A Phase III Open Label, Multicenter, Extension Study to Assess the Safety and Efficacy of Recombinant Coagulation Factor VIII (rVIII-SingleChain, CSL627) in Subjects With Severe Hemophilia A
Phase: PHASE3
Conditions: Hemophilia A, Severe Hemophilia A
Sponsor: CSL Behring

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CCI

 
Study Number: CSL627_3001 
Study Product: rVIII-SingleChain  
 
CRD-TPL-077 Version 1.0 
26 May 2020 
Page 2 of 149 
 
Confidential 
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. 
 

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CCI

 
Study Number: CSL627_3001 
Study Product: rVIII-SingleChain  
 
CRD-TPL-077 Version 1.0 
26 May 2020 
Page 4 of 149 
 
Confidential 
Primary Endpoints 
• 
Arm 1 and Arm 3 (PTPs): incidence of inhibitor formation to 
FVIII in at least 200 PTPs with at least 100 EDs of 
rVIII-SingleChain 
• 
Arm 2 (PUPs): 
• 
Incidence of high-titer inhibitor formation to FVIII 
(ie, inhibitor titer of ≥ 5 Bethesda units [BU]/mL) in PUPs 
with at least 50 EDs of rVIII-SingleChain. 
• 
Treatment success for major bleeding episodes, defined as a 
rating of "excellent" or "good" on the investigator’s clinical 
assessment of hemostatic efficacy 4-point scale. 
• 
Annualized spontaneous bleeding rate (AsBR) during 
prophylaxis and on-demand treatment. 
Secondary Objectives 
• 
Arm 1 and Arm 3 (PTPs): 
• 
To characterize the safety profile of rVIII-SingleChain with 
respect to inhibitor development after 10 EDs and after 
50 EDs. 
• 
To characterize the safety profile of rVIII-SingleChain with 
respect to antibodies against rVIII-SingleChain and antibodies 
to Chinese hamster ovary (CHO) proteins. 
• 
To collect and evaluate efficacy information on the 
prophylaxis and treatment of bleeding episodes. 
• 
To assess the hemostatic efficacy of rVIII-SingleChain for 
PTPs who undergo surgery, using the 4-point efficacy 
evaluation of surgical treatment scale. 
• 
Arm 2 (PUPs): 
• 
To further characterize the safety profile of rVIII-SingleChain 
with respect to inhibitor development. 
• 
To characterize the safety profile of rVIII-SingleChain with 
respect to antibodies against rVIII-SingleChain and antibodies 
to CHO proteins. 
• 
To collect and evaluate the number of rVIII-SingleChain 
injections required for the treatment of bleeding episodes. 
• 
To characterize consumption of rVIII-SingleChain in 
prophylaxis, on-demand treatment, and surgery. 
• 
To assess the hemostatic efficacy of rVIII-SingleChain for 
PUPs who undergo surgery, using the 4-point efficacy 
evaluation of surgical treatment scale. 
• 
To assess the occurrence of clinically significant abnormalities 
in vital signs after rVIII-SingleChain administration. 
Secondary Endpoints 
• 
Arm 1 and Arm 3 (PTPs): 
• 
Incidence of inhibitor formation to FVIII in at least 200 PTPs 
after 10 EDs and after 50 EDs with rVIII-SingleChain 
• 
Percentage of PTPs who develop antibodies against 
rVIII-SingleChain. 
• 
Percentage of PTPs who develop antibodies to CHO proteins. 

 
Study Number: CSL627_3001 
Study Product: rVIII-SingleChain  
 
CRD-TPL-077 Version 1.0 
26 May 2020 
Page 5 of 149 
 
Confidential 
• 
Annualized bleeding rate (ABR) (traumatic and non-traumatic) 
during prophylaxis and on-demand treatment. 
• 
Treatment success for bleeding episodes defined as a rating of 
"excellent" or "good" on the investigator’s clinical assessment 
of hemostatic efficacy 4-point scale. 
• 
Percentage of bleeding episodes requiring 1, 2, 3, or 
> 3 injections of rVIII-SingleChain to achieve hemostasis. 
• 
Mean actual dose per kg per subject per year; consumption of 
rVIII-SingleChain, expressed as number of injections and 
IU/kg per month and per year, as well as IU/kg per event 
(prophylaxis, on-demand, and surgery). 
• 
Treatment success for surgery, using the 4-point efficacy 
evaluation of surgical treatment scale. 
• 
Arm 2 (PUPs): 
• 
Incidence of high-titer inhibitor formation to FVIII 
(ie, inhibitor titer of ≥ 5  BU/mL) after 10 EDs with 
rVIII-SingleChain in PUPs. 
• 
Incidence of low-titer inhibitor formation (ie, inhibitor titer of 
< 5 BU/mL) to FVIII after 10 EDs and after 50 EDs with 
rVIII-SingleChain in PUPs. 
• 
Incidence of total (low- and high-titer) inhibitor formation to 
FVIII after 10 EDs and after 50 EDs with rVIII-SingleChain in 
PUPs. 
• 
Percentage of PUPs who develop antibodies against 
rVIII-SingleChain. 
• 
Percentage of PUPs who develop antibodies to CHO proteins. 
• 
Treatment success for non-major bleeding episodes, defined 
as a rating of "excellent" or "good" on the investigator's 
clinical assessment of hemostatic efficacy 4-point scale. 
• 
Percentage of bleeding episodes requiring 1, 2, 3 or 
> 3 injections of rVIII-SingleChain to achieve hemostasis.  
• 
ABR during prophylaxis and on-demand treatment. 
• 
Mean actual dose per kg per subject per year; consumption of 
rVIII-SingleChain, expressed as number of injections and 
IU/kg per month and per year, as well as IU/kg per event 
(prophylaxis, on-demand, and surgery). 
• 
Treatment success for surgery, using the 4-point efficacy 
evaluation of surgical treatment scale. 
• 
Percentage of PUPs with clinically significant abnormal values 
for blood pressure, or heart rate, or body temperature at 1, 2, 3, 
or 6 hours after the first rVIII-SingleChain injection. 
• 
Percentage of PUPs with treatment-emergent clinically 
significant abnormal values for blood pressure, heart rate or 
body temperature during the course of the study. 

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Study Number: CSL627_3001 
Study Product: rVIII-SingleChain 
 
CRD-TPL-077 Version 1.0 
26 May 2020 
Page 11 of 149 
 
Confidential 
Schedule of Assessments: 
Schedule of Assessments for Arm 1 (PTPs from rVIII-SingleChain Study) 
Assessments 
 
 
 
 
 
 
 
 
 
Visits 
Day 1 
Every 3 monthsA 
(± 7 days) 
EOSB 
Informed consent 
X 
  
 
Demographic information 
XC 
  
 
Medical and surgical history 
XC 
 
 
Review of inclusion / exclusion criteria; subject eligibility 
X 
 
 
Hemophilia A history (previous FVIII treatment, blood group, and gene defect) 
XC 
 
 
Hemophilia A social history and activity level 
XC 
X 
X 
Blood sample for gene defect, if no medical record 
← At any time during the studyD→ 
Serum chemistry and hematologyE,F 
XC 
X  
 
CD4 lymphocyte count (for HIV+ subjects) 
X 
 
 
Vital signsF 
XC 
X 
 
Physical examinationF 
XC 
X 
 
Body weight and heightG 
X 
X 
 
Incremental recoveryH 
X 
←-----At specified timepoints---→ 
  
Inhibitor to FVIIII,J 
XC 
←-----At specified timepoints----→ 
X 
Antibodies against rVIII-SingleChain and CHO proteinsI,J 
XC 
←-----At specified timepoints----→ 
 
Virology retention sampleK 
XC 
 
X 
Distribute and train subject on eDiary 
X 
 
 
Review subject eDiary 
 
X 
X 
Collect subject eDiary 
 
 
X 
Assign treatment regimen 
X 
 
 
Distribute rVIII-SingleChain 
X 
X L 
 
Record investigator assessment for treatment efficacy 
 
X 
X 
Collect used and partially used vials of rVIII-SingleChainM 
 
X 
X 
Drug accountability 
 
X 
X 
Adverse eventsN 
←---------------------On an ongoing basis----------------------→ 
Concomitant medications 
←---------------------On an ongoing basis----------------------→ 

 
Study Number: CSL627_3001 
Study Product: rVIII-SingleChain 
 
CRD-TPL-077 Version 1.0 
26 May 2020 
Page 12 of 149 
 
Confidential 
Abbreviations: CD4 = cluster of differentiation 4; CHO = Chinese hamster ovary; eCRF = electronic case report form; ED = exposure day; eDiary = electronic 
diary; EOS = End of Study; FVIII = coagulation factor VIII; HIV = human immunodeficiency virus; IR = incremental recovery; PTP = previously treated 
patient; rVIII-SingleChain = single chain recombinant coagulation factor VIII. 
Notes to the Schedule of Assessments: 
A: One month is 28 days. 
B: The EOS visit should take place at the end of the planned treatment period, if the subject discontinues prematurely, or if the sponsor terminates the study. 
C: Data will be acquired from the EOS visit from previous CSL-sponsored rVIII-SingleChain studies for Day 1 assessments and will include demographic 
information, medical and surgical history, hemophilia A history, hemophilia A social history and activity level, serum chemistry, hematology, vital signs, 
physical examination, blood sample for inhibitors and antibodies, virology retention sample, adverse events, and concomitant therapy, if available. If not 
available, these assessments will be performed at the Day 1 visit. 
D: If no medical record. Blood sample for gene defect should preferably be taken at Day 1. If this is not possible, sample can be taken at any time during study. 
E: Hematology: hemoglobin, hematocrit, red blood cell (erythrocyte) count, white blood cell (leukocyte) count, and platelet count. 
Serum chemistry: creatinine, alanine aminotransferase, aspartate aminotransferase, and total bilirubin. 
F: Hematology, serum chemistry, physical examinations, and vital signs will be performed during every site visit until the subject reaches 50 EDs, then yearly 
until EOS. 
G: Body weight will be measured for all subjects during each site visit. Height will be measured at each site visit only for subjects < 18 years old. 
H: Blood samples will be collected to assess IR and be analyzed in the central laboratory. If possible, subjects should have a 4-day washout after last FVIII 
injection before blood draws. A pre-dose blood sample will be drawn. Subjects will then receive their prophylaxis dose of rVIII-SingleChain injection in the 
clinic. For on-demand subjects, the usual dose used to treat a bleeding episode or any other dose determined by the investigator will be administered in the 
clinic. A post-dose blood sample will be drawn 30 to 60 minutes (± 5 minutes) after the injection. Incremental recovery will be collected at Day 1 and at the 
closest visits after 10 EDs, after 50 EDs, and after 100 EDs (see Section 8.6.2). Exposure days are cumulative from previous lead-in studies (calculated from 
the first dose of rVIII-SingleChain in any study. 
I: Data will be acquired from the EOS visit from previous CSL-sponsored rVIII-SingleChain studies for inhibitors to FVIII, antibodies against 
rVIII-SingleChain and antibodies against CHO proteins for Day 1. Additional blood samples for inhibitors to FVIII and antibodies to rVIII-SingleChain and 
antibodies to CHO proteins will be collected at the closest visits after 10 EDs, after 50 EDs, and after 100 EDs. For the inhibitor blood samples, subjects 
should have a 4-day washout from last FVIII injection before blood draw if possible. 
J: If the investigator collects blood samples for FVIII levels or inhibitor assessment at any other time during the study, the local laboratory results must be 
recorded in the eCRF and a duplicate sample must be submitted for analysis to the central laboratory (see Section 8.6). 
K: Virology retention sample: CSL will retain a sample for 5 years from EOS. 
L: rVIII-SingleChain may be dispensed at more frequent schedules if need is determined by the investigator. 
M: Unused vials near expiration or with insufficient shelf life to cover time duration until next visit should be returned at the next scheduled visit. All unused 
vials will be returned at the EOS visit. 
N: 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 EOS visit. However, adverse events ongoing at the EOS visit will be followed until 
resolution or 28 days after the final administration of rVIII-SingleChain during this study, whichever is sooner. 
 

 
Study Number: CSL627_3001 
Study Product: rVIII-SingleChain 
 
CRD-TPL-077 Version 1.0 
26 May 2020 
Page 13 of 149 
 
Confidential 
Schedule of Assessments for Arm 2 PUPs With or Without Bleeding Episode at Screening and Assigned to 
PROPHYLAXIS 
Assessments 
 
 
 
 
 
 
Visits 
Screening 
(Up to 28 days 
before Visit 1)A 
Visit 1A 
Every month 
(± 7 days): 
Until 25 EDs 
achievedB,C,D,E 
Every 3 months 
(± 7 days): 
From 25 EDs until 
EOSB,C,D,E 
EOSE 
Informed consent / assent 
X 
 
 
 
 
Demographic information 
X 
 
 
 
 
Medical and surgical history 
X 
 
 
 
 
Review of inclusion / exclusion criteria; subject eligibility 
X 
XF 
 
 
 
Hemophilia A history (blood group, and gene defect) 
X 
 
 
 
 
Hemophilia A social history and activity level 
X 
X 
X 
X 
X 
Review of prior medications (previous 28 days) 
X 
 
 
 
 
Blood sample for gene defect, if no medical recordG 
 
← At any time during studyG → 
Serum chemistry and hematologyH 
X 
 
X 
X 
X 
CD4 lymphocyte count (for HIV+ subjects)I  
X 
 
 
 
 
Vital signs 
X 
XJ 
X 
X 
X 
Physical examination 
X 
 
X 
X 
X 
Body weight and height 
X 
X 
X 
X 
X 
Inhibitor to FVIIIK,L 
X 
 
XS 
XS 
X 
Antibodies against rVIII-SingleChain and CHO proteins K,L 
X 
 
X 
X 
X 
Plasma FVIII activity 
XM 
 
 
 
 
Virology retention sample 
 
XN 
 
 
X 
Distribute and train subject on eDiary 
 
X 
 
 
 
Review subject eDiary and collect at EOS visit 
 
 
X 
X 
X 
Administer first rVIII-SingleChain dose at clinicO 
 
XO 
 
 
 
Local tolerability (if rVIII-SingleChain administered at clinic) 
 
X 
X 
X 
 
Record investigator assessment for treatment efficacy 
 
X 
X 
X 
X 
Assign treatment regimen 
 
X 
XP 
XP 
 
Distribute rVIII-SingleChain 
 
X 
X 
X 
 
Collect used and partially used vials of rVIII-SingleChainQ 
 
 
X 
X 
X 
Perform drug accountability 
 
 
X 
X 
X 

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CCI

 
Study Number: CSL627_3001 
Study Product: rVIII-SingleChain 
 
CRD-TPL-077 Version 1.0 
26 May 2020 
Page 16 of 149 
 
Confidential 
Schedule of Assessments for Arm 2 PUPs WITHOUT Bleeding Episode at Screening and Assigned to 
ON-DEMAND 
Assessments 
 
 
 
 
 
 
Visits 
Screening 
(up to 28 days 
before Visit 1) 
Visit 1 
Follow-up visits 
1 month (± 7 days) after 
each rVIII-SingleChain 
doseA,C,E 
Monthly phone calls 
(± 7 days) if duration 
between visits is 
> 1 monthB,C,E 
EOSD 
Informed consent / assent 
X 
 
 
 
 
Review of inclusion / exclusion criteria; subject eligibility 
X 
XF 
 
 
 
Demographic information 
X 
 
 
 
 
Medical and surgical history 
X 
 
 
 
 
Hemophilia A history (blood group, gene defect)  
X 
 
 
 
 
Hemophilia A social history and activity level 
X 
X 
X 
 
X 
Review of prior medications (previous 28 days) 
X 
 
 
 
 
Blood sample for gene defectG 
← At any timeG → 
Serum chemistry and hematologyH 
X 
 
X 
 
X 
CD4 lymphocyte count (for HIV+ subjects)I 
X 
 
 
 
 
Vital signs 
X 
XJ 
X 
 
X 
Physical examination 
X 
 
X 
 
X 
Body weight and height 
X 
X 
X 
 
X 
Inhibitor to FVIIIL 
XK 
 
XU 
 
X 
Antibodies against rVIII-SingleChain and CHO proteinsL 
XK 
 
X 
 
X 
FVIII activity level 
XM 
 
 
 
 
Virology retention sample 
 
XN 
 
 
X 
Distribute and train subject on eDiary 
 
X 
 
 
 
Review subject eDiary and collect at EOS visit 
 
 
X 
X 
X 
Administer rVIII-SingleChain at clinicO 
 
XO 
(X)P 
 
 
Investigator assessment for treatment efficacy 
 
 
X 
 
X 
Local tolerability (if rVIII-SingleChain administered at clinic) 
 
X 
X 
 
 
Assign treatment regimen 
 
XQ 
XQ 
 
 
Distribute rVIII-SingleChain 
 
XR 
XR 
 
 
Collect used / partially used rVIII-SingleChain vials S 
 
 
X 
 
X 
Perform drug accountability 
 
 
X 
 
X 
Record date and details of phone contact 
 
 
 
X 
 

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CCI

 
Study Number: CSL627_3001 
Study Product: rVIII-SingleChain 
 
CRD-TPL-077 Version 1.0 
26 May 2020 
Page 19 of 149 
 
Confidential 
Schedule of Assessments for Arm 2 PUPs WITH Bleeding Episode at Screening and Assigned to 
ON-DEMAND 
Assessments 
 
 
 
 
 
 
Visits 
Screening 
(up to 28 days 
before Visit 1)A 
Visit 1A 
Follow-up visits 
1 month (± 7 days) after 
each rVIII-SingleChain 
doseB,D,F 
Monthly phone calls 
(± 7 days) if duration 
between visits is 
> 1 monthC,D,F 
EOSE 
Informed consent / assent 
X 
 
 
 
 
Review of inclusion / exclusion criteria; subject eligibility 
X 
XG 
 
 
 
Demographic information 
X 
 
 
 
 
Medical and surgical history 
X 
 
 
 
 
Hemophilia A history (blood group, gene defect) 
X 
 
 
 
 
Hemophilia A social history and activity level 
X 
X 
X 
 
X 
Review of prior medications (previous 28 days) 
X 
 
 
 
 
Blood sample for gene defectH 
← At any time H → 
Serum chemistry and hematologyI 
X 
 
X 
 
X 
CD4 lymphocyte count (for HIV+ subjects)J 
X 
 
 
 
 
Vital signs 
X 
XK 
X 
 
X 
Physical examination 
X 
 
X 
 
X 
Body weight and height 
X 
X 
X 
 
X 
Inhibitor to FVIIIM 
XL 
 
XV 
 
X 
Antibodies against rVIII-SingleChain and CHO proteinsM 
XL 
 
X 
 
X 
FVIII activity level 
XN 
 
 
 
 
Virology retention sample 
 
XO 
 
 
X 
Distribute and train subject on eDiary 
 
X 
 
 
 
Review subject eDiary and collect at EOS visit 
 
 
X 
X 
X 
Administer rVIII-SingleChain at clinicP 
 
XP 
(X)Q 
 
 
Investigator assessment for treatment efficacy 
 
X 
X 
 
X 
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X 
X 
 
 
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XR 
XR 
 
 
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XS 
XS 
 
 
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X 
Perform drug accountability 
 
 
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X 
Record date and details of phone contact 
 
 
 
X 
 

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Study Number: CSL627_3001 
Study Product: rVIII-SingleChain 
 
CRD-TPL-077 Version 1.0 
26 May 2020 
Page 22 of 149 
 
Confidential 
Schedule of Assessments for Arm 3 (PTPs Not Currently Enrolled in a rVIII-SingleChain Study) 
Assessments 
 
 
 
 
 
 
 
 
Visits 
Screening 
(Up to 28 days 
before Visit 1 
Day 1 
Every 3 monthsA 
(± 7 days) 
EOSB 
Informed consent 
X 
 
  
 
Demographic information 
X 
 
  
 
Medical and surgical history 
X 
 
 
 
Review of inclusion / exclusion criteria; subject eligibility 
X 
 
 
 
Hemophilia A history (previous FVIII treatment, blood group, and gene defect) 
X 
 
 
 
Hemophilia A social history and activity level 
X 
 
X 
X 
Review of prior medications (previous 28 days) 
X 
 
 
 
Blood sample for gene defect, if no medical record C 
 
← At any time during the studyC → 
Serum chemistry and hematologyD,E 
X 
 
X  
X 
CD4 lymphocyte count (for HIV+ subjects) 
X 
 
 
 
Vital signsE 
X 
X 
X 
X 
Physical examinationE 
X 
 
X 
X 
Body weight and heightF 
X 
X 
X 
X 
FVIII activity levelG 
X 
 
 
 
Incremental recoveryH 
 
X 
←-----At specified timepointsH ---→ 
 
Inhibitor to FVIIII,J 
X 
 
←-----At specified timepointsI ----→ 
X 
Antibodies against rVIII-SingleChain and CHO proteinsI,J 
X 
 
←-----At specified timepointsI ----→ 
X 
Virology retention sampleK 
 
XK 
 
X 
Distribute and train subject on eDiary 
 
X 
 
 
Review subject eDiary and collect at EOS visit 
 
 
X 
X 
Assign treatment regimen 
 
X 
 
 
Distribute rVIII-SingleChain 
 
X 
X L 
 
Record investigator assessment for treatment efficacy 
 
 
X 
X 
Assessment of local tolerability (if rVIII-SingleChain administered at clinic) 
 
 
X 
 
Collect used and partially used vials of rVIII-SingleChainM 
 
 
X 
X 
Perform drug accountability 
 
 
X 
X 
Adverse eventsN 
←---------------------On an ongoing basis----------------------→ 
Concomitant medications 
←---------------------On an ongoing basis----------------------→ 

 
Study Number: CSL627_3001 
Study Product: rVIII-SingleChain 
 
CRD-TPL-077 Version 1.0 
26 May 2020 
Page 23 of 149 
 
Confidential 
Abbreviations: CD4 = cluster of differentiation 4; CHO = Chinese hamster ovary; eCRF = electronic case report form; ED = exposure day; eDiary = electronic 
diary; EOS = End of Study; FVIII = coagulation factor FVIII; HIV = human immunodeficiency virus; PTP = previously treated patient; 
rVIII-SingleChain = single chain recombinant coagulation factor VIII. 
Notes to the Schedule of Assessments: 
A: One month is 28 days. 
B: The EOS visit should take place at the end of the planned treatment period, if the subject discontinues prematurely, or if the sponsor terminates the study. 
C: Blood sample for gene defect should preferably be taken at Day 1. If this is not possible, the sample can be taken at any time during the study. 
D: Hematology: hemoglobin, hematocrit, red blood cell (erythrocyte) count, white blood cell (leukocyte) count, and platelet count. 
Serum chemistry: creatinine, alanine aminotransferase, aspartate aminotransferase, and total bilirubin. 
E: Hematology, serum chemistry, physical examinations, and vital signs will be performed during every site visit until the subject reaches 50 EDs, then yearly 
until EOS. 
F: Body weight will be measured for all subjects during each site visit. Height will be measured at each site visit only for subjects < 18 years. 
G: If not available in subject’s medical records, FVIII activity level must be determined at Screening at the local laboratory, and the result must be available 
before enrollment. 
H: Blood samples will be collected to assess IR and analyzed in the central laboratory. Subjects should have a 4-day washout after last FVIII injection before 
blood draws if possible. A pre-dose blood sample will be drawn. Subjects will then receive their prophylaxis dose of rVIII-SingleChain injection in the 
clinic. For on-demand subjects, the usual dose used to treat a bleeding episode or any other dose determined by the investigator will be administered in the 
clinic. A post-dose blood sample will be drawn 30 to 60 minutes (± 5 minutes) after injection. Incremental recovery will be collected at Day 1, at the closest 
visits after 10 EDs, after 50 EDs, and after 100 EDs (see Section 8.6.2). 
I: Blood samples for inhibitors to FVIII, antibodies against rVIII-SingleChain, and antibodies to CHO proteins will be collected at Screening and at the closest 
visit after 10 EDs, after 50 EDs, and after 100 EDs. For the inhibitor blood samples, subjects should have a 4-day washout from last FVIII injection before 
blood draw if possible. 
J: If the investigator collects blood samples for FVIII levels or inhibitor assessment at any other time during the study, the local laboratory results must be 
recorded in the eCRF and a duplicate sample must be submitted for analysis to the central laboratory (see Section 8.6). 
K: Virology retention samples: The Visit 1 sample must be taken before first rVIII-SingleChain injection. CSL will retain samples for 5 years from EOS. 
L: rVIII-SingleChain may be dispensed at more frequent schedules if need is determined by the investigator. 
M: Unused vials near expiration or with insufficient shelf life to cover time duration until next visit should be returned at the next scheduled visit. All unused 
vials will be returned at the EOS visit. 
N: 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 EOS visit. However, adverse events ongoing at the EOS visit will be followed until 
resolution or 28 days after the final administration of rVIII-SingleChain during this study, whichever is sooner. 
 

 
Study Number: CSL627_3001 
Study Product: rVIII-SingleChain 
 
CRD-TPL-077 Version 1.0 
26 May 2020 
Page 24 of 149 
 
Confidential 
Schedule of Assessments for Surgery Substudy (Arms 1, 2 and 3) 
Period 
Before surgery 
During Surgery 
After Surgery 
Body weight 
X 
 
 
Hemoglobin measurement  
X 
 
XA 
Predicted intraoperative estimated blood loss during surgery 
X 
 
 
Predicted transfusions during surgery 
X 
 
 
Actual consumption of rVIII-SingleChain 
X 
X 
X 
Record surgery type, relationship to hemophilia 
X 
 
 
Record FVIII plasma activity results and time of collection (if available)B 
←--------------------On an ongoing basis------------------→ 
Estimated blood loss during surgery 
 
X 
 
Additional hemostatic intervention or blood transfusions administeredC 
 
X 
X 
Investigator assessment of hemostatic efficacyD 
 
 
X 
Presence and extent of surgical wound hematomas 
 
 
X 
Measurement of drainage volume through surgical drains 
 
 
X 
Occurrence of late re-bleeding episodes 
 
 
X 
Inhibitors to FVIII 
XE 
 
XF 
Antibodies against rVIII-SingleChain and CHO proteins 
 
 
XF 
Adverse events  
←--------------------On an ongoing basis------------------→ 
Concomitant therapy 
←--------------------On an ongoing basis------------------→ 
Date of discharge 
 
 
X 
Abbreviations: CHO = Chinese hamster ovary; eCRF = electronic case report form; FVIII = coagulation factor FVIII; rVIII-SingleChain = single chain 
recombinant coagulation factor VIII. 
Notes to the Schedule of Assessments during Surgery Substudy: 
A: Lowest (nadir) hemoglobin measurement after surgery. 
B: If the investigator collects a blood sample for FVIII levels at any time during the substudy, the local laboratory results must be recorded in the eCRF and a 
duplicate sample must be submitted for analysis to the central laboratory. 
C: Hemostatic interventions or transfusions other than rVIII-SingleChain (eg, other coagulation factors, whole blood, red blood cells, fresh frozen plasma or 
platelets). 
D: Hemostatic efficacy assessment will be determined by the investigator based on a 4-point scale (Section 8.5.2.1). 
E: Arm 2 (PUPs): Blood sampling for inhibitor testing before surgery is recommended. Inhibitor testing may be performed at the local laboratory, and an 
additional sample must be sent to the central laboratory. 

 
Study Number: CSL627_3001 
Study Product: rVIII-SingleChain 
 
CRD-TPL-077 Version 1.0 
26 May 2020 
Page 25 of 149 
 
Confidential 
F: For subjects in all study arms, blood samples will be collected at least 28 days after surgery for analysis at the central laboratory for the presence of 
inhibitors to FVIII, antibodies against rVIII-SingleChain, and antibodies against CHO proteins. 
 

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CCI

 
Study Number: CSL627_3001 
Study Product: rVIII-SingleChain 
 
CRD-TPL-077 Version 1.0 
26 May 2020 
Page 29 of 149 
 
Confidential 
8.5.1.3 
After Surgery ............................................................................................ 74 
8.5.2 
Surgery Substudy Assessments .................................................................... 75 
8.5.2.1 
Efficacy Assessment by Investigator for Surgery ..................................... 75 
8.5.3 
Return to Treatment Regimen Following Surgery ....................................... 76 
8.6 
Blood Samples for Inhibitors, Antibodies, Incremental Recovery and FVIII 
Activity Level ................................................................................................... 77 
8.6.1 
Blood Samples for Inhibitors and Antibodies .............................................. 77 
8.6.2 
Blood Samples for Incremental Recovery .................................................... 78 
8.6.3 
Blood Samples for FVIII Activity Level ...................................................... 79 
8.7 
Retention of Samples ........................................................................................ 79 
8.8 
Prior and Concomitant Therapies ..................................................................... 80 
8.9 
Assessment of Local Tolerability ..................................................................... 80 
8.9.1 
Subject / Caregiver Assessment of Local Tolerability .................................. 80 
8.9.2 
Investigator Assessment of Local Tolerability (Arm 2 and Arm 3 Only) .... 80 
8.10 
Visit Schedules ................................................................................................. 81 
8.10.1 
Visit schedule for Arm 1 (PTPs) ................................................................... 82 
8.10.1.1 
Day 1 Visit ................................................................................................ 82 
8.10.1.2 
Treatment Period ....................................................................................... 83 
8.10.2 
Visit Schedule for Arm 2 (PUPs) ................................................................. 84 
8.10.2.1 
Visit Schedule for Arm 2 PUPs With or Without Bleeding Episode at 
Screening and Assigned to PROPHYLAXIS ........................................... 88 
8.10.2.2 
Visit Schedule for Arm 2 PUPs WITHOUT Bleeding Episode at 
Screening and Assigned to ON-DEMAND .............................................. 92 
8.10.2.3 
Visit Schedule for Arm 2 PUPs WITH Bleeding Episode at Screening and 
Assigned to ON-DEMAND ...................................................................... 95 
8.10.3 
Visit Schedule for Arm 3 (PTPs) .................................................................. 98 
8.10.3.1 
Screening .................................................................................................. 98 
8.10.3.2 
Day 1 ......................................................................................................... 99 
8.10.3.3 
Treatment Period ..................................................................................... 100 
8.10.4 
Follow-up Period ........................................................................................ 100 
8.10.5 
Unscheduled visits ...................................................................................... 101 
8.10.6 
End of Study ............................................................................................... 101 
8.10.6.1 
End of Study Visit for Arm 1 .................................................................. 101 
8.10.6.2 
End of Study Visit for Arms 2 and 3 ....................................................... 102 
9 
Adverse Events ................................................................................................... 102 
9.1 
Definitions ...................................................................................................... 102 

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Study Number: CSL627_3001 
Study Product: rVIII-SingleChain 
 
CRD-TPL-077 Version 1.0 
26 May 2020 
Page 35 of 149 
 
Confidential 
Abbreviation 
Definition 
rFVIII 
Recombinant factor VIII 
rVIII-SingleChain 
Single chain recombinant factor VIII 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SOC 
System Organ Class 
TEAE 
Treatment-emergent adverse event 
ULN 
Upper limit of normal 
US 
United States 
WFH 
World Federation of Hemophilia 
 

 
Study Number: CSL627_3001 
Study Product: rVIII-SingleChain 
 
CRD-TPL-077 Version 1.0 
26 May 2020 
Page 36 of 149 
 
Confidential 
1 
Introduction 
1.1 
Background 
Hemophilia A is a rare, but serious X-linked recessive bleeding disorder that affects males 
and is characterized by a deficiency in the plasma protein known as coagulation factor VIII 
(FVIII). In patients with hemophilia A, primary hemostasis is not affected but fibrin 
generation is defective because inadequate amounts of thrombin are generated. The patients 
suffer from spontaneous bleeding episodes, as well as substantially prolonged bleeding upon 
injury. Rare but life-threatening bleeding may also occur. The patients exhibit a range of 
clinical severity depending on the extent of residual activity of the deficient factor that can be 
detected in the circulation of individual patients. The severity of hemophilia A is based upon 
the activity level (%) of FVIII. The World Federation of Hemophilia (WFH) has defined 
individuals with < 1% FVIII activity to have severe hemophilia A and characteristically have 
spontaneous bleeding (predominantly in joints and muscles) that often results in permanent, 
disabling joint damage. Individuals with 1% to 5% FVIII activity are considered to have 
moderate hemophilia A. Individuals with 5% to 40% FVIII activity are considered to have 
mild hemophilia A [WFH, 2012]. 
The recommended treatment for patients with hemophilia A is to treat or prevent hemorrhage 
with clotting FVIII replacement therapy. However, some patients develop inhibitors against 
the exogenous clotting factor, causing these patients to become refractory to replacement 
therapy with the deficient factor. Inhibitor development occurs in all ethnic types and with 
both plasma-derived and recombinant FVIII concentrates [DiMichele, 2007]. The actual 
percentage of patients who develop inhibitors to FVIII fluctuates in the literature with reports 
of up to 30% of all patients with hemophilia A developing inhibitors [Gouw et al., 2013]. 
Inhibitors are typically classified as either high- or low-responding, depending on how an 
individual’s immune system is stimulated following repeated exposures to FVIII. 
High-responding inhibitors can rise quickly to very high levels (Bethesda titer ≥ 5 units) if 
the immune system reacts briskly or strongly to repeated exposure to FVIII. In high-titer 
inhibitors without continued exposure (a period of months or years), the titer level could 
decrease to a low level. Low-responding inhibitors demonstrate a slower or weaker 
responding immune system and the Bethesda titer will remain low (Bethesda titer < 5 units). 
However, the characteristics of an inhibitor can change over time. Low-titer inhibitors may 
also disappear spontaneously within several weeks or months, achieving immune tolerance in 
patients [DiMichele, 2008]. 

Study Number: CSL627_3001 
Study Product: rVIII-SingleChain 
CRD-TPL-077 Version 1.0 
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Page 37 of 149 
Confidential 
“The union of Factor VIII with its inhibitor is not associated with allergic reactions. The 
presence of an inhibitor does not change the typical site, frequency, or severity of bleeding, 
however the inhibitor makes control of hemorrhages more difficult.” [Kasper, 2004]. 
Inhibitor development usually occurs between a median age of 1.7 and 3.3 years regardless of 
the replacement factor product used, and occurs less frequently after the age of 5 years. 
Inhibitors are generally detected between a mean of 9 and 21 exposure days (EDs) with a 
median of 12 EDs following exposure to factor replacement products. Inhibitor development 
is most commonly detected within the first 50 EDs, and new inhibitors are rarely detected 
after 200 treatment days with the replacement factor [DiMichele, 2002]. 
Previously untreated patients (PUPs) are at particular high risk to develop high- and low-titer 
inhibitors. In the most recent studies (SIPPET), a 35.4% cumulative incidence of inhibitors in 
patients with severe hemophilia was reported within the first 50 EDs [Peyvandi et al., 2016]. 
In patients with inhibitors, particularly high titer, further replacement therapy with FVIII is 
futile and bleeds must be treated with by passing products [EMA reflection paper on ITI, 
2013]. However, bypassing agents are not as effective as FVIII replacement in patients 
without an inhibitor [Witmer and Young, 2013]. Inhibitor eradication has been achieved with 
immune tolerance induction (ITI) therapy in a significant proportion of patients 
(approximately 70% to 85%)[Oldenburg et al., 2014]. Since patients with inhibitors have a 
higher disease burden and an increased mortality and morbidity compared to those without 
inhibitors [Witmer and Young, 2013; Walsh et al., 2015], inhibitor eradication by ITI is the 
gold standard of therapy. 
The main goal of ITI is to restore responsiveness to FVIII treatment [Mariani  et al., 2003]. 
ITI treatment regimens utilize ongoing, frequent, uninterrupted exposure to FVIII over a 
period of a few months to 2 or more years with the goal of inducing antigen-specific 
tolerance [DiMichele, 2007]. Multiple ITI dosing regimens have been established in different 
parts of the world without clear evidence of the superiority of one regimen over the other. 
Low-dose regimens typically utilize substitution of 50 IU/kg 3 times weekly, whereas 
intermediate- to high-dose regimens employ intense therapies with 100 IU/kg daily or twice 
daily. While these doses would lead to high FVIII levels in patients without inhibitors and, in 
single cases, might constitute a risk for thromboembolic events, patients with inhibitors have 
a marginal incremental recovery (IR) of FVIII, resulting in low or non-detectable FVIII 
levels in plasma during ITI therapy. To compensate for increasing FVIII activity in successful 
or partially successful ITI (ie, declining inhibitor titers), some physicians decrease the 
treatment intensity when the inhibitor titer is found to decrease and the IR of FVIII found to 

 
Study Number: CSL627_3001 
Study Product: rVIII-SingleChain 
 
CRD-TPL-077 Version 1.0 
26 May 2020 
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Confidential 
increase. Regular monitoring of inhibitor titers (once monthly) is recommended, given the 
potential dynamic changes in the inhibitor titer during ITI therapy. Successful ITI leads to 
normalization of the IR and FVIII half-life. Based on the results from the International 
ITI study and other available evidence, ITI treatment guidelines for patients with 
hemophilia A have been developed [Valentino et al., 2015]. 
This extension study is being conducted to: 
• gain additional safety and efficacy information on the long-term use of single chain 
recombinant FVIII (rVIII-SingleChain, CSL627) in patients with severe congenital 
hemophilia A who were enrolled in prior CSL Behring GmbH (CSL)-sponsored clinical 
studies with rVIII-SingleChain (hereafter referred to as previously treated patients 
[PTPs]). 
• assess the risk of inhibitor formation to FVIII in patients with severe congenital 
hemophilia A with no prior exposure to any FVIII product (hereafter referred to as 
PUPs), in accordance with the European Medicines Agency (EMA) guideline on clinical 
investigation of recombinant and human plasma-derived factor VIII products 
[EMA, 2011; EMA, 2016].  
• investigate the use of rVIII-SingleChain in ITI in PUPs who develop a confirmed 
inhibitor to rVIII-SingleChain (ITI substudy), supported by recent evidence-based ITI 
treatment guidelines [Valentino et al., 2015] and the EMA reflection paper on ITI 
[EMA, 2013]. 
1.2 
Background Information on rVIII-SingleChain 
1.2.1 
Overview 
rVIII-SingleChain, a unique single-chain recombinant FVIII, is under clinical development 
for the treatment of subjects with severe hemophilia A. 
The structure of FVIII has 2 linked protein chains—a heavy and a light chain. Under certain 
conditions, this structure can dissociate, resulting in the formation of separated or 
"dissociated" FVIII chains. rVIII-SingleChain uses a strong, covalent bond that connects the 
light and heavy chains, thereby creating a single-chain recombinant FVIII that is very 
unlikely to dissociate. 
Nonclinical studies have shown that the molecular integrity of rVIII-SingleChain is 
significantly increased using this single-chain design, resulting in a more stable, homogenous 
product. In addition, in-vitro studies have shown that rVIII-SingleChain demonstrates a very 

 
Study Number: CSL627_3001 
Study Product: rVIII-SingleChain 
 
CRD-TPL-077 Version 1.0 
26 May 2020 
Page 39 of 149 
 
Confidential 
strong affinity for von Willebrand factor and a faster and more efficient binding to 
von Willebrand factor than wild-type FVIII. The FVIII-von Willebrand factor complex plays 
an important role in the physiological activity and clearance of FVIII and has been shown to 
have an influence on the presentation of FVIII to the immune system resulting in the 
potential of reduced inhibitor formation. 
1.2.2 
Nonclinical Evaluation 
In nonclinical studies, CSL tested the activity of rVIII-SingleChain in a tail clip model of 
hemophilia A in mice. In this model, rVIII-SingleChain was compared to marketed 
recombinant products, Helixate FS (manufactured by Bayer Healthcare LLC for 
CSL Behring) and ReFacto (Wyeth Pharmaceuticals, Inc., Philadelphia, PA). Blood loss was 
measured after dosing the animals with all 3 recombinant products and a plasma-derived 
FVIII (Humate-P / Haemate-P, CSL Behring). Plasma levels of FVIII were determined by 
chromogenic substrate (CS) assay, except for the plasma-derived product. All of the products 
tested showed comparable efficacy in arrest of bleeding in this animal model. 
Pharmacokinetic (PK) data from studies in cynomolgus monkeys showed a favorable PK 
profile of rVIII-SingleChain in comparison to the other products, whereupon the area under 
the concentration curve for 24 hours and clearance of rVIII-SingleChain improved by a factor 
of up to 1.6 and 1.8, respectively. 
The CS assay correlated best with clotting activity from doses of the rVIII-SingleChain and 
will be used for potency testing. Further details on the outcomes of nonclinical studies are 
available in the Investigator’s Brochure for rVIII-SingleChain. 
1.2.3 
Previous Clinical Experience 
Study CSL627_1001 is a completed 3-part study. Part 1 was a PK comparison of 
rVIII-SingleChain and octocog alfa (Advate, Baxter Healthcare Corporation, Deerfield, IL, 
United States [US]). Part 2 continued treatment of subjects from Part 1 with continued dosing 
of rVIII-SingleChain on an ongoing basis either as prophylaxis or on-demand treatment and 
evaluated efficacy and safety. Part 3 of the study evaluated the efficacy and safety of 
continued dosing of rVIII-SingleChain in subjects with severe hemophilia A. Part 3 included 
a single-dose, repeat PK assessment in a number of subjects. Parts 2 and 3 also included a 
surgery substudy. Doses and frequency of dosing for subjects undergoing surgery were based 
upon the subject’s PK profile, rVIII-SingleChain PK data, previous FVIII treatment regimen 
before enrollment, and bleeding phenotype, and were at the investigator’s discretion. The 
dose regimen of rVIII-SingleChain for subjects undergoing surgery was individualized based 

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Study Number: CSL627_3001 
Study Product: rVIII-SingleChain 
 
CRD-TPL-077 Version 1.0 
26 May 2020 
Page 44 of 149 
 
Confidential 
2.2 
Secondary Objectives and Endpoints 
2.2.1 
Secondary Objectives 
In Arms 1 and 3 (PTPs), the secondary objectives are: 
• To characterize the safety profile of rVIII-SingleChain with respect to inhibitor 
development after 10 EDs and after 50 EDs. 
• To characterize the safety profile of rVIII-SingleChain with respect to antibodies against 
rVIII-SingleChain and antibodies to Chinese hamster ovary (CHO) proteins. 
• To collect and evaluate efficacy information on the prophylaxis and treatment of 
bleeding episodes. 
• To assess the hemostatic efficacy of rVIII-SingleChain for PTPs who undergo surgery, 
using the 4-point efficacy evaluation of surgical treatment scale. 
In Arm 2 (PUPs), the secondary objectives are: 
• To further characterize the safety profile of rVIII-SingleChain with respect to inhibitor 
development. 
• To characterize the safety profile of rVIII-SingleChain with respect to antibodies against 
rVIII-SingleChain, and antibodies to CHO proteins. 
• To collect and evaluate the number of rVIII-SingleChain injections required for the 
treatment of bleeding episodes. 
• To characterize consumption of rVIII-SingleChain in prophylaxis, on-demand treatment, 
and surgery. 
• To assess the hemostatic efficacy of rVIII-SingleChain for PUPs who undergo surgery, 
using the 4-point efficacy evaluation of surgical treatment scale. 
• To assess the occurrence of clinically significant abnormalities in vital signs after 
rVIII-SingleChain administration. 
2.2.2 
Secondary Endpoints 
2.2.2.1 
Efficacy 
In Arm 1 and Arm 3 (PTPs), the secondary efficacy endpoints are: 
• Annualized bleeding rate (ABR) (traumatic and non-traumatic) during prophylaxis and 
on-demand treatment. 
• Treatment success for bleeding episodes defined as a rating of "excellent" or "good" on 
the investigator’s clinical assessment of hemostatic efficacy 4-point scale. 

 
Study Number: CSL627_3001 
Study Product: rVIII-SingleChain 
 
CRD-TPL-077 Version 1.0 
26 May 2020 
Page 45 of 149 
 
Confidential 
• Percentage of bleeding episodes requiring 1, 2, 3, or > 3 injections of rVIII-SingleChain 
to achieve hemostasis. 
• Mean actual dose per kg per subject per year; consumption of rVIII-SingleChain, 
expressed as number of injections and IU/kg per month and per year, as well as IU/kg 
per event (prophylaxis, on-demand, and surgery). 
• Treatment success for surgery, using the 4-point efficacy evaluation of surgical treatment 
scale. 
In Arm 2 (PUPs), the secondary efficacy endpoints are: 
• Treatment success for non-major bleeding episodes, defined as a rating of "excellent" or 
"good" on the investigator's clinical assessment of hemostatic efficacy 4-point scale. 
• Percentage of bleeding episodes requiring 1, 2, 3 or > 3 injections of rVIII-SingleChain 
to achieve hemostasis. 
• ABR during prophylaxis and on-demand treatment. 
• Mean actual dose per kg per subject per year; consumption of rVIII-SingleChain, 
expressed as number of injections and IU/kg per month and per year, as well as IU/kg 
per event (prophylaxis, on-demand, and surgery). 
• Treatment success for surgery, using the 4-point efficacy evaluation of surgical treatment 
scale. 
2.2.2.2 
Safety 
In Arm 1 and Arm 3 (PTPs), the secondary saf ety endpoints are: 
• Incidence of inhibitor formation to FVIII in at least 200 PTPs after 10 EDs and after 
50 EDs with rVIII-SingleChain. 
• Percentage of PTPs who develop antibodies against rVIII-SingleChain. 
• Percentage of PTPs who develop antibodies to CHO proteins. 
In Arm 2 (PUPs), the secondary safety endpoints are: 
• Incidence of high-titer inhibitor formation to FVIII (ie, inhibitor titer of ≥ 5 BU/mL) 
after 10 EDs with rVIII-SingleChain in PUPs. 
• Incidence of low-titer inhibitor formation (ie, inhibitor titer of < 5 BU/mL) to FVIII after 
10 EDs and after 50 EDs with rVIII-SingleChain in PUPs. 
• Incidence of total (low- and high-titer) inhibitor formation to FVIII after 10 EDs and 
after 50 EDs with rVIII-SingleChain in PUPs. 
• Percentage of PUPs who develop antibodies against rVIII-SingleChain. 

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On-demand or prophylaxis regimen 
until at least 100 EDs with rVIII-SingleChain achieved 
On-demand or prophylaxis regimen
until at least 75 EDs with rVIII-SingleChain achieved 
On-demand or prophylaxis regimen 
until at least 100 EDs with rVIII-SingleChain achieved 
ARM 1: PTPs rolling over directly 
from previous CSL-sponsored 
rVIII-SingleChain study
ARM 2: PUPs with no previous 
exposure to any FVIII product
ARM 3: PTPs not currently 
participating in any CSL-
sponsored rVIII-SingleChain study
Day 1
Month 12
Month 24
Month 48 
Month 36
Surgery substudy B
Month 60A
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CSL627_3001 Subject Disposition Plan
Inhibitor Negative
Inhibitor Positive
Upon completion of 75 
Exposure Days, the 
patient must be rolled off 
the study
Main Study
Inhibitor Treatment 
Period:  
24 months from regimen 
adjustment to treat the 
inhibitor
If no regimen is assigned 
to treat the inhibitor, the 
duration will be 24 
months from the 
inhibitor diagnosis date
Post Eradication follow 
up:  
12 months from the 
inhibitor eradication date
Upon completion of the 
post eradication follow 
up, patients must be 
rolled off the study
Inhibitor Treatment 
Period:  
Upon completion of the 
, the subject 
will return to the main
Main Study
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Study Number: CSL627_3001 
Study Product: rVIII-SingleChain 
 
CRD-TPL-077 Version 1.0 
26 May 2020 
Page 50 of 149 
 
Confidential 
PK data, previous FVIII treatment regimen, bleeding phenotype (if available), and taking 
into consideration the WFH guidelines [WFH, 2012]. 
• In Arm 2 (PUPs), the investigator will determine the rVIII-SingleChain dose and dosing 
schedule at their discretion, taking into consideration the WFH guidelines [WFH, 2012], 
subject’s age and other disease characteristics (eg, bleeding phenotype). 
3.2.2 
Treatment of Bleeding Episodes in Subjects on Prophylaxis
 
and in Subjects On-Demand Treatment Regimens 
In the event of a bleeding episode, subjects will be treated at a dose pre-determined by the 
investigator based on the type and severity of the bleeding episode. All subjects should treat 
bleeding episodes with rVIII-SingleChain when they occur, regardless of the assigned 
treatment regimen. The desired FVIII level for the treatment of a bleeding episode 
(on-demand treatment) is based on the recommendations of the WFH [WFH, 2012]. 
All subjects will be dosed according to the actual potency printed on the vial label and will be 
treated by IV injection. 
3.2.3 
Preventive and Additional Doses 
In all study arms, preventive doses of rVIII-SingleChain are allowed. A preventive dose is 
defined as a dose that is taken prior to an activity or a minor procedure to prevent or 
minimize a bleeding episode. 
In all study arms, additional doses of rVIII-SingleChain are allowed. An additional dose is 
defined as a dose that is taken beyond the need to control hemostasis and does not contribute 
to the efficacy evaluation of the bleeding episode. These preventive and additional doses will 
not contribute to the efficacy evaluation of the bleeding episode but should be captured in the 
subject’s electronic diary (eDiary) or electronic case report form (eCRF), if administered in 
the hospital. Preventive and additional doses will contribute to EDs and consumption data. 
3.2.4 
Surgery Doses 
In all study arms, the investigator will determine the rVIII-SingleChain dose and treatment 
schedule for a subject who is scheduled for surgery based on the type of surgery and the 
clinical status of the subject. The PK data of the study subject or population (if available) will 
be utilized for calculating the dose regimen of rVIII-SingleChain before, during and after 
surgery to achieve and maintain the FVIII activity level recommended by the WFH 
Guidelines [WFH, 2012]. 

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Study Number: CSL627_3001 
Study Product: rVIII-SingleChain 
 
CRD-TPL-077 Version 1.0 
26 May 2020 
Page 54 of 149 
 
Confidential 
Further details on the composition, responsibilities, meeting schedule, data for review, and 
recommendations of the IDMC are available in the IDMC Charter. 
3.6.2 
Other Monitoring Committees 
3.6.2.1 
CSL Safety Management Team 
The purpose of the internal cross-functional Safety Management Team is to ensure a 
systematic proactive approach to developing and performing safety surveillance and risk 
management, with the primary goal of minimizing risk to subjects and patients during clinical 
development and post-authorization. 
4 
Selection and Withdrawal of Subjects 
4.1 
Eligibility Criteria 
The study population (male subjects with severe hemophilia A) will be selected on the basis 
of the inclusion and exclusion criteria for Arms 1, 2 and 3 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. 
4.1.1 
Inclusion Criteria 
4.1.1.1 
Arm 1 (PTPs) 
Subjects meeting all of the following inclusion criteria may be enrolled into Arm 1 of the 
study: 
1. Capable of providing written informed consent and willing and able to adhere to all 
protocol requirements, or the subject’s parent(s) or legally acceptable representative(s) 
capable of providing written informed consent. 
2. Participated in a previous CSL-sponsored rVIII-SingleChain investigational study. 
4.1.1.2 
Arm 2 (PUPs) 
Subjects meeting all of the following inclusion criteria may be enrolled into Arm 2 of the 
study: 
1. Age 0 to < 18 years of age with severe congenital hemophilia A (factor VIII activity 
< 1%, determined in local laboratory before enrollment or documented in subject’s 
medical record). 

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Study Number: CSL627_3001 
Study Product: rVIII-SingleChain 
 
CRD-TPL-077 Version 1.0 
26 May 2020 
Page 56 of 149 
 
Confidential 
3. 
Mental condition rendering the subject (or the subject's legally acceptable 
representative[s]) unable to understand the nature, scope and possible consequences 
of the study. 
4. 
Known or suspected hypersensitivity to rVIII-SingleChain or to any excipients of 
rVIII-SingleChain or CHO proteins. 
5. 
Any issue that, in the opinion of the investigator, would render the subject unsuitable 
for participation in the study. 
4.1.2.2 
Arm 2 (PUPs) 
Subjects meeting any of the following exclusion criteria must not be enrolled into the study: 
1. 
Any first-order family (eg, siblings) history of FVIII inhibitors. 
2. 
Any known congenital or acquired coagulation disorder other than congenital FVIII 
deficiency (with the exception of resolved vitamin K deficiency of the newborn). 
3. 
Currently receiving a therapy not permitted during the study, as defined in 
Section 7.3. 
4. 
Evidence of thrombosis, including deep vein thrombosis, stroke, pulmonary 
embolism, myocardial infarction and arterial embolus within 3 months before 
Screening. 
5. 
Known or suspected hypersensitivity to rVIII-SingleChain, to any excipients of 
rVIII-SingleChain, or CHO proteins. 
6. 
Platelet count < 100,000/µL at Screening. 
7. 
Human immunodeficiency virus (HIV) positive subjects (if the patient has received 
any blood components or per investigator discretion considering the subject’s medical 
history) with a CD4 count < 200/mm3 in their medical history or at Screening if 
available results are older than 1 year (HIV-positive subjects may participate in the 
study and antiviral therapy is permitted, at the discretion of the investigator). 
8. 
Serum aspartate aminotransferase (AST) or serum alanine aminotransferase (ALT) 
values > 5 times the upper limit of normal (× ULN) at Screening. 
9. 
Serum creatinine values > 2 × ULN at Screening. 
10. 
Demonstrated or suspected inability (eg, language problem or mental condition) or 
unwillingness to comply with study procedures or history of noncompliance. 
11. 
Employee at the study site, or spouse /partner or relative of the investigator or 
sub-investigators. 
12. 
Mental condition rendering the subject (or the subject’s legally acceptable 
representative[s]) unable to understand the nature, scope and possible consequences 
of the study. 

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Study Number: CSL627_3001 
Study Product: rVIII-SingleChain 
 
CRD-TPL-077 Version 1.0 
26 May 2020 
Page 60 of 149 
 
Confidential 
Packaging form 
Sterile, preservative-free solution for injection 
containing either 250 IU, 500 IU, 1000 IU, 2000 IU, 
and 3000 IU per single use vial 
Mode of administration 
Intravenous injection 
Abbreviations: FVIII = coagulation factor VIII. 
Each vial of rVIII-SingleChain powder will be reconstituted with 1 vial of sterile water for 
injection (2.5 mL for 250, 500 or 1000 IU vials; 5.0 mL for 2000 or 3000 IU vials). The label 
of each rVIII-SingleChain vial will include the actual number of units of FVIII contained 
within that particular vial. Refer to the Investigator’s Brochure for further details. 
The study product, rVIII-SingleChain, will be manufactured by CSL Behring GmbH in 
accordance with Good Manufacturing Practice guidelines and local regulatory requirements. 
5.1.2 
Comparator Product 
Not applicable 
5.2 
Packaging, Labeling, Supply and Storage 
5.2.1 
Packaging and Labeling 
rVIII-SingleChain 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 
rVIII-SingleChain will be supplied by CSL Behring. 
The rVIII-SingleChain study product must be shipped and stored at 2 to 8°C (36 to 46°F) in a 
closed carton, protected from light. The rVIII-SingleChain study product must not be frozen. 
The rVIII-SingleChain study product must be stored separately from normal hospital or 
practice inventories, in a locked facility with access limited to the investigator and authorized 
personnel. The investigator must ensure that the rVIII-SingleChain study product is 
dispensed only to subjects enrolled in this study according to this study protocol. Storage and 
handling instructions of the rVIII-SingleChain study product maintained at the subject’s 
home are described in the subject’s IMP handling instructions. 

 
Study Number: CSL627_3001 
Study Product: rVIII-SingleChain 
 
CRD-TPL-077 Version 1.0 
26 May 2020 
Page 61 of 149 
 
Confidential 
5.3 
Accountability and Destruction 
The investigator or delegate will confirm receipt of all shipments of the rVIII-SingleChain 
study product in writing using the receipt form(s) provided by the sponsor or vendor. 
All supplies of rVIII-SingleChain must be accounted for throughout the study. At the end of 
the study, the original Drug Inventory Log, dated and signed by the investigator or delegate 
(eg, pharmacist), must be retained at the study site as verification of final accountability of 
rVIII-SingleChain. 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). 
Records for the delivery of rVIII-SingleChain to the study site, the inventory at the study site, 
the use by each subject, and the destruction or return of rVIII-SingleChain to CSL must be 
maintained by the investigator (or delegate). 
Any unused or partially used rVIII-SingleChain or empty vials must not be destroyed until 
the drug accountability documentation has been checked by the study monitor and specific 
permission for destruction has been given by the sponsor. Any destruction of the 
rVIII-SingleChain study product must be documented on the form provided for this purpose. 
5.4 
Other Intervention(s) 
Not applicable. 
5.5 
Rescue Therapy 
Other marketed FVIII products should be used as rescue medication only when there is 
poor / no hemostatic response to rVIII-SingleChain as defined in Section 8.4.1 or when 
rVIII-SingleChain is not available (eg, emergency use). 
The PUPs in Arm 2 using a FVIII product as rescue medication must be withdrawn from the 
study (see Section 4.2.1). The PTPs in Arms 1 and 3 using a FVIII product as rescue 
medication do not need to be withdrawn from the study. 
The use of bypassing agents (ie, activated recombinant factor VII [rFVIIa] or activated 
prothrombin complex concentrate [aPCC] / factor eight inhibitor bypassing agent [FEIBA]) 
is permitted in subjects with inhibitors. 

 
Study Number: CSL627_3001 
Study Product: rVIII-SingleChain 
 
CRD-TPL-077 Version 1.0 
26 May 2020 
Page 62 of 149 
 
Confidential 
6 
Allocation, Dosing and Administration 
6.1 
Allocation to Treatment 
6.1.1 
Subject Assignment 
After providing written informed consent, a subject identification number will be used to 
identify the subject for the duration of the study. Subjects in Arm 1 will retain their subject 
identification number from the preceding rVIII-SingleChain study they participated in. 
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 rVIII-SingleChain only to subjects 
included in this study following the procedures set out in this study protocol. 
6.2.1 
Prophylaxis Treatment and On-Demand Treatment Regimens 
The investigator will assign subjects to either a prophylaxis or on-demand treatment regimen. 
All subjects should treat bleeding episodes with rVIII-SingleChain when they occur, 
regardless of the assigned treatment regimen. The rVIII-SingleChain dose and dosing 
schedule will be determined at the investigator’s discretion based upon the criteria detailed in 
Section 3.2. 
Special consideration for PUPs in Arm 2: 
1. 
All PUPs in Arm 2 must receive their first rVIII-SingleChain dose at Visit 1 at the 
clinic under medical supervision of the investigator (or a delegate experienced in the 
treatment of hemophilia patients). The subject must remain at the clinic and must be 
observed for at least 6 hours after this first dose to monitor for signs of 
injection-related reactions and to perform vital signs assessments. Refer to 
Sections 8.10.2.1, 8.10.2.2, and 8.10.2.3 for details of the visit schedules and required 
activities at each visit for Arm 2. 

 
Study Number: CSL627_3001 
Study Product: rVIII-SingleChain 
 
CRD-TPL-077 Version 1.0 
26 May 2020 
Page 63 of 149 
 
Confidential 
2. 
If assigned to an on-demand regimen, PUPs in Arm 2 may be provided with 
rVIII-SingleChain for home treatment after the first dose administered at the site, if 
the subject / caregiver has received appropriate training for home treatment and if 
agreeable by the investigator (see Sections 8.10.2.1, 8.10.2.2, and 8.10.2.3). 
6.2.2 
Preventive or Additional Treatment 
In some cases, an additional dose of rVIII-SingleChain beyond what is required to stop a 
bleeding episode may be taken to maintain hemostasis and this dose will not be counted in 
the evaluation of efficacy. Preventive and additional doses should be documented in the 
eCRF. These doses will be counted towards the number of EDs and consumption of 
rVIII-SingleChain but will not be counted toward the treatment for an on-demand bleeding 
episode or in the evaluation of efficacy assessment. 
6.2.3 
Surgery Treatment 
Subjects from all study arms may participate in the surgery substudy. The investigator will 
assign the rVIII-SingleChain dose based on the type of surgery and the subject’s clinical 
status. The subject’s previous PK data (if available) can be used to calculate the dose regimen 
of rVIII-SingleChain before, during, and after surgery to achieve and to maintain a FVIII 
activity level recommended by the WFH guidelines [WFH, 2012] in Table 2. Any subject 
required to have surgery during the study should suspend his normally-assigned 
rVIII-SingleChain treatment, as indicated by the treating physician. Subjects should be 
treated with rVIII-SingleChain before, during, and after surgery, under the supervision of and 
as prescribed by the treating physician. Additional injections of rVIII-SingleChain may be 
needed to maintain the required plasma FVIII activity level. 
Table 2: 
WFH suggested plasma factor level and duration of administration 
Type of hemorrhage 
Desired FVIII (IU/dL) 
Duration (days) 
Surgery (major) 
 
 
• Pre-operative 
80-100 
 
• Post-operative 
60-80 
1-3 
 
40-60 
4-6 
 
30-50 
7-14 
Surgery (minor) 
 
 

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Study Number: CSL627_3001 
Study Product: rVIII-SingleChain 
 
CRD-TPL-077 Version 1.0 
26 May 2020 
Page 66 of 149 
 
Confidential 
To be used with caution: 
With the exception of selective cyclooxygenase-2 inhibitors, nonsteroidal anti-inflammatory 
drugs are known to have an effect on blood clotting. It is therefore important that the 
investigator gives careful consideration to the use of nonsteroidal anti-inflammatory drugs in 
subjects participating in this study. If possible, alternative medication for pain relief, such as 
paracetamol, which is acetaminophen, should be used. 
7.3 
Prohibited Therapies 
The administration of rVIII-SingleChain is prohibited to any subject not meeting the 
eligibility criteria for this study, or to any subject not enrolled in this study. 
In Arms 1 and 3, the following therapies are NOT PERMITTED during the study: 
• Any IMPs other than rVIII-SingleChain. 
• Other marketed FVIII products or coagulations factors, except as a rescue medication. 
 
In Arm 2 (PUPs), the following therapies are NOT PERMITTED during the study: 
• Any IMPs other than rVIII-SingleChain. 
• Other marketed FVIII products. 
• Intravenous immunomodulating agents such as immunoglobulin G or > 2 weeks of 
systemic steroids. 
7.4 
Dietary and Lifestyle Restrictions 
Not applicable. 
7.5 
Overdose 
The effects of any potential overdose with the rVIII-SingleChain study product have not been 
studied. Any potential overdose should be documented in the eCRF. Section 9.7.1 defines a 
potential overdose and describes the reporting and documentation procedures. 
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 3 and Table 4. Refer to the 
Laboratory Manual for detailed instructions on how the assessments should be performed. 

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CCI

 
Study Number: CSL627_3001 
Study Product: rVIII-SingleChain 
 
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26 May 2020 
Page 68 of 149 
 
Confidential 
Assessment 
Description 
Local tolerability 
Arm 1: Subject / caregiver assessment (documented in 
eDiary) 
Arm 3: 
- 
Subject / caregiver assessment (documented in 
eDiary) 
- 
Investigator assessment for rVIII-SingleChain 
injections administered at the clinic 
Abbreviations: CHO = Chinese hamster ovary; eDiary = electronic diary; FVIII = coagulation factor VIII; 
PTP = previously treated patient. 
Table 4: 
Clinical procedures: demographics and safety evaluation in Arm 2 
(PUPs) 
Assessment 
Description 
Demographics 
Date of birth, age, sex, race and ethnicity 
Medical and hemophilia A 
history 
Gene defect 
Blood group 
Family history of hemophilia 
History of inhibitors 
Co-morbidity or co-medication which would significantly 
impact blood coagulation or immunoreaction 
Current / concomitant therapies 
Hemophilia A history 
Hemophilia A social history and physical activity level 
Physical examination 
As per the site’s standard procedures. The following body 
systems must be assessed: general appearance, skin, eyes, 
ears, nose, throat, heart, lungs, abdomen, neurological 
system, lymph nodes, spine, and extremities. 
Vital signs 
Height and body weight 
Blood pressure (systolic and diastolic) 
Heart rate 
Body temperature 
Hematology  
Hemoglobin and hematocrit 
Red blood cell (erythrocyte) count 
White blood cell (leukocyte) count 
Platelet count 

 
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Study Product: rVIII-SingleChain 
 
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Assessment 
Description 
Serum chemistry  
Sodium 
Potassium  
Chloride 
Blood urea nitrogen 
Creatinine 
Gamma-glutamyl transferase 
Alkaline phosphatase 
Alanine aminotransferase 
Aspartate 
aminotransferase 
Albumin 
Total bilirubin 
Total protein 
Glucose 
Calcium 
Urea 
Serology 
Blood samples are to be collected and stored and will be 
tested if suspicion of viral infection 
Immunogenicity 
Blood analyzed for the presence of inhibitors to FVIII, 
antibodies against rVIII-SingleChain, and antibodies 
against CHO proteins 
FVIII activity level 
If not available in subject’s medical records, FVIII activity 
level will be determined at the local laboratory at 
Screening, as per laboratory standard procedures 
Local tolerability  
Subject / caregiver assessment (documented in eDiary) 
Investigator assessment for rVIII-SingleChain injections 
administered at the clinic 
Abbreviations: CHO = Chinese hamster ovary; eDiary = electronic diary; FVIII = coagulation factor VIII; 
PTP = previously treated patient; rVIII-SingleChain = single chain recombinant factor VIII. 
The timing and frequency of all clinical procedures are described in the Schedules of 
Assessments. 
A positive inhibitor result (local or central) must be repeated and a duplicate sample must be 
submitted to the central laboratory as soon as possible after receiving the laboratory report to 
rule out laboratory errors. Refer to the Laboratory Manual for details about the collection, 
storage, handling and transportation of biological specimens. 
8.2 
Subject Training 
At Day 1 (Arm 1) / Visit 1 (Arms 2 and 3) and all follow-up visits, the investigator or 
delegate will ensure that the subject has been trained sufficiently to allow for home treatment 
to occur in the subsequent months of the study, as needed. At this time, the subject will be 
instructed in the following: 
• Correct reconstitution technique for rVIII-SingleChain. 
• Correct IV access and administration technique. 
• Correct drug storage. 

 
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Study Product: rVIII-SingleChain 
 
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• AE reporting. 
• Correct completion of eDiary. 
8.3 
Treatment Assessments 
8.3.1 
Subject / Caregiver Treatment Assessments 
For treatment received by the subject at home, the subject will report (not limited to) the 
following information in the eDiary: 
• Details of the rVIII-SingleChain administration (eg, total actual IU per injection, number 
of vials used, and start date and time of injection). 
• Type of treatment (routine prophylaxis, on-demand, prevention before activity, additional 
doses, post-surgery). 
• Bleeding episodes, including: 
• Site of the bleeding episode (ie, joint, muscle, mucosal membrane) and specific 
location. 
• Time of onset of symptoms of bleeding. 
• Reason for use of rVIII-SingleChain and type of the bleeding episode (traumatic or 
non-traumatic). 
• Date and start time of each injection. 
• Local tolerability assessment. 
• Any concomitant therapy and other hemostatic product usage will be noted in the 
eDiary and reported to the investigator. 
8.3.2 
Treatment Assessment Performed at Study Site 
Major bleeding episodes are defined as bleeding episodes for which a subject is required to 
seek treatment at the hemophilia center from the treating physician for any episode that 
threatens the subject’s life or a loss of limb. Examples of major bleeding episodes include 
intracranial hemorrhage, gastrointestinal bleeding, and severe bleeding. All other bleeding 
episodes will be classified as non-major unless the investigator assessment notes otherwise. 
The following will be recorded in the eCRF following treatment of a bleeding episode by the 
investigator: 
• Reason for use of rVIII-SingleChain and type of the bleeding episode (major or 
non-major, traumatic or non-traumatic). 
• Location of bleeding. 

 
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Study Product: rVIII-SingleChain 
 
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• Time of the start of bleeding. 
• Dose of rVIII-SingleChain (IU/kg). 
• Number of used vials and total actual IU infused. 
• Date and start time of each injection. 
• Concomitant therapy and other hemostatic product usage (if any). 
• Efficacy evaluation by the investigator. 
• AEs. 
• Arms 2 and 3 only: investigator assessment of local tolerability if rVIII-SingleChain 
administered at the clinic. 
8.4 
Efficacy Evaluation by Investigator 
8.4.1 
Efficacy Assessment by Investigator for Bleeding Episodes 
The investigator will assess the hemostatic efficacy of rVIII-SingleChain after each treated 
bleeding episode, using the following efficacy evaluation scales for non-major bleeding 
episodes (Table 5) and major bleeding episodes (Table 6). 
Table 5: 
Efficacy evaluation scale for non-major bleeding episodes by 
investigator 
Category 
Description 
Excellent 
Definite pain relief and / or improvement in signs of bleeding 
(ie, swelling, tenderness, and / or increased range of motion in the 
case of musculoskeletal hemorrhage) within approximately 8 hours 
after the first rVIII-SingleChain injection. 
Good 
Definite pain relief and / or improvement in signs of bleeding at 
approximately 8 hours after the first rVIII-SingleChain injection, but 
requires 2 injections for complete resolution. 
Moderate 
Probable or slight beneficial effect within approximately 8 hours 
after the first rVIII-SingleChain injection; requires more than 
2 injections for complete resolution. 
Poor / No response 
No improvement at all or condition worsens (ie, signs of bleeding) 
after the first rVIII-SingleChain injection and additional hemostatic 
intervention is required with another FVIII product, cryoprecipitate, 
or plasma for complete resolution. 
Abbreviations: FVIII = coagulation factor VIII; rVIII-SingleChain = single chain recombinant factor VIII. 
 

 
Study Number: CSL627_3001 
Study Product: rVIII-SingleChain 
 
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Table 6: 
Efficacy evaluation scale for major bleeding episodes by 
investigator 
Category 
Description 
Excellent 
Hemostasis clinically not significantly different from (eg, achieved 
hemostasis comparable to that expected for a similar bleeding 
episode in a non-factor deficient patient) and estimated 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 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 FVIII product, 
cryoprecipitate, or plasma more than expected for the type of injury 
or problem 
Abbreviations: FVIII = coagulation factor VIII. 
 
8.5 
Treatment for Surgery 
Subjects undergoing surgery may be treated with rVIII-SingleChain (see Section 3.2.4 and 
Section 6.2.3 for surgery dose and surgery treatment). All subjects undergoing surgery may 
enroll in the surgery substudy. Subjects who enroll in the surgery substudy will return to the 
main study at the end of participation, as outlined in Section 8.5.3. Doses of 
rVIII-SingleChain administered before and after surgery will be documented. 
All invasive procedures other than surgery will not be included in the surgery substudy. 
Subjects undergoing an invasive procedure other than surgery may be treated with 
rVIII-SingleChain. However, invasive procedures other than surgery are considered medical 
events of special interest and should be documented in the eCRF. 
If a subject has an emergency surgery and rVIII-SingleChain is not available, the subject may 
substitute rVIII-SingleChain with a marketed FVIII product during surgery; the surgery will 

 
Study Number: CSL627_3001 
Study Product: rVIII-SingleChain 
 
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not be included in the surgery substudy. Subjects in Arms 1 and 3 (PTPs) may return to the 
study after the emergency surgery at the discretion of the investigator and sponsor. If a 
subject has a planned surgery and uses any FVIII product other than rVIII-SingleChain, the 
subject must be withdrawn from the study. 
Subjects in Arm 2 (PUPs) must be withdrawn from the study if they receive any FVIII 
product other than rVIII-SingleChain, irrespective of the type of surgery (emergency or 
planned) for which that FVIII product was administered. Inhibitor positive patients who 
require surgery are not eligible for the surgery substudy, as the surgical procedure should be 
covered by bypassing agent. 
8.5.1 Surgery Substudy Clinical Procedures 
The timing and frequency of clinical procedures before, during and after surgery are 
presented in the Schedule of Assessments for Surgery Substudy. The surgical substudy period 
starts when the first surgery rVIII-SingleChain dose is administered and ends when the 
subject returns to the scheduled dosing regimen in the main study. 
If the investigator collects a blood sample for FVIII activity level or inhibitor assessment at 
any time during the substudy, the local laboratory results (and time of specimen collection) 
must be recorded in the eCRF and a duplicate sample must be submitted for analysis to the 
central laboratory. 
8.5.1.1 
Before Surgery 
The following procedures will be performed before surgery: 
• Obtain body weight. 
• Obtain blood sample for hemoglobin measurement (to be assessed by local laboratory). 
• Arm 2 (PUPs) only: Obtain blood sample for inhibitor testing (recommended). If 
determined at the local laboratory, the results and time of specimen collection must be 
recorded in the eCRF. A duplicate sample must be submitted for analysis to the central 
laboratory. 
Before surgery, the surgeon (or physician performing the procedure) will perform the 
following estimates: 
• Predicted intraoperative blood loss (average and maximum): the predicted blood loss is 
the amount of blood loss predicted by the surgical team (anesthesiologist and / or 
surgeon) prior to the start of surgery for a patient without hemophilia undergoing the 
same surgery. 

 
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• Predicted transfusions during surgery based on a patient without hemophilia undergoing 
the same surgical procedure. 
The investigator will document the following information before surgery: 
• Actual rVIII-SingleChain consumption before surgery (including dose regimen, and 
number of injections per day). 
• Type of surgery (emergency or non-emergency). 
• Relationship to hemophilia (related or non-related). 
• Local laboratory results of FVIII activity level (and time of specimen collection), if 
performed (a duplicate sample must be submitted to the central laboratory). 
• AEs. 
• Concomitant medications. 
8.5.1.2 
During Surgery 
The investigator will document the following information based on data collected during 
surgery: 
• Estimated blood loss as assessed by the surgical team (anesthesiologist and / or surgeon) 
performing the procedure (including both blood loss expected as integral to the procedure 
and unexpected blood loss due to unforeseen surgical complications). 
• Additional hemostatic interventions and / or transfusions required (including blood 
products and other coagulation factor[s]) during surgery. 
• Actual rVIII-SingleChain consumption during surgery (including dose regimen, and 
number of injections per day). 
• Local laboratory results of FVIII activity level (and time of specimen collection), if 
performed (a duplicate sample must be submitted to the central laboratory). 
• AEs. 
• Concomitant medications. 
8.5.1.3 
After Surgery 
The following information will be obtained after surgery: 
• Investigator assessment of hemostatic efficacy: The investigator will assess surgery 
hemostatic efficacy of rVIII-SingleChain by using a 4-point surgical treatment rating 
scale of “excellent”, “good”, “moderate”, or “poor / no response” (see Table 7 in 
Section 8.5.2.1). 
• rVIII-SingleChain consumption (including dose regimen, and number of injections per 
day). 

 
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Study Product: rVIII-SingleChain 
 
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• Additional hemostatic intervention or blood transfusions administered. 
• Presence and extent of any surgical wound hematomas noting whether they require 
surgical evacuation. 
• Measurement of drainage volume through surgical drains. 
• Occurrence of late re-bleeding episodes. 
• Lowest (nadir) postoperative hemoglobin level. 
• Local laboratory results of FVIII activity level (and time of specimen collection), if 
performed (a duplicate sample must be submitted to the central laboratory). 
• Obtain blood sample for inhibitors to FVIII. 
• Obtain blood sample for antibodies against rVIII-SingleChain and CHO proteins. 
• AEs. 
• Concomitant therapies. 
• Record date of discharge. 
28-day follow-up laboratory inhibitor sample 
• Collect a blood sample at least 28 days after surgery to test for inhibitors to FVIII, 
antibodies to rVIII-SingleChain, and antibodies to CHO proteins. 
8.5.2 
Surgery Substudy Assessments 
8.5.2.1 
Efficacy Assessment by Investigator for Surgery 
The investigator will assess the efficacy of rVIII-SingleChain by using a 4-point surgical 
treatment rating scale of “excellent”, “good”, “moderate”, or “poor / no response” after the 
end of surgery and record results in the eCRF (see Table 7). 

 
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Study Product: rVIII-SingleChain 
 
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Table 7: 
Investigator assessment of hemostatic efficacy of 
rVIII-SingleChain for surgery substudy 
Category 
Description 
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 
hemostatic intervention and estimated blood loss during surgery is 
not more than 20% higher than the 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 hemostatic intervention) or estimated 
blood loss is greater than 20% but less than or equal to 30% higher 
than the 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 FVIII product, 
cryoprecipitate, or plasma for complete resolution. 
Abbreviations: FVIII = coagulation factor VIII; rVIII-SingleChain = single chain recombinant factor VIII. 
 
8.5.3 
Return to Treatment Regimen Following Surgery 
Subjects will be treated with rVIII-SingleChain during the recovery period as prescribed by 
the treating physician. 
Following surgery, once the subject is determined to be hemostatically stable and receives 
their last prescribed post-operative dose, the subject should resume their treatment regimen 
with rVIII-SingleChain, as determined by the investigator. This is the end of the surgery 
substudy. 

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CCI

 
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Study Product: rVIII-SingleChain 
 
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If an inhibitor is suspected (eg, lack of efficacy of IMP), additional visits may be scheduled 
for inhibitor assessment. If a subject undergoes surgery, blood samples will be collected at 
least 28 days after surgery to test for inhibitors to FVIII, antibodies against 
rVIII-SingleChain, and antibodies against CHO proteins in all study arms. In addition, a 
pre-surgery blood sample for inhibitor testing is recommended for PUPs in Arm 2. 
8.6.2 
Blood Samples for Incremental Recovery 
In Arms 1 and 3 (PTPs), IR will be collected at Day 1 and at the closest visits after 10 EDs, 
after 50 EDs, and after 100 EDs, as outlined in Table 8. Incremental recovery 
([IU/mL] / [IU/kg]) is defined as FVIII activity (IU/mL) obtained 30 to 60 minutes following 
injection, per dose of (IU/kg) injection. Incremental recovery values will be 
baseline-corrected for pre-injection plasma FVIII activity. 
If possible, subjects should have a 4-day washout from their last FVIII infusion before the IR 
samples are drawn. A pre-dose blood sample will be drawn. Subjects will then receive their 
prophylaxis dose of rVIII-SingleChain injection. For on-demand subjects, the usual dose 
used to treat a bleeding episode may be administered or any other dose determined by the 
investigator. A post-dose blood sample will be drawn 30 to 60 minutes (± 5 minutes) after the 
injection. The exact times of blood draws and the actual dose (IU/kg actual potency) 
administered will be recorded. Blood sample collection timepoints are presented in Table 8. 

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CCI

 
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Study Product: rVIII-SingleChain 
 
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8.8 
Prior and Concomitant Therapies 
All drugs taken by a subject within 28 days prior to enrollment into the study are regarded as 
prior therapy and must be documented as such in the eCRF. 
All drugs currently being taken by a subject at enrollment into the study, and which continue 
to be taken in addition to rVIII-SingleChain during the study, are regarded as concomitant 
therapy and must be documented as such in the eCRF. 
Subjects should not be enrolled into the study if they receive any prohibited concomitant 
therapy or any concomitant therapy in a prohibited dosage that cannot be discontinued or 
reduced to a permitted level. Any IMPs other than rVIII-SingleChain are prohibited. 
8.9 
Assessment of Local Tolerability 
8.9.1 
Subject / Caregiver Assessment of Local Tolerability 
In all study arms, local tolerability at the injection site will be assessed by the subject or the 
subject’s caregiver after each rVIII-SingleChain injection administered by the subject or 
caregiver. Subjects (if capable) or the subject’s caregiver will record in the subject diary a 
general judgment on the overall perception of the local reactions approximately 30 minutes 
after the end of the injection on a 5-point scale of none (0), very slight (1), slight (2), 
moderate (3), and severe (4). In addition, subjects will have the ability to record information 
in the diary regarding side effects. 
8.9.2 
Investigator Assessment of Local Tolerability (Arm 2 and 
Arm 3 Only) 
In PUPs in Arm 2 and PTPs in Arm 3, the Investigator will perform an assessment of local 
tolerability at 30 ±10 minutes after each rVIII-SingleChain injection administered at the clinic. 

 
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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 scales: 
Erythema 
Table 9: 
Erythema Rating Scale 
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 by 
questioning the subject based on the following classification: none (0), very slight (1), 
slight (2), moderate (3), and severe (4). 
8.10 
Visit Schedules 
In all study arms, 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. 
Written informed parental or guardian consent and assent of minors (if the subject is capable 
of providing assent) must be obtained before a subject can start any of the procedures at 
Screening (Arms 2 and 3) / Day 1 (Arm 1). The procedure(s) for obtaining written informed 
consent and assent of minor (if the subject is capable of providing assent) are described in 
Section 13.3. Standard of care and local laboratory procedures performed before the signing 
of informed consent may be used if they occur before Screening / Day 1. 

 
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The detailed visit schedules for all study arms are presented in the subsections specified 
below: 
1. 
Arm 1 (PTPs): Section 8.10.1 
2. 
Arm 2 (PUPs): Section 8.10.2 
3. 
Arm 3 (PTPs): Section 8.10.3 
8.10.1 
Visit schedule for Arm 1 (PTPs) 
8.10.1.1 
Day 1 Visit 
Subjects who have participated in a previous CSL-sponsored rVIII-SingleChain study may 
enroll directly into Arm 1 of Study CSL627_3001. Data from the End of Study Visit from 
lead-in studies will be used as Day 1 parameters for this study. The following procedures will 
be conducted and documented at Day 1: 
• Obtain written informed consent and assent of minors. 
• Review of inclusion / exclusion criteria for Arm 1. 
• Obtain blood sample for gene defect, if not previously obtained or gene defect not 
previously documented in medical records (Note: This sample should preferably be taken 
on Day 1. If this is not possible, the sample can be taken at any time during the study). 
• Obtain blood sample for CD4 lymphocyte count (for HIV+ subjects). 
• Obtain blood sample for IR. 
• Record weight and height. 
• Distribute eDiary and train subject on correct use. 
• Assign treatment regimen (on-demand or prophylaxis). 
• Distribute rVIII-SingleChain and train parents / caregivers as necessary. 
 
The following procedures will be conducted and documented at Day 1 if not performed and 
documented at the previous rVIII-SingleChain study’s End of Study Visit: 
• Demographic information. 
• Medical and surgical history. 
• Hemophilia A history (previous FVIII treatment, blood group, and gene defect). 
• Hemophilia A social history and activity level. 
• Serum chemistry and hematology. 
• Vital signs. 
• Physical examination. 
• Inhibitors to FVIII. 

 
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• Antibodies against rVIII-SingleChain. 
• Antibodies against CHO proteins. 
• Virology retention sample. 
• AEs. 
• Concomitant medications. 
Subjects who complete all of these assessments and who fulfill the eligibility criteria for 
Arm 1 will be enrolled into the study. If the subject is not eligible for the study, the primary 
reason for screen failure must be entered in the eCRF. 
8.10.1.2 
Treatment Period 
Subjects in Arm 1 will return to the study site every 3 months (± 7 days) for assessment. At 
each visit, the following procedures will be conducted and documented: 
• Hemophilia A social history and activity level. 
• Serum chemistry and hematology (until 50 EDs, then yearly). 
• Vital signs (until 50 EDs, then yearly). 
• Physical examination (until 50 EDs, then yearly). 
• Weight. 
• Height only for subjects < 18 years old. 
• Incremental recovery (at the closest visits after 10 EDs, after 50 EDs, and after 100 EDs). 
• Inhibitors to FVIII (at the closest visits after 10 EDs, after 50 EDs, and after 100 EDs). 
• Antibodies against rVIII-SingleChain (at the closest visits after 10 EDs, after 50 EDs, and 
after 100 EDs). 
• Antibodies against CHO proteins (at the closest visits after 10 EDs, after 50 EDs, and 
after 100 EDs). 
• Review of subject eDiary. 
• Distribution of rVIII-SingleChain. 
• Record investigator assessment for treatment efficacy of any treated bleeding episodes. 
• Collection of used and partially used vials of rVIII-SingleChain. 
• Collection of unused vials near expiration or with insufficient shelf life to cover time 
duration until next visit. 
• Drug accountability. 
• AEs. 
• Concomitant medications. 
For the procedures at the End of Study Visit, see Section 8.10.6.1. 

 
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8.10.2 
Visit Schedule for Arm 2 (PUPs) 
Summary of visit schedule for PUPs assigned to PROPHYLAXIS: 
1. All PUPs assigned to prophylaxis receive their first rVIII-SingleChain dose in the clinic 
at Visit 1, either as a treatment dose for a bleeding episode, or as their first prophylactic 
dose under medical supervision. 
2. At Visit 1, subjects will be provided with rVIII-SingleChain for prophylaxis therapy at 
home, if agreeable by the investigator. 
3. After Visit 1, subjects will have monthly follow-up visits. Monthly visits continue until 
the subject reaches 25 EDs. 
4. Once 25 EDs are reached, subjects will have 3-monthly follow-up visits until End of 
Study. 
Summary of visit schedule for PUPs assigned to ON-DEMAND: 
• All PUPs assigned to on-demand will receive their first rVIII-SingleChain dose in the 
clinic at Visit 1, either as a treatment dose for their first bleeding episode, or as their first 
exposure under medical supervision. 
• Thereafter, the subject / caregiver can treat bleeding episodes with rVIII-SingleChain 
themselves, if agreeable by the investigator. 
• Follow-up visits will occur 1 month after each rVIII-SingleChain dose. The following 
should be taken into consideration for scheduling these follow-up visits: 
o If the subject has a bleeding episode that spans multiple days or requires 
multiple doses, the follow-up visit should be scheduled based on the date of 
the last rVIII-SingleChain dose given for this bleeding episode. 
o If the subject has multiple rVIII-SingleChain doses within a 10-day 
timeframe, then the associated follow-up visits can be combined into a single 
visit if they occur ≤ 10 calendar days apart. In contrast, if the doses and the 
resulting follow-up visits occur at > 10 calendar days apart, separate follow-up 
visits must be performed (see example in Figure 4). 
• If the interval between follow-up visits is > 1 month, monthly phone calls will be 
performed until the subject returns to the clinic for the next follow-up visit. These phone 
calls are mainly intended to collect information on bleeding status and AEs. 
The timing of visits depends on the treatment assignment (ie, prophylaxis or on-demand) as 
well as on the clinical presentation at Screening for subjects assigned to an on-demand 

 
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Study Product: rVIII-SingleChain 
 
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regimen (ie, without or with a bleeding episode). This results in 3 different visit schedule 
options detailed in the following subsections and depicted in the algorithm in Figure 3: 
1. PUPs with or without bleeding episode at Screening and assigned to PROPHYLAXIS: 
Section 8.10.2.1 
2. PUPs WITHOUT bleeding episode at Screening and assigned to ON-DEMAND: 
Section 8.10.2.2 
3. PUPs WITH bleeding episode at Screening and assigned to ON-DEMAND: 
Section 8.10.2.3 
 

 
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Study Product: rVIII-SingleChain 
 
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Figure 3: 
Algorithm for treatment assignment and visit structure in Arm 2 PUPs 
PUP enters study
Choose 
modality
Prophylaxis
On Demand
Presentation 
with bleed?
Screen/
Administer first 
prophylaxis dose
Screen/Treat 
bleed
Y
N
Visit every month 
until 25 ED
Visit every 3 
months until EOS
EOS
Presentation 
with bleed?
Screen / Treat 
bleed
Screen/
Administer dose
Y
N
Follow-up visit 
1 month after rVIII-
SingleChain dose * 
rVII-SingleChain* 
administered
 if interval >1 month, 
initiate monthly phone 
calls
Regimen 
switch
Notes: * After each rVIII-SingleChain 
dose on the on-demand regimen, 
the subject should present to the 
site for a follow-up visit 1 month 
after dose.  If the bleeding episode 
spans multiple days or requires 
multiple doses, the follow-up visit 
should be scheduled based on the 
date of the last dose for this 
bleeding episode. In addition, 
follow-up visits scheduled to occur 
within 10 days of one another may 
be combined into a single visit.
Treatment in hemophilia center
Prophylaxis 
schedule 
administered
Home therapy if appropriate
Key
 
Abbreviations: ED = exposure day; EOS = End of Study; INH = inhibitor; N = no; PUP = previously untreated patient; Y = yes. 

 
Study Number: CSL627_3001 
Study Product: rVIII-SingleChain 
 
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Figure 4: 
Example of visit structure for PUPs assigned to on-demand treatment 
Follow-up visits scheduled to occur within 10 days of one another may be combined into one follow-up visit.  Combinations are at the Investigator‘s 
discretion. Below is an example of possible combinations of follow-up visits.
• 
Visit 2 is the follow-up visit for the first rVIII-SingleChain dose at Screening/Visit 1
• 
Visit 3 is the combined follow-up visit for rVIII-SingleChain doses 2 and 3.
• 
Visit 4 is  the combined follow-up visit for rVIII-SingleChain doses 4 and 5.  
• 
Due to the timing of rVIII-SingleChain doses, additional combinations of follow-up visits are possible.
 
Abbreviations: PUP = previously untreated patient 
 

 
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Study Product: rVIII-SingleChain 
 
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8.10.2.1 
Visit Schedule for Arm 2 PUPs With or Without Bleeding 
Episode at Screening and Assigned to PROPHYLAXIS 
8.10.2.1.1 
Screening 
For subjects presenting with a bleeding episode at Screening, it is anticipated that the 
Screening and Visit 1 assessments (ie, administration of first dose of rVIII-SingleChain and 
relevant efficacy assessments) may occur on the same calendar day due to the emergency 
nature of such presentation. The following procedures will be conducted and documented at 
Screening (within 28 days before Visit 1): 
• Obtain written informed consent and assent of minors. 
• Review of inclusion / exclusion criteria for Arm 2. 
• Demographic information. 
• Medical and surgical history. 
• Hemophilia A history (blood group, and gene defect). 
• Hemophilia A social history and activity level. 
• Review of prior medications within the 28 days before Screening. 
• Obtain blood sample for serum chemistry and hematology. Analyses should be 
determined at the local laboratory, and the results must be available before enrollment. 
• Obtain blood sample for CD4 lymphocyte count (for HIV+ subjects; if the subject has 
received any blood components or per investigator discretion considering the subject’s 
medical history). 
• Vital signs. 
• Physical examination. 
• Record weight and height. 
• Obtain blood sample for inhibitors to FVIII (analysis at central laboratory). 
• Obtain blood sample for antibodies against rVIII-SingleChain and CHO proteins 
• If FVIII activity level < 1% is not documented in subject’s medical record: Obtain blood 
sample for plasma FVIII activity level and determine FVIII activity level at the local 
laboratory. The result must be available before enrollment. 
• Review AEs. 
• Review concomitant medications. 
Subjects who complete all of these assessments and who fulfill all eligibility criteria for 
Arm 2 will be enrolled into the study. If the subject is not eligible for the study, the primary 
reason for screen failure must be entered in the eCRF. 

 
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Study Product: rVIII-SingleChain 
 
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8.10.2.1.2 
Visit 1 
The following procedures will be conducted and documented at Visit 1: 
• If Screening and Visit 1 do not occur on the same calendar day: 
Review inclusion / exclusion criteria and reconfirm subject eligibility. 
• Obtain blood sample for gene defect if sample not previously obtained or gene defect not 
previously documented in medical records (Note: This sample should preferably be 
taken at Visit 1. If this is not possible, the sample can be taken at any time during the 
study). 
• Obtain virology retention sample. 
• Hemophilia A social history and activity level. 
• Record weight and height. 
• Vital signs (before administration of rVIII-SingleChain). 
• Administer first rVIII-SingleChain dose. 
• If applicable: record investigator assessment of efficacy. 
• Record investigator assessment of local tolerability. 
• Observe subject for at least 6 hours after dosing. 
• Vital signs (at 1, 2, 3, and 6 hours [± 15 minutes] after administration of 
rVIII-SingleChain). 
• Distribute eDiary and train subject on correct use. 
• Assign treatment regimen. 
• Distribute rVIII-SingleChain and train parents / caregivers as necessary. 
• Review AEs. 
• Review concomitant medications. 
• Adequate training of parents / caregivers in administration of further prophylaxis doses, 
identification and treatment of bleeding episodes, or provision of support to parents for 
training in factor administration as per standard local clinical practice. Further 
prophylaxis doses, or treatment doses, can be administered under supervision of the 
investigator as necessary. These administrations do not require further post-injection 
observations as above, unless clinically indicated). 
• Instruct the subject and parent / caregiver on the visit schedule for the treatment period 
and schedule Visit 2. 

 
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8.10.2.1.3 
Treatment Period 
8.10.2.1.3.1 
Monthly Visits from Visit 2 until 25 Exposure Days 
After Visit 1, subjects on prophylaxis will have site visits every month (± 7 days) (Visits 2, 
etc) until 25 EDs with rVIII-SingleChain are achieved. The following procedures will be 
conducted and documented at each of these visits: 
• Obtain blood sample for inhibitors to FVIII. 
• Obtain blood sample for antibodies against rVIII-SingleChain and CHO proteins. 
• Obtain blood sample for serum chemistry and hematology. 
• Hemophilia A social history and activity level. 
• Vital signs. 
• Physical examination. 
• Record weight and height. 
• Review subject eDiary. 
• Record investigator assessment for treatment efficacy of any treated bleeding episodes 
• If rVIII-SingleChain administered at the clinic: 
o Record investigator assessment of local tolerability. 
o Record investigator assessment for treatment efficacy. 
• Collection of used and partially used vials of rVIII-SingleChain. 
• Collection of unused vials near expiration or with insufficient shelf life to cover time 
duration until next visit. 
• Perform drug accountability. 
• Distribute rVIII-SingleChain and train parents / caregivers as necessary. 
• Review AEs. 
• Review concomitant medications. 
• If treatment regimen is changed (ie, either switch to on-demand or change in prophylaxis 
regimen), instruct the subject and parent / caregiver on the change in visit schedule and 
update the eCRF (see Section 3.2.5). 

 
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8.10.2.1.3.2 
Three-monthly Visits from 25 Exposure Days Until End 
of Study 
After completion of their last monthly visit after the 25th ED, the subject will have site visits 
every 3 months (± 7 days) until End of Study. The following procedures will be conducted 
and documented at each of these visits: 
• Obtain blood sample for inhibitors to FVIII. 
• Obtain blood sample for antibodies against rVIII-SingleChain and CHO proteins. 
• Obtain blood sample for serum chemistry and hematology. 
• Hemophilia A social history and activity level. 
• Vital signs. 
• Physical examination. 
• Record weight and height. 
• Review of subject eDiary. 
• Record investigator assessment for treatment efficacy of any treated bleeding episodes. 
• If rVIII-SingleChain administered at the clinic: 
o Record investigator assessment of local tolerability. 
o Record investigator assessment for treatment efficacy. 
• Collection of used and partially used vials of rVIII-SingleChain. 
• Collection of unused vials near expiration or with insufficient shelf life to cover time 
duration until next visit. 
• Perform drug accountability. 
• Distribute rVIII-SingleChain and train parents / caregivers as necessary. 
• Review AEs. 
• Review concomitant medications. 
• If treatment regimen (ie, either switch to on-demand or change in prophylaxis regimen) 
is changed, instruct the subject and parent / caregiver on the change in visit schedule and 
update the eCRF (see Section 3.2.5). 
For the procedures at the End of Study Visit, see Section 8.10.6.2. 

 
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Study Product: rVIII-SingleChain 
 
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8.10.2.2 
Visit Schedule for Arm 2 PUPs WITHOUT Bleeding 
Episode at Screening and Assigned to ON-DEMAND 
8.10.2.2.1 
Screening 
The following procedures will be conducted and documented at Screening (within 28 days 
before Visit 1): 
• Obtain written informed consent and assent of minors. 
• Review of inclusion / exclusion criteria for Arm 2. 
• Demographic information. 
• Medical and surgical history. 
• Hemophilia A history (blood group and gene defect). 
• Hemophilia A social history and activity level. 
• Review of prior medications within the 28 days before Screening. 
• Obtain blood sample for serum chemistry and hematology. Analyses should be 
determined at the local laboratory, and the results must be available before enrollment. 
• Obtain blood sample for CD4 lymphocyte count (for HIV+ subjects; if the subject has 
received any blood components or per investigator discretion considering the subject’s 
medical history). 
• Vital signs. 
• Physical examination. 
• Record weight and height. 
• Obtain blood samples for 
o Inhibitors to FVIII (analysis at central laboratory). 
o Antibodies against rVIII-SingleChain and CHO proteins. 
• If FVIII activity level < 1% is not documented in subject’s medical record: Obtain blood 
sample for plasma FVIII activity level and determine FVIII activity level at the local 
laboratory. The result must be available before enrollment. 
• Review AEs. 
• Review concomitant medications. 
Subjects who complete all of these assessments and who fulfill the eligibility criteria for 
Arm 2 will be enrolled into the study. If the subject is not eligible for the study, the primary 
reason for screen failure must be entered in the eCRF. 

 
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8.10.2.2.2 
Visit 1 
The following procedures will be conducted and documented at Visit 1: 
• If Screening and Visit 1 do not occur on the same calendar day: review of 
inclusion / exclusion criteria for Arm 2 and reconfirm subject eligibility. 
• Body weight and height. 
• Obtain virology retention sample (sample must be taken before administration of first 
rVIII-SingleChain dose). 
• Hemophilia A social history and activity level. 
• Vital signs (before administration of rVIII-SingleChain). 
• Administer first rVIII-SingleChain dose. 
• Observe subject for at least 6 hours after dosing. 
• Record investigator assessment of local tolerability. 
• Vital signs (at 1, 2, 3, and 6 hours [± 15 minutes] after administration of 
rVIII-SingleChain). 
• Obtain blood sample for gene defect if sample not previously obtained or gene defect not 
previously documented in medical records (Note: This sample should preferably be 
taken at Visit 1. If this is not possible, the sample can be taken at any time during the 
study). 
• Assign treatment regimen. 
• Distribute eDiary and train subject on correct use. 
• Review AEs. 
• Review concomitant medications. 
• Adequate training of parents / caregivers in administration of rVIII-SingleChain, 
identification and treatment of bleeding episodes, or provision of support to parents for 
training in factor administration as per standard local clinical practice. Further 
rVIII-SingleChain doses can be administered under supervision of the investigator as 
necessary. These administrations do not require further post-injection observations as 
above, unless clinically indicated. 
• Instruct the subject and parent / caregiver on the visit schedule for the treatment period 
and schedule the first follow-up visit. 
After Visit 1, the subject can receive rVIII-SingleChain for on-demand treatment of bleeding 
episodes at home, if agreeable by the investigator. If home treatment is started after Visit 1, 
the following is to be performed: 
• Distribute rVIII-SingleChain and train parents / caregivers as necessary. 

 
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8.10.2.2.3 
Treatment Period 
8.10.2.2.3.1 
Follow-up Visits After Each rVIII-SingleChain Dose 
While on an on-demand regimen, subjects will have follow-up visits 1 month (± 7 days) 
after each rVIII-SingleChain dose, until End of Study. 
The following procedures will be conducted and documented at each follow-up visit: 
• Obtain blood sample for inhibitors to FVIII. 
• Obtain blood sample for antibodies against rVIII-SingleChain and CHO proteins. 
• Obtain blood sample for serum chemistry and hematology. 
• Hemophilia A social history and activity level. 
• Vital signs. 
• Physical examination. 
• Record weight and height. 
• Review of subject eDiary. 
• Record investigator assessment for treatment efficacy of any bleeding episodes treated at 
home. 
• If rVIII-SingleChain administered at the clinic: record investigator assessment of local 
tolerability. 
• Collection of used and partially used vials of rVIII-SingleChain. 
• Collection of unused vials near expiration or with insufficient shelf life to cover time 
duration until next visit. 
• Perform drug accountability. 
• Distribute rVIII-SingleChain and train parents / caregivers as necessary. 
• Review AEs. 
• Review concomitant medications. 
• If treatment regimen is changed, instruct the subject and parent / caregiver on the change 
in visit schedule and update the eCRF (see Section 3.2.5). 
For the procedures at the End of Study Visit, see Section 8.10.6.2. 

 
Study Number: CSL627_3001 
Study Product: rVIII-SingleChain 
 
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8.10.2.2.3.2 
Monthly Telephone Calls 
Subjects who do not experience a bleeding episode requiring treatment with 
rVIII-SingleChain within 1 month after the preceding visit will have monthly telephone calls 
(time window: ± 7 days) until the next bleeding episode / rVIII-SingleChain dose occurs. The 
following assessments will be performed at each monthly telephone call: 
• Record date of telephone contact. 
• Record name of staff member who contacted the subject. 
• Confirm that no bleeding episodes have occurred since last visit. 
• Review eDiary entries with subject. 
• Review AEs. 
• Review concomitant medications. 
• Record data from telephone contact in eCRF. 
• Arrange unscheduled visit if needed. 
8.10.2.3 
Visit Schedule for Arm 2 PUPs WITH Bleeding Episode at 
Screening and Assigned to ON-DEMAND 
8.10.2.3.1 
Screening 
For subjects presenting with a bleeding episode at Screening, it is anticipated that the 
Screening and Visit 1 assessments (ie, administration of first dose of rVIII-SingleChain and 
relevant efficacy assessments) may occur on the same calendar day due to the emergency 
nature of such presentation. The following screening procedures will be completed and 
documented in the Screening eCRF: 
• Obtain written informed consent and assent of minors. 
• Review of inclusion / exclusion criteria for Arm 2. 
• Demographic information. 
• Medical and surgical history. 
• Hemophilia A history (blood group, and gene defect). 
• Hemophilia A social history and activity level. 
• Review of prior medications within 28 days before Screening. 
• Obtain blood sample for serum chemistry and hematology. Analyses should be 
determined at the local laboratory, and the results must be available before enrollment. 
• Obtain blood sample for CD4 lymphocyte count (for HIV+ subjects; if the subject has 
received any blood components or per investigator discretion considering the subject’s 
medical history). 

 
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• Vital signs. 
• Physical examination. 
• Record weight and height. 
• Obtain blood samples for 
o Inhibitors to FVIII (analysis at central laboratory). 
o Antibodies against rVIII-SingleChain and CHO proteins. 
Note: rVIII-SingleChain administration does not need to be deferred until the results 
of inhibitor and antibodies tests are available. 
• If FVIII activity level < 1% is not documented in subject’s medical record: Obtain blood 
sample for plasma FVIII activity level and determine FVIII activity level at the local 
laboratory. The result must be available before enrollment. 
• Review AEs. 
• Review concomitant medications. 
Subjects who complete all of these assessments and who fulfill the eligibility for Arm 2 will 
be enrolled into the study. If the subject is not eligible for the study, the primary reason for 
screen failure must be entered in the eCRF. 
8.10.2.3.2 
Visit 1 
The following procedures will be conducted and documented at Visit 1: 
• If Screening and Visit 1 do not occur on the same calendar day: review of 
inclusion / exclusion criteria for Arm 2 and reconfirm subject eligibility. 
• Body weight and height. 
• Obtain virology retention sample. 
• Hemophilia A social history and activity level. 
• Vital signs (before administration of rVIII-SingleChain). 
• Administer first rVIII-SingleChain dose. 
• Observe subject for at least 6 hours after dosing. 
• Record investigator assessment of local tolerability. 
• Vital signs (at 1, 2, 3, and 6 hours [± 15 minutes] after administration of 
rVIII-SingleChain). 
• Record investigator assessment for treatment efficacy. 
• Obtain blood sample for gene defect if sample not previously obtained or gene defect not 
previously documented in medical records (Note: This sample should preferably be 
taken at Screening. If this is not possible, the sample can be taken at any time during the 
study). 

 
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Study Product: rVIII-SingleChain 
 
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• Distribute eDiary and train subject on correct use. 
• Assign treatment regimen. 
• Review AEs. 
• Review concomitant medications. 
• Adequate training of parents / caregivers in administration of rVIII-SingleChain, 
identification and treatment of bleeding episodes, or provision of support to parents for 
training in factor administration as per standard local clinical practice. Further 
rVIII-SingleChain doses can be administered under supervision of the investigator as 
necessary. These administrations do not require further post-injection observations as 
above, unless clinically indicated. 
• Instruct the subject and parent / caregiver on the visit schedule for the treatment period 
and schedule the first follow-up visit. 
After Visit 1, the subject can receive rVIII-SingleChain for on-demand treatment of bleeding 
episodes at home, if agreeable by the investigator. If home treatment is started after Visit 1, 
the following is to be performed: 
• Distribute rVIII-SingleChain and train parents / caregivers as necessary. 
8.10.2.3.3 
Treatment Period 
8.10.2.3.3.1 
Follow-up Visits After Each rVIII-SingleChain Dose 
While on an on-demand regimen, subjects will have follow-up visits 1 month (± 7 days) 
after each rVIII-SingleChain dose, until End of Study (ie, at least 75 EDs or early 
discontinuation). 
The following procedures will be conducted and documented at each follow-up visit: 
• Obtain blood sample for inhibitors to FVIII. 
• Obtain blood sample for antibodies against rVIII-SingleChain and CHO proteins. 
• Obtain blood sample for serum chemistry and hematology. 
• Hemophilia A social history and activity level. 
• Vital signs. 
• Physical examination. 
• Record weight and height. 
• Review of subject eDiary. 
• Record investigator assessment for treatment efficacy of any treated bleeding episodes. 
• If rVIII-SingleChain administered at the clinic: record investigator assessment of local 
tolerability. 

 
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Study Product: rVIII-SingleChain 
 
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• Collection of used and partially used vials of rVIII-SingleChain. 
• Collection of unused vials near expiration or with insufficient shelf life to cover time 
duration until next visit. 
• Perform drug accountability. 
• Distribute rVIII-SingleChain and train parents / caregivers as necessary. 
• Review AEs. 
• Review concomitant medications. 
• If treatment regimen is changed, instruct the subject and parent / caregiver on the change 
in visit schedule and update the eCRF (see Section 3.2.5). 
For the procedures at the End of Study Visit, see Section 8.10.6.2. 
8.10.2.3.3.2 
Monthly Telephone Calls 
Subjects who do not experience a bleeding episode requiring treatment with 
rVIII-SingleChain within 1 month after their preceding visit will have monthly telephone 
calls (time window: ± 7 days) until the next bleeding episode / rVIII-SingleChain dose 
occurs. The following assessments will be performed at each monthly telephone call: 
• Record date of telephone contact. 
• Record name of staff member who contacted the subject. 
• Confirm that no bleeding episodes have occurred since last visit. 
• Review eDiary entries with subject. 
• Review AEs. 
• Review concomitant medications. 
• Record data from telephone contact in eCRF. 
• Arrange unscheduled visit if needed. 
8.10.3 
Visit Schedule for Arm 3 (PTPs) 
8.10.3.1 
Screening 
The following procedures will be conducted and documented at Screening (within 28 days 
before Day 1): 
• Obtain written informed consent and assent of minors. 
• Review of inclusion / exclusion criteria for Arm 3. 
• Demographic information. 
• Medical and surgical history. 
• Hemophilia A history (blood group, and gene defect). 
• Hemophilia A social history and activity level. 

 
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• Review of prior medications within the 28 days before Screening. 
• Obtain blood sample for serum chemistry and hematology. 
• Obtain blood sample for CD4 lymphocyte count (for HIV+ subjects). 
• Vital signs. 
• Physical examination. 
• Record weight and height. 
• If FVIII activity level < 1% is not documented in subject’s medical record: Obtain blood 
sample for plasma FVIII activity level and determine FVIII activity level at the local 
laboratory. The result must be available before enrollment. 
• Obtain blood sample for inhibitors to FVIII. 
• Obtain blood sample for antibodies against rVIII-SingleChain and CHO proteins. 
• Review AEs. 
• Review concomitant medications. 
Subjects who complete all of these assessments and who fulfill the eligibility criteria 
(ie, eligible subjects) for Arm 3 will be enrolled into the study. If the subject is not eligible for 
the study, the primary reason for screen failure must be entered in the eCRF. 
8.10.3.2 
Day 1 
The following procedures will be conducted and documented at Day 1: 
• Obtain blood sample for gene defect, if sample not previously obtained or gene defect 
not previously documented in medical records (Note: This sample should preferably be 
taken on Day 1. If this is not possible, the sample can be taken at any time during the 
study). 
• Vital signs. 
• Weight. 
• Height only for subjects < 18 years of age. 
• Obtain blood sample for IR. 
• Obtain virology retention sample. 
• Distribute eDiary and train subject on correct use. 
• Assign treatment regimen (on-demand or prophylaxis). 
• Distribute rVIII-SingleChain and training of parents / caregivers as necessary. 
• Review AEs. 
• Review concomitant medications. 
• Instruct the subject and parent / caregiver on the visit schedule for the treatment period 
and schedule the next visit to occur 3 months ± 7 days after Day 1. 

 
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Study Product: rVIII-SingleChain 
 
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8.10.3.3 
Treatment Period 
Subjects in Arm 3 will visit the site every 3 months (± 7 days). At each visit, the following 
procedures will be conducted and documented: 
• Hemophilia A social history and activity level. 
• Serum chemistry and hematology (until 50 EDs, then yearly). 
• Vital signs (until 50 EDs, then yearly). 
• Physical examination (until 50 EDs, then yearly). 
• Weight. 
• Height only for subjects < 18 years of age. 
• IR (at the closest visits after 10 EDs, after 50 EDs, and after 100 EDs). 
• Inhibitors to FVIII (at the closest visits after 10 EDs, after 50 EDs, and after 100 EDs). 
• Antibodies against rVIII-SingleChain (at the closest visits after 10 EDs, after 50 EDs, 
and after 100 EDs). 
• Antibodies against CHO proteins (at the closest visits after 10 EDs, after 50 EDs, and 
after 100 EDs). 
• Review of subject eDiary. 
• Distribute rVIII-SingleChain. 
• Record investigator assessment for treatment efficacy of any treated bleeding episodes. 
• If rVIII-SingleChain administered at the clinic: record investigator assessment of local 
tolerability. 
• Collection of used and partially used vials of rVIII-SingleChain. 
• Collection of unused vials near expiration or with insufficient shelf life to cover time 
duration until next visit. 
• Perform drug accountability. 
• Review AEs. 
• Review concomitant medications. 
For the procedures at the End of Study Visit, see Section 8.10.6.2. 
8.10.4 
Follow-up Period 
Not applicable. 

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Study Product: rVIII-SingleChain 
 
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8.10.6.2 
End of Study Visit for Arms 2 and 3 
In Arms 2 and 3, the following procedures will be performed at the End of Study Visit: 
• Obtain hemophilia A social history and activity level. 
• Obtain blood sample for serum chemistry and hematology. 
• Vital signs. 
• Physical examination. 
• Record weight and height. 
• Obtain blood sample for inhibitors to FVIII. 
• Obtain blood sample for antibodies against rVIII-SingleChain and CHO proteins. 
• Obtain virology retention sample. 
• Review and collect of subject eDiary. 
• Record investigator assessment for treatment efficacy of any treated bleeding episodes. 
• Collect all vials (used, partially used, and unused) of rVIII-SingleChain. 
• Perform drug accountability. 
• Review AEs. 
• Review concomitant medications. 
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 
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). 
AEs 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 

 
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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 rVIII-SingleChain administration. 
• Intercurrent illnesses with an onset after administration of rVIII-SingleChain. 
 
AEs do not include: 
• Events identified at screening that meet exclusion criteria. 
• Medical procedures (the condition that leads to the procedure is the 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). 
o Hospitalizations for a diagnostic procedure where the hospital stay is less than 
24 hours in duration or for normal management procedures (eg, chemotherapy). 
• Overdose of rVIII-SingleChain or any concomitant therapy that does not result in any 
adverse signs or symptoms. 
• Major or minor bleeding episodes that occur as a result of the subject’s unchanged, 
pre-existing severe hemophilia A. 
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 be 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 screening, 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 
Events of Special Interest 
Medical events of special interest include: 
• Invasive procedures other than surgery. 
• Hospital admission for less than 24 hours for events not considered as SAEs. 
• Positive test result for inhibitors performed at local laboratory. 
AEs of special interest include: 
• Hypersensitivity reactions (including anaphylactic reactions). 
• Thromboembolic events. 
• Any AE related to rVIII-SingleChain associated with double or higher dose than 
prescribed. 
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, chemotherapy) 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. 
AEs that do not fall into the above categories are defined as nonserious AEs. 
All low-titer and high-titer inhibitors confirmed by the central laboratory are defined as SAEs 
(SAE criterion: “medically significant”) and must be reported and followed up accordingly. 

 
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9.2 
Severity of Adverse Events 
The severity of each AE (ie, nonserious and serious AEs) is to be assessed by the investigator 
as follows: 
Table 10: 
Severity of Adverse Events 
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. 
Abbreviations: AE = adverse event; CDISC = Clinical Data Interchange Standards Consortium; 
SDTM = Severity Intensity Scale for Adverse Event Terminology. 
9.3 
Causality of Adverse Events 
The causal relationship of an AE to rVIII-SingleChain must always be assessed by the 
investigator. All AEs will be classified as either related or not related to rVIII-SingleChain. 
If a causality assessment is not provided for an AE (including an SAE), that AE will be 
considered related to rVIII-SingleChain. 
The degree of certainty with which an AE is attributed to rVIII-SingleChain 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 rVIII-SingleChain. 
• 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). 
• Plausibility supported by the temporal relationship (eg, the event being related by time to 
administration or termination of treatment with rVIII-SingleChain, drug withdrawal or 
reproduced on rechallenge). 

 
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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 rVIII-SingleChain (irrespective 
of whether or not it is considered by the investigator to be causally related to 
rVIII-SingleChain), 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 28 days after the final administration of 
rVIII-SingleChain, whichever is sooner. Inhibitor SAEs in Arm 2 (PUPs) will be followed up 
for 28 days after the End of Study Visit (see Section 9.10). 
If, during the study period, a subject presents with a preexisting condition that was not noted 
at the time of study entry, the condition should be retrospectively recorded in the Medical 
History section of the eCRF. 
9.5.2 
Events of Special Interest Reporting 
Any AE of special interest or medical event of special interest will be recorded in the eCRF 
and will be automatically reported to the sponsor via email alert. 
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). 

 
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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 
rVIII-SingleChain, 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. 
AEs occurring in the period between the times the subject gave written informed consent and 
the first exposure to rVIII-SingleChain 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 
rVIII-SingleChain 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. 
Contact details and guidance for reporting SAEs will be provided to study site before the 
study site is initiated. 
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. 

 
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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 IEC / IRB (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. 
9.7 
Other Significant Event Reporting 
9.7.1 
Overdose 
Details (ie, volume, location of injections, injection rate) of an overdose of rVIII-SingleChain 
or any concomitant therapy must be recorded in the eCRF. Any overdose that is considered 
by the investigator to be medically significant must be reported as an SAE (see Section 9.6). 
Any AE related to rVIII-SingleChain associated with ≥ 2 times the prescribed dose is 
considered an overdose. 
9.7.2 
Pregnancy and Lactation 
A female partner of a male subject who becomes pregnant while participating in the study, or 
up to and including 28 days after the last dose of rVIII-SingleChain, must notify the 
investigator immediately. 
CSL must be notified within 5 days of the investigator becoming aware of the pregnancy. 

 
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Whenever possible, a pregnancy in a female partner of a male subject exposed to 
rVIII-SingleChain 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 stabilizes, or until 28 days 
after the final administration of rVIII-SingleChain, whichever is sooner. 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. 
For the specific follow-up procedures for inhibitor SAEs in Arm 2 (PUPs) after the End of 
Study Visit, see Section 9.10. 
9.10 
Follow-up of Inhibitor SAEs in Arm 2 (PUPs) 
PUPs in Arm 2 who develop an inhibitor SAE (ie, low-titer or high-titer inhibitors confirmed 
by the central laboratory) will be followed up for 28 days after their End of Study Visit. All 
follow-up information (and attempted follow-up contacts) should be documented in the 
subject’s medical records and submitted to CSL Global Clinical Safety and 
Pharmacovigilance. At a minimum, the following specific information should be documented 
and submitted: 
• 
Information on last inhibitor titer. 
• 
Details and outcome of major / life-threatening bleeding episodes. 

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10.3 
Safety Assessments 
Safety will be assessed based on the following variables: 
• 
AEs and SAEs. 
• 
Serum chemistry and hematology. 
• 
Physical examination. 
• 
Vital signs. 
• 
Inhibitors to FVIII. 
• 
Antibodies against rVIII-SingleChain. 
• 
Antibodies against CHO proteins. 
• 
Subject / caregiver assessment of local tolerability. 
• 
Arms 2 and 3 only: investigator assessment of local tolerability for rVIII-SingleChain 
injections administered at the clinic. 
Clinical laboratory tests will be performed at timepoints as detailed in the Schedules of 
Assessments. More frequent evaluations may be performed, if clinically indicated, at the 
discretion of the investigator. 
10.4 
Pharmacokinetic and Pharmacodynamics 
• 
IR (see Section 8.6). 
10.5 
Other Assessments 
• 
FVIII activity level at Screening (Arms 2 and 3), if not available in subject’s medical 
records. FVIII activity level must be determined at the local laboratory, and the result 
must be available before enrollment. 
11 
Statistics 
11.1 
Sample Size Estimation 
The sample size was based on the EMA guidelines for the clinical investigation of 
recombinant and human plasma-derived factor VIII products [EMA, 2011]. Therefore, no 
sample size calculations were performed. The target enrollment is at least 200 PTPs (Arms 1 
and 3) completing at least 100 EDs during enrollment in all CSL-sponsored 
rVIII-SingleChain studies and 24 PUPs (Arm 2) completing 50 EDs of rVIII-SingleChain in 
this study. Thus, the study will enroll at total of least 224 subjects with severe hemophilia A. 

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11.3 
Statistical Analyses and Methods 
All safety and efficacy data will be summarized or listed as appropriate. Continuous data will 
be summarized using descriptive statistics and categorical data will be summarized using 
frequency counts and percentages. There are no plans to produce p values. Confidence 
intervals (CIs) will be provided for key parameters where noted here or in the final statistical 
analysis plan. Except where otherwise noted, the CIs will be two-sided at the 95% level. 
All analyses will be performed separately for PTPs and PUPs, including the analyses in the 
surgical substudy. 
A complete description of the statistical analyses and methods will be available in the 
statistical analysis plan, which will be finalized before the database is locked. 
11.3.1 
Subject Disposition and Characteristics 
11.3.1.1 
Subject Disposition 
The number of subjects who enrolled into this study, completed the study, withdrew from the 
study or discontinued the IMP will be presented in summary tables. The reason for 
discontinuing the IMP or withdrawing a subject from the study will be summarized. 
The same methods will be applied to the substudies. 
11.3.1.2 
Subject Characteristics 
Demographics and baseline subject characteristics will be presented in summary tables and 
data listings. Age will be described as both a continuous and a discrete variable. Supportive 
data will be listed by subject. A listing of gene abnormalities by subject will be prepared. 
11.3.2 
Efficacy Analyses 
The efficacy data from the main study will be summarized and analyzed for the efficacy 
population unless otherwise specified. The surgery substudy efficacy data will be summarized 
for the surgery population. 
11.3.2.1 
Primary Efficacy Analysis 
For Arms 1 and 3 (PTPs), there is no primary efficacy endpoint. 
For Arm 2 (PUPs), the analyses of the primary efficacy endpoints are outlined below: 

 
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• 
The investigator’s clinical assessment of hemostatic efficacy for the treatment of major 
bleeding episodes, based on the 4-point ordinal scale (excellent, good, moderate, 
poor / no response), will be tabulated. The percentage of major bleeding episodes treated 
successfully (defined as ratings of excellent or good) will be summarized, and reported 
together with a two-sided 95% CI. To estimate the proportion, the denominator will 
include all treated bleeding episodes categorized as major. To account for within-subject 
correlation, generalized linear modeling using SAS’ GENMOD procedure will be 
utilized. The model will contain only the intercept term. The binomial distribution with 
logit link function will be specified. 
• 
The AsBR will be derived for each subject as follows: ((number of spontaneous bleeding 
episodes) / (observed treatment period of interest))*365.25. The AsBR will be 
summarized by regimen (on-demand or prophylaxis) using descriptive statistics. In 
addition, the number of spontaneous bleeding episodes per year and associated 95% CI 
will be estimated based on a Poisson model. Generalized linear modeling using SAS’ 
GENMOD procedure will be utilized. The Poisson distribution with log link function, 
and log_time offset will be specified. The Poisson-based number of spontaneous 
bleeding episodes per year will be presented by regimen (on-demand or prophylaxis). 
11.3.2.2 
Secondary Efficacy Analyses 
• 
In all study arms, the analyses of the secondary efficacy endpoints are as follows: The 
primary efficacy analyses outlined in Section 11.3.2.1 for the AsBR will be repeated for 
the ABR (traumatic, non-traumatic, and unknown). 
• 
The number of bleeding episodes and the number of treated bleeding episodes will be 
presented. The number and percentage of bleeding episodes requiring 1, 2, 3, or 
> 3 injections of rVIII-SingleChain to achieve hemostasis will be tabulated. The total 
dose per bleeding episode (IU/kg) will be summarized using descriptive statistics. 
• 
The consumption of rVIII-SingleChain, will be derived and expressed in terms of IU/kg 
per month, IU/kg per year, total IU per injection, per month and per year. Consumption 
will be summarized using descriptive statistics for on-demand, prophylaxis, and surgery. 
• 
The investigator’s clinical assessment of hemostatic efficacy for surgery based on the 
4-point ordinal scale will be tabulated. 
 
In Arms 1 and 3 (PTPs), the following analysis will be performed in addition to those 
above: 

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Study Number: CSL627_3001 
Study Product: rVIII-SingleChain 
 
CRD-TPL-077 Version 1.0 
26 May 2020 
Page 116 of 149 
 
Confidential 
In Arm 2 (PUPs), the primary safety endpoint is the incidence of high-titer inhibitor 
formation to FVIII in PUPs with at least 50 EDs of rVIII-SingleChain. 
11.3.3.2 
Primary Safety Analysis 
The incidence of inhibitor formation to FVIII, based on the number of EDs and subjects 
specified in Section 11.3.3.1 will be reported together with a (2-sided) 95% CI. However, if 
no inhibitor formation is observed, then the upper one-sided 97.5% confidence limit will be 
reported. For calculation of the incidence for each study arm, the numerator will include all 
subjects who develop inhibitors in each arm and the denominator will include: 
a) all PTPs with at least 100 EDs plus PTPs with less than 100 EDs but with inhibitors. 
b) all PUPs with at least 50 EDs plus PUPs with less than 50 EDs but with high-titer 
inhibitors. 
11.3.3.3 
Secondary Safety Endpoints 
See Section 2.2.2.2. 
11.3.3.4 
Secondary Safety Analysis 
11.3.3.4.1 
Incidence of Inhibitor Formation to FVIII at 
Intermediate Timepoints of Exposure to rVIII-
SingleChain 
Arms 1 and 3 (PTPs) 
To calculate the inhibitor incidence after 10 EDs (after 50 EDs, and after 100 EDs), the 
numerator will include all subjects with inhibitors observed at the closest visit up to 10 EDs 
(≤ 10 EDs) (up to 50 EDs, and up to 100 EDs). The denominator will include all subjects 
with at least 10 EDs (≥ 10 EDs) (at least 50 EDs, and at least 100 EDs) plus subjects with 
less than 10 EDs (< 10 EDs) (less than 50 EDs, and less than 100 EDs) but with inhibitors. 
Arm 2 (PUPs) 
Inhibitor incidence in PUPs will be analyzed analogously to PTPs. The same principles will 
be applied, taking into account: number of subjects at risk for the relevant number of EDs 
(after 10 EDs and after 50 EDs) and inhibitor type (low, low + high). 

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Study Number: CSL627_3001 
Study Product: rVIII-SingleChain 
 
CRD-TPL-077 Version 1.0 
26 May 2020 
Page 121 of 149 
 
Confidential 
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. 
This study will be conducted under a US FDA Investigational New Drug application and also 
in other regions 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 and guardian assent in the Declaration of Helsinki must 
be implemented in this clinical study before protocol-specified procedures are carried out. 

 
Study Number: CSL627_3001 
Study Product: rVIII-SingleChain 
 
CRD-TPL-077 Version 1.0 
26 May 2020 
Page 122 of 149 
 
Confidential 
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. 
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). 

 
Study Number: CSL627_3001 
Study Product: rVIII-SingleChain 
 
CRD-TPL-077 Version 1.0 
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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 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. 

 
Study Number: CSL627_3001 
Study Product: rVIII-SingleChain 
 
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Confidential 
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 IEC / IRB-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 rVIII-SingleChain 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 diary will be completed by the subject at home. At each visit, the subject will 
present the completed diary to the investigator for review of entries and transfer of relevant 
information to the eCRF. 

 
Study Number: CSL627_3001 
Study Product: rVIII-SingleChain 
 
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Confidential 
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 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’s 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 (or 1 or more of the 
study arms, or the substudies) 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 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 the investigators 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 

 
Study Number: CSL627_3001 
Study Product: rVIII-SingleChain 
 
CRD-TPL-077 Version 1.0 
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Page 126 of 149 
 
Confidential 
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. 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 final 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. 
 

 
Study Number: CSL627_3001 
Study Product: rVIII-SingleChain 
 
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15 
References 
Calvez T, Chambost H, Claeyssens-Donald S. Recombinant factor VIII products and inhibitor 
development in previously untreated boys with severe hemophilia A. Blood. 2014: 
124(23):3398-3408. 
Collins P, Palmer BP, Chalmers EA. Factor VIII brand and the incidence of factor VIII 
inhibitors in previously untreated UK children with severe hemophilia A, 2000-2011. Blood. 
2014:124(23):3389-3397. 
DiMichele, D. Inhibitors: resolving diagnostic and therapeutic dilemmas. Haemophilia. 
2002;8(3):280-287. 
DiMichele, D. Inhibitor development in haemophilia B: an orphan disease in need of 
attention. Br J Haematol. 2007;138(3):305-315. 
DiMichele, D. Inhibitors in Haemophilia: A Primer; Treatment of Haemophilia. Montreal: 
World Federation of Hemophilia; 2008. 
European Medicines Agency (EMA). Guideline on the clinical investigation of recombinant 
and human plasma-derived factor VIII products; 2011. 
European Medicines Agency (EMA). Guideline on the clinical investigation of recombinant 
and human plasma-derived factor VIII products; revision 1; 28 January 2016. 
European Medicines Agency (EMA). Guideline on the clinical investigation of recombinant 
and human plasma-derived factor VIII products; revision 2; 26 July 2018. 
European Medicines Agency (EMA). Reflection paper on immune tolerance induction in 
haemophilia A patients with inhibitors; 21 March 2013. 
Gouw SC, van der Bom JG, Ljung R, et al. Factor VIII products and inhibitor development in 
severe hemophilia A. N Engl J Med. 2013;368:23:1-9. 
Kasper C. Diagnosis and management of inhibitors to factors VIII and IX: treatment of 
Haemophilia. Montreal: WFH; 2004. 
Mariani G, Siragusa S, Kroner BL. Immune tolerance induction in hemophilia A: a review. 
Semin Thromb Hemost. 2003;29:69-76. 

 
Study Number: CSL627_3001 
Study Product: rVIII-SingleChain 
 
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26 May 2020 
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Confidential 
Oldenburg J, Jiménez-Yuste V, Peiró-Jordán R, et al. Primary and rescue immune tolerance 
induction in children and adults: a multicentre international study with a VWF-containing 
plasma-derived FVIII concentrate. Haemophilia. 2014;20:83-91. 
Peyvandi F, Manucci PM, Garagiola I, et al. A randomized trial of Factor VIII and 
neutralizing antibodies in hemophilia A. N Engl J Med, 2016;374:2054-2064. 
Van den Berg, Fischer K, Carcao M, et al. Timing of inhibitor development in more than 
1000 previously untreated patients with severe hemophilia A. Blood. 2019;134:317-320.  
Valentino LA, Kempton CL, Kruse-Jarres R, et al. US guidelines for immune tolerance 
induction in patients with haemophilia a and inhibitors. Haemophilia. 2015;21:559-567. 
Walsh CE, Soucie JM, Miller CH; United States Hemophilia Treatment Center Network. 
Impact of inhibitors on hemophilia A mortality in the United States. Am J Hematol. 
2015;90:400-405. 
Witmer C, Young G. Factor VIII inhibitors in hemophilia A: rationale and latest evidence. 
Ther Adv Hematol. 2013;4:59-72. 
World Federation of Hemophilia (WFH). Guidelines for the Management of Hemophilia. 
Montreal: WFH; 2012. 
 

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Study Number: CSL627_3001 
Study Product: rVIII-SingleChain 
 
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Page 149 of 149 
 
Confidential 
 
Signature of Principal Investigator 
Study Title: 
A Phase 3 Open-Label, Multicenter, Extension Study to Assess the 
Safety and Efficacy of Recombinant Coagulation Factor VIII 
(rVIII-SingleChain, CSL627) in Subjects with Severe Hemophilia A 
Protocol 
Number: 
CSL627_3001 
Site Number: 
 
I have read the Clinical Study Protocol Amendment 5 titled “A Phase 3 Open-Label, 
Multicenter, Extension Study to Assess the Safety and Efficacy of Recombinant Coagulation 
Factor VIII (rVIII-SingleChain, CSL627) in Subjects with Severe Hemophilia A”. 
By signing this Clinical Study 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 Clinical Study Protocol, the standards of Good Clinical Practice (as 
defined by the International Conference on Harmonisation) and applicable regulatory 
requirements. 
Changes to the Clinical Study Protocol will only be implemented after written approval is 
received from CSL Behring 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 Clinical Study Protocol. 
 
 
 
(Signature) 
 
 
Date (DD MMM YYYY) 
(Printed name) 
 
 
 
(Title) 
 
 
 

V er si o n: 1. 0
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