A Phase 3b Open-label, Multicenter, Safety and Efficacy Extension Study of a Recombinant Coagulation Factor IX Albumin Fusion Protein (rIX-FP) in Subjects With Hemophilia B
Phase: PHASE3
Conditions: Hemophilia B
Sponsor: CSL Behring

 
 
 
 
 
 
CRD-TPL-077 Version 1.0 
 
Page 1 of 187 
 
Confidential 
 
 
 
CLINICAL STUDY PROTOCOL 
 
 
A Phase 3b Open-label, Multicenter, Safety and Efficacy Extension Study of a 
Recombinant Coagulation Factor IX Albumin Fusion Protein (rIX-FP) in Subjects with 
Hemophilia B 
Study Number: 
CSL654_3003 
Study Product: 
Recombinant fusion protein linking coagulation factor IX with 
albumin (rIX-FP) 
Development Phase: 
3b 
Sponsor: 
CSL Behring GmbH (CSL) 
Emil-von-Behring-Strasse 76 
35041 Marburg 
Germany 
Protocol Version: 
Amendment 6, FINAL  
EudraCT Number: 
2012-005489-37 
IND Number: 
 
Protocol Date: 
03 February 2020 
Compliance: 
This study will be conducted in accordance with standards of 
Good Clinical Practice (as defined by the International Conference 
on Harmonisation), ethical principles that have their origin in the 
Declaration of Helsinki and all applicable national and local 
regulations.   
 
This protocol includes information and data that contain trade secrets and privileged or confidential information 
that is the property of the sponsor (“CSL”).  This information must not be made public without written 
permission from CSL.  These restrictions on disclosure will apply equally to all future information supplied to 
you.  This material may be disclosed to and used by your staff and associates as may be necessary to conduct the 
clinical study. 
 
CCI

 
Study Number : 
CSL654_3003 
Study Product: 
rIX-FP  
 
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03 February 2020 
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LIST OF PERSONNEL AND ORGANIZATIONS RESPONSIBLE FOR CONDUCT 
OF THE STUDY 
 
A list of personnel and organizations responsible for the conduct of the study will be supplied 
to study sites as part of the Investigator’s Study File.  This list will be updated by CSL (or 
delegate) and provided to the study sites as needed.   
 
 

CS[ 
SIGNATURE ON BEHALF OF SPONSOR 
Study Number : 
Study Product: 
CSL654 3003 
rIX-FP 
Study Title: 
A Phase 3b Open-label, Multicenter, Safety and Efficacy Extension Study of a 
Recombinant Coagulation Factor IX Albumin Fusion Protein (rIX-FP) in Subjects with 
Hemophilia B. 
Protocol Number: 
CSL654 3003 
I have read the protocol amendment 6 titled "A Phase 3b Open-label, Multicenter, Safety and 
Efficacy Extension Study of a Recombinant Coagulation Factor IX Albumin Fusion Protein 
(rIX-FP) in Subjects with Hemophilia B" and confirm that, to the best of my knowledge, the 
protocol accurately describes the design and conduct of the study. 
 
, CRD H&T TA, Global 
Clinical Development Hematology & 
Thrombosis 
Clinical Development 
Amendment 6 
CRD-TPL-077 Version 1.0 
03 February 2020 
Confidential 
 
Date 
(DD MMM YYYY) 
Page 3 of 187 
PPD
PPD
PPD
PPD

 
Study Number : 
CSL654_3003 
Study Product: 
rIX-FP  
 
Amendment 6 
03 February 2020 
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SIGNATURE OF INVESTIGATOR 
 
 
Study Title: A Phase 3b Open-label, Multicenter, Safety and Efficacy Extension Study of a 
Recombinant Coagulation Factor IX Albumin Fusion Protein (rIX-FP) in Subjects with 
Hemophilia B. 
Protocol Number: 
 CSL654_3003 
I have read the protocol amendment 6 titled “A Phase 3b Open-label, Multicenter, Safety and 
Efficacy Extension Study of a Recombinant Coagulation Factor IX Albumin Fusion Protein 
(rIX-FP) in Subjects with Hemophilia B”. 
By signing this protocol, I agree to conduct the clinical study, after approval by an 
Institutional Review Board or Independent Ethics Committee (as appropriate), in accordance 
with the protocol, the principles of the Declaration of Helsinki (2008), the standards of Good 
Clinical Practice (as defined by the International Conference on Harmonisation) and 
applicable regulatory requirements.   
Changes to the protocol will only be implemented after written approval is received from 
CSL Behring GmbH (CSL) and the Institutional Review Board or Independent Ethics 
Committee (as appropriate), with the exception of medical emergencies.   
I will ensure that study staff fully understand and follow the protocol. 
 
 
 
Name of investigator 
Affiliation of investigator 
 
 
Date  
(DD MMM YYYY) 
 
 

 
Study Number: 
CSL654_3003 
Study Product: 
rIX-FP  
 
Amendment 6 
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REVISION HISTORY 
Date 
Version  
Summary of Changes 
14 May 2013 FINAL 
(Original)  
Not applicable 
17 
September 
2013 
Amendment 1 
1. Addition of a third group of subjects (Arm 3) to the study 
design.  Arm 3 comprises subjects who have not previously 
completed a CSL-sponsored rIX-FP lead-in study and who 
are scheduled to have a major non-emergency surgery within 
8 weeks from the start of the initial pharmacokinetic rIX-FP 
(100 IU/kg) evaluation period. 
2. Change in the sample size from 85 to 95. 
3. 
 
4. Minor corrections and clarifications, including word 
modifications and administrative changes.  
17 February 
2014 
Amendment 2 
(France Only) 
1. To add a restriction excluding additional new surgical 
subjects in France from enrolling in Arm 3. 
2. To exclude French subjects enrolled from the lead-in studies 
from the 21-day prophylaxis regimen. 
3. To clarify treatment of a subject if an inhibitor to Factor IX 
(FIX) is confirmed. 
03 June 2014 Amendment 3 
 Per agreement with The Paediatric Committee (PDCO) / 
European Medicines Agency, study in previously untreated 
patients (PUPs) is added into this study. 
1. To add PUPs with severe hemophilia B (FIX activity 
≤2%) who have never been treated with FIX clotting 
factor products (except previous exposure to blood 
components) as study Arm 4. 
2. Change in the sample size from 95 to 115, to include at 
least 20 PUPs. 
3. Independent Data Monitoring Committee is being utilized 
to provide an independent evaluation of the study. 
14 October 
2015 
Amendment 4 
Addition of substudy to assess the pharmacokinetics and safety 
following subcutaneous administration of rIX-FP in hemophilia 
B subjects.  This substudy will comprise subjects who are 
currently enrolled in the main study protocol CSL654_3003. 
CCI

 
Study Number: 
CSL654_3003 
Study Product: 
rIX-FP  
 
Amendment 6 
03 February 2020 
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Date 
Version  
Summary of Changes 
14 October 
2015 
Administrative 
Letter 1 
Clarification: Amendment 3 is not in effect in the following 
countries: Bulgaria, Canada, France, Israel, Malaysia, South 
Africa.  PUPs may not be enrolled into Arm 4 in these countries. 
02 December 
2016 
Amendment 5 
1. Main study: Addition of the ABR for total treated bleeding 
episodes to the comparisons between prophylaxis regimens 
for subjects from Study CSL654_3001. Addition of multiple 
testing procedure to control the overall Type I error rate for 
ABR and AsBR comparisons between prophylaxis regimens. 
2. Main study: Update of overall study duration and study 
participation of Arms 1, 2 and 3 subjects to approximately 5 
years, and addition of visits beyond 36 months. 
3. Main study and subcutaneous (SC) substudy: Addition of 
final analyses of the a) previously treated patient (PTP) data 
when all PTPs have completed the study and b) SC substudy 
data when all subjects have completed the SC substudy. 
4. Main study: Minor corrections and clarifications, including 
word modifications and administrative changes throughout 
the document. 
5. SC substudy: Change in SC dosing in Cohort 3 from single 
to repeated SC dosing (including home treatment).  
6. SC substudy: Addition of optional Cohort 4 for repeated SC 
dosing that will be opened if additional data are needed to 
inform further clinical development. 
7. SC substudy: Addition of details regarding local tolerability 
assessments. 
8. SC substudy: Addition of SC substudy information to the 
main study protocol where relevant (eg, objectives and 
endpoints). 

 
Study Number: 
CSL654_3003 
Study Product: 
rIX-FP  
 
Amendment 6 
03 February 2020 
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Date 
Version  
Summary of Changes 
03 February 
2020 
Amendment 6 
1. Adjustment of number of PUPs from “at least 20” to “at least 
13” to reflect PDCO opinion to allow early termination of 
PUP enrolment. 
2. As study has been completed for PTPs, adjustment of number 
of PTPs in final PTP analysis (N=83). 
3. Adjustment of overall number of subjects to reflect 1 and 2. 
4. The frequency of the CSL Safety Management Team 
meetings has been updated from approximately every 
6 months to approximately every 3 months, to reflect an 
internal process change. 
Note: Although the study has been closed for PTPs, the PTP 
information has been retained in the study protocol to avoid 
substantial rework of the document. 

 
Study Number: 
CSL654_3003 
Study Product: 
rIX-FP  
 
Amendment 6 
03 February 2020 
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PROTOCOL SYNOPSIS 
Title 
A Phase 3b Open-label, Multicenter, Safety and Efficacy Extension 
Study of a Recombinant Coagulation Factor IX Albumin Fusion Protein 
(rIX-FP) in Subjects with Hemophilia B 
Study Number 
CSL654_3003 
Sponsor 
CSL Behring GmbH (CSL) 
Development Phase 
3b 
Study Product 
Recombinant fusion protein linking coagulation factor IX with 
albumin (rIX-FP) 
Indication 
Prophylaxis of bleeding episodes in patients with congenital factor IX 
deficiency (hemophilia B); control and prevention of bleeding episodes 
in patients with hemophilia B. 
Study Summary 
This phase 3b study aims to evaluate the long-term safety and efficacy 
of rIX-FP for routine prophylaxis and on-demand treatment of bleeding 
episodes in children and adults with severe hemophilia B (ie, FIX 
activity of ≤ 2%).  The study will include the following study arms: 
Arm 1: subjects who have completed Study CSL654_3001 Arm 1, 
Study CSL654_3002, or any other CSL-sponsored rIX-FP 
(CSL654) lead-in study. 
Arm 2: subjects who were enrolled in Study CSL654_3001 Arm 2. 
Arm 3 (No subjects in France may enroll in Arm 3): subjects who 
have not previously completed a CSL-sponsored rIX-FP lead-in 
study who are scheduled to have a major non-emergency surgery 
within approximately 8 weeks from receiving the first rIX-FP 
injection (ie, during the pharmacokinetics [PK] evaluation period). 
Arm 4: previously untreated patients (PUPs) with severe hemophilia 
B (FIX activity ≤2%) who have never been treated with FIX 
clotting factor products (except previous exposure to blood 
components). 
The study consists of a treatment period of up to approximately 5 years 
for Arms 1, 2 and 3, and up to approximately 3 years for Arm 4. During 
the treatment period, subjects will administer rIX-FP as routine 
prophylaxis, prevention, and on-demand treatment.   
All subjects in Arm 3 (No subjects in France may enroll in Arm 3) will 
undergo an initial rIX-FP (100 IU/kg) PK evaluation period and 

 
Study Number: 
CSL654_3003 
Study Product: 
rIX-FP  
 
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complete a surgery substudy before having the option to start routine 
prophylaxis. 
All subjects in Arm 4 will undergo an rIX-FP (50 IU/kg) PK evaluation 
at Day 1 as the first dose if feasible or during the study after at least 7 
days washout from the previous rIX-FP dose, when the subject is in 
non-bleeding state.  
Up until the month 6 visit, subjects in Arm 1-3 will administer rIX-FP 
routine prophylaxis with the following treatment intervals:  
Arm 1: rIX-FP administered once every 7, 10, or 14 days. 
Arm 2: rIX-FP administered once every 7 days (subjects from study 
CSL654_3001 Arm 2 with less than 26-weeks experience with 
weekly prophylaxis). 
rIX-FP administered once every 14 days (subjects from study 
CSL654_3001 Arm 2 with at least 26-weeks experience with 
weekly prophylaxis).    
Arm 3 (No subjects in France may enroll in Arm 3): rIX-FP 
administered once every 7 days until the month 6 visit. 
 
After the month 6 visit, all subjects (Arms 1, 2, and 3) will administer 
rIX-FP once every 7, 10, or 14 days for approximately 30 months. 
Subjects ≥ 18 years of age (except subjects from France, regardless the 
age) also have the option to administer rIX-FP once every 21 days. 
Any subject transferring to a 21-day treatment interval for the first 
time must have completed at least 6 months of prophylaxis treatment 
with a 14-day treatment interval and have undergone a PK evaluation 
with a single rIX-FP injection of 100 IU/kg. 
At the end of the study, subjects from the lead-in studies are expected 
to have accumulated at least 100 rIX-FP exposure days (EDs) during 
their enrollment in all CSL-sponsored rIX-FP studies. 
Arm 4: 
Subjects in Arm 4 will administer rIX-FP as weekly prophylaxis and / 
or on-demand, prevention during the first 12 months, and then on 
weekly routine prophylaxis until completing 50 EDs.  Subjects who 
complete 50 EDs are permitted to continue weekly routine prophylaxis 
with rIX-FP until the completion of the study.   

 
Study Number: 
CSL654_3003 
Study Product: 
rIX-FP  
 
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Surgical Prophylaxis Substudy 
All subjects in Arm 3 (No subjects in France may enroll in Arm 3) 
should start the surgery substudy within approximately 8 weeks from 
receiving the first rIX-FP injection (ie, during the PK evaluation 
period).  If a subject in either Arms 1 or 2 requires a major or minor 
surgical non-emergency procedure during the study, or if a subject in 
Arm 4 requires a minor surgical procedure during the study, the subject 
may also be enrolled in the surgery substudy.   
Approximately 3 hours before the surgical procedure, the subject will 
receive a single bolus injection of rIX-FP in order to increase the plasma 
FIX activity level to 60% to 80%, or higher.  At the investigator’s 
discretion, additional bolus injections of rIX-FP may be administered 
during surgery or during the postoperative period, defined as the start 
of wound closure, to maintain a required trough FIX activity level. 
Subcutaneous (SC) Substudy 
Subjects enrolled in this substudy will be sequentially assigned to a 
cohort (Cohort 1 [single dose of 25 IU/kg], Cohort 2 [single dose of 50 
IU/kg], Cohort 3 [15 doses of 25 IU/kg every 3 days], and an optional 
Cohort 4 [15 doses of ≤ 50 IU/kg every 5 days, with the actual dose in 
this cohort to be determined by CSL based on the PK results from 
Cohort 3).  In all cohorts, rIX-FP will be administered SC at least 
14 days after the previous intravenous (IV) rIX-FP administration.  
In Cohorts 1 and 2, blood samples for PK analysis will be collected at 
selected time points through Day 15 (336 hours).  Following collection 
of the last SC PK sample at the 336 hour time point on Day 15, a single 
IV dose of 50 IU/kg rIX-FP will be administered and blood samples for 
PK analysis will be collected at selected time points. Subjects will return 
in 2 weeks (Day 28) for an end of substudy visit to assess safety.  After 
the end of substudy visit on Day 28, Cohort 1 and 2 subjects will return 
to their IV rIX-FP prophylaxis regimen in the main study.   
In Cohorts 3 and 4, blood samples for PK analysis will be collected at 
before the first SC dose, before selected SC doses, as well as for a serial 
PK profile after the first and the final SC doses. Subjects will return 2 
weeks after their last SC dose for an end of substudy visit for collection 
of the final SC PK sample and for safety assessments. After the end of 
substudy visit, Cohort 3 and 4 subjects will return to their IV rIX-FP 
prophylaxis regimen in the main study. 

 
Study Number: 
CSL654_3003 
Study Product: 
rIX-FP  
 
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Primary Objective(s) 
The primary objective of this study is to evaluate the safety of rIX-FP 
as measured by new cases of inhibitors against FIX in all subjects, 
including PUPs, with severe hemophilia B. The PK parameter in PUPs 
will also be collected.  
Primary Endpoint(s) 
 
The total number subjects who develop inhibitors against FIX 
during the approximately 3-year participation in this study. 
 
PK parameters of incremental recovery (IU/dL per IU/kg) of 
50 IU/kg rIX-FP (Arm 4 only) 
Secondary Objective(s) 
The secondary objectives of the study are: 
 To evaluate the efficacy of rIX-FP routine prophylaxis when 
administered at various treatment intervals. 
 To compare the efficacy of rIX-FP routine prophylaxis between 
2 different treatment intervals and versus on-demand treatment.   
 To further evaluate the safety of rIX-FP. 
 To evaluate the efficacy of treatment of bleeding episodes in 
Arm 4 PUPs. 
Secondary Endpoint(s) 
 Annualized bleeding rate (ABR) for spontaneous treated bleeds 
and total treated bleeds for each assigned treatment interval (7 
days, 10 days, 14 days, and 21 days). 
 Comparison of the AsBR and ABR between: 
o 14-day routine prophylactic treatment in this study compared 
with on-demand only treatment from Study CSL654_3001 
Arm 2.   
o 7-day prophylaxis regimen with the 14-day prophylaxis 
regimen.   
o 7-day prophylaxis regimen with the extended prophylaxis 
regimen (10-day or 14-day).  
 Consumption of rIX-FP during routine prophylaxis expressed as 
IU/kg per month per subject. 
 Incidence of adverse events and related adverse events to rIX-FP 
over the course of the study. 
 Hemostatic response to treatment of bleeding episodes with rIX-
FP as assessed by the investigator based on a 4-point scale (Arm 
4 only). 
 
CCI

 
Study Number: 
CSL654_3003 
Study Product: 
rIX-FP  
 
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Study Design 
Multicenter, open-label, phase 3b study.   
Number of Subjects 
This study will enroll approximately 96 male subjects, including all 
eligible subjects from rIX-FP lead-in studies, approximately 10 subjects 
requiring major non-emergency surgery and at least 13 PUPs.  
CCI
CCI

 
Study Number: 
CSL654_3003 
Study Product: 
rIX-FP  
 
Amendment 6 
03 February 2020 
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Any subjects requiring non-emergency surgery or any subjects in Arm 
4 requiring minor surgery during the course of the study may be enrolled 
in the surgery substudy.  Up to a maximum of 24 subjects will enroll in 
the SC substudy. 
Study Duration 
For subjects in Arms 1, 2, and 3, the duration of the study for an 
individual subject is expected to be approximately 5 years or the time it 
takes to achieve a total of 100 EDs during the subject’s enrollment in 
any CSL-sponsored rIX-FP studies. For subjects in Arm 4, the duration 
of the study is expected to be approximately 3 years or the time it takes 
to achieve a total of 50 EDs.  The study may be stopped at a specific 
study site after all subjects at the site have completed the 5-year study 
period or ≥ 50 subjects overall have achieved a total of 100 EDs or after 
regulatory approval and rIX-FP becomes commercially available in the 
respective country. 
The duration of the SC substudy for an individual subject is expected to 
be approximately 30 days in Cohorts 1 and 2, approximately 57 days in 
Cohort 3, and approximately 85 days in Cohort 4. 
Study Population and 
Main Criteria for 
Eligibility 
Exclusion Criteria 
Subjects meeting any of the following exclusion criteria must not be 
enrolled into the study: 
All subjects: 
 
Arms 1, 2, 3 and 4: Currently receiving a therapy not permitted 
during the study, as defined in Section 7.3. 
 
Arms 1 and 2 only: Unwilling to participate in the study for a total 
of 100 EDs. 
 
Arms 1, 2, 3 and 4: Any issue that, in the opinion of the 
investigator, would render the subject unsuitable for participation 
in the study. 
Inclusion Criteria 
Arm 1 and Arm 2: 
Subjects who completed either Study CSL654_3001, Study 
CSL654_3002, or any other CSL-sponsored rIX-FP (CSL654) lead-in 
study. 
Arm 3: The main eligibility criteria for subjects in Arm 3 (However, 
subjects(s) in France will NOT be eligible to be enrolled into Arm 3 of 
the study):  

 
Study Number: 
CSL654_3003 
Study Product: 
rIX-FP  
 
Amendment 6 
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Inclusion Criteria 
 Scheduled to have a major non-emergency surgery within 
approximately 8 weeks from the anticipated date of receiving the 
first rIX-FP injection.  
 Not previously completed a CSL-sponsored rIX-FP lead-in 
study. 
 Male, 12 to 70 years of age. 
 Documented severe hemophilia B (FIX activity of ≤ 2%), or 
confirmed at screening by the central laboratory. 
 Subjects who have received FIX products (plasma-derived 
and / or recombinant FIX) for > 150 EDs, confirmed by their 
treating physician. 
 No confirmed history of FIX inhibitor formation at screening by 
the central laboratory. 
Exclusion Criteria 
 Known hypersensitivity (ie, allergic reaction or anaphylaxis) to 
any FIX product or hamster protein. 
 Known congenital or acquired coagulation disorder other than 
congenital FIX deficiency. 
 Currently receiving IV immunomodulating agents such as 
immunoglobulin or chronic systemic corticosteroid treatment. 
 Low platelet count, kidney or liver disease. 
 Human immunodeficiency virus positive with a CD4 count 
< 200/mm3.   
 
Arm 4: The main eligibility criteria for subjects in Arm 4 are:   
Inclusion Criteria 
 Male, up to 18 years of age. 
 Documented severe hemophilia B (FIX activity of ≤ 2%), or 
confirmed at screening by local or central laboratory. 
 Subjects who have never been treated with FIX clotting factor 
products (except previous exposure to blood components). 
 No confirmed history of FIX inhibitor formation.  
Exclusion Criteria 
 Known congenital or acquired coagulation disorder other than 
congenital FIX deficiency (except for vitamin K deficiency of 
the newborn). 

 
Study Number: 
CSL654_3003 
Study Product: 
rIX-FP  
 
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 Known kidney or liver dysfunction or any condition which, in 
the investigator’s opinion, place the subject at unjustifiable risk. 
 
SC Substudy:  The main eligibility criteria for subjects in the SC 
substudy are:  
Inclusion Criteria 
 Male subjects, at least 18 years of age. 
 Subjects who are currently enrolled in Study CSL654_3003 with 
hemophilia B (FIX activity ≤ 2%). 
 Subjects who have received rIX-FP for ≥ 100 EDs (Cohorts 1 
and 2) or for ≥ 50 EDs (Cohorts 3 and 4). 
 Body weight between 50.0 and 100.0 kg, both inclusive.  
 Body mass index (BMI) between 18.0 and 29.9 kg/m2. 
Exclusion Criteria 
 Use of rIX-FP within 14 days before SC administration of rIX-
FP. 
 Experienced a life-threatening bleeding episode or had major 
surgery during the 3 months prior to substudy entry (Day 1). 
Study Product  Dose, 
Dosing Regimen and 
Administration  
Subjects in Arms 3 and 4 will receive their first 2 doses at the study 
center and be monitored for at least 3 hours. Following WFH’s 
guideline, subjects in Arm 4 must be treated in a clinic or hospital 
setting under the medical supervision of a physician experienced in the 
treatment of hemophilia patients and where proper medical care for 
possible allergic reaction can be provided during the initial 10 to 20 
treatments with rIX-FP.   
Prophylaxis Treatment 
Subjects in Arm 1, 2 or 3:  Before the month 6 visit, subjects will 
administer rIX-FP as routine prophylaxis using either a 7-, 10-, or 14-
day treatment interval. After the month 6 visit, subjects may remain on 
their current treatment interval or they may be switched to a 7-, 10-, 14-
, or 21-day treatment interval. Subjects in France may not take part in 
the 21-day treatment regimen. 
Subjects in Arm 4:  Before the month 12 visit, subjects may receive 
rIX-FP as weekly routine prophylaxis (preferred) or only on-demand 
treatment when bleeding occurs (may combine prevention doses) at the 
investigator’s discretion. After the month 12 visit, subjects will be on 
weekly prophylaxis for the remaining duration of the study.     

 
Study Number: 
CSL654_3003 
Study Product: 
rIX-FP  
 
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The dose of rIX-FP administered for routine prophylaxis will be based 
on the subject’s previous experience (ie, in a lead-in study) and / or the 
targeted FIX activity trough level (target FIX activity level > 2%, but 
optimally between 5% and 15%.  The maximum dose of rIX-FP for 
routine prophylaxis will be 50 IU/kg per injection for subjects using a 
7-day treatment interval, 75 IU/kg per injection for subjects using a 10- 
or 14-day treatment interval, and 100 IU/kg per injection for subjects 
using a 21-day treatment interval. Subjects in France may not take part 
in the 21-day treatment regimen. The dose of rIX-FP for a subject using 
the 7-day treatment interval should not be higher than the dose they used 
in the lead-in study and / or a trough FIX activity of 20%. 
On-demand Treatment 
On-demand treatment with rIX-FP will be used for all bleeding episodes 
requiring treatment. The dose of rIX-FP (35 to 75 IU/kg) will be 
determined by the investigator, based on the effective on-demand 
treatment dose used in the lead-in study and / or the subject’s PK data 
(determined in a lead-in study or Study CSL654_3003). 
Prevention Before Vigorous Physical Activity or Physical Therapy  
During the study, subjects may administer rIX-FP as a preventative 
treatment before vigorous physical activity or before physical therapy 
(ie, as a part of rehabilitation after major surgery) that, in the subject’s 
experience, is likely to result in bleeding.   
Preventative treatment before vigorous physical activity should not be 
used more frequently than once per month. 
Preventative treatment before physical therapy (ie, after major surgery) 
should not be used more frequently than once per week during the first 
3 months of either starting the prophylaxis treatment period (subjects in 
Arm 3, which excludes subjects in France) or returning to routine 
prophylaxis (subjects in Arms 1 or 2). 
The dose of rIX-FP will be 35 to 50 IU/kg, as determined by the 
investigator and / or based on the subject’s previous experience.   
Subcutaneous Treatment in the Subcutaneous Substudy 
Subjects will be sequentially assigned to a cohort, and receive a single 
SC dose of rIX-FP (in Cohorts 1 and 2) or repeated SC doses of rIX-FP 
(in Cohorts 3 and 4).  The SC doses of rIX-FP will be administered at 
up to 4 injection sites, a minimum of 2.5 cm apart, with a volume of up 
to 4 mL per site.  Subcutaneous administration may occur on the 

 
Study Number: 
CSL654_3003 
Study Product: 
rIX-FP  
 
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stomach, thigh or upper arm.  The first SC rIX-FP dose should be 
administered at least 14 days after the previous IV rIX-FP 
administration (21 days if subject is on a 21-day prophylaxis regimen 
in the main study).  In Cohorts 1 and 2, subjects will be administered a 
single IV dose of 50 IU/kg rIX-FP at Day 15 (336 hours). After the end 
of substudy visit, Cohort 3 and 4 subjects will return to their IV rIX-FP 
prophylaxis regimen in the main study. 
Comparator Product,  
Dose, Dosing Regimen 
and Administration 
Not applicable. 
Efficacy Assessments 
The efficacy of rIX-FP treatment in the prevention and treatment of 
bleeding episodes will be assessed based on the following: 
 
Total consumption of rIX-FP (number of EDs and mean IU/kg per 
year per subject and per bleeding episode) and consumption per 
routine prophylaxis, prevention before physical activity, and 
on-demand treatment. 
 
Number of spontaneous and total bleeding episodes and 
corresponding ABRs per treatment interval. 
 
Investigator’s overall clinical assessment of hemostatic efficacy 
for treatment of major bleeding episodes. 
 
Number of rIX-FP injections required to achieve hemostasis. 
Safety Assessments 
Safety will be assessed based on the following variables: 
 
Adverse events and serious adverse events. 
 
Local tolerability. 
 
Serum biochemistry and hematology. 
 
Physical examination and vital signs. 
 
Inhibitors against FIX. 
 
Antibodies against rIX-FP and Chinese hamster ovary cell-derived 
proteins. 
Pharmacokinetics 
Subjects beginning routine prophylaxis treatment using a treatment 
interval of 21 days for the first time (age ≥ 18 years, excludes subjects 
in France) and subjects in Arm 3 (also excluded in France) will undergo 
a PK evaluation with a single injection of rIX-FP (100 IU/kg).  Subjects 
in Arm 4 may also undergo a PK evaluation at the beginning of the study 
with a single injection of rIX-FP (50 IU/kg). For this PK evaluation, 
blood samples will be taken for the measurement of the FIX activity 
level and incremental recovery. 

 
Study Number: 
CSL654_3003 
Study Product: 
rIX-FP  
 
Amendment 6 
03 February 2020 
Page 18 of 187 
CRD-TPL-077 Version 1.0 
Confidential 
In addition, PK evaluation of 50, 75, or 100 IU/kg rIX-FP may also be 
assessed at the investigator’s discretion or CSL’s request, in the event 
of (but not limited to), poor efficacy, suspicion of inhibitor 
development, or before major surgery. Subjects in France may be 
discontinued from receiving the study product and participating in any 
further study procedures if the subject is confirmed to have developed 
an inhibitor against FIX with a titer > 5 Bethesda units (BU)/mL. 
The trough FIX activity level will be assessed after each major bleeding 
episode (if feasible) and at specified visits. 
See Appendix 2 for PK assessments in the SC substudy. 
Pharmacodynamics 
Not applicable. 
Other Assessments 
Other assessments to be made during the study include: 
 
A hemophilia-specific treatment satisfaction 
questionnaire (Hemo-Sat; CSL654_3002 lead-in study only). 
 
 
 
Social and physical activity assessment. 
Statistical Analyses 
All safety and efficacy data will be summarized using descriptive 
statistics for continuous data, or frequencies and percentages for 
categorical data.  
Efficacy Analyses 
AsBRs and ABRs will be derived for each treatment interval assigned 
to the subject while on routine prophylaxis (7-day, 10-day, 14-day, and 
21-day), and will not include the time either during or the first 3 months 
after the surgery substudy, the time during the SC substudy, and 
subjects in Arm 4.  
AsBRs and ABRs will be summarized across subjects using descriptive 
statistics. A crude rate will also be calculated for each treatment interval 
along with an exact two-sided 95% confidence interval assuming a 
Poisson-distributed event rate. 
A comparison of AsBRs and ABRs  will be performed between 14-day 
routine prophylaxis treatment in this study compared with on-demand 
only treatment from Study CSL654_3001 Arm 2.  A further analysis 
will be conducted with the subjects from lead-in Study CSL654_3001 
to assess whether the 14-day prophylaxis regimen is non-inferior to the 
7-day prophylaxis regimen from Study CSL654_3001 (plus data 
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Study Number: 
CSL654_3003 
Study Product: 
rIX-FP  
 
Amendment 6 
03 February 2020 
Page 19 of 187 
CRD-TPL-077 Version 1.0 
Confidential 
obtained from the extension study, if available) based on the mean of 
AsBR and ABR. The non-inferority analysis will also be conducted for 
extended regimens (either 14-day or 10-day regimen) and the 7-day 
prophylaxis regimen.  Non-inferiority will be evaluated by comparing 
the lower bound of a 95% confidence interval for a mean difference  
with a pre-established margin.   
Consumption of rIX-FP will be summarized with descriptive statistics 
according to treatment interval and overall.   
For subjects from Study CSL654_3002, responses to the treatment 
satisfaction questionnaire and age group-specific 
 questionnaire 
(Hemo-Sat and 
, respectively) will be summarized with 
descriptive statistics. 
Data from the surgery substudy will be summarized as case narratives 
or with descriptive statistics or counts, where appropriate. 
Safety Analyses 
The number and proportion of subjects with positive tests for inhibitors 
to FIX during the study will be tabulated separately for PTPs (Arm 1, 2 
and 3) and PUPs (Arm 4).  Inhibitor antibodies against FIX will be 
categorized as low titer (≥ 0.6 to 5 BU/mL) and high titer (> 5 BU/mL).  
An exact 95% binomial confidence interval for inhibitor development 
among subjects treated with rIX-FP will be presented.  
The number and proportion of subjects with adverse events and serious 
adverse events, which are study-emergent, will be tabulated.  
Laboratory, vital signs and physical examination assessments will be 
summarized. 
Pharmacokinetic Analyses 
Incremental recovery and FIX activity levels will be summarized using 
descriptive statistics. 
 
See Appendix 2 for the statistical analyses planned in the SC substudy. 
 
Further details regarding the statistical analysis will be provided in the 
Statistical Analysis Plan (SAP). 
Interim Analyses 
No interim analyses are planned. The following analyses are planned 
before study closure:  
1. The final analysis of the SC substudy data will be conducted 
once all subjects have completed the SC substudy. 
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Study Number: 
CSL654_3003 
Study Product: 
rIX-FP  
 
Amendment 6 
03 February 2020 
Page 20 of 187 
CRD-TPL-077 Version 1.0 
Confidential 
2. The final analysis of PTPs (including surgical data from PTPs) 
will be conducted when all PTPs have completed the study.  
In addition, safety, efficacy and / or PK data and subject 
characteristics may be reported to regulatory authorities before study 
closure. 
 

 
Study Number:  
CSL654_3003 
Study Product: 
rIX-FP 
 
Amendment 6 
03 February 2020 
Page 21 of 187 
CRD-TPL-077 
Confidential 
TABLE A - SCHEDULE OF ASSESSMENTS: TREATMENT PERIOD (ARMS 1, 2 AND 3) 
Assessments 
 
Day 1 B 
Arm 1 & 2 
Month A 
50 EDs D 
End of 
Study 
3 C 
6L 
9 C 
12 
18, 30, 42, 54  24, 36, 48, 60 
Informed consent 
X 
  
  
  
  
 
 
  
 
Demographics, lead-in study data 
X 
  
  
  
  
 
 
  
 
Eligibility assessment  
X 
  
  
  
  
 
 
  
 
Social and physical activity 
X 
   
X 
 
X 
X 
X 
 
X 
Relevant medical history E 
X 
 
 
 
 
 
 
 
 
Physical examination 
X 
  
  
  
X 
 
X 
 
X 
Vital signs 
X 
  
  
  
X 
 
X 
 
X 
Body weight and height F 
X 
X 
X 
X 
X 
X 
X 
 
 
Blood biochemistry and hematology (LL) 
X 
 
  
  
 X 
 
 
 
X 
Inhibitors against FIX (CL) 
X 
 
X 
 
X 
X 
X 
X 
X 
Ab against rIX-FP & CHO cell proteins (CL) G 
X 
 
 
 
X 
 
X 
X 
X 
Plasma FIX activity (CL) 
XM 
 
X 
 
X 
X 
X 
  
 
Plasma FIX activity (LL) 
  
  
 X 
  
X 
 
 
  
 
Retain blood sample H 
  
  
  
  
  
 
 
 
X 
Dispense subject eDiary 
X 
 
 
 
 
 
 
 
 
Review subject eDiary  
  
X 
X 
X 
X 
X 
X 
 
X 
Assess treatment efficacy for a major bleed 
 
X 
X 
X 
X 
X 
X 
 
X 
Review treatment regimen I 
 
 
X 
 
X 
X 
X 
 
 
Hemo-Sat questionnaire J 
 
 
  
  
X 
  
 
  
 
 
  
 
  
  
X 
  
 
  
 
Retrieve eDiary 
 
 
X 
Adverse events  
<-------------------------------On an ongoing basis-------------------------------> 
X 
X K 
Concomitant therapy 
<-------------------------------On an ongoing basis-------------------------------> 
X 
X 
Ab = antibody; CHO = Chinese hamster ovary; CL = central laboratory; ED = exposure day; eDiary = electronic diary; FIX = coagulation factor IX; LL = local 
laboratory; 
; rIX-FP = recombinant coagulation factor IX albumin fusion protein.  
 
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Study Number:  
CSL654_3003 
Study Product: 
rIX-FP 
 
Amendment 6 
03 February 2020 
Page 22 of 187 
CRD-TPL-077 
Confidential 
Notes to the schedule of assessments:  
A: Time window: ± 2 weeks.  All visits should occur within 2 calendar days before the next scheduled prophylactic administration of rIX-FP.  A month is 
28 days. 
B: Day 1 assessments to be completed only by subjects in Arms 1 or 2. Data that will be transferred from the end of study visit or earlier visit (where relevant) 
of the lead-in study include demographics, rIX-FP EDs, age cohort in lead-in study, arm in lead-in study, social and physical activity, laboratory assessments 
(serum biochemistry, hematology), vital signs, physical examination, body height and weight, and antibody assessments (inhibitors against FIX, antibodies 
against rIX-FP & CHO cell-derived proteins), plasma FIX activity (in subjects from CSL654_3001 study only), adverse events, and concomitant therapy. 
C: For subjects from lead-in Study CSL654_3001 Arm 1, the month 3 and month 9 visits may be conducted via telephone, if the investigator deems that there is 
no safety risk to the subject.  For subjects from lead-in Study CSL654_3001 and CSL654_3002, the month 9 visit may be conducted via telephone, if the 
investigator deems that there is no safety risk to the subject.  The month 3 visit may be omitted for subjects in Arm 2 who have attended a follow-up after 
visit in the previous 3 months to transition from a 7-day rIX-FP treatment interval to a 14-day rIX-FP treatment interval. 
D: Visit to occur within a month after a subject has experienced a total of 50 rIX-FP EDs in this extension study. If the 50 EDs visit is to occur within 3 months 
of a follow-up visit, the scheduled follow-up visit may be omitted by conducting all follow-up assessments, in addition to assessments required for the 
50 EDs visit, during the 50 EDs visit. 
E: Record genotype and current joint score including scoring system and date of the assessment. 
F: Height to be recorded on day 1 and thereafter at annual intervals only (ie, month 12, 24, etc).  Height measurements on the month 12, 24, 36, and 48 visits 
are optional for subjects ≥ 18 years of age. Measurement of body weight may be omitted at month 3 and month 9 if the visit is conducted via telephone. 
G: A sample that tests positive for antibodies against rIX-FP will be retested to discriminate between plasma-derived FIX, recombinant FIX and albumin 
antibodies. 
H: Retain samples will be collected for potential serology testing at a later date. 
I: 
Investigator to review treatment efficacy and change treatment regimen (dose and / or treatment interval), if necessary. 
J: 
 
 
 
 
K: The observation period for adverse event (and serious adverse event) reporting in an individual subject will start at the time of giving written informed 
consent for participation in the current study and finish with the end of study visit.  However, adverse events ongoing at the end of study visit will be 
followed until resolution or 30 days after the final administration of rIX-FP during this study, whichever is sooner. 
L: Arm 2 Subjects should attend an unscheduled visit and complete assessments as specified for the 6-month visit if they are to switch to a 14-day treatment 
interval before completion of the 6-month period.  Under such circumstances, the 3-month visit may be omitted. 
M: Sample collected in subjects coming from Study CSL654_3002 after consenting for CSL654_3003.  
 
CCI

 
Study Number:  
CSL654_3003 
Study Product: 
rIX-FP 
 
Amendment 6 
03 February 2020 
Page 23 of 187 
CRD-TPL-077 
Confidential 
TABLE B - SCHEDULE OF ASSESSMENTS: PHARMACOKINETIC PERIOD  
 
 
50 IU/kg (Arm 4) or 100 IU/kg rIX-FP PK Visit A 
Assessments 
Before injection 
0 hour 
(injection) 
30 min 
72 hours B 
(3 days)  
168 hours C 
(7 days) 
336 hours D 
(14 days) 
504 hours D 
(21 days) 
Time Window < 12 hours 
before injection 
 
± 5 min 
± 24 hrs 
± 24 hrs 
± 24 hrs 
± 24 hrs 
Weight and height  
X 
 
 
 
 
 
 
Plasma FIX level (central) 
X 
 
X 
X 
X 
X 
X 
Retain blood sample E 
X 
 
 
 
 
 
 
Administration of rIX-FP 
 
X 
 
 
 
 
 
Dispense subject eDiary F  
 
X 
 
 
 
 
 
Training of self-administration F 
 
X 
X 
X 
X 
 
 
Adverse events  
 
<--------------------------------------On an ongoing basis--------------------------------------> 
Concomitant therapy 
 
<--------------------------------------On an ongoing basis--------------------------------------> 
eDiary = electronic diary; FIX = coagulation factor IX; PK = pharmacokinetic; rIX-FP = recombinant coagulation factor IX albumin fusion protein. 
A: 100 IU/kg PK completed only by subjects in Arm 3 (no subjects in France may enroll in Arm 3) or subjects ≥18 years who have completed at least 6 months 
of treatment and planning to begin routine prophylaxis treatment using a 21-day treatment interval for the first time.  Subjects in France may not take part in 
the 21 day treatment regimen. The PK evaluation should be performed after a washout period of at least either 4 days for a current marketed FIX product (ie, 
subjects in Arm 3 (no subjects in France may enroll in Arm 3) or 14 days for rIX-FP (subjects currently being treated with rIX-FP).  50 IU/kg PK completed 
by subjects in Arm 4 (see Table D for assessments prior to rIX-FP injection).  The investigator may also choose to complete a PK assessment of 50, 75 or 
100 IU/kg (as appropriate) rIX-FP with selected time points before starting surgical prophylaxis with rIX-FP, at the investigator’s discretion or CSL’s 
request, or in the event of (but not limited to) poor efficacy or suspicion of inhibitor development.  Samples may be tested in the local laboratory in addition 
to the central laboratory. Subjects in France may be discontinued from receiving the study product and participating in any further study procedures if the 
subject is confirmed to have developed an inhibitor against FIX with a titer > 5 BU/mL. 
B: Optional time point for subjects planning to be switched to a 21-day treatment interval, and Arm 4. 
C: Optional time point for Arm 4 subjects. 
D: Optional time point for subjects in Arm 3 before major surgery (No subjects in France may enroll in Arm 3).  Not done for Arm 4.  
E: Retain samples will be collected before the first injection of rIX-FP (subjects in Arm 3 only, excludes subjects in France) for potential serology testing at a 
later date. 

 
Study Number:  
CSL654_3003 
Study Product: 
rIX-FP 
 
Amendment 6 
03 February 2020 
Page 24 of 187 
CRD-TPL-077 
Confidential 
F: Subjects in Arm 3 only (subjects in France may not enroll in Arm 3). Before completion of the PK evaluation period (at a time point determined by the 
investigator), the eDiary should be dispensed and subjects should be trained on injection technique, dosing regimen, and use of the eDiary. 
 
 

Study Number: 
CSL654_3003 
Study Product: 
rIX-FP 
Amendment 6 
03 February 2020 
Page 25 of 187 
CRD-TPL-077 
Confidential 
TABLE C - SCHEDULE OF ASSESSMENTS: SUBJECTS IN ARM 3(NO SUBJECTS IN FRANCE MAY ENROLL IN 
ARM 3)  
Screening 
PK Period 
Before 
surgery 
Surgery 
Substudy 
Day 1 A 
Arm 3
Treatment 
Period 
Time window 
Assessments 
-1 to -28 days
7 to 56 days 
after PK 
injection 
Surgery day to 
28 ± 7 days 
after surgery 
Informed consent 
X 
Complete Schedule of 
Assessments: Pharmacokinetic 
Period (Table B) 
Complete Schedule of Assessments: 
Surgery Substudy – Major Surgery  
Complete Schedule of 
Assessments: Treatment Period 
(Table A) 
Demographics 
X 
Eligibility assessment 
X 
Social and physical activity 
X 
Relevant medical and treatment history B 
X 
Physical examination 
X 
Vital signs
X 
Body weight and height 
X 
 
X C 
Blood biochemistry and hematology (LL)
X 
Inhibitors against FIX (CL)
X 
Ab against rIX-FP & CHO cell proteins (CL) D 
X 
Plasma FIX activity (CL and LL) 
X 
Begin prophylaxis treatment with rIX-FP 
X E 
Adverse events 
X 
X 
X 
Prior / concomitant therapy 
X 
X 
X 
Ab = antibody; CHO = Chinese hamster ovary; CL = central laboratory; eDiary = electronic diary; FIX = coagulation factor IX; LL = local laboratory; 
PK = pharmacokinetics; rIX-FP = recombinant coagulation factor IX albumin fusion protein. 
Notes to the schedule of assessments:  
A: The Day 1 visit should occur after completion of the surgery substudy and should occur at the same time as the End of Surgery Substudy visit. 
B: Record history of hemophilia B including genotype and current joint score (including scoring system and date of the assessment), and 
treatment history with a marketed FIX. 
C: Body weight only. 
D: A sample that tests positive for antibodies against rIX-FP will be retested to discriminate between plasma-derived FIX, recombinant FIX and 
albumin antibodies.  

 
Study Number:  
CSL654_3003 
Study Product: 
rIX-FP 
 
Amendment 6 
03 February 2020 
Page 26 of 187 
CRD-TPL-077 
Confidential 
E: Subjects in Arm 3 (No subjects in France may enroll in Arm 3) who require physical therapy (ie, rehabilitation after surgery), may administer 
rIX-FP as preventative treatment (no more than once per week) in addition to the administration of rIX-FP as routine prophylaxis. Preventative 
treatment before physical therapy is permitted only during the first 3 months of the treatment period. 
 
 

 
Study Number:  
CSL654_3003 
Study Product: 
rIX-FP 
 
Amendment 6 
03 February 2020 
Page 27 of 187 
CRD-TPL-077 
Confidential 
TABLE D - SCHEDULE OF ASSESSMENTS: SUBJECTS IN ARM 4  
Assessments 
ScreenB 
(up to 28
days) 
(PKA) 
MonthsI  (±1 week) 
Months  (±2 week) 
50 
EDs EoS L 
Prior 
dose 
30±5 
mins 
Day  
3 
Day 
7 
1 
2 
3 
4 
5 
6 
7 
8 
9 10 11 12 15 18 21 24 27 30 33  
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility assessment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Relevant medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
 
 
 
 
X X X X X X X X X X X X X X X X X X X 
 
X 
Vital signsC 
X 
 
 
 
 
X X X X X X X X X X X X X X X X X X X 
 
X 
Body weight and height 
X 
X 
 
 
 
X X X X X X X X X X X X X X X X X X X 
 
 
Biochemistry&hematologyD 
D
XE 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X
 
 
 
X 
 
 
 
 
X 
Inhibitors against FIX (CL) 
XE 
 
 
 
 
X X X X X X 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Ab to rIX-FP/CHO (CL)F 
XE 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
Plasma FIX activity (CL)H 
 
X 
X 
X 
X 
X X X 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
Plasma FIX activity (LL) 
XJ  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Retain blood sampleG 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Dispense subject eDiaryK 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Review subject eDiary 
 
 
 
 
 
 <---------------- On an ongoing basis during eDiary usage  ----------------> 
 
X 
Review treatment efficacy  
 
 
 
 
 
<------------------------------- On an ongoing basis --------------------> 
 
X 
Adverse events  
<------------------------------------------------ On an ongoing basis ----------------------------------------------------> 
Concomitant therapy 
<------------------------------------------------ On an ongoing basis ----------------------------------------------------> 
Ab = antibody; CHO = Chinese hamster ovary; CL = central laboratory; eDiary = electronic diary; FIX = coagulation factor IX; LL = local laboratory; 
PK = pharmacokinetics; rIX-FP = recombinant coagulation factor IX albumin fusion protein; EoS=End of Study. 
Subjects will be treated in the study center or medical facility under medical supervision during the initial 10 to 20 treatment with rIX-FP.  The first 
2 infusions must be monitored on-site for at least 3 hours.   

 
Study Number:  
CSL654_3003 
Study Product: 
rIX-FP 
 
Amendment 6 
03 February 2020 
Page 28 of 187 
CRD-TPL-077 
Confidential 
A:   PK can start at Day 1 as the first dose or/and during the study after ≥7 days washout from the previous rIX-FP dose, when the subject is in 
non-bleeding state.  See Table D for PK sampling time points. (Day 1 is the day subject receives his first dose with rIX-FP) 
B:   Tests that require blood sample for screening period (from ICF day to Day 1 prior to dose) can be divided to multiple days or combined with 
Day 1 tests.   The screening day can be the same day for first dose of rIX-FP (either on-demand, prophylaxis or PK dose). 
C:   Vital signs include blood pressure, temperature and heart rate.  
D:   Includes liver and renal function test (Albumin, Alanine Aminotransferase, Aspartate Aminotransferase, Alkaline Phosphatase, Bilirubin, 
Direct Bilirubin, Protein, Blood Urea Nitrogen or Urea, and Creatinine).  
E:    Documented biochemistry & hematology results from 6 months prior to screening are acceptable; otherwise, samples may be collected during 
the screening period or at Day 1. Samples for antibodies/inhibitor must be collected during the screening period or prior to first dose of rIX-
FP. 
F:    A sample that tests positive for antibodies against rIX-FP will be retested to discriminate between pdFIX, rFIX and albumin antibodies. 
G:   Retain samples will be collected prior to the first dose of rIX-FP for potential serology testing at a later date. 
H:   Optional samples at Day 3 or Day 7 of PK assessment, or during the month 1, 2 or 3 for FIX activity if feasible.    
I:    If subjects receive treatment for less than 3 doses per month, they may omit the site visit(s) until they received ~5 doses.    
J:    FIX activity tested at local Laboratory if no previous FIX data available in medical records.  
K:   Subject eDiary may be dispensed once caregiver is trained to administer rIX-FP at home, but not prior to receiving a minimum of 10 infusions 
at the study center or medical facility under medical supervision. 
L:  End of Study for Arm 4 is the Month 36 visit.

 
Study Number: 
CSL654_3003 
Study Product: 
rIX-FP 
 
Amendment 6 
03 February 2020 
Page 29 of 187 
CRD-TPL-077 
Confidential 
 
Table of Contents 
SIGNATURE ON BEHALF OF SPONSOR ............................................................................ 3 
SIGNATURE OF INVESTIGATOR ........................................................................................ 4 
REVISION HISTORY............................................................................................................... 5 
PROTOCOL SYNOPSIS........................................................................................................... 8 
TABLE A - SCHEDULE OF ASSESSMENTS: TREATMENT PERIOD (ARMS 1, 2 AND 
3) ......................................................................................................................................... 21 
TABLE B - SCHEDULE OF ASSESSMENTS: PHARMACOKINETIC PERIOD .............. 23 
TABLE C - SCHEDULE OF ASSESSMENTS: SUBJECTS IN ARM 3(NO SUBJECTS IN 
FRANCE MAY ENROLL IN ARM 3) .............................................................................. 25 
TABLE D - SCHEDULE OF ASSESSMENTS: SUBJECTS IN ARM 4 .............................. 27 
TABLE OF CONTENTS ......................................................................................................... 29 
LIST OF ABBREVIATIONS .................................................................................................. 35 
1. INTRODUCTION .............................................................................................................. 37 
1.1 
BACKGROUND ......................................................................................................... 37 
1.2 
BACKGROUND INFORMATION ON RECOMBINANT FUSION PROTEIN 
LINKING COAGULATION FACTOR IX WITH ALBUMIN (RIX-FP) ................. 38 
1.2.1 
Overview ....................................................................................................... 38 
1.2.2 
Nonclinical Evaluation .................................................................................. 38 
1.2.3 
Previous Clinical Experience ........................................................................ 40 
1.3 
STUDY OVERVIEW .................................................................................................. 43 
1.4 
POTENTIAL RISKS AND BENEFITS ...................................................................... 46 
2. STUDY OBJECTIVES AND ENDPOINTS ...................................................................... 48 
2.1 
PRIMARY OBJECTIVE AND ENDPOINT .............................................................. 48 
2.1.1 
Primary Objective .......................................................................................... 48 
2.1.2 
Primary Endpoints ......................................................................................... 48 
2.2 
SECONDARY OBJECTIVES AND ENDPOINTS .................................................... 48 
2.2.1 
Secondary Objectives .................................................................................... 48 
2.2.2 
Secondary Endpoints ..................................................................................... 48 
2.3 
 
 
 
3. STUDY DESIGN ................................................................................................................ 51 
3.1 
STUDY DESIGN AND RATIONALE ....................................................................... 51 
3.1.1 
Routine Prophylaxis: First 6 Months ............................................................. 52 
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Study Number: 
CSL654_3003 
Study Product: 
rIX-FP 
 
Amendment 6 
03 February 2020 
Page 30 of 187 
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3.1.2 
Routine Prophylaxis: 6 Months to End of Treatment Period ........................ 54 
3.1.3 
Pharmacokinetic Evaluation of rIX-FP (100 IU/kg) ..................................... 54 
3.1.4 
On-demand Treatment of Bleeding Episodes ................................................ 55 
3.1.5 
Preventative Treatment Before Vigorous Physical Activity or Physical 
Therapy .......................................................................................................... 56 
3.1.6 
Surgical Prophylaxis ...................................................................................... 56 
3.1.7 
Subcutaneous Substudy ................................................................................. 56 
3.2 
DOSE AND DOSING REGIMEN .............................................................................. 57 
3.2.1 
Routine Prophylaxis Treatment ..................................................................... 57 
3.2.2 
On-demand Treatment of Bleeding Episodes ................................................ 59 
3.2.3 
Prevention Before Vigorous Physical Activity or Physical Therapy ............ 60 
3.3 
PLANNED STUDY DURATION ............................................................................... 60 
3.4 
PLANNED NUMBER OF SITES ............................................................................... 61 
3.5 
PLANNED NUMBER OF SUBJECTS ...................................................................... 61 
3.6 
STUDY MONITORING PROCEDURES .................................................................. 61 
3.6.1 
Independent Data Monitoring Committee ..................................................... 61 
3.6.2 
Other Monitoring Committees ...................................................................... 62 
4. SELECTION AND WITHDRAWAL OF SUBJECTS ...................................................... 62 
4.1 
ELIGIBILITY CRITERIA ........................................................................................... 62 
4.1.1 
Inclusion Criteria ........................................................................................... 63 
4.1.2 
Exclusion Criteria .......................................................................................... 64 
4.2 
SUBJECT WITHDRAWAL ........................................................................................ 65 
4.2.1 
Subject Withdrawal ....................................................................................... 65 
4.2.2 
Procedures for Handling Withdrawals .......................................................... 66 
4.2.3 
Replacement Policy ....................................................................................... 67 
5. STUDY INTERVENTIONS ............................................................................................... 67 
5.1 
DESCRIPTION OF INVESTIGATIONAL PRODUCT ............................................. 67 
5.1.1 
Recombinant fusion protein linking coagulation factor IX with albumin 
(rIX-FP) ......................................................................................................... 67 
5.1.2 
Comparator Product ....................................................................................... 68 
5.2 
PACKAGING, LABELING, SUPPLY AND STORAGE .......................................... 68 
5.2.1 
Packaging and Labeling ................................................................................ 68 
5.2.2 
Supply and Storage ........................................................................................ 68 
5.3 
ACCOUNTABILITY AND DESTRUCTION ............................................................ 68 
5.4 
OTHER INTERVENTION(S) ..................................................................................... 68 
5.5 
RESCUE THERAPY ................................................................................................... 69 
6. ALLOCATION, DOSING AND ADMINISTRATION .................................................... 69 

 
Study Number: 
CSL654_3003 
Study Product: 
rIX-FP 
 
Amendment 6 
03 February 2020 
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6.1 
ALLOCATION TO TREATMENT ............................................................................ 69 
6.1.1 
Subject Assignment ....................................................................................... 69 
6.1.2 
Randomization Procedures ............................................................................ 69 
6.1.3 
Blinding Procedures ...................................................................................... 69 
6.2 
DOSING AND ADMINISTRATION ......................................................................... 69 
6.2.1 
Adjustment of Dose for Prophylaxis and On-demand Treatment ................. 70 
6.3 
TREATMENT COMPLIANCE .................................................................................. 71 
7. CONTRAINDICATIONS, PERMITTED THERAPIES AND PROHIBITED 
THERAPIES ....................................................................................................................... 72 
7.1 
CONTRAINDICATIONS AND PRECAUTIONS TO FURTHER DOSING ........... 72 
7.2 
PERMITTED THERAPIES......................................................................................... 72 
7.3 
PROHIBITED THERAPIES ....................................................................................... 72 
7.4 
DIETARY AND LIFESTYLE RESTRICTIONS ....................................................... 73 
7.5 
OVERDOSE ................................................................................................................ 73 
8. STUDY PROCEDURES AND VISIT SCHEDULE .......................................................... 73 
8.1 
CLINICAL PROCEDURES ........................................................................................ 73 
8.2 
SUBJECT/CAREGIVER TRAINING AND TREATMENT AT HOME .................. 75 
8.3 
CONTROL OF MAJOR BLEEDING EPISODES ..................................................... 76 
8.4 
CONTROL OF MINOR AND MODERATE BLEEDING EPISODES (ARM 4 
ONLY) ......................................................................................................................... 77 
8.5 
TREATMENT FOR A SURGICAL PROCEDURE ................................................... 78 
8.6 
INHIBITORS AND ANTIBODIES ............................................................................ 79 
8.7 
RETENTION OF SAMPLES ...................................................................................... 79 
8.8 
CONCOMITANT THERAPIES ................................................................................. 80 
8.9 
VISIT SCHEDULE ..................................................................................................... 80 
8.9.1 
Screening Visit (Arms 3 and 4 only) or Day 1 Visit (Arms 1 and 2 only) .... 80 
8.9.2 
Day 1 Visit (Arms 3 and 4) ........................................................................... 83 
8.9.3 
Other Visits during the Treatment Period (Arm 1, 2 and 3) .......................... 85 
8.9.4 
Other Visits During the Treatment Period (Arm 4 only) .............................. 88 
8.9.5 
Completion of 50 rIX-FP EDs During the Study (all subjects) ..................... 91 
8.9.6 
Unscheduled Visits if Inhibitor to FIX is confirmed ..................................... 91 
8.9.7 
End of Study (all subjects) ............................................................................ 92 
8.9.8 
Pharmacokinetic Evaluation of 100 IU/kg rIX-FP ........................................ 92 
8.9.9 
Pharmacokinetic Evaluation of 50 IU/kg rIX-FP (Arm 4) ............................ 94 
8.9.10 
Unscheduled Visits ........................................................................................ 94 
9. ADVERSE EVENTS .......................................................................................................... 94 
9.1 
DEFINITIONS ............................................................................................................. 94 
9.1.1 
Adverse Event ............................................................................................... 94 

 
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9.1.2 
Adverse Events of Special Interest ................................................................ 97 
9.1.3 
Serious Adverse Event .................................................................................. 97 
9.2 
SEVERITY OF ADVERSE EVENTS ........................................................................ 98 
9.3 
CAUSALITY OF ADVERSE EVENTS ..................................................................... 98 
9.4 
OBSERVATION PERIOD FOR ADVERSE EVENTS ............................................. 99 
9.5 
ADVERSE EVENT REPORTING.............................................................................. 99 
9.5.1 
Adverse Events .............................................................................................. 99 
9.5.2 
Adverse Events of Special Interest ................................................................ 99 
9.6 
SERIOUS ADVERSE EVENT REPORTING .......................................................... 100 
9.6.1 
Requirements for Immediate Reporting of Serious Adverse Events ........... 101 
9.7 
OTHER SIGNIFICANT EVENT REPORTING....................................................... 102 
9.7.1 
Overdose ...................................................................................................... 102 
9.7.2 
Pregnancy and Lactation ............................................................................. 102 
9.8 
IRB / IEC REPORTING REQUIREMENTS ............................................................ 102 
9.9 
FOLLOW-UP OF ADVERSE EVENTS................................................................... 102 
10. 
ASSESSMENTS ........................................................................................................ 103 
10.1 
SUBJECT CHARACTERISTICS ............................................................................. 103 
10.2 
EFFICACY ASSESSMENTS ................................................................................... 103 
10.3 
SAFETY ASSESSMENTS ........................................................................................ 103 
10.4 
PHARMACOKINETIC AND PHARMACODYNAMICS ...................................... 104 
10.4.1 
Pharmacokinetic Analyses ........................................................................... 104 
10.4.2 
Pharmacodynamic Analyses ........................................................................ 105 
10.4.3 
Pharmacokinetic / Pharmacodynamic Relationships ................................... 105 
10.4.4 
Pharmacokinetic Analyses (Subcutaneous Substudy) ................................. 105 
10.5 
OTHER ASSESSMENTS ......................................................................................... 105 
11. 
STATISTICS ............................................................................................................. 105 
11.1 
SAMPLE SIZE ESTIMATION ................................................................................. 105 
11.2 
DESCRIPTION OF ANALYSIS DATASETS ......................................................... 106 
11.2.1 
Pharmacokinetic Population ........................................................................ 106 
11.2.2 
Safety Population ......................................................................................... 106 
11.2.3 
Efficacy Population ..................................................................................... 106 
11.2.4 
Per-protocol Population ............................................................................... 106 
11.2.5 
Surgical Population ..................................................................................... 107 
11.2.6 
Subcutaneous Population ............................................................................. 107 
11.3 
STATISTICAL ANALYSES AND METHODS ...................................................... 107 
11.3.1 
Subject Disposition and Characteristics ...................................................... 107 
11.3.2 
Efficacy Analyses ........................................................................................ 108 
11.3.3 
Safety Analyses ........................................................................................... 113 

 
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11.3.4 
Pharmacokinetics and Pharmacodynamic Data ........................................... 116 
11.3.5 
Other Analyses ............................................................................................ 116 
11.3.6 
Interim Analysis .......................................................................................... 117 
12. 
QUALITY ASSURANCE ......................................................................................... 117 
13. 
REGULATORY AND ETHICS CONSIDERATIONS ............................................ 117 
13.1 
REGULATORY CONSIDERATIONS ..................................................................... 117 
13.2 
INSTITUTIONAL REVIEW BOARD / INDEPENDENT ETHICS COMMITTEE
.................................................................................................................................... 118 
13.3 
SUBJECT INFORMATION AND INFORMED CONSENT ................................... 118 
13.4 
SUBJECT IDENTIFICATION AND CONFIDENTIALITY ................................... 119 
13.5 
INDEMNITY AND COMPENSATION ................................................................... 119 
14. 
ADMINISTRATIVE CONSIDERATIONS .............................................................. 119 
14.1 
CLINICAL TRIAL AGREEMENT .......................................................................... 119 
14.2 
CLINICAL STUDY REGISTRATION AND RESULTS DISCLOSURE ............... 120 
14.3 
IMPLEMENTATION OF THE PROTOCOL / PROTOCOL AMENDMENT(S) ... 120 
14.4 
PROTOCOL DEVIATIONS ..................................................................................... 121 
14.5 
DOCUMENTATION AND RECORD KEEPING ................................................... 121 
14.5.1 
Data Collection ............................................................................................ 121 
14.5.2 
Data Quality Assurance ............................................................................... 122 
14.5.3 
Record Retention ......................................................................................... 122 
14.6 
STUDY AND SITE CLOSURE ................................................................................ 122 
14.7 
CLINICAL STUDY REPORT .................................................................................. 123 
14.8 
USE OF DATA AND PUBLICATIONS .................................................................. 123 
15. 
REFERENCES .......................................................................................................... 123 
APPENDIX 1. 
SURGERY SUBSTUDY ....................................................... 126 
APPENDIX 2. 
SUBCUTANEOUS SUBSTUDY .......................................... 147 
APPENDIX 3. 
WORLD FEDERATION OF HEMOPHILIA 
RECOMMENDED PLASMA FACTOR LEVEL AND DURATION OF 
ADMINISTRATION FOR ON-DEMAND TREATMENT AND SURGERY ............... 186 
 
List of Tables 
Table 1. Dose Guidelines for Routine Prophylaxis Treatment .............................................. 59 
Table 2.   Clinical Procedures: Demographics and Safety Evaluation .................................... 74 
Table 3.  Efficacy Evaluation for Treatment of Major Bleeding Episodes ............................. 77 
Table 4.  Efficacy Evaluation for Treatment of Minor and Moderate Bleeding Episodes ...... 78 

 
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List of Figures 
Figure 1. Study Overview ....................................................................................................... 51 
Figure 2 Subcutaneous Substudy: Dosing / PK Sampling Scheme and Substudy Visit Days 
for Cohorts 3 and 4 ................................................................................................ 166 
 
 

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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
Ab 
Antibody 
ABR 
Annualized bleeding rate 
AsBR 
AE 
Annualized spontaneous bleeding rate 
Adverse event 
AESI 
Adverse event of special interest 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AR 
Accumulation ratio 
AST 
Aspartate aminotransferase 
AUC 
Area under the concentration-time curve 
AUC0-last 
Area under the concentration-time curve from zero up to an infinite time 
AUC0-inf 
Area under the concentration-time curve from zero up to the last 
measurable time 
BU 
Bethesda unit 
CHO 
CL 
Chinese hamster ovary 
Central Laboratory 
Cmax 
Maximum concentration 
EBL 
Estimated blood loss 
eCRF 
Electronic case report form 
ED 
Exposure day 
eDiary 
Electronic diary 
FDA 
Food and Drug Administration 
FIX 
Coagulation factor IX 
GCP 
Good Clinical Practice 
ICF 
Informed Consent Form  
ICH 
IDMC 
International Conference on Harmonisation of Technical Requirements 
for Registration of Pharmaceuticals for Human Use 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
IR 
Incremental recovery 
IRB 
Institutional Review Board 
IU 
International unit 
IV 
Intravenous 
LL 
MedDRA 
Local Laboratory 
Medical Dictionary for Regulatory Activities 
CCI
CCI
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Abbreviation 
Definition 
PK 
Pharmacokinetic 
PP 
Per-protocol 
PT 
Preferred term 
PTP 
Previously Treated Patient 
PUP 
Previously Untreated Patient 
rIX-FP 
Recombinant coagulation factor IX albumin fusion protein 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SC 
Subcutaneous 
SD 
Standard deviation 
SMT 
Safety Management Team 
SOC 
System organ class 
SRC 
t1/2 
TAT 
Tmax 
Safety Review Committee 
Terminal half-life 
Thrombin-antithrombin 
Time to reach Cmax 
Tmax, ss 
Time to reach Cmax at steady state 
Vss 
Volume of distribution at steady state 
WFH 
World Federation of Hemophilia  
CCI

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1.
INTRODUCTION
1.1
BACKGROUND 
Hemophilia B is an X-linked recessive inherited bleeding disorder resulting from a deficiency 
of coagulation factor IX (FIX), a coagulation factor central to the process of blood 
coagulation [Giangrande, 2005].  Signs and symptoms of hemophilia B are variable, depending 
on the severity of FIX deficiency and the location of bleeding.  Most often, bleeding is 
characterized by spontaneous or trauma-induced hemorrhage into joints, muscles, and soft 
tissues.  Recurrent bleeding in the same location may lead to permanent injury of the joint.  
Rare but life-threatening bleeding may also occur in the central nervous system, throat, or 
gastrointestinal tract. 
The goal of therapy for hemophilia B is to treat or prevent hemorrhage, thereby reducing 
disabling joint and tissue damage, and improving 
.  Replacement therapy 
with FIX provides a temporary correction of the factor deficiency and reduces bleeding 
tendencies.  Currently, plasma-derived and recombinant FIX products are used for the 
prophylactic and on-demand treatment of hemophilia B.  However, plasma-derived products 
are associated with risks related to transmission of infectious viruses such as human 
immunodeficiency virus, hepatitis B virus, and hepatitis C virus.  Both plasma-derived and 
recombinant FIX products have a short half-life and, therefore, require dosing 2 to 3 times a 
week in order to achieve a significant reduction of bleeding episodes.  In addition, repeat dosing 
may be required to control bleeding episodes with a relatively short bleeding-free period 
following administration.  The need for frequent intravenous (IV) injections of either plasma-
derived or recombinant FIX products carries significant burden for patients and the physicians 
treating their disorder.  Such a regimen in younger children often (but not always), requires the 
insertion of a venous access device that must be kept extremely clean to avoid infectious 
complications and prevent the development of clots in the line.  The risk and morbidity 
associated with such devices may prevent some very young children with hemophilia from 
receiving adequate care. 
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A FIX product that has a prolonged half-life and better recovery rate may allow patients to 
achieve adequate hemostasis with fewer injections. 
1.2
BACKGROUND INFORMATION ON RECOMBINANT FUSION PROTEIN 
LINKING COAGULATION FACTOR IX WITH ALBUMIN (rIX-FP) 
1.2.1 Overview 
Recombinant fusion protein linking coagulation factor IX with albumin (rIX-FP) is a purified 
recombinant protein, generated by the genetic fusion of recombinant human albumin to the 
c-terminus of recombinant FIX, with a cleavable linker.  The protein comprises 1018 amino
acids in a single chain glycopeptide with a molecular weight of approximately 125 kDa.
Albumin is an abundant natural carrier molecule that is not involved in immune defense and
does not act as an adjuvant for the immune system.
rIX-FP is produced in Chinese hamster ovary (CHO) cells, which have been characterized and 
shown to be free of known infectious agents.  rIX-FP is not derived from human blood and 
contains no preservatives or added animal or human components.  In addition, 3 (2 dedicated) 
virus inactivation / reduction steps are applied in the manufacturing process (see the 
Investigator’s Brochure for further details). 
This phase 3b study of rIX-FP is intended to evaluate long-term data on the safety and efficacy 
of rIX-FP for routine prophylaxis and on-demand treatment of bleeding episodes in children 
and adults with severe hemophilia B (ie, FIX activity of ≤ 2%). 
1.2.2 Nonclinical Evaluation 
Nonclinical studies of rIX-FP have demonstrated an acceptable safety profile, favorable 
pharmacokinetic (PK) properties and hemostatic efficacy. 
Single and repeat dose nonclinical rIX-FP safety studies have been conducted in rats and 
cynomolgus monkeys.  In both species, the IV administration of rIX-FP, either as a single 

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injection (500 IU/kg) or as a daily injection (up to 500 IU/kg/day) over 28 consecutive days, 
was well tolerated with no toxicologically significant changes [rats: studies APQ0005, 
8244656, and APQ0009 and cynomolgus monkeys: studies APQ0002 and APQ0001].  In both 
species, the no observed adverse effect level for repeat doses of rIX-FP was 500 IU/kg [studies 
APQ0009 and APQ0001], representing at least a 5-fold safety margin over the proposed 
standard clinical dose of rIX-FP.  Repeat dosing was associated with the development of 
antihuman FIX antibodies (rats and cynomolgus monkeys) and antihuman albumin antibodies 
(rats and 1 cynomolgus monkey).   
Studies 
investigating 
local 
tolerance 
[Study 
APQ0008] 
and 
the 
thrombogenic 
potential [Study S22456] of rIX-FP have been conducted in rabbits.  There was no local 
irritation, or treatment-related macroscopic or microscopic pathology findings, irrespective of 
the route of administration of rIX-FP (ie, IV, intra-arterial and perivenous injection).  In 
addition, there was no thrombogenic activity observed in a rabbit venous stasis model (Wessler 
test) at any of the rIX-FP doses tested (75, 150, and 500 IU/kg).   
Nonclinical studies have shown that rIX-FP has favorable PK properties, which might allow 
the reduction of dosing frequency in patients with hemophilia B.   In a PK study in cynomolgus 
monkeys, rIX-FP was administered as a single IV injection at doses of 50 or 100 IU/kg body 
weight [Study APQ0002].  The PK properties of rIX-FP were linear (ie, dose independent) 
over the dose range tested and were independent of sex.  The mean terminal half-life (t1/2) was 
42.2 hours, which is more than 3 times greater than published data for a recombinant human 
FIX product (t1/2 = ~12.7 h) [McCarthy et al., 2002].   Studies in rats, rabbits, and FIX-deficient 
mice have also demonstrated that rIX-FP has improved PK parameters (ie, increased recovery, 
terminal half-life and area under the concentration-time curve [AUC]) compared with 
published results of a currently marketed recombinant FIX product [Metzner at al., 2009].   
The pharmacodynamic activity of rIX-FP has been studied in 2 animal models deficient in FIX 
(dogs and mice).  In the dog model, administration of rIX-FP (100 IU/kg IV) was associated 

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with a shortening of the activated partial thromboplastin time and whole blood clotting time 
[Study 040200011].  In FIX deficient mice, the IV administration of rIX-FP (50, 100, and 200 
IU/kg) was associated with a significant dose-dependent reduction of total blood loss, time to 
hemostasis and activated partial thromboplastin time compared with the control (isotonic 
saline) [Study NBM 04/09].   
Further details on the outcomes of nonclinical studies are available in the 
Investigator’s Brochure for rIX-FP. 
1.2.3 
Previous Clinical Experience 
1.2.3.1 Study CSL654_2001: phase 1, open-label, multicenter, dose-escalation, safety and 
pharmacokinetic study 
The primary study objective of Study CSL654_2001 was to assess the safety of the IV 
administration 
of 
rIX-FP 
in 
previously 
treated 
subjects 
with 
hemophilia 
B 
[Study CSL654_2001].  Subjects (age: 15 to 58 years) were administered a single injection of 
rIX-FP at a dose of either 25 IU/kg (9 subjects), 50 IU/kg (14 subjects), or 75 IU/kg 
(9 subjects).  rIX-FP was well tolerated for the duration of the study.  Of the 25 unique study 
subjects, 3 subjects reported a total of 4 adverse events (AEs) that were possibly related to rIX-
FP treatment.  Two of these AEs (1 subject: a mild headache and feeling hot 50 minutes after 
injection) resolved in 5 to 10 minutes without treatment.  The other 2 AEs (1 subject: mild 
constipation; 1 subject: erythema at injection site), resolved within the same day without 
treatment.  None of the subjects, including 7 subjects exposed to 2 doses of rIX-FP, had 
developed inhibitors to FIX, or antibodies to rIX-FP or albumin 4 weeks after the first injection 
of rIX-FP.   
The study also investigated the PK profile of rIX-FP in 22 subjects.  At an rIX-FP dose of 
50 IU/kg (n = 13), the mean baseline-adjusted incremental recovery (IR) (0 to 30 minutes) was 
higher for rIX-FP compared with both recombinant FIX (46% higher; n = 8) and 
plasma-derived FIX (25% higher; n = 4).  rIX-FP also exhibited an approximately 5-fold longer 

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mean baseline-corrected half-life (mean ± standard deviation [SD]: 91.57 ± 20.74 hours), 7-
fold larger mean baseline-adjusted AUC and 7-fold slower clearance when compared with the 
subject’s previous FIX product.  In addition, rIX-FP maintained a baseline-corrected mean 
trough level of 7.4% and 2.5% at Day 7 and Day 14, respectively, after administration of 
25 IU/kg rIX-FP. 
1.2.3.2 Study CSL654-2004: phase 1/2, open-label, multicenter, pharmacokinetic, safety 
and efficacy study 
Study CSL654_2004 evaluated the safety, PK, and efficacy of rIX-FP for both prophylaxis and 
on-demand treatment of bleeding episodes in subjects with hemophilia B.  A total of 17 male 
subjects were enrolled from hemophilia treatment centers in Israel and Bulgaria; the mean age 
was 26 years (range 13 to 46 years).  The study design consisted of an initial 10 to 14-day PK 
evaluation period, followed by an approximately 11-month safety and efficacy evaluation 
period of both prophylaxis and on-demand treatment of bleeding episodes with rIX-FP.  
Subjects could remain on study and receive rIX-FP treatment until their enrollment in the 
CSL654_3001 study. 
A total of 14/17 (82.4%) subjects reported 46 treatment-emergent AEs, none of which were 
considered related to rIX-FP by the investigator.  All AEs were mild or moderate in severity.  
There were no serious adverse events (SAEs) reported, and there were no withdrawals due to 
AEs.  No inhibitors to FIX were reported, and there were no clinically significant changes in 
serum biochemistry, hematology, urinalysis, or vital signs.  Before dosing with rIX-FP, 
1 subject had positive antibodies to rIX-FP, plasma-derived FIX, and BeneFIX.  However, by 
week 12, this subject tested negative for all antibodies tested (rIX-FP, plasma-derived FIX and 
BeneFIX®).   
All subjects receiving prophylaxis therapy were placed on a weekly (ie, 7-day treatment 
interval) rIX-FP treatment regimen throughout the study.  For each subject, the dose of rIX-FP 
was initially determined based upon the PK profile of rIX-FP and the subject’s bleeding 
phenotype, but could be adjusted at the investigator’s discretion.   The mean FIX consumption 

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was reduced compared with the previous FIX therapy; the mean weekly dose of rIX-FP was 
58.6 ± 10.7 IU/kg during the last 12 weeks of the study, compared with a mean weekly dose of 
their previous product of 87.7 ± 45.8 IU/kg. 
In the prophylaxis treatment group, 8/13 (61.5%) subjects reported a total of 47 bleeding 
episodes that required treatment with rIX-FP.  In the on-demand treatment group (n = 4), all 
subjects (ie, 4 subjects) reported a total of 38 bleeding episodes that required treatment.  All 
bleeding episodes requiring treatment (n = 85) were successfully treated with 1 or 2 doses of 
rIX-FP.  The mean ABR was lower for both spontaneous and total bleeding episodes in the 
prophylaxis group (mean ± SD: spontaneous ABR = 1.3 ± 1.5; total ABR = 4.4 ± 4.7; n = 13) 
compared with the on-demand treatment group (mean ± SD: spontaneous ABR = 21.7 ± 4.0; 
total ABR = 26.8 ± 2.7; n = 4).  The annualized rate of traumatic bleeding episodes was similar 
for the prophylaxis and on-demand treatment groups.  In both treatment groups, there were no 
major bleeding episodes and no maintenance doses of rIX-FP required.   
The PK of rIX-FP were evaluated in 13 subjects receiving either prophylactic or on-demand 
therapy.  After a single IV injection of 25 IU/kg rIX-FP, the mean FIX activity level was 3.75% 
and 2.67% above baseline at Day 7 and Day 14, respectively, and the mean half-life of rIX-FP 
was 95 hours.    
1.2.3.3 Studies CSL654_3001 and CSL654_3002 
Studies CSL654_3001 and CSL654_3002 are pivotal studies that evaluate the PK, safety, and 
efficacy of rIX-FP for the prophylaxis and on-demand treatment of bleeding episodes in 
subjects with hemophilia B.   
Study CSL654_3001, which will enroll approximately 60 subjects (age: 12 to 65 years), will 
consist of an initial 10- to 14-day PK evaluation period.  After this period, subjects will receive 
either prophylaxis therapy or on-demand treatment with rIX-FP: 
Subjects in Arm 1 (approximately 35 subjects) will receive prophylaxis therapy for a
period of approximately 13 months.   Initially, subjects will administer rIX-FP (initial

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dose: 25 to 50 IU/kg) with a treatment interval of 7 days.  After at least 26 weeks of 
prophylaxis therapy, subjects will either switch to a treatment interval of 10 or 14 days, 
or continue using a treatment interval of 7 days.  The dose of rIX-FP will be adjusted for 
each subject to target a trough FIX activity of > 1% between doses.   
Subjects in Arm 2 (approximately 21 subjects) will receive on-demand treatment with
rIX-FP for approximately 26 weeks and then switch to prophylaxis therapy for the
remainder of the study (approximately 30 weeks).  During prophylaxis therapy, subjects
will administer rIX-FP (initial dose: 35 to 50 IU/kg) with a treatment interval of 7 days.
The dose of rIX-FP will be adjusted for each subject to target a trough FIX activity
of > 1% between doses.
Study CSL654_3002, which will enroll approximately 24 subjects (age: < 12 years), will 
consist of an initial 14-day PK evaluation period, and an approximately 11-month (50 exposure 
days [EDs]) treatment period, during which, subjects will receive prophylaxis therapy with 
rIX-FP (initial dose: 35 to 50 IU/kg) administered with a treatment interval of 7 days. 
Both studies (CSL654_3001 and CSL654_3002) will also evaluate the hemostatic efficacy of 
rIX-FP for surgical prophylaxis.   
Study CSL654_3001 began enrolling subjects in February 2012 and Study CSL654_3002 
began enrolling subjects in January 2013. 
1.3
STUDY OVERVIEW 
This is a prospective, open-label study to evaluate the long term safety and efficacy of 
rIX-FP, which is being developed for the prophylaxis and treatment of bleeding episodes in 
subjects with hemophilia B.  The study will include, but not limited to, study subjects who 
were enrolled in either Study CSL654_3001 or CSL654_3002, in addition to the subjects 
requiring major non-emergency surgery who have not previously completed a CSL-
sponsored rIX-FP lead-in study. Previously untreated patients (PUPs), who have never been 
treated with FIX clotting factor products (except previous exposure to blood components) and 

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meet the enrollment requirements may also be enrolled after at least 10 subjects (<12 years of 
age, including a minimum of 5 subjects < 6 years of age) completed 50 EDs and PK 
investigations are completed (as required in EMA guideline).  At the end of this study, 
subjects from the lead-in studies CSL654_3001 or CSL654_3002 are expected to have 
accumulated at least 100 rIX-FP EDs during enrollment in all CSL-sponsored rIX-FP studies.  
During the study, subjects may also participate in the surgical prophylaxis substudy (see 
Appendix 1) or in the subcutaneous (SC) substudy (see Appendix 2).   
This extension study consists of a prophylaxis treatment period (up to approximately 5 years 
for Arms 1, 2 and 3; up to approximately 3 years for Arm 4) during which subjects will 
administer rIX-FP as routine prophylaxis.  During an initial 6-month period, subjects will 
receive prophylactic treatment with rIX-FP administered using the following treatment 
intervals: 
Arm 1: Once every 7, 10, or 14 days (subjects who have completed studies
CSL654_3001 Arm 1 or CSL654_3002, or any other CSL-sponsored rIX-FP [CSL654]
lead-in study).
Arm 2: Once every 7 days (subjects from Study CSL654_3001 Arm 2 with less than 26
weeks of experience with weekly prophylaxis) or once every 14 days (subjects from
Study CSL654_3001 Arm 2 with at least 26-weeks experience with weekly
prophylaxis).
Arm 3: Once every 7 days (subjects who have not previously completed a CSL-
sponsored rIX-FP [CSL654] lead-in study).  No subjects in France may enroll in Arm 3.
After this initial 6-month period, all subjects in Arm 1, 2 and 3 will receive prophylactic therapy 
with rIX-FP administered once every 7, 10, 14, or 21 days for an additional approximately 
30 months.  Subjects in France may not take part in the 21-day treatment regimen. Subjects 
transferring to a 21-day treatment interval must be ≥ 18 years of age.  Any subject transferring 
to a 21-day treatment interval for the first time must have completed at least 6 months of 
prophylactic treatment with a 14-day treatment interval and must undergo an initial PK 

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evaluation period with a single rIX-FP dose of 100 IU/kg.  During the study, a subject may 
undergo additional rIX-FP PK evaluations at the investigator’s discretion or CSL’s request. 
Subjects in Arm 3 who require major non-emergency surgery will undergo an initial PK 
evaluation (100 IU/kg rIX-FP) to determine the incremental recovery and FIX activity.  These 
subjects will then complete the surgery substudy (see Appendix 1) after which they may start 
the prophylaxis treatment period. 
If any subject from a lead-in study requires a major or minor surgical non-emergency procedure 
during the prophylaxis treatment period, the subject may be enrolled in the surgery substudy 
(see Appendix 1).   
Arm 4: During an initial 6-month period, subjects will receive prophylactic treatment with 
rIX-FP administered using once every 7 days as preferred regimen.  Nevertheless, during the 
first 12 months, subjects may also receive on-demand and / or prevention treatment only.   
Subjects in Arm 4 will undergo an rIX-FP (50 IU/kg) PK evaluation at Day 1 as the first dose 
if feasible or during the study after at least 7 days washout from the previous rIX-FP dose, 
when the subject is in non-bleeding state.  
If any Arm 4 subjects require a minor surgical non-emergency procedure during the study, 
the subject may be enrolled in the surgery substudy (see Appendix 1).   
Subcutaneous Substudy (see Appendix 2) 
Subjects enrolled in the SC substudy will be sequentially assigned to a dose cohort (Cohort 1 
[single dose of 25 IU/kg], Cohort 2 [single dose of 50 IU/kg], Cohort 3 [15 doses of 25 IU/kg 
every 3 days], and an optional Cohort 4 [15 doses of ≤ 50 IU/kg every 5 days, with the actual 
dose in this cohort to be determined by CSL based on the PK results from Cohort 3]).   

 
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Subjects will return 2 weeks after their last SC dose for an end of substudy visit to collect the 
final SC PK sample and assess safety. After the end of substudy visit, Cohort 3 and 4 subjects 
will return to their IV rIX-FP prophylaxis regimen in the main study. 
1.4 
POTENTIAL RISKS AND BENEFITS  
The use of a replacement FIX product with a longer half-life and better recovery rate than 
currently available products should enable a longer interval between infusions for patients with 
hemophilia B.  By reducing the burden on patients and physicians treating this disorder, such 
a product may also result in an improvement in patient compliance.  In addition, it may permit 
primary prophylaxis in some young children without requiring the insertion of a venous access 
device. 
Potential risks associated with rIX-FP are expected to be similar to the currently marketed 
recombinant FIX products and include the development of antibodies against FIX and 
development of thromboembolic complications.  In addition, there is a risk of development of 
albumin and CHO cell-derived protein antibodies.  The potential risks associated with 
treatment with rIX-FP are discussed in detail in Section 7.4 of the Investigator’s Brochure. 
The results from the rIX-FP nonclinical program and the data from previous clinical studies, 
support the evaluation of an rIX-FP treatment interval of between 7 and 14 days.  The safety 
and efficacy of rIX-FP (100 IU/kg) using a 21-day treatment interval will also be examined in 
this study.  Given that nonclinical studies in rats and cynomolgus monkeys have shown a no 
observed adverse effect level of 500 IU/kg, there is not expected to be any additional safety 
concerns regarding the use of rIX-FP at a dose of 100 IU/kg.  There is a risk that administration 
of rIX-FP at a treatment interval of 21 days might be less effective at preventing bleeds than 
when administered at a treatment interval of 14 days or less.  However, the PK evaluation of 
rIX-FP at a dose of 100 IU/kg will provide information on the trough FIX activity level using 
this dose of rIX-FP.  In addition, prophylaxis treatment using a 21-day treatment interval will 
only be available to subjects ≥ 18 years of age and who have completed at least 6 months of 
prophylaxis treatment with a 14-day treatment interval, with subjects in France excluded.  If 

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subjects do not benefit from a treatment interval of 21 days, they will be able to transfer to the 
7-, 10-, or 14-day treatment interval at any time, at the discretion of the investigator. 
This study will document all key safety factors including immunogenicity, thrombogenicity, 
hypersensitivity, and other AEs in the intended therapeutic population. 
Thus, the associated benefit-risk assessment of the study is acceptable for subjects enrolled in 
the study. 

 
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2. 
STUDY OBJECTIVES AND ENDPOINTS 
2.1 
PRIMARY OBJECTIVE AND ENDPOINT 
2.1.1 
Primary Objective 
The primary objective of this study is to evaluate the safety of rIX-FP as measured by new 
cases of inhibitors against FIX in subjects, including PUPs, with severe hemophilia B. The 
PK parameters in PUPs will also be collected.  
2.1.2 
Primary Endpoints 
 The total number of subjects who develop inhibitors against FIX during the 
approximately 3-year participation in this study. 
 PK parameter of incremental recovery (IU/dL per IU/kg) of 50 IU/kg rIX-FP (Arm 4 
only). 
2.2 
SECONDARY OBJECTIVES AND ENDPOINTS  
2.2.1 
Secondary Objectives 
The secondary objectives of the study are: 
 To evaluate the efficacy of rIX-FP routine prophylaxis when administered at various 
treatment intervals. 
 To compare the efficacy of rIX-FP routine prophylaxis between 2 different treatment 
intervals and versus on-demand treatment.   
 To further evaluate the safety of rIX-FP. 
 To evaluate the efficacy of treatment for bleeding episodes in PUPs. 
2.2.2 
Secondary Endpoints 
 Annualized bleed rate (ABR) for spontaneous treated and total treated bleeds for each 
assigned treatment interval (7 days, 10 days, 14 days, and 21 days). 

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Comparison of the annualized spontaneous bleeding rate (AsBR) and ABRbetween:
o
14-day routine prophylactic treatment in this study compared with on-demand only
treatment from Study CSL654_3001 Arm 2.
o
7-day prophylaxis regimen with the 14-day prophylaxis regimen.
o
7-day prophylaxis regimen with the extended prophylaxis regimen (10-day or 14-
day).
Consumption of rIX-FP during routine prophylaxis expressed as IU/kg per month per
subject.
Incidence of AEs and related AEs to rIX-FP over the course of the study.
Hemostatic response to treatment of bleeding episodes with rIX-FP in PUPs as assessed
by the investigator based on a 4-point scale (Arm 4 only).
CCI
CCI
CCI

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CCI

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3.
STUDY DESIGN
3.1
STUDY DESIGN AND RATIONALE 
This is a multicenter, open-label, phase 3b study to investigate the long-term safety and efficacy 
of rIX-FP for the routine prophylaxis and on-demand treatment of bleeding episodes in subjects 
with hemophilia B.  Subjects will be eligible to enter the study if they have completed studies 
CSL654_3001 or CSL654_3002, or any other CSL-sponsored rIX-FP (CSL654) study and 
meet all other eligibility criteria.  In addition, subjects who have not previously completed a 
CSL-sponsored rIX-FP lead-in study may be eligible to enter the study if they require major 
non-emergency surgery and meet all other eligibility criteria, or if they are PUPs who meet the 
eligibility criteria.  
Figure 1. Study Overview 

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1. Subjects from studies CSL654_3001 Arm 1, CSL654_3002, and subjects who have completed any other
CSL-sponsored rIX-FP study are to participate in Arm 1 of the study.
2. Following the initial 6-month treatment period, all subjects may continue to use the same treatment interval,
or change to 7, 10, or 14 days.  Subjects ≥ 18 years of age, who have completed at least 6 months of
prophylaxis treatment with a 14-day treatment interval, may also change to a 21-day treatment interval (not
applicable for France).  The treatment interval may be changed at each 6-month follow-up assessment or
earlier if deemed medically necessary by the investigator.  Subjects must undergo an initial
pharmacokinetics evaluation with a single injection of rIX-FP (100 IU/kg) before starting treatment with a
21-day treatment interval for the first time (Subjects in France may not be assigned to a 21-day treatment
regimen). Dose of rIX-FP administered for routine prophylaxis regimens is to be based on the subject’s
previous response to rIX-FP therapy and / or FIX trough activity. During routine prophylaxis therapy,
subjects may also administer rIX-FP as on-demand (OD) therapy for bleeding episodes and may enroll in the
surgery substudy (see Appendix 1) if they require a major or minor non-emergency surgical procedure.
3. Treatment interval (7, 10, or 14 days) for each subject to be determined by the investigator based on the
treatment interval used in the lead-in study and / or investigator and subject preference.
4. All subjects who participated in Arm 2 of the CSL654_3001 lead-in study and who have < 26 weeks
experience with a 7-day treatment interval at the start of this extension study are to continue a 7-day
treatment interval for the first 6 months of the study or until they have accumulated ≥ 26 weeks experience
with a 7-day treatment interval.  At the end of this period, subjects in this group will be encouraged to switch
to a 14-day treatment interval for a period of at least 6 months.
5. All subjects who participated in Arm 2 of the CSL654_3001 lead-in study and who have ≥ 26 weeks
experience with a 7-day treatment interval at the start of this extension study are to start a 14-day treatment
interval for the first 6 months of the study.
6. Subjects in Arm 3 (no subjects in France may participate in Arm 3) must undergo an initial rIX-FP
pharmacokinetics evaluation before starting the surgery substudy. No subjects from France may enroll in
Arm 3.
7. After completion of the surgery substudy, subjects may begin prophylaxis treatment with a 7-day treatment
interval. Subjects in Arm 3 who require physical therapy (ie, rehabilitation after surgery), may administer
rIX-FP as preventative treatment (no more than once per week) in addition to the administration of rIX-FP as
routine prophylaxis. Preventative treatment before physical therapy is permitted only during the first 3
months of the treatment period.
8. Subjects in Arm 4 will administer rIX-FP as weekly prophylaxis and / or on-demand, prevention during the
first 12 months, and then on weekly routine prophylaxis until completing 50 EDs.  Subjects who complete
50 EDs are permitted to continue weekly routine prophylaxis with rIX-FP until the completion of the study..
3.1.1 
Routine Prophylaxis: First 6 Months 
Arm 1: Subjects from all lead-in studies (excluding CSL654_3001 Arm 2)  
During the first 6 months, subjects in Arm 1 will administer rIX-FP as routine prophylaxis 
either using the same treatment interval as in the lead-in study or using a different treatment 
interval of 7, 10, or 14 days, as determined by the investigator.  The dose of rIX-FP 
administered will be based on the subject’s previous response to rIX-FP therapy and / or trough 
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Arm 2 
Subjects from lead-in Study CSL654_3001 Arm 2 who have ≥ 26 weeks experience with rIX-FP
prophylaxis therapy with a 7-day treatment interval 
During the first 6 months, subjects in this group will administer rIX-FP (75 IU/kg) as routine 
prophylaxis using a treatment interval of 14 days. 
Subjects from lead-in Study CSL654_3001 Arm 2 who have < 26 weeks experience with
prophylaxis rIX-FP therapy with a 7-day treatment interval 
During the first 6 months, subjects in this group will administer rIX-FP as routine prophylaxis 
using a treatment interval of 7 days.  The dose of rIX-FP administered will be the same as the 
dose used by the subject for routine prophylaxis in the lead-in study (see Section 6.2.1).   
After a subject has accumulated at least 26 weeks experience with prophylaxis rIX-FP therapy 
(ie, lead-in study and current study combined), they may switch to a 14-day treatment interval 
or continue using a 7-day treatment interval until completion of the initial 6-month period.  
Subjects should attend an unscheduled visit and complete assessments as specified for the 
6-month visit if they are to switch to a 14-day treatment interval before completion of the
6-month period.  Under such circumstances, the 3-month visit may be omitted.
Arm 3 (Does not include any subjects in France)
Upon completion of the surgery substudy, subjects in Arm 3 may begin the prophylaxis 
treatment period in the main study.  During the first 6 months, subjects will administer rIX-FP 
as prophylaxis using a treatment interval of 7 days.  The dose (25 to 50 IU/kg) of rIX-FP 
administered will be based on the subject’s trough FIX activity (see Section 6.2.1).  During the 
first 3 months of the treatment period (ie, after surgery), subjects may also administer rIX-FP, 
no more than once per week, as a preventative treatment before physical therapy, if needed (see 
Section 3.2.3).    
Arm 4
Subjects in Arm 4 will administer rIX-FP as weekly prophylaxis and / or on-demand, 
prevention during the first 12 months, and then on weekly routine prophylaxis until completing 

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50 EDs.  Subjects who complete 50 EDs are permitted to continue weekly routine prophylaxis 
with rIX-FP until the completion of the study. The dose (25-50 IU/kg initially, up to 75 IU/kg) 
of rIX-FP administered will be based on the subject’s clinical response, PK information or FIX 
trough activity. 
3.1.2 
Routine Prophylaxis: 6 Months to End of Treatment Period 
After completion of the initial 6-month treatment period, subjects from Arms 1, 2 and 3 will 
administer rIX-FP as routine prophylaxis using a treatment interval of 7, 10, or 14 days for the 
remainder of the study.  Subjects from lead-in Study CSL654_3001 Arm 2, who were using a 
7-day treatment interval during the previous 6 months, will switch to a 14-day treatment
interval for at least 6 months.
From 6 months onwards, subjects (Arm 1, 2 and 3) may use the same treatment interval or they 
may change treatment interval in consultation with the investigator at any of the subsequent 
6-month follow-up visits (see Section 3.2.1.2).  For the first 12 months of the study, subjects
in Arm 4 are encouraged, but not required, to be on weekly prophylaxis. The dose of rIX-FP
administered will be between 35 and 75 IU/kg (see Section 6.2.1).
Subjects ≥ 18 years of age may also administer rIX-FP as routine prophylaxis using a 21-day 
treatment interval at a dose of 100 IU/kg.  Subjects in France may NOT switch to a routine 
prophylaxis regimen using a 21-day treatment interval. Subjects < 18 years of age are not 
permitted to use a treatment interval of 21 days. 
Subjects who transfer to a 21-day treatment interval for the first time must have completed at 
least 6 months of prophylaxis treatment with a 14-day treatment interval and have undergone 
PK evaluation with 100 IU/kg rIX-FP (see Section 3.1.3). 
3.1.3 
Pharmacokinetic Evaluation of rIX-FP (100 IU/kg) 
Subjects must undergo a PK evaluation with a single injection of rIX-FP (100 IU/kg) if either 
1) they are in Arm 3 (excludes subjects in France) or 2) they intend to begin administering rIX-

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FP as routine prophylaxis using a 21-day treatment interval for the first time.  The PK 
evaluation should be performed after a washout period of either at least 4 days for a current 
marketed FIX product (Arm 3) or at least 14 days for rIX-FP.  Samples for PK evaluation will 
be collected before administration of rIX-FP, 30 minutes after the completion of the injection 
(to evaluate peak FIX activity level and incremental recovery) and at specified time points after 
injection (see Table B - Schedule of Assessments: Pharmacokinetic Period).      
3.1.3.1
Pharmacokinetic Evaluation of rIX-FP as Needed 
The investigator may also choose to complete a PK assessment of 50, 75 or 100 IU/kg (as 
appropriate) rIX-FP with selected time points before starting surgical prophylaxis with rIX-FP 
(for subjects from lead-in studies), at the investigator’s discretion or CSL’s request, or in the 
event of (but not limited to) poor efficacy or suspicion of inhibitor development. Subjects in 
France may be discontinued from receiving the study product and participating in any further 
study procedures if the subject is confirmed to have developed an inhibitor against FIX with a 
titer > 5 BU/mL. 
3.1.3.2
Pharmacokinetic Evaluation of rIX-FP for Arm 4 
For Arm 4 subjects, a PK assessment of 50 IU/kg rIX-FP with selected time points (Table B - 
Schedule of Assessments: Pharmacokinetic Period) or incremental recovery is to be done only 
at the beginning of the study, and also may be done at the investigator’s discretion at any time. 
3.1.4 
On-demand Treatment of Bleeding Episodes 
During the study, on-demand treatment with rIX-FP will be used for all bleeding episodes 
requiring treatment.  The dose of rIX-FP will be determined by the investigator, based on the 
subject’s previous experience during the lead-in study or this study, and the dose and / or 
maintenance dose required to achieve and maintain the FIX activity level recommended by the 
World Federation of Hemophilia (WFH) (see Section 3.2.2 for further details) or the 
investigator’s local hospital treatment guidelines. 

 
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3.1.5 
Preventative Treatment Before Vigorous Physical Activity or Physical Therapy 
During the study, subjects may also administer rIX-FP as a single injection immediately before 
vigorous physical activity that, in the subject’s experience, is likely to result in bleeding or 
before physical therapy (ie, rehabilitation after surgery) (see Section 3.2.3).  The recommended 
dose of rIX-FP is between 35 and 50 IU/kg, administered as a single injection. 
3.1.6 
Surgical Prophylaxis 
All subjects in Arm 3 (excludes subjects in France) should start the surgery substudy (Appendix 
1) within 8 weeks from receiving the first rIX-FP injection (ie, during the PK evaluation 
period).  
If a subject in either Arms 1 or 2 requires major or minor non-emergency surgery or subject in 
Arm 4 requires minor surgery during the study, the subject may also be enrolled in the surgery 
substudy.  A major surgery is defined as a surgical procedure that involves anesthesia (general, 
spinal, epidural, or regional block) or respiratory assistance or one that requires hemostatic 
support for a period exceeding 5 consecutive days (including but not limited to orthopedic and 
cardiac surgery) [Srivastava et al., 2013].  However, some common surgeries (such as 
permanent venous access placement or removal, circumcision and some simple dental 
procedures) for the subjects in Arm 4 may not be able to be avoided, therefore, they may be 
permitted in consultation with the CSL medical monitor.  Details of the surgery substudy, 
including study design, visit schedules and study assessments are presented in Appendix 1. 
If a subject requires an extremely minor surgical procedure during the study (ie, a procedure 
that would be expected to require only a maintenance dose of rIX-FP after the procedure), the 
subject may be administered a single prophylaxis injection of rIX-FP before the surgery, 
without enrollment into the surgery substudy.  
3.1.7 
Subcutaneous Substudy 
See Appendix 2 for details.  

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3.2
DOSE AND DOSING REGIMEN 
3.2.1 
Routine Prophylaxis Treatment 
3.2.1.1
rIX-FP Treatment Interval 
During the first 6 months of the study, subjects or their caregivers will administer rIX-FP as 
routine prophylaxis using the following treatment intervals: 
Arm 1: 7, 10, or 14 days.
Arm 2: 7 or 14 days.
Arm 3: 7 days. (No subjects in France may participate in Arm 3)
Arm 4: 7 days (preferred for the first 12 months of the study; required after the first 12
months of the study).
For subjects in Arm 1, the treatment interval will be chosen by the investigator at the beginning 
of the study based on the subject’s previous experience (ie, during the lead-in study) and subject 
preference.   
For subjects in Arm 2, the treatment interval will be based on the duration of their prophylaxis 
treatment in the lead-in study; a 14-day treatment interval will be assigned to subjects who 
completed at least 26 weeks of prophylaxis treatment during the lead-in study and a 7-day 
treatment interval will be assigned to subjects who did not complete at least 26 weeks of 
prophylaxis treatment during the lead-in study.  Subjects in Arm 2 who start on a 7-day 
treatment interval and complete a total (ie, during the lead-in study and this study) of at least 
26 weeks of prophylaxis treatment, should then switch to a 14-day treatment interval for a 
period of at least 6 months.   
Upon completion of the surgery substudy, subjects in Arm 3 (not applicable to France) may 
begin the prophylaxis treatment period in the main study.  During the first 6 months, subjects 
in this group will administer rIX-FP as routine prophylaxis using a treatment interval of 7 days.  
The dose (25 to 50 IU/kg) of rIX-FP administered will be based on the subject’s trough FIX 
activity (see Section 6.2.1). 

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At the end of the initial 6-month period, subjects in Arm 1, 2 and 3 may remain on their current 
treatment interval or they may be switched to a 7, 10, or 14-day treatment interval.  Subjects 
≥ 18 years of age may also be switched to a 21-day treatment interval after completing at least 
6 months of a 14-day prophylaxis regimen and a 100 IU/kg rIX-FP PK evaluation period (see 
Section 3.1.3). Subjects in France may NOT switch to a routine prophylaxis regimen using a 
21-day treatment interval.
3.2.1.2
Changing the rIX-FP Treatment interval (subjects in Arm 1, 2 and 3) 
During each 6 months of the treatment period, the treatment interval should not be changed 
unless deemed necessary by the investigator for the subject’s safety (with the exception of 
subjects from lead-in Study CSL654_3001 Arm 2 who have <26 weeks experience with 
prophylaxis rIX-FP therapy with a 7-day treatment interval).  At the end of each 6-month period 
(ie, at the 6 month, 12 month, etc follow-up visits) the investigator may choose to change the 
treatment interval based on their assessment of efficacy / safety, subject treatment compliance, 
and / or subject preference. 
3.2.1.3
Changing the rIX-FP Treatment interval (subjects in Arm 4) 
During the first 12-month period, subjects in Arm 4 are encouraged, but not required to be on 
weekly prophylaxis regimen with rIX-FP.  At the end of the initial 12-month period, subjects 
are required to be on a weekly prophylaxis regimen for rest of the study.   
3.2.1.4
rIX-FP Dose 
The dose of rIX-FP administered for routine prophylaxis will be based on the subject’s previous 
experience (ie, during a lead-in study) and / or the targeted FIX activity trough level (target 
FIX activity level > 2%, but optimally, between 5% and 15%).  The FIX activity trough level 
must not be targeted to ≥ 20% without approval from CSL. 
The maximum dose of rIX-FP for routine prophylaxis will be 50 IU/kg per injection for 
subjects using a 7-day treatment interval and 75 IU/kg per injection for subjects using a 10- or 
14-day treatment interval (Table 1), unless a higher dose for a given subject is approved by

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CSL.  The dose of rIX-FP will be 100 IU/kg per injection for subjects using a 21-day treatment 
interval (Table 1).  For all treatment intervals, the total dose of rIX-FP administered for routine 
prophylaxis over a 28-day period is not to exceed 250 IU/kg, without approval from CSL.  
Table 1. 
Dose Guidelines for Routine Prophylaxis Treatment 
Treatment interval 
7 Days 
10 Days 1 
14 Days 
21 Days 
Suggested dose (IU/kg) 
25 to 50 
50 to 75 
75 
100 
Maximum dose (IU/kg) 
50 2
75 
75 
100 
1. The 10-day treatment interval may be based on a schedule of once every 10 calendar days or 3 times a month
(ie, 1st, 11th and 21st day of each month).
2. An rIX-FP dose higher than 50 IU/kg is acceptable if the FIX activity trough level is < 5% at Day 7 and a
higher trough level is necessary to prevent spontaneous bleeding.
3.2.2 
On-demand Treatment of Bleeding Episodes 
On-demand treatment with rIX-FP will be used for all bleeding episodes requiring treatment.  
If a subject experiences a bleeding episode, rIX-FP should be administered within 4 hours after 
the start of the bleeding episode.  The dose of rIX-FP will be determined by the investigator, 
based on the effective on-demand treatment dose used in the lead-in study and / or the subject’s 
PK data with a minimum rIX-FP dose of 35 IU/kg and a maximum dose of 75 IU/kg.  After 
hemostasis is achieved, maintenance dose(s) of rIX-FP may be prescribed at the discretion of 
the investigator.   
Subjects receiving on-demand treatment for a bleeding episode should maintain or delay (but 
not skip) the prophylaxis treatment schedule, at the investigator’s discretion.  The window 
between the last treatment for the bleeding episode and the next prophylaxis injection should 
not be longer than the number of days of the current treatment interval (ie, 7, 10, 14, or 21 days).  
In addition, any two injections of rIX-FP should be at least 24 hours apart. 

 
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3.2.3 
Prevention Before Vigorous Physical Activity or Physical Therapy 
During the study, subjects may administer rIX-FP as a preventative treatment before vigorous 
physical activity or before physical therapy (ie, as a part of rehabilitation after major surgery) 
that, in the subject’s experience, is likely to result in bleeding.  rIX-FP should be administered 
as preventative treatment at a dose of 35 to 50 IU/kg, as determined by the investigator based 
on the subject’s previous experience.   
Preventative treatment should be administered in addition to routine prophylactic treatment (ie, 
subjects administering rIX-FP as a preventative treatment should maintain the routine 
prophylaxis treatment schedule) or may be combined with on-demand regimen (may combine 
with prevention doses) during the first 12 months in Arm 4 subjects only. 
Prevention Before Vigorous Physical Activity 
Preventative treatment before vigorous physical activity should not be used more frequently 
than once per month. If more frequent treatment is required (eg, because of participation in 
regular sporting activities), the treatment interval or dose used for prophylaxis treatment should 
be adjusted, as appropriate (eg, reduction of the treatment interval from 14 days to 7 days or 
increase in the rIX-FP dose if the subject is using a 7-day treatment interval).   
Prevention Before Physical Therapy 
Preventative treatment before physical therapy should not be used more frequently than once 
per week during the first 3 months of either starting the prophylaxis treatment period (subjects 
in Arm 3) or returning to routine prophylaxis (subjects in Arms 1 or 2). After this 3-month 
period, preventative treatment should not be used more often than once per month. 
3.3 
PLANNED STUDY DURATION 
For subjects in Arms 1, 2, and 3, the duration of the study for an individual subject is expected 
to be approximately 5 years or the time it takes to achieve a total of 100 EDs during enrollment 
in any CSL-sponsored rIX-FP studies. For subjects in Arm 4, the duration of the study is 
expected to be approximately 3 years or the time it takes to achieve a total of 50 EDs. 

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The overall study duration (ie, first subject’s first visit to the last subject’s end of study visit) 
is expected to be approximately 5 years.  The study may end after 100 EDs of rIX-FP have 
been achieved in ≥ 50 subjects overall for rIX-FP (ie, treatment received across all studies).  
The study may be stopped at a specific study site after all subjects at the site have either 
completed the 5-year study period, or ≥ 50 subjects overall have achieved a total of 100 EDs, 
or after regulatory approval and rIX-FP becomes commercially available in the respective 
country. 
3.4 
PLANNED NUMBER OF SITES 
The study is planned to be conducted at approximately 40 study sites worldwide.  
3.5
PLANNED NUMBER OF SUBJECTS 
This study will enroll approximately 96 male subjects, including all eligible subjects from 
CSL-sponsored rIX-FP (CSL654) lead-in studies, approximately 10 subjects who require 
major non-emergency surgery and at least 13 PUPs.   
3.6
STUDY MONITORING PROCEDURES 
3.6.1 
Independent Data Monitoring Committee 
The Independent Data Monitoring Committee (IDMC) is an independent expert advisory group 
consisting of three medically qualified persons with appropriate expertise in subjects with 
hemophilia B, in the treatment with FIX replacement therapy and / or evaluation of AEs and 
laboratory results relevant for detecting any possible safety issues, and one statistician.  An 
IDMC is being utilized to provide an independent evaluation of the study at predefined 
intervals with regard to the progress of Arm 4 of the study and the safety data, namely for the 
incidence, frequency, and nature of AEs and bleeding events.  Meetings will be held 
approximately every 6 months, with ad hoc meetings scheduled as needed, including after 
every newly confirmed inhibitor (≥ 0.6 BU/mL) and / or severe allergic reaction in Arm 4 
subjects.  The initial meeting will occur after the first 5 PUP subjects have been dosed and 

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reached the Month 1 FIX inhibitor evaluation, or there is a confirmed inhibitor or severe 
allergic reaction. 
3.6.2 
Other Monitoring Committees 
3.6.2.1
CSL Safety Management Team 
The primary goal of the CSL Safety Management Team (SMT) is to minimize risk to subjects 
in clinical trials.  The SMT supports the Global Clinical Safety and Pharmacovigilance group 
in the evaluation of safety-related information and makes decisions to accomplish this goal.  
Core membership includes representatives from the following groups: Global Clinical Safety 
and Pharmacovigilance (ie, Clinical Safety Physician, Clinical Safety Scientist), Clinical 
Development (ie, Clinical Program Director, Medical Monitor, and Clinical Scientist), Clinical 
Operations and Biostatistics. The SMT is responsible for the identification and evaluation of 
safety issues, risk management, and risk communication.  Meetings will be held approximately 
every 3 months, with ad hoc meetings scheduled as needed, including after every newly 
confirmed inhibitor in Arm 4.   
3.6.2.2
Safety Review Committee in the Subcutaneous Substudy 
See Appendix 2, sections “Study Design and Rationale” and “Study Monitoring Procedures” 
for details. 
4.
SELECTION AND WITHDRAWAL OF SUBJECTS
4.1
ELIGIBILITY CRITERIA 
The study population will be selected on the basis of the inclusion and exclusion criteria 
described in the sections below.  Subject eligibility should be reviewed and documented by an 
appropriately medically qualified member of the investigator’s study team before subjects are 
included in the study. 

 
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4.1.1 
Inclusion Criteria 
Subjects meeting all of the following inclusion criteria may be enrolled into the study 
(However, subject(s) in France will NOT be eligible to be enrolled into Arm 3 of the study): 
 Arms 1, 2, 3 and 4: Written informed consent for study participation obtained before 
undergoing any study-specific procedures. 
 Arms 1 and 2: Completed a CSL-sponsored rIX-FP (CSL654) study, including studies 
CSL654_3001 or CSL654_3002.    
 Arms, 1, 2, 3 and 4: Investigator believes that the subject or subject’s parent(s) or 
legally acceptable representative(s) is willing and able to adhere to all protocol 
requirements including correct use of the electronic diary (eDiary). 
Arm 3 only (No subjects in France may enroll in Arm 3):  
 Scheduled to have a major non-emergency surgery within approximately 8 weeks from 
the anticipated date of receiving the first rIX-FP injection.  
 Not previously completed a CSL-sponsored rIX-FP lead-in study. 
 Male subjects, 12 to 70 years of age. 
 Documented severe hemophilia B (FIX activity of ≤ 2%), or confirmed at screening by 
the central laboratory. 
 Subjects who have received FIX products (plasma-derived and / or recombinant FIX) 
for > 150 exposure days (EDs), confirmed by their treating physician. 
 No confirmed history of FIX inhibitor formation (defined as two consecutive positive 
tests –requiring a confirmatory test on a second separately drawn blood sample shortly 
after the previous positive test), no confirmed detectable inhibitors (defined as 
< 0.6 Bethesda units [BU]/mL) at screening by the central laboratory, and no family 
history of inhibitor formation against FIX. 
Arm 4 only:  
 Male, up to 18 years of age. 
 Documented severe hemophilia B (FIX activity of ≤ 2%), or confirmed at screening by 
local or central laboratory. 

 
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 Subjects who have never been treated with FIX clotting factor products (except previous 
exposure to blood components). 
 No confirmed history of FIX inhibitor formation.  
4.1.2 
Exclusion Criteria 
Subjects meeting any of the following exclusion criteria must not be enrolled into the study 
(However, subject(s) in France will NOT be eligible to be enrolled into Arm 3 of the study): 
All subjects: 
 Arms 1, 2, 3 and 4: Currently receiving a therapy not permitted during the study, as 
defined in Section 7.3. 
 Arms 1 and 2 only: Unwilling to participate in the study for a total of 100 EDs. 
 Arms 1, 2, 3 and 4: Any issue that, in the opinion of the investigator, would render the 
subject unsuitable for participation in the study. 
Arm 3 only (No subjects in France may enroll in Arm 3):  
 Known hypersensitivity (allergic reaction or anaphylaxis) to any FIX product or hamster 
protein. 
 Known congenital or acquired coagulation disorder other than congenital FIX 
deficiency. 
 Currently receiving IV immunomodulating agents such as immunoglobulin or chronic 
systemic corticosteroid treatment. 
 Platelet count < 100,000/µL at screening. 
 Human immunodeficiency virus-positive subjects with a CD4 count < 200/mm3.  A 
human immunodeficiency virus-positive subject may participate in the study and receive 
antiviral therapy at the discretion of the investigator. 
 Serum aspartate aminotransferase (AST) or serum alanine aminotransferase (ALT) 
concentration > 5 x ULN at Screening. 
 Serum creatinine concentration > 2 x ULN at Screening. 
 Evidence of thrombosis, including deep vein thrombosis, stroke, myocardial infarction 
or arterial embolus within 4 months before the first administration of rIX-FP. 

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Use of any investigational medicinal product other than rIX-FP within 4 weeks before
the first administration of rIX-FP.
Arm 4 only: 
Known congenital or acquired coagulation disorder other than congenital FIX
deficiency (except for vitamin K deficiency of the newborn).
Known kidney or liver dysfunction or any condition which, in the investigator’s
opinion, place the subject at unjustifiable risk.
Use of any investigational medicinal product within 4 weeks before the first
administration of rIX-FP.
If a subject experiences a life-threatening bleeding episode or requires a major surgical
procedure before the first administration of rIX-FP.
4.2
SUBJECT WITHDRAWAL 
4.2.1 
Subject Withdrawal 
Subjects may withdraw from the study at any time at their own request, or they may be 
withdrawn at any time at the discretion of the investigator or CSL for safety, behavioral or 
administrative reasons (eg, due to an AE, protocol violation, loss to follow-up, subject 
noncompliance, and study termination).   
In accordance with the International Conference on Harmonisation (ICH) principles of Good 
Clinical Practice (GCP) the investigator always has the option to advise a subject to withdraw 
from the study if the subject's safety or well-being is compromised by his further participation 
in the study.  Concern for the interests of the subject must always prevail over the interests of 
the study.   
Subjects may be discontinued from receiving the study product and participating in any further 
study procedures if: 
Subjects in France may be discontinued from receiving the study product and
participating in any further study procedures if the subject is confirmed to have

 
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developed an inhibitor against FIX with a titer > 5 BU/mL. Alternatively, at the 
investigator’s discretion, a subject who develops inhibitors to rIX-FP may remain in the 
study until a better treatment option becomes available to the subject or until the end of 
study visit, whichever comes first.  
 The subject uses a marketed FIX during the study, except when rIX-FP is not available 
and / or if a marketed FIX is required as rescue medication.   
 The subject does not comply with the assigned treatment schedule or is, in the opinion 
of the investigator and / or CSL, delinquent or delayed in using the eDiary. 
 For subjects in Arm 3 only (not applicable to France: if a major non-emergency 
surgical procedure is not performed within approximately 8 weeks of starting the rIX-FP 
(100 IU/kg) PK evaluation period, CSL may request the subject to be rescreened or 
withdrawn from the study. 
 For subjects in Arm 4 only: if a major surgery (except permanent venous access 
placement or removal, circumcision and some non-complicated unavoidable dental 
procedures) is required during the study or severe hypersensitivity or inhibitor to FIX 
(titer > 5 BU/mL) occurred, the subject should be withdrawn from the study.   
If a subject is withdrawn from the study or further participation is declined, they will continue 
to have access to medical care and will be treated as per routine medical practice. 
4.2.2 Procedures for Handling Withdrawals 
If a subject declines further participation or is withdrawn from the study, attempts will be made 
to complete and document the end of study assessments.  If the subject is withdrawn from the 
study after receiving rIX-FP, every effort will be made to ensure that the relevant safety 
assessments are completed.  The subject may also be asked by the investigator to complete 
other study assessments. 
If the subject withdraws from the study, and also withdraws consent for disclosure of future 
information, CSL may retain and continue to use any data collected before such withdrawal of 
consent. 

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In the event that a subject withdraws from the study, the investigator should record the reason 
and date of withdrawal in the electronic case report form (eCRF) and in the subject's medical 
records. 
4.2.3 
Replacement Policy 
Subjects in Arms 1 or 2 withdrawn from the study will not be replaced. Subjects in Arm 3 
withdrawn from the study before completing the surgery substudy may be replaced. Subjects 
in Arm 4 withdrawn prior to completing 50 EDs may be replaced.  
5.
STUDY INTERVENTIONS
5.1
DESCRIPTION OF INVESTIGATIONAL PRODUCT 
5.1.1 
Recombinant fusion protein linking coagulation factor IX with albumin 
(rIX-FP) 
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5.1.2
Comparator Product 
Not applicable. 
5.2
PACKAGING, LABELING, SUPPLY AND STORAGE 
5.2.1
Packaging and Labeling 
rIX-FP will be packaged and labeled according to current ICH Good Manufacturing Practice 
and GCP guidelines, and national legal requirements. 
5.2.2
Supply and Storage 
rIX-FP will be supplied to the study sites.  rIX-FP must be stored at the investigator site under 
temperature-monitored conditions in a secure storage area as specified in the Investigator 
Manual. 
Instructions for the storage and handling of rIX-FP at the subject’s home are described in the 
Investigator Manual. 
5.3
ACCOUNTABILITY AND DESTRUCTION 
All supplies of rIX-FP must be accounted for throughout the study.  Drug inventory and 
accountability logs / reports, dated and signed by the investigator or delegate (eg, pharmacist), 
must be retained at the study site as verification of final accountability of rIX-FP.  For Japan
sites only, the drug inventory and accountability logs / reports must be dated and signed by the 
head of the medical institute or the study drug storage manager (if assigned by the head of 
medical institute). 
Information on the accountability, return and destruction of rIX-FP is provided in the site’s 
Investigator Manual. 
5.4
OTHER INTERVENTION(S) 
Not applicable. 

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5.5
RESCUE THERAPY 
A marketed FIX concentrate may only be used as rescue medication for the treatment of a 
bleeding episode when rIX-FP is not available or in the event that hemostatic control is not 
achieved after at least 2 injections of rIX-FP. 
6.
ALLOCATION, DOSING AND ADMINISTRATION
6.1
ALLOCATION TO TREATMENT 
6.1.1 
Subject Assignment 
After providing written informed consent, the subject will be issued with a unique subject 
identification number.  Subjects in Arms 1 or 2 will be issued with the identification number 
that was assigned in the lead-in study. Subjects in Arms 3 (excludes subjects in France) and 4 
will be issued with a new unique identification number. The subject identification number will 
be used to identify the subject for the duration of the study.  Subject identification numbers 
will not be reassigned or reused.   
6.1.2 
Randomization Procedures 
Not applicable. 
6.1.3 
Blinding Procedures 
Not applicable. 
6.2
DOSING AND ADMINISTRATION 
The investigator (or delegate) will administer or dispense rIX-FP only to subjects included in 
this study or their caregivers following the procedures set out in this study protocol.  Subjects 
or their caregivers or qualified study personnel will administer the rIX-FP as a bolus IV 
injection.  For subjects in Arm 4, the rate of administration should be at approximately 200  IU 

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per minute in young children or determined by the subject’s comfort level at investigator’s 
discretion. 
In the SC substudy, subjects will be sequentially assigned to a dose cohort, and receive a single 
SC dose of rIX-FP (25 IU/kg in Cohort 1; 50 IU/kg in Cohort 2) or repeated SC doses of rIX-
FP (25 IU/kg every 3 days in Cohort 3; ≤ 50 IU/kg every 5 days in optional Cohort 4, with the 
actual dose in this cohort to be determined by CSL based on the PK results from Cohort 3).  
See Appendix 2 for details. 
rIX-FP is supplied in single-use vials, which contain nominally 
The actual IU, which is printed on the rIX-FP vial label, will be used for the calculation and 
documentation of each dose of rIX-FP.  
When making the dose calculation, the total actual units (ie, as per the prescribed dose) may 
be rounded up or down to target full vials (as actual IU), if possible, but the final dose needs to 
be within 10% of the prescribed dose.  The dose of rIX-FP is based on the subject’s most 
current body weight as recorded in the eCRF.  
6.2.1 
Adjustment of Dose for Prophylaxis and On-demand Treatment 
The dose of rIX-FP required for either prophylaxis or on-demand treatment will be based on 
the subject’s previous experience (ie, during Study CSL654_3001 or CSL654_3002) and / or 
the target FIX activity.  The following formula will be used to calculate dose based on FIX 
activity: 
Number of 
factor IX IU 
required (IU) 
= 
Body 
weight 
(kg) 
X 
Desired 
factor IX 
increase  
(% or IU/dL) 
X 
Reciprocal of 
observed recovery 
(IU/kg per IU/dL) 
The target trough FIX activity for routine prophylaxis is greater than 2%, but optimally, 
between 5 and 15% above baseline.   
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The target FIX activity for on-demand therapy (ie, for treatment of a bleeding episode) is 
between 40% and 80%. 
6.3
TREATMENT COMPLIANCE 
Subjects will record the dose, time of the dose and rIX-FP consumption for prophylaxis, 
prevention and on-demand treatment of bleeding episodes in the eDiary.  In addition, subjects 
will bring all of their used vials (and unused, if requested) of rIX-FP to the study site at every 
visit.  Treatment compliance will be monitored by counting the number of returned vials, the 
results of which will be recorded in the Drug Accountability Log.  rIX-FP use, as reported by 
the subject in the eDiary, will also be reconciled to the returned vials. 
For prophylaxis treatment, a subject will be regarded as compliant with treatment if both 
criteria below are met: 
Regimen compliance: The subject receives at least 80% of the injections of rIX-FP at
the scheduled injection frequency during the study period where dosing is expected to
occur within the following target days:
o
For the 7-day treatment interval: injection of rIX-FP occurs between Days 6 and 8
after the previous prophylaxis injection.
o
For the 10-day treatment interval (ie, every 10 days or 3 times per month): injection
of rIX-FP occurs between Days 8 and 11 after the previous prophylaxis injection.
o
For the 14-day treatment interval: injection of rIX-FP occurs between Days 13 and
15 after the previous prophylaxis injection.
o
For the 21-day treatment interval (not applicable to subjects in France): injection of
rIX-FP occurs between Days 20 and 22 after the previous prophylaxis injection.
Dose compliance: The subject receives 80% to 120% of the prescribed dose, based on
the actual dose, for at least 80% of injections.

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7.
CONTRAINDICATIONS, PERMITTED THERAPIES AND
PROHIBITED THERAPIES
7.1
CONTRAINDICATIONS AND PRECAUTIONS TO FURTHER DOSING 
In the event the subject experiences a hypersensitivity reaction, the study treatment must be 
stopped immediately by discontinuation of the injection.  In the event the subject experiences 
a hypersensitivity reaction or develops an inhibitor to FIX or antibodies to rIX-FP, the CSL 
medical monitor must be contacted before the administration of additional doses of rIX-FP.  
Subjects in France may be discontinued from receiving the study product and participating in 
any further study procedures if the subject is confirmed to have developed an inhibitor against 
FIX with a titer > 5 BU/mL. 
7.2 
PERMITTED THERAPIES 
The following therapies are PERMITTED during the study, if needed: 
Blood product transfusion (whole blood, erythrocytes [red blood cells], FFP or platelets)
and emergency use of FIX concentrate when rIX-FP is not available or in the event that
hemostatic control is not achieved after at least 2 injections.
Heparin use is limited to 200 IU/day, if needed, to maintain patency of IV lines.
Antifibrinolytic agents.
Antibiotic and antiviral agents.
Standard thrombosis prophylaxis is permitted, and should be documented in the eCRF. 
7.3 
PROHIBITED THERAPIES 
The following therapies are NOT PERMITTED during the study: 
Elective use of FIX concentrates other than rIX-FP.
Any investigational product other than rIX-FP.
To be used with caution: with the exception of selective cyclooxygenase-2 inhibitors, non-
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important that the investigator give careful consideration to the use of non-steroidal anti-
inflammatory drugs in subjects participating in this study.  If possible, alternative medication 
for pain relief, such as paracetamol / acetaminophen, should be used. 
Subjects are not to be enrolled into the study if they receive any prohibited therapy or any 
therapy in a prohibited dosage that cannot be discontinued or reduced to a permitted dose before 
enrollment.   
If administration of any prohibited therapy becomes necessary during the study, the subject 
may be withdrawn from further study participation. 
7.4
DIETARY AND LIFESTYLE RESTRICTIONS 
Not applicable. 
7.5
OVERDOSE 
Overdose is defined as the accidental or intentional injection of any dose of a product that is 
considered by the investigator to be excessive.  The effects of any potential overdose with rIX-
FP have not been studied.  Any overdose (ie, a single dose > 100 IU/kg rIX-FP, except when 
used for surgical prophylaxis or prophylaxis treatment administered every 21 days) should be 
documented in the eCRF, as described in Section 9.7.1. 
8.
STUDY PROCEDURES AND VISIT SCHEDULE
8.1
CLINICAL PROCEDURES 
The clinical procedures that will be conducted during this study related to the evaluation of 
population demographics and safety are provided in Table 2.  Refer to the Laboratory Manual 
for detailed instructions on how the assessments should be performed.   

 
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Table 2.   Clinical Procedures: Demographics and Safety Evaluation 
 
Assessment 
Description 
Demographics 
Date of birth, age, sex, race and ethnicity. 
Medical and surgical 
history 
(Arm 3 and 4) 
Relevant medical history especially regarding the history of hemophilia B 
including: 
 Date severe or moderately severe hemophilia B first diagnosed. 
 Number of bleeding episodes (spontaneous, trauma, surgery-
associated, and unknown) during the previous 12 months.   
 Human immunodeficiency virus status. 
Medical history 
(Arm 4 only) 
 Family history of inhibitors against FIX 
Treatment history 
(Arm 3 only) 
Treatment history with FIX including: 
 Date of first prophylaxis treatment. 
 Product type (pdFIX, rFIX, investigational product). 
 Drug name. 
 Modality of treatment (on-demand, routine prophylaxis, post-surgery, 
prevention prior to activity). 
 Dose and treatment schedule. 
 Estimated or documented treatment exposure days 
Lead-in study data 
(Arms 1 and 2 only) 
 Total rIX-FP exposure days 
 Prior therapies including treatment regimen at the end of the lead-in 
study 
 Age cohort at start of lead-in study (subjects from CSL654_3002 only) 
 Study arm in lead-in study (subjects from CSL654_3001 only) 
Social and physical 
activity (Arms 1, 2 
and 3 only) 
 Subject’s living arrangement 
 Number of days the subject missed from school or work (if relevant) 
 Number of days the caregiver(s) missed from work due to the need of 
caring for the subject (if relevant) 
 Number of important life activities missed due to hemophilia for 
subject and caregiver (if relevant) 
 Hospital visits due to hemophilia (not including study-related visits).   
 Overall activity level and sport(s) activities 
Relevant medical 
history 
 Genotype 
 Current joint score, scoring system and date of the assessment 
Physical examination As per the site’s standard procedure 
Vital signs 
 Body temperature 
 Height and body 
weight 
 Blood pressure (systolic and diastolic) 
 Heart rate (per minute) 

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Assessment 
Description 
Biochemistry 

Albumin

ALP

ALT

AST

Protein

Creatinine

Bilirubin

Blood Urea
Nitrogen or Urea

Direct Bilirubin
Hematology 

Hemoglobin

Hematocrit

Platelet count

Red blood cell (erythrocyte) count

White blood cell (leukocyte) count

White blood cell differential (optional)

Hemo-Sat questionnaire (subjects from CSL654_3002 only)
 
Immunogenicity 
Factor IX inhibitors and antibodies specific to rIX-FP and Chinese hamster 
ovary cell-derived proteins. 
Genotype (Arm 4) 
If FIX inhibitor is confirmed, genotype of FIX 
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; FIX = 
coagulation factor IX; pdFIX = plasma-derived factor IX; 
; rFIX = recombinant FIX; 
rIX-FP = recombinant fusion protein linking coagulation factor IX with albumin.  
The timing and frequency of all clinical procedures are described in the Section 8.9 and Table A 
- Schedule of Assessments: Treatment Period and Table C - Schedule of Assessments: Subjects
in Arm 3 and Table D – Schedule of Assessment: Subjects in Arm 4. See Appendix 2 for details
and the Schedules of Assessment for the SC substudy.
Refer to the Laboratory Manual for details about the collection, storage, handling and 
transportation of biological specimens. 
8.2
SUBJECT/CAREGIVER TRAINING AND TREATMENT AT HOME 
On Day 1 (Arms 1 and 2) or during the PK evaluation period (Arm 3) or during visits prior to 
provide eDiary to caregiver (Arm 4), and all follow-up visits, the investigator or delegate will 
ensure that the subject and / or caregiver has been trained sufficiently to allow for home therapy 
to occur in the subsequent months of the study (see Appendix 2 for details regarding the SC 
substudy).  At this time, the subject/caregiver will be instructed in the following: 

Correct reconstitution technique for rIX-FP.

Correct IV access and administration technique.

Correct drug storage.
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
Adverse event reporting.

Correct completion of eDiary.
For treatment received by the subject at home, the subject / caregiver will report (not limited 
to) the following information in the eDiary: 
Details of the rIX-FP administration (eg, total actual IU per injection, number of vials
used, and start date and time of injection).
Type of treatment (routine prophylaxis, prevention [before vigorous physical activity or
physical therapy], on-demand, post-surgery).
For bleeding episodes: 
Type of bleeding episode (spontaneous, traumatic, unknown, or post-surgery).
Site of the bleed (ie, joint, muscle, mucosal membrane) and specific location.
Time of start of symptoms of bleeding.
Local tolerability at the injection site will be assessed throughout the study by the subject. 
Subjects will record in the eDiary their judgment on the overall perception of the local 
reactions on a scale of none (0), very slight (1), slight (2), moderate (3) and severe (4) 
approximately 30 minutes after the end of the rIX-FP infusion. 
8.3
CONTROL OF MAJOR BLEEDING EPISODES 
Major bleeding episodes are defined as a bleed for which a subject is required to seek treatment 
at the hemophilia center from the treating physician.  A major bleeding episode includes intra-
cranial hemorrhage, gastrointestinal, and severe bleeding into a joint or muscle (ie. iliopsoas 
muscle).  All other bleeding episodes will be classified as minor / moderate unless the 
investigator assessment notes otherwise.   
The investigator will record the following in the eCRF: 
Reason for use of rIX-FP and type of the bleeding episode (spontaneous, traumatic,
unknown, or post-surgery).
Time of the start of bleeding.
Dose of rIX-FP (IU/kg).

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Number of used vials and total actual IU used.
Date and start time of each injection.
Local tolerability.
Concomitant therapy and other hemostatic product usage (if any).
Rescue FIX concentrate usage (if any).
Response to rIX-FP treatment using a 4-point scale (Table 3).
Table 3.  Efficacy Evaluation for Treatment of Major Bleeding Episodes 
Excellent 
Hemostasis clinically not significantly different from (eg, achieved 
hemostasis comparable to that expected for a similar bleed in a non-
factor deficient patient) or actual blood loss is not more than 20% 
higher than the estimated predicted blood loss for the type of injury or 
problem  
Good 
Normal or mildly abnormal hemostasis in terms of quantity and / or 
quality (eg, slight oozing, prolonged time to hemostasis with somewhat 
increased bleeding compared to a non-factor deficient patient) or 
estimated actual blood loss is greater than 20% but less than or equal to 
30% higher than the estimated predicted blood loss for this type of 
injury or problem 
Moderate 
Moderately abnormal hemostasis in terms of quantity and / or quality 
(eg, moderate hemorrhage that is difficult to control) with estimated 
blood loss greater than what is defined as Good 
Poor / No response 
Severely abnormal hemostasis in terms of quantity and / or quality 
(eg, severe hemorrhage that is difficult to control) and / or additional 
hemostatic intervention required with other FIX product, 
cryoprecipitate, or plasma more than expected for the type of injury or 
problem 
8.4
CONTROL OF MINOR AND MODERATE BLEEDING EPISODES (Arm 4 
only) 
Caregivers of Arm 4 subjects will record information (see Section 8.2) in the eeDiary on the 
bleeding episode and treatment received by the subject at home after the caregiver has been 
trained on home infusion.  If the subject receives treatment at the site, the investigator will 
record information on the bleeding episode and treatment in the eCRF. 

 
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The caregiver should contact site study staff at approximately 24 hours after the first treatment 
dose for the bleeding episode to report the response to treatment, including objective signs of 
bleeding (ie, swelling, tenderness, and / or decreased range of motion in the case of 
musculoskeletal hemorrhage) and to discuss if additional treatment or maintenance dose will 
be needed.    
The response to rIX-FP treatment will be evaluated via a 4-point scale (Table 4) by the 
Investigator at each Visit after a review of the treatment record.   
Table 4.  Efficacy Evaluation for Treatment of Minor and Moderate Bleeding Episodes 
Excellent 
(effective) 
No additional infusion required after the first infusion in order to 
achieve hemostasis, unmistakable/obvious improvement in objective 
signs of bleeding (ie, swelling, tenderness, and / or decreased range of 
motion in the case of musculoskeletal hemorrhage) approximately 24 
hours after the first FIX infusion.  
Good 
(effective) 
Requires a second infusion in order to achieve hemostasis,  
significant/recognized improvement in signs of bleeding at 
approximately 24 hours after the first infusion.   
Moderate 
(not effective) 
Requires more than two infusions to achieve hemostasis, and slight 
beneficial effect at approximately 24 hours after the first infusion.  
Poor/No response 
(not effective) 
Requires additional hemostatic intervention with other FIX product, 
or plasma to achieve hemostasis and no improvement at all or 
condition worsens (ie, signs of bleeding) at approximately 24 hours 
after the first infusion.   
The Investigator rating of hemostatic efficacy will take into account both the number of 
infusions required to achieve hemostasis (primary factor for PI’s assessment) and the objective 
signs of bleeding approximately 24 hours after the first infusion as reported to the site by the 
caregiver or observed by site personnel.  
8.5 
TREATMENT FOR A SURGICAL PROCEDURE 
If a non-emergency surgical procedure is necessary, the subject may be enrolled in the surgery 
substudy.  The details of the substudy are described in Appendix 1.   

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8.6
INHIBITORS AND ANTIBODIES 
The presence of antibodies against rIX-FP and CHO cells and inhibitors of FIX will be assessed 
by the central laboratory.  Details regarding sample collection, handling, deep freezing of 
samples and shipment to the central laboratory are given in the Laboratory Manual in the 
Investigator Site File. 
A tiered approach for immunogenicity testing for antibodies to rIX-FP will be employed during 
the study: 
1. Screening assay: The screening assay is a direct-binding ELISA assay, capable of
detecting antibodies against rIX-FP in blood samples from subjects.
2. Confirmation assays: If the antibody titer is above the cut-off level for the screening
assay, the same sample will be tested in a separate direct-binding ELISA assay to
confirm the specific antibody signal and to discriminate between plasma-derived FIX,
rIX-FP, and albumin antibodies.  In the event that all confirmation assays are negative,
the screening assay will be considered a false positive result.
3. Neutralization assay for inhibitors: The neutralizing capacity of antibodies will be
assessed by a FIX potency assay.  To quantify anti-FIX neutralizing antibodies, the
Bethesda assay with the Nijmegen modification will be used, and the results expressed
as Bethesda Units per mL (BU/mL).
In cases where the inhibitor titer is determined to be above the cut-off level (0.6 BU/mL), a 
second blood sample should be collected and be tested by the central laboratory for 
confirmation, and additional testing such as PK / incremental recovery tests will be performed.  
The subject’s information will be presented to the SMT and IDMC for its recommendation. 
8.7
RETENTION OF SAMPLES 
Retention samples of serum will be obtained before the first dose of rIX-FP (subjects in Arms 3 
and 4 only) and at the end of study visit for later viral safety testing, if needed and with the 
subject’s consent. Retention samples will be stored by CSL for 5 years. 

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8.8
CONCOMITANT THERAPIES 
For subjects in Arms 3 and 4, all drugs taken by a subject within 30 days before the screening 
visit and during screening are regarded as prior therapy and must be documented in the eCRF. 
All therapies currently being administered to a subject either at the time of or after signing 
informed consent, and which continue to be administered in addition to rIX-FP during the 
study, are regarded as concomitant therapies and must be documented as such in the eCRF.  
Nonpharmacological interventions (eg, physical therapy or a minor surgical procedure 
performed outside of the surgical substudy) are also regarded as concomitant therapy and 
must be documented in the eCRF. 
8.9
VISIT SCHEDULE 
The timing and frequency of the study visits in the main study are described in the Table A - 
Schedule of Assessments: Treatment Period and the Table C - Schedule of Assessments: 
Subjects in Arm 3 and Table D – Schedule of Assessment: Subjects in Arm 4. 
See Appendix 1 for details on study visits and the Schedule of Assessments in the surgery 
substudy. 
See Appendix 2 for details on study visits and the Schedules of Assessments in the 
SC substudy. 
8.9.1 
Screening Visit (Arms 3 and 4 only) or Day 1 Visit (Arms 1 and 2 only) 
All subjects must provide written informed consent before any study-specific assessments 
or procedures are performed.   
Written informed consent is not required for assessments or procedures performed according 
to standard of care (eg, for diagnosis or treatment); results from such assessments may be used 
in the determination of study eligibility.  In addition, results from laboratory / clinical 
assessments (eg, biochemistry, hematology, vital signs, body height and weight, physical 

 
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examination) and antibody assessments collected at the end of study visit of the lead-in study 
will be used as Day 1 values (Arms 1 and 2 only).   
If the subject is not eligible for the study, the primary reason for screen failure must be 
entered in the eCRF.   
8.9.1.1 
Screening Visit (Arm 3 only) 
The following procedures will be performed and documented by the investigator or delegate: 
 Demographics. 
 Review inclusion and exclusion criteria.  
 Social and physical activity. 
 Relevant medical and treatment history. 
 Physical examination. 
 Vital signs. 
 Body weight and height. 
 Obtain blood samples for biochemistry and hematology. 
 Obtain blood samples for: 
o Inhibitors against FIX. 
o Antibodies against rIX-FP. 
o Antibodies against CHO cell-derived proteins. 
 Obtain blood sample for measurement of plasma FIX. 
 Prior and concomitant therapy. 
 Start monitoring of AEs. 
8.9.1.2 
Screening Visit (Arm 4 only) 
The following procedures will be performed and documented by the investigator or delegate: 
 Demographics. 
 Review inclusion and exclusion criteria.  
 Relevant medical history. 
 Family history of inhibitor against FIX.  

 
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 Physical examination. 
 Vital signs. 
 Body weight and height. 
 Obtain blood samples for biochemistry and hematology, if feasible, unless results within 
6 months are available in the subject’s medical records. 
 Obtain blood sample for measurement of plasma FIX (LL), unless data is available in 
the subject’s medical records. 
 Obtain blood samples for: 
o Inhibitors against FIX. 
o Antibodies against rIX-FP. 
o Antibodies against CHO cell-derived proteins. 
 Prior and concomitant therapy. 
 Start monitoring of AEs. 
 If a subject experiences a life-threatening bleeding episode (including bleeding in the 
central nervous system, gastrointestinal tract, neck/throat, or severe trauma-induced 
bleeding) or requires a major surgical procedure prior to the first administration of rIX-
FP, the subject will not be enrolled into the study and will be counted as a screen failure.   
8.9.1.3 
Day 1 Visit (Arms 1 and 2 only) 
The following information will be transferred from the end of study visit or earlier visit 
(where relevant) of the lead-in study: 
 Information on demographics. 
 Lead-in study data (rIX-FP EDs, age cohort in lead-in study [CSL654_3002 study only], 
arm in lead-in study [CSL654_3001 study only], prior therapies including treatment 
regimen at the end of the lead-in study).   
 Social and physical activity. 
 Physical examination. 
 Vital signs. 
 Body weight and height. 

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Results from biochemistry and hematology assessments.
Results for inhibitors against FIX, antibodies against rIX-FP, antibodies against CHO
cell-derived proteins.
Results for plasma FIX activity (CSL654_3001 subjects only).
Concomitant therapy.
Ongoing AEs.
The following procedures will be conducted at the Day 1 visit: 
Review inclusion and exclusion criteria.
Record relevant medical history (genotype and joint score including scoring system and
date of assessment).
Obtain blood sample for measurement of plasma FIX activity (central laboratory) for
subjects from the CSL654_3002 study.
Start monitoring of AEs.
Any new concomitant therapy (ie, not reported at the end of study visit of the lead-in
study).
Record the dose regimen (dose and treatment interval) and administration information in
the eCRF, if the subject is administered the first injection of rIX-FP during the visit.
Dispense eDiary.
If considered necessary, reinstruct subject on injection technique, dosing regimen, and
use of eDiary.
Schedule next visit.
8.9.2 
Day 1 Visit (Arms 3 and 4) 
8.9.2.1
Day 1 (Arm 3 only, which excludes any subjects from France) 
After completion of the surgery substudy, subjects must complete the Day 1 visit if they choose 
to remain in the study.  This Day 1 visit will occur on the same day as the End of Surgery 

 
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Substudy visit.  At this visit, the following procedures will be performed by the investigator or 
delegate: 
 If necessary, reinstruct subject on injection technique. 
 Body weight. 
 Assign and instruct subject on dosing regimen. 
 Record AEs and concomitant therapies. 
 After the Day 1 visit, subjects in Arm 3 should complete the study according to Table A 
- Schedule of Assessments: Treatment Period.   
8.9.2.2 
Day 1 visit (Arm 4 only) 
The Day 1 visit may occur on the same day as the Screening visit, if all inclusion criteria are 
met. 
The following procedures will be conducted at the Day 1 visit PRIOR to the administration of 
rIX-FP: 
 Review inclusion and exclusion criteria to confirm eligibility for the study. 
 Physical examination. 
 Vital signs. 
 Body weight and height. 
 Collect blood samples prior to first dose of rIX-FP (if not collected at Screening):   
o Biochemistry and hematology (LL), unless results within 6 months are available in 
the subject’s medical records. 
o Plasma FIX level (CL). 
o Inhibitors against FIX (CL). 
o Antibodies against rIX-FP and CHO cell-derived proteins (CL). 
 Prior and concomitant therapy. 
 Administer the first dose of rIX-FP.  
The following procedures will be conducted at the Day 1 visit FOLLOWING the 
administration of rIX-FP: 
 Monitor subject for at least 3 hours under medical supervision. 

 
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 Record the dose, administration information and reason for the dose in the eCRF. 
 If the first dose is for PK assessment, sample for FIX activity will be collected 30 
minutes post administration.  
 Record AEs and concomitant therapy. 
8.9.3 
Other Visits during the Treatment Period (Arm 1, 2 and 3) 
8.9.3.1 
Month 3 Visit and Month 9 Visit  
The following procedures will be performed and documented by the investigator or delegate: 
 Body weight (omitted if visit conducted via telephone). 
 Review subject eDiary. 
 Assess treatment efficacy for major bleeding episodes, if applicable. 
 Record AEs and concomitant therapies. 
 If considered necessary, reinstruct subject on injection technique, dosing regimen, and 
use of eDiary.  
 Schedule next visit. 
For subjects from lead-in Study CSL654_3001 Arm 1, the visit at month 3 may be conducted 
via telephone, if the investigator deems that there is no safety risk to the subject.  
For all Arm 2 and 3 subjects, the visit at month 9 may be conducted via telephone, if the 
investigator deems that there is no safety risk to the subject. 
The month 3 visit may be omitted for subjects in Arm 2 who have attended a follow-up after 
visit in the previous 3 months to transition from a 7-day rIX-FP treatment interval to a 14-day 
rIX-FP treatment interval. 
8.9.3.2 
Month 6 Visit  
The following procedures will be performed and documented by the investigator or delegate: 
 Record social and physical activity. 
 Body weight. 

 
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 Obtain blood samples for: 
o Inhibitors against FIX. 
o Plasma FIX activity) (central and local laboratory). 
 Review subject eDiary. 
 Assess treatment efficacy for major bleeding episodes, if applicable. 
 Review treatment regimen (ie, dose and / or treatment interval) and modify, if 
necessary.  Record any changes in treatment regimen in the eCRF. 
 Record AEs and concomitant therapies. 
 If considered necessary, reinstruct subject on injection technique, dosing regimen, and 
use of eDiary. 
 Schedule next visit. 
8.9.3.3 
Month 12 Visit  
The following procedures will be performed by the investigator or delegate: 
 Record social and physical activity. 
 Physical examination. 
 Vital signs. 
 Body weight and height (height optional for subjects ≥ 18 years). 
 Obtain blood sample for biochemistry and hematology assessments. 
 Obtain blood samples for: 
o Inhibitors against FIX. 
o Antibodies against rIX-FP. 
o Antibodies against CHO cell-derived proteins. 
 Obtain blood sample for measurement of plasma FIX activity (central and local 
laboratory). 
 Review subject eDiary. 
 Assess treatment efficacy for major bleeding episodes, if applicable. 
 Review treatment regimen (ie, dose and / or treatment interval) and modify, if 
necessary.  Record any changes in treatment regimen in the eCRF. 

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Record AEs and concomitant therapies.
Parents or the caregiver of subjects to complete Hemo-Sat questionnaire (for subjects
who transferred from the CSL654_3002 lead-in study).
If considered necessary, reinstruct subject on injection technique, dosing regimen, and
use of eDiary.
Schedule next visit.
8.9.3.4 
Months 18, 30, 42, and 54 Visits 
The following procedures will be performed by the investigator or delegate: 
Record social and physical activity.
Body weight.
Obtain blood samples for inhibitors against FIX.
Obtain blood sample for measurement of plasma FIX activity (central laboratory).
Review subject eDiary.
Assess treatment efficacy for major bleeding episodes, if applicable.
Review treatment regimen (ie, dose and treatment interval) and modify, if necessary.
Record any changes in treatment regimen in the eCRF.
Record AEs and concomitant therapies.
If considered necessary, reinstruct subject on injection technique, dosing regimen, and
use of eDiary.
Schedule next visit.
CCI

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8.9.3.5 
Months 24, 36, 48, and 60 Visits 
The following procedures will be performed by the investigator or delegate: 
Record social and physical activity.
Physical examination.
Vital signs.
Body weight and height.
Obtain blood samples for:
o
Inhibitors against FIX.
o
Antibodies against rIX-FP.
o
Antibodies against CHO cell-derived proteins
Obtain blood sample for measurement of plasma FIX activity (central laboratory).
Review subject eDiary.
Assess treatment efficacy for major bleeding episodes, if applicable.
Review treatment regimen (ie, dose and treatment interval) and modify, if necessary.
Record any changes in treatment regimen in the eCRF.
Record AEs and concomitant therapies.
If considered necessary, reinstruct subject on injection technique, dosing regimen, and
use of eDiary.
Schedule next study visit.
8.9.4 
Other Visits During the Treatment Period (Arm 4 only) 
8.9.4.1
First 10 to 20 administrations of rIX-FP 
Subjects must be treated in a clinic/hospital setting capable of treating severe allergic reactions 
during the initial 10 (required minimum) to 20 (at investigator’s discretion) infusions.  The first 
two doses must be monitored under medical supervision for at least 3 hours, and the remaining 
doses are monitored for at least 30 minutes.  Some of those visits for administrations of rIX-
FP can occur during the scheduled monthly visits after samples for laboratory testing are 

 
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collected.  The dose, administration information, reason for the dose and assessment of local 
tolerability must be recorded in the eCRF. 
8.9.4.2 
Visit at Month 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12   
Subjects will visit the study center as outlined in the Schedule of Assessments (Table D), 
preferably within 2 days prior to the next planned infusion of rIX-FP (or as close to the next 
rIX-FP infusion as possible) if subject is receiving routine prophylaxis.  
The following procedures will be performed at every visit:  
 Physical examination.  
 Vital signs.  
 Weight and height. 
 Review concomitant therapy. 
 Review AEs since last visit. 
 Review the subject eDiary (if applicable) and investigator assessment of efficacy for 
treated bleeding events. 
 If considered necessary, reinstruct subject/caregiver on injection technique, dosing 
regimen, and use of eDiary. 
The following procedures will be performed, in addition to the procedures listed above:  
 Blood samples for FIX inhibitors at Months 1, 2, 3, 4, 5, 6, 9 and 12 (CL). In addition, 
inhibitor testing should be performed at any time if there is any suspicion of inhibitor 
development. 
 Blood samples for antibodies against rIX-FP and CHO cells at Months 6 and 12 (CL).  
 Blood samples for local laboratory safety evaluation (hematology and Biochemistry) at 
Month 12 visit.  
 Blood samples for FIX activity level at Months 1, 2, 3, 6 and 12 (CL).  
 
If a subject receives less than 3 doses per month, they may omit the site visit(s) until the first 
5 doses have been administered.   

 
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In the event a subject misses a study visit, the study personnel should contact the study subject 
by telephone and collect pertinent study-related information and document accordingly in the 
medical record. All subject data should be reviewed at the next scheduled visit and recorded in 
the CRF.   
In the event a subject misses any visit at which testing for inhibitor is required, an unscheduled 
visit should be arranged as soon as possible during the subject’s first 20 EDs, otherwise all 
required laboratory tests can be conducted during the next site visit.    
The subject’s caregiver may begin administering rIX-FP at home after the subject has 
received a minimum of 10 treatments of rIX-FP at the site.  The investigator or delegate will 
ensure that the caregiver has been trained sufficiently to allow for home therapy to occur in 
the subsequent months of the study.  The study center personnel will instruct the caregiver on 
the reconstitution and administration of rIX-FP and correct completion of the eDiary prior to 
issuing  the eDiary as outlined in Section 8.2. 
8.9.4.3 
Months 15, 18, 21, 24, 27, 30 and 33 Visits 
Subjects will visit the study center as outlined in the Schedule of Assessments (Table D), 
preferably within 24 hours (or as close to the next rIX-FP infusion as possible) prior to the next 
planned infusion of rIX-FP.  
The following procedures will be performed by the investigator or delegate at every visit: 
 Physical examination.  
 Vital signs. 
 Weight and height. 
 Review concomitant therapy. 
 Review AEs. 
 Review the subject eDiary (if applicable) and investigator assessment of efficacy. 
 If considered necessary, reinstruct caregiver/subject on injection technique, dosing 
regimen, and use of eDiary. 

 
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The following procedures will be performed, in addition to the procedures listed above at 
Month 18, 24 and 30 Visit ONLY: 
 Obtain blood samples for inhibitor to FIX (CL). 
 
The following procedures will be performed, in addition to the procedures listed above at 
Month 24 Visit ONLY: 
 Obtain blood sample for biochemistry and hematology assessments (LL). 
 Blood samples for FIX activity and antibodies against rIX-FP and CHO cells (CL). 
8.9.5 
Completion of 50 rIX-FP EDs During the Study (all subjects) 
The following procedures will be performed by the investigator or delegate: 
 Obtain central laboratory blood samples for: 
o Inhibitors against FIX. 
o Antibodies against rIX-FP  
o Antibodies against CHO cell-derived proteins. 
 Record AEs and concomitant therapies. 
8.9.6 
Unscheduled Visits if Inhibitor to FIX is confirmed 
The following procedures will be performed: 
 Obtain blood sample for genotyping if no test results are available in subject medical 
records. 
 Obtain blood samples for PK assessment if feasible. 
 Review concomitant therapy. 
 Review AEs. 
 Review the eDiary (if applicable) and investigator assessment of efficacy of any treated 
bleeding episodes. 

 
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8.9.7 
End of Study (all subjects) 
The scheduled end of study participation for an individual subject occurs with completion of 
the end of study visit, after which, no further study-related procedures will be performed.   The 
end of study visit may be combined with another planned visit if the two visits are less than 2 
months apart.  The following procedures will be performed by the investigator or delegate at 
the end of study visit: 
 Record social and physical activity (except Arm 4). 
 Physical examination. 
 Vital signs. 
 Obtain blood sample for biochemistry and hematology. 
 Obtain blood samples for: 
o Inhibitors against FIX. 
o Antibodies against rIX-FP. 
o Antibodies against CHO cell-derived proteins. 
o FIX activity (Arm 4 only). 
 Obtain retain blood sample for serology. 
 Review subject eDiary and ensure all data have been submitted. 
 Retrieve eDiary. 
 Assess treatment efficacy for major bleeding episodes, if applicable. 
 Record AEs and concomitant therapies. 
8.9.8 
Pharmacokinetic Evaluation of 100 IU/kg rIX-FP  
Subjects in France will not take part in the PK of 100 IU/kg rIX-FP. 
Before a subject either begins administering rIX-FP as routine prophylaxis using a 21-day 
treatment interval (excludes subjects in France), or begins administering rIX-FP for the first 
time (Arm 3), they must first undergo a PK evaluation period with a single injection of 
rIX-FP (100 IU/kg).  The PK evaluation should be performed after a washout period of either 

 
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at least 4 days for a marketed FIX (subjects in Arm 3) or at least 14 days for rIX-FP (subjects 
currently being treated with rIX-FP). 
The following procedures will be conducted during the PK evaluation period:  
 Body weight. 
 Obtain blood sample for measurement of plasma FIX activity (central laboratory) before 
injection of rIX-FP. 
 Obtain retain blood sample (Arm 3 only). 
 Investigator or delegate to administer a single injection of rIX-FP at a dose of 100 IU/kg 
rIX-FP. 
 Obtain blood samples for measurement of plasma FIX activity at the following time 
points after injection of rIX-FP:  
o 30 ± 5 minutes. 
o 72 ± 24 hours (ie, 3 ± 1 days) as an optional time point for subjects planning to be 
switched to 21-day treatment interval.  
o 168 ± 24 hours (ie, 7 ± 1 days).   
o 336 ± 24 hours (ie, 14 ± 1 days).  This time point is optional for subjects in Arm 3. 
o 504 ± 24 hours (ie, 21 ± 1 days). This time point is optional for subjects in Arm 3. 
Samples are to be taken only if no bleeding occurred before sample collection. 
 Record AEs and concomitant therapies before, during and after injection of rIX-FP. 
 If considered necessary, reinstruct subject on injection technique, dosing regimen, and 
use of eDiary. 
 Schedule next study visit. 
For subjects in Arm 3 only, before the end of the PK evaluation period, the investigator or 
delegate should: 
 Dispense eDiary.  
 Instruct subject on injection technique, dosing regimen, and use of eDiary. 

 
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8.9.9 
Pharmacokinetic Evaluation of 50 IU/kg rIX-FP (Arm 4) 
The subjects in Arm 4 may be first undergoing a PK evaluation as the first dose with a single 
injection of rIX-FP (50 IU/kg) or during the study.  
The following procedures will be conducted PRIOR to rIX-FP administration:  
 Body weight and height. 
 Obtain blood sample for measurement of plasma FIX activity (central laboratory) before 
injection of rIX-FP. 
 Investigator or delegate to administer a single injection of rIX-FP at a dose of 50 IU/kg 
rIX-FP. 
The following procedures will be conducted FOLLOWING rIX-FP administration:  
 Obtain blood samples for measurement of plasma FIX activity at the following time 
points after injection of rIX-FP:  
o 30 ± 5 minutes. 
o 72 ± 24 hours as an optional time point.  
o 168 ± 24 hours as an optional time point.   
 Record AEs and concomitant therapies before, during and after injection of rIX-FP. 
8.9.10 Unscheduled Visits  
Unscheduled visits, including brief PK assessments, may be arranged at any time point during 
the study, at the discretion of the investigator or upon request of the subject or CSL. 
9. 
ADVERSE EVENTS 
9.1 
DEFINITIONS 
9.1.1 
Adverse Event 
As per the ICH guidelines, an AE is any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 

 
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have a causal relationship with this treatment.  An AE can, therefore, be any unfavorable and 
unintended sign (including an abnormal, clinically significant laboratory finding), symptom, 
or disease temporally associated with the use of a medicinal (investigational) product, whether 
or not considered related to the medicinal (investigational) product.   
The period of observation for AEs extends from the time the subject gives informed consent 
until the end of study (see Section 9.4 for further details). 
Adverse events may include: 
 Exacerbation (ie, an increase in the frequency or severity) of a pre-existing condition.  
Illness present before study entry should be recorded in the medical history section of 
the eCRF and only be reported as an AE if there is an increase in the frequency or 
severity of the condition during the study.   
 A clinical event occurring after consent but before rIX-FP administration. 
 Intercurrent illnesses with an onset after administration of rIX-FP. 
Adverse events do not include: 
 A bleeding episode that occurs as a result of the subject’s unchanged, pre-existing 
hemophilia condition. 
 Events identified at baseline that meet exclusion criteria. 
 Medical or surgical procedures (the condition that leads to the procedure may be 
reported as the AE, as appropriate). 
 A trauma itself, however, an injury other than bleeding (eg, bone fracture) resulting 
from the trauma should be documented as an AE. 
 Situations where an untoward medical occurrence has not taken place.  For example: 
o Planned hospitalizations due to pre-existing conditions, which have not worsened. 
o Hospitalizations that occur for procedures not due to an AE (eg, cosmetic surgery, 
elective surgery or social admission). 
o Hospitalizations for a diagnostic procedure where the hospital stay is less than 
24 hours in duration or for normal disease management procedures. 

 
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 Overdose of rIX-FP or any concomitant therapy that does not result in any adverse 
signs or symptoms.   
If a bleeding episode occurs, whether spontaneous or as the result of trauma or injury, ONLY 
the injury should be recorded as an AE or SAE.  The bleeding episode, whether spontaneous 
or resulting from the injury, should not be recorded as an AE, but as a bleeding episode on 
the appropriate eCRF page.   
For laboratory safety parameters, any instances of absolute values being outside the reference 
range or changes at any visit after study start that are considered by the investigator as clinically 
significant must recorded in the eCRF as AEs.  In addition, at the investigator’s discretion, any 
changes or trends over time in laboratory parameters can be recorded in the eCRF as AEs if 
such changes or trends are considered to be clinically relevant, even if the absolute values are 
within the reference range. 
Laboratory findings do not need to be reported as AEs in the following cases: 
 Laboratory parameters already beyond the reference range at Day 1 of the lead-in study 
(subjects in Arms 1 or 2) or at screening (subjects in Arm 3 or Arm 4), unless a further 
increase/decrease can be considered an exacerbation of a pre-existing condition.   
 Abnormal laboratory parameters caused by mechanical or physical influences on the 
blood sample (eg, in vitro hemolysis) and flagged as such by the laboratory in the 
laboratory report. 
 Abnormal parameters that are obviously biologically implausible (eg, values that are 
incompatible with life or outside the measuring range). 
 An abnormal laboratory value that cannot be confirmed after repeat analysis, preferably 
in the same laboratory (ie, the previous result could be marked as not valid and should 
not necessarily be reported as an AE).   

 
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9.1.2 
Adverse Events of Special Interest 
There are several AEs that will be monitored closely as adverse events of special interest 
(AESIs) to enable an adequate risk-benefit evaluation of rIX-FP versus standard therapy during 
the study and additional data may be requested for these events.  The AESIs will be: 
 AEs associated with confirmed (ie, with second blood sample) inhibitor formation.  
 Thrombotic and / or embolic events. 
 Anaphylaxis. 
AESIs should be considered medically significant and are therefore SAEs.  The expedited 
reporting procedures for SAEs are described in detail in Section 9.6. 
9.1.3 
Serious Adverse Event 
An SAE is defined as any untoward medical occurrence that at any dose: 
 Results in death – The event must be the cause of death for the SAE to meet this 
serious criterion. 
 Is life-threatening – The term “life-threatening” refers to an event in which the subject 
was at risk of death at the time of the event; it does not refer to an event that 
hypothetically might have caused death if it had been more severe. 
 Requires in-patient hospitalization or prolongation of existing hospitalization – 
CSL considers “hospitalization or prolongation of existing hospitalization” for at least 
24 hours as the defining criterion for an SAE.  Hospital admissions for planned surgery 
or for normal disease management procedures (eg, for treating major bleeding episodes, 
diagnostic procedures, admission or procedures that are not considered AEs [see Section 
9.1.1]) are not considered as defining criteria for SAEs.   
 Results in persistent or significant disability or incapacity. 
 Is a congenital anomaly or birth defect. 
 Is medically significant – A medically significant event is defined as an event that does 
not necessarily meet any of the SAE criteria, but which is judged by a physician to 
potentially jeopardize the subject or require medical or surgical intervention to prevent 
one of the above outcomes listed as an SAE criterion. 

 
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Adverse events that do not fall into the above categories are defined as nonserious AEs. 
9.2 
SEVERITY OF ADVERSE EVENTS 
The severity of each AE (ie, nonserious and SAEs) is to be assessed by the investigator as 
follows: 
Severity 
Definition 
Mild 
A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention.  The event does not generally interfere with usual activities 
of daily living. 
Moderate 
A type of AE that is usually alleviated with additional specific therapeutic 
intervention.  The event interferes with usual activities of daily living, causing 
discomfort but poses no significant or permanent risk of harm to the subject. 
Severe 
A type of AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention. 
CDISC SDTM Severity Intensity Scale for Adverse Event Terminology 
9.3 
CAUSALITY OF ADVERSE EVENTS 
The causal relationship of an AE to rIX-FP must always be assessed by the investigator.  All 
AEs will be classified as either related or not related to rIX-FP.  If a causality assessment is 
not provided for an AE (including an SAE) at the time of database lock, that AE will be 
considered related to rIX-FP.   
The degree of certainty with which an AE is attributed to rIX-FP or an alternative cause 
(eg, natural history of the underlying disease, concomitant therapy) will be determined by how 
well the event can be understood in terms of: 
 Known pharmacology of rIX-FP. 
 Clinically and / or pathophysiologically plausible context. 
 Reaction of a similar nature previously observed with similar products, or reported in 
the literature for similar products as being product related (eg, headache, facial flushing, 
pallor). 

 
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 Plausibility supported by the temporal relationship (eg, the event being related by time 
to administration or termination of treatment with rIX-FP, drug withdrawal or 
reproduced on rechallenge). 
9.4 
OBSERVATION PERIOD FOR ADVERSE EVENTS 
The observation period for AE (and SAE) reporting in an individual subject will start at the 
time of giving written informed consent for participation in the current study and finish with 
the end of study visit.   
If the investigator becomes aware of an SAE that has started after the observation period has 
finished, and the event could in some way be associated with rIX-FP, then this must also be 
reported to CSL and included in the clinical database (see Section 9.6). 
9.5 
ADVERSE EVENT REPORTING 
9.5.1 
Adverse Events 
At each clinical evaluation, the investigator (or delegate) will determine whether any AEs have 
occurred.  AEs will be recorded in the AE page of the eCRF.  If known, the medical diagnosis 
of an AE should be recorded in preference to the listing of individual signs and symptoms.  The 
investigator must follow up on the course of an AE until resolution or stabilization.  If an AE 
is ongoing after the end of study visit, the AE will continue to be followed up until resolution, 
stabilization, or for 30 days after the final administration of rIX-FP during the study, whichever 
is sooner. 
9.5.2 
Adverse Events of Special Interest 
Any AESI should be reported as an SAE as described in detail in Section 9.6. 

 
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9.6 
SERIOUS ADVERSE EVENT REPORTING 
This study will comply with all applicable regulatory requirements and adhere to the full 
requirements of ICH Topic E2A (Clinical Safety Data Management: Definitions and Standards 
for Expedited Reporting). 
For SAEs occurring during the study, the investigator or delegate will enter all relevant 
information in the AE page of the eCRF.  An electronic document containing the AE page and 
other applicable pages of the eCRF must be sent (via facsimile or email) to the sponsor together 
with a Notification of Serious Adverse Event at Investigator Site cover page, which has 
been signed and dated by the Investigator.  If an electronic document is not able to be generated 
(eg, internet access problem), a handwritten paper SAE report must be completed, which must 
be signed and dated by the investigator.   
All SAEs that occur during the course of the study, whether or not causally related to 
rIX-FP, must be reported immediately (within 24 hours of the investigator becoming 
aware of the event) to CSL.  For Japan sites only, the investigator must also inform the 
head of the medical institution of the SAE and related information in accordance with the 
Japanese regulatory requirements and ICH GCP. 
Adverse events occurring in the period between the times the subject gave written informed 
consent and the first exposure to rIX-FP that meet one or more of the seriousness criteria for 
AEs must be reported to CSL in the same manner as other SAEs and will be included in the 
clinical study database.   
Any SAE that occurs after the end of study visit that is considered to be causally related to rIX-
FP must be reported immediately (ie, within 24 hours of the investigator becoming aware 
of the event) to CSL.  For Japan sites only, the investigator must also inform the head of 
the medical institution of the SAE and related information in accordance with the Japanese 
regulatory requirements and ICH GCP. 

 
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Contact details and guidance for reporting SAEs will be provided to study site before the study 
starts. 
9.6.1 
Requirements for Immediate Reporting of Serious Adverse Events 
The minimum reporting requirements for immediate reporting of SAEs include: 
 Identifiable subject. 
 Suspected medicinal product and / or procedure. 
 Event term. 
 Identifiable reporting source. 
In addition, the investigator must: 
 Report all SAEs to the relevant Institutional Review Board (IRB) / Independent Ethics 
Committee (IEC) within the timeframe specified by the IRB / IEC. 
 Submit follow-up reports to CSL Clinical Safety and Pharmacovigilance until the SAE 
has resolved, or, in the case of permanent impairment, until stabilized. 
 Ensure that the causality assessment for all SAEs is entered in the eCRF. 
If the minimum requirements for reporting are fulfilled, the investigator should not wait to 
receive additional information to fully document the event before notifying CSL.   
When submitting SAE reports and any other related reports (eg, discharge summaries) to CSL, 
subjects should be identified only by their subject number and study number.  The investigator 
should not include the subject’s name, date of birth, or address. 
In cases of death, the investigator should supply CSL and the IRB / IEC (as applicable) with 
any additional information as it becomes available (eg, autopsy reports and detailed medical 
reports). 
The procedure to be followed if an ongoing AE becomes an SAE after the end of the 
observation period for AEs is described in Section 9.9. 

 
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9.7 
OTHER SIGNIFICANT EVENT REPORTING 
9.7.1 Overdose 
Any overdose that is considered by the investigator to be medically significant and resulting 
in adverse signs and symptoms must be reported as an SAE (see Section 9.6). 
9.7.2 
Pregnancy and Lactation  
The subject must immediately notify the investigator if his female partner becomes pregnant 
while participating in the study, or up to and including 30 days after the last dose of rIX-FP.   
CSL must be notified within 5 days of the investigator becoming aware of the pregnancy.  
Whenever possible, a pregnancy in a female partner of a male subject exposed to rIX-FP should 
be followed to term so as to assess any potential occurrence of congenital anomalies or birth 
defects.  Any follow-up information, including premature termination and the status of the 
mother and child after delivery, should be reported by the investigator to CSL using a 
Pregnancy Reporting / Outcome Form.   
9.8 
IRB / IEC REPORTING REQUIREMENTS 
The time frame within which an IRB / IEC must be notified of deaths and investigational 
product-related unexpected SAEs is stipulated by each IRB / IEC.  It is the investigator’s 
responsibility to comply with the requirements for IRB / IEC notification.  CSL will provide 
investigators with all details of all SAEs reported to regulatory authorities. 
9.9 
FOLLOW-UP OF ADVERSE EVENTS 
Every effort should be made to follow-up subjects who continue to experience an AE or an 
SAE on completion of the study until either the AE resolves or there has been a period of 
30 days after the final administration of rIX-FP during this study.  All follow-up information 
(and attempted follow-up contacts) should be documented in the subject’s medical records.  
Details of the subject’s progress should also be submitted to CSL Global Clinical Safety and 
Pharmacovigilance. 

 
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10. ASSESSMENTS 
10.1 
SUBJECT CHARACTERISTICS 
Subject characteristics to be evaluated will include: 
 Demographic data. 
 Medical and surgical history. 
 Treatment history (rIX-FP or other FIX). 
10.2 
EFFICACY ASSESSMENTS 
The efficacy of rIX-FP treatment in the prevention and treatment of bleeding episodes will be 
assessed based on the following: 
 Total consumption of rIX-FP (number of EDs and mean IU/kg per year per subject and 
per bleeding episode) and consumption per routine prophylaxis, prevention before 
physical activity, and on-demand treatment. 
 Number of spontaneous and total bleeding episodes and corresponding ABRs per 
treatment interval. 
 Investigator’s overall clinical assessment of hemostatic efficacy for treatment of major 
bleeding episodes. 
 Number of rIX-FP injections required to achieve hemostasis. 
10.3 
SAFETY ASSESSMENTS 
Safety will be assessed based on the following variables: 
 Inhibitors against FIX. 
 AEs and SAEs. 
 Local tolerability. 
 Serum biochemistry and hematology. 
 Physical examination. 
 Vital signs. 
 Antibodies against rIX-FP. 

 
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 Antibodies against CHO cell-derived proteins. 
Clinical laboratory tests will be performed at time points as detailed in the Table A - 
Schedule of Assessments: Treatment Period.  More frequent evaluations may be performed, if 
clinically indicated, at the discretion of the investigator. 
10.4 
PHARMACOKINETIC AND PHARMACODYNAMICS 
10.4.1 Pharmacokinetic Analyses 
10.4.1.1 
Trough factor IX activity level 
During the study, blood samples will be taken for the assessment of trough FIX activity level 
at each major bleeding episode (if feasible) and the specified visits.   
10.4.1.2 
Pharmacokinetic Evaluation of rIX-FP 
In addition, subjects beginning routine prophylaxis treatment using a treatment interval of 
21 days (not applicable for subjects in France) for the first time and subjects in Arm 3, will 
undergo a PK evaluation with a single injection of rIX-FP (100 IU/kg).  For this PK evaluation, 
blood samples will be taken for the measurement of the FIX activity level at the following time 
points (required or optional; see Section 8.9.8) after injection. 
 30 ± 5 minutes 
 72 ± 24 hours (ie, 3 ± 1 days) 
 168 ± 24 hours (ie, 7 ± 1 days) 
 336 ± 24 hours (ie, 14 ± 1 days) 
 504 ± 24 hours (ie, 21 ± 1 days) (not applicable for subjects in France)  
If during the PK assessment period, a subject experiences a bleeding episode, no further blood 
samples will be taken as part of PK assessment, regardless of whether the bleeding episode is 
treated or not.  The PK may or may not need to be repeated.   
A PK evaluation of 50, 75, or 100 IU/kg rIX-FP (with selected time points) may also be 
assessed (for Arm 4 subjects 50 IU/kg only), at the investigator’s discretion or CSL’s request, 

 
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in the event of (but not limited to) poor efficacy, suspicion of inhibitor development, or before 
major surgery. 
The incremental recovery and FIX activities will be reported.  Additional PK parameters 
(eg, AUC, t1/2) may be calculated, if deemed appropriate. 
10.4.2 Pharmacodynamic Analyses 
Not applicable. 
10.4.3 Pharmacokinetic / Pharmacodynamic Relationships 
Not applicable. 
10.4.4 Pharmacokinetic Analyses (Subcutaneous Substudy) 
See Appendix 2. 
10.5 
OTHER ASSESSMENTS 
Other assessments to be made during the study include: 
 A hemophilia-specific treatment satisfaction questionnaire (Hemo-Sat) will be 
completed by parents or caregivers of subjects from the CSL654_3002 lead-in study. 
 
 
 Social and physical activity. 
11. STATISTICS 
11.1 
SAMPLE SIZE ESTIMATION 
The choice of sample size for this study is not based on statistical power considerations.  This 
study will enroll approximately 96 subjects, including all eligible subjects from rIX-FP lead-in 
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studies and approximately 10 subjects requiring major non-emergency surgery who have not 
previously received treatment with rIX-FP and at least 13 PUPs.  The target is at least 50 
subjects completing 100 EDs during enrollment in all CSL-sponsored rIX-FP studies, as per 
the European Medicines Agency guidelines [EMA, 2009]. 
11.2 
DESCRIPTION OF ANALYSIS DATASETS 
11.2.1 Pharmacokinetic Population 
The PK population will comprise subjects who have received at least 1 dose of rIX-FP and 
have blood samples drawn for PK assessment.  For the PK parameter assessment of the 100 
IU/kg rIX-FP dose, subjects will be excluded from analysis if an insufficient number of 
analyzable PK samples were obtained to permit the evaluation of at least 1 PK parameter for 
rIX-FP, excluding samples obtained after receiving a dose of rIX-FP or any other FIX product 
for the treatment of a bleeding episode during the PK sampling period. 
11.2.2 Safety Population 
The safety population will consist of all subjects who received at least 1 dose of rIX-FP in 
this extension study. 
11.2.3 Efficacy Population 
The efficacy population will consist of all subjects in the safety population who participate in 
the non-surgical efficacy portion of the study. 
11.2.4 Per-protocol Population 
The per-protocol (PP) population will include all subjects in the efficacy population who 
complete the study without any major protocol deviations that would affect the assessment of 
the efficacy endpoints.  In some cases, subjects may be retained in the PP population with 
partial data up to the point of a major deviation.   

 
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11.2.5 Surgical Population 
The surgical population, which is a subset of the safety population, will include all subjects 
who have received at least 1 dose of rIX-FP for a surgical procedure in this study. 
11.2.6 Subcutaneous Population 
The SC population, which is a subset of the safety population, will include all subjects who 
have received at least 1 SC dose of rIX-FP in the SC substudy. 
11.3 
STATISTICAL ANALYSES AND METHODS 
All safety and efficacy data will be summarized.  Unless otherwise indicated, all summaries 
and analyses will be based on the experience of subjects in this study only and not on the 
combined experience in this plus lead-in studies.  Continuous data will be summarized using 
descriptive statistics including means, standard deviations, medians, first and third quartiles, 
and minimums and maximums.  Categorical variables will be summarized with frequencies 
and percentages. 
Unless otherwise indicated, baseline is defined as the Day 1 visit in this study.  In general, only 
available data will be used in summaries and analyses unless otherwise specified in the 
Statistical Analysis Plan (SAP).   
A complete description of the statistical analyses and methods will be provided in an SAP, 
which will be finalized before the database is locked. 
Note: The planned statistical analyses for the SC substudy are detailed in Appendix 2. 
11.3.1 Subject Disposition and Characteristics 
11.3.1.1 
Subject Disposition 
The number of subjects who enrolled into this study, who completed the study, who 
discontinued the study, who completed 100 EDs, and who failed to complete 100 EDs in this 

 
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study by reason for discontinuing the rIX-FP or withdrawing from the study, will be presented 
in summary tables.  The reason for discontinuing the rIX-FP or withdrawing a subject from the 
study will be listed by subject.  The number of subjects in each analysis population will be 
summarized overall. 
11.3.1.2 
Subject Characteristics 
Demographics and baseline subject characteristics at the time of enrollment in this study will 
be presented in summary tables and data listings.  Select information such as medical history 
at enrollment and treatment regimen at end of study, will also be presented in summary tables 
to help characterize the subject population in this study.  The data source for these additional 
summaries will be the datasets used to report final results (details on the choice of variables 
and their source will be provided in the SAP). 
11.3.2 Efficacy Analyses 
All efficacy summaries and analyses for non-surgical efficacy data will be performed on the 
efficacy population.  Additional analyses may be performed on the PP population.  Where 
noted here or in the SAP, overall summaries may be further broken down by lead-in study (and 
by Arm in Study CSL654_3001) or new subjects, age group, or geographic region. 
Efficacy summaries and analyses of surgical data will be performed on the surgical population. 
11.3.2.1 
Primary Efficacy Analysis 
This study does not have a primary efficacy endpoint since the evaluation of efficacy is not a 
primary objective. 
11.3.2.2 
Secondary Efficacy Analyses 
The AsBR and ABR will be derived for each treatment interval assigned to the subject (7 days, 
10 days, 14 days, and 21 days), and will not include the time either during or the first 3 months 
after the surgery substudy, the time during the SC substudy, and subjects in Arm 4.  Rates will 
be calculated as the number of applicable bleeding episodes divided by the total duration the 

 
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subject was assigned prophylaxis treatment for the given treatment interval.  Disjoint periods 
of observation with the same treatment interval may be combined within a subject for those 
periods when the subject was treated for at least 3 months to insure stable treatment.  Duration 
of treatment for each period will begin when the subject receives the first dose of the assigned 
prophylaxis regimen.  ABRs will be summarized across subjects using descriptive statistics.  A 
crude rate will also be calculated for each treatment interval along with an exact two-sided 
95% confidence interval under the assumption that counts follow a Poisson distribution with 
common underlying intensity. 
AsBR and ABR are considered secondary endpoints in this study.  Other types of bleeding 
episodes (eg, traumatic) will be summarized in a similar manner as these secondary endpoints. 
A comparison of AsBR and ABR will be performed between 14-day routine prophylactic 
treatment in this study compared with on-demand only treatment from Study CSL654_3001 
(Arm 2).  A Wilcoxon rank sum test will be performed on the matched-pairs at the two-sided 
0.05 level to test the hypothesis that the median difference in rates differs from zero.  
Descriptive statistics will also be provided.     
The analysis of AsBR will also be conducted with subjects from both Study CSL654_3001 and 
the present extension study to assess whether a similar treatment effect exists between the 7-
day prophylaxis regimen and the 14-day prophylaxis regimen.   
In order to demonstrate that a similar treatment effect also exists for the 14-day prophylaxis 
regimen and 7-day prophylaxis regimen, the mean AsBR will be compared between the 
2 prophylaxis regimens to evaluate non-inferiority. Following the same clinically acceptable 
difference used in the CSL654_3001 study, a non-inferiority margin of 6 spontaneous 
bleeds/year has been selected.   
The null and alternative hypotheses for the AsBR are as follows: 
H0:  µ7-day – µ14-day  -6 
H1:  µ7-day – µ14-day > -6 

 
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To establish non-inferiority of the 14-day regimen versus the 7-day regimen for the AsBR, the 
lower confidence limit of the 95% confidence interval, based on a one-sample (paired) 
t-distribution, for the difference between the two means (7-day regimen - 14-day regimen) must 
be greater than -6 spontaneous bleeds/year.   
The same analysis will be conducted for the comparison of ABR. The clinical difference of 
6 total bleeds/year is selected when switching from 7-day prophylaxis regimen to 14-day 
prophylaxis regimen. Futhermore, the non-inferority analysis of AsBR and ABR between the 
extended regimens (14-day or 10-day) and the 7-day regimen will be conducted in a similar 
manner. 
Similar comparisons of ABR and AsBR between treatment regimens will also be conducted 
for the subgroup of pediatric subjects. 
Multiple comparisons and multiplicity: A fixed-sequence multiple testing procedure will be 
used to control the overall Type I error rate at the two-sided 0.05 level for the secondary 
efficacy analysis.  Specifically, the test between 14-day prophylaxis regimen and On-demand 
will first be performed at the two-sided 0.05 level of significance. Only if the 14-day regimen 
is found to be effective, will the 14-day prophylaxis regimen be non-inferior to 7-day 
prophylaxis regimen at pre-specified margin. Only if 14-day prophylaxis regimen is 
demonstrated non-inferior to the 7-day regimen, will the extended prophylaxis regimen (10-day 
or 14-day) be non-inferior to the 7-day regimen. 
Consumption of rIX-FP will be summarized with descriptive statistics according to treatment 
interval and overall.  No formal statistical inferences will be performed on these summary 
measures.  Standardized yearly totals will be calculated for each subject by dividing the 
subject’s observed total by total duration (days/365.25 days per year); standardized monthly 
totals will be calculated by dividing the yearly estimate by 12.  Calculation of duration will 
begin on the date of the first prophylactic injection at the assigned treatment interval.  Periods 
when the subject is not receiving routine prophylaxis (surgery substudy, SC substudy) or 

 
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treatment for any bleeding episodes including preventative injections, will not be included in 
summaries of consumption or in the calculation of ABRs.   
Five measures of consumption will be reported: number of injections per subject (per month 
and per year), IU/kg per subject (per month and per year), and IU/kg per event.  One measure 
is identified as a secondary endpoint in this study: IU/kg per month per subject for routine 
prophylaxis treatment.  All measures will be summarized by treatment modality (continuous 
prophylaxis, intermittent prophylaxis, on-demand treatment, and total) and by lead-in study.  
Additionally, IU/kg per subject will be summarized by geographic region.  Other related 
measures may be reported, such as total IUs per subject, as specified in the SAP. 
Investigator assessment of hemostatic response to treatment of bleeding episodes in Arm 4 
subjects will be summarized using descriptive statistics.    
 
 
 
 
 
 
 
 
 
 
 
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11.3.2.4 
Additional Efficacy Information from the Surgery and Subcutaneous  
Substudies 
Surgical data will be summarized as case narratives or with descriptive statistics or counts 
where appropriate. 
The investigator’s overall clinical assessment of hemostatic efficacy for surgical prophylaxis, 
based on the four point ordinal scale (excellent, good, moderate, poor/none), will be presented. 
The change in hemoglobin level between baseline and nadir-intra- and post-operation may be 
presented. 
A comparison of the pre-operative predicted surgical blood loss (average and maximum) for a 
non-hemophilic individual undergoing the same type and extent of surgical procedure and the 
estimated interoperative blood loss may be presented.  Additionally, a comparison of pre-
operative predicted transfusion requirements for a non-hemophilic individual undergoing the 
same type and extent of surgical procedure and the actual transfusion may be presented. 
Additional surgical displays will include the type of surgery, the relationship to hemophilia 
(related / not related), rIX-FP consumption (including dose regimen, IU and IU/kg per dose, 
and time relationship for each injection during the surgery substudy and per surgery), and 
complications.   
No additional efficacy data will be obtained from the SC substudy. 
11.3.3 Safety Analyses 
Safety summaries will be performed on the safety population unless otherwise specified.  No 
formal statistical comparisons will be made unless specified. 
11.3.3.1 
Primary Safety Analysis 
The number and proportion of subjects with positive tests for inhibitors to FIX during the study 
will be tabulated.  Subjects must have two tests that are positive to be classified as having an 

 
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inhibitor.  Inhibitor antibodies against FIX will be categorized as low titer (≥ 0.6 to 5 BU/mL) 
and high titer (> 5 BU/mL).  A two-sided 95% exact Clopper-Pearson binomial confidence 
interval (one-sided if no events are observed) for inhibitor development among subjects treated 
with rIX-FP, by PTP and PUP, will be presented.   
11.3.3.2 
Adverse Events 
Adverse events will be recorded from the time when informed consent is granted at the start of 
this extension study until study completion (or the end of study visit upon early termination).  
In this study, study-emergent AEs are defined as those with onset on or after Day 1 in this 
extension study.   
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA).  The number and percentage of subjects who experience AEs will be summarized 
overall by system organ class (SOC) and preferred term (PT) and will also be summarized 
based on maximum severity and relationship to rIX-FP.   
Descriptive analysis of AEs will include: 
 Incidence of study-emergent AEs, AESIs and SAEs grouped by SOC and PT. 
 Incidence of study-emergent AEs, grouped by SOC and PT, with reference to the 
relationship to rIX-FP and maximum severity. 
 Incidence of study-emergent AEs leading to withdrawal grouped by SOC and PT. 
 Incidence of related AEs to rIX-FP over the course of the study. 
Individual listings of all AEs will also be provided. 
Serious AEs, deaths, and discontinuations due to AEs will be summarized and supported by 
individual subject data listings. 
A summary of study-emergent AEs by SOC and PT will be provided by treatment interval.  
Subjects who change the frequency of dosing during the duration of this extension study may 
be counted more than once in this summary. 

 
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11.3.3.3 
Local Tolerability 
Local tolerability will be assessed via the frequency and severity of reported local reactions 
including the subject assessment and investigator assessment. 
11.3.3.4 
Laboratory Safety Parameters 
Laboratory results along with the change from baseline will be summarized by parameter and 
study visit.  The change from baseline to the smallest value after first dose of study product, 
largest value after first dose of study product, and final value will also be summarized.  For 
laboratory parameters with positive or negative results, the number and proportion with 
positive study-emergent results will be summarized at each visit. 
The number and proportion of subjects with study-emergent abnormal laboratory values will 
be tabulated.  Study-emergent abnormal laboratory values are those in which the baseline value 
is normal and post-baseline value is abnormal.  Laboratory values will be converted to the 
project-defined unit of measurement. 
11.3.3.5 
Vital Signs 
Vital signs results along with the change from baseline will be summarized by parameter and 
study visit.  The number and proportion of subjects with study-emergent potentially clinically 
significant vital sign values by study visit (blood pressure, heart rate, and body temperature) 
will be tabulated.  Criteria for potentially clinically significant values will be documented in 
the SAP. 
11.3.3.6 
Virus Safety 
Results from virus safety samples (if tested) will be displayed in a listing. 
11.3.3.7 
Inhibitors to Factor IX 
The number and proportion of subjects with a confirmed FIX inhibitor titer above the cut-off 
level (≥ 0.6 BU/mL) will be tabulated. 

 
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11.3.3.8 
Antibodies to rIX-FP and CHO Cell-derived Proteins 
The number and percentage of subjects with rIX-FP and CHO cell-derived protein antibody 
titers above the cut-off level for the respective confirmation assays will be tabulated. 
11.3.3.9 
Additional Safety Information from the Surgery and Subcutaneous Substudies 
Safety assessments and events, including AEs, which occur during the protocol-defined 
preoperative, intraoperative, or postoperative periods of the surgery substudy and in the SC 
substudy will be summarized in separate tables. 
11.3.4 Pharmacokinetics and Pharmacodynamic Data 
11.3.4.1 
Pharmacokinetics 
In the main study, incremental recovery will be calculated using the PK samples obtained 
following injection of 100 IU/kg rIX-FP or 50 IU/kg rIX-FP for subjects in Arm 4.  Incremental 
recovery (IU/mL per IU/kg) is defined as FIX activity (IU/mL) obtained 30 minutes following 
injection, per dose of (IU/kg) injection.  Incremental recovery and FIX activity levels will be 
summarized. 
FIX activity levels from central and local laboratories will be summarized with descriptive 
statistics and listed by subject and assessment.  Trough levels, if available, will be summarized 
by treatment interval. 
See Appendix 2 for details on the PK analyses in the SC substudy. 
11.3.4.2 
Pharmacodynamics 
Not applicable. 
11.3.5 Other Analyses 
Subgroup analyses may be performed, and these will be specified in the SAP. 

 
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11.3.6 Interim Analysis 
No interim analyses are planned. The following analyses are planned before study closure: 
1. The final analysis of the SC substudy data will be conducted when all subjects have 
completed the SC substudy. 
2. The final analysis of PTPs (including surgical data from PTPs) will be conducted when all 
PTPs have completed the study. 
In addition, safety, efficacy and / or PK data and subject characteristics may be reported to 
regulatory authorities before study closure. 
12. QUALITY ASSURANCE 
The study may be subject to an audit by CSL, an authorized representative(s) of CSL and / or 
inspections by an authorized regulatory authority (eg, US Food and Drug Administration 
[FDA]).  Regulatory authorities may request access to all study documentation, including 
source documents for inspection and copying, in keeping with local regulations.  CSL will 
immediately notify the investigator of an upcoming audit / inspection. 
In the event of an audit, all pertinent study-related documentation must be made available to 
the auditor(s).  If an audit or inspection occurs, the investigator at each study site will permit 
the auditor / inspector direct access to all relevant documents and allocate their time as well as 
the time of relevant staff to discuss the findings and any relevant issues. 
13. REGULATORY AND ETHICS CONSIDERATIONS 
13.1 
REGULATORY CONSIDERATIONS 
CSL or its agents will submit the appropriate documents to the local regulatory agencies and 
will await approval before study start. 

 
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This study will be conducted under a Clinical Trial Application, a Clinical Trial Notification 
or an FDA Investigational New Drug application, as appropriate and documented in accordance 
with the applicable regulatory guidelines and requirements. 
The procedures set out in this study protocol are designed to ensure that CSL and the 
investigator abide by the principles of the current ICH GCP guideline on the conduct, 
evaluation and documentation of this study, as described in ICH Topic E6 (Guideline for GCP).  
The study will also be carried out according to all applicable international and national 
regulatory requirements. 
13.2 
Institutional Review Board / Independent Ethics Committee 
The investigator must submit the protocol and informed consent forms (ICFs) for review by an 
authorized and properly constituted (according to local guidelines) IRB / IEC.  Written 
approval must be received from the IRB / IEC before commencement of the study. 
13.3 
SUBJECT INFORMATION AND INFORMED CONSENT 
The principles of informed consent in the Declaration of Helsinki must be implemented in this 
clinical study before protocol-specified procedures are carried out.  Information should be 
given in both oral and written form whenever possible and deemed appropriate by the 
IRB / IEC.  Subjects, their relatives (or if necessary, legally acceptable representatives) must 
be given ample opportunity to inquire about details of the study. 
Should there be any amendments to the protocol that would directly affect the subject’s 
participation in the study (eg, a change in any procedure), the ICF must be amended to 
incorporate this modification.  Subject must be informed of the change and they must sign the 
amended ICF indicating that they re-consent to participate in the study. 

 
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13.4 
SUBJECT IDENTIFICATION AND CONFIDENTIALITY 
All subject names and contact details will be kept confidential.  Subjects will be identified 
throughout documentation and evaluation by the number allotted to them during the study.  
Each subject will be told that all study findings will be handled in the strictest confidence. 
The investigator at the study site will be responsible for retaining sufficient information about 
each subject (eg, name, address, phone number and identity in the study) so that regulatory 
agencies or CSL may access this information should the need arise.  These records should be 
retained in a confidential manner as long as legally mandated according to local requirements. 
Subject medical records pertaining to the study may be inspected / audited at any time by CSL 
employees or their duly authorized representatives, a regulatory authority or the IRB / IEC.  All 
records accessed will be strictly confidential.  Consent to participate in the study includes 
consent to these inspections / audits. 
13.5 
INDEMNITY AND COMPENSATION 
It is CSL policy that persons who participate in CSL’s clinical studies should be no worse off 
for their having been involved in the study.  These persons include the subjects / volunteers, 
the investigator, the hospital and the IRB / IEC.   
CSL has taken out insurance to cover its obligations under both the Indemnity and the 
Compensation guidelines for injury to subjects involved in the study. 
Other details regarding compensation and the obligations of the investigator / CSL are provided 
in the Clinical Trial Agreement for the study (see Section 14.1). 
14. ADMINISTRATIVE CONSIDERATIONS 
14.1 
CLINICAL TRIAL AGREEMENT 
This study will be conducted under a Clinical Trial Agreement between CSL (“Sponsor”) and 
the institution(s) representing the investigational study site(s) (“Authority”).  Financial support 

 
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to the investigational site(s) will be detailed in the Clinical Trial Agreement.  The Clinical Trial 
Agreement must be signed before the commencement of the study and will clearly delineate 
the responsibilities and obligations of investigator and CSL, and will form the contractual basis 
under which the clinical study will be conducted.   
14.2 
CLINICAL STUDY REGISTRATION AND RESULTS DISCLOSURE  
CSL will provide the relevant study protocol information in public database(s) before or at 
commencement of the study.  CSL may also provide study information for inclusion in national 
registries according to local regulatory requirements. 
Results of this study will be disclosed according to the relevant regulatory requirements.  All 
publications in peer-reviewed medical journals resulting from this study will be listed in the 
original study protocol registration record. 
14.3 
IMPLEMENTATION OF THE PROTOCOL / PROTOCOL 
AMENDMENT(S) 
With the exception of medical emergencies, no changes or deviations in the conduct of the 
signed protocol will be permitted without documented approval of the CSL Medical Monitor 
and the IRB / IEC.  In the event of a medical emergency, the investigator at the study site will 
institute any medical procedures deemed appropriate.  However, all such procedures must be 
promptly reported to the CSL Medical Monitor and the IRB / IEC.   
Modifications to the protocol that may affect subject safety or the way the study is to be 
conducted will be documented in a protocol amendment, which must be approved by the IRB / 
IEC.   
Administrative changes to the protocol, defined as minor corrections and / or clarifications that 
have no effect on the way the study is to be conducted, will not require IRB / IEC approval, 
but will be submitted to the IRB / IEC for their information. 

 
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14.4 
PROTOCOL DEVIATIONS 
All instances where the requirements of the study protocol were not complied with will be 
tracked.   Corresponding subjects may be withdrawn from the study at the discretion of the 
investigator and / or CSL.  Study protocol deviations arise when subjects who have been 
entered in the study deviate from the IRB / IEC-approved study protocol.   
If a major protocol deviation (ie, a deviation that could have a significant effect on the subject’s 
safety, rights, or welfare and / or on the integrity of the study data) occurs, the investigator 
must notify CSL and the appropriate IRB / IEC as soon as possible or as per local requirements.   
14.5 
DOCUMENTATION AND RECORD KEEPING  
14.5.1 Data Collection 
The investigator (or delegate) will maintain individual records for each subject.  These records 
should include dates when a subject visited the study site, records of vital signs, medical 
history, or physical examinations, administration of rIX-FP or concomitant therapy, any AEs 
experienced, and other notes as appropriate.  These records constitute source data.   
An eCRF will be provided by CSL (or delegate) for each subject enrolled into the study.  The 
investigator is responsible for ensuring accurate and proper completion of the eCRF in a timely 
manner so that it always reflects the latest observations on the subjects enrolled in the study.  
All entries on the eCRF must be backed up by source data unless there is prior agreement that 
the eCRF is the source data.   
All source data will be kept according to all applicable regulatory requirements.  Source data 
must be completed legibly for each subject enrolled into the study and signed by the 
investigator (or delegate). 
The subject eDiary will be completed by the subject, or caregiver, at home.  Data entered into 
the eDiary constitute electronic source data.  At each clinic / telephone visit, the investigator 
will review the eDiary entries with the subject.    

 
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14.5.2 Data Quality Assurance 
Data generated throughout the study will be monitored and the eCRFs checked against the 
subject records for completeness and accuracy.  CSL’s study monitor (or delegate) will perform 
this function. 
Following completion of eCRF pages and entry of the data into a database, the data will be 
checked electronically for consistency and plausibility.  Queries will be generated for 
questionable data and clarification sought from the investigator.  These data queries must be 
resolved in a timely manner by the investigator (or delegate). 
14.5.3 Record Retention 
An investigator study file prepared by CSL (or delegate), containing all applicable documents 
for use at the study site, will be made available to the investigator before the start of the study.  
All study documentation and materials maintained in the investigator study file must be kept 
in conformance with applicable national laws and regulations.   
All study documentation and materials maintained in the investigator study file at the study site 
must be available for inspection by the CSL’s study monitor (or delegate) to determine that all 
required documentation is present and correct.   
The study may be audited or inspected by qualified delegates from CSL or a competent 
regulatory authority. 
Following completion of the study, the investigator is responsible for archiving the investigator 
study file, the subject’s records and the source data according to applicable regulatory 
requirements.   
14.6 
STUDY AND SITE CLOSURE 
CSL reserves the right to prematurely discontinue or suspend the study either at a particular 
site or at all study sites at any time and for any reason.  If such action is taken, the CSL Study 

 
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Monitor (or delegate) will discuss this with the investigator (for Japan sites only: the head of 
the medical institute) at each study site at that time and notify them in writing.  If the study is 
suspended or terminated for safety reasons all investigators (for Japan sites only: the heads of 
the medical institutes) and the relevant regulatory agencies will be immediately notified of the 
action as well as the reason for it.  The investigator (for Japan sites only: the head of the medical 
institute) at each study site will advise the IRB / IEC overseeing the study at their site. 
14.7 
CLINICAL STUDY REPORT 
A final clinical study report will be written after the completion of the study.  In addition, study 
reports will be written when a) all subjects have completed the SC substudy and b) when all 
PTPs have completed the study (see Section 11.3.6). These reports will be integrated into the 
final clinical study report.  
CSL or its agent will write the report in consultation with the investigator or, if applicable, a 
nominated coordinating investigator (or delegate).  It is required by CSL that the coordinating 
investigator will sign the clinical study report.   
Progress reports may be provided to the relevant regulatory bodies in accordance with their 
requirements. 
14.8 
USE OF DATA AND PUBLICATIONS 
The rights and obligations of investigators and CSL concerning any formal presentation or 
publication of data collected as a direct or indirect result of this study will be addressed 
specifically in the Clinical Trial Agreement for the study. 
 
15. REFERENCES 
Giangrande P.  Hemophilia B: Christmas disease.  Expert Opin Pharmacother. 2005;6:1517-
24. 

 
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Guideline on clinical investigation of recombinant and human plasma-derived factor IX 
products, 21 July 2011, EMA/CHMP/BPWP/144552/2009. 
McCarthy K, Stewart P, Sigman J, et al.  Pharmacokinetics of recombinant FIX after 
intravenous and subcutaneous administration in dogs and cynomolgus monkeys.  Thromb 
Haemost. 2002;87:824-30. 
Metzner HJ, et al. Genetic fusion to albumin improves the pharmacokinetic properties of factor 
IX. Thromb Haemost. 2009;102:634-44. 
Srivastava A, Brewer, AK, Mauser-Bunschoten, EP, et al. WFH guidelines: Guidelines for the 
management of haemophilia. Haemophilia 2013;19:e1-e47. 
Study 8244656.  Nonclinical study report.  rIX-FP and rIX-FP-B: Single dose intravenous 
(bolus) administration toxicity study in the rat followed by a 5 day treatment-free period.  2011. 
Study 040200011.  Nonclinical study report.  rIX-FP: Single dose pharmacokinetic and 
pharmacodynamic study by Intravenous (bolus) administration to hemophilia B dogs.  2010. 
Study APQ0001.  Nonclinical study report.  rIX-FP: Toxicity study by intravenous (bolus) 
administration to cynomolgus monkeys for 4 Weeks.  2010. 
Study APQ0002.  Nonclinical study report.  rIX-FP: Single dose pharmacokinetic study by 
intravenous (bolus) administration to cynomolgus monkeys.  2010. 
Study APQ0005.  Nonclinical study report.  rIX-FP: Single dose toxicity study by intravenous 
(bolus) administration to CD rats.  2010. 
Study APQ0008.  Nonclinical study report rIX-FP: Local tolerance study in the rabbit 
following intravenous, intra-arterial or perivenous injection.  2010. 
Study APQ0009.  Nonclinical study report.  rIX-FP: Toxicity study by intravenous (bolus) 
administration to CD rats for 4 weeks followed by a 2 week recovery period.  2010. 
Study NBM 04/09.  Nonclinical study report.  Correction of hemostasis in FIX ko mice 
following treatment with rIX-FP.  2010. 
Study S22456.  Nonclinical study report.  In vivo thrombogenicity test in the rabbit.  2010. 
Study CSL654_2001.  Clinical study report.  An open-label, multicenter, dose-escalation safety 
and pharmacokinetic study of a recombinant coagulation FIX albumin fusion protein (rIX-FP) 
in subjects with hemophilia B.  December 2011. 
Study CSL654_2004.  Clinical study report.  A phase 1/2 open-label, multicenter, safety and 
efficacy study of a recombinant coagulation factor IX albumin fusion protein (rIX-FP) in 
subjects with hemophilia B.  August 2012. 
Study CSL654_3001.  Clinical study report.  A phase 2/3 open-label, multicenter, safety and 
efficacy study of a recombinant coagulation factor IX albumin fusion protein (rIX-FP) in 
subjects with hemophilia B.  November 2014. 

 
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Study CSL654_3002.  Clinical study report.  A phase 3 open-label, multicenter, 
pharmacokinetics, safety, and efficacy study of a recombinant fusion protein linking 
coagulation factor IX with albumin (rIX-FP) in previously treated children with hemophilia B.  
January 2014. 

 
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Appendix 1. 
SURGERY SUBSTUDY 
Table of Contents: Surgery Substudy 
SCHEDULE OF ASSESSMENTS: SURGERY SUBSTUDY – MAJOR SURGERY ........ 127 
SCHEDULE OF ASSESSMENTS: SURGERY SUBSTUDY – MINOR SURGERY ........ 129 
INTRODUCTION ................................................................................................................. 131 
STUDY OBJECTIVES AND ENDPOINTS ......................................................................... 131 
Primary Objective and Endpoint ................................................................................ 131 
Secondary Objective and Endpoints .......................................................................... 131 
STUDY DESIGN................................................................................................................... 132 
SELECTION OF SUBSTUDY POPULATION ................................................................... 133 
ALLOCATION, DOSING AND ADMINISTRATION ....................................................... 133 
Dose and Dosing Rationale ........................................................................................ 133 
CONCOMITANT THERAPY ............................................................................................... 134 
VISIT SCHEDULE ............................................................................................................... 135 
A.  Major Surgery ...................................................................................................... 135 
B.  Minor Surgery ...................................................................................................... 140 
C.  End of Participation in the Substudy (Major and Minor Surgery) ....................... 143 
D.  Discontinuation Procedures for the Substudy (Major and Minor Surgery) ......... 143 
STUDY VARIABLES AND METHODS OF ASSESSMENT ............................................ 144 
Subject Characteristics ............................................................................................... 144 
Efficacy Variables ...................................................................................................... 144 
Safety Variables ......................................................................................................... 146 
STATISTICS ......................................................................................................................... 146 

 
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SCHEDULE OF ASSESSMENTS: SURGERY SUBSTUDY – MAJOR SURGERY 
Period 
Before Surgery 
During 
Surgery 
After Surgery 
Timing  
 
-3 hours 
 N/A 
0 hours 
Every 24 hours  
up to 72 hours 
or discharge A 
End of 
Substudy 
Day 28 B  
Time Window 
Up to 28 
days 
before 
-6 hours 
  
+6 hours 
± 6 hours 
 ± 7 days 
Eligibility assessment  
 
X 
  
  
  
 
Surgery description 
 
X 
 
 
 
 
Physical examination 
 
X 
  
 X 
X 
X 
Vital signs 
 
X 
 X 
X 
X 
X 
Body weight 
 
X 
 
 
 
 
 
Hematology C 
 
X 
 X 
X  
X 
X 
Plasma FIX activity D 
X E 
 
X F 
X G 
X G 
X G 
X  
FIX inhibitors H 
X 
 
 
 
 
 
X 
antibodies against rIX-FP H 
X 
 
 
 
 
 
X 
Planned rIX-FP dose 
X 
 
 
 
 
 
 
Blood loss estimate 
X 
 
 
 
X 
 
 
Hemostatic intervention I 
X 
 
 
X 
X 
X 
 
Administer rIX-FP  J 
X 
 
X G 
X G 
X G 
 
Hemostasis assessment K 
 
 
 
X 
X 
 
Efficacy assessment 
 
 
  
 X 
 X 
 
Adverse events  
X 
<-------------------------------------------------------On an ongoing basis-----------------------------------> 
Concomitant therapy 
X 
<-------------------------------------------------------On an ongoing basis----------------------------------> 
FIX = coagulation factor IX; N/A = not applicable; rIX-FP = recombinant coagulation factor IX albumin fusion protein. 
 

 
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Notes to the Schedule of Assessments: Surgery Substudy – Major Surgery 
A: Assessments to be completed every 24 hours up to 72 hours or up to hospital discharge, whichever occurs first. 
B: Assessments to be completed at end of surgery substudy for all subjects (Day 28).  This visit is also the Day 1 visit for subjects in Arm 3, if they choose to 
remain in the main study after surgery.    
C: Hematology assessments (local laboratory) include: hemoglobin, hematocrit, platelet count, red blood cell (erythrocyte) count, white blood cell (leukocyte) 
count, white blood cell differential (optional). 
D: Plasma FIX activity will be assessed by both the local laboratory and a central laboratory.   
E: Assessment is not required if the FIX recovery rate has been assessed within the previous 28 days or for subjects in Arm 3.   
F: Blood samples will be taken between ~30 minutes after the administration of rIX-FP and before major surgery (timing dependent on the time required for the 
local laboratory to process the sample).   
G: If an additional injection of rIX-FP is needed during the perioperative period, a blood sample should be taken before the administration of rIX-FP for the 
assessment of FIX activity by the local laboratory.   
H: To be completed only for subjects in Arms 1 or 2. 
I: 
Planned and actual hemostatic interventions or transfusions other than rIX-FP (eg, whole blood, red blood cells, fresh frozen plasma or platelets). 
J: 
Additional injections of rIX-FP may be needed to maintain the required plasma FIX activity level.  Blood samples should be taken and tested for plasma FIX 
activity before each injection of rIX-FP, if feasible, so that the required dose can be calculated based on the plasma FIX activity. 
K: Hemostasis assessment includes: quantitation of postoperative bleeding through surgical drains and the occurrence of late rebleeding episodes; the presence 
and extent of any surgical wound hematomas and whether they require surgical evacuation. 

 
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SCHEDULE OF ASSESSMENTS: SURGERY SUBSTUDY – MINOR SURGERY 
Period 
Before Surgery 
During 
Surgery 
After Surgery 
Timing  
-3 hours 
 N/A 
0 hours 
At Discharge 
End of Substudy 
Time Window 
Up to -6 hours 
  
+6 hours 
± 6 hours 
  
Eligibility assessment  
X 
 
  
  
  
 
Surgery description 
X 
 
 
 
 
 
Physical examination 
 
 
  
 X 
X 
X 
Vital signs 
 
 
  
X 
X 
X 
Body weight 
X 
 
 
 
 
 
Plasma FIX activity A 
X B 
 
X B 
X C 
X C 
X C 
X 
Sample for FIX inhibitors 
 
 
 
 
 
X 
Sample for antibodies 
against rIX-FP 
 
 
 
 
 
X 
Blood loss estimate 
 
X 
 
X 
 
 
Hemostatic intervention D 
 
X 
X 
 
 
 
Planned rIX-FP dose 
during surgery 
 
X 
 
 
 
 
Administer rIX-FP 
X 
 
X C 
X C 
X C 
 
Hemostasis assessment E 
 
 
 
X 
X 
 
Efficacy assessment 
 
 
  
 X 
 X 
 
Adverse events  
X 
<-------------------------------------------------------On an ongoing basis-------------------------------------------------------> 
Concomitant therapy 
X 
<-------------------------------------------------------On an ongoing basis-------------------------------------------------------> 
FIX = coagulation factor IX; N/A = not applicable; rIX-FP = recombinant coagulation factor IX albumin fusion protein. 
 
 

 
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Notes to the Schedule of Assessments: Surgery Substudy – Minor Surgery 
A: Plasma FIX activity may be assessed by the local laboratory and / or the central laboratory.   
B: Blood samples (optional) may be taken before and ~30 minutes after rIX-FP administration to confirm the incremental recovery.   
C: Additional injections of rIX-FP may be needed to maintain the required plasma FIX activity level.  Blood samples should be taken and tested for plasma FIX 
activity before each injection of rIX-FP, if feasible, so that the required dose can be calculated based on the plasma FIX activity. 
D: Planned and actual hemostatic interventions or transfusions other than rIX-FP (eg, whole blood, red blood cells, fresh frozen plasma or platelets. 
E: Hemostasis assessment includes estimated actual intraoperative blood loss, blood loss expected as integral to the procedure and unexpected blood loss due to 
unforeseen complications. 
 
 

 
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INTRODUCTION 
This substudy of Study CSL654_3003 will examine the efficacy of rIX-FP in patients with 
hemophilia B who are undergoing non-emergency major or minor surgery.  Efficacy will be 
measured in both the intraoperative and postoperative periods.  In addition, safety endpoints, 
including antibodies against rIX-FP, inhibitors to FIX and other AEs throughout the duration 
of the study in all study subjects will be monitored.   
The substudy will be conducted in compliance with this study protocol, ICH GCP, and the 
applicable regulatory requirement(s). 
STUDY OBJECTIVES AND ENDPOINTS 
Primary Objective and Endpoint 
Primary Objective 
The primary objective of the substudy is to evaluate the efficacy of rIX-FP in the prevention 
and control of bleeding in patients with severe hemophilia B during surgical procedures. 
Primary Endpoint 
Investigator’s (or surgeon’s) overall clinical assessment of hemostatic efficacy for surgical 
prophylaxis, based on a four point ordinal scale (excellent, good, moderate, poor / none)    
Secondary Objective and Endpoints 
Secondary Objective 
The secondary objective of the study is to evaluate the safety of rIX-FP during the 
intraoperative and postoperative periods. 
Secondary Endpoints 
The secondary endpoints of this surgery substudy are: 
 The frequency of AEs related to rIX-FP during the intraoperative and postoperative 
periods.   
 The occurrence of FIX inhibitors.   
 The occurrence of antibodies against rIX-FP.   

 
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 Comparison of predicted and intraoperative estimated blood loss. 
 Comparison of predicted and actual transfusion requirements. 
 Change in hemoglobin levels between baseline, intraoperatively and postoperatively. 
STUDY DESIGN 
This is a prospective, open-label substudy to evaluate the efficacy and safety of rIX-FP to 
prevent bleeding during surgery in patients with congenital FIX deficiency (hemophilia B).  
The study will consist of intraoperative and postoperative safety and efficacy evaluation 
periods with rIX-FP.  Subjects must meet all of the inclusion criteria of the main study and 
require non-emergency major or minor surgery.  A major surgery is defined as a surgical 
procedure that involves anesthesia (general, spinal, epidural or regional block), respiratory 
assistance, or requires hemostatic therapy for periods exceeding 5 consecutive days 
(including but not limited to orthopedic and cardiac surgery).   
Approximately 3 hours before the non-emergency surgical procedure, the subject will receive 
a single bolus injection of rIX-FP in order to increase the plasma FIX activity level to either 
60% to 80%, or higher, as recommended by the WFH for major surgery, or higher if 
recommended by the guidelines of the local hospital / practice.  Additional bolus injections of 
rIX-FP may be administered during a major surgery, if needed.  Blood samples for the 
determination of FIX levels will be collected before administration of additional doses of 
rIX-FP, if feasible.  During the postoperative period, defined as the start of wound closure, 
additional bolus injections of rIX-FP may be administered to maintain a required trough FIX 
activity level as recommended by the WFH, at the investigator’s discretion. 
Details of the surgical procedure are to be documented as outlined in Perioperative Prophylaxis 
for Surgeries.  Efficacy and safety data during and after surgery will be recorded, including 
time / dose of rIX-FP with documentation of total consumption, investigator’s assessments of 
blood loss and overall efficacy, transfusion requirements and AEs. 

 
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Number of Subjects 
Any subjects requiring surgery during the course of the main study (CSL654_3003) will be 
enrolled in the surgery substudy, with a combined target enrollment of at least 5 subjects and 
10 major surgeries across the lead-in studies and this study.   
Duration 
The substudy design includes a 1 to 14 day (or longer, if needed) active treatment period.  
Subjects will then return to the treatment plan of the main study at Day 28 ± 7 days.  The 
duration of the active treatment period will depend on the type of surgery and local standard.  
SELECTION OF SUBSTUDY POPULATION 
To be eligible for the substudy, subjects must meet all eligibility criteria of the main study 
protocol and: 
 Must require non-emergency surgery. 
 Must provide written informed consent for substudy participation. 
ALLOCATION, DOSING AND ADMINISTRATION 
Dose and Dosing Rationale 
There will be 3 treatment periods in this substudy: preoperative, intraoperative and 
postoperative.  The dose of rIX-FP will be selected based on the subject’s PK data obtained 
during the lead-in study or this (CSL654_3003) study, including incremental recovery and 
clearance, and the recommendations of the WFH. 
The desired FIX increase (% or IU/dL), as recommended by the WFH (see Appendix 3) for the 
control of bleeding during surgery should be calculated based on an individual subject’s PK 
data using the following formula: 
Number 
of factor 
IX IU 
required 
(IU) 
= 
Body 
weight 
(kg) 
X 
Desired 
factor IX 
increase 
(% or 
IU/dL) 
X 
Reciprocal of 
observed 
recovery 
(IU/kg per 
IU/dL) 

 
Study Number: 
CSL654_3003 
Study Product: 
rIX-FP 
 
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Selection and Timing of Dose for Each Subject in the Substudy 
Preoperative treatment 
Approximately 3 hours before the start of the scheduled surgery, the subject will be 
administered 1 bolus injection of rIX-FP.  The dose of rIX-FP (50 to 100 IU/kg, or higher) will 
be selected based on the subject’s individual PK parameters, in order to increase the FIX levels 
to 60% to 80%, or higher.   
Intraoperative treatment 
The subject may receive intraoperative doses of rIX-FP, depending on the FIX activity levels, 
type of surgery and local standard of care.  FIX activity levels should be measured before 
major surgery to ensure the trough FIX activity level is maintained at 60% to 80% during 
major surgical procedures.  In the event of the need for repeat dosing during the surgery, the 
FIX activity level should be measured. 
Postoperative treatment 
The subject will receive postoperative injections of rIX-FP from 1 to 14 days (or longer, if 
needed), depending on the FIX activity levels, type of surgery and as recommended by the 
WFH.  FIX activity levels should be measured before repeat dosing.  Removal of sutures or 
drains is best carried out at the time of peak FIX activity level. 
CONCOMITANT THERAPY 
All drugs currently being taken by a subject after the screening visit, and which continue to 
be taken during the substudy, are regarded as concomitant therapy and must be documented 
in the eCRF. Nonpharmacological intervention (eg, physical therapy or a minor surgical 
procedure performed outside of the surgical substudy) is also regarded as concomitant 
therapy and must be documented in the eCRF. 
 

 
Study Number: 
CSL654_3003 
Study Product: 
rIX-FP 
 
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The following concomitant therapy is PERMITTED during the study if needed: 
 Blood product transfusion (whole blood, erythrocytes [red blood cells], FFP or 
platelets), documented as planned blood product transfusion before the start of the 
surgery, if its use is planned. 
 Heparin use is limited to 200 U/day, if needed, to maintain patency of IV lines. 
 Antifibrinolytic agents. 
 Antibiotic and antiviral agents. 
 Tranexamic acid or epsilon aminocaproic acid.   
 Local hemostatic measures (eg, oxidized cellulose and fibrin glue). 
 Standard thrombosis prophylaxis. 
 Marketed FIX concentrate may be used ONLY as rescue medication. 
As recommend in WFH guidelines, postoperative pain may be managed initially by IV 
morphine or other narcotic analgesics, followed by an oral opioid.  As pain decreases, 
paracetamol or acetaminophen may be used. 
VISIT SCHEDULE 
A.  Major Surgery 
Procedures to be performed before and after major surgery are provided in the Schedule of 
Assessments: Surgery Substudy – Major Surgery. 
The following procedures will be performed BEFORE (within 30 minutes preferred, unless 
otherwise stated) administration of rIX-FP: 
 Eligibility assessment. 
 Record type of surgery and association (if any) with hemophilia.   
 Physical examination. 
 Vital signs. 
 Body weight. 
 Obtain blood sample for hematology (local laboratory). 

 
Study Number: 
CSL654_3003 
Study Product: 
rIX-FP 
 
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 Obtain blood samples for measurement of plasma FIX activity before and ~30 minutes 
after rIX-FP administration to confirm the incremental recovery (up to 28 days before 
surgery; central and local laboratory).   
 Obtain blood samples for: 
o Inhibitors against FIX (up to 28 days before surgery for subjects in Arms 1 or 2; 
central laboratory). 
o Antibodies against rIX-FP (up to 28 days before surgery for subjects in Arms 1 or 2: 
central laboratory). 
 Review concomitant therapy. 
 Review AEs since last visit. 
 rIX-FP should be administered approximately 3 to 6 hours before surgery.   
 Blood samples for measurement of plasma FIX activity should be collected 30 minutes 
after administration of rIX-FP and immediately before a major surgery starts.  If 
feasible, the samples should be tested at the local laboratory as well as the central 
laboratory. 
Before surgery, the following estimates must be made by the surgeon or physician 
performing the procedure: 
 Estimate of intraoperative predicted blood loss (PBL) (average and maximum). 
 Estimate planned hemostatic intervention (other than rIX-FP). 
 Estimate planned transfusion during surgery. 
 Estimate planned rIX-FP dose during surgery. 
 Estimates must be based on a patient without hemophilia, undergoing the same surgical 
procedure. 
During Surgery 
The following information should be recorded during surgery: 
 Vital signs. 
 Blood samples before injection of rIX-FP for plasma FIX activity level (central and 
local laboratory). 

 
Study Number: 
CSL654_3003 
Study Product: 
rIX-FP 
 
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 Dose of rIX-FP administered (if needed).  If the dose of rIX-FP is more than the planned 
dose, the reason for the discrepancy should be documented, including any unforeseen 
complications. 
 Additional hemostatic interventions and / or transfusions required during surgery 
(including blood products and other coagulation factor[s]).  In the event that the actual 
additional hemostatic interventions and / or transfusions required are higher than the 
estimated planned hemostatic interventions (other than rIX-FP) and / or transfusions 
required, the possible reason(s) should be documented as: 
o Inadequate hemostasis. 
o Incorrect dose or dose regimen of rIX-FP. 
o Expected as integral to the extended procedure. 
o Unexpected or unforeseen complication. 
o Other. 
 Obtain blood sample for hematology (local laboratory). 
Immediately After (0 hours) Surgery 
 Physical examination. 
 Vital signs. 
 Blood sample for hematology (local laboratory). 
 Blood samples before injection of rIX-FP (if needed) for plasma FIX activity level 
(central and local laboratory). 
 Dose of rIX-FP (if needed). 
 Additional hemostatic interventions and / or transfusions required (including blood 
products and other coagulation factor[s]).  In the event that the actual additional 
hemostatic interventions and / or transfusions required are higher than the estimated 
planned hemostatic interventions (other than rIX-FP) and / or transfusions required, the 
possible reason(s) should be documented as: 
o Inadequate hemostasis. 
o Incorrect dose or dose regimen of rIX-FP. 
o Expected as integral to the extended procedure. 

 
Study Number: 
CSL654_3003 
Study Product: 
rIX-FP 
 
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o Unexpected or unforeseen complication. 
o Other. 
 Record AEs and concomitant therapies. 
 Using clinical judgment, the investigator (in consultation with the surgeon) will evaluate 
the intraoperative hemostasis of the subject after the end of the surgical procedure 
according to the efficacy scale (Investigator’s Evaluation of Efficacy of Surgical 
Treatment).   
 Intraoperative estimated blood loss (EBL).  The estimated EBL will be based on the 
anesthesiologist’s record of EBL during the surgical procedure.  If an anesthesiologist 
was not present during the procedure, EBL will be estimated by the surgeon or 
physician performing the procedure.  In the event that the actual intraoperative EBL is 
higher than the intraoperative PBL, the possible reason(s) should be documented as: 
o Inadequate hemostasis. 
o Incorrect dose or dose regimen of rIX-FP. 
o Blood loss expected as integral to the procedure. 
o Unexpected blood loss due to unforeseen complications. 
o Other. 
After Surgery (24 to 72 Hours or up to Discharge) 
After surgery, the following procedures should be performed (ie, during hospital / clinical 
care and discharge): 
 Physical exam every 24 hours up to 72 hours postoperation or hospital discharge, 
whichever is earlier. 
 Vital signs every 24 hours up to 72 hours postoperation or hospital discharge, whichever 
is earlier. 
 Blood sample for hematology every 24 hours from 0 hours to 72 hours postoperation or 
hospital discharge, whichever is earlier. 
 Quantitation of postoperative bleeding through surgical drains and the occurrence of late 
rebleeding episodes up to 72 hours or hospital discharge, whichever is earlier. 

 
Study Number: 
CSL654_3003 
Study Product: 
rIX-FP 
 
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 The presence and extent of any surgical wound hematomas and whether they require 
surgical evacuation. 
 Blood samples before injection of rIX-FP (if needed) and 30 minutes after additional 
doses of rIX-FP are administered (if needed) for plasma FIX activity level (central and 
local laboratory). 
 Dose of rIX-FP (if needed). 
 Additional hemostatic interventions and / or transfusions required during surgery 
(including blood products and other coagulation factor[s]). 
 Record AEs and concomitant therapies. 
 Investigator evaluation of efficacy every 24 hours, from wound closure (0 hours) to 
72 hours, or until hospital discharge or until discontinuation of therapy, whichever is 
earlier. 
 Post-surgery prophylactic injections, with or without additional preventative treatment 
before physical therapy should be administered from post-surgery to the end of the 
surgery substudy.    
 If a subject does not start / restart prophylaxis, the subject should be withdrawn from the 
study and the rationale for the decision should be documented in the eCRF. In addition, 
attempts should be made to complete and document the end of study assessments (main 
study). 
End of Participation in the Surgery Substudy (Day 28) 
After surgery and discharge from the hospital or treating clinic, the subject may require 
rehabilitation or physical therapy, depending on the type of surgery.  All injections of rIX-FP 
administered should be documented in the eDiary or eCRF.   
The End of Substudy visit should be conducted at Day 28 after last surgery (in the event that 
an additional surgery is performed) (see Section C) and routine prophylaxis therapy with rIX-
FP should be started (subjects in Arm 3) or restarted (subjects in Arms 1 or 2).   

 
Study Number: 
CSL654_3003 
Study Product: 
rIX-FP 
 
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B.  Minor Surgery 
Procedures to be performed before and after minor surgery are provided in the Schedule of 
Assessments: Surgery Substudy – Minor Surgery.  If, during the surgery, unforeseen 
circumstances result in the procedure fitting the definition of a major surgical procedure (ie, 
requires anesthesia, respiratory assistance or hemostatic support for a period exceeding 
5 consecutive days), the assessments detailed for major surgery (Section A) should be 
completed. 
Before Surgery 
The following procedures will be performed BEFORE administration of rIX-FP for surgical 
prophylaxis: 
 Eligibility assessment. 
 Record type of surgery and association (if any) with hemophilia.   
 Body weight. 
 Obtain blood samples (optional) for measurement of plasma FIX activity level (central 
and / or local laboratory). 
 Review concomitant therapy. 
 Review AEs since last visit. 
 rIX-FP should be administered approximately 3 to 6 hours before surgery.   
 Blood samples (optional) for measurement of plasma FIX activity should be collected 
30 minutes after administration of rIX-FP and, if feasible, tested at the local laboratory 
immediately before the surgery.  Alternatively, the subject’s incremental recovery rate 
will be used to calculate the dose of rIX-FP without testing the FIX activity level at the 
local laboratory. 
Before surgery, if feasible, the following estimates must be made by the surgeon or physician 
performing the procedure: 
 Estimate of intraoperative predicted blood loss (PBL) (average and maximum). 
 Estimate planned hemostatic intervention (other than rIX-FP). 
 Estimate planned transfusion during surgery. 

 
Study Number: 
CSL654_3003 
Study Product: 
rIX-FP 
 
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 Estimate planned rIX-FP dose during surgery. 
 Estimates must be based on a patient without hemophilia, undergoing the same surgical 
procedure. 
During Surgery 
The following information should be recorded: 
 Blood samples before injection of rIX-FP (if an additional dose is needed and sample 
collection is feasible) for plasma FIX activity level (central and local laboratory). 
 Dose of rIX-FP administered (if needed).  If the dose of rIX-FP is more than the planned 
dose, the reason for the discrepancy should be documented, including any unforeseen 
complications. 
 Additional hemostatic interventions and / or transfusions required during surgery 
(including blood products and other coagulation factor[s]).  In the event that the actual 
additional hemostatic interventions and / or transfusions required are higher than the 
estimated planned hemostatic interventions (other than rIX-FP) and / or transfusions 
required, the possible reason(s) should be documented as: 
o Inadequate hemostasis. 
o Incorrect dose or dose regimen of rIX-FP. 
o Unexpected or unforeseen complication. 
o Other. 
Immediately After (0 hours) Surgery 
 Physical examination. 
 Vital signs. 
 Blood samples before injection of rIX-FP (if needed) for plasma FIX activity level 
(central and local laboratory). 
 Dose of rIX-FP (if needed). 
 Record AEs and concomitant therapies. 
 Using clinical judgment, the investigator (in consultation with the surgeon) will evaluate 
the intraoperative hemostasis of the subject after the end of the surgical procedure 

 
Study Number: 
CSL654_3003 
Study Product: 
rIX-FP 
 
Amendment 6 
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according to the efficacy scale (Investigator’s Evaluation of Efficacy of Surgical 
Treatment).   
 Intraoperative estimated blood loss (EBL).  The EBL will be based on the 
anesthesiologist’s record of EBL during the surgical procedure.  If an anesthesiologist 
was not present during the procedure, EBL will be estimated by the surgeon or 
physician performing the procedure.  In the event that the actual intraoperative EBL is 
higher than the intraoperative PBL, the possible reason(s) should be documented as: 
o Inadequate hemostasis. 
o Incorrect dose or dose regimen of rIX-FP. 
o Blood loss expected as integral to the procedure. 
o Unexpected blood loss due to unforeseen complications. 
o Other. 
At Discharge 
At discharge, the following procedures should be performed: 
 Physical examination. 
 Vital signs. 
 Blood samples for FIX activity level (central and local laboratory). 
 Dose of rIX-FP (if needed). 
 Record AEs and concomitant therapies. 
 Quantification of postoperative bleeding. 
 Investigator evaluation of overall efficacy. 
 Prophylaxis rIX-FP therapy should be restarted as soon after the surgical procedure as 
medically appropriate.  If a subject does not restart prophylaxis, the subject should be 
withdrawn from the study and the rationale for the decision should be documented in the 
eCRF. In addition, attempts should be made to complete and document the end of study 
assessments (main study). 

 
Study Number: 
CSL654_3003 
Study Product: 
rIX-FP 
 
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C.  End of Participation in the Substudy (Major and Minor Surgery)  
The end of substudy participation for an individual subject occurs with the end of the 
postoperative period, which is defined as completion of the final substudy visit and the 
resumption of the main study protocol.  Subjects in Arm 3 may end participation in the study 
at this visit or start routine prophylaxis treatment in the main study. 
The following procedures will be performed at the final substudy visit: 
 Physical examination. 
 Vital signs. 
 Blood samples for hematology (major surgery only). 
 Blood samples for antibodies against rIX-FP and FIX inhibitor (central laboratory). 
 Blood sample for FIX activity level (central and local laboratory). 
 Record AEs and concomitant therapies. 
For some minor surgical procedures, the End of Surgery Substudy visit may be combined 
with hospital discharge.  
D.  Discontinuation Procedures for the Substudy (Major and Minor Surgery) 
The following assessments must be performed at an early termination visit for any subject who 
has received rIX-FP and discontinues participation in the study (main study and substudy) 
prematurely: 
 Vital signs. 
 Physical examination. 
 Blood samples for laboratory safety evaluation (hematology and serum chemistry). 
 Blood samples for antibodies against rIX-FP, FIX inhibitor and CHO cells (central lab). 
 Blood sample for FIX activity level (central and local lab). 
 Retain blood sample. 
 Record AEs and concomitant therapies. 

 
Study Number: 
CSL654_3003 
Study Product: 
rIX-FP 
 
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STUDY VARIABLES AND METHODS OF ASSESSMENT 
For an overview of the study variables and measurement times, see the Schedule of 
Assessments: Surgery Substudy – Major Surgery and the Schedule of Assessments: Surgery 
Substudy – Minor Surgery.   
Subject Characteristics 
See Section 10.1 for details. 
Efficacy Variables 
Overview of Variables 
The primary clinical efficacy parameters assessed in the study are study product usage and 
hemostasis assessments by the Investigator.   
Primary efficacy variable:   
Investigator’s evaluation of efficacy of rIX-FP prophylaxis during surgery. 
Secondary efficacy variables: 
 Comparison of predicted and estimated intraoperative blood loss. 
 Comparison of predicted and actual transfusion requirements. 
 Change in hemoglobin levels between baseline, intra-operation and post-operation. 
Methods of Assessment 
Perioperative Prophylaxis for Surgeries 
The investigator will document the following: 
 Type of surgery. 
 Relationship to hemophilia: related/not related. 
 Dose of rIX-FP. 
 Preoperative predicted blood loss (average and maximum) for a non-hemophilic 
individual undergoing the same type and extent of surgical procedure. 

 
Study Number: 
CSL654_3003 
Study Product: 
rIX-FP 
 
Amendment 6 
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 Predicted hemostatic intervention other than rIX-FP and transfusion requirements (if 
any) for a non-hemophilic individual undergoing the same type and extent of surgical 
procedure. 
 Actual use of additional hemostatic interventions other than rIX-FP and transfusion 
blood products following the start of injection with rIX-FP (including blood products 
and other coagulation factor[s]). 
 The estimated intraoperative blood loss. 
 The presence and extent of any surgical wound hematomas noting whether they require 
surgical evacuation. 
 Quantification of postoperative bleeding through surgical drains and the occurrence of 
late rebleeding episodes. 
 Hemoglobin levels at baseline and nadir-intra- and post-operation.   
Investigator’s Evaluation of Efficacy of Surgical Treatment 
Excellent 
Hemostasis clinically not significantly different from normal (eg, achieved 
hemostasis comparable to that expected during similar surgery in a non 
factor-deficient patient) in the absence of other (unplanned) hemostatic 
intervention or estimated actual blood loss during surgery is not more than 
20% higher than the estimated predicted blood loss for the intended surgery. 
Good 
Normal or mildly abnormal hemostasis in terms of quantity and / or quality 
(eg, slight oozing, prolonged time to hemostasis with somewhat increased 
bleeding compared to a non-factor deficient patient in the absence of other 
[unplanned] hemostatic intervention) or estimated actual blood loss is 
greater than 20% but less than or equal to 30% higher than the estimated 
predicted blood loss for intended surgery. 
Moderate 
Moderately abnormal hemostasis in terms of quantity and / or quality (eg, 
moderate hemorrhage that is difficult to control) with estimated blood loss 
greater than what is defined as Good.   
Poor / No 
Response 
Severely abnormal hemostasis in terms of quantity and / or quality 
(eg, severe hemorrhage that is difficult to control) and / or additional 
hemostatic intervention required with another factor IX product for complete 
resolution. 
 

 
Study Number: 
CSL654_3003 
Study Product: 
rIX-FP 
 
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Safety Variables 
Overview of Variables 
Safety will be assessed on the basis of the following variables: 
 AEs including SAEs and AESIs. 
 Laboratory safety parameters (blood tests). 
 Vital signs. 
 Physical examination. 
 Antibodies against rIX-FP. 
 Inhibitors against FIX. 
Methods of Assessment 
See Section 10.2 and Section 10.3 for details. 
STATISTICS 
Determination of Sample Size 
The number of subjects in the surgery substudy is not powered for statistical significance.   
Analysis Populations 
Surgical population 
See Section 11.2.5 for details. 
Statistical Analyses and Methods 
See Section 11.3 for details. 
 
 
 
 

 
Study Number: 
CSL654_3003 
Study Product: 
rIX-FP 
 
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Appendix 2. 
SUBCUTANEOUS SUBSTUDY 
Table of Contents: Subcutaneous Substudy 
SCHEDULE OF ASSESSMENTS FOR COHORTS 1 AND 2: SUBCUTANEOUS 
ADMINISTRATION SUBSTUDY SCREENING, PK ASSESSMENT AND 
SAFETY FOLLOW-UP ............................................................................................ 149 
SUBCUTANEOUS SUBSTUDY - SCHEDULE OF ASSESSMENTS FOR COHORT 3: 
DOSING AND VISIT SCHEDULE .......................................................................... 151 
SUBCUTANEOUS SUBSTUDY – COHORT 3 SAMPLING SCHEDULE AND 
INVESTIGATOR LOCAL TOLERABILITY ASSESSMENTS FOR SC DOSES 
ADMINISTERED AT STUDY SITE ....................................................................... 154 
SUBCUTANEOUS SUBSTUDY - SCHEDULE OF ASSESSMENTS FOR COHORT 4: 
DOSING AND VISIT SCHEDULE .......................................................................... 156 
SUBCUTANEOUS SUBSTUDY - COHORT 4 SAMPLING SCHEDULE AND 
INVESTIGATOR LOCAL TOLERABILITY ASSESSMENTS FOR SC DOSES 
ADMINISTERED AT STUDY SITE ....................................................................... 159 
INTRODUCTION ................................................................................................................. 161 
Background ................................................................................................................ 161 
Nonclinical Evaluation ............................................................................................... 161 
Potential Risks and Benefits ...................................................................................... 162 
STUDY OBJECTIVES AND ENDPOINTS ......................................................................... 162 
 
 
STUDY DESIGN................................................................................................................... 163 
Study Design and Rationale ....................................................................................... 163 
Dose and Dosing Regimen......................................................................................... 166 
Planned Substudy Duration........................................................................................ 166 
Planned Number of Subjects ...................................................................................... 167 
Study Monitoring Procedures .................................................................................... 167 
SELECTION OF SUBSTUDY POPULATION ................................................................... 168 
Inclusion Criteria ....................................................................................................... 168 
Exclusion Criteria ...................................................................................................... 168 
ALLOCATION, DOSING AND ADMINISTRATION ....................................................... 169 
CONTRAINDICATIONS, PERMITTED THERAPIES AND PROHIBITED THERAPIES
.................................................................................................................................... 170 
Contraindications and Precautions to Further Dosing ............................................... 170 
Permitted Therapies ................................................................................................... 170 
Prohibited Therapies .................................................................................................. 170 
STUDY PROCEDURES ....................................................................................................... 170 
CCI
CCI

 
Study Number: 
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Study Product: 
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VISIT SCHEDULE ............................................................................................................... 172 
Screening Visit (All Cohorts) .................................................................................... 172 
Day 1 Visit (All Cohorts) ........................................................................................... 172 
Follow-up Period for Cohorts 1 and 2 ....................................................................... 174 
Repeated-dose & Follow-up Period for Cohorts 3 and 4 ........................................... 175 
Unscheduled Visits .................................................................................................... 179 
ASSESSMENTS .................................................................................................................... 180 
Safety Assessments .................................................................................................... 180 
Pharmacokinetic Analyses ......................................................................................... 180 
Other Assessments ..................................................................................................... 184 
STATISTICS ......................................................................................................................... 184 
Sample Size Estimation ............................................................................................. 184 
Description of Analysis Datasets ............................................................................... 184 
Statistical Analyses and Methods .............................................................................. 185 
Substudy SRC Data Review ...................................................................................... 185 
 

 
Study Number: 
CSL654_3003 
Study Product: 
rIX-FP 
 
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A. SINGLE-DOSE COHORTS 1 AND 2 
SCHEDULE OF ASSESSMENTS FOR COHORTS 1 AND 2: SUBCUTANEOUS ADMINISTRATION SUBSTUDY 
SCREENING, PK ASSESSMENT AND SAFETY FOLLOW-UP 
 
Screening 
Active Treatment Period 
PK & Safety 
Follow-up 
Substudy Day 
 
Day 1 A 
(before 
SC 
dose) 
Day 1 
Day 1 
(after 
SC 
dose) 
Day 1 
Day 2 
Day 3 
Day 4 
Day 6 
Day 8 
Day 11 
Day 15 B 
Day 15 
Day 28 
Assessment Time Point  
 
 
0 h 
0.5 h 
3 h 
24 h 
48 h 
72 h 
120 h 
168 h 
240 h 
336 h 
0.5 h 
 
Assessment Time Window  
1 to -28 d 
 
 
± 10 m 
± 30 m  
± 3 h 
± 6 h 
± 6 h 
± 6 h 
± 6 h 
± 6 h 
± 6 h 
± 10 m 
± 4 d 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility assessment 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination  
 
X 
 
 
 
 
 
 
 
 
 
X 
 
X 
Vital signs C 
 
X 
 
X 
 
 
 
 
 
 
 
X 
 
X 
Plasma FIX activity (CL, optional 
LL)D 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Inhibitors against FIX (CL) 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
X 
Antibodies against rIX-FP and CHO 
cells (CL)E 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
X 
Activation of coagulation tests 
(CL)F 
 
X 
 
X 
X 
X 
 
 
 
 
 
 
 
 
SC dosing of rIX-FP G 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
IVdosing of rIX-FP IV 
 
 
 
 
 
 
 
 
 
 
 
X H 
 
 

 
Study Number: 
CSL654_3003 
Study Product: 
rIX-FP 
 
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Screening 
Active Treatment Period 
PK & Safety 
Follow-up 
Substudy Day 
 
Day 1 A 
(before 
SC 
dose) 
Day 1 
Day 1 
(after 
SC 
dose) 
Day 1 
Day 2 
Day 3 
Day 4 
Day 6 
Day 8 
Day 11 
Day 15 B 
Day 15 
Day 28 
Assessment Time Point  
 
 
0 h 
0.5 h 
3 h 
24 h 
48 h 
72 h 
120 h 
168 h 
240 h 
336 h 
0.5 h 
 
Assessment Time Window  
1 to -28 d 
 
 
± 10 m 
± 30 m  
± 3 h 
± 6 h 
± 6 h 
± 6 h 
± 6 h 
± 6 h 
± 6 h 
± 10 m 
± 4 d 
Adverse events 
 
< -----------------------------------------------------------------------On an Ongoing Basis-----------------------------------------------------------------
Concomitant therapies 
 
< -----------------------------------------------------------------------On an Ongoing Basis-----------------------------------------------------------------
CHO = Chinese hamster ovary; CL = central laboratory; d = day; FIX = coagulation factor IX; IU = international unit; IV = intravenous; LL = local laboratory;  
m = minutes; rIX-FP = recombinant coagulation factor IX albumin fusion protein; SC = subcutaneous; TAT = thrombin-antithrombin.   
Notes to the Schedule of Assessments for Cohorts 1 and 2:  
A: Subjects are considered to be in the main study until Day 1 of the substudy. 
B: Day 15 assessments, including administration of IV rIX-FP, may occur earlier if the LL FIX activity is ≤ 2 IU/dL. 
C: Vital signs include measurement of body weight.  Weight only measured Day 1 (prior to dose), Day 15 and Day 28. 
D: Blood PK samples are at predose and at 0.5, 3, 24, 48, 72, 120, 168, 240 and 336 hours after the start of SC administration; at predose and at 0.5 hours post IV administration 
and at End of Substudy (Day 28).  Samples will be tested by the central laboratory; however, the site may request to have additional samples tested by the local laboratory (LL).    
If LL FIX activity is ≤ 2 IU/dL, at any time point, subsequent time points may be omitted and the IV dose may be administered.  If LL FIX activity is > 5 IU/dL at 336 hours, 
up to 3 additional blood PK samples may be taken every 48 hours (384, 432, and 480 hours) until LL is < 5 IU/dL, and the IV dose delayed until completion of the additional 
PK sampling at the discretion of the investigator. 
E: A sample that tests positive for antibodies against rIX-FP will be retested to discriminate between plasma-derived FIX, recombinant FIX and albumin antibodies. 
F: Blood samples for activation of coagulation tests include D-dimer, TAT, and prothrombin F1+2. 
G: SC rIX-FP should be administered at least 14 days after the previous IV rIX-FP administration (21 days if subject is on a 21-day prophylaxis regimen).  
H: Intravenous administration of rIX-FP will occur after the Day 15 blood draws. 
 

 
Study Number: 
CSL654_3003 
Study Product: 
rIX-FP 
 
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B. REPEATED-DOSE COHORTS 3 AND 4 
SUBCUTANEOUS SUBSTUDY - SCHEDULE OF ASSESSMENTS FOR COHORT 3: DOSING AND VISIT SCHEDULE 
 
 
Dose 1 
Dose 2 
Dose 3 
Doses 4 to 12; Dose 14 
Dose 13  
Dose 15 
PK & Safety Follow-up C 
Substudy Day for Cohort 3 A 
Scree-
ning 
Day 1 B 
Days 2 to 4 
Day 7 
Days 10 to 34; Day 40  
Day 37 
Day 43 
Days 44, 45, 46, 47, 
and 53 
Day 57 
(EOS) 
Time Windows  
1 to -28 
days 
See “Cohort 3 Sampling Schedule” for 
details 
 
See “Cohort 3 Sampling Schedule” for details 
Informed consent 
X 
 
 
 
 
 
 
 
 
Eligibility assessment 
X 
X 
 
 
 
 
 
 
 
Physical examination  
 
X 
 
 
 
 
 
 
X 
Vital signs  
 
X D 
 
 
 
 
X D 
 
X D 
Predose plasma FIX activity (CL) 
 
X  
 
X 
 
X 
X  
 
 
Postdose plasma FIX activity (CL) E 
 
X  
X 
 
 
 
X 
X 
X 
Inhibitors against FIX (CL) 
 
X F 
 
 
 
 
 
 
X F 
Antibodies against rIX-FP and CHO 
cells (CL) 
 
X F 
 
 
 
 
 
 
X F 
Activation of coagulation tests (CL) E 
 
X 
X 
 
 
 
X 
X 
X 
SC dosing of rIX-FP at study site 
 
X G 
X 
X 
 
X 
X 
 
 
Training for SC home administration 
 
 
 
X 
 
 
 
 
 
Dispense IMP H 
 
 
 
X 
 
X 
 
 
 
SC dosing of rIX-FP at home 
 
 
 
 
X 
 
 
 
 
eDiary review 
 
 
X 
X 
 
X 
X 
X 
X 
IMP return/accountability 
 
 
 
 
 
X 
X 
 
 

 
Study Number: 
CSL654_3003 
Study Product: 
rIX-FP 
 
Amendment 6 
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Dose 1 
Dose 2 
Dose 3 
Doses 4 to 12; Dose 14 
Dose 13  
Dose 15 
PK & Safety Follow-up C 
Substudy Day for Cohort 3 A 
Scree-
ning 
Day 1 B 
Days 2 to 4 
Day 7 
Days 10 to 34; Day 40  
Day 37 
Day 43 
Days 44, 45, 46, 47, 
and 53 
Day 57 
(EOS) 
Time Windows  
1 to -28 
days 
See “Cohort 3 Sampling Schedule” for 
details 
 
See “Cohort 3 Sampling Schedule” for details 
Investigator assessment of local 
tolerability I 
 
X 
X 
X 
 
X 
X 
X 
X 
Subject assessment of local 
tolerability  
 
 
 
 
X J 
 
 
 
 
Adverse events 
 
< -----------------------------------------------------------------------On an Ongoing Basis-------------------------------------------------------
-> 
Concomitant therapies 
 
< -----------------------------------------------------------------------On an Ongoing Basis-------------------------------------------------------
-> 
CHO = Chinese hamster ovary; CL = central laboratory; EOS = end of substudy; FIX = coagulation factor IX; IU = international unit; IV = intravenous; rIX-FP = recombinant 
coagulation factor IX albumin fusion protein; PK = pharmacokinetics; SC = subcutaneous; TAT = thrombin-antithrombin.   
Notes to the Schedule of Assessments for Cohort 3:  
A: 
Dosing schedule in Cohort 3: 25 IU/kg every 3 days. Doses 4 to 12 and Dose 14 are administered by the subject at home. 
B: 
Subjects are considered to be in the main study until Day 1 of the substudy. 
C: 
For subjects who discontinue before SC Dose 15, the site should perform the serial PK assessments after the subject’s final SC dose, if possible. If this is not possible, 
at a minimum an EOS PK sample should be taken. 
D: 
SBP, DBP, heart rate, and body temperature assessed before dose and at 30 min after dose. In addition, body weight and height at Day 1 (before dose), and body 
weight at the EOS visit (336 hours after final SC dose). 
E: 
See the “Cohort 3 Sampling Schedule” for details on the sampling time points and time windows. 
F: 
Blood samples for inhibitors against FIX and for antibodies against rIX-FP and CHO cells must be taken a) before the first SC dose and b) after the final SC dose but 
before the subject returns to IV treatment in the main study. See the “Cohort 3 Sampling Schedule” for details. 
G: 
First rIX-FP SC dose should be administered at least 14 days after the previous rIX-FP IV administration in the main study (21 days if subject is on a 21-day 
prophylaxis regimen). 
H: 
Includes IMP for SC home administration and for on-demand IV treatment of any bleeding episodes that may occur during the SC home administration periods. 

 
Study Number: 
CSL654_3003 
Study Product: 
rIX-FP 
 
Amendment 6 
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I: 
See the “Cohort 3 Sampling Schedule” for the time points of local tolerability assessment by the investigator. 
J: 
Subjects will record their overall perception of local tolerability in the eDiary at 0.5, 8, and 24 hours after each SC injection at home. 

 
Study Number: 
CSL654_3003 
Study Product: 
rIX-FP 
 
Amendment 6 
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SUBCUTANEOUS SUBSTUDY – COHORT 3 SAMPLING SCHEDULE AND INVESTIGATOR LOCAL TOLERABILITY 
ASSESSMENTS FOR SC DOSES ADMINISTERED AT STUDY SITE 
SC Dose A 
1 
 
2 
3 & 13 
15 
PK & Safety Follow-upD 
Substudy Day A 
1 
2 
3 
4 
7 & 37 
43 
44 
45 
46 
47 
53 
57 
Time Point 
Pre
B 
0.5 h 
3 & 8 h 
24 h 
48 h 
72 h 
C 
Pre 
Pre 
0.5 h 
3 & 8 
h 
24 h 
48 h 
72 h 
96 h 
240 h 
336 h 
Time Windows  
 
±10 m 
±30 m 
±3 h 
±24 h 
±6 h 
±24 h 
±24 
h 
±10 m 
±30 m  
±3 h 
±6 h 
±6 h 
±6 h 
±6 h 
±6 h 
Plasma FIX activity (CL) 
X  
X 
X 
X 
X 
XE 
XE 
XE 
X 
X 
X  
X 
X 
X 
X 
X 
Inhibitors against FIX (CL) 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
Antibodies against rIX-FP and 
CHO cells (CL)F 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Activation of coagulation tests 
(CL)G 
X 
X 
X 
X 
 
 
 
X 
X 
X 
X 
 
 
 
 
X 
Investigator assessment of 
local tolerability 
 
X 
X 
X 
X 
X H 
X H 
 
X 
X 
X 
X 
X 
X 
X 
X 
CHO = Chinese hamster ovary; CL = central laboratory; FIX = coagulation factor IX; IU = international unit; IV = intravenous; rIX-FP = recombinant coagulation factor IX 
albumin fusion protein; PK = pharmacokinetics; SC = subcutaneous; TAT = thrombin-antithrombin.   
Notes to the Cohort 3 Sampling Schedule: 
A: 
Doses 4 to 12 and Dose 14 are administered by the subject at home (see “Schedule of Assessments for Cohort 3 – Dosing and Visit Schedule”). 
B: 
Pre = predose PK sample  
C: 
The 72-h FIX activity sample represents the predose sample for Dose 2. 

 
Study Number: 
CSL654_3003 
Study Product: 
rIX-FP 
 
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D: 
For subjects who discontinue from the SC substudy before SC Dose 15, the site should perform the serial PK assessments after the subject’sfinal SC dose, if possible. 
If this is not possible, at a minimum an EOS PK sample should be taken. 
E: 
This plasma FIX activity sample must be taken BEFORE the dose given at these visits. 
F: 
A sample that tests positive for antibodies against rIX-FP will be retested to discriminate between plasma-derived FIX, recombinant FIX and albumin antibodies. 
G: 
Blood samples for activation of coagulation tests include D-dimer, TAT, and prothrombin F1+2. 
H: 
Local tolerability assessment at 30 min after Doses 2, 3, and 13. 

 
Study Number: 
CSL654_3003 
Study Product: 
rIX-FP 
 
Amendment 6 
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SUBCUTANEOUS SUBSTUDY - SCHEDULE OF ASSESSMENTS FOR COHORT 4: DOSING AND VISIT SCHEDULE  
 
 
Dose 1 
Dose 2 
Dose 3 
Doses 4 to 12; Dose 14 
Dose 13  
Dose 15 
PK & Safety Follow-up C 
Substudy Day for Cohort 4 A 
Scree-
ning 
Day 1 B 
Days 2, 3, 
4, 6 
Day 11 
Days 16 to 56; Day 66  
Day 61 
Day 71 
Days 72, 73, 74, 75, 
81 
Day 85 
(EOS) 
Time Windows  
1 to -28 
days 
See “Cohort 4 Sampling Schedule” 
for details 
 
See “Cohort 4 Sampling Schedule” for details 
Informed consent 
X 
 
 
 
 
 
 
 
 
Eligibility assessment 
X 
X 
 
 
 
 
 
 
 
Physical examination  
 
X 
 
 
 
 
 
 
X 
Vital signs  
 
X D 
 
 
 
 
X D 
 
X D 
Predose plasma FIX activity (CL) 
 
X 
 
X 
 
X 
X  
 
 
Postdose plasma FIX activity (CL) E 
 
X 
X 
 
 
 
X 
X 
X 
Inhibitors against FIX (CL) 
 
X F 
 
 
 
 
 
 
X F 
Antibodies against rIX-FP and CHO 
cells (CL) 
 
X F 
 
 
 
 
 
 
X F 
Activation of coagulation tests (CL) E 
 
X  
X 
 
 
 
X 
X 
X 
SC dosing of rIX-FP at study site 
 
X G 
X 
X 
 
X 
X 
 
 
Training for SC home administration 
 
 
 
X 
 
 
 
 
 
Dispense IMP H 
 
 
 
X 
 
X 
 
 
 
SC dosing of rIX-FP at home 
 
 
 
 
X 
 
 
 
 
eDiary review 
 
 
X 
X 
 
X 
X 
X 
X 
IMP return/accountability 
 
 
 
 
 
X 
X 
 
 

 
Study Number: 
CSL654_3003 
Study Product: 
rIX-FP 
 
Amendment 6 
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Page 157 of 187 
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Dose 1 
Dose 2 
Dose 3 
Doses 4 to 12; Dose 14 
Dose 13  
Dose 15 
PK & Safety Follow-up C 
Substudy Day for Cohort 4 A 
Scree-
ning 
Day 1 B 
Days 2, 3, 
4, 6 
Day 11 
Days 16 to 56; Day 66  
Day 61 
Day 71 
Days 72, 73, 74, 75, 
81 
Day 85 
(EOS) 
Time Windows  
1 to -28 
days 
See “Cohort 4 Sampling Schedule” 
for details 
 
See “Cohort 4 Sampling Schedule” for details 
Investigator assessment of local 
tolerability I 
 
X 
X 
X 
 
X 
X 
X 
X 
Subject assessment of local 
tolerability  
 
 
 
 
X J 
 
 
 
 
Adverse events 
 
< -----------------------------------------------------------------------On an Ongoing Basis-------------------------------------------------------
-> 
Concomitant therapies 
 
< -----------------------------------------------------------------------On an Ongoing Basis-------------------------------------------------------
-> 
CHO = Chinese hamster ovary; CL = central laboratory; EOS = end of substudy; FIX = coagulation factor IX; IU = international unit; IV = intravenous; rIX-FP = recombinant 
coagulation factor IX albumin fusion protein; PK = pharmacokinetics; SC = subcutaneous; TAT = thrombin-antithrombin.   
Notes to the Schedule of Assessments for Cohort 4:  
A: 
Dosing schedule in Cohort 4: ≤50 IU/kg every 5 days (Sponsor will determine the actual dose based on PK results from Cohort 3). Doses 4 to 12 and Dose 14 are 
administered by the subject at home. 
B: 
Subjects are considered to be in the main study until Day 1 of the substudy. 
C: 
For subjects who discontinue before SC Dose 15, the site should perform the serial PK assessments after subject’s final SC dose, if possible. If this is not possible, at a 
minimum an EOS PK sample should be taken. 
D: 
SBP, DBP, heart rate, and body temperature assessed before dose and at 30 min after dose. In addition, body weight and height at Day 1 (before dose), and body 
weight at the EOS visit (336 hours after final SC dose). 
E: 
See the “Cohort 4 Sampling Schedule” for details on the sampling time points and time windows. 
F: 
Blood samples for inhibitors against FIX and for antibodies against rIX-FP and CHO cells must be taken a) before the first SC dose and b) after the final SC dose but 
before the subject returns to IV treatment in the main study. See the “Cohort 4 Sampling Schedule” for details. 

 
Study Number: 
CSL654_3003 
Study Product: 
rIX-FP 
 
Amendment 6 
03 February 2020 
Page 158 of 187 
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G: 
First rIX-FP SC dose should be administered at least 14 days after the previous rIX-FP IV administration in the main study (21 days if subject is on a 21-day 
prophylaxis regimen). 
H: 
Includes IMP for SC home administration and for on-demand IV treatment of any bleeding episodes that may occur during the SC home administration periods. 
I: 
See the “Cohort 4 Sampling Schedule” for the time points of local tolerability assessment by the investigator. 
J: 
Subjects will record their overall perception of local tolerability in the eDiary at 0.5, 8, and 24 hours after each SC injection at home. 

 
Study Number: 
CSL654_3003 
Study Product: 
rIX-FP 
 
Amendment 6 
03 February 2020 
Page 159 of 187 
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SUBCUTANEOUS SUBSTUDY - COHORT 4 SAMPLING SCHEDULE AND INVESTIGATOR LOCAL TOLERABILITY 
ASSESSMENTS FOR SC DOSES ADMINISTERED AT STUDY SITE 
SC Dose A 
1 
 
2 
3 & 13 
15 
PK & Safety Follow-up D 
Substudy Day A 
1 
2 
3 
4 
6 
11 & 61 
71 
72 
73 
74 
75 
81 
85 
Time Point 
Pre
B 
0.5 h 
3 & 
8 h 
24 h 
48 h 
72 h 
120 
hC 
Pre 
Pre 
0.5 h 
3 & 8 
h 
24 h 
48 h 
72 h 
96 h 
240 h 
336 h 
Time Windows  
 
±10 m 
±30 
m 
±3 h 
±6 h 
±6 h 
±24 h 
±24 h 
±24 
h 
±10 m 
±30 m  ±3 h 
±6 h 
±6 h 
±6 h 
±6 h 
±6 h 
Plasma FIX activity (CL) 
X  
X 
X 
X 
X 
X 
X E 
XE 
X E 
X 
X 
X  
X 
X 
X 
X 
X 
Inhibitors against FIX (CL) 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
Antibodies against rIX-FP and 
CHO cells (CL)F 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Activation of coagulation tests 
(CL)G 
X 
X 
X 
X 
 
 
 
 
X 
X 
X 
X 
 
 
 
 
X 
Investigator assessment of 
local tolerability 
 
X 
X 
X 
X 
X 
X H 
X H 
 
X 
X 
X 
X 
X 
X 
X 
X 
CHO = Chinese hamster ovary; CL = central laboratory; FIX = coagulation factor IX; IU = international unit; IV = intravenous; rIX-FP = recombinant coagulation factor IX 
albumin fusion protein; PK = pharmacokinetics; SC = subcutaneous; TAT = thrombin-antithrombin.   
Notes to the Cohort 4 Sampling Schedule:  
A: 
Doses 4 to 12 and Dose 14 are administered by the subject at home (see “Schedule of Assessments for Cohort 4 – Dosing and Visit Schedule”). 
B: 
Pre = predose PK sample 
C: 
The 120-h FIX activity sample represents the predose sample for Dose 2. 

 
Study Number: 
CSL654_3003 
Study Product: 
rIX-FP 
 
Amendment 6 
03 February 2020 
Page 160 of 187 
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D: 
For subjects who discontinue before SC Dose 15, the site should perform the serial PK assessments after the subject’s final SC dose, if possible. If this is not possible, 
at a minimum an EOS PK sample should be taken. 
E: 
This plasma FIX activity sample must be taken BEFORE the dose given at these visits.  
F: 
A sample that tests positive for antibodies against rIX-FP will be retested to discriminate between plasma-derived FIX, recombinant FIX and albumin antibodies. 
G: 
Blood samples for activation of coagulation tests include D-dimer, TAT, and prothrombin F1+2. 
H: 
Local tolerability assessment at 0.5 h after Doses 2, 3, and 13. 

 
Study Number: 
CSL654_3003 
Study Product: 
rIX-FP 
 
Amendment 6 
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INTRODUCTION 
Background 
This substudy of CSL654_3003 will evaluate the safety and PK of single and repeated 
subcutaneous (SC) administration of rIX-FP in adults with severe hemophilia B (ie, FIX 
activity of ≤ 2%) who are currently enrolled in the main CSL654_3003 study. Safety will be 
measured by the frequencies of AEs, SAEs, investigator and subject assessments of local 
tolerability, and the incidence of inhibitors to rIX-FP. Pharmacokinetic endpoints will be 
measured based on FIX activity. 
Nonclinical Evaluation 
PK characteristics following SC administration of rIX-FP were assessed in hemophilia B 
mice, rabbits, pigs and cynomolgus monkeys. SC administration of rIX-FP in all species was 
systemically and locally well tolerated.  Respective bioavailabilities following SC 
administration were 31% to 50% (hemophilia B mice), 43% to 55% (rabbits), 22% (pigs) and 
9.29% to 17% (cynomolgus monkeys). Furthermore, exposure values in hemophilia B mice, 
rabbits, and cynomolgus monkeys were higher than those of marketed human FIX products 
(BeneFIX® or Berinin® P). 
A single SC dose in hemophilia B mice provided a clear hemostatic effect compared to the 
control group, with a significant reduction in time to hemostasis and total blood loss. Efficacy 
of SC rIX-FP treatment was also superior to BeneFIX® administered SC. Additional activated 
partial thromboplastin time (aPTT) measurement at the end of the study demonstrated a 
significant reduction of aPTT values versus saline controls as well as BeneFIX® treated mice.    
Tolerability of SC injection was investigated in the rabbit.  A single SC injection of rIX-FP 
was tolerated with no observed in-life findings, and minor local findings in histopathology, 
potentially being volume dose-dependent. 

 
Study Number: 
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Study Product: 
rIX-FP 
 
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Collectively, the nonclinical data demonstrate that SC administration of rIX-FP to various 
animal species was tolerated with only minor local findings in rabbits and resulted in 
adequate bioavailability leading to pharmacodynamically-relevant exposure levels. 
Potential Risks and Benefits  
Potential risks associated with SC administration of rIX-FP are expected to be similar to the 
IV route of administration, and include the development of antibodies against FIX (including 
neutralizing antibodies [inhibitors]) and hypersensitivity reactions. The potential risks 
associated with treatment with rIX-FP and specifically with SC administration are discussed 
in detail in Section 7.4 of the Investigator’s Brochure. 
The use of a FIX replacement product with an extended half-life could be significantly 
beneficial to those affected by hemophilia B.  SC administration of rIX-FP may allow routine 
prophylaxis treatment for hemophilia B patients without the need for IV injections.  This 
route of administration may be beneficial particularly for those patients who have poor 
venous access, and may eliminate the need for an indwelling catheter. 
The associated benefit-risk assessment of the substudy is acceptable for subjects enrolled in 
the substudy. 
STUDY OBJECTIVES AND ENDPOINTS 
 
 
  
CCI
CCI

 
Study Number: 
CSL654_3003 
Study Product: 
rIX-FP 
 
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STUDY DESIGN 
Study Design and Rationale 
This is an open-label, multicenter substudy to assess the safety, tolerability, and PK following 
single and repeated ascending SC doses of rIX-FP in hemophilia B subjects.  Subjects will be 
treated in 1 or more of the 4 planned, sequential dose cohorts. Note: Cohort 4 is optional and 
will only be opened if the results of Cohorts 1 to 3 reveal that additional data on repeated SC 
dosing is required to inform the further clinical development.  Each cohort will enroll a 
minimum of 4 and a maximum of 6 subjects.   
 Cohort 1:  single SC dose of 25 IU/kg rIX-FP. 
 Cohort 2:  single SC dose of 50 IU/kg rIX-FP. 
CCI

 
Study Number: 
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Study Product: 
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 Cohort 3:  repeated SC doses of 25 IU/kg rIX-FP every 3 days (15 doses). 
 Cohort 4:  repeated SC doses of ≤ 50 IU/kg rIX-FP every 5 days (15 doses); actual 
dose to be used in this cohort will be determined by the Sponsor based on PK results 
from Cohort 3. 
Male hemophilia B patients, ≥ 18 years, currently enrolled in CSL654_3003, who have at 
least 100 EDs (Cohorts 1 and 2) or 50 EDs (Cohorts 3 and 4) to rIX-FP and weigh ≥50 kg to 
≤ 100 kg will be eligible for the substudy.  
Up to 28 days prior to SC administration of rIX-FP, subjects will be screened to determine 
eligibility for the substudy.  Subjects will be sequentially assigned to a cohort (Cohort 1, 2, 3 
or 4).  SC administration of rIX-FP will be performed at least 14 days after the previous IV 
rIX-FP administration (21 days if subject is on a 21-day prophylaxis regimen).  Blood 
samples for PK analysis will be collected at the time points detailed in the Schedule of 
Assessments for Cohorts 1 and 2).   
In Cohorts 1 and 2, following collection of the last SC PK sample, a single IV dose of 
50 IU/kg rIX-FP will be administered.  If LL FIX activity is > 5 IU/dL at 336 hours, up to 
3 additional PK blood samples may be taken every 48 hours (384, 432, and 480 hours) until 
LL is < 5 IU/dL, and the IV dose delayed until completion of the additional PK sampling at 
the discretion of the investigator.  Following IV administration of rIX-FP, blood samples for 
PK analysis will be collected at selected time points (see Schedule of Assessments for 
Cohorts 1 and 2). Subjects will return in 2 weeks (Day 28) for an end of substudy visit to 
assess safety.  After the end of substudy visit on Day 28, subjects will return to their IV rIX-
FP regimen in the main study.   
After at least 4 subjects in Cohort 1 have reached Day 15, plasma exposure after SC 
administration (FIX activity levels) and safety, including inhibitor results, will be reviewed 
by a Safety Review Committee (SRC).  If no safety concerns are identified, dosing of Cohort 
2 may start.   

 
Study Number: 
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Study Product: 
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After at least 4 subjects in Cohort 2 have reached Day 15, plasma exposure after SC 
administration (FIX activity levels) and safety will be reviewed by an SRC. After review of 
the data, a decision will be made to enroll Cohort 3.   
In Cohorts 3 and 4, subjects will be sequentially assigned to SC doses of 25 IU/kg every 
3 days (Cohort 3) or to SC doses of ≤ 50 IU/kg every 5 days (Cohort 4), for a total of 15 SC 
doses in each cohort. rIX-FP will be administered SC at least 14 days after the previous IV 
rIX-FP administration (21 days for subjects on a 21-day IV regimen in the main study). 
Blood samples for PK analysis will be collected before the first SC dose, before selected 
SC doses administered at the study site, and for a serial PK profile after the first and the final 
SC doses. Doses 4 to 12 and Dose 14 will be administered by subjects/caregivers at home.  
Subjects will return 14 days after their final SC dose for an end of substudy visit for 
collection of the final PK sample and for safety assessments.  After the end of substudy visit, 
subjects will return to their IV rIX-FP regimen in the main study. 
After at least 4 subjects in Cohort 3 have completed SC treatment, plasma exposure after SC 
administration (FIX activity levels) and safety will be reviewed by the SRC.  
An overview of the SC substudy design for Cohorts 3 and 4 is presented in Figure 2. 

 
Study Number: 
CSL654_3003 
Study Product: 
rIX-FP 
 
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Figure 2 
Subcutaneous Substudy: Dosing / PK Sampling Scheme and Substudy Visit 
Days for Cohorts 3 and 4 
 
EOS = end of substudy; PK = pharmacokinetic; SC = subcutaneous. 
Notes:  
1. The 120-h sample after SC Dose 1 will only be taken in Cohort 4. 
2. Doses with an asterisk will be administered by the subject/caregiver at home. All other doses will be given at 
the study site. 
If a subject experiences a bleeding episode during the PK sampling period, the subject should 
treat the bleed with his standard on-demand IV dose of rIX-FP as prescribed in the main 
study.   
Dose and Dosing Regimen 
Each SC dose of rIX-FP will be administered in up to 4 injection sites, with a volume of up to 
4 mL per site.   
The starting dose will be 25 IU/kg (as a single dose in Cohort 1 and as repeated doses in 
Cohort 3), with dose escalation in Cohort 2 to 50 IU/kg (single dose) and to ≤ 50 IU/kg 
(repeated doses) in optional Cohort 4.   
Planned Substudy Duration 
The maximum total substudy duration of each subject will be approximately 30 days for 
subjects in Cohorts 1 and 2, approximately 57 days for subjects in Cohort 3, and 

 
Study Number: 
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Study Product: 
rIX-FP 
 
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approximately 85 days for subjects in Cohort 4. Subjects will then return to the IV treatment 
plan of the main study.  
The overall substudy duration (ie, first subject’s Day 1 visit to the last subject’s end of 
substudy visit) is expected to be 18 to 22 months and includes estimated durations for 
screening, enrollment of the subjects into the substudy, and the final visit.   
Planned Number of Subjects 
This substudy will enroll approximately 4 to 6 male subjects each in Cohorts 1 to 4 (ie, up to 
a maximum of 24 subjects). Subjects may enroll in more than 1 cohort.  
Study Monitoring Procedures 
Adverse events and local tolerability will be monitored for all subjects enrolled in the 
substudy, and AE reporting will be performed as described in the main protocol. After at least 
4 subjects in Cohort 1 have reached Day 15, SC exposure (FIX activity levels) and safety 
assessments will be reviewed by the SRC.  If no safety concerns are identified, dosing of 
Cohort 2 may start.  The same procedure will be followed before a decision is made to enroll 
subjects in Cohorts 3 and 4.   
Enrollment into the substudy and further SC administration of rIX-FP will be halted for 
review by the SRC and recommendation for continuation if any of the following occurs: 
 One subject experiences anaphylaxis that is causally related to SC administration of 
rIX-FP. 
 One subject experiences a serious hypersensitivity event that is causally related to SC 
administration of rIX-FP. 
Cohorts 1 and 2: The SRC will meet after a cohort has data available through Day 15 for 4 
subjects and will review safety and SC exposure (FIX activity levels).  If no safety concerns 
are identified, the SRC will make a recommendation to continue to the next cohort.   

 
Study Number: 
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Study Product: 
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Cohorts 3 and 4: The SRC will meet after at least 4 subjects from Cohort 3 have completed 
the SC treatment period; a decision regarding Cohort 4 will be made after this meeting. In 
addition, there will be an ad-hoc meeting of the SRC if any of the following occurs: 
 One subject experiences anaphylaxis that is causally related to SC administration of 
rIX-FP. 
 One subject experiences a serious hypersensitivity event that is causally related to SC 
administration of rIX-FP. 
The substudy will be stopped if 1 subject develops an inhibitor to FIX during the substudy. 
SELECTION OF SUBSTUDY POPULATION 
Inclusion Criteria 
Subjects meeting all of the following inclusion criteria may be enrolled into the substudy: 
1. Male subjects, at least 18 years of age. 
2. Subjects who are currently enrolled in Study CSL654_3003 with hemophilia B (FIX 
activity ≤ 2%). 
3. Subjects who have received rIX-FP for ≥ 100 EDs (Cohorts 1 and 2) or for ≥ 50 EDs 
(Cohorts 3 and 4). 
4. Body weight between 50.0 and 100.0 kg, both inclusive.  
5. Body mass index (BMI) between 18.0 and 29.9 kg/m2. 
6. Written informed consent for substudy participation obtained before undergoing any 
specific procedures. 
Exclusion Criteria 
Subjects meeting any of the following exclusion criteria must not be enrolled into the 
substudy: 
1. Use of rIX-FP within 14 days before SC administration of  rIX-FP. 

 
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2. Suspected inability (eg, language problems) or unwillingness to comply with substudy 
procedures. 
3. Experienced a life-threatening bleeding episode or had major surgery during the 
3 months prior to substudy entry (Day 1). 
ALLOCATION, DOSING AND ADMINISTRATION 
Cohorts 1 and 2 
Subjects will be sequentially assigned to a cohort, and receive a single SC dose of rIX-FP.  
The SC dose of rIX-FP will be administered at up to 4 injection sites, a minimum of 2.5 cm 
apart, with a volume of up to 4 mL per site.  SC administration may occur on the stomach, 
thigh, or upper arm.  The SC rIX-FP dose should be administered at least 14 days after the 
previous rIX-FP administration (21 days if subject is on a 21-day prophylaxis regimen).  At 
Day 15 (336 hours), subjects will be administered a single IV dose of 50 IU/kg rIX-FP.   
If a subject experiences a bleeding episode during the PK sampling period (prior to Day 15), 
the subject should treat the bleed with his standard on-demand dose of rIX-FP as prescribed 
in the main study, dosed IV.  If LL FIX activity is ≤ 2 IU/dL, at any time point, subsequent 
time points may be omitted and the IV dose may be administered.  If LL FIX activity is 
> 5 IU/dL at 336 h, up to 3 additional blood PK samples may be taken every 48 hours (384, 
432, and 480 hours) until LL is < 5 IU/dL, and the IV dose delayed until completion of the 
additional PK sampling at the discretion of the investigator.  If the treatment of a bleed occurs 
within 7 days of the Day 15 visit, the IV dose is optional.  A subject may be treated with an 
additional IV dose of rIX-FP as long as the dose is given within the visit window. 
Cohorts 3 and 4 
Subjects will be sequentially assigned to a cohort, and receive repeated SC doses of rIX-FP 
for a total of 15 doses. Each SC dose of rIX-FP will be administered at up to 4 injection sites, 
a minimum of 2.5 cm apart, with a volume of up to 4 mL per site. SC administration may 
occur on the stomach, thigh, or upper arm. The first SC rIX-FP dose should be administered 

 
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at least 14 days after the previous rIX-FP administration (21 days if subject is on a 21-day 
prophylaxis regimen). The subject will return to their regular IV treatment schedule in the 
main study once they have completed the end of substudy visit 14 days after the final SC 
dose. 
If a subject experiences a bleeding episode during the PK sampling period, the subject should 
treat the bleeding episode with his standard on-demand IV dose of rIX-FP as prescribed in 
the main study. The subject should continue in the SC substudy following the same schedule 
of SC injections, regardless of the IV treatment of that bleeding episode.    
CONTRAINDICATIONS, PERMITTED THERAPIES AND PROHIBITED 
THERAPIES 
Contraindications and Precautions to Further Dosing 
In the event the subject experiences a hypersensitivity reaction (including anaphylaxis), the 
study treatment must be stopped immediately by discontinuation of the injection.  In the 
event the subject experiences a hypersensitivity reaction or develops an inhibitor to FIX or 
antibodies to rIX-FP, the CSL medical monitor must be contacted before the administration 
of additional doses of rIX-FP.   
Permitted Therapies 
See Section 7.2 of the main protocol. 
Prohibited Therapies 
See Section 7.3 of the main protocol. 
STUDY PROCEDURES 
The clinical procedures that will be conducted during this study related to the evaluation of 
population demographics and safety are provided in Table A1.  Refer to the Laboratory 
Manual for detailed instructions on how the laboratory assessments should be performed.   

 
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Table A1.   Clinical Procedures: Safety Evaluation 
 
Assessment 
Description 
Physical examination As per the site’s standard procedure 
Vital signs 
 
Body temperature 
 
Body weight 
 
Blood pressure (systolic and diastolic) 
 
Heart rate (beats per minute) 
Markers of activation 
of coagulation 
 
Prothrombin fragment 1+2 
 
Thrombin-antithrombin (TAT) 
 
D-dimer 
Immunogenicity 
Factor IX inhibitors and antibodies specific to rIX-FP and CHO cell-derived 
proteins. 
Local tolerability 
 
Investigator assessment: assessment of erythema, edema or 
induration, and itching, local pain, or local heat after injections 
administered at the study site 
 
Subject assessment: overall perception of local tolerability after 
injections administered at home 
CHO = Chinese hamster ovary; rIX-FP = recombinant fusion protein linking coagulation factor IX with 
albumin; TAT = thrombin-antithrombin.   
The timing and frequency of all clinical procedures are described in the Schedules of 
Assessments.  Refer to the Laboratory Manual for details about the collection, storage, 
handling, and transportation of biological specimens. 
Subject/Caregiver Training and SC Self-Administration at Home   
At the visits for SC Dose 3, the investigator or delegate will ensure that the subject and / or 
caregiver has been trained sufficiently to allow for SC self-administration at home. At this time, 
the subject/caregiver will be instructed in the following: 
 Correct reconstitution technique for rIX-FP. 
 Correct selection of SC administration sites and administration technique. 
 Correct drug storage. 
 Adverse event reporting. 
 Local tolerability assessments. 
 Correct completion of eDiary. 

 
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For SC injections received by the subject at home, the subject / caregiver will report (not 
limited to) the following information in the eDiary: 
 Details of the rIX-FP administration (eg, total actual IU per injection, number of vials 
used, and start date and time of injection). 
 Local tolerability assessments. 
For bleeding episodes: 
 Type of bleeding episode (spontaneous, traumatic, unknown, or post-surgery). 
 Site of the bleeding episode (ie, joint, muscle, mucosal membrane) and specific location. 
 Time of start of symptoms of bleeding.  
 Details of rIX-FP IV treatment of the bleeding episode (eg, total actual IU per injection, 
number of vials used, and start date and time of injection). 
VISIT SCHEDULE 
The timing and frequency of the substudy visits are described in the Schedules of 
Assessments. 
Screening Visit (All Cohorts) 
All subjects must provide written informed consent before any substudy-specific 
assessments or procedures are performed.   
Written informed consent is not required for assessments or procedures performed according 
to standard of care (eg, for diagnosis or treatment); results from such assessments may be 
used in the determination of substudy eligibility.   
The Day 1 visit may occur on the same day as the screening visit. 
Day 1 Visit (All Cohorts) 
rIX-FP SC should be administered at least 14 days after the previous rIX-FP administration in 
the main study (21 days if subject is on a 21-day prophylaxis regimen).   

 
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The following procedures will be performed PRIOR to the SC administration of rIX-FP on 
Day 1: 
 Review inclusion and exclusion criteria. 
 Physical examination. 
 Vital signs (including weight and height). 
 Blood samples for: 
o Plasma FIX activity. 
o Inhibitors against FIX. 
o Antibodies against rIX-FP.  
o Antibodies against CHO cell-derived proteins. 
o Activation of coagulation tests. 
 Record AEs. 
 Record concomitant therapies. 
The following procedures, in addition to documenting any AEs and concomitant therapies, 
will be performed FOLLOWING the start of SC injection of rIX-FP:  
 30 minutes after start of injection (all cohorts): 
o Vital signs. 
o Blood sample for plasma FIX activity. 
o Blood samples for activation of coagulation tests. 
o Investigator assessment of local tolerability. 
 3 hours after start of injection (all cohorts): 
o Blood sample for plasma FIX activity.  
o Blood samples for activation of coagulation tests. 
o Investigator assessment of local tolerability. 
 8 hours after start of injection (Cohorts 3 and 4 only): 
o Blood sample for plasma FIX activity  
o Blood samples for activation of coagulation tests. 

 
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o Investigator assessment of local tolerability. 
Follow-up Period for Cohorts 1 and 2 
Follow-up Period: 24, 48, 72, 120, 168, and 240  Hour Visits (Days 2 to 11) 
The following procedures will be performed at each visit: 
 Blood sample for plasma FIX activity.  
 Blood samples for activation of coagulation tests (24 hours only). 
 Record AEs.  
 Record concomitant therapies. 
Follow-up Period: Day 15 (336 Hour) Visit 
The following procedures will be performed PRIOR to the IV administration of rIX-FP: 
 Physical examination. 
 Vital signs (including weight). 
 Blood samples for: 
o Plasma FIX activity.  
o Inhibitors against FIX. 
o Antibodies against rIX-FP.  
o Antibodies against CHO cell-derived proteins. 
 Record AEs.  
 Record concomitant therapies. 
The following procedures, in addition to documenting any AEs and concomitant therapies, 
will be performed FOLLOWING the start of IV infusion of rIX-FP:  
 30 minutes after start of infusion: 
o Blood sample for plasma FIX activity. 
Follow-up Period: Day 28 Visit – End of Subcutaneous Substudy 
The following procedures will be performed: 
 Physical examination. 

 
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 Vital signs (including weight [only if the dose is to be adjusted to return to the main 
study]). 
 Blood samples for: 
o Plasma FIX activity (final PK sample in the SC substudy).  
o Inhibitors against FIX. 
o Antibodies against rIX-FP.  
o Antibodies against CHO cell-derived proteins. 
 Record AEs  
 Record concomitant therapies. 
 Schedule next visit for the main study. 
Repeated-dose & Follow-up Period for Cohorts 3 and 4 
Visits After SC Dose 1 
- 
Visits at 24, 48, and 72* h after SC Dose 1 for Cohort 3 (Days 2 to 4) 
- 
Visits at 24, 48, 72, and 120* hours after SC Dose 1 for Cohort 4 (Days 2 to 6) 
* Note: For Cohort 3, the 72-h FIX activity sample represents the predose sample for SC Dose 2. 
For Cohort 4, the 120-h FIX activity sample represents the predose sample for SC Dose 2.  
 
The following procedures will be performed at each of these visits: 
 Blood sample for plasma FIX activity.  
 Blood samples for activation of coagulation tests (at 24 hours only). 
 Investigator assessment of local tolerability. 
 Record AEs.  
 Record concomitant therapies. 

 
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Visits for SC Doses 2 and 3 
Subjects in Cohorts 3 and 4 will return to the study site for SC Doses 2 and 3 and the 
associated assessments. The following procedures will be performed PRIOR to SC Doses 2 
and 3: 
 Review eDiary.  
 Record AEs.  
 Record concomitant therapies. 
In addition, the following procedure will be performed PRIOR to SC Dose 3: 
 Blood sample for plasma FIX activity 
The following procedures will be performed AFTER SC Doses 2 and 3: 
 Investigator assessment of local tolerability (at 30 min). 
 Record AEs.  
 Record concomitant therapies. 
In addition, the following procedures will be performed at the visit for SC Dose 3: 
 Provide training to subject (and caregiver, if applicable) for SC self-administration at 
home.  
 Dispense IMP for self-administration of SC Doses 4 to 12 at home, and IV IMP for on-
demand treatment of bleeding episodes. 
 Instruct subject (and caregiver, if applicable) on subject assessment of local tolerability. 
 Instruct subject (and caregiver, if applicable) on correct completion of eDiary.  
 Schedule the next study site visit for SC Dose 13. 

 
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SC Self-administration at Home, Doses 4 to 12 and Dose 14 
Subjects in Cohorts 3 and 4 will administer SC Doses 4 to 12 and SC Dose 14 at home (every 
3 days for Cohort 3, every 5 days for Cohort 4). Subjects will assess the following after each 
SC dose and will record the information in their eDiary: 
 Local tolerability assessment at 30 min, at 8 h, and at 24 h. 
 If bleeding episodes occur:  
o Details on bleeding episodes. 
o Details of rIX-FP IV treatment of bleeding episodes (if applicable). 
Visit for SC Dose 13 
Subjects will return to the study site for SC Dose 13. The following procedures will be 
performed PRIOR to SC Dose 13: 
 Blood sample for plasma FIX activity. 
 Review subject eDiary 
The following procedures will be performed AFTER SC Dose 13: 
 Investigator assessment of local tolerability (at 30 min). 
 Record AEs.  
 Record concomitant therapies. 
The following procedures will be performed at any time at this visit: 
 Review subject eDiary. 
 IMP return and accountability. 
 Dispense IMP for self-administration of SC Dose 14 at home, and IV IMP for on-
demand treatment of bleeding episodes. 
 Schedule the next study site visit for SC Dose 15. 

 
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Visit for SC Dose 15 (Or Final Dose for Subjects Who Discontinue from Substudy) 
The following procedure will be performed PRIOR to SC Dose 15 (or final dose for subjects 
who discontinue from the substudy): 
 Blood sample for plasma FIX activity. 
 Blood samples for activation of coagulation tests. 
 Review subject eDiary. 
 SBP, DBP, heart rate, body temperature. 
The following procedures will be performed at 30 min AFTER the dose: 
 Blood sample for plasma FIX activity.  
 Blood samples for activation of coagulation tests.  
 SBP, DBP, heart rate, body temperature. 
 Investigator assessment of local tolerability. 
 Record AEs.  
 Record concomitant therapies. 
The following procedures will be performed at 3 hours and at 8 hours AFTER the dose: 
 Blood sample for plasma FIX activity.  
 Blood samples for activation of coagulation tests.  
 Investigator assessment of local tolerability. 
 Record AEs.  
 Record concomitant therapies. 
The following procedures will be performed at any time at this visit: 
 eDiary review of recorded data. 
 IMP return and accountability. 
Visits at 24, 48, 72, 96, and 240 hours after SC Dose 15 (or Final Dose) 
The following procedures will be performed at each of these visits: 
 Blood sample for plasma FIX activity.  

 
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 Blood samples for activation of coagulation tests (at 24 hours only). 
 Investigator assessment of local tolerability. 
 Review subject eDiary. 
 Record AEs.  
 Record concomitant therapies. 
Visit at 336 Hours (14 Days) after SC Dose 15 (or Final Dose)– End of Subcutaneous 
Substudy 
The following procedures will be performed at this end of substudy visit: 
 Physical examination. 
 Vital signs (except height) 
 Blood samples for: 
o Plasma FIX activity (final PK sample in the SC substudy).  
o Inhibitors against FIX. 
o Antibodies against rIX-FP.  
o Antibodies against CHO cell-derived proteins. 
o Activation of coagulation tests.  
 Investigator assessment of local tolerability. 
 Review subject eDiary. 
 Record AEs.  
 Record concomitant therapies. 
 Schedule next visit for the main study. 
Unscheduled Visits  
Unscheduled visits, including brief PK assessments, may be arranged at any time point 
during the substudy, at the discretion of the investigator or upon request of the subject. 

 
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ASSESSMENTS 
Safety Assessments 
Safety will be assessed based on the following variables: 
 AEs and SAEs. 
 Investigator’s assessment of local tolerability. 
 Subject’s assessment of local tolerability. 
 Physical examination. 
 Vital signs. 
 Inhibitors against FIX. 
 Antibodies against rIX-FP. 
 Antibodies against CHO cell-derived proteins. 
 Activation of coagulation tests. 
Clinical laboratory tests will be performed at time points as detailed in the Schedule of 
Assessments for the SC substudy.  More frequent evaluations may be performed, if clinically 
indicated, at the discretion of the investigator. 
Pharmacokinetic Analyses 
Pharmacokinetic Evaluation of rIX-FP 
Cohorts 1 and 2: 
If during the PK assessment period, a subject experiences a bleeding episode, no further 
blood samples will be taken as part of PK assessment, regardless of whether the bleeding 
episode is treated or not.  The PK may or may not need to be repeated.   
If LL FIX activity is ≤ 2 IU/dL, at any time point, subsequent time points may be omitted and 
the IV dose may be administered. 
 

 
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If LL FIX activity is > 5 IU/dL at 336 hours, up to 3 additional blood PK samples may be 
taken every 48 hours (384, 432, and 480 hours) until LL is < 5 IU/dL, and the IV dose 
delayed until completion of the additional PK sampling at the discretion of the investigator. 
Cohorts 3 and 4:  
If a subject experiences a bleeding episode during the PK assessment period, the subject 
should treat the bleeding episode with his standard on-demand IV dose of rIX-FP as 
prescribed in the main study. The subject should continue in the SC substudy following the 
same schedule of SC injections, regardless of the IV treatment of that bleeding episode. All 
PK sampling should be completed as outlined in the Schedule of Assessments for the SC 
substudy. See section “Substudy Pharmacokinetic Population” for details on the PK inclusion 
of these subjects. 
Overview of Variables 
The SC PK of rIX-FP and the subject’s previous FIX product will be assessed on the basis of 
measurements of FIX activity levels in plasma.  PK samples will be used to measure the 
following PK parameters: 
Cohorts 1 and 2: 
 Cmax 
 Incremental recovery (the peak level recorded 30 minutes after injection and reported as 
[IU/mL]/[IU/kg]) 
 Terminal elimination half-life (t1/2) 
 Area under the concentration-time curve (AUC0-last) 
 Clearance 
 Volume of distribution at steady state (Vss) 
 Tmax 
Cohorts 3 and 4: 
 Cmax after first dose (Cmax, Dose 1) and Cmax at steady state after final SC dose (Cmax,ss) 

 
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 Incremental recovery (the peak level recorded 30 minutes after injection and reported as 
[IU/mL]/[IU/kg]) 
 
 t1/2 after final SC dose  
 
 Clearance 
 Volume of distribution at steady state (Vss) 
 
 Tmax after first dose (Tmax, Dose 1) and Tmax after final dose (Tmax, ss) 
Methods of Assessment 
Blood samples for determination of FIX activity will be obtained before and after SC 
injection of rIX-FP at the time points detailed in the Schedule of Assessments for the SC 
substudy. 
A zero-time will be assigned as the start of the injection, and the residual FIX at the predose 
time point will be used as the baseline value for each administration.  FIX activity will be 
measured at a central laboratory using a validated one-stage clotting method. 
Details regarding sample collection, handling, deep freezing of samples and shipment to the 
central laboratory are given in the Laboratory Manual in the Investigator Site File. 
CCI
CCI
CCI

 
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Local Tolerability Assessments 
Investigator assessment: For the SC injections administered at the study site (Doses 1, 2, 3, 
13, and 15), the investigator will perform assessments of local tolerability at the SC injection 
site(s). If several injection sites are used, each site will be judged but only the site with the 
strongest reaction will be recorded, according to the following scale: 
Erythema 
Description 
Score 
None 
0 
Very slight (barely perceptible) 
1 
Well-defined 
2 
Moderate to severe 
3 
Severe (beet redness) to slight eschar formations (injuries in depth) 
4 
 
Edema or Induration 
The size of any edema or induration will be determined by measuring the smallest and largest 
diameters. 
Itching, Local Pain, or Local Heat 
The severity of any local reactions of itching, local pain, or local heat will be assessed based 
on the following classification: none (0), very slight (1), slight (2), moderate (3), and severe 
(4).  
The investigator will perform local tolerability assessments at the time points detailed in the 
Cohort 3 Sampling Schedule and the Cohort 4 Sampling Schedule. 
Subject assessment: The subject (or caregiver) will assess local tolerability at the SC injection 
site during SC administration at home. Subjects will record in the eDiary their judgment on 
the overall perception of the local reactions on a scale of none (0), very slight (1), slight (2), 
moderate (3), and severe (4) approximately 30 minutes, 8 hours, and 24 hours after the end of 
each SC dose given at home. If several injection sites are used, each site will be judged but 

 
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only the site with the strongest reaction will be recorded. The investigator will review these 
eDiary data at the next visit and will record local reactions as AEs. 
Note: If a local reaction AE is reported, it also needs to be included in local tolerability 
assessment (by subject and / or investigator) to ensure consistency of reporting between AEs 
and local tolerability assessments. 
Other Assessments 
Markers of Activation of Coagulation 
Activation of coagulation tests, including prothrombin fragment 1+2, thrombin-antithrombin 
and D-dimer, will be assessed by the central laboratory at the time points detailed in the 
Cohort 3 Sampling Schedule and the Cohort 4 Sampling Schedule.  
STATISTICS 
Sample Size Estimation 
Sample size for this substudy is based upon empirical considerations and no formal sample 
size calculation will be performed.  A maximum of up to 24 subjects will be recruited into the 
substudy.  If a subject drops out prior to Day 1, the subject may be replaced. 
Description of Analysis Datasets 
Substudy Safety Population 
The safety population will consist of all subjects who received at least 1 SC dose of rIX-FP in 
this substudy.  All safety analyses will be performed on the safety population. 
Substudy Pharmacokinetic Population 
The PK population will comprise subjects who have received at least 1 dose of rIX-FP 
administered SC and have blood samples drawn for PK assessment. Subjects will be excluded 
from analysis if an insufficient number of analyzable PK samples were obtained to permit the 
evaluation of at least 1 PK parameter for rIX-FP, excluding samples obtained after receiving 
an IV dose of rIX-FP or any other FIX product for the treatment of a bleeding episode during 
the PK sampling period. 

 
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The FIX activity in subjects receiving on-demand IV treatment for bleeding episodes during 
the SC substudy will not be utilized from the IV treatment onward in the PK summary 
statistics, but may be included in the Population PK analysis if dose records are available. 
Statistical Analyses and Methods 
All safety data will be summarized separately for the substudy.  Continuous data will be 
summarized using descriptive statistics including means, standard deviations, medians, first 
and third quartiles, and minimums and maximums.  Categorical variables will be summarized 
with frequencies and percentages. 
Safety Analyses 
Safety data from the SC substudy will be summarized using descriptive statistics and will 
include AEs, vital signs, physical examination, investigator’s and subject’s assessments of 
local tolerability, neutralizing antibodies against FIX, antibodies against rIX-FP and CHO 
cells, and markers of activation of coagulation (prothrombin fragment 1+2, TAT, and D-
dimer).  (See Section 11.3.3 of the main protocol.) 
Substudy Pharmacokinetics Data  
A noncompartmental analysis will be performed to allow individual PK data analysis.  
Noncompartmental PK analysis will be performed for FIX activity in plasma, and PK 
parameters will be listed and summarized by treatment group. Individual subject and subgroup 
mean plasma concentration-time data will be plotted for each treatment group on linear and 
semi-logarithmic scales. 
Population PK methodology will be applied for derivation of some of PK parameters, 
including calculation of bioavailability. Prior rIX-FP IV PK data (from 
Studies CSL654_2001, CSL654_2004, CSL654_3001, CSL654_3002, and / or 
CSL654_3003) will be utilized for Population PK modeling purposes that will be 
documented separately. 

 
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Substudy SRC Data Review 
Safety and SC exposure (FIX activity levels) will be analyzed and reviewed by an SRC 
following Cohorts 1, 2, and 3. The final analysis of the SC substudy will be performed when 
all subjects have completed the SC substudy.  

 
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Appendix 3. 
WORLD FEDERATION OF HEMOPHILIA RECOMMENDED 
PLASMA FACTOR LEVEL AND DURATION OF ADMINISTRATION FOR ON-
DEMAND TREATMENT AND SURGERY 
Type of Hemorrhage 
Desired level of FIX 
Duration (days) 
Joint 
40% – 60% 
1 – 2 
Muscle (except iliopsoas) 
40% – 60% 
2 – 3  
Iliopsoas 
 Initial 
 Maintenance 
 
60% – 80% 
30% – 60% 
 
1 – 2 
3 – 5 
CNS/head 
 Initial 
 Maintenance 
 
60% – 80% 
30% 
 
1 – 7 
8 – 21 
Throat and neck 
 Initial 
 Maintenance 
 
60% – 80% 
30% 
 
1 – 7 
8 – 14 
Gastrointestinal 
 Initial 
 Maintenance 
 
60% – 80% 
30% 
 
7 – 14 
Renal 
40% 
3 – 5 
Deep laceration 
40% 
5 – 7 
Surgery (minor) 
 
 Preoperative 
 Postoperative 
 
50% – 80% 
30% – 80% 
 
 
1 – 5 
Surgery (major) 
 Preoperative 
 Postoperative 
 
60% – 80% 
40% – 60% 
30% – 50% 
20% – 40% 
 
 
1 – 3 
4 – 6 
7 – 14 
World Federation of Hemophilia Guidelines, 2012 

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Print Date: 18-Aug-2021 09:55:08 GMT-04:00
Signature Page
CSL654_3003 - Protocol Amendment - 6 - 03Feb2020
Signed By
Date (GMT)
Approved-Clinical Safety Physician Approval
 19:48:37
Approved-
 Approval
 20:28:59
Approved-
 Approval
 21:13:48
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PPD
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PPD