BAX 326 (rFIX) Continuation Study

• Sponsor: Baxalta now part of Shire (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01286779
• Collaborator: (none)
• Enrollment: 117
• Locations: 42
• Arm: 1
• Actual Duration (Months): 74.6
• Patients Per Site: 2.8
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

The purpose of this BAX 326 Continuation Study is to further investigate incremental recovery over time, the hemostatic efficacy, the safety, immunogenicity, and health-related quality of life (HR QoL) of BAX 326 in previously treated patients (PTPs) with severe and moderately severe hemophilia B who participated in BAX 326 pivotal study 250901 or BAX 326 pediatric study 251101.

Condition or Disease	Intervention/Treatment	Phase
Hemophilia B	Biological: BAX 326 (Recombinant factor IX)	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 117 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: BAX 326 (Recombinant Factor IX): Evaluation of Safety, Immunogenicity, and Hemostatic Efficacy in Previously Treated Patients With Severe (FIX Level < 1%) or Moderately Severe (FIX Level <= 2%) Hemophilia B - A Continuation Study
• Actual Study Start Date: Apr 12, 2011
• Actual Primary Completion Date: Jun 29, 2017
• Actual Study Completion Date: Jun 29, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: BAX 326	Biological: BAX 326 (Recombinant factor IX); The treatment with BAX 326 will be at the discretion of the investigator and will consist of either twice weekly prophylactic treatment with 50 IU/kg, modified prophylaxis, or on-demand treatment.

Outcome Measures

Primary Outcome Measures

1. Adverse Events Possibly or Probably Related to the Investigational Product [Assessed (based on patient diary) every 3 months until study completion (when BAX326 is licensed in the respective country or the participant has accumulated approximately 100 exposure days to BAX 326, whichever is last).]

   Possibly or probably related adverse events that occurred during or after first BAX326 infusion.

Secondary Outcome Measures

1. Treatment of Bleeding Episodes: Number of Infusions Per Bleeding Episode Required Until Bleed Resolution [Throughout the study from screening to study completion (when BAX326 is licensed in the respective country or the participant has accumulated approximately 100 exposure days to BAX 326, whichever is last).]

   Number of Infusions of BAX326 that were required until bleed resolution.

2. Treatment of Bleeding Episodes: Overall Hemostatic Efficacy Rating at Resolution of Bleed [Throughout the study from screening to study completion (when BAX326 is licensed in the respective country or the participant has accumulated approximately 100 exposure days to BAX 326, whichever is last).]

   Overall clinical efficacy rating of bleeding episodes was done at resolution of bleed according these rating scale: Excellent=Full relief of pain and cessation of objective signs of bleeding after a single infusion. No additional infusion is required for the control of bleeding. Administration of further infusion would not affect the 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.

3. Annualized Bleed Rate During Prophylaxis Treatment [For prophylactic treatment the period from first to last prophylactic infusion is considered.]

   Annualized bleed rate (ABR) was calculated as (number of bleeding episodes/observed treatment period in days)*365.25

4. Consumption of BAX 326: Number of Infusions Per Month and Per Year [Throughout the study from screening to study completion (when BAX326 is licensed in the respective country or the participant has accumulated approximately 100 exposure days to BAX 326, whichever is last).]

   The number of infusions consumed per month and per year for the prophylactic and on-demand treatment regimens.

5. Consumption of BAX 326: Weight Adjusted Consumption Per Month and Per Year [Throughout the study from screening to study completion (when BAX326 is licensed in the respective country or the participant has accumulated approximately 100 exposure days to BAX 326, whichever is last).]

   The weight adjusted consumption of BAX 326 per month and per year for the prophylactic and on-demand treatment regimens.

6. Consumption of BAX326: Weight Adjusted Consumption Per Bleeding Episode [Throughout the study from screening to study completion (when BAX326 is licensed in the respective country or the participant has accumulated approximately 100 exposure days to BAX 326, whichever is last).]

   The weight adjusted consumption of BAX 326 per bleeding episode for the prophylactic and on-demand treatment regimens. Only infusions required until the resolution of bleed are considered.

7. Development of Inhibitory and Total Binding Antibodies to Factor IX [Laboratory assessment for immunology were done at screening, at exposure day 1, at week 4 (± 1 week), at month 3 (±1 week), thereafter, every 3 months (± 1 week) and at study completion/termination.]

   Testing for inhibitory and total binding antibodies to Factor IX (FIX). Development during study means negative at screening and positive at any subsequent visit. Treatment emergent means more than 2-dilution increase as compared to the pre-study titer at screening.

8. Development of Antibodies to Chinese Hamster Ovary Proteins (CHO Proteins) and rFurin [Laboratory assessment for immunology were done at screening, at exposure day 1, at week 4 (± 1 week), at month 3 (±1 week), thereafter, every 3 months (± 1 week) and at study completion/termination.]

   Testing for antibodies to CHO proteins and rFurin. Development during study means negative at screening and positive at any subsequent visit. Treatment emergent means more than 2-dilution increase as compared to the pre-study titer at screening.

9. Occurrence of Severe Allergic Reactions and Thrombotic Events [Throughout the study from screening to study completion (when BAX326 is licensed in the respective country or the participant has accumulated approximately 100 exposure days to BAX 326, whichever is last).]

   The occurrence of severe allergic reactions and thrombotic events was assessed.

10. Clinical Significant Changes in Routine Laboratory Parameters and Vital Signs [Measurements at screening and at study completion/termination are included in the analysis.]

    Hematology panel consists of complete blood count (hemoglobin, hematocrit, erythrocytes, leukocytes) with differential (ie, basophils, eosinophils, lymphocytes, monocytes, neutrophils), mean corpuscular volume, mean corpuscular hemoglobin concentration and platelet count. Clinical chemistry panel consists of sodium, potassium, chloride, bicarbonate, total protein, albumin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, alkaline phosphatase, blood urea nitrogen, creatinine and glucose. Vital signs include body temperature, respiratory rate, pulse rate, supine systolic and diastolic blood pressure. CS=clinically significant, NCS=not clinically significant. Change from Screening to End of Study is reported.

11. Pharmacokinetics: Incremental Recovery (IR) Over Time [IR over time was measured as Baseline and at Completion/Termination visit within 30 minutes pre-infusion and at 30 (± 5) minutes post-infusion.]

    PK infusion with investigational product was administered after a wash out period of at least 5 days. Incremental recovery is calculated as IR30min = (C30min [IU/dL] - Cpre-infusion [IU/dL]) / dose per kg body weight [IU/kg] where C30min and Cpre-infusion relate to the unadjusted concentration values.

12. Pharmacokinetics: Area Under the Plasma Concentration Versus Time Curve From Time 0 to Infinity (AUC 0-∞) [PK assessments were done within 30 minutes pre-infusion and post-infusion at 30 (± 5) minutes, 9 hours (± 30 minutes), 24 (± 2) hours, 48 (± 2) hours and 72 (± 2) hours]

    After a wash out period of at least 5 days PK infusion with investigational product was administered. AUC 0-∞ is defined as AUC 0-t + Ct/lambda z, where t is the time of last quantifiable concentration, Ct is the last quantifiable concentration.

13. Pharmacokinetics: Elimination Phase Half-life (T1/2) [PK assessments were done within 30 minutes pre-infusion and post-infusion at 30 (± 5) minutes, 9 hours (± 30 minutes), 24 (± 2) hours, 48 (± 2) hours and 72 (± 2) hours]

    PK infusion with investigational product was administered after a wash out period of at least 5 days. Elimination phase half-life is calculated as T1/2=log e (2) / lambda z where the elimination rate constant (lambda z) will be obtained by log e - linear fitting using least squares deviation to at least the last 3 quantifiable concentrations above pre-infusion level.

14. Pharmacokinetics: Mean Residence Time (MRT) [PK assessments were done within 30 minutes pre-infusion and post-infusion at 30 (± 5) minutes, 9 hours (± 30 minutes), 24 (± 2) hours, 48 (± 2) hours and 72 (± 2) hours]

    PK infusion with investigational product was administered after a wash out period of at least 5 days. Mean residence time is calculated as total area under the moment curve divided by the total area under the curve. MRT=(AUMC0-∞[h2*IU/dL])/(AUC0-∞[h*IU/dL]) - TI/2 where AUMC0-∞ is determined in a similar manner as AUC0-∞ and TI represents infusion duration in hours.

15. Pharmacokinetics: Systemic Clearance (CL) [PK assessments were done within 30 minutes pre-infusion and post-infusion at 30 (± 5) minutes, 9 hours (± 30 minutes), 24 (± 2) hours, 48 (± 2) hours and 72 (± 2) hours]

    PK infusion with investigational product was administered after a wash out period of at least 5 days. Systemic clearance is balculated as the dose in IU/kg divided by the total AUC. CL= Dose[IU/kg] / AUC0-∞[h*IU/dL]

16. Pharmacokinetics: Volume of Distribution at Steady State (Vss) [PK assessments were done within 30 minutes pre-infusion and post-infusion at 30 (± 5) minutes, 9 hours (± 30 minutes), 24 (± 2) hours, 48 (± 2) hours and 72 (± 2) hours]

    PK infusion with investigational product was administered after a wash out period of at least 5 days. Apparent steady state volume of distribution is calculated as Vss = CL * MRT CL=Systemic Clearance and MRT=Mean residence time

17. Pharmacokinetics: Incremental Recovery (IR) [PK assessments were done within 30 minutes pre-infusion and post-infusion at 30 (± 5) minutes, 9 hours (± 30 minutes), 24 (± 2) hours, 48 (± 2) hours and 72 (± 2) hours.]

    PK infusion with investigational product was administered after a wash out period of at least 5 days. Incremental recovery is calculated as IR30min = (C30min [IU/dL] - Cpre-infusion [IU/dL]) / dose per kg body weight [IU/kg] where C30min and Cpre-infusion relate to the unadjusted concentration values.

18. Changes in Health Related Quality of Life (HR QoL) Based on Questionnaire SF-36 [Baseline at exposure day 1 and at study completion/termination.]

    The Short Form (36) Health Survey (SF-36) is a 36-item validated, generic HR QoL instrument suitable for participants of 17 years of age or older. The SF-36 consists of eight scaled scores (vitality, physical functioning, bodily pain, general health, mental health, physical role functioning, emotional role functioning, social role functioning) which are the weighted sums of the questions in their section. Each scale is directly transformed into a 0-100 scale on the assumption that each question carries equal weight. The lower the score the more disability. The higher the score the less disability. The mental health component summary score ranged from 19.5 to 64.2 with higher scores indicating less disability. The physical health component summary scores ranged from 18.6 to 59.6 with higher scores indicating less disability.

19. Changes in Health Related Quality of Life Using the Peds QL [Baseline at exposure day 1 and at study completion/termination.]

    The Pediatric Quality of Life Inventory (Peds QL) is a generic health related quality of life instrument designed specifically for a pediatric population and captures following domains: physical functioning, emotional functioning, social functioning and school functioning. The Peds-QL total score consist of all 23 items of all domains. Score range from 0-100 and higher scores indicate better quality of life (collected scores ranged from 44.6 to 98.9). The Peds-QL Physical Health Summary score consists of 8 items from the physical functioning domain. Score range from 0-100 and higher scores indicate better quality of life (collected scores ranged from 40.6 to 100.0) The Psychosocial Health Summary score consists of 15 items from the emotional, social and school functioning domains. Score range from 0 to 100 and higher scores indicate better quality of life (collected scores ranged from 46.7 to 100.0).

20. Changes in Health Related Quality of Life (HR QoL) Based on Questionnaire Haemo-QoL and Haem-A-QoL [Baseline at exposure day 1 and at study completion/termination.]

    The Hemophilia Quality of Life Questionnaire (Haemo-QoL) and the Hemophilia Quality of Life Questionnaire for Adults (Haem-A-Qol) instruments have been developed and used in hemophilia A patients. As a hemophilia-specific instrument, this measure assesses very specific aspects of dealing with hemophilia. The areas covered by this instrument are: physical health, sports/leisure, school/work, dealing with hemophilia, and outlook for the future. Haemo-QoL is used for participants aged 8 to 16 years and total scores range from 0 to 100 with higher scores indicating low quality of life (collected scores ranged from 0.0 to 44.3) Haem-A-QoL is used for participants aged 17 years and older and total scores range from 0 to 100 with higher scores indicating low quality of life (collected scores ranged from 4.9 to 76.8).

21. Changes in Health Related Quality of Life (HR QoL) Based on Questionnaire EQ-5D and Pain Score. [Baseline at exposure day 1 and at study completion/termination.]

    The EQ-5D captures overall HR QoL (phyiscal, mental and social functioning). A health utility score can be calculated from this measure, adult and proxy versions available. EQ-5D Visual Analog Scale (EQ-5D VAS):Respondents specify their level of agreement to a statement by indicating a position along a continuous line between two endpoints (scale range from 0 to 100). Score 0 corresponds to the worst health you can imagine and score 100 corresponds to the best health you can imagine (collected scores ranged from 10-100). EQ-5D Total Index is based on general population valuation surveys. Responses to 5 questions are converted to an Index value and score range from 0 to 1, with higher scores indicating better quality of life. Total Index was derived on US population (collected scores ranged from 0.4-1). General pain assessment (Pain score) is done through a visual analog scale (VAS), scores ranging from 0 to 100 with higher scores indicating more pain (collected scores ranged 0-87).

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Main Inclusion Criteria:

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

• Subject has completed Baxter clinical study 250901 (pivotal study) or Baxter clinical study 251101 (pediatric study)

• Subject was 12 to 65 years old at the time of screening for Study 250901 or < 12 years old at the time of screening for Study 251101

• Subject has severe (FIX level < 1%) or moderately severe (FIX level 1-2%) hemophilia B (based on the one stage activated partial thromboplastin time (aPTT) assay), as tested at screening at the central laboratory

• Subject has not developed an inhibitory FIX antibody during Baxter Pivotal Study 250901 or Pediatric Study 251101

Main Exclusion Criteria:

• Subject received factor IX product(s) other than BAX 326 upon completion of Baxter Pivotal Study 250901 or Pediatric Study 251101

• Subject has been diagnosed with an acquired hemostatic defect other than hemophilia B

• For subjects transferring from Pivotal Study 250901: Subject's weight is < 35 kg or > 120 kg

• Subject is planned to take part in any other clinical study, with the exception of BAX 326 Surgery study as described in this protocol, during the course of the Continuation Study

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Instituto de Hematología y Medicina Clíncia Rubén Dávoli	Rosario		Argentina	2000
2	UNIFESP - Universidade Estadual de Sao Paulo	Sao Paulo		Brazil	040024-002
3	Specialized Haematological Hospital "Joan Pavel"	Sofia		Bulgaria	1233
4	Hospital Dr. Sotero del Rio	Santiago		Chile
5	Hospital de San Jose	Bogotá		Colombia
6	Centro Medico Imbanaco	Cali		Colombia
7	Hospital Pablo Tobon Uribe	Medellin		Colombia	005543
8	Klinika detské hematologie a onkologie	Prague		Czechia	150 06
9	Maulana Azad Medical College and Associated Hospital	New Delhi		India	110002
10	St. James's Hospital, National Center for Hereditary Coagulation Disorders	Dublin		Ireland	8
11	University Hospital Policlinico Vittorio Emanuele, Hospital Ferrarotto Alessi	Catania		Italy	95124
12	University Hospital Careggi, Agency of Hemophilia - Regional Reference Center for Inherited Bleeding	Florence		Italy	50134
13	University of Foggia Riuniti Hospital, Department of Clinical and Experimental Medicine	Foggia		Italy	71100
14	Hospital San Giovanni Bosco, Center for Hemophilia and Thrombosis, Department of Hematology	Naples		Italy	80144
15	Padova University Hospital, Medical Clinic II, Center for Hemophilia	Padova		Italy	35128
16	Nara Medical University, Department of Pediatrics	Nara		Japan	634-8251
17	Tokyo Medical University	Tokyo		Japan	160-0023
18	Ogikubo Hospital	Tokyo		Japan	167-0035
19	Hematology and Transplantology Clinic, University Clinic Centre - Medical University Hospital	Gdansk		Poland	80-952
20	University Pediatric Hospital in Cracow	Krakow		Poland	30-663
21	Medical College of the Jagiellonian University, Department of Hematology	Krakow		Poland	31-501
22	Copernicus Hospital, Medical University in Lodz, Department of Hematology	Lodz		Poland	93-510
23	Professor Tadeusz Sokolowski Independent Public Teaching Hospital No. 1 of the Pomeranian Medical University in Szczecin	Szczecin		Poland	71-252
24	Klinika Hematologii	Warsaw		Poland	00-579
25	Institute of Haematology and Transfusion Medicine	Warsaw		Poland	02-776
26	Prof. Dr. C.T. Nicolau National Institute for Transfusional Hematology	Bucharest		Romania	11156
27	Louis Turcanu Emergency Clinical Children´s Hospital	Timisoara		Romania
28	Regional clinical hospital	Ekaterinburg		Russian Federation	620149
29	Federal State Institution Kirov Hematology and Blood Transfusion Research Institute under the Federal Agency for High-Tech Medical Care	Kirov		Russian Federation	610027
30	Pediatric Regional Clinical Hospital, Hematology Department	Krasnodar		Russian Federation	350007
31	Hematology Research Center RAMS, Department of Reconstructive Orthopedics for Haemophilia Patients	Moscow		Russian Federation	125167
32	Republican Center for Hemophilia Treatment Outpatient Clinic No. 37	St. Petersburg		Russian Federation	195213
33	Malmö University Hospital, Department of Coagulation Disorders	Malmö		Sweden	205 02
34	Taipei Medical University Hospital	Taipei City	Taipei	Taiwan	110
35	Chung-Ho Memorial Hospital	Kaohsiung		Taiwan	807
36	China Medical University Hospital	Taichung		Taiwan	40447
37	Taichung Veterans General Hospital	Taichung		Taiwan	40705
38	National Taiwan University Hospital	Taipei		Taiwan	10002
39	Tri-Service General Hospital	Taipei		Taiwan	114
40	State Institution "Institute of Blood Pathology and Transfusion Medicine of the Academy of Medical Sciences of Ukraine"	Lviv		Ukraine	79044
41	Katharine Dormandy Haemophilia Centre and Haemostasis Unit, Royal Free Hospital	London		United Kingdom	NW3 2QG
42	Manchester Children's Hospital	Manchester		United Kingdom	M13 9WL

Sponsors and Collaborators

• Baxalta now part of Shire

Investigators

• Study Director: Study Director, Takeda

Study Documents (Full-Text)

• Study Protocol - Oct 19, 2015
• Statistical Analysis Plan - Sep 27, 2017

More Information

Publications

None provided.

• Responsible Party: Baxalta now part of Shire
• ClinicalTrials.gov Identifier: NCT01286779
• Other Study ID Numbers: 251001; 2010-022726-33
• First Posted: Jan 31, 2011
• Last Update Posted: May 20, 2021
• Last Verified: Apr 1, 2021

• Additional relevant MeSH terms: Hemophilia A; Hemophilia B

Study Results

Participant Flow

Recruitment Details	Enrollment was conducted at 40 clinical sites in 18 countries. A total of 117 participants were enrolled. Of these, 65 participants transitioned from BAX326 pivotal study, 20 participants transitioned from BAX326 pediatric study and 32 participants were newly recruited.
Pre-assignment Detail	Of 117 enrolled participants, 115 received treatment with IP. All 85 participants who transitioned from the pivotal/pediatric studies continued to receive IP in this study. Of the 32 newly recruited participants, 30 received treatment with IP. 1 participant did not meet the entry criteria and 1 participant discontinued the study prior treatment.

Arm/Group Title	BAX 326
Arm/Group Description	Participants treated with BAX 326
Period Title: Overall Study
STARTED	115
COMPLETED	96
NOT COMPLETED	19

Baseline Characteristics

Arm/Group Title	BAX 326
Arm/Group Description	Participants treated with BAX 326
Overall Participants	115
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	29.6 (16.39)
Sex: Female, Male (Count of Participants)
Female	0 0%
Male	115 100%
Race/Ethnicity, Customized (Count of Participants)
White	99 86.1%
Black or African American	1 0.9%
Asian	10 8.7%
Other	5 4.3%

Outcome Measures

1. Primary Outcome

Title	Adverse Events Possibly or Probably Related to the Investigational Product
Description	Possibly or probably related adverse events that occurred during or after first BAX326 infusion.
Time Frame	Assessed (based on patient diary) every 3 months until study completion (when BAX326 is licensed in the respective country or the participant has accumulated approximately 100 exposure days to BAX 326, whichever is last).

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	BAX 326
Arm/Group Description	Participants treated with BAX 326
Measure Participants	115
Number [Adverse Events]	2

2. Secondary Outcome

Title	Treatment of Bleeding Episodes: Number of Infusions Per Bleeding Episode Required Until Bleed Resolution
Description	Number of Infusions of BAX326 that were required until bleed resolution.
Time Frame	Throughout the study from screening to study completion (when BAX326 is licensed in the respective country or the participant has accumulated approximately 100 exposure days to BAX 326, whichever is last).

Outcome Measure Data

Analysis Population Description

Only bleeding episodes that were exclusively treated with BAX 326 are considered.

Arm/Group Title	BAX 326	Standard Prophylaxis	Modified Prophylaxis	PK Tailored Prophylaxis	Overall Prophylaxis	On-Demand
Arm/Group Description	Participants treated with BAX 326	Participants treated with BAX 326 with twice weekly prophylactic infusions of 50 IU/kg	Participants treated with BAX 326 with prophylactic treatment determined by the investigator. The dose could be increased up to 100 IU/kg if indicated.	Participants treated with BAX 326 with PK tailored prophylaxis base on participant's individual PK with maximum dose of 120 IU/kg.	All participants who received BAX 326 as prophylactic regimen (standard prophylaxis, modified prophylaxis and PK-tailored prophylaxis)	All participants who received BAX 326 as on-demand regimen.
Measure Participants	115	108	26	3	110	13
Measure Bleeding episodes	1112	542	108	8	658	454
Mean (Standard Deviation) [Number of infusions]	1.8 (1.65)	2.1 (2.12)	1.9 (1.41)	1.3 (0.46)	2.0 (2.01)	1.5 (0.79)

3. Secondary Outcome

Title	Treatment of Bleeding Episodes: Overall Hemostatic Efficacy Rating at Resolution of Bleed
Description	Overall clinical efficacy rating of bleeding episodes was done at resolution of bleed according these rating scale: Excellent=Full relief of pain and cessation of objective signs of bleeding after a single infusion. No additional infusion is required for the control of bleeding. Administration of further infusion would not affect the 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	Throughout the study from screening to study completion (when BAX326 is licensed in the respective country or the participant has accumulated approximately 100 exposure days to BAX 326, whichever is last).

Outcome Measure Data

Analysis Population Description

Only bleeding episodes that were exclusively treated with BAX 326 are considered.

Arm/Group Title	BAX 326	Standard Prophylaxis	Modified Prophylaxis	PK Tailored Prophylaxis	Overall Prophylaxis	On-Demand
Arm/Group Description	Participants treated with BAX 326	Participants treated with BAX 326 with twice weekly prophylactic infusions of 50 IU/kg	Participants treated with BAX 326 with prophylactic treatment determined by the investigator. The dose could be increased up to 100 IU/kg if indicated.	Participants treated with BAX 326 with PK tailored prophylaxis base on participant's individual PK with maximum dose of 120 IU/kg.	All participants who received BAX 326 as prophylactic regimen (standard prophylaxis, modified prophylaxis and PK-tailored prophylaxis)	All participants who received BAX 326 as on-demand regimen.
Measure Participants	115	108	26	3	110	13
Measure Bleeding Episodes	1112	542	108	8	658	454
Excellent	341	168	51	0	219	122
Good	650	281	40	0	321	329
Fair	115	90	17	6	113	2
None	6	3	0	2	5	1

4. Secondary Outcome

Title	Annualized Bleed Rate During Prophylaxis Treatment
Description	Annualized bleed rate (ABR) was calculated as (number of bleeding episodes/observed treatment period in days)*365.25
Time Frame	For prophylactic treatment the period from first to last prophylactic infusion is considered.

Outcome Measure Data

Analysis Population Description

Only participants with an observation period of at least 3 months with BAX326 on prophylactic treatment were included in the analysis.

Arm/Group Title	Standard Prophylaxis	Modified Prophylaxis	PK Tailored Prophylaxis	Overall Prophylaxis
Arm/Group Description	Participants treated with BAX 326 with twice weekly prophylactic infusions of 50 IU/kg	Participants treated with BAX 326 with prophylactic treatment determined by the investigator. The dose could be increased up to 100 IU/kg if indicated.	Participants treated with BAX 326 with PK tailored prophylaxis base on participant's individual PK with maximum dose of 120 IU/kg.	All participants who received BAX 326 as prophylactic regimen (standard prophylaxis, modified prophylaxis and PK-tailored prophylaxis)
Measure Participants	106	22	2	108
Median (Full Range) [Bleeds per year]	1.3	1.4	1.9	1.3

5. Secondary Outcome

Title	Consumption of BAX 326: Number of Infusions Per Month and Per Year
Description	The number of infusions consumed per month and per year for the prophylactic and on-demand treatment regimens.
Time Frame	Throughout the study from screening to study completion (when BAX326 is licensed in the respective country or the participant has accumulated approximately 100 exposure days to BAX 326, whichever is last).

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Standard Prophylaxis	Modified Prophylaxis	PK Tailored Prophylaxis	Overall Prophylaxis	On-Demand
Arm/Group Description	Participants treated with BAX 326 with twice weekly prophylactic infusions of 50 IU/kg	Participants treated with BAX 326 with prophylactic treatment determined by the investigator. The dose could be increased up to 100 IU/kg if indicated.	Participants treated with BAX 326 with PK tailored prophylaxis base on participant's individual PK with maximum dose of 120 IU/kg.	All participants who received BAX 326 as prophylactic regimen (standard prophylaxis, modified prophylaxis and PK-tailored prophylaxis)	All participants who received BAX 326 as on-demand regimen.
Measure Participants	108	26	3	110	13
Number of infusions per month	8.5 (1.25)	10.8 (4.34)	4.0 (0.60)	8.4 (1.38)	3.6 (2.44)
Number of infusions per year	101.8 (15.03)	130.2 (52.13)	48.3 (7.23)	101.1 (16.50)	43.1 (29.28)

6. Secondary Outcome

Title	Consumption of BAX 326: Weight Adjusted Consumption Per Month and Per Year
Description	The weight adjusted consumption of BAX 326 per month and per year for the prophylactic and on-demand treatment regimens.
Time Frame	Throughout the study from screening to study completion (when BAX326 is licensed in the respective country or the participant has accumulated approximately 100 exposure days to BAX 326, whichever is last).

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Standard Prophylaxis	Modified Prophylaxis	PK Tailored Prophylaxis	Overall Prophylaxis	On-Demand
Arm/Group Description	Participants treated with BAX 326 with twice weekly prophylactic infusions of 50 IU/kg	Participants treated with BAX 326 with prophylactic treatment determined by the investigator. The dose could be increased up to 100 IU/kg if indicated.	Participants treated with BAX 326 with PK tailored prophylaxis base on participant's individual PK with maximum dose of 120 IU/kg.	All participants who received BAX 326 as prophylactic regimen (standard prophylaxis, modified prophylaxis and PK-tailored prophylaxis)	All participants who received BAX 326 as on-demand regimen.
Measure Participants	108	26	3	110	13
Weight adjusted BAX 326 consumption per month	462.3 (102.05)	684.4 (337.70)	250.9 (41.37)	464.2 (111.46)	199.8 (124.18)
Weight adjusted BAX 326 consumption per year	5547.8 (1224.65)	8212.4 (4052.36)	3010.3 (496.44)	5570.7 (1337.53)	2397.4 (1490.22)

7. Secondary Outcome

Title	Consumption of BAX326: Weight Adjusted Consumption Per Bleeding Episode
Description	The weight adjusted consumption of BAX 326 per bleeding episode for the prophylactic and on-demand treatment regimens. Only infusions required until the resolution of bleed are considered.
Time Frame	Throughout the study from screening to study completion (when BAX326 is licensed in the respective country or the participant has accumulated approximately 100 exposure days to BAX 326, whichever is last).

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Standard Prophylaxis	Modified Prophylaxis	PK Tailored Prophylaxis	Overall Prophylaxis	On-Demand
Arm/Group Description	Participants treated with BAX 326 with twice weekly prophylactic infusions of 50 IU/kg	Participants treated with BAX 326 with prophylactic treatment determined by the investigator. The dose could be increased up to 100 IU/kg if indicated.	Participants treated with BAX 326 with PK tailored prophylaxis base on participant's individual PK with maximum dose of 120 IU/kg.	All participants who received BAX 326 as prophylactic regimen (standard prophylaxis, modified prophylaxis and PK-tailored prophylaxis)	All participants who received BAX 326 as on-demand regimen.
Measure Participants	108	26	3	110	13
Measure Bleeding episodes	542	109	8	659	453
Mean (Standard Deviation) [IU/kg]	124.2 (140.70)	114.8 (99.41)	67.4 (34.39)	122.0 (134.02)	82.6 (48.21)

8. Secondary Outcome

Title	Development of Inhibitory and Total Binding Antibodies to Factor IX
Description	Testing for inhibitory and total binding antibodies to Factor IX (FIX). Development during study means negative at screening and positive at any subsequent visit. Treatment emergent means more than 2-dilution increase as compared to the pre-study titer at screening.
Time Frame	Laboratory assessment for immunology were done at screening, at exposure day 1, at week 4 (± 1 week), at month 3 (±1 week), thereafter, every 3 months (± 1 week) and at study completion/termination.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	BAX 326
Arm/Group Description	Participants treated with BAX 326
Measure Participants	115
Inhibitory antibodies to FIX-develop. during study	0 0%
Inhibitory antibodies to FIX-treatment emergent	0 0%
Total bind. antibodies to FIX-develop.during study	0 0%
Total binding antibodies to FIX-treatment emergent	0 0%

9. Secondary Outcome

Title	Development of Antibodies to Chinese Hamster Ovary Proteins (CHO Proteins) and rFurin
Description	Testing for antibodies to CHO proteins and rFurin. Development during study means negative at screening and positive at any subsequent visit. Treatment emergent means more than 2-dilution increase as compared to the pre-study titer at screening.
Time Frame	Laboratory assessment for immunology were done at screening, at exposure day 1, at week 4 (± 1 week), at month 3 (±1 week), thereafter, every 3 months (± 1 week) and at study completion/termination.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	BAX 326
Arm/Group Description	Participants treated with BAX 326
Measure Participants	115
Antibodies to CHO - developed during study	0 0%
Antibodies to CHO - treatment emergent	0 0%
Antibodies to rFurin - developed during study	4 3.5%
Antibodies to rFurin - treatment emergent	4 3.5%

10. Secondary Outcome

Title	Occurrence of Severe Allergic Reactions and Thrombotic Events
Description	The occurrence of severe allergic reactions and thrombotic events was assessed.
Time Frame	Throughout the study from screening to study completion (when BAX326 is licensed in the respective country or the participant has accumulated approximately 100 exposure days to BAX 326, whichever is last).

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	BAX 326
Arm/Group Description	Participants treated with BAX 326
Measure Participants	115
Severe allergic reactions	0 0%
Thrombotic events	0 0%

11. Secondary Outcome

Title	Clinical Significant Changes in Routine Laboratory Parameters and Vital Signs
Description	Hematology panel consists of complete blood count (hemoglobin, hematocrit, erythrocytes, leukocytes) with differential (ie, basophils, eosinophils, lymphocytes, monocytes, neutrophils), mean corpuscular volume, mean corpuscular hemoglobin concentration and platelet count. Clinical chemistry panel consists of sodium, potassium, chloride, bicarbonate, total protein, albumin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, alkaline phosphatase, blood urea nitrogen, creatinine and glucose. Vital signs include body temperature, respiratory rate, pulse rate, supine systolic and diastolic blood pressure. CS=clinically significant, NCS=not clinically significant. Change from Screening to End of Study is reported.
Time Frame	Measurements at screening and at study completion/termination are included in the analysis.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	BAX 326
Arm/Group Description	Participants treated with BAX 326
Measure Participants	115
Hematology: Change from normal to abnormal CS	2 1.7%
Hematology:Change from abnormal NCS to abnormal CS	1 0.9%
Chemistry: Change from normal to abnormal, CS	1 0.9%
Chemistry: Change from abnormal NCS to abnormal CS	3 2.6%
Change in vital signs	0 0%

12. Secondary Outcome

Title	Pharmacokinetics: Incremental Recovery (IR) Over Time
Description	PK infusion with investigational product was administered after a wash out period of at least 5 days. Incremental recovery is calculated as IR30min = (C30min [IU/dL] - Cpre-infusion [IU/dL]) / dose per kg body weight [IU/kg] where C30min and Cpre-infusion relate to the unadjusted concentration values.
Time Frame	IR over time was measured as Baseline and at Completion/Termination visit within 30 minutes pre-infusion and at 30 (± 5) minutes post-infusion.

Outcome Measure Data

Analysis Population Description

Analysis was done on all participants who received investigational product. All cases with a dosage higher than 120 IU/kg were excluded from the analysis.

Arm/Group Title	BAX 326
Arm/Group Description	Participants treated with BAX 326
Measure Participants	115
Baseline	0.85 (0.207)
End of Study	0.85 (0.286)
Change from baseline to end of study	-0.005 (0.259)

13. Secondary Outcome

Title	Pharmacokinetics: Area Under the Plasma Concentration Versus Time Curve From Time 0 to Infinity (AUC 0-∞)
Description	After a wash out period of at least 5 days PK infusion with investigational product was administered. AUC 0-∞ is defined as AUC 0-t + Ct/lambda z, where t is the time of last quantifiable concentration, Ct is the last quantifiable concentration.
Time Frame	PK assessments were done within 30 minutes pre-infusion and post-infusion at 30 (± 5) minutes, 9 hours (± 30 minutes), 24 (± 2) hours, 48 (± 2) hours and 72 (± 2) hours

Outcome Measure Data

Analysis Population Description

The pharmacokinetic analysis set comprises all participants who underwent an abbreviated PK study.

Arm/Group Title	BAX 326
Arm/Group Description	Participants treated with BAX 326
Measure Participants	6
Mean (Standard Deviation) [IU*hr/dL]	1335.56 (299.83)

14. Secondary Outcome

Title	Pharmacokinetics: Elimination Phase Half-life (T1/2)
Description	PK infusion with investigational product was administered after a wash out period of at least 5 days. Elimination phase half-life is calculated as T1/2=log e (2) / lambda z where the elimination rate constant (lambda z) will be obtained by log e - linear fitting using least squares deviation to at least the last 3 quantifiable concentrations above pre-infusion level.
Time Frame	PK assessments were done within 30 minutes pre-infusion and post-infusion at 30 (± 5) minutes, 9 hours (± 30 minutes), 24 (± 2) hours, 48 (± 2) hours and 72 (± 2) hours

Outcome Measure Data

Analysis Population Description

The pharmacokinetic analysis set comprises all participants who underwent an abbreviated PK study.

Arm/Group Title	BAX 326
Arm/Group Description	Participants treated with BAX 326
Measure Participants	6
Mean (Standard Deviation) [hours]	28.52 (4.12)

15. Secondary Outcome

Title	Pharmacokinetics: Mean Residence Time (MRT)
Description	PK infusion with investigational product was administered after a wash out period of at least 5 days. Mean residence time is calculated as total area under the moment curve divided by the total area under the curve. MRT=(AUMC0-∞[h2*IU/dL])/(AUC0-∞[h*IU/dL]) - TI/2 where AUMC0-∞ is determined in a similar manner as AUC0-∞ and TI represents infusion duration in hours.
Time Frame	PK assessments were done within 30 minutes pre-infusion and post-infusion at 30 (± 5) minutes, 9 hours (± 30 minutes), 24 (± 2) hours, 48 (± 2) hours and 72 (± 2) hours

Outcome Measure Data

Analysis Population Description

The pharmacokinetic analysis set comprises all participants who underwent an abbreviated PK study.

Arm/Group Title	BAX 326
Arm/Group Description	Participants treated with BAX 326
Measure Participants	6
Mean (Standard Deviation) [hours]	29.97 (2.72)

16. Secondary Outcome

Title	Pharmacokinetics: Systemic Clearance (CL)
Description	PK infusion with investigational product was administered after a wash out period of at least 5 days. Systemic clearance is balculated as the dose in IU/kg divided by the total AUC. CL= Dose[IU/kg] / AUC0-∞[h*IU/dL]
Time Frame	PK assessments were done within 30 minutes pre-infusion and post-infusion at 30 (± 5) minutes, 9 hours (± 30 minutes), 24 (± 2) hours, 48 (± 2) hours and 72 (± 2) hours

Outcome Measure Data

Analysis Population Description

The pharmacokinetic analysis set comprises all participants who underwent an abbreviated PK study.

Arm/Group Title	BAX 326
Arm/Group Description	Participants treated with BAX 326
Measure Participants	6
Mean (Standard Deviation) [dL/kg/hours]	0.06 (0.014)

17. Secondary Outcome

Title	Pharmacokinetics: Volume of Distribution at Steady State (Vss)
Description	PK infusion with investigational product was administered after a wash out period of at least 5 days. Apparent steady state volume of distribution is calculated as Vss = CL * MRT CL=Systemic Clearance and MRT=Mean residence time
Time Frame	PK assessments were done within 30 minutes pre-infusion and post-infusion at 30 (± 5) minutes, 9 hours (± 30 minutes), 24 (± 2) hours, 48 (± 2) hours and 72 (± 2) hours

Outcome Measure Data

Analysis Population Description

The pharmacokinetic analysis set comprises all participants who underwent an abbreviated PK study.

Arm/Group Title	BAX 326
Arm/Group Description	Participants treated with BAX 326
Measure Participants	6
Mean (Standard Deviation) [dL/kg]	1.78 (0.42)

18. Secondary Outcome

Title	Pharmacokinetics: Incremental Recovery (IR)
Description	PK infusion with investigational product was administered after a wash out period of at least 5 days. Incremental recovery is calculated as IR30min = (C30min [IU/dL] - Cpre-infusion [IU/dL]) / dose per kg body weight [IU/kg] where C30min and Cpre-infusion relate to the unadjusted concentration values.
Time Frame	PK assessments were done within 30 minutes pre-infusion and post-infusion at 30 (± 5) minutes, 9 hours (± 30 minutes), 24 (± 2) hours, 48 (± 2) hours and 72 (± 2) hours.

Outcome Measure Data

Analysis Population Description

The pharmacokinetic analysis set comprises all participants who underwent an abbreviated PK study.

Arm/Group Title	BAX 326
Arm/Group Description	Participants treated with BAX 326
Measure Participants	6
Mean (Standard Deviation) [(IU/dL):(IU/kg)]	0.85 (0.196)

19. Secondary Outcome

Title	Changes in Health Related Quality of Life (HR QoL) Based on Questionnaire SF-36
Description	The Short Form (36) Health Survey (SF-36) is a 36-item validated, generic HR QoL instrument suitable for participants of 17 years of age or older. The SF-36 consists of eight scaled scores (vitality, physical functioning, bodily pain, general health, mental health, physical role functioning, emotional role functioning, social role functioning) which are the weighted sums of the questions in their section. Each scale is directly transformed into a 0-100 scale on the assumption that each question carries equal weight. The lower the score the more disability. The higher the score the less disability. The mental health component summary score ranged from 19.5 to 64.2 with higher scores indicating less disability. The physical health component summary scores ranged from 18.6 to 59.6 with higher scores indicating less disability.
Time Frame	Baseline at exposure day 1 and at study completion/termination.

Outcome Measure Data

Analysis Population Description

Only newly recruited participants are included as baseline values were not reported for transitioning participants. Only subjects how received prophylaxis treatment are included.

Arm/Group Title	BAX 326
Arm/Group Description	Participants treated with BAX 326
Measure Participants	24
SF-36 Bodily Pain	6.7 (12.66)
SF-36 General Health	3.2 (9.32)
SF-36 Mental Health	0.7 (14.72)
SF-36 Mental Health Component Score	0.8 (12.08)
SF-36 Physical Functioning	4.2 (10.46)
SF-36 Physical Health Component Score	5.7 (8.43)
SF-36 Role-Emotional	2.3 (11.57)
SF-36 Role-Physical	4.5 (10.28)
SF-36 Social Functioning	4.5 (11.67)
SF-36 Vitality	2.0 (8.87)

20. Secondary Outcome

Title	Changes in Health Related Quality of Life Using the Peds QL
Description	The Pediatric Quality of Life Inventory (Peds QL) is a generic health related quality of life instrument designed specifically for a pediatric population and captures following domains: physical functioning, emotional functioning, social functioning and school functioning. The Peds-QL total score consist of all 23 items of all domains. Score range from 0-100 and higher scores indicate better quality of life (collected scores ranged from 44.6 to 98.9). The Peds-QL Physical Health Summary score consists of 8 items from the physical functioning domain. Score range from 0-100 and higher scores indicate better quality of life (collected scores ranged from 40.6 to 100.0) The Psychosocial Health Summary score consists of 15 items from the emotional, social and school functioning domains. Score range from 0 to 100 and higher scores indicate better quality of life (collected scores ranged from 46.7 to 100.0).
Time Frame	Baseline at exposure day 1 and at study completion/termination.

Outcome Measure Data

Analysis Population Description

Only newly recruited participants are included as baseline values were not reported for transitioning participants. Only subjects how received prophylaxis treatment are included.

Arm/Group Title	BAX 326
Arm/Group Description	Participants treated with BAX 326
Measure Participants	4
Peds-QL Physical Health Summary Score	-2.3 (18.47)
Peds-QL Psychosocial Health Summary Score	3.8 (5.99)
Peds-QL Total Score	1.6 (10.14)

21. Secondary Outcome

Title	Changes in Health Related Quality of Life (HR QoL) Based on Questionnaire Haemo-QoL and Haem-A-QoL
Description	The Hemophilia Quality of Life Questionnaire (Haemo-QoL) and the Hemophilia Quality of Life Questionnaire for Adults (Haem-A-Qol) instruments have been developed and used in hemophilia A patients. As a hemophilia-specific instrument, this measure assesses very specific aspects of dealing with hemophilia. The areas covered by this instrument are: physical health, sports/leisure, school/work, dealing with hemophilia, and outlook for the future. Haemo-QoL is used for participants aged 8 to 16 years and total scores range from 0 to 100 with higher scores indicating low quality of life (collected scores ranged from 0.0 to 44.3) Haem-A-QoL is used for participants aged 17 years and older and total scores range from 0 to 100 with higher scores indicating low quality of life (collected scores ranged from 4.9 to 76.8).
Time Frame	Baseline at exposure day 1 and at study completion/termination.

Outcome Measure Data

Analysis Population Description

Only newly recruited participants are included as baseline values were not reported for transitioning participants. Only subjects how received prophylaxis treatment are included.

Arm/Group Title	BAX 326
Arm/Group Description	Participants treated with BAX 326
Measure Participants	16
Haem-A-QoL Total Score	-3.0 (9.45)
Haemo-QoL Total Score	-0.7 (NA)

22. Secondary Outcome

Title	Changes in Health Related Quality of Life (HR QoL) Based on Questionnaire EQ-5D and Pain Score.
Description	The EQ-5D captures overall HR QoL (phyiscal, mental and social functioning). A health utility score can be calculated from this measure, adult and proxy versions available. EQ-5D Visual Analog Scale (EQ-5D VAS):Respondents specify their level of agreement to a statement by indicating a position along a continuous line between two endpoints (scale range from 0 to 100). Score 0 corresponds to the worst health you can imagine and score 100 corresponds to the best health you can imagine (collected scores ranged from 10-100). EQ-5D Total Index is based on general population valuation surveys. Responses to 5 questions are converted to an Index value and score range from 0 to 1, with higher scores indicating better quality of life. Total Index was derived on US population (collected scores ranged from 0.4-1). General pain assessment (Pain score) is done through a visual analog scale (VAS), scores ranging from 0 to 100 with higher scores indicating more pain (collected scores ranged 0-87).
Time Frame	Baseline at exposure day 1 and at study completion/termination.

Outcome Measure Data

Analysis Population Description

Only newly recruited participants are included as baseline values were not reported for transitioning participants. Only subjects how received prophylaxis treatment are included.

Arm/Group Title	BAX 326
Arm/Group Description	Participants treated with BAX 326
Measure Participants	26
EQ-5D Total Index	0.0 (0.13)
EQ-5D VAS	5.1 (21.75)
Pain Score	-8.0 (36.62)

Adverse Events

Time Frame	Throughout the entire study period from screening to completion/termination. Overall 6 years and 2 months. For each participant the duration of study depended on when the participant has accumulated a total of 100 exposure days during the course of the pivotal/pediatric studies and this study.
Arm/Group Title	BAX 326
Arm/Group Description	Participants treated with BAX 326
All Cause Mortality
	BAX 326
	Affected / at Risk (%)	# Events
Total	0/115 (0%)
Serious Adverse Events
	BAX 326
	Affected / at Risk (%)	# Events
Total	9/115 (7.8%)
Gastrointestinal disorders
Abdominal pain	1/115 (0.9%)	1
Duodenal ulcer hemorrhage	1/115 (0.9%)	1
Infections and infestations
Corneal abscess	1/115 (0.9%)	1
Injury, poisoning and procedural complications
Brain contusion	1/115 (0.9%)	1
Extradural hematoma	1/115 (0.9%)	1
Head injury	1/115 (0.9%)	1
Scroctal haematoma	1/115 (0.9%)	1
Nervous system disorders
Seizure	1/115 (0.9%)	1
Transient ischaemic attack	1/115 (0.9%)	1
Renal and urinary disorders
Haematuria	1/115 (0.9%)	3
Renal colic	2/115 (1.7%)	3
Reproductive system and breast disorders
Testicular appendage torsion	1/115 (0.9%)	1
Other (Not Including Serious) Adverse Events
	BAX 326
	Affected / at Risk (%)	# Events
Total	63/115 (54.8%)
General disorders
Pyrexia	14/115 (12.2%)	23
Infections and infestations
Bronchitis	6/115 (5.2%)	8
Influenza	8/115 (7%)	8
Nasopharyngitis	25/115 (21.7%)	55
Pharyngitis	6/115 (5.2%)	8
Rhinitis	8/115 (7%)	15
Upper respiratory tract infection	11/115 (9.6%)	17
Musculoskeletal and connective tissue disorders
Arthralgia	15/115 (13%)	48
Nervous system disorders
Headache	8/115 (7%)	20
Respiratory, thoracic and mediastinal disorders
Cough	11/115 (9.6%)	15
Oropharyngeal pain	6/115 (5.2%)	6
Vascular disorders
Hypertension	6/115 (5.2%)	6

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

Agreements may vary with individual PIs, but contain common elements. For this study, PIs are restricted from independently publishing results until the earlier of the primary multicenter publication or up to 2 years after study completion. The sponsor requires a review of results communication (e .g. for confidential information) ≥ 60 days prior to submission and may request an additional delay up to 6 months (e .g. for intellectual property protection). Prior authorization may be required.