Trapezoidal Linear/Log Interpolation). Participants in the pharmacokinetic full analysis set (PKFAS) analysis set received an initial infusion of ADVATE for pharmacokinetic analysis (PK-1) followed by a washout period and an infusion of BAX 855 for a second pharmacokinetic analysis (PK-2). After at least 50 EDs of BAX 855, participants in the PK subgroup received another infusion of BAX 855 for pharmacokinetic analysis (PK-3).
Time Frame	Within 30 minutes prior to start of infusion; and post-infusion at 10, 30 minutes, and 1, 3, 6, 9, 24, 32, 48, 56, 72 (PK2 and PK3 only), and 96 hours (PK2 and PK3 only).

Outcome Measure Data

Analysis Population Description

Pharmacokinetic full analysis set (PKFAS)

Arm/Group Title	Pharmacokinetic Analysis Participants
Arm/Group Description
Measure Participants	26
PK-1: ADVATE	1168.0 (425.40)
PK-2: BAX 855	2073.3 (778.41)
PK-3: BAX 855, After ≥50 Exposure Days (N=22)	2008.7 (631.53)

16. Secondary Outcome

Title	Pharmacokinetics (Pk) - Apparent Volume of Distribution at Steady State (Vss) (One-stage Clotting Assay)
Description	The apparent volume of distribution at steady state (Vss) will be calculated as: Vss = Clearance * Mean Residence Time. Participants in the pharmacokinetic full analysis set (PKFAS) analysis set received an initial infusion of ADVATE for pharmacokinetic analysis (PK-1) followed by a washout period and an infusion of BAX 855 for a second pharmacokinetic analysis (PK-2). After at least 50 EDs of BAX 855, participants in the PK subgroup received another infusion of BAX 855 for pharmacokinetic analysis (PK-3).
Time Frame	Within 30 minutes prior to start of infusion; and post-infusion at 10, 30 minutes, and 1, 3, 6, 9, 24, 32, 48, 56, 72 (PK2 and PK3 only), and 96 hours (PK2 and PK3 only).

Outcome Measure Data

Analysis Population Description

Pharmacokinetic full analysis set (PKFAS)

Arm/Group Title	Pharmacokinetic Analysis Participants
Arm/Group Description
Measure Participants	26
PK-1: ADVATE	0.5487 (0.20213)
PK-2: BAX 855	0.4715 (0.14602)
PK-3: BAX 855, After ≥50 Exposure Days (N=22)	0.4970 (0.15756)

17. Secondary Outcome

Title	Pharmacokinetics (Pk) - Maximum Plasma Concentration (Cmax) (One-stage Clotting Assay)
Description	Participants in the pharmacokinetic full analysis set (PKFAS) analysis set received an initial infusion of ADVATE for pharmacokinetic analysis (PK-1) followed by a washout period and an infusion of BAX 855 for a second pharmacokinetic analysis (PK-2). After at least 50 EDs of BAX 855, participants in the PK subgroup received another infusion of BAX 855 for pharmacokinetic analysis (PK-3).
Time Frame	Within 30 minutes prior to start of infusion; and post-infusion at 10, 30 minutes, and 1, 3, 6, 9, 24, 32, 48, 56, 72 (PK2 and PK3 only), and 96 hours (PK2 and PK3 only).

Outcome Measure Data

Analysis Population Description

Pharmacokinetic full analysis set (PKFAS)

Arm/Group Title	Pharmacokinetic Analysis Participants
Arm/Group Description
Measure Participants	26
PK-1: ADVATE	108.45 (26.250)
PK-2: BAX 855	113.68 (30.259)
PK-3: BAX 855, After ≥50 Exposure Days (N=22)	103.34 (29.311)

18. Secondary Outcome

Title	Pharmacokinetics (Pk) -Time to Maximum Concentration in Plasma (Tmax) (One-stage Clotting Assay)
Description	Tmax in hours will be defined as the time to reach Cmax. Participants in the pharmacokinetic full analysis set (PKFAS) analysis set received an initial infusion of ADVATE for pharmacokinetic analysis (PK-1) followed by a washout period and an infusion of BAX 855 for a second pharmacokinetic analysis (PK-2). After at least 50 EDs of BAX 855, participants in the PK subgroup received another infusion of BAX 855 for pharmacokinetic analysis (PK-3).
Time Frame	Within 30 minutes prior to start of infusion; and post-infusion at 10, 30 minutes, and 1, 3, 6, 9, 24, 32, 48, 56, 72 (PK2 and PK3 only), and 96 hours (PK2 and PK3 only).

Outcome Measure Data

Analysis Population Description

Pharmacokinetic full analysis set (PKFAS)

Arm/Group Title	Pharmacokinetic Analysis Participants
Arm/Group Description
Measure Participants	26
PK-1: ADVATE	0.296 (0.1662)
PK-2: BAX 855	0.397 (0.2632)
PK-3: BAX 855, After ≥50 Exposure Days (N=22)	0.467 (0.6044)

19. Secondary Outcome

Title	Change in Vital Signs From Screening - Temperature
Time Frame	Screening, week 2, week 4, exposure day 10-15, month 3, study completion/termination

Outcome Measure Data

Analysis Population Description

Safety Analysis Set

Arm/Group Title	Prophylaxis	On-demand
Arm/Group Description
Measure Participants	119	17
Week 2 (N= 118, 17)	0.00	0.00
Week 4 (N= 118, 15)	0.00	0.00
Exposure day 10-15 (N= 31, 10)	-0.10	0.00
Month 3 (N= 112, 17)	0.00	0.00
Completion/Termination (N= 116, 15)	0.00	0.00

20. Secondary Outcome

Title	Change in Vital Signs From Screening - Pulse Rate
Time Frame	Screening, week 2, week 4, exposure day 10-15, month 3, study completion/termination

Outcome Measure Data

Analysis Population Description

Safety Analysis Set

Arm/Group Title	Prophylaxis	On-demand
Arm/Group Description
Measure Participants	118	17
Week 2 (N= 118, 17)	3.0	2.0
Week 4 (N= 117, 15)	2.0	2.0
Exposure day 10-15 (N= 31, 10)	3.0	4.0
Month 3 (N= 112, 17)	2.0	1.0
Completion/Termination (N= 116, 15)	2.0	3.0

21. Secondary Outcome

Title	Change in Vital Signs From Screening - Respiratory Rate
Time Frame	Screening, week 2, week 4, exposure day 10-15, month 3, study completion/termination

Outcome Measure Data

Analysis Population Description

Safety Analysis Set

Arm/Group Title	Prophylaxis	On-deamand
Arm/Group Description
Measure Participants	118	17
Week 2 (N= 117, 17)	0.0	0.0
Week 4 (N= 118, 15)	0.0	0.0
Exposure day 10-15 (N= 31, 10)	0.0	0.0
Month 3 (N= 112, 16)	0.0	0.0
Completion/Termination (N= 115, 15)	0.0	-1.0

22. Secondary Outcome

Title	Changes in Vital Signs From Screening - Blood Pressure
Description	Systolic Blood Pressure (SBP) Diastolic Blood Pressure (DBP)
Time Frame	Screening, week 2, week 4, exposure day 10-15, month 3, study completion/termination

Outcome Measure Data

Analysis Population Description

Safety Analysis Set

Arm/Group Title	Prophylaxis	On-demand
Arm/Group Description
Measure Participants	118	17
SBP-Week 2 (N= 118, 17)	0.0	-2.0
SBP-Week 4 (N= 118, 15)	-0.5	-1.0
SBP-Exposure day 10-15 (N= 31, 10)	0.0	3.5
SBP-Month 3 (N= 112, 17)	0.0	-5.0
SBP-Completion/Termination (N= 116, 15)	0.0	0.0
DBP-Week 2 (N= 118, 17)	0.0	-2.0
DBP-Week 4 (N= 118, 15)	-0.5	-6.0
DBP-Exposure day 10-15 (N= 31, 10)	0.0	-2.5
DBP-Month 3 (N= 112, 17)	0.0	-4.0
DBP-Completion/Termination (N= 116, 15)	0.0	-2.0

23. Secondary Outcome

Title	Changes in Clinical Chemistry Laboratory Assessments From Screening - Albumin and Protein
Time Frame	Screening, week 2, week 4, month 3, study completion/termination

Outcome Measure Data

Analysis Population Description

Safety Analysis Set - Subset of participants with both screening visit data and follow on time point data.

Arm/Group Title	Prophylaxis	On-demand
Arm/Group Description
Measure Participants	115	17
Albumin: Week 2 (N= 112, 17)	-1.0	-1.0
Albumin: Week 4 (N= 112, 14)	-1.0	-1.0
Albumin: Month 3 (N= 106, 17)	-1.0	-1.0
Albumin: Completion/Termination (N= 112, 14)	0.0	-1.0
Protein: Week 2 (N= 115, 17)	-1.0	-2.0
Protein: Week 4 (N= 114, 14)	-1.0	-2.0
Protein: Month 3 (N= 109, 17)	-1.0	-1.0
Protein: Completion/Termination (N= 114, 15)	-1.0	-1.0

24. Secondary Outcome

Title	Changes in Clinical Chemistry Laboratory Assessments From Screening - Alkaline Phosphatase, Alanine Aminotransferase, Aspartate Aminotransferase
Description	Alkaline Phosphatase (Alk Phos); Alanine Aminotransferase (Ala Amino); Aspartate Aminotransferase (Asp Amino)
Time Frame	Screening, week 2, week 4, month 3, study completion/termination

Outcome Measure Data

Analysis Population Description

Safety Analysis Set - Subset of participants with both screening visit data and follow on time point data.

Arm/Group Title	Prophylaxis	On-demand
Arm/Group Description
Measure Participants	115	17
Alk Phos: Week 2 (N= 115, 17)	-1.0	-5.0
Alk Phos: Week 4 (N= 114, 14)	-4.0	-4.5
Alk Phos: Month 3 (N= 109, 17)	-2.0	-5.0
Alk Phos: Completion/Termination (N= 114, 15)	0.0	-5.0
Ala Amino: Week 2 (N= 112, 17)	1.0	-2.0
Ala Amino: Week 4 (N= 112, 14)	0.0	-2.5
Ala Amino: Month 3 (N= 106, 17)	1.0	1.0
Ala Amino: Completion/Termination (N= 112, 14)	-1.0	2.5
Asp Amino: Week 2 (N= 110, 17)	0.5	-1.0
Asp Amino: Week 4 (N= 110, 14)	0.0	-3.5
Asp Amino: Month 3 (N= 103, 17)	1.0	1.0
Asp Amino: Completion/Termination (N= 110, 14)	1.0	3.5

25. Secondary Outcome

Title	Changes in Clinical Chemistry Laboratory Assessments From Screening - Bicarbonate, Chloride, Glucose, Potassium, Sodium, Blood Urea Nitrogen (BUN)
Time Frame	Screening, week 2, week 4, month 3, study completion/termination

Outcome Measure Data

Analysis Population Description

Safety Analysis Set - Subset of participants with both screening visit data and follow on time point data.

Arm/Group Title	Prophylaxis	On-demand
Arm/Group Description
Measure Participants	115	17
Bicarbonate: Week 2 (N= 111, 16)	0.10	1.10
Bicarbonate: Week 4 (N= 110, 13)	0.40	0.10
Bicarbonate: Month 3 (N= 111, 16)	0.60	0.60
Bicarbonate: Completion/Termination (N= 117, 13)	1.20	2.20
Chloride: Week 2 (N= 115, 17)	0.0	-2.0
Chloride: Week 4 (N= 114, 14)	1.0	-1.0
Chloride: Month 3 (N= 109, 17)	0.0	1.0
Chloride: Completion/Termination (N= 114, 15)	0.0	-1.0
Glucose: Week 2 (N= 112, 17)	-0.10	-0.30
Glucose: Week 4 (N= 112, 14)	0.10	-0.05
Glucose: Month 3 (N= 106, 17)	0.00	0.10
Glucose: Completion/Termination (N= 115, 14)	0.00	-0.10
Potassium: Week 2 (N= 115, 17)	0.00	0.10
Potassium: Week 4 (N= 114, 14)	0.05	0.10
Potassium: Month 3 (N= 109, 17)	0.00	0.10
Potassium: Completion/Termination (N= 114, 15)	0.00	0.00
Sodium: Week 2 (N= 115, 17)	0.0	-1.0
Sodium: Week 4 (N= 114, 14)	0.0	-1.5
Sodium: Month 3 (N= 109, 17)	0.0	0.0
Sodium: Completion/Termination (N= 114, 15)	-1.0	-1.0
BUN: Week 2 (N= 115, 17)	0.00	-0.20
BUN: Week 4 (N= 113, 14)	0.00	-0.10
BUN: Month 3 (N= 109, 17)	0.30	-0.40
BUN: Completion/Termination (N= 114, 15)	0.30	0.00

26. Secondary Outcome

Title	Changes in Clinical Chemistry Laboratory Assessments From Screening - Creatinine, and Bilirubin
Time Frame	Screening, week 2, week 4, month 3, study completion/termination

Outcome Measure Data

Analysis Population Description

Safety Analysis Set - Subset of participants with both screening visit data and follow on time point data.

Arm/Group Title	Prophylaxis	On-demand
Arm/Group Description
Measure Participants	115	17
Creatinine: Week 2 (N= 115, 17)	0.0	1.0
Creatinine: Week 4 (N= 114, 14)	0.0	0.5
Creatinine: Month 3 (N= 109, 17)	0.0	3.0
Creatinine: Completion/Termination (N= 114, 15)	0.0	6.0
Bilirubin: Week 2 (N= 109, 17)	0.00	-2.00
Bilirubin: Week 4 (N= 109, 14)	0.00	-0.50
Bilirubin: Month 3 (N= 103, 17)	0.00	1.00
Bilirubin: Completion/Termination (N= 109, 14)	0.00	-0.50

27. Secondary Outcome

Title	Changes in Hematology Laboratory Assessments From Screening - Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, Platelets, and Leukocytes
Time Frame	Screening, week 2, week 4, month 3, study completion/termination

Outcome Measure Data

Analysis Population Description

Safety Analysis Set - Subset of participants with both screening visit data and follow on time point data.

Arm/Group Title	Prophylaxis	On-demand
Arm/Group Description
Measure Participants	109	17
Basophils: Week 2 (N= 108, 17)	0.000	0.000
Basophils: Week 4 (N= 109, 14)	0.000	0.005
Basophils: Month 3 (N= 103, 16)	0.000	0.000
Basophils: Completion/Termination (N= 107, 14)	-0.010	0.000
Eosinophils: Week 2 (N= 108, 17)	0.010	0.030
Eosinophils: Week 4 (N= 109, 14)	0.020	0.035
Eosinophils: Month 3 (N= 103, 16)	0.010	0.010
Eosinophils: Completion/Termination (N= 107, 14)	0.010	0.045
Lymphocytes: Week 2 (N= 108, 17)	-0.005	0.280
Lymphocytes: Week 4 (N= 109, 14)	-0.060	0.175
Lymphocytes: Month 3 (N= 103, 16)	0.030	0.130
Lymphocytes: Completion/Termination (N= 107, 14)	0.040	0.030
Monocytes: Week 2 (N= 108, 17)	0.005	0.060
Monocytes: Week 4 (N= 109, 14)	0.020	-0.010
Monocytes: Month 3 (N= 103, 16)	0.000	0.020
Monocytes: Completion/Termination (N= 107, 14)	0.010	0.060
Neutrophils: Week 2 (N= 108, 17)	-0.165	0.060
Neutrophils: Week 4 (N= 109, 14)	-0.130	-0.140
Neutrophils: Month 3 (N= 103, 16)	-0.070	-0.425
Neutrophils: Completion/Termination (N= 107, 14)	0.050	0.055
Platelets: Week 2 (N= 107, 16)	-1.0	13.5
Platelets: Week 4 (N= 108, 13)	2.0	-8.0
Platelets: Month 3 (N= 102, 15)	1.5	-3.0
Platelets: Completion/Termination (N= 105, 13)	0.0	-1.0
Leukocytes: Week 2 (N= 108, 17)	-0.185	0.030
Leukocytes: Week 4 (N= 109, 14)	-0.180	-0.005
Leukocytes: Month 3 (N= 103, 16)	-0.040	0.220
Leukocytes: Completion/Termination (N= 107, 14)	-0.020	0.250

28. Secondary Outcome

Title	Changes in Hematology Laboratory Assessments From Screening - Hematocrit
Time Frame	Screening, week 2, week 4, month 3, study completion/termination

Outcome Measure Data

Analysis Population Description

Safety Analysis Set - Subset of participants with both screening visit data and follow on time point data.

Arm/Group Title	Prophylaxis	On-demand
Arm/Group Description
Measure Participants	108	17
Week 2 (N= 107, 17)	-0.010	0.000
Week 4 (N= 108, 13)	-0.010	-0.010
Month 3 (N= 102, 16)	0.000	0.000
Completion/Termination (N= 106, 14)	0.000	-0.005

29. Secondary Outcome

Title	Changes in Hematology Laboratory Assessments From Screening - Hemoglobin
Time Frame	Screening, week 2, week 4, month 3, study completion/termination

Outcome Measure Data

Analysis Population Description

Safety Analysis Set - Subset of participants with both screening visit data and follow on time point data.

Arm/Group Title	Prophylaxis	On-demand
Arm/Group Description
Measure Participants	109	17
Week 2 (N= 108, 17)	-1.0	3.0
Week 4 (N= 109, 14)	-1.0	0.0
Month 3 (N= 103, 16)	1.0	3.5
Completion/Termination (N= 107, 14)	2.0	4.5

30. Secondary Outcome

Title	Changes in Hematology Laboratory Assessments From Screening - Erythrocytes
Time Frame	Screening, week 2, week 4, month 3, study completion/termination

Outcome Measure Data

Analysis Population Description

Safety Analysis Set - Subset of participants with both screening visit data and follow on time point data.

Arm/Group Title	Prophylaxis	On-demand
Arm/Group Description
Measure Participants	109	17
Week 2 (N= 108, 17)	-0.10	0.10
Week 4 (N= 109, 14)	0.00	0.00
Month 3 (N= 103, 16)	0.00	0.00
Completion/Termination (N= 107, 14)	0.00	0.00

31. Secondary Outcome

Title	Changes in Lipid Panel Assessments From Screening - Cholesterol; High Density Lipoprotein (HDL); Low Density Lipoprotein (LDL); Triglycerides; and Very Low Density Lipoprotein (VLDL)
Time Frame	Screening, week 2, week 4, month 3, study completion/termination

Outcome Measure Data

Analysis Population Description

Safety Analysis Set - Subset of participants with both screening visit data and follow on time point data.

Arm/Group Title	Prophylaxis	On-demand
Arm/Group Description
Measure Participants	115	17
Cholesterol: Week 2 (N= 115, 17)	-0.130	-0.100
Cholesterol: Week 4 (N= 114, 14)	-0.050	-0.190
Cholesterol: Month 3 (N= 109, 17)	-0.070	0.040
Cholesterol: Completion/Termination (N= 114, 15)	-0.015	0.080
HDL: Week 2 (N= 115, 17)	0.000	-0.130
HDL: Week 4 (N= 114, 14)	-0.015	-0.095
HDL: Month 3 (N= 109, 17)	0.010	-0.020
HDL: Completion/Termination (N= 114, 15)	-0.020	0.030
LDL: Week 2 (N= 114, 17)	-0.070	-0.090
LDL: Week 4 (N= 112, 13)	-0.080	-0.320
LDL: Month 3 (N= 108, 17)	-0.030	0.000
LDL: Completion/Termination (N= 113, 15)	0.050	-0.050
Triglycerides: Week 2 (N= 115, 17)	-0.0600	0.1700
Triglycerides: Week 4 (N= 114, 14)	-0.0800	0.1500
Triglycerides: Month 3 (N= 109, 17)	-0.1600	0.3600
Triglycerides: Completion/Termination (N= 114, 15)	0.0000	0.1200
VLDL: Week 2 (N= 114, 17)	-0.0150	0.0800
VLDL: Week 4 (N= 112, 13)	-0.0350	0.0400
VLDL: Month 3 (N= 108, 17)	-0.0700	0.1600
VLDL: Completion/Termination (N= 113, 15)	0.0000	0.0600

Adverse Events

Time Frame	From first exposure to BAX 855 until the end of the study, [at least 50 exposure days or 6 months (±2 weeks), whichever occurs last, for the prophylaxis arm; and 6 months (± 2 weeks) for the on-demand arm].
Adverse Event Reporting Description	All study participants were analyzed in a single arm/group.
Arm/Group Title	All Study Participants
Arm/Group Description	All study participants were analyzed in a single arm/group.
All Cause Mortality
	All Study Participants
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	All Study Participants
	Affected / at Risk (%)	# Events
Total	5/137 (3.6%)
Infections and infestations
HERPES ZOSTER INFECTION NEUROLOGICAL	1/137 (0.7%)	1
Injury, poisoning and procedural complications
HUMERUS FRACTURE	1/137 (0.7%)	1
Musculoskeletal and connective tissue disorders
MUSCLE HAEMORRHAGE	1/137 (0.7%)	1
OSTEOARTHRITIS	1/137 (0.7%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
NEUROENDOCRINE CARCINOMA	1/137 (0.7%)	1
Other (Not Including Serious) Adverse Events
	All Study Participants
	Affected / at Risk (%)	# Events
Total	26/137 (19%)
Infections and infestations
Nasopharyngitis	13/137 (9.5%)	16
Upper respiratory tract infection	9/137 (6.6%)	10
Nervous system disorders
Headache	7/137 (5.1%)	13

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

Baxalta's agreements with PIs may vary per individual PI, but contain common elements. For this study, PIs may be restricted from independently publishing results without prior approval.