Conditions: Antibody-mediated Rejection
Keywords: Antibody-mediated kidney transplant rejection Renal
Allocation: RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 63
Healthy volunteers: no

Brief summary:
This is a double-blind, randomized-withdrawal, placebo-controlled study in kidney transplant patients with AMR to evaluate the efficacy and safety of human plasma-derived C1-esterase inhibitor as add-on to standard of care (IVIG).

Detailed description:

Arms:
arm 1: C1-esterase inhibitor arm 2: Excipients of C1-INH plus albumin

Interventions: intervention 1: C1-esterase inhibitor intervention 2: Placebo
Intervention descriptions: intervention 1: C1-esterase inhibitor is a human plasma-derived lyophilised powder for reconstitution intervention 2: Excipients of C1-INH plus albumin

Protocol document:
Prot_000.pdf: 
 
Substantial Amendment 3 
 
Page 1 of 131 
Date: 31 Jan 2020 
 
CS-SOP-04-T02 Version 1.0 
Confidential 
CLINICAL STUDY PROTOCOL 
SUBSTANTIAL STUDY PROTOCOL AMENDMENT NO. 3  
 
A Double-blind, Randomized-withdrawal, Placebo-controlled Study to 
Evaluate the Efficacy and Safety of Human Plasma-derived C1-esterase 
Inhibitor as Add-on to Standard of Care for the Treatment of Refractory 
Antibody Mediated Rejection in Adult Renal Transplant Recipients 
Study Number: 
CSL842_3001 
Study Product: 
C1-esterase Inhibitor, Human (500 IU/mL) 
Development Phase: 
Phase 3 
Sponsor: 
CSL Behring LLC 
1020 First Avenue  
King of Prussia, PA 19406 
United States 
EudraCT Number: 
2017-000348-17 
Protocol Version: 
Amendment 3  
Protocol Date: 
31 Jan 2020 
Compliance: 
This study will be conducted in accordance with standards of 
Good Clinical Practice (as defined by the International Council 
for Harmonisation) and all applicable national and local 
regulations. 
This clinical study protocol includes information and data that contain trade secrets and privileged or 
confidential information that is the property of the sponsor (“CSL”). This information must not be made public 
without written permission from CSL. These restrictions on disclosure will apply equally to all future 
information supplied to you. This material may be disclosed to and used by your staff and associates as may be 
necessary to conduct the clinical study. 


CSL Behring LLC 
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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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Confidential 
Revision History 
Date 
Version  
Summary of Significant Changes 
01 March 2017 
 
Original 
Not applicable 
27 June 2017 
 
Country-specific 
Amendment 1  
(United Kingdom) 
1. Addition of pregnancy testing monthly during the 
Treatment Period 1 and Treatment Period 2, and 
Retreatment Period. 
2. Section 6.1.3.2, clarification of unblinding 
procedure.   
28 November 
2017 
Substantial Amendment 1 
1. A Non-responder Follow-up Period is added for 
subjects who are non-responders after Treatment 
Period 1. These subjects will be followed until graft 
failure or up to 48 months after enrollment. 
Statistical analyses are amended to reflect this 
change. 
2. Pregnancy tests are added at monthly intervals. 
3. Additional timepoints are added for C1-esterase 
inhibitor activity/antigen and collection of retention 
samples in Treatment Period 1. 
4. Administration of IVIg is tailored to current 
standard of care practice and may be given when 
DSA is ≥ 2000 MFI during Treatment Period 2 and 
the Retreatment Period. 
5. A provision is added to enroll up to 136 subjects in 
Treatment Period 1. 
6. Exclusion criterion 3 is deleted, ie, subjects with 
evidence of chronic changes on biopsy (interstitial 
fibrosis [ci], arterial fibrointimal, arterial hyalinosis 
[ah], or chronic glomerulopathy [cg] scores of 3), 
ongoing dialysis, active infection, coagulopathy 
disorder, or hepatobiliary disease are now permitted 
to participate in the study. 


CSL Behring LLC 
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C1-esterase Inhibitor, Human (500 IU/mL) 
Substantial Amendment 3 
 
Page 4 of 131 
Date: 31 Jan 2020 
Confidential 
Date 
Version  
Summary of Significant Changes 
28 November 
2017 
Substantial Amendment 1 
(continued) 
7. Inclusion criterion 5 is amended to add that 
subjects must achieve steady-state eGFR within 60 
days post-transplant, and that subjects with slow or 
delayed graft function must have a 50% increase in 
urine output with a 50% decrease in serum 
creatinine 7 days post-transplant. 
 
8. Exclusion criterion 4a (previously 5a) amended to 
include HBV as part of the viral hepatitis criterion. 
The criterion now includes instructions for 
confirmed HCV or HBV, ie subjects must be 
receiving or have received antiviral therapy and 
have no history of cirrhosis. 
9. New exclusion criterion 5 includes a history of HIV 
as collected in medical history at Screening  
10. Procedures for breaking the blind are clarified. 
11. Dry body weight measured at Screening is changed 
to body weight and date of biopsy is added to 
medical history. 
12. The criteria used to determine frequency of blood 
draws for creatinine measurement is changed from 
an increase of 20% to 10% above the previous value 
in Treatment Period 2. 
13. Secondary endpoints are clarified to reduce 
redundancy.  
14. The statistical plan is revised to address the change 
to the study design. 
15. Study durations are changed from years to months 
16. Virus testing is clarified. 
17. Language on Banff criteria for AMR diagnosis is 
clarified and made consistent throughout the 
protocol. 
18. Baseline eGFR is clarified. 
19. Blood sample collection and recording is clarified. 
20. Banff Scoring System is updated in Appendix 3. 
23 January 2019 
Substantial Amendment 2 
1. Plasmapheresis is no longer mandatory if DSA is 
≥ 5000 MFI 
 
Plasmapheresis should be performed if a 
subject has DSA with clinical significance 
based on the investigator’s medical judgement 
2. Dosing at Week 13 is clarified 
 
The dose administered at the Week 13 visit  
will be the first dose of Treatment Period 2 for 
responders (ie blinded) 
 
The 2nd dose at Week 12 is the final open label 
dose for Treatment Period 1 for both 
responders and non-responders 
 


C S L Be hri n g L L C  
C S L 8 4 2 _ 3 0 0 1  
C 1 -ester ase I n hi bit or, H u m a n ( 5 0 0 I U/ m L)  
S u bsta ntial A me n d me nt 3  
 
Pa ge 5  of 1 3 1  
Date: 3 1 Ja n 2 0 2 0  
C o nfi de ntial  
D ate  
Versi o n  
S u m m ar y of Si g nific a nt C h a n ges  
 
S u bsta ntial  A me n d me nt 2 
(c o nti n ue d) 
3.  T he first d ose of I VI g will occ ur o n Wee k 4 if t he 
s u bject recei ve d hi g h d ose I VI g wit hi n 4 wee ks of 
St u d y Da y 1 as sta n dar d of care.   
4.  Mea n c or p usc ular he m o gl o bi n c o nce ntrati o n a n d 
mea n c or p usc ular v ol u me are n ot re q uire d safet y 
assess me nts b ut ca n be c ollecte d if a vaila ble. 
5.  Wee k 1 3 visit is clarifie d as t he e n d of Treat me nt 
Peri o d 1 f or n o nres p o n ders a n d start of Treat me nt 
Peri o d 2 f or res p o n ders.  
6.  T he or der of Visit 1 3 assess me nt is c ha n ge d t o ali g n 
wit h t he e n d of Treat me nt Peri o d 1 assess me nts 
verses start of Treat me nt Peri o d 2 assess me nts a n d 
a hea der is a d de d t o hi g hli g ht t he Treat me nt Peri o d 
1 earl y wit h dra wal assess me nts.  
3 1 Ja n uar y  2 0 2 0  
S u bsta ntial A me n d me nt 3  
1.  T he res p o n der defi niti o n is re vise d.  
2.  Defi niti o n of l oss -of -res p onse is c ha n ge d. 
3.  T he pri mar y e n d p oi nt is c ha n ge d fr o m ti me t o 
l oss-of -res p o nse t o l oss-of -res p o nse stat us ( bi nar y 
yes  / n o) . 
4.  T he sec o n dar y e n d p oi nts are re vise d . 
5.  T he n u m ber of pla n ne d s u bjects a n d sites are 
i ncrease d. 
6.  A sc he d ule of assess me nts is a d de d f or t he N o n -
res p o n der F oll o w-u p P eri o d. 
7.  De vel o p me nt of rec urre nt or persiste nt A M R is 
a d de d as a n efficac y assess me nt . 
8.  Ti mi n g f or c ollecti n g ser u m creati ni ne is a me n de d . 
9.  M o nit ori n g of ki d ne y f u ncti o n is a d de d d uri n g t he 
Res p o n der F oll o w -u p P eri o d. 
1 0.  P ote ntial ri s ks a n d be nefits are u p date d base d o n t he 
m ost rece nt peri o dic r e p orts a n d I n vesti gat or 
Br oc h ure  u p date s. 
1 1.  
 
 
 
1 2.  St u d y desi g n rati o nale is re vise d  t o s u p p ort c ha n ges 
t o t he pri mar y e n d p oi nt. 
1 3.  I ncl usi o n criteria 5, 6, a n d 7 are a me n de d. 
1 4.  E xcl usi o n criteri o n 8 is a me n de d . 
1 5.  D osi n g of C 1 -I N H a n d place b o base d o n b o d y 
wei g ht is clarifie d . 
1 6.  S hi p pi n g of i n vesti gati o nal pr o d uct t o s u bjects is 
a d de d 
1 7.  Dia g n osis of  A M R base d o n i ncl usi o n bi o ps y is 
clarifie d . 
1 8.  Meas ure d e G F R ti mi n g is clarifie d . 
1 9.  Re -scree ni n g after scree n fail ure i nstr ucti o ns are 
a me n de d . 
C CI


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Substantial Amendment 3 
 
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Confidential 
20. Assessment of biopsy-confirmed AMR is added 
during the Responder Follow-up Period. 
21. Assessments during the Non-responder Follow-up 
Period are amended. 
22. The adverse event observation period is amended. 
23. Statistical analyses are amended to support changes 
implemented by Amendment 3. 
24. New literature references are added. 


CSL Behring LLC 
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C1-esterase Inhibitor, Human (500 IU/mL) 
Substantial Amendment 3 
 
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Date: 31 Jan 2020 
Confidential 
Protocol Synopsis 
Title 
A Double-blind, Randomized-Withdrawal, Placebo-Controlled Study to Evaluate the 
Efficacy and Safety of Human Plasma-derived C1-esterase Inhibitor as Add-on to 
Standard of Care for the Treatment of Refractory Antibody Mediated Rejection in 
Adult Renal Transplant Recipients 
Study Number 
CSL842_3001 
Sponsor 
CSL Behring LLC (CSL) 
Development Phase 
Phase 3 
Study Product 
C1-esterase Inhibitor, Human (500 IU/mL); throughout the protocol, the study product 
will be abbreviated as C1-INH. 
Indication 
Chronic treatment of refractory antibody-mediated rejection (AMR) in adult kidney 
transplant recipients in combination with intravenous immunoglobulin (IVIg) 
containing regimens. 
Study Summary and 
Overview 
This is a double-blind, randomized-withdrawal, placebo-controlled study consisting of 
2 treatment periods, a Responder Follow-up Period and Retreatment Period(s) (if 
needed). 
Eligible subjects will enter into the open-label Treatment Period 1 (TP1), during which 
all subjects will receive C1-INH. Subjects who respond to treatment with C1-INH by 
Week 12 as assessed by pre-defined responder criteria will be randomized into 
Treatment Period 2 (TP2) of the study; those subjects who do not respond to treatment 
will enter a Non-responder Follow-up Period (up to 48 months). Subjects who are 
responders will be randomized to receive either C1-INH or placebo during TP2. All 
subjects will receive standard of care throughout TP1 and TP2 (IVIg 2 grams/kg once 
every 4 weeks in TP1 and at investigator discretion in TP2; plasmapheresis, as needed 
in TP1 and TP2). At the End-of-TP2 at Week 38, subjects will then enter a 39-month 
Responder Follow-up Period. Subjects will receive treatment consistent with their local 
standard of care during the Responder Follow-up Period, and their allograft status, 
kidney function, and survival will be monitored.   
During the Responder Follow-up Period, subjects with biopsy proven AMR (recurrent 
or persistent disease) may receive retreatment with blinded investigational product (in 
combination with standard of care) as a part of the Retreatment Period. 
An illustrated overview of the study is presented on the next page. 


CSL Behring LLC 
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Study Overview: 
 
 
AMR = antibody-mediated rejection; C1-INH = C1-esterase inhibitor, human; DSA = donor-specific 
antibody; eGFR = estimated glomerular filtration rate; IV = intravenous; IVIg = intravenous 
immunoglobulin; TP1 = Treatment Period 1; TP2 = Treatment Period 2 
Note: Post-treatment Follow-up Period is for responders. 
a Intravenous immunoglobulin (IVIg) will be administered every 4 weeks to all subjects at a dose of 
2 grams/kg. The dose must be administered over a minimum period of at least 2 days, and may be 
administered over a period of up to 5 days.  Plasmapheresis may be administered based on local DSA 
results and Principal Investigator’s judgement. 
b Intravenous C1-INH (60 IU/kg) will be administered to each subject over the first 13 days of TP1 for a 
total of 5 doses. Thereafter, subcutaneous C1-INH (60 IU/kg twice weekly) will be administered to each 
subject for the remainder of TP1. 
c If DSA ≥ 2000 MFI in local lab in TP2 or Retreatment Period, IVIg may be administered to subjects at a 
dose of 2 grams/kg every 4 weeks. The dose must be administered over a minimum period of at least 2 
days, and may be administered over a period of up to 5 days.  Plasmapheresis may be administered 
based on local DSA results and Principal Investigator’s judgement. 
d During the TP2, eligible subjects will be randomized 1:1 to receive treatment with investigational product 
(C1-INH [60 IU/kg]) or placebo] subcutaneously twice weekly.   
e Retreatment period(s) are blinded and subjects will receive the same investigational product treatment 
assignment as received during TP2. 
f Response is defined as an End-of-TP1 eGFR (mean of Week 11 and Week 12 eGFR) that is 
≥ 20 mL/min/1.73 m2 and ≥ 90% of the baseline eGFR (mean of  Screening and the Day 1 eGFR) 
(Section 10.3.1).  
g AMR Recurrence  or persistence in Follow-up Period is proven by biopsy, evidenced by infiltrating 
neutrophils and/or monocytes with or without the presence of C4d (g > 0, v > 0, and/or ptc > 0; if C4d is 
negative, g + ptc ≥ 2 (Section 8.1.3.3). 
Primary Objective 
The primary objective of the study is to evaluate the efficacy of C1-INH in the 
treatment of refractory AMR in renal allograft recipients. 
Primary Endpoint 
Proportion of subjects with loss-of-response at the End-of-TP2. Loss-of-response is 
defined as any 1 of the following 3 conditions:  
 
End-of-TP2 glomerular filtration rate (eGFR) (mean of Week 36 and Week 38 
eGFR) that is not stable, defined as: 
o 
End-of-TP2 eGFR that is < 90% of the End-of-TP1 eGFR for subjects whose 
End-of-TP1 eGFR (mean of Week 11 and Week 12 eGFR) is ≥ 100% of 
baseline;  
o 
End-of-TP2 eGFR that is < 90% of baseline for subjects whose End-of-TP1 
eGFR is ≥ 90% of baseline and < 100% of baseline 
IVIg c + C1-INH d
IVIg c + Placebo d
IVIg a
+ 
C1-INH b
1º endpoint
assessed
Open-label
Treatment Period 1: 
13 weeks
Double-blind
Treatment Period 2: 
25 weeks
Post-treatment 
Follow-up Period:
39 months
End of 
Study
Non-responsef
Responsef
Non-responder follow-up until graft failure or up to 48 months
Retreatment Periodc,e
AMR 
Recurrence g
Re-enter 
Follow-up 
Period


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Substantial Amendment 3 
 
Page 9 of 131 
Date: 31 Jan 2020 
Confidential 
 
Allograft failure (defined by allograft nephrectomy, or institution of permanent 
dialysis, or return to the transplant waitlist for renal transplant, whichever occurs 
first) 
 
Subject death by any cause. 
Secondary 
Objectives 
The secondary objectives of the study are: 
1. To further evaluate the efficacy of C1-INH in the treatment of refractory AMR in 
renal allograft recipients. 
2. To evaluate the safety of C1-INH in the treatment of refractory AMR in renal 
allograft recipients. 
3. To evaluate the pharmacokinetics of C1-INH during the treatment of refractory 
AMR in renal allograft recipients. 
Secondary 
Endpoints 
 
Proportion of subjects with all-cause allograft failure status through the Responder 
Follow-up Period (ie, within 48 months after enrollment). Allograft failure is 
defined as 1 of the following:  
o 
Allograft nephrectomy, institution of permanent dialysis, or return to the 
transplant waitlist for renal transplant, whichever occurs first, OR  
o 
Subject death by any cause. 
 
The difference in eGFR from the End-of-TP1 eGFR and baseline eGFR. 
 
The difference between the End-of-TP2 eGFR and the End-of-TP1 eGFR. 
 
The rate of change of eGFR during TP2, ie, the slope of the mean regression line 
in TP2. 
 
Time (weeks) to all-cause allograft failure through the Responder Follow-up 
Period (within 48 months after enrollment). 
 
Proportion of responders at the End-of-TP1. Response is defined as an End-of-TP1 
eGFR that is ≥ 20 mL/min/1.73 m2 and ≥ 90% of the baseline eGFR. 
 
Proportion of subjects surviving through the Responder Follow-up Period. 
 
Proportion of subjects with any adverse event assessed as related to investigational 
product. 
 
Mean pre-dose C1-esterase inhibitor functional activity at Day 1, Week 12, and 
Week 38. 
 
C1-esterase inhibitor functional activity Cmax and AUC0-t for IV and SC 
administration. 
Number of Subjects 
Approximately 120 subjects (and up to 175) are planned to participate in the open-label 
TP1 in order to randomize 60 subjects into the double-blind TP2. 
Study Duration 
The duration of the study for an individual subject is expected to be approximately 
210 weeks, or 48 months). This estimation is based on: 
 
A 2-week Screening Period. 
 
A 13-week Open-label Treatment Period (TP1). 
 
A 25-week Double-blind Treatment Period (TP2). 
 
Follow-up Periods: 


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Confidential 
o 
39-month (170 weeks) Responder Follow-up Period (up to 48 months 
following enrollment), or 
o 
45-month Non-responder Follow-up period (up to 48 months following 
enrollment).  
The overall study duration (ie, first subject’s Screening Visit to last subject’s final 
study visit) is anticipated to be approximately 6 years. 
Study Population 
and Main Criteria 
for Eligibility 
Adult renal allograft recipients with biopsy confirmed acute antibody-mediated 
rejection as defined by Banff 2015 criteria that is clinically unresponsive to an 
IVIg-containing regimen given as standard of care. 
Investigational 
Product Dose, 
Dosing Regimen, 
and Administration  
C1-esterase inhibitor is a lyophilized powder (1500 IU C1-INH per single-use vial) 
reconstituted with 3 mL water for injection. After reconstitution, C1-INH is available 
at a concentration of 500 IU/mL. 
The comparator product, placebo, which contains the excipients of C1-INH plus 
albumin, will be reconstituted with 3 mL water for injection. 
The terminology ‘Investigational Product’ is inclusive of both C1-INH and placebo. 
Timeframe 
Intravenous 
Administration 
Subcutaneous  
Administration 
Treatment Period 1: a 
The Day 1 Visit to 
the Day 13 Visit 
60 IU/kg C1-INH 
Not applicable 
Treatment Period 1: a 
The Day 14 Visit to 
the Week 12 2nd dose 
Not Applicable 
60 IU/kg C1-INH 
Treatment Period 2: b 
Week 13 to the Week 38 Visit 
Not Applicable 
60 IU/kg C1-INH 
OR 
0.12 mL/kg placebo 
Retreatment Period: c 
The Retreatment Day 1 Visit to 
the Retreatment Week 26 Visit 
Not Applicable 
60 IU/kg C1-INH 
OR 
0.12 mL/kg placebo 
a Treatment Period 1 is open-label and all subjects will receive C1-INH. C1-INH (60 IU/kg) 
will be administered IV to each subject over the first 13 days of Treatment Period 1 for a 
total of 5 doses. Thereafter, C1-INH (60 IU/kg twice weekly) will be administered SC to 
each subject for the remainder of Treatment Period 1.  
b Treatment Period 2 is blinded and subjects will be randomized 1:1 to treatment with 
investigational product (C1-INH [60 IU/kg] or placebo) subcutaneously twice weekly. 
c Retreatment Period(s) are blinded and subjects will receive the same investigational product 
treatment assignment subcutaneously as received during Treatment Period 2. 
Note: Week 13 is the final visit of Treatment Period 1 for non-responders and the first visit of 
Treatment Period 2 for responders.  


C S L Be hri n g L L C  
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S u bsta ntial A me n d me nt 3  
 
Pa ge 1 1  of 1 3 1  
Date: 3 1 Ja n 2 0 2 0  
C o nfi de ntial  
Effic ac y 
Assess me nts  
Efficac y assess me nts c o n d ucte d d uri n g t he st u d y will i ncl u de:  
 
e G FR.  
 
Res p o n der stat us (ie, res p o nse/l oss -of -res p o nse). 
 
Bi o ps y hist o pat h ol o g y.  
 
S ple nect o m y.  
 
D o n or -s pecific a nti b o dies ( D S A). 
 
 
 
All o graft fail ure.  
 
S u bject s ur vi val.   
 
 
 
De vel o p me nt of rec urre nt or persiste nt A M R  
S afet y Assess me nts  
Safet y assess me nts c o n d ucte d d uri n g t he st u d y will i ncl u de:  
 
P h ysical e xa mi nati o n.  
 
Vital si g ns.  
 
A d verse e ve nts.  
 
He mat ol o g y.  
 
Ser u m bi oc he mistr y, i ncl u di n g creati ni ne.  
 
I m m u n o ge nicit y t o C 1-I N H. 
 
Vir us testi n g.  
 
Pre g na nc y test . 
P h ar m ac o ki netics  
Bl o o d sa m ples will be ta ke n f or t he assess me nt of C 1 -esterase i n hi bit or f u ncti o nal 
acti vit y, C 1-esterase i n hi bit or a nti ge n c o nce ntrati o ns, a n d i m m u n o gl o b uli n 
c o nce ntrati o ns.  
 
 
 
Ot her Assess me nts  
T he E Q -5 D -3 L healt h -relate d q ualit y of life q uesti o n naire will be a d mi nistere d t o 
s u bjects w h o partici pate i n t he st u d y.  
St atistic al A n al yses  
Deter mi nati o n of t he sa m ple size is base d o n t he f oll o wi n g ass u m pti o ns:  
 
T he pr o p orti o ns of s u bjects e x perie nci n g l oss -of -res p o nse at t he E n d-of -T P 2 will 
be 0. 7 5  wit h p lace b o a n d 0.3 0  wit h C 1 -I N H. 
 
T here will be at least 9 0 % p o wer t o detect a statis ticall y si g nifica nt effect wit h 
t w o-si de d test wit h al p ha =  0. 0 5.  
 
L o gistic re gressi o n m o del wit h treat me nt effect will be use d f or t he pri mar y 
efficac y a nal ysis. Wal d test statistic f or treat me nt effect fr o m L o gistic re gressi o n 
has a p pr o xi matel y sa me distr i b uti o n as c hi-s q uare [ Fleiss et al, 2 0 0 3].  T heref ore, 
t he sa m ple size calc ulati o n base d o n c hi-s q uare test is use d t o e ns ure si milar p o wer 
f or h y p ot hesis testi n g. 
 
Treat me nt all ocati o n will be 1: 1.  
 
T he pla n ne d i nteri m a nal ys is f or f utilit y will n ot i m pact t he t y pe 1 err or f or t he 
fi nal a nal ysis. 
U n der t hese ass u m pti o ns, a t otal of 6 0 s u bjects ( 3 0 ra n d o mize d t o C 1 -I N H a n d 
3 0  ra n d o mize d t o place b o) will pr o vi de a p pr o xi matel y 9 5 % p o wer. T he st u d y will 
C CI
C CI
C CI
C CI


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enroll a sufficient number of subjects to ensure that 60 subjects are randomized. 
The primary analysis of the primary efficacy endpoint of loss-of-response status at the 
End-of-TP2 will be based on the proportion of subjects with loss-of-response between 
the randomized treatment groups (C1-INH or placebo) using a logistic regression 
model. 
The key secondary efficacy endpoint of all-cause allograft failure at the end of 
48 months after enrollment will be analyzed between the randomized treatment groups 
(C1-INH or placebo) using a logistic regression model. 
All efficacy analyses will be conducted based on the Modified Intent-to-Treat analysis 
set. Sensitivity analyses for efficacy endpoints will be based on the Intent-to-Treat 
analysis set. 
Safety will be analyzed for all subjects who receive at least 1 dose of the 
investigational product. The extent of exposure to open-label C1-INH, and to 
double-blind C1-INH or placebo will be summarized using descriptive statistics. 
Treatment-emergent adverse events will be summarized by Medical Dictionary for 
Regulatory Activities (MedDRA) System Organ Class and Preferred Term. Clinical 
laboratory parameters will be summarized using descriptive statistics, or frequency 
counts and percentages. 


C S L Be hri n g L L C  
C S L 8 4 2 _ 3 0 0 1  
C 1 -ester ase I n hi bit or, H u m a n ( 5 0 0 I U/ m L)  
S u bsta ntial A me n d m e nt 3 
 
Pa ge 1 3  of 1 3 1  
Date: 3 1 Ja n 2 0 2 0  
C o nfi de ntial  
Ta ble 1  
Sc he d ule of Assess me nts: Scree ni n g a n d O pe n -l a bel Tre at me nt Peri o d 1 
St u d y Peri o d  
Scree ni n g  
Tre at me nt Peri o d 1 ( O pe n -l a bel) 
St u d y Visit  
Scree ni n g  
 
E o T P 1 a 
St u d y Wee k  
- 2 t o 0  
1  
2  
3  
4  
5  
6  
7  
8  
9  
1 0  
1 1  
1 2  
1 3  
St u d y D a y  
-1 4 t o 1  
1 b  
4  
7  
1 0  
1 3  
1 4  
2 1  
2 8  
3 5  
4 2  
4 9  
5 6  
6 3  
7 0  
7 7  
8 4  
9 1  
Wi n d o w i n D a ys  
 
 
± 1  
± 1  
± 1  
± 1  
± 1  
± 1  
± 2  
± 2  
± 2  
± 2  
± 2  
± 2  
± 2  
± 2  
± 2  
± 2  
I nf or me d C o nse nt/I R T Re gistrati o n 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
I ncl usi o n/ E xcl usi o n Criteria 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
De m o gra p hics/ Me dical Hist or y c 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
P h ysical E xa mi nati o n d 
X  
X  
 
X  
 
 
X  
 
X  
 
 
 
X  
 
 
 
 
X  
Vital Si g ns e 
X  
X  
 
X  
 
 
X  
 
X  
 
 
 
X  
 
 
 
 
X  
Bl o o d Dr a ws  
Pre g na nc y Test f 
X  
X  
 
 
 
 
 
 
X  
 
 
 
X  
 
 
 
X  
 
H B V / H C V  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Rete nti o n Sa m ple g 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X a 
 
Creati ni ne [ C L] h 
X  
X  
 
X  
 
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X a 
 
Ser u m Bi oc he mistr y Pa nel h 
X  
X  
 
X  
 
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X a 
 
He mat ol o g y  
X  
X  
 
X  
 
 
X  
 
 
 
 
 
 
 
 
 
X a 
 
 a n d D S A i 
 
X  
 
 
 
 
 
 
X  
 
 
 
X  
 
 
 
X a 
 
C 1 -esterase I n hi bit or Acti vit y/ A nti ge n  
 
X  
X  
X  
X  
 
X  
 
X  
 
 
 
X  
 
X  
 
X a 
 
I m m u n o gl o b uli n C o nce ntrati o n 
 
X  
 
 
 
 
 
 
X  
 
 
 
X  
 
 
 
X a 
 
P K/ 
 Sa m pli n g S u bset j 
 
 
 
 
X  
 
 
 
 
 
 
 
 
 
 
X  
 
 
A nti b o dies t o C 1 -esterase I n hi bit or  
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
I ntra ve n o us C 1 -I N H k 
 
X  
X  
X  
X  
X  
 
 
 
 
 
 
 
 
 
 
 
 
S u bc uta ne o us C 1 -I N H l 
 
 
 
 
 
 
 
 
I ntra ve n o us I mm u n o gl o b uli n (I VI g) m  
 
X  
 
 
 
 
 
 
X  
 
 
 
X  
 
 
 
X  
 
Res p o n der Stat us/ Ra n d o mizati o n o 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
E Q -5 D -3 L Q uesti o n naire  
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
 
Dis pe nse C 1 -I N H p 
 
 
 
 
 
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
S u bjects Ret ur n Use d C 1 -I N H q 
 
 
 
 
 
 
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
A d verse E ve nts  
 
Pri or/ C o nc o mita nt T hera pies  
 
C 1 -I N H = C 1-esterase I n hi bit or, H u ma n ( 5 0 0 I U/ m L); [ C L] = ce ntral la b orat or y; D S A = d o n or -s pecific a nti b o dies; e C R F = electr o nic case re p ort f or m; E o T P 1 = E n d of 
Treat me nt Peri o d 1; e C R F  =  electr o nic case re p ort f or m; G F R = gl o mer ular filtrati o n rate; H B V = he patitis B vir us; H C V = he patitis C vir us; I R T = i ntera cti ve res p o nse 
C CI
C CI
C CI
C CI
C CI


C S L Be hri n g L L C  
C S L 8 4 2 _ 3 0 0 1  
C 1 -ester ase I n hi bit or, H u m a n ( 5 0 0 I U/ m L)  
S u bsta ntial A me n d m e nt 3 
 
Pa ge 1 4  of 1 3 1  
Date: 3 1 Ja n 2 0 2 0  
C o nfi de ntial  
tec h n ol o g y; I VI g = i ntra ve n o us i m m u n o gl o b uli n; M FI =  mea n fl u oresce nce i nte nsit y; 
; P K = p harmac o ki netic ; T P 1 = Treat me nt Peri o d 1; T P 2 = 
Treat me nt Peri o d 2 .  
N ote:  All pr oce d ures s h o ul d be c o m plete d bef ore t he a d mi nistrati o n of C 1 -I N H, e xce pt f or t he a d mi nistrati o n of I VI g, u nless ot her wise n ote d.  
F o ot n otes t o t he Sc he d ule of Assess me nts ( Scree n i n g a n d Tre at me nt Peri o d 1):  
a  If a s u bject is wit h dra w n/ disc o nti n ue d fr o m t he st u d y f or a n y reas o n d uri n g Treat me nt Peri o d 1, t he n t he i n vesti gat or s h o ul d ma ke e ver y eff ort t o perf or m t he assess me nts 
sc he d ule d f or t he Wee k 1 3  Visit, i n a d diti o n t o selecte d bl o o d dra ws (see Secti o n 8. 5. 3. 1 4 ). I n a d diti o n, i n vesti gat ors s h o ul d als o c o ntact t hese s u bjects b y tele p h o ne 
a p pr o xi matel y 3 0 da ys after t he E n d -of -T P 1 Visit t o c ollect f oll o w -u p safet y i nf or mati o n. Scree n i n g a n d Da y 1 assess me nts ca n occ ur o n t he sa me da y. N ote: Wee k 1 3 is t he 
E n d -of -T P 1  f or n o n-res p o n ders a n d t he start of T P 2  f or res p o n ders.   
b  All pr oce d ures sc he d ule d f or t he Da y 1 Visit s h o ul d be c o m plete d bef ore t he first d oses of C 1 -I N H a n d I VI g are  a d mi nistere d.  
c  Me dical hist or y will i ncl u de d oc u me ntati o n of date of bi o ps y, creati ni ne at ti me of i ncl usi o n bi o ps y, t hr o m b otic micr oa n gi o pa t h y a n d t he Ba nff cate g or y sc ores (A p pe n di x 3 ) 
fr o m t he pre-e nr oll me nt ki d ne y bi o ps y t hat was use d t o q ualif y f or partici pati o n.  
d  A p h ysical e xa mi nati o n will be c o n d ucte d per t he i n vesti gat or’s sta n dar d pr oce d ure, a n d will als o i ncl u de assess me nt of u nila teral pai n a n d/ or s welli n g of t he l o wer e xtre mities 
f or t he p ur p ose of scree ni n g f or dee p vei n t hr o m b osis. 
e  Vital si g ns assess me nts will i ncl u de bl o o d press ure, p ulse rate, b o d y te m perat ure, a n d b o d y wei g ht ( use d t o deter mi ne t he v ol u me of C 1 -I N H t o be a d mi nistere d). Hei g ht will 
als o be meas ure d at Scree ni n g  ( o nl y). 
f  A p re g na nc y test will be c o n d ucte d f or w o me n of c hil d beari n g p ote ntial, o nl y. Ser u m pre g na nc y test will be c o n d ucte d at Scree ni ng a n d Wee k  1 2. Uri ne or ser u m pre g na nc y 
tests will be c o n d ucte d at all ot her ti me p oi nts.  If t he scree ni n g pre g na nc y test is c o n d ucte d wit hi n 2 4 h o urs of Da y 1, t he n a n a d diti o nal pre g na nc y test is n ot nee de d o n Da y 1. 
g  A bl o o d sa m ple will be retai ne d f or p ote ntial f ut ure ser ol o g y assess me nts.  
h  Creati ni ne will be meas ure d b y t he ce ntral la b orat or y ([ C L]) a n d as a part of t he ser u m  bi oc he mistr y pa nel b y t he l ocal la b orat or y. T he c o m plete list of assess me nts i ncl u de d as a 
part of t he bi oc he mistr y pa nel is prese nte d i n Ta ble 1 3 .  
i  D o n or -s pecific a nti b o dies will be meas ure d i n b ot h t he ce ntral a n d l ocal la b orat ories. Ce ntral la b orat or y res ults will be use d f or a nal yses. L ocal la b orat or y res ults will be use d b y 
t he i n vesti gat or t o ma ke treat me nt decisi o ns, i ncl u di n g t he i nitiati o n of plas ma p heresis. D o n or-s pecific a nti b o dies s h o ul d be teste d i n t he l ocal la b orat or y wit hi n bet wee n 2 4 a n d 
7 2 h o urs after c o m pleti n g plas ma p heresis.  
j  Se q ue ntial P K/ 
 sa m pli n g fr o m a s u bset of s u bjects will occ ur o n t he Da y 1 0 a n d Wee k 1 1 Visits. See Ta ble 6  f or a d diti o nal details.  
k  I ntra ve n o us C 1 -I N H will be a d mi nistere d at a d ose of 6 0 I U/ k g at t he st u d y site. I ntra ve n o us C 1 -I N H s h o ul d be a d mi nistere d wit h a mi ni m u m of 4 8 h o urs bet wee n eac h d ose.  
l  S u bc uta ne o us C 1 -I N H will be a d mi nistere d at a d ose of 6 0 I U/ k g e ver y 3 or 4 da ys (ie, t wice wee kl y) at t he st u d y site , at h o me b y a me dical pr ofessi o nal, or at h o me b y t he 
s u bject u n der t he s u per visi o n of a me dical pr ofessi o nal. T he first d ose of s u bc uta ne o us C 1 -I N H s h o ul d be a d mi nistere d bet wee n 2 4 a n d 4 8 h o urs after t he last d ose of 
i ntra ve n o us C 1 -I N H.  
m   I ntra ve n o us i m m u n o gl o b uli n will be a d mi nistere d at a d ose of 2 gra ms/ k g. A d mi nistrati o n of t he d ose will be gi n at t he visit. T he d ose m ust be a d mi nistere d o ver a mi ni m u m 
peri o d of at least 2 da ys, a n d ma y be a d mi nistere d o ver a peri o d of u p t o 5 da ys (see Secti o n 5. 4. 1  f or details).  
n  
 
o  Res p o n ders will be ra n d o mize d t o treat me nt wit h bli n de d i n vesti gati o nal pr o d uct d uri n g Treat me nt Peri o d 2. T he defi niti o n of res p o nse is pr o vi de d i n Secti o n 1 0. 3. 1 . 
N o n -res p o n ders will e nter a 4 5-m o nt h N o n -res p o n der F oll o w-u p Peri o d.  
C CI
C CI
C CI


CSL Behring LLC 
CSL842_3001 
C1-esterase Inhibitor, Human (500 IU/mL) 
Substantial Amendment 3 
 
Page 15 of 131 
Date: 31 Jan 2020 
Confidential 
p  If investigational product will be administered off-site after the completion of the visit, then it will be dispensed to the subject. Only subjects who are randomized may receive 
blinded investigational product at the Week 13 Visit. 
q  Throughout Treatment Period 1, subjects will return any used or partially used vials of C1-INH. Subjects should then return all vials (ie, used, partially used, and unused) of 
C1-INH at the Week 13 Visit.  


C S L Be hri n g L L C  
C S L 8 4 2 _ 3 0 0 1  
C 1 -ester ase I n hi bit or, H u m a n ( 5 0 0 I U/ m L)  
S u bsta ntial A me n d me nt 3  
 
Pa ge 1 6  of 1 3 1  
Date: 3 1 Ja n 2 0 2 0  
C o nfi de ntial  
Ta ble 2  
Sc he d ule of Assess me nts: Bli n de d Tre at me nt Peri o d 2  
St u d y Peri o d  
Tre at me nt Peri o d 2 ( Bli n de d)  
St u d y Visit  
N o n -visit w ee ks  
 
E o T P 2 a 
St u d y Wee k  
1 4  
1 5  
1 6  
2 0  
2 4  
2 8  
3 2  
3 8  
St u d y D a y  
 
 
1 1 2  
1 4 0  
1 6 8  
1 9 6  
2 2 4  
2 6 6  
Wi n d o w i n D a ys  
 
 
± 7  
± 7  
± 7  
± 7  
± 7  
± 7  
P h ysical E xa mi nati o n b 
 
 
 
 
X  
 
 
X  
Vital Si g ns c 
 
 
 
 
X  
 
 
X  
Bl o o d Dr a ws  
Creati ni ne [ C L] d 
 
Ser u m Bi oc he mistr y d, e 
 
 
 
X  
 
X  
 
X  
He mat ol o g y  
 
 
 
X  
 
X  
 
X  
 a n d D S A f 
 
 
X  
X  
X  
X  
X  
X  
Pre g na nc y Test g 
 
 
X  
X  
X  
X  
X  
X  
Rete nti o n Sa m ple h 
 
 
 
 
 
 
 
X  
C 1 -esterase I n hi bit or Acti vit y/ A nti ge n  
 
 
X  
 
 
 
X  
X  
I m m u n o gl o b uli n C o nce ntrati o n 
 
 
 
 
 
 
X  
 
A nti b o dies t o C 1 -esterase I n hi bit or  
 
 
 
 
 
 
 
X  
S u bc uta ne o us I n vesti gati o nal Pr o d uct i 
 
 
 
I ntra ve n o us I m m u n o gl o b uli n (I VIg)  j 
 
 
X  
X  
X  
X  
X  
 
Ki d ne y All o graft Bi o ps y   
 
 
 
 
 
 
 
X  
E Q -5 D -3 L Q uesti o n naire  
 
 
 
 
  
 
 
X  
Dis pe nse I n vesti gati o nal Pr o d uct l 
 
 
X  
X  
X  
X  
X  
 
S u bjects Ret ur n Use d I n vesti gati o nal Pr o d uct m  
 
 
X  
X  
X  
X  
X  
X  
A d verse E ve nts  
 
 
 
C o nc o mita nt T hera pies  
 
 
 
C 1 -I N H = C 1-esterase I n hi bit or, H u ma n ( 5 0 0 I U/ m L); [ C L] = ce ntral la b orat or y; D S A = d o n or -s pecific a nti b o dies; e C R F =  electr o nic case re p ort f or m; E o T P 2 = E n d of 
Treat me nt Peri o d 2; G F R = gl o mer ular filtrati o n rate; I VI g  =  i ntra ve n o us i m m u n ogl o b uli n; M FI = mea n fl u oresce nce i nte nsit y; 
; P K = p har mac o ki netic. 
N ote 1:  All pr oce d ures s h o ul d be c o m plete d bef ore t he a d mi nistrati o n of C 1 -I N H, e xce pt f or t he a d mi nistrati o n of I VI g, u nless ot her wise n ote d. 
N ote 2:  Bet wee n t he Wee k  1 3 Visit a n d t he  Wee k 1 6 Visit, eac h s u bject w h o is eli gi ble t o partici pate i n Treat me nt Peri o d 2 will a d mi nister i n vesti gat i o nal pr o d uct ( C 1-I N H or 
place b o) as per t he ra n d o mizati o n sc he d ule ( F o ot n ote I, bel o w) a n d will ha ve bl o o d dra w n f or creati ni ne m eas ure me nt ( F o ot n ote D, bel o w).  
C CI
C CI
C CI
C CI


C S L Be hri n g L L C  
C S L 8 4 2 _ 3 0 0 1  
C 1 -ester ase I n hi bit or, H u m a n ( 5 0 0 I U/ m L)  
S u bsta ntial A me n d me nt 3  
 
Pa ge 1 7  of 1 3 1  
Date: 3 1 Ja n 2 0 2 0  
C o nfi de ntial  
F o ot n otes t o t he Sc he d ule of Assess me nts ( Tre at me nt Peri o d 2):  
a  If a s u bject is wit h dra w n fr o m t he st u d y f or a n y reas o n d uri n g Treat me nt Peri o d 2, t he n t he i n vesti gat or s h o ul d ma ke e ver y ef f ort t o perf or m t he assess me nts sc he d ule d f or t he 
Wee k  3 8  Visit. I n a d diti o n, i n vesti gat ors s h o ul d c o ntact t hese s u bjects b y tele p h o ne a p pr o xi matel y 3 0 da ys after t he Wee k 3 8 Visit (i e, t he E n d of Treat me nt Peri o d 2 Visit) t o 
c ollect f oll o w -u p safet y i nf or mati o n.  
b  A p h ysical e xa mi nati o n will be c o n d ucte d per t he i n vesti gat or’s sta n dar d pr oce d ure, a n d will als o i ncl u de assess me nt of u nilateral pai n a n d/ or s we lli n g of t he l o wer e xtre mities 
f or t he p ur p ose of scree ni n g f or dee p vei n t hr o m b osis. 
c  Vital si g ns assess me nts will i ncl u de bl o o d  press ure, p ulse rate, b o d y te m perat ure, a n d b o d y wei g ht.  
d  Be gi n ni n g d uri n g Treat me nt Peri o d 2, a bl o o d sa m ple f or creati ni ne meas ure me nt at t he ce ntral la b orat or y [ C L] will be dra w n o nce e ver y 1 4  da ys  ( ± 7  da ys) at t he st u d y site or 
at h o me b y a me dica l pr ofessi o nal. Bl o o d dra ws f or creati ni ne meas ure me nts ma y occ ur m ore fre q ue ntl y at t he i n vesti gat or’s discreti o n.  
e  T he bi oc he mistr y pa nel i ncl u des assess me nt of creati ni ne; t he c o m plete list of assess me nts i ncl u de d as a part of t he bi oc he mi str y pa nel is prese nte d i n Ta ble 1 3 .  
f  D o n or -s pecific a nti b o dies will be meas ure d i n b ot h t he ce ntral a n d l ocal la b orat ories. Ce ntral la b orat or y res ults will be use d f or a nal yses. L ocal la b orat or y res ults will be use d b y 
t he i n vesti gat or t o ma ke treat me nt decisi o ns, i ncl u di n g t he i nitiati o n of I VI g a n d plas ma p heresis. A d diti o nal bl o o d dra ws f or a ssess me nt of D S A will occ ur after plas ma p heresis, 
as descri be d i n Secti o n 5. 4. 2 .  
g   A pre g na nc y test will be c o n d ucte d f or w o me n of c hil d beari n g p ote ntial, o nl y. Ser u m pre g na nc y test will be c o n d ucte d at Wee k 1 6 a n d E o T P 2. Uri ne or ser u m pre g na nc y tests 
will be c o n d ucte d at all ot her ti me p oi nts.  
h  A bl o o d sa m ple will be retai ne d f or p ote ntial f ut ure ser ol o g y assess me nts.  
i  T hr o u g h o ut Treat me nt Peri o d 2, s u bc uta ne o us i n vesti gati o nal pr o d uct ( C 1 -I N H or place b o) will be a d mi nistere d as per t he ra n d o mizati o n sc he d ule e ver y 3 or 4 da ys (ie, t wice 
wee kl y) at t he st u d y site, at h o me b y a me dica l pr ofessi o nal, or b y t he s u bject u n der t he s u per visi o n of a me dical pr ofessi o nal. T he first d ose of ra n d o mize d i n vesti gati o nal 
pr o d uct will be a d mi nistere d at t he wee k 1 3 visit.  
j  If D S A ≥ 2 0 0 0 M FI, i ntra ve n o us i m m u n o gl o b uli n ma y be a d mi nistere d at a d ose of 2 gra ms/ k g. A d mi nistrati o n of t he d ose will be gi n at t he visit. T he d ose m ust be 
a d mi nistere d o ver a mi ni m u m peri o d of at least 2 da ys, a n d ma y be a d mi nistere d o ver a peri o d of u p t o 5 da ys.  
k  
. 
l  If i n vesti gati o nal pr o d uct will be a d mi nistere d off-site after t he c o m pleti o n of t he visit, t he n it will be dis pe nse d t o t he s u bject. 
m  T hr o u g h o ut Treat me nt Peri o d 2, s u bjects s h o ul d ret ur n a n y use d or partiall y use d vials of i n ves ti gati o nal pr o d uct. S u bjects s h o ul d t he n ret ur n all vials (ie, use d, partiall y use d, 
a n d u n use d) of i n vesti gati o nal pr o d uct at t he Wee k 3 8 Visit.  
C CI


C S L Be hri n g L L C  
C S L 8 4 2 _ 3 0 0 1  
C 1 -ester ase I n hi bit or, H u m a n ( 5 0 0 I U/ m L)  
S u bsta ntial A me n d me nt 3  
 
Pa ge 1 8  of 1 3 1  
Date: 3 1 Ja n 2 0 2 0  
C o nfi d e ntial 
Ta ble 3  
Sc he d ule of Assess me nts: Res p o n der  F oll o w -u p Peri o d  
St u d y Peri o d  
Res p o n der  F o ll o w-u p Peri o d  
St u d y Visit  
 
E o S a 
St u d y M o nt h  
1 2  
1 8  
2 4  
3 0  
3 6  
4 2  
4 8  
St u d y Wee k  
5 2  
7 8  
1 0 4  
1 3 0  
1 5 6  
1 8 2  
2 0 8  
Wi n d o w i n D a ys  
± 2 8  
± 2 8  
± 2 8  
± 2 8  
± 2 8  
± 2 8  
± 2 8  
Bl o o d Dr a ws  
Creati ni ne [ C L] b 
X  
X  
X  
X  
X  
X  
X  
A nti b o dies t o C 1 -esterase I n hi bit or  
C 1 -esterase I n hi bit or Acti vit y/ A nti ge n 
X  
 
 
 
 
 
 
Bi o ps y -c o nfir me d A M R ( yes/ n o) c 
X  
X  
X  
X  
X  
X  
X  
E Q -5 D -3 L Q uesti o n naire  
X  
 
X  
 
X  
 
X  
All o graft Fail ure d 
X  
X  
X  
X  
X  
X  
X  
S u bject S ur vi val  
X  
X  
X  
X  
X  
X  
X  
A M R  = a nti b o d y -me diate d rejecti o n ; [ C L] = ce ntral la b orat or y; e C R F = electr o nic case re p ort f or m; E o S =  E n d of St u d y; 
. 
N ote:  Assess me nt of D S A a n d/ or all o graft bi o ps y will be c o n d ucte d as per l ocal sta n dar d of care.  
F o ot n otes t o t he Sc he d ule of Assess me nts ( Res p o n der  F oll o w -u p Peri o d):  
a  If a s u bject is wit h dra w n fr o m t he st u d y f or a n y reas o n d uri n g t he F oll o w-u p Peri o d, t he n t he i n vesti gat or s h o ul d ma ke 
e ver y eff ort t o perf or m t he assess me nts sc he d ule d f or t he M o nt h  4 8  Visit.  
b  Creati ni ne will be meas ure d b y t he c e ntral la b orat or y.  
c  Occ urre nce of bi o ps y -c o nfir me d A M R ( Secti o n 8. 1. 3. 3 ) si nce t he last visit, base d o n d oc u me ntati o n i n t he s u bject’s 
me dical rec or d. Res p o nses will be rec or de d i n t he e C R F.  
d  T he defi niti o n of all o graft fail ure is prese nte d i n Secti o n 8. 1. 3. 7 . 
 
C CI
C CI
C CI


CSL Behring LLC 
CSL842_3001 
C1-esterase Inhibitor, Human (500 IU/mL) 
Substantial Amendment 3 
 
Page 19 of 131 
Date: 31 Jan 2020 
Confidential 
Table 4 
Schedule of Assessments: Non-responder Follow-up Period 
Study Period 
Non-responder Follow-up Period 
Study Visit 
 
EoS a 
Study Month 
6 
12 
18 
24 
30 
36 
42 
48 
Window in Days 
± 28 
± 28 
± 28 
± 28 
± 28 
± 28 
± 28 
± 28 
Creatinine [CL] b 
X 
X 
X 
X 
X 
X 
X 
X 
Biopsy-confirmed AMR (yes/no)c 
X 
X 
X 
X 
X 
X 
X 
X 
EQ-5D-3L Questionnaire 
 
X 
 
X 
 
X 
 
X 
Allograft Failure d 
X 
X 
X 
X 
X 
X 
X 
X 
Subject Survival 
X 
X 
X 
X 
X 
X 
X 
X 
AMR = antibody-mediated rejection; [CL] = central laboratory; DSA = donor-specific antibodies; eCRF = electronic case 
report form; EoS = End of Study. 
Note 1: Assessment of DSA and/or allograft biopsy will be conducted as per local standard of care.  
Note 2: Data for subjects entering the Non-responder Follow-up period prior to Amendment 3 can be collected from medical 
history within 60 days of study entry. Data for subjects who enter after Amendment 3 will be collected prospectively. 
Footnotes to the Schedule of Assessments (Non-responder Follow-up Period):  
a  If a subject is withdrawn from the study for any reason during the Non-responder Follow-up Period, then the investigator 
should make every effort to perform the assessments scheduled for the Month 48 Visit. 
b  Creatinine will be measured by the central laboratory for prospectively collected samples from subjects who enter the 
Non-responder Follow-up Period after Amendment 3. Creatinine values may be obtained retrospectively from medical 
records if samples cannot be drawn prospectively. 
c Occurrence of biopsy-confirmed AMR (Section 8.1.3.3) since the last visit, based on documentation in the subject’s 
medical record. Responses will be recorded in the eCRF. 
d  The definition of allograft failure is presented in Section 8.1.3.7. 
 
 


CSL Behring LLC 
CSL842_3001 
C1-esterase Inhibitor, Human (500 IU/mL) 
Substantial Amendment 3 
 
Page 20 of 131 
Date: 31 Jan 2020 
Confidential 
Table 5 
Schedule of Assessments: Blinded Retreatment Period 
Study Period 
Retreatment Period (Blinded) 
Study Visit 
 
EoRP a 
Retreatment Week 
1 
4 
8 
12 
16 
22 
26 
Retreatment Day 
1 
7 
28 
56 
84 
112 
154 
182 
Window in Days 
 
± 2 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
Physical Examination b 
X 
 
 
 
X 
 
 
X 
Vital Signs 
X 
 
 
 
X 
 
 
X 
Blood 
Draws 
Pregnancy Testc 
X 
 
X 
X 
X 
X 
X 
X 
Retention Sample d 
X 
 
 
 
 
 
 
X 
Creatinine [CL] e 
X 
X 
X 
X 
X 
X 
X 
X 
Subcutaneous Investigational Product f 
 
Intravenous Immunoglobulin (IVIg) g 
X 
 
X 
X 
X 
X 
X 
 
Dispense Investigational Product h 
X 
X 
X 
X 
X 
X 
X 
 
Subjects Return Used Investigational Product i 
 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
 
Concomitant Therapies 
 
AMR = antibody-mediated rejection; C1-INH = C1-esterase Inhibitor, Human (500 IU/mL); [CL] = central laboratory; 
DSA = donor-specific antibodies; EoRP = End of Retreatment Period; GFR = glomerular filtration rate; IVIg = intravenous 
immunoglobulin; MFI = mean fluorescence intensity. 
Note 1:  Subjects may undergo retreatment during the Responder Follow-up Period with the blinded investigational product 
in Treatment Period 2. Retreatment may occur following a diagnosis of recurrent or persistent AMR by biopsy, 
evidenced by infiltrating neutrophils and/or monocytes with or without the presence of C4d (g > 0, v > 0, and/or 
ptc > 0; if C4d is negative, g + ptc ≥ 2 ). Retreatment may start at any time during the Responder Follow-up 
Period, and will last for 25 weeks or until the Month 48 Visit, whichever occurs first. The Retreatment Period may 
also be shorter than 25 weeks at the investigator’s discretion. Following blinded retreatment, subjects will enter the 
Responder Follow-up Period.  
Note 2: All procedures conducted during a Retreatment Period should be completed before the administration of C1-INH, 
except for the administration of IVIg, unless otherwise noted. 
Note 3: Assessment of DSA will be conducted as per local standard of care.  
Footnotes to the Schedule of Assessments (Retreatment Period): 
a  If a subject is withdrawn from the study for any reason during a Retreatment Period, then the investigator should make 
every effort to perform the assessments scheduled for the Retreatment Week 26 Visit. In addition, investigators should 
contact these subjects by telephone approximately 30 days after the Retreatment Week 26 Visit (the End of Retreatment 
Period Visit) to collect follow-up safety information. 
b  A physical examination will be conducted per the investigator’s standard procedure, and will also include assessment of 
unilateral pain and/or swelling of the lower extremities for the purpose of screening for deep vein thrombosis.  
c Serum pregnancy tests will be conducted at Retreatment Day 1 and Week 26 (EoRP). Urine or serum pregnancy tests 
should be conducted at all other timepoints. 
d  A blood sample will be retained for potential future serology assessments.  
e  Creatinine will be measured by the central laboratory. 
f  Subcutaneous investigational product (C1-INH or placebo) will be administered as per the randomization schedule every 
3 or 4 days (ie, twice weekly) at the study site, at home by a medical professional, or by the subject under the supervision 
of a medical professional.  
g  If DSA ≥ 2000 MFI, intravenous immunoglobulin may be administered at a dose of 2 grams/kg. Administration of the 
dose will begin at the visit. The dose must be administered over a minimum period of at least 2 days, and may be 
administered over a period of up to 5 days.  
h  If investigational product will be administered off-site after the completion of the visit, then it will be dispensed to the 
subject. 


CSL Behring LLC 
CSL842_3001 
C1-esterase Inhibitor, Human (500 IU/mL) 
Substantial Amendment 3 
 
Page 21 of 131 
Date: 31 Jan 2020 
Confidential 
i  Throughout a Retreatment Period, subjects should return any used or partially used vials of investigational product. 
Subjects should then return all vials (ie, used, partially used, and unused) of investigational product at the Week 26 
Retreatment Visit.  
 


C S L Be hri n g L L C  
C S L 8 4 2 _ 3 0 0 1  
C 1 -ester ase I n hi bit or, H u m a n ( 5 0 0 I U/ m L)  
S u bsta ntial A me n d me nt 3  
 
Pa ge 2 2  of 1 3 1  
Date: 3 1 Ja n 2 0 2 0  
C o nfi d e ntial 
Ta ble 6  
Sc he d ule of Assess me nts: Se q ue nti al P h ar m ac o ki netic / 
 S a m pli n g C o n d ucte d i n a S u bset of S u bjects 
Acti vit y  
Ti me p oi nt  
Ti me p oi nt Wi n d o w  
D a y 1 0 Visit ( D a y 1 0 ± 1 D a y)  
Bl o o d Dra w  
- 3 0 mi n utes  
± 3 0 mi n utes  
I ntra ve n o us A d mi nistrati o n of C 1 -I N H 6 0 I U/ k g  
0 mi n utes  
N A  
Bl o o d Dra w  
1 5 mi n utes  
± 5 mi n utes  
Bl o o d Dr a w 
3 h o urs  
± 3 0 mi n utes  
Bl o o d Dra w  
8 h o urs  
± 1 h o ur  
Bl o o d Dra w  
2 4 h o urs  
± 6 h o urs  
Bl o o d Dra w  
4 8 h o urs  
± 6 h o urs  
Bl o o d Dra w  
7 2 h o urs  
± 6 h o urs  
Wee k 1 1 Visit  ( D a y 7 7 ± 2 D a ys) 
Bl o o d Dra w  
- 3 0 mi n utes  
± 3 0 mi n utes  
S u bc uta ne o us A d mi nistrati o n of C 1 -I N H 6 0 I U/ k g  
0 mi n utes  
N A  
Bl o o d Dra w  
2 4 h o urs  
± 6 h o urs  
Bl o o d Dra w  
4 8 h o urs  
± 6 h o urs  
Bl o o d Dra w  
7 2 h o urs  
± 6 h o urs  
C 1 -I N H = C 1-esterase I n hi bit or, H u ma n ( 5 0 0 I U/ m L).  
N ote 1:   All bl o o d dra ws will be ti me d relati ve t o t he start of C 1 -I N H a d mi nistrati o n.  
N ote 2:   
 
 
 
 
C CI
C CI


C S L Be hri n g L L C  
C S L 8 4 2 _ 3 0 0 1  
C 1 -ester ase I n hi bit or, H u m a n ( 5 0 0 I U/ m L)  
S u bsta ntial A me n d me nt 3  
 
Pa ge 2 3  of 1 3 1  
Date: 3 1 Ja n 2 0 2 0  
C o nfi d e ntial 
Ta ble of C o nte n ts 
List of Pers o n nel a n d Or ga nizati o ns Res p o nsi ble f or C o n d uct of t he St u d y  ............................. 2  
Re visi o n Hist or y  ........................................................................................................................ 3  
Pr ot oc ol S y n o psis  ...................................................................................................................... 7  
Ta ble of C o nte nts  ..................................................................................................................... 2 3  
List of Ta bles  ............................................................................................................................ 2 7  
List of Fi g ures  .......................................................................................................................... 2 8  
List of A p pe n dices  ................................................................................................................... 2 8  
List of A b bre viati o ns  ............................................................................................................... 2 9  
C o n ve nti o ns  ............................................................................................................................. 3 1  
1  I ntr o d ucti o n ....................................................................................................................... 3 2  
1. 1  
Bac k gr o u n d  ................................................................................................................... 3 2  
1. 2  
Bac k gr o u n d I nf or mati o n o n C 1 -esterase i n hi bit or ........................................................ 3 3  
1. 2. 1  
O ver vie w  ................................................................................................................... 3 3  
1. 2. 2  
N o ncli nical E val uati o n  .............................................................................................. 3 4  
1. 2. 3  
Cli nical E x perie nce wit h C 1 -I N H i n Tra ns pla nt ....................................................... 3 4  
1. 3  
St u d y O ver vie w  ............................................................................................................. 3 6  
1. 4  
P ote ntial Ris ks a n d Be nefits  .......................................................................................... 3 7  
2  St u d y O bjecti ves a n d E n d p oi nts  ........................................................................................ 3 9  
2. 1  
Pri mar y O bjecti ve a n d E n d p oi nt  ................................................................................... 3 9  
2. 1. 1  
Pri mar y O bjecti v e ...................................................................................................... 3 9  
2. 1. 2  
Pri mar y E n d p oi nt  ...................................................................................................... 3 9  
2. 2  
Sec o n dar y O bjecti ves a n d E n d p oi nts  ............................................................................ 3 9  
2. 2. 1  
Sec o n dar y O bjecti ves  ................................................................................................ 3 9  
2. 2. 2  
Sec o n dar y E n d p oi nts  ................................................................................................. 4 0  
2. 3  
2. 3. 1
2. 3. 2
3  St u d y O ver vie w  ................................................................................................................. 4 3  
3. 1  
St u d y Desi g n  ................................................................................................................. 4 3  
3. 2  
D ose a n d D osi n g Re gi me n  ............................................................................................ 4 5  
C CI


CSL Behring LLC 
CSL842_3001 
C1-esterase Inhibitor, Human (500 IU/mL) 
Substantial Amendment 3 
 
Page 24 of 131 
Date: 31 Jan 2020 
Confidential 
3.3 
Scientific Rationale ....................................................................................................... 47 
3.3.1 
Study Design Rationale ............................................................................................. 47 
3.3.2 
Dose Rationale .......................................................................................................... 49 
3.4 
Planned Study Duration................................................................................................. 50 
3.5 
Planned Number of Subjects and Sites ......................................................................... 51 
3.6 
Definition of End of the Clinical Study......................................................................... 51 
3.7 
Study Oversight ............................................................................................................. 51 
3.7.1 
Data Monitoring Committee(s) ................................................................................. 51 
3.8 
Study Stopping Criteria for a Thromboembolic Event ................................................. 52 
4 
Selection and Withdrawal of Subjects ............................................................................... 52 
4.1 
Eligibility Criteria .......................................................................................................... 52 
4.1.1 
Inclusion Criteria ....................................................................................................... 52 
4.1.2 
Exclusion Criteria ...................................................................................................... 53 
4.2 
Discontinuation of Treatment and/or Subject Withdrawal ............................................ 55 
4.2.1 
Reasons for Discontinuation of Treatment and/or Subject Withdrawal .................... 55 
4.2.2 
Procedures for Handling Withdrawals ...................................................................... 55 
4.2.3 
Replacement Policy ................................................................................................... 56 
5 
Study Interventions ............................................................................................................ 56 
5.1 
Description of Investigational Product(s) ...................................................................... 56 
5.1.1 
C1-esterase Inhibitor, Human (500 IU/mL) .............................................................. 56 
5.1.2 
Placebo ...................................................................................................................... 57 
5.2 
Packaging, Labeling, Supply and Storage ..................................................................... 57 
5.2.1 
Packaging and Labeling ............................................................................................ 57 
5.2.2 
Supply and Storage .................................................................................................... 57 
5.2.3 
Direct to Patient ......................................................................................................... 58 
5.3 
Accountability and Destruction ..................................................................................... 58 
5.4 
Other Intervention(s) ..................................................................................................... 59 
5.4.1 
Intravenous Immunoglobulin .................................................................................... 59 
5.4.2 
Plasmapheresis .......................................................................................................... 59 
5.5 
Dose Modification ......................................................................................................... 60 
6 
Allocation, Dosing, and Administration ............................................................................ 60 
6.1 
Allocation to Treatment ................................................................................................. 60 
6.1.1 
Subject Assignment ................................................................................................... 60 


C S L Be hri n g L L C  
C S L 8 4 2 _ 3 0 0 1  
C 1 -ester ase I n hi bit or, H u m a n ( 5 0 0 I U/ m L)  
S u bsta ntial A me n d me nt 3  
 
Pa ge 2 5  of 1 3 1  
Date: 3 1 Ja n 2 0 2 0  
C o nfi d e ntial 
6. 1. 2  
Ra n d o mizati o n Pr oce d ures  ........................................................................................ 6 0  
6. 1. 3  
Bli n di n g Pr oce d ures  .................................................................................................. 6 1  
6. 2  
D osi n g a n d A d mi nistrati o n  ............................................................................................ 6 2  
6. 3  
Treat me nt C o m plia nce  .................................................................................................. 6 2  
7  C o ntrai n dicati o ns, Per mitte d T hera pies, a n d Pr o hi bite d T hera pies  .................................. 6 2  
7. 1  
C o ntrai n dicati o ns a n d Preca uti o ns t o F urt her D osi n g  ................................................... 6 2  
7. 2  
Per mitte d T hera pies  ....................................................................................................... 6 2  
7. 3  
Pr o hi bite d T hera pies  ...................................................................................................... 6 2  
7. 4  
Lifest yle Restricti o ns  ..................................................................................................... 6 3  
7. 5  
O ver d ose  ........................................................................................................................ 6 4  
8  St u d y Pr oce d ures a n d Visit Sc he d ule  ................................................................................ 6 4  
8. 1  
Cli nical Pr oce d ures ........................................................................................................ 6 4  
8. 1. 1  
De m o gra p hics a n d Safet y Assess me nts  .................................................................... 6 5  
8. 1. 2  
P har mac o ki netic a n d 
 Assess me nts ............................................. 6 6  
8. 1. 3  
Efficac y Assess me nts  ................................................................................................ 6 7  
8. 1. 4  
Healt h -relate d Q ualit y of Life Assess me nts .............................................................. 7 1  
8. 2  
Bl o o d Sa m ples  ............................................................................................................... 7 2  
8. 3  
Rete nti o n of Sa m ples ..................................................................................................... 7 2  
8. 4  
Pri or a n d C o nc o mita nt T hera pies  .................................................................................. 7 3  
8. 5  
Visit Sc he d ule  ................................................................................................................ 7 3  
8. 5. 1  
Assess me nt Ti me Wi n d o ws  ....................................................................................... 7 3  
8. 5. 2  
Scree ni n g  ................................................................................................................... 7 3  
8. 5. 3  
Treat me nt Peri o d 1  .................................................................................................... 7 5  
8. 5. 4  
Treat me nt Peri o d 2  .................................................................................................... 8 3  
8. 5. 5  
Res p o n der F oll o w -u p Peri o d  ..................................................................................... 8 8  
8. 5. 6  
Retreat me nt Peri o d(s)  ................................................................................................ 9 0  
8. 5. 7  
N o n -res p o n der F oll o w-u p Peri o d  .............................................................................. 9 3  
8. 5. 8  
S u bject Wit h dra wal/ Disc o nti n uati o n  ......................................................................... 9 4  
9  A d verse E ve nts  .................................................................................................................. 9 5  
9. 1  
Defi niti o ns  ..................................................................................................................... 9 5  
9. 1. 1  
A d verse E ve nt  ........................................................................................................... 9 5  
9. 1. 2  
A d verse E ve nt of S pecial I nterest  ............................................................................. 9 6  
9. 1. 3  
Seri o us A d ve rse E ve nt ............................................................................................... 9 7  
C CI


C S L Be hri n g L L C  
C S L 8 4 2 _ 3 0 0 1  
C 1 -ester ase I n hi bit or, H u m a n ( 5 0 0 I U/ m L)  
S u bsta ntial A me n d me nt 3  
 
Pa ge 2 6  of 1 3 1  
Date: 3 1 Ja n 2 0 2 0  
C o nfi d e ntial 
9. 2  
Se verit y of A d verse E ve nts  ........................................................................................... 9 8  
9. 3  
Ca usalit y of A d verse E ve nts .......................................................................................... 9 8  
9. 4  
O bser vati o n Peri o d f or A d verse E ve nts  ........................................................................ 9 9  
9. 5  
F oll o w -u p of  A d verse E ve nts  ........................................................................................ 9 9  
9. 6  
A d verse E ve nt Re p orti n g  .............................................................................................. 9 9  
9. 6. 1  
A d verse E ve nts  .......................................................................................................... 9 9  
9. 6. 2  
Seri o us A d verse E ve nt Re p orti n g  ............................................................................ 1 0 0  
9. 6. 3  
Ot her Si g nific a nt E ve nt Re p orti n g  .......................................................................... 1 0 1  
9. 6. 4  
O ver d ose  .................................................................................................................. 1 0 1  
9. 6. 5  
Pre g na nc y a n d Breastfee di n g  .................................................................................. 1 0 1  
9. 7  
I R B/I E C Re p orti n g Re q uire me nts............................................................................... 1 0 2  
1 0  Statistics  ........................................................................................................................... 1 0 2  
1 0. 1  Sa m ple Size Esti mati o n  ............................................................................................... 1 0 2  
1 0. 1. 1  
Sa m ple Size Base d o n t he Pri mar y Efficac y E n d p oi nt  ........................................... 1 0 2  
1 0. 1. 2  
P o wer f or All o graft S ur vi val  ................................................................................... 1 0 3  
1 0. 1. 3  
Sa m ple Size Re -esti mati o n ...................................................................................... 1 0 4  
1 0. 2  Descri pti o n of St u d y A nal ysis Sets  ............................................................................. 1 0 5  
1 0. 2. 1  
Scree ne d A nal ysis Set  ............................................................................................. 1 0 5  
1 0. 2. 2  
E nr olle d A nal ysis Set  .............................................................................................. 1 0 5  
1 0. 2. 3  
I nte nt-t o-Treat A nal y sis Set ..................................................................................... 1 0 5  
1 0. 2. 4  
M o difie d I nte nt -t o-Treat A nal ysis Set  ..................................................................... 1 0 5  
1 0. 2. 5  
Safet y A nal ysis Sets  ................................................................................................ 1 0 5  
1 0. 2. 6  
P har mac o ki netic A nal ysis Set  ................................................................................. 1 0 6  
1 0. 2. 7  
 
1 0. 3  Statistical A nal yses a n d Met h o ds  ................................................................................ 1 0 6  
1 0. 3. 1  
Defi niti o ns  ............................................................................................................... 1 0 7  
1 0. 3. 2  
S u bject Dis p ositi o n a n d C haracteristics  .................................................................. 1 0 8  
1 0. 3. 3  
Eff icac y A nal yses .................................................................................................... 1 0 8  
1 0. 3. 4  
Safet y A nal yses  ....................................................................................................... 1 1 3  
1 0. 3. 5  
P har mac o ki netics A nal yses  ..................................................................................... 1 1 3  
1 0. 3. 6  
 
1 0. 3. 7  
 
1 0. 3. 8  
Ot her A nal yses  ........................................................................................................ 1 1 4  
1 0. 3. 9  
I nteri m A nal ysis ...................................................................................................... 1 1 4  
1 1  Q ualit y Ass ura nce  ............................................................................................................ 1 1 5  
C CI
C CI
C CI


C S L Be hri n g L L C  
C S L 8 4 2 _ 3 0 0 1  
C 1 -ester ase I n hi bit or, H u m a n ( 5 0 0 I U/ m L)  
S u bsta ntial A me n d me nt 3  
 
Pa ge 2 7  of 1 3 1  
Date: 3 1 Ja n 2 0 2 0  
C o nfi d e ntial 
1 2  Re g ulat or y a n d Et hics C o nsi derati o ns  ............................................................................. 1 1 5  
1 2. 1  Re g ulat or y C o nsi derati o ns  .......................................................................................... 1 1 5  
1 2. 2  I nstit uti o nal Re vie w B oar d/I n de pe n de nt Et hics C o m mittee ....................................... 1 1 5  
1 2. 3  S u bject I nf or mati o n a n d I nf or me d C o nse nt  ................................................................ 1 1 6  
1 2. 4  S u bject  C o nfi de ntialit y  ................................................................................................ 1 1 6  
1 2. 5  I n de m nit y a n d C o m pe nsati o n ...................................................................................... 1 1 6  
1 3  A d mi nistrati ve C o nsi derati o ns  ........................................................................................ 1 1 7  
1 3. 1  Cli nical Trial Researc h A gree me nt .............................................................................. 1 1 7  
1 3. 2  Cli nical St u d y Re gistrati o n a n d Res ults Discl os ure  .................................................... 1 1 7  
1 3. 3  I m ple me ntati o n of t he Pr ot oc ol/ Pr ot oc ol A me n d me nt(s) ........................................... 1 1 7  
1 3. 4  Pr ot oc ol De viati o ns  ..................................................................................................... 1 1 8  
1 3. 5  D oc u me ntati o n a n d Rec or d Kee pi n g  .......................................................................... 1 1 8  
1 3. 5. 1  
Data C ollecti o n  ........................................................................................................ 1 1 8  
1 3. 5. 2  
Data Q ualit y Ass ura nce  ........................................................................................... 1 1 8  
1 3. 5. 3  
Rec or d Rete nti o n  ..................................................................................................... 1 1 9  
1 3. 6  St u d y a n d Site Cl os ure  ................................................................................................ 1 1 9  
1 3. 7  Cli nical St u d y Re p ort  .................................................................................................. 1 1 9  
1 3. 8  Use of Data a n d P u blicati o ns  ...................................................................................... 1 2 0  
1 4  Refere nces  ....................................................................................................................... 1 2 1  
1 5  A p pe n dices  ...................................................................................................................... 1 2 6  
 
List of Ta bles  
Ta ble 1  
Sc he d ule of Assess me nts: Scree ni n g a n d O pe n -la bel Treat me nt Peri o d 1 ...... 1 3  
Ta ble 2  
Sc he d ule of Assess me nts: Bli n de d Treat me nt Peri o d 2  ................................... 1 6  
Ta ble 3  
Sc he d ule of Assess me nts: Res p o n der F oll o w -u p Peri o d  ................................. 1 8  
Ta ble 4  
Sc he d ule of Assess me nts: N o n -res p o n der F oll o w-u p Peri o d  .......................... 1 9  
Ta ble 5  
Sc he d ule of Assess me nts: Bli n de d Retreat me nt Peri o d  .................................. 2 0  
Ta ble 6  
Sc he d ule of Assess me nts: Se q ue ntial P har mac o ki netic / 
 
Sa m pli n g C o n d ucte d i n a S u bs et of S u bjects  .................................................. 2 2  
Ta ble 7  
Pri mar y E n d p oi nt  ............................................................................................. 3 9  
C CI


C S L Be hri n g L L C  
C S L 8 4 2 _ 3 0 0 1  
C 1 -ester ase I n hi bit or, H u m a n ( 5 0 0 I U/ m L)  
S u bsta ntial A me n d me nt 3  
 
Pa ge 2 8  of 1 3 1  
Date: 3 1 Ja n 2 0 2 0  
C o nfi d e ntial 
Ta ble 8  
Sec o n dar y E n d p oi nts  ....................................................................................... 4 0  
Ta ble 9  
 
Ta ble 1 0  
S u m mar y of A d mi nistrati o n of I n vesti gati o nal Pr o d uct  .................................. 4 5  
Ta ble 1 1  
Descri pti o n of C 1 -I N H .................................................................................... 5 6  
Ta ble 1 2  
Descri pti o n of Place b o  ..................................................................................... 5 7  
Ta ble 1 3  
St u d y Pr oce d ures: De m o gra p hics a n d Safet y Assess me nts  ............................. 6 5  
Ta ble 1 4  
P har mac o ki netic a n d 
 A nal ytes .......................................... 6 7  
Ta ble 1 5  
Se verit y of A d verse E ve nts  .............................................................................. 9 8  
List of Fi g ures  
Fi g ure 1  
St u d y O ver vie w  ............................................................................................... 4 4  
 
 List of A p pe n dices  
A p pe n di x 1  
Si g nat ure o n Be half of S p o ns or  ..................................................................... 1 2 6  
A p pe n di x 2  
Si g nat ure of Pri nci pal I n vesti gat or  ................................................................ 1 2 7  
A p pe n di x 3  
Ba nff 2 0 1 5 Sc ori n g S yste m f or A nti b o d y -me diate d Rejecti o n [ L o u p y et al, 
2 0 1 7]  .............................................................................................................. 1 2 8  
 
 
C CI
C CI


C S L Be hri n g L L C  
C S L 8 4 2 _ 3 0 0 1  
C 1 -ester ase I n hi bit or, H u m a n ( 5 0 0 I U/ m L)  
S u bsta ntial A me n d me nt 3  
 
Pa ge 2 9  of 1 3 1  
Date: 3 1 Ja n 2 0 2 0  
C o nfi d e ntial 
List of A b bre vi ati o ns  
A b bre vi ati o n  
Ter m  
A E  
A d verse E ve nt  
A M R  
A nti b o d y -me diate d Rejecti o n  
C 1 -I N H 
C S L Be hri n g’s C 1 -esterase I n hi bit or, H u ma n ( 5 0 0 I U/ m L)  
CI  
C o nfi de nce I nter val  
[ C L] 
Ce ntral La b orat or y  
C S L  
C S L Be hri n g L L C  
D S A  
D o n or -s pecific A nti b o d y 
e C R F 
Electr o nic Case Re p ort F or m  
e G F R 
Esti mate d Gl o mer ular Filtrati o n Rat e 
g  
Gl o mer ulitis [ Ba nff Cate g or y Sc ore]  
G B M  
Gl o mer ular base me nt me m br a ne  
G C P  
G o o d Cli nical Practice  
G F R  
Gl o mer ular Filtrati o n Rate  
H A E  
Here ditar y a n gi oe de ma  
H C V  
He patitis C Vir us  
H L A  
H u ma n Le u k oc yte A nti ge n  
H R  
Hazar d Rati o  
I C H 
I nter nati o nal C o u nci l f or Har m o nizati o n  
I D M C 
I n de pe n de nt Data M o nit ori n g C o m mittee 
I E C 
I n de pe n de nt Et hics C o m mittee 
I R B 
I nstit uti o nal Re vie w B oar d 
I R T 
I nteracti ve Res p o nse Tec h n ol o g y  
I T T 
I nte nt-t o-Treat  
I U 
I nter nati o nal U nits 
I V 
I ntra ve n o us 
I VI g 
I ntra ve n o us I m m u n o gl ob uli n  
M D R D  
M o dificati o n of Diet i n Re nal Disease  
M FI  
Mea n fl u oresce nce i nte nsit y  
P K  
P har mac o ki netic  
ptc  
Perit u b ular Ca pillaritis [ Ba nff Cate g or y Sc ore]  
P T C  
Perit u b ular Ca pillar y  
Ri S  
R u n -in Safet y  
R W S  
Ra n d o mize d Wit h dra wal Safet y  
C CI
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Abbreviation 
Term 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous 
Scr 
Serum Creatinine 
TEE 
Thromboembolic Events 
TG 
Transplant glomerulopathy 
TP1 
Treatment Period 1 
TP2 
Treatment Period 2 
U 
Units 
Note:  Throughout this document, abbreviations are used for all units of measure. These abbreviations are not 
defined at the first appearance in the text. 
 


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Conventions 
 Throughout the protocol, the active study product “C1-esterase Inhibitor, Human 
(500 IU/mL)” will be abbreviated “C1-INH”. Where referenced, other C1-esterase 
inhibitor products will be specified by their branded names (eg, Berinert, Cinryze) or 
using the terminology “C1-esterase inhibitor product”. 
 The terminology ‘Investigational Product’ is inclusive of both C1-INH and placebo, and 
excludes intravenously administered immunoglobulin. 
 Nomenclature for study visits will use the following conventions: 
 Scheduled study visits occurring during the first 2 weeks of the open-label Treatment 
Period 1 (TP1) will be referenced using days (eg, the Day 1 Visit, the Day 14 Visit, 
etc). 
 Scheduled study visits occurring after the first 2 weeks of the open-label TP1 and 
during the blinded Treatment Period 2 (TP2) will be referenced using weeks (eg, the 
Week 3 Visit, the Week 12 Visit, the Week 38 Visit, etc). 
 Scheduled study visits occurring during the Responder Follow-up Period will be 
referenced using months (eg, the Month 12 Visit, the Month 48 Visit, etc). 
 Scheduled study visits occurring during the first week of a Retreatment Period will be 
referenced using days and will be designated as retreatment visits (ie, the Day 1 
Retreatment Visit and the Day 7 Retreatment Visit). Scheduled study visits occurring 
after the first week of a Retreatment Period will be referenced using weeks and will 
be designated as retreatment visits (eg, the Week 2 Retreatment Visit, the Week 22 
Retreatment Visit, etc).  
 For the purposes of the conduct of this study, the following equivalencies will be used:  
 24 hours is equal to 1 day. 
 1 week is equal to 7 days.  
 1 month is equal to 28 days. 
 52 weeks is equal to 1 year. 
 In this protocol, the term ‘therapy’ (eg, prior and/or concomitant therapy) is inclusive of 
any intervention, medication, or other treatment that a subject may receive. 


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1 Introduction 
1.1 Background 
Antibody-mediated rejection (AMR) is associated with poor long-term allograft and patient 
survival [Takemoto et al, 2004; Dalla Vecchia et al, 1997; Emonds et al, 2000; Fine et al, 
1979; Stegall et al, 2011; Montgomery et al, 2011b]. Antibody-mediated rejection is mediated 
primarily by donor-specific antibody (DSA) directed against the human leukocyte antigen 
(HLA) class I and/or class II molecules present on the vascular endothelium and tubules of 
the transplanted kidney [Miller et al, 2004; Montgomery et al, 2011a; Pascual et al, 2008; 
Stegall et al, 2012; Gulleroglu et al, 2013]. This antibody-antigen interaction activates the 
classical complement pathway, resulting in direct cellular damage and initiation of an 
inflammatory response which results in further damage to the allograft [Burns et al, 2008; 
Grafals and Akalin, 2009; Stegall et al, 2011; Stegall et al, 2012]. Left unchecked, the 
endothelial damage caused by complement activation can result in allograft thrombosis, 
tissue necrosis, and endothelial cell detachment from the basement membrane, which is all 
characteristic histological features of AMR [Nguyen and Butani, 2013]. This early injury is 
later complicated by the proliferation of myofibroblasts leading to progressive scarring of the 
kidney graft [Gulleroglu et al, 2013]. This process eventually leads to transplant 
glomerulopathy (TG), as evidenced by double contouring of the glomerular basement 
membrane. These irreversible anatomical lesions, including intimal thickening of the 
peritubular capillaries (PTCs), permanently compromise allograft function [Colvin, 2007; 
Cornell et al, 2008; Kittleson and Kobashigawa, 2012; Nankivell and Alexander, 2010; 
Crespo et al, 2001; Loupy et al, 2017; Stites et al, 2015].  
Clinically, patients with AMR may have fever, fatigue, irritability, pain over the allograft site, 
and rapid onset of renal dysfunction (decrease in urine output and estimated glomerular 
filtration rate [eGFR]). Several risk factors have been associated with the occurrence of acute 
AMR; the patients at greatest risk are sensitized (DSA positive) to their donors after exposure 
to human HLA proteins through a prior transplant, blood transfusion, and/or pregnancy 
[Stegall et al, 2011; Lefaucheur et al, 2010; Eurotransplant, 2013]. Patients may also develop 
AMR post-transplant via (de novo) production of DSA in response to the allograft HLA 
proteins. Renal failure patients with DSA are generally excluded from receiving a transplant; 
therefore, AMR is a rare (5 to 7%), but serious and morbid complication of kidney 
transplantation. 


C S L Be hri n g L L C  
C S L 8 4 2 _ 3 0 0 1  
C 1 -ester ase I n hi bit or, H u m a n ( 5 0 0 I U/ m L)  
S u bsta ntial A me n d me nt 3  
 
Pa ge 3 3  of 1 3 1  
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T here are n o a p pr o ve d t hera pies f or A M R; h o we ver, i ntra ve n o us i m m u n o gl o b uli n (I VI g) 
t hera p y wit h plas ma p heresis ca n s uccessf ull y treat 5 0 t o 7 5 % of cases o n t he s h ort ter m 
[M o nt g o mer y et al, 2 0 1 6 ]. If o n g oi n g A M R is i na de q uatel y treate d, or is refract or y t o 
treat me nt, tra ns pla nt gl o mer ul o pat h y occ urs. C o nc urre ntl y, t here is a pr o gressi ve decli ne i n 
re nal f u ncti o n [Dja mali et al, 2 0 1 4 ] ma nifeste d b y decli ne i n gl o mer ular filtrati o n rate ( G F R) 
u ntil t he all o graft is l ost a n d dial ysis a n d/ or re -tra ns pla ntati o n is necessar y. 
Si nce D S A acti vates t he classical c o m ple me nt pat h wa y w hic h res ults i n i nfla m mati o n a n d 
e ve nt ual T G, c o m ple me nt i n hi biti o n s h o ul d pre ve nt t he da ma ge w hic h is ass ociate d wit h 
earl y graft l oss.
 
 
 
st u d y of c o m ple me nt i n hi biti o n s h o we d t hat l o n g-ter m s u p pressi ve t hera p y wit h a 
C 1 -esterase i n hi bit or pr o d uct c o ul d be use d t o resc ue patie nts wit h A M R refract or y t o I VI g 
a n d plas ma p heresis [ Vi glietti et al, 2 0 1 6a ]. T his pr ot oc ol see ks t o st u d y c o m ple me nt 
i n hi biti o n b y C 1 -esterase i n hi bit or i n a place b o -c o ntr olle d ma n ner as a treat me nt f or 
refract or y A M R i n re nal tra ns pla nt reci pie nts. 
1. 2  B ac k gr o u n d I nf or m ati o n o n C 1 -ester ase i n hi bit or  
1. 2. 1  O ver vie w  
C 1 -esterase i n hi bit or bel o n gs t o t he fa mil y of seri ne pr otease i n hi bit ors. It h as i m p orta nt 
i n hi biti n g p ote ntial o n se veral of t he maj or casca de s yste ms of t he h u ma n b o d y, i ncl u di n g t he 
c oa g ulati o n, c o m ple me nt, a n d c o ntact casca des, as well as t he fi bri n ol ytic s yste m. I n t he 
c o m ple me nt casca de s yste m C 1 -esterase i n hi bit or i nacti vates  its s u bstrates b y c o vale ntl y 
bi n di n g t o t he acti ve sites pre ve nti n g t he acti o ns of C 1r  (s u bc o m p o ne nt of c o m ple me nt 
c o m p o ne nt C 1), C 1s (acti vate d f or m of c o m ple me nt c o m p o ne nt C 1), a n d ma n ose -ass ociate d 
seri ne pr oteases. 
C 1 -esterase i n hi bit or is a s ol u ble, si n gle c hai n gl yc o pr otei n c o ntai ni n g 4 7 8 a mi n o aci d 
resi d ues or ga nize d i nt o t hree beta s heets a n d ei g ht or ni ne al p ha helices. T he hea vil y 
gl yc os ylate d m olec ule has a n a p pare nt m olec ular wei g ht of 1 0 5 k D, of w hic h t he 
car b o h y drate c hai ns c o m prise 2 6 % t o 3 5 %.  
C S L Be hri n g ’s C 1-esterase i n hi bit or pr o d uct (“C 1 -esterase I n hi bit or, H u ma n [ 5 0 0 I U/ m L] ”, 
a b bre viate d as “C 1 -I N H”) is h u ma n plas ma-deri ve d, a n d a vaila ble at a c o nce ntrati o n of 
5 0 0  I U/ m L after rec o nstit uti o n. A detaile d descri pti o n of t he c he mistr y, p harmac ol o g y, 
C CI


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S u bsta ntial A me n d me nt 3  
 
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efficac y, a n d safet y of C 1 -I N H is pr o vi de d i n t he I n vesti gat or’s Br oc h ure [C 1 -I N H 
( 5 0 0 I U/ m L) I n vesti gat or’s Br oc h ure, 2 0 19 ]. 
1. 2. 2  N o ncli nic al E v al u ati o n  
N o ncli nical st u dies of C 1 -esterase i n hi bit or pr o d ucts ha ve de m o nstra te d a n acce pta ble safet y 
pr ofile a n d p har mac o ki netic ( P K) pr o perties.  
I n n o ncli nical st u dies wit h t he c urre ntl y mar kete d C 1-esterase i n hi bit or pr o d uct Beri nert 
( C S L Be hri n g), C 1-esterase i n hi bit or was well t olerate d a n d n o t o xicit y was o bser ve d i n 
si n gle-d ose i ntra ve n o us (I V) t o xicit y st u dies i n rats a n d mice at d oses u p t o 6 0 0 0 I U/ k g, a n d 
i n a re peate d-d ose I V t o xicit y st u d y i n rats at a d ose of 2 0 0 I U/ k g f or 1 4 da ys [ C 1 -I N H 
( 5 0 0 I U/ m L) I n vesti gat or’s Br oc h ure, 2 0 19 ]. 
L ocal t o lera nce st u dies i n ra b bits were c o n d ucte d wit h Beri nert , i n vesti gati n g I V a n d 
s u bc uta ne o us ( S C) r o utes of a d mi nistrati o n [C 1 -I N H ( 5 0 0 I U/ m L) I n vesti gat or’s Br oc h ure, 
2 0 1 9 ]. N o treat me nt-relate d l ocal reacti o ns were o bser ve d at I V Beri nert  i njecti o n sites; 
er yt he ma a n d e de ma were o bser ve d at S C Beri nert  i njecti o n sites wit h a sli g htl y hi g her 
i nci de nce a n d/ or i nte nsit y w he n c o m pare d t o c o ntr ol sites. O verall, a si n gle I V, i ntra-arterial, 
S C, or i ntra m usc ular i njecti o n of Beri nert  was l ocall y well -t olerate d i n ra b bits. 
To i n vesti gate t he t hr o m b o ge nic p ote ntial of C 1 -esterase i n hi bit or pr o d ucts ( Beri nert a n d 
C 1 -I N H), t hr o m b o ge nicit y st u dies base d o n t he esta blis he d Wessler ra b bit m o del of ve n o us 
stasis-i n d uce d t hr o m b osis were c o n d ucte d [C 1 -I N H ( 5 0 0 I U/ m L) I n vesti gat or’s Br oc h ure, 
2 0 1 9 ]. P ote ntial pr o-t hr o m b otic effects of C 1 -esterase i n hi bit or  were st u die d f oll o wi n g I V 
a d mi nistrati o n, as t his r o ute of a d mi nistrati o n lea ds t o hi g her pea k plas ma le vels, w hic h are 
c o nsi dere d m ost rele va nt f or p ote ntial pr o -t hr o m b otic effects. F oll o wi n g si n gle I V 
a d mi nistrati o n of d oses u p t o 8 0 0 I U/ k g t o ra b bits, n o t hr o m b us f or mati o n c o ul d be o bser ve d.  
1. 2. 3  Cli nic al E x perie nce wit h C 1 -I N H i n Tr a ns pl a nt 
C 1 -esterase i n hi bit or pr o d u cts ha ve bee n st u die d i n ki d ne y tra ns pla nt patie nts f or t he 
treat me nt of ac ute A M R, pre ve nti o n of A M R, a n d f or t he treat me nt of refract or y A M R. Case 
re p orts a n d s mall cli nical trials ha ve bee n c o n d ucte d, 
 
 
C 1 -esterase i n hi bit or has bee n e val uate d f or t he pre ve nti o n of A M R i n H L A -se nsitize d 
ki d ne y tra ns pla nt reci pie nts. A p hase 1/ 2, e x pl orat or y, ra n d o mize d, place b o -c o ntr olle d, si n gle 
ce nter trial usi n g Beri n ert was c o n d ucte d i n 2 0 dese nsitize d ( pri or t o tra ns pla nt) s u bjects f or 
C CI


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the prevention of AMR following renal allograft transplantation [Vo et al, 2015]. Subjects 
received either 20 IU/kg Berinert or placebo intra-operatively (intravenously), then twice 
weekly for 7 doses. No subjects developed AMR in the Berinert group; 1 (10%) developed 
AMR in the placebo group at 1 month following treatment. At 6 months, 2 (20%) subjects 
developed AMR in the Berinert group; 3 (30%) developed AMR in the placebo group. 
Berinert was generally well tolerated in this population, with no study drug related serious 
adverse events (SAEs). 
Another C1-INH product (Cinryze; Shire Viropharma Incorporated) was evaluated as 
treatment in subjects with AMR. A phase 2b, multicenter, double-blind, randomized, 
placebo-controlled pilot study was conducted to evaluate the use of Cinryze as add-on 
therapy to standard of care (ie, IVIg/plasmapheresis) in 18 subjects with acute AMR 
[Montgomery et al, 2016]. Subjects received IV Cinryze (n = 9) or placebo (n = 9); treatment 
was 5000 U (approximately 60 U/kg) IV on Day 1 then 2500 U (approximately 30 U/kg) IV 
every other day (6 doses) for 2 weeks for a total of 20,000 units. Both groups showed similar 
improvements in histopathology parameters on biopsies (Banff Classification) obtained one 
week after cessation of study drug (Day 20). Seven of 9 (78%) subjects receiving Cinryze 
and 6 of 9 (67%) receiving placebo had resolution of their AMR; the most prominent feature 
of the improvement on biopsy was seen as a decrease in C4d staining. Cinryze-treated 
subjects achieved supra-physiologic C1-esterase inhibitor levels of a median 1.73-fold above 
normal, and Cinryze was considered to be generally well tolerated without any serious safety 
concerns. 
A prospective, historically matched controlled single-arm pilot study was conducted to 
evaluate the efficacy and safety of Berinert added to high-dose IVIg for the treatment of 
refractory AMR (nonresponsive to standard of care) in 6 subjects [Viglietti et al, 2016a]. 
Subjects received 20 IU/kg Berinert intravenously on Days 1, 2, and 3 and then twice weekly 
and 2 grams/kg IVIg (Privigen; CSL) every month for 6 months. All Berinert-treated subjects 
showed an improvement in eGFR after 6 months of treatment. At Month 6, study subjects 
with positive C4d staining in peritubular capillaries decreased from 83% (5/6) at baseline to 
17% (1/6) with treatment, and anti-HLA DSA C1q binding decreased from 100% (6/6) to 
17% (1/6). No death or allograft loss was observed in patients treated with Berinert. One 
SAE (gastrointestinal bleeding) occurred in 1 subject, which was considered not related to the 
study drug. One subject experienced an adverse event (AE) of an episode of deep vein 
thrombosis of a lower limb 5 months after inclusion in the study, which led to discontinuation 


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of Berinert. The episode was subsequently determined to be caused by local venous 
compression due to a popliteal cyst, and was considered not related to study drug. 
1.3 Study Overview 
Eligible subjects will enter into the open-label TP1, during which all subjects will receive 
C1-esterase Inhibitor, Human (500 IU/mL) (C1-INH) at a dose of 60 IU/kg (Table 1). 
Subjects who respond to treatment with C1-INH by Week 12 as assessed by pre-defined 
responder criteria (Section 8.1.3.2) will be randomized into TP2 of the study; those subjects 
who do not respond to treatment will enter a Non-responder Follow-up Period during which 
they will be followed up to 48 months following enrollment. Subjects who are responders 
will be randomized to receive either C1-INH or placebo during TP2 (Table 2). All subjects 
will receive standard of care treatment for AMR throughout TP1 and TP2, including IVIg 
2 grams/kg once every 4 weeks for at least the first 12 weeks of treatment, with 
plasmapheresis as needed. At the End-of-TP2 at Week 38, subjects will then enter a 39-month 
Responder Follow-up Period (Table 3). Subjects will receive treatment consistent with their 
local standard of care during the Responder Follow-up Period, and their allograft status, 
kidney function, and survival will be monitored. During the Responder Follow-up Period, 
recurrence or persistence of biopsy proven AMR recurrences may receive retreatment with 
blinded investigational product (in combination with standard of care) as part of Retreatment 
Period(s) (Table 5). 
While recognizing the need for a randomized placebo-controlled study to confirm the 
efficacy of C1-INH in this patient population, it would be unethical to withhold C1-INH 
therapy from patients already determined to be refractory to standard of care. Upfront 
randomization to placebo or cross over designs would not be appropriate, as subjects in the 
placebo cohort would continue to receive therapy deemed ineffective. A randomized 
withdrawal design allows for all study subjects to receive active treatment for a 
pre-determined period of time and randomization of subjects with a positive response at the 
end of the open label run-in allows for enrichment of the study population that would most 
benefit from complement inhibition. Randomization of responders to C1-INH or placebo 
would then confirm the efficacy of C1-INH as placebo subjects would be hypothesized to 
lose their response to investigational product over time. Any difference that emerges between 
the group receiving continued treatment and the group randomized to placebo would 
demonstrate the effect of the active treatment [International Conference on Harmonisation, 
2000]. Hence, this is a multicenter, double-blind, randomized-withdrawal, placebo-controlled 


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study to investigate the efficacy of C1-INH in the treatment of refractory AMR in renal 
allograft recipients.   
1.4 Potential Risks and Benefits  
Consistent safety of Berinert administered intravenously for the on-demand, acute treatment 
of hereditary angioedema (HAE) attacks has been observed in over 30 years of use. Since 
1985 to 04 August 2019, 1,506,583,576 IU of Berinert IV have been sold worldwide, 
corresponding to 1,004,389 standard doses and an estimated exposure of 83,699 patient 
years. Cumulatively since 2017 to 04 Aug 2019, 596,094,000 IU of Berinert SC have been 
sold worldwide, corresponding to 132,465 standard doses and an estimated exposure of 1274 
patient years. Post-marketing surveillance has shown that Berinert is safe and well tolerated 
when used at the recommended dosage for the treatment of acute HAE attacks. No case 
reports concerning proven Hepatitis A Virus, Hepatitis B Virus, Hepatitis C Virus (HCV), or 
Human Immunodeficiency Virus-1 or -2 infections resulting from the use of Berinert have 
been received. 
The PK of CSL Behring’s current formulation of C1-INH (500 IU/mL) and Berinert after IV 
and SC administration have been investigated in Phase 1 healthy volunteer studies and a 
Phase 2 study in HAE patients. An acceptable safety and local tolerability profile was 
demonstrated for C1-INH (500 IU/mL) in healthy and HAE subjects. Following IV and SC 
administrations of C1-INH (500 IU/mL) (1500 IU) and Berinert (1500 IU), there were no 
severe AEs, no SAEs, no clinically significant laboratory parameters, no thromboembolic 
events (TEEs), and no anti-C1-INH antibodies (including inhibitory antibodies). In two 
Phase 3 studies in HAE subjects, subcutaneous administration of 40 and 60 IU/kg of C1-INH 
(500 IU/mL) was well tolerated. No inhibitory antibodies to C1-INH, cases of anaphylaxis, or 
seroconversions for human immunodeficiency virus, hepatitis B virus, or HCV were 
identified during the study. Although noninhibitory antibodies to C1-INH were detected 
during the study, there was no apparent association between treatment and the detection of 
these antibodies. Injection site reactions and injection site pain occurred frequently and were 
the most commonly reported AEs in these studies. 
 
 
Risks associated with C1-esterase inhibitor products include hypersensitivity/anaphylactic-
type reactions, TEEs, and potential virus transmission: 
 Hypersensitivity/Anaphylactic-type Reactions: Hypersensitivity and anaphylactic-type 
reactions have been reported rarely with the use of C1-esterase inhibitor products in 


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patients with HAE. Hypersensitivity or anaphylactic reactions in this study population are 
expected to be rare because the subjects have normal, physiologic C1-esterase inhibitor, 
as opposed to in the HAE population. Nonetheless, anaphylaxis will be specifically 
monitored during this study. 
 Thromboembolic Events: Thromboembolic events have been occasionally reported 
following the use of C1-esterase inhibitor products, in particular in patients receiving 
off-label high doses of up to 500 IU/kg IV in the context of cardiac surgery and 
extracorporeal circulation [Arzteblatt, 2000]. At the doses to be used in this clinical study 
(60 IU/kg IV; 60 IU/kg SC), a causal relationship between TEEs and the use of 
C1-esterase inhibitor has not been established. Nonetheless, TEEs will be specifically 
monitored during this study. 
 Potential Virus Transmission: C1-INH contains human plasma-derived C1-esterase 
inhibitor and, therefore, has the potential for virus transmission to recipients. However, 
Berinert and C1-INH has a very high margin of virus safety with the risk of virus 
transmission minimized by donor selection and screening criteria, and by reducing 
enveloped and non-enveloped viruses using pasteurization, nanofiltration methods, and 
chromatography in the manufacturing process [De Serres et al, 2003]. Each subject will 
provide a retention sample before and after treatment with the investigational product for 
potential future serology assessments. 
Additional information on C1-INH can be found in the C1-INH investigator’s brochure 
[C1-INH (500 IU/mL) Investigator’s Brochure, 2019]. 
Without treatment, up to 90% of study subjects with refractory AMR would otherwise go on 
to lose their kidney graft and have associated mortality risk [Viglietti et al, 2016b]. Given the 
low probability of potential risks and the implementation of study procedures that will 
closely monitor the safety of study subjects, the associated benefit/risk assessment is 
acceptable for subjects who participate in the study. 


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2 Study Objectives and Endpoints 
2.1 Primary Objective and Endpoint 
2.1.1 
Primary Objective 
The primary objective of the study is to evaluate the efficacy of C1-INH in the treatment of 
refractory AMR in renal allograft recipients. 
2.1.2 
Primary Endpoint 
Table 7 
Primary Endpoint 
Endpoint 
Summary Measure 
Loss-of-response 
during TP2. 
Proportion of subjects with loss-of-response at the End-of-
TP2.  
Loss-of-response at the End-of-TP2 is defined as any 1 of the 
following 3 conditions: 
 End-of-TP2 eGFR (mean of Week 36 and Week 38 eGFR) 
that is not stable, defined as: 
o End-of-TP2 eGFR that is < 90% of the End-of-TP1 
eGFR for subjects whose End-of-TP1 eGFR (mean of 
Week 11 and Week 12 eGFR) is ≥ 100% of baseline;  
o End-of-TP2 eGFR that is < 90% of baseline for 
subjects whose end-of- TP1 eGFR is ≥ 90% of baseline 
and < 100% of baseline 
 Allograft failure (defined by allograft nephrectomy, or 
institution of permanent dialysis, or return to the transplant 
waitlist for renal transplant, whichever occurs first) 
 Subject death by any cause  
eGFR = estimated glomerular filtration rate; TP1= Treatment Period 1; TP2 = Treatment Period 2 
2.2 Secondary Objectives and Endpoints 
2.2.1 
Secondary Objectives 
The secondary objectives of the study are: 
1. To further evaluate the efficacy of C1-INH in the treatment of refractory AMR in renal 
allograft recipients. 
2. To evaluate the safety of C1-INH in the treatment of refractory AMR in renal allograft 
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3. To evaluate the PK of C1-INH during the treatment of refractory AMR in renal allograft 
recipients. 
2.2.2 
Secondary Endpoints 
Table 8 
Secondary Endpoints 
Secondary 
Objective 
Endpoints 
Summary Measure 
1 
All-cause 
allograft failure 
through the 
Responder 
Follow-up Period 
(key secondary). 
Proportion of subjects with all-cause allograft failure 
through the Responder Follow-up Period (ie, within 48 
months after enrollment). Allograft failure is defined as 
1 of the following (see also Section 8.1.3.7):  
 Allograft nephrectomy, institution of permanent 
dialysis, or return to the transplant waitlist for renal 
transplant, whichever occurs first, OR  
 Subject death by any cause. 
1 
Change in eGFR 
from baseline to 
TP1 
The difference between the End-of-TP1 eGFR and 
baseline eGFR. 
1 
Change in eGFR 
from TP1 to the 
End-of -TP2. 
The difference between the End-of-TP2 eGFR and the 
End-of-TP1 eGFR. 
1 
The rate of 
change of eGFR. 
The rate of change of eGFR during TP2 as defined by 
the slope of the mean regression of eGFR over time in 
TP2. 
1 
Time (weeks) to 
all-cause allograft 
failure through 
the Responder 
Follow-up Period 
(key secondary). 
Time (weeks) to all-cause allograft failure through the 
Responder Follow-up Period (ie, within 48 months after 
enrollment).  
1 
Responder status 
at the End-of-
TP1. 
Proportion of responders at the End-of-TP1. Response is 
defined as End-of-TP1 eGFR that is ≥ 20 mL/min/1.73 
m2 and ≥ 90% of the baseline eGFR. 
1 
Subject death 
through the 
Responder 
Follow-up Period. 
Proportion of subjects surviving through the Responder 
Follow-up Period. 


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Secondary 
Objective 
Endpoints 
Summary Measure 
2 
Any AE assessed 
as related to 
investigational 
product during 
TP1 and during 
TP2. 
Proportion of subjects with any AE assessed as related 
to investigational product. 
3 
Pre-dose C1-
esterase inhibitor 
functional activity 
at Day 1, Week 
12, and Week 38. 
Mean pre-dose C1-esterase inhibitor functional activity 
at Day 1, Week 12, and Week 38. 
3 
For the subset of 
subjects with 
sequential PK 
sampling, C1-
esterase inhibitor 
functional activity 
Cmax, and AUC0-t 
after IV and/or 
SC administration 
of C1-INH. 
C1-esterase inhibitor functional activity Cmax and AUC0-t 
for IV and SC administration. 
AE = adverse event; AUC0-t = area under the plasma-concentration time curve 0 to a definite time; Cmax = 
maximum concentration; eGFR = estimated glomerular filtration rate; IV = intravenous; PK = pharmacokinetic; 
SC = subcutaneous; TP1 = Treatment Period 1; TP2 = Treatment Period 2 


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2. 3  
 
2. 3. 1  
 
2. 3. 2  
 
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Pa ge 4 3  of 1 3 1  
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3  St u d y O ver vie w  
3. 1  St u d y Desi g n  
T his is a d o u ble -bli n d, ra n d o mize d -wit h dra wal, place b o -c o ntr olle d st u d y  c o nsisti n g of 
2  treat me nt peri o ds, a n d a Res p o n der  F oll o w -u p Peri o d d uri n g w hic h retreat me nt is per mitte d 
if nee de d: 
 D uri n g o pe n -la bel T P 1, all eli gi ble s u bjects will recei ve treat me nt wit h C 1 -I N H 
( 6 0 I U/ k g) i n c o m bi nati o n wit h sta n dar d of care f or 1 3 weeks. At t he c o ncl usi o n of T P 1 , 
s u bjects w h o de m o nstrate a treat me nt res p o nse (see Secti o n  8. 1. 3. 2 ) will be ra n d o mize d 
t o c o nti n ue i n t he st u d y i n T P 2. S u bjects w h o are c o nsi dere d n o n -res p o n ders will e nter 
t he N o n-res p o n der F oll o w-u p P eri o d d uri n g w hic h t he y will be f oll o we d f or u p t o 4 8 
m o nt hs . 
 D uri n g t he bli n de d T P 2, ra n d o mize d s u bjects will eit her c o nti n ue treat me nt wit h C 1 -I N H 
( 6 0 I U/ k g) or be gi n treat me nt wit h place b o ( b ot h i n c o m bi nati o n wit h I VI g a n d 
plas ma p heresis) f or 2 5 wee ks, acc or di n g t o t he ra n d o mizati o n sc he d ule.  
 At t he c o ncl usi o n of T P 2, ra n d o miz e d s u bjects will e nter t he Res p o n der  F oll o w -u p 
Peri o d, w here t he y will be o bser ve d f or a p pr o xi matel y 3 9 m o nt hs u ntil St u d y M o nt h 4 8.  
Ra n d o mize d s u bjects w h o e x perie nce a bi o ps y -pr o ve n A M R rec urre nce or w h o ha ve 
persiste nt A M R d uri n g t he Re p o n der  F oll o w -u p will be per mitte d t o u n der g o bli n de d 
retreat me nt wit h eit her C 1-I N H or place b o ( b ot h i n c o m bi nati o n wit h sta n dar d of care 
treat me nt). S u bjects w h o partici pate i n a Retreat me nt Peri o d will recei ve bli n de d 
i n vesti gati o nal pr o d uct ( C 1-I N H or place b o) acc or di n g t o t heir T P 2 treat me nt assi g n me nt, i n 
c o m bi nati o n wit h sta n dar d of care.  
T he rati o nale f or t his st u d y desi g n is prese nte d i n Secti o n 3. 3. 1 . 
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Figure 1 
Study Overview 
 
AMR = antibody-mediated rejection; C1-INH = C1-esterase inhibitor; human;IVIg = intravenous immunoglobulin; MFI = 
mean fluorescence intensity; TP1 = Treatment Period 1; Treatment Period 2 
Note: Post-treatment Follow-up Period is for responders. 
a Intravenous immunoglobulin (IVIg) will be administered every 4 weeks to all subjects at a dose of 2 grams/kg. The dose 
must be administered over a minimum period of at least 2 days, and may be administered over a period of up to 5 days. 
Plasmapheresis may be administered based on local DSA results and Principal Investigator’s judgement (Section 5.4.2). 
b Intravenous (IV) C1-INH (60 IU/kg) will be administered to each subject over the first 13 days of TP1for a total of 5 
doses. Thereafter, subcutaneous (SC) C1-INH (60 IU/kg twice weekly) will be administered to each subject for the 
remainder of TP1. 
c If DSA ≥ 2000 MFI in local lab in TP2 or Retreatment Period, IVIg may be administered to subjects at a dose of 
2 grams/kg every 4 weeks. The dose must be administered over a minimum period of at least 2 days, and may be 
administered over a period of up to 5 days. Plasmapheresis may be administered based on local DSA results and 
Principal Investigator’s judgement (Section 5.4.2). 
d During the TP2, eligible subjects will be randomized 1:1 to receive treatment with investigational product (C1-INH 
[60 IU/kg] or placebo) subcutaneously twice weekly.   
e Retreatment Period(s) are blinded and subjects will receive the same investigational product treatment assignment as 
received during Treatment Period 2. 
f Response is defined as an End-of-TP1 eGFR (mean of Week 11 and Week 12 eGFR) that is ≥ 20 mL/min/1.73 m2 and 
≥ 90% of the baseline eGFR (mean of Screening and the Day 1 eGFR) (Section 10.3.1).  
g AMR Recurrence or persistence in Responder Follow-up Period is proven by biopsy, evidenced by infiltrating 
neutrophils and/or monocytes with or without the presence of C4d (g > 0, v > 0, and/or ptc > 0 (if C4d is negative, g + 
ptc ≥ 2, Section 8.1.3.3). 
IVIg c + C1-INH d
IVIg c + Placebo d
IVIg a
+ 
C1-INH b
1º endpoint
assessed
Open-label
Treatment Period 1: 
13 weeks
Double-blind
Treatment Period 2: 
25 weeks
Post-treatment 
Follow-up Period:
39 months
End of 
Study
Non-responsef
Responsef
Non-responder follow-up until graft failure or up to 48 months
Retreatment Periodc,e
AMR 
Recurrence g
Re-enter 
Follow-up 
Period


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3.2 Dose and Dosing Regimen 
Table 10 
Summary of Administration of Investigational Product 
Timeframe 
Intravenous 
Administration 
Subcutaneous 
Administration 
Treatment Period 1: The Day 1 Visit to the Day 13 Visit a 
60 IU/kg C1-INH 
Not applicable 
Treatment Period 1: The Day 14 Visit to the Week 12 2nd 
dose a 
Not Applicable 
60 IU/kg C1-INH 
Treatment Period 2: Week 13 to the Week 38 Visit b 
Not Applicable 
60 IU/kg C1-INH 
OR 
0.12 mL/kg placebo 
Retreatment Period: The Retreatment Day 1 Visit to 
the Retreatment Week 26 Visitc 
Not Applicable 
60 IU/kg C1-INH 
OR 
0.12 mL/kg placebo 
IV = intravenous; SC = subcutaneous 
a Treatment Period 1 is open-label and each subject will receive C1-INH. C1-INH (60 IU/kg) will be administered IV to 
each subject over the first 13 days of Treatment Period 1 for a total of 5 doses. Thereafter, C1-INH (60 IU/kg twice 
weekly) will be administered SC to each subjects for the remainder of Treatment Period 1. The first dose of randomized 
investigational product will be administered to responders at the Week 13 Visit. 
b Treatment Period 2 is blinded and subjects will be randomized 1:1 to treatment with investigational product (C1-INH 
[60 IU/kg] or placebo) subcutaneously twice weekly. 
c Retreatment Period(s) are blinded and subjects will receive the same investigational product treatment assignment as 
received during Treatment Period 2. 
Note: Week 13 is the final visit of Treatment Period 1 for non-responders and the first visit of Treatment Period 2 for 
responders. 
Treatment Period 1 
C1-INH will be administered to all subjects during TP1 in an open-label manner. 
C1-INH will be administered intravenously to subjects at the Day 1, 4, 7, 10, and 13 Visits 
for a total of 5 doses. Intravenous C1-INH will be administered at the study site during site 
visits. 
Subcutaneous C1-INH will be administered every 3 to 4 days (ie, twice weekly) beginning at 
the Day 14 Visit and for the remainder of TP1. Subcutaneous C1-INH is required to be 
administered at the study site during site visits, but at other times may instead be 
administered at home by a medical professional (eg, a home visit nurse) or by the subject 
under the supervision of a medical professional. 


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Treatment Period 2 
Investigational product (ie, C1-INH or placebo) will be administered to all subjects during 
TP2 in a double-blind manner. 
Subcutaneous investigational product will be administered every 3 to 4 days (ie, twice 
weekly) during TP2. Subcutaneous C1-INH is required be administered at the study site 
during site visits, but at other times may instead be administered at home by a medical 
professional (eg, a home visit nurse) or by the subject under the supervision of a medical 
professional. 
Retreatment Period 
Subjects may undergo retreatment during the Responder Follow-up Period with the blinded 
investigational product to which they were randomized in TP2. Retreatment may occur 
following a diagnosis of recurrent or persistent AMR by biopsy, evidenced by infiltrating 
neutrophils and/or monocytes with or without the presence of C4d (glomerulitis [g] > 0, 
intimal arteritis [v] > 0, and/or peritubular capillaritis [ptc] > 0; if C4d is negative, g+ptc ≥ 2). 
Retreatment may start at any time during the Responder Follow-up Period, and will last for 
26 weeks or until the Month 48 Visit, whichever occurs first. The Retreatment Period may 
also be shorter than 26 weeks at the investigator’s discretion. 
During the Retreatment Period, SC investigational product will be administered twice weekly 
(approximately every 3 to 4 days). During the Retreatment Period (if needed), SC C1-INH 
will be administered either at the site or may be dispensed to the subject and administered SC 
at home either by a medical professional or by the subject under the supervision of a medical 
professional.  
Subcutaneous Administration of the Investigational Product 
Subcutaneous administration of the investigational product should be via a single SC 
injection in the abdomen, thigh, upper arm, or other appropriate location. The injection site 
should be changed for each new administration and should be at least 5 cm (2 inches) away 
from the previous injection site.  
The twice weekly administration of investigational product beginning at the Day 14 Visit and 
during any Retreatment Period (if applicable) should ideally be scheduled on fixed days of 
the week (eg, Monday and Thursday). The suggested interval between each administration of 
investigational product is 3 or 4 days (ie, twice weekly). In addition, the investigational 
product should ideally be administered at approximately the same time on each day. A missed 


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injection should be administered as soon as possible, unless within 24 hours of the next 
scheduled injection; in this situation, the missed injection should be omitted, and the 
administration of investigational product should occur at the next scheduled day and time. 
The volume of investigational product to be administered will be based on each subject’s 
body weight (from the Screening physical examination) and will not be adjusted during the 
study. 
3.3 Scientific Rationale 
3.3.1 
Study Design Rationale 
Antibodies directed against a transplanted donor organ (ie, DSA) activate the complement 
system, resulting in direct and indirect damage to the allograft. Complement-mediated 
damage as a result of AMR is recognized as an important cause of poor long-term allograft 
and patient survival.  
Although no therapies have been approved for the treatment of AMR, the current standard of 
care most commonly consists of intravenously administered immunoglobulin (IVIg) with or 
without plasmapheresis and/or rituximab. These regimens can result in acceptable short-term 
allograft survival for kidney transplant patients with AMR. However, approximately 25% of 
patients with AMR are refractory to standard therapies, and eGFR continues to decline 
despite first-line treatment [Viglietti et al, 2016a]. Approximately 20% of patients with active 
AMR have simultaneous chronic active AMR [Viglietti et al, 2018, Aubert et al, 2019], which 
is generally not amenable to treatment and whose natural history is progressive loss of 
function [Loupy and Lefaucheur, 2018]. In addition, approximately 50% of patients with 
active AMR have simultaneous chronic active T-cell mediated rejection [Viglietti et al, 
2018]. Not surprisingly, therefore, up to 90% of grafts in these patients fail within 4 years of 
the diagnosis of refractory AMR. The addition of complement inhibition therapy to standard 
of care has been reported in the literature to successfully treat acute AMR that is 
unresponsive to treatment with a standard of care regimen [Viglietti et al, 2016a].  
In that study, all subjects showed an improvement in eGFR as the key indicator of clinical 
response to complement inhibitor therapy. Estimated GFR is a functionally important, 
therapeutically relevant, and clinically accepted surrogate marker of allograft survival. In a 
recent AMR workshop sponsored by the FDA, GFR was considered as a potentially 
acceptable surrogate marker for pivotal clinical trial(s) of an interventional therapy to treat 
acute AMR [Archdeacon et al, 2011]. Studies in transplantation have shown that eGFR by the 


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Pa ge 4 8  of 1 3 1  
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M o dificati o n of Diet i n Re nal Disease ( M D R D) e q uati o n m ore acc uratel y reflecte d cli nical 
f u ncti o n t han meas ure d G F R b y p las ma i ot hala mate meas ure me nts [Tort oricci et al, 2 0 1 3 ]. 
F urt her, ot her met h o ds of meas uri n g G F R are c o m plicate d b y i nacc uracies ass ociate d wit h 
sa m ple c ollecti o ns a n d feasi bilit y c o ncer ns i n cli nical stu d y sce nari os. T h us, e G F R a p pears t o 
be t he m ost relia ble e n d p oi nt meas ure of ki d ne y all o graft f u ncti o n.  
T his p hase 3 pi v otal trial is desi g ne d t o assess t he efficac y a n d safet y of C 1 -I N H i n 
c o m bi nati o n wit h I VI g -c o ntai ni n g sta n dar d of care re gi me ns i n s u bjects t hat ha ve faile d 
sta n dar d of care t hera p y al o ne, a n d he nce, ha ve ver y li mite d o pti o ns t o pre ve nt all o graft 
fail ure. S u bject res p o nse will be assesse d b y para meters i ncl u di n g e G F R, all o graft fail ure, 
a n d deat h. As c urre nt treat me nt f or A M R var y b y ce nter a n d re gi o ns, t he bac k gr o u n d I VI g 
re gi me n is sta n dar dize d d uri n g t he st u d y t o re d uce varia bilit y. 
Refract or y A M R patie nts ha ve alrea d y faile d sta n dar d t hera p y, a n d t here is a si g nal t hat 
h u ma n plas ma -deri ve d C 1 -I N H has a n effect i n pre ve nti n g all o graft da ma ge i n ki d ne y 
tra ns pla nt patie nts wit h ac ute A M R all o wi n g f or i m pr o ve me nt i n re nal all o graft f u ncti o n 
[
 Vi glietti et al, 2 0 1 6a ]. T he m ost feasi ble a n d a p pr o priate desi g n of 
a n y ra n d o mize d place b o c o ntr olle d st u d y i n s u bjects wit h refract or y A M R is a n o pe n -la bel 
r u n-i n, ra n d o mize d wit h dra wal desi g n. I n t his st u d y desi g n, all s u bjects recei ve acti ve 
treat me nt beca use t heir u nres p o nsi ve ness t o sta n dar d t hera p y i n dicates t hat t he y w o ul d l ose 
t heir all o graft wit h o ut a d diti o nal i nter ve nti o n. Res p o n ders w o ul d t he n be ra n d o mize d t o 
eit her acti ve treat me nt or place b o i n or der t o test t he l o n ger ter m effects of C 1 -I N H t hera p y. 
A n y differe nce t hat e mer ges bet wee n t he gr o u p r ecei vi n g c o nti n ue d acti ve treat me nt a n d t he 
gr o u p ra n d o mize d t o place b o w o ul d t he n de m o nstrate t he effect of t he acti ve treat me nt 
[I nter nati o nal C o nfere nce o n Har m o nisati o n, 2 0 0 0]. 
Base d o n a pil ot st u d y of s u bjects wit h refract or y A M R [ Vi glietti et al, 2 0 1 6a ], all s u bjects 
s h o we d s o me i m pr o ve me nt of all o graft f u ncti o n b y 1 2 wee ks. T h us, t he o pe n la bel r u n -i n 
p orti o n of t his st u d y was li mite d t o 1 2 wee ks. F o ur of 6 s u bjects i n t hat st u d y re q uire d  
retreat me nt t o preser ve t heir all o graft f u ncti o n wit h s o me of t h ose retreate d se veral m o nt hs 
after cessati o n of C 1 -I N H t hera p y ( pers o nal c o m m u nicati o n). T h us, it was deter mi ne d 
necessar y t o o bser ve s u bjects o n i n vesti gati o nal pr o d uct f or at least 6 m o nt hs  after 
ra n d o mizati o n t o c o nfir m t he efficac y of c o nti n ue d C 1-I N H t hera p y i n t he bli n de d p orti o n of 
t his st u d y. 
S u bjects i n t his st u d y will ha ve bee n deter mi ne d “res p o n ders” t o C 1-I N H t hera p y if t heir 
e G F R at t he E n d -of -T P 1 ( mea n of Wee k 1 1 a n d Wee k 1 2) is sta ble, defi ne d as ≥ 9 0 % of 
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baseline and ≥ 20 mL/min/1.73m2 (see Section 10.3.1), since patients with refractory AMR 
would be expected to have declining eGFR. This may be considered a more realistic and 
clinically important indication of investigational product effect compared with an 
improvement of renal allograft function, particularly since the improvement seen in Vigletti’s 
pilot study with a sample size of 6 [Viglietti et al, 2016a] may not be reproducible in a larger, 
multicenter study. Loss of this response is the primary endpoint as determined by Week 38 
post-randomization, concurrent with end of investigational product therapy. Taking into 
account usual fluctuations of measured creatinine in transplant patients and standard 
deviations of accredited assays, loss-of-response has been defined using the criteria specified 
in Section 10.3.1. 
Because this study investigates the efficacy of C1-INH therapy on stabilizing allograft 
function diminished by acute AMR, it will be necessary to confirm this effect on long-term 
allograft survival to 4 years after enrollment. As investigational product will be tested as 
add-on therapy to standard of care, it is necessary to allow for the use of IVIg and / or 
plasmapheresis for all study subjects if the investigator deems it necessary. In such instances, 
study subjects may receive 5 plasmapheresis runs. Also, if there is evidence of recurrent 
AMR on any for-cause biopsy obtained in the Responder Follow-up Period (including the 
Week 38 biopsy), a subject may be retreated with the same investigational product the subject 
received in TP2 (ie, blinded C1-INH or placebo). 
3.3.2 
Dose Rationale 
C1-esterase inhibitor is consumed in the process of inhibiting complement; therefore, the 
initial IV dosing regimen is intended to rapidly attenuate AMR progression. The initial IV 
dosing regimen of C1-INH (60 IU/kg, 5 doses over 13 days) is based on the following 
in vitro and clinic data, and PK simulations:  
 In vitro studies show that an approximate 2-fold C1-INH increase above normal 
physiologic levels suppressed 90% of complement activity in rat and human plasma 
[C1-INH (500 IU/mL) Investigator’s Brochure, 2019]. Therefore, targeting C1-INH peak 
functional levels in AMR patients of approximately 2-fold above normal physiologic 
levels should inhibit approximately 90% of complement activity.  
 A total of 20,000 IU C1-INH, administered in 5 doses over 13 days, was administered to 
kidney allograft recipients with acute AMR. C1-esterase inhibitor functional activity 
reached a median of 1.73-fold higher than normal physiologic levels [Montgomery et al, 
2016]. 


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 C1-esterase inhibitor PK simulations estimate peak IV C1-esterase inhibitor functional 
levels of 2.3-fold above normal physiologic levels. 
The continued SC maintenance dosing regimen of C1-INH (60 IU/kg every 3 or 4 days) is 
based on the following:  
 Providing sustained average C1-INH levels of 1.5-fold above normal levels (based on PK 
simulation estimation), thereby maintaining suppression of complement activity by 
approximately 75%, and replacing endogenous C1-esterase inhibitor functional protein 
that is consumed due to the residual AMR inflammatory processes. 
 C1-esterase inhibitor PK simulations estimate mean peak SC C1-esterase inhibitor 
functional levels of 1.7-fold above normal physiologic levels. 
The planned dosing regimen is anticipated to be safe and effective based on existing in vitro 
and nonclinical data, as well as previous human experience in both kidney transplant and 
hereditary angioedema patients [Montgomery et al, 2016; Viglietti et al, 2016a; Vo et al, 
2015; C1-INH (500 IU/mL) Investigator’s Brochure, 2019]. 
3.4 Planned Study Duration 
The duration of the study for an individual subject is expected to be approximately 
210 weeks (48 months). This estimation is based on: 
 A 2-week Screening Period. 
 A 13-week open-label treatment period (TP1). 
 A 25-week double-blind treatment period (TP2). 
 Follow-up Periods 
o A 39-month (170 weeks) Responder Follow-up Period (up to 48 months 
following enrollment). 
o 45-month Non-responder Follow-up Period (up to 48 months following 
enrollment).  
The overall study duration (ie, first subject’s Screening Visit to last subject’s final study visit) 
is anticipated to be approximately 6 years. 


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3.5 Planned Number of Subjects and Sites 
Approximately 120 subjects (up to 175) are planned to participate in the open-label TP1 in 
order to randomize 60 subjects into the double-blind TP2.  
The study is planned to be conducted at approximately 35 sites globally. 
3.6 Definition of End of the Clinical Study 
The end of the clinical study (ie, completion of the study at all participating study sites) is 
defined as the date of the last visit of the last subject. 
3.7 Study Oversight 
3.7.1 
Data Monitoring Committee(s)  
The independent data monitoring committee (IDMC) is an independent expert advisory 
group consisting of medically qualified transplant nephrologists or surgeons with appropriate 
expertise in subjects with AMR, kidney transplant recipients, and/or evaluation of AEs and 
laboratory results relevant for detecting any possible safety issues, and a statistician. The 
IDMC is being utilized to provide an independent evaluation of the study at regular intervals 
with regard to the progress of the study and the safety data, namely for the incidence, 
frequency and nature of AEs, and in particular for TEEs. In particular, any systemic TEE, not 
associated with dialysis access or other vascular access devices, reported as related to the 
administration of investigational product by the investigator, will be reviewed ad hoc by the 
IDMC. The IDMC will adjudicate the causality assessment for the TEE based on the 
unblinded case report. In addition, the IDMC will review the primary efficacy endpoint data 
only at the planned interim analysis. Other data (eg, PK) may also be reviewed, as 
appropriate. Unblinding of data and provision of unblinded data to the IDMC will be 
performed by an independent statistical data analysis center that is not associated in any other 
way with the study. After this review, recommendations will be issued to CSL Behring (CSL) 
regarding the continuation of the study, eventual need for protocol modifications, or study 
termination.  
The analysis plan for all IDMC data reviews will be outlined in the IDMC charter. The 
composition, activities, and responsibilities of the IDMC will also be described in the IDMC 
charter. 


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3.8 Study Stopping Criteria for a Thromboembolic Event 
In the case of any systemic TEE, not associated with dialysis access or other vascular access 
devices, and reported as related to the administration of investigational product by the 
investigator, administration of the investigational product will be halted for that subject until 
the IDMC adjudicates the causality assessment for the TEE based on evaluation of the 
unblinded case report. However, dosing will continue for all other subjects who are already 
enrolled. Details of the IDMC adjudication process for TEE evaluation, as well as required 
timelines for the adjudication will be contained in the IDMC charter. 
All subjects will receive regular physical examinations, and will have medically appropriate 
follow-up for any sign of a TEE.  
The IDMC will meet on a regular basis and will have the opportunity to assess AEs per 
treatment assignment as it relates to the overall safety of the ongoing trial. 
4 Selection and Withdrawal of Subjects 
4.1 Eligibility Criteria 
The study population will be selected on the basis of the inclusion and exclusion criteria 
described in the sections below. Each subject must meet all of the inclusion criteria and none 
of the exclusion criteria for this study. Subject eligibility will 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 
To be enrolled into the study, subjects must meet all of the following inclusion criteria: 
1. Provide written informed consent and willing and able to adhere to all protocol 
requirements. 
2. At least 18 years of age at the time of providing written informed consent.  
3. Evidence of at least one DSA (to HLA class I and/or class II) 
4. Recipient of a kidney transplant from an ABO compatible or ABO incompatible donor, 
living or deceased. 
5. At least one of the following if clinical data are available: 
a. Achieved a steady-state, post-transplant eGFR ≥ 40 mL/min/1.73 m2  (as 
determined by local practice) within 60 days post-transplant, OR  


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b. A 50% increase in urine output with a 50% decrease in serum creatinine over the 
first 7 days post-transplant in subjects with slow or delayed graft function. 
6. Acute AMR, defined per Banff 2015 criteria [Loupy et al, 2017], on pre-enrollment 
kidney biopsy (performed within 90 days of enrollment), as the following: 
a. Histologic evidence of acute tissue inflammation with presence of neutrophils 
and/or monocytes (g > 0, v > 0, and/or ptc > 0), AND  
b. C4d positive or, if C4d negative, then g + ptc ≥ 2. 
NOTE: Subjects who have mixed cellular rejection with AMR are eligible for 
participation. 
7. Acute AMR that is unresponsive (ie, no improvement in renal function as determined 
by the treating physician) after standard of care treatment: 
a. If standard of care treatment is ≥ 100 mg/kg IVIg and plasmapheresis (with or without 
rituximab): ≥ 7 days since the current AMR diagnosis at the Day 1 Visit, OR 
b. If standard of care treatment is ≥ 1 gram/kg IVIg without plasmapheresis (with or 
without rituximab): ≤ 45 days since the current AMR diagnosis. 
8. Subject must be willing and able to comply with the requirements of the study 
protocol. 
9. Investigator believes that the subject understands the nature, scope and possible 
consequences of the study.  
4.1.2 
Exclusion Criteria 
Subjects must not be enrolled into the study if they meet any of the following exclusion 
criteria: 
1. Recipient of an en bloc kidney transplant. 
2. Ongoing dialysis > 2 weeks at Screening. 
3. Hepatobiliary disease as indicated by 1 of the following: 
a. Viral hepatitis ie, positive for HCV or HBV confirmed by nucleic acid testing (if 
positive, subjects must be receiving or have received antiviral therapy and have no 
history of cirrhosis), OR 
b. Alanine aminotransferase > 3 times upper limit of normal, OR  
c. Total bilirubin > 1.5 times upper limit of normal. 
4. History of human immunodeficiency virus with acquired immunodeficiency syndrome 
at Screening.  


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5. Active bacterial or fungal infection that is clinically significant in the opinion of the 
investigator. 
6. Not otherwise explained thrombotic microangiopathy on pre-enrollment kidney 
biopsy. 
7. Known congenital bleeding or coagulopathy disorder.  
8. Evidence of non-catheter or non-dialysis access-related deep vein thrombosis, stroke, 
myocardial infarction, or arterial embolus within the 3 months before the Day 1 Visit; 
catheter-related thrombosis or history of clotting a dialysis access is NOT 
exclusionary, unless a  hereditary coagulopathy has been diagnosed. 
9. Treatment with a complement inhibitor (eg, Soliris [eculizumab], Berinert [C1-INH], 
Cinryze [C1-INH]), or experimental therapies for the treatment of AMR other than 
IVIg or rituximab (eg, bortezomib) within 14 days before administration of C1-INH at 
the Day 1 Visit. 
10. Current cancer or a history of cancer within 2 years before providing informed 
consent, with the exception of successfully treated non-metastatic basal or squamous 
cell carcinoma of the skin, in situ breast or other in situ lesions considered cured by 
therapy. 
11. Any medical condition that, in the opinion of the investigator, might interfere with the 
subject participation in the study, poses an added risk to the subject, or confounds the 
assessment of the subject. 
12. Female subjects who are pregnant (as evidenced by a positive serum pregnancy test for 
choriogonadotropin beta at Screening) or breast feeding. 
13. Female subject of childbearing potential or male subject not using or not willing to use 
a medically reliable method of contraception from the first dose of investigational 
product in any treatment period until 1 month after the last dose of investigational 
product in the same treatment period. 
NOTE: Childbearing potential and the acceptable methods of contraception are defined 
in Section 7.4. 
14. Participation in another interventional clinical study for AMR at Screening; subject 
may have been withdrawn from an AMR study at any time before Screening. 
15. Known or suspected hypersensitivity to the investigational product (ie, C1-INH or 
placebo), to any excipients of the investigational product, or to any other C1-esterase 
inhibitor preparation (eg, Berinert) or albumin preparation. 


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16. Involved in the planning and/or conduct of the study (applies to CSL staff, staff at the 
study site, and third-party vendors). 
4.2 Discontinuation of Treatment and/or Subject Withdrawal 
4.2.1 
Reasons for Discontinuation of Treatment and/or Subject 
Withdrawal 
Subjects may discontinue treatment with investigational product or withdraw from the study 
at any time at their own request, or at the discretion of the investigator or CSL for safety, 
behavioral or administrative reasons (eg, due to an AE, protocol deviation, loss to follow-up, 
subject noncompliance, study termination).  
In accordance with International Council for Harmonisation (ICH) principles of Good 
Clinical Practice (GCP), the investigator always has the option to advise a subject to 
withdraw from the study if the subject's safety or well-being is compromised by his or her 
further participation in the study. Concern for the interests of the subject must always prevail 
over the interests of the study.  
The investigator should record in the electronic case report form (eCRF) and in the subject's 
medical records the reason and date of subject withdrawal or discontinuation of treatment 
with investigational product. 
4.2.2 
Procedures for Handling Withdrawals 
If a subject declines further participation or is withdrawn from the study, attempts will be 
made to complete and document the assessments scheduled as described in Section 8.5.8.  
If the subject is withdrawn from the study after receiving Investigational Product, every effort 
will be made to ensure that the relevant safety assessments are completed. The subject may 
also be asked by the investigator to complete other study assessments. 
If a subject discontinues treatment with investigational product but remains in the study, they 
should complete follow-up assessments as detailed in the Schedule of Assessments. 
If the subject withdraws from the study, and also withdraws consent for disclosure of future 
information, CSL may retain and continue to use any data collected before such withdrawal 
of consent. CSL may also continue to collect the subject’s allograft function and survival 
information from the study site, with the subject’s consent. 


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4.2.3 
Replacement Policy 
Subjects withdrawn from the study following randomization will not be replaced. 
5 Study Interventions 
5.1 Description of Investigational Product(s) 
5.1.1 
C1-esterase Inhibitor, Human (500 IU/mL) 
Table 11 
Description of C1-INH 
Substance name 
C1-esterase Inhibitor, Human (500 IU/mL) 
Active substance 
C1-esterase inhibitor 
Trade name 
Not applicable 
Dosage form 
Lyophilized powder for reconstitution; 1500 IU C1-INH per 
single-use vial. 
Dose 
60 IU/kg  
Mode of administration 
Intravenous/subcutaneous injection 
C1-esterase Inhibitor, Human (500 IU/mL) will be manufactured by CSL in accordance with 
ICH Good Manufacturing Practice guidelines and local regulatory requirements. 
Before use, each vial of C1-INH is reconstituted with 3 mL water for injection. 60 IU/kg 
C1-INH is equivalent to a volume of 0.12 mL/kg. 
Instructions for reconstitution are presented in the Investigational Medicinal Product 
Handling Instructions. 
The dose of C1-INH will be based on the body weight obtained with vital signs assessment at 
the Screening Visit, and will not be changed throughout the study. The actual dose of C1-INH 
will be rounded to the lowest 500 IU, as this corresponds with a practical volume of 1 mL of 
C1-INH. Refer to the Investigational Medicinal Product Handling Instructions. 


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5.1.2 
Placebo 
Table 12 
Description of Placebo 
Substance name 
placebo 
Substance 
Excipients of C1-INH plus albumin 
Trade name 
Not applicable 
Dosage form 
Lyophilized powder for reconstitution 
Dose 
0.12 mL/kg 
Mode of administration 
Subcutaneous injection 
Placebo will be manufactured by CSL in accordance with ICH Good Manufacturing Practice 
guidelines and local regulatory requirements. 
Before use, each vial of placebo is reconstituted with 3 mL water for injection.  
Instructions for reconstitution are presented in the Investigational Medicinal Product 
Handling Instructions. 
The volume of placebo will be based on the body weight obtained with vital signs assessment 
at the Screening Visit, and will not be changed through the study. The actual dose of placebo 
will be rounded to the lowest 1 mL as if the subject receiving C1-INH. 
5.2 Packaging, Labeling, Supply and Storage 
5.2.1 
Packaging and Labeling 
The investigational products will be packaged and labeled according to current ICH Good 
Manufacturing Practice and GCP guidelines, and national legal requirements. 
The investigational product used in TP1 (ie, C1-INH only) will be packaged in a way to make 
it visually distinct from the investigational product used in TP2 (ie, C1-INH or placebo).  
5.2.2 
Supply and Storage 
The investigational product will be supplied to the study sites by CSL or delegate. 
The investigational product must be stored under temperature-controlled and monitored 
conditions at the predefined temperature range in a secure storage area as specified in the site 
Investigational Product Handling Instructions. 


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5.2.3 
Direct to Patient 
Investigational product may be shipped directly to the subject’s home in those countries 
where it is acceptable. To ensure proper patient data confidentiality a dedicated process with 
a special courier service will be implemented. 
5.3 Accountability and Destruction 
The investigational product must be used only as directed in the clinical study protocol. 
The investigator (or delegate) will confirm receipt of all shipments of investigational product 
in the interactive response technology (IRT). 
All supplies of investigational product must be accounted for throughout the study. 
Records for the delivery of investigational product to the study site, the inventory at the study 
site, the use by each subject, and the destruction or return of investigational product to 
CSL/designee must be maintained by the investigator (or delegate) using the appropriate 
form or IRT. 
The investigator (or delegate) must provide reasons for any discrepancies in drug 
accountability. 
Used and partially used vials of investigational product will be collected, as applicable. Any 
unused, partially used, or empty vials of investigational product should not be destroyed until 
the drug accountability documentation or institution specific destruction procedure has been 
checked by the study monitor. Any destruction of investigational product must be 
documented and provided to CSL. 
All drug accountability records must be stored in the site file and must be readily available 
for inspection by the study monitor and/or auditor, and open to regulatory inspection at any 
time. 
Further details regarding accountability and destruction of investigational product are 
provided in the site Investigational Product Handling Instructions. 


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5.4 Other Intervention(s) 
5.4.1 
Intravenous Immunoglobulin 
During the open-label TP1, IVIg will be administered every 4 weeks at a dose of 2 grams/kg. 
The dose must be administered over a minimum period of at least 2 days, and may be 
administered over a period of up to 5 days. The administration of IVIg will begin on Study 
Day 1 with the following exceptions: 
1. For subjects who have received their last dose of IVIg < 1 gram/kg as part of standard 
of care within the 2 weeks before Study Day 1 OR 
2. For subjects who have received their last dose of IVIg ≥ 1 gram/kg as part of standard 
of care within the 4 weeks before Study Day 1 
For these subjects, the administration of IVIg will begin on the Week 4 Visit. 
During TP2 and Retreatment Period, IVIg may be administered if DSA ≥ 2000 mean 
fluorescence intensity (MFI) based on the clinical judgement of the investigator. 
The complete schedules for IVIg dosing during TP1, TP2, and any Retreatment Period are 
presented in Table 1, Table 2, and Table 5, respectively. 
All blood draws scheduled for the same visit as IVIg dosing should be taken BEFORE the 
initiation of IVIg dosing. 
If a scheduled dose of IV C1-INH is the same day as IVIg administration, it should be 
administered AFTER the IVIg dose. Subcutaneous C1-INH may be administered during an 
IVIg infusion. 
5.4.2 
Plasmapheresis 
Donor-specific antibodies will be measured in both the central and local laboratories (see 
Section 8.1.3.5). Central laboratory results will be used for analyses. Local laboratory results 
will be used by the investigator in addition to other clinical findings to make treatment 
decisions, including the initiation of plasmapheresis.  
Plasmapheresis should be performed if a subject has DSA with clinical significance based on 
the PI’s medical judgement.  


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The timing and duration of plasmapheresis should occur as per the local standard of care and 
be documented in the eCRF. The use of any replacement fluid should also be documented.  
If blood draws for laboratory testing (including PK samples) are scheduled at the same visit 
as plasmapheresis, blood samples should be taken BEFORE plasmapheresis. 
If a scheduled dose of C1-INH is the same day as plasmapheresis, it should be administered 
AFTER plasmapheresis.  
If plasmapheresis occurs during a scheduled IVIg administration, administration of IVIg 
should be postponed until the plasmapheresis session is complete. 
Donor-specific antibodies should be tested in the local laboratory within between 24 and 
72 hours after completing plasmapheresis. 
If the strongest DSA does not decrease by ≥ 50% of pre-plasmapheresis MFI, then 
plasmapheresis may be repeated, at the discretion of the investigator. 
5.5 Dose Modification 
Modifications of the C1-INH dose (ie, dose increase or dose decrease) are not permitted 
during the study. 
6 Allocation, Dosing, and Administration 
6.1 Allocation to Treatment 
6.1.1 
Subject Assignment 
After providing written informed consent, the subject will be issued with a study-level unique 
subject identification number. The subject identification number will be used to identify the 
subject for the duration of the study. Subject identification numbers will not be reassigned or 
reused. 
6.1.2 
Randomization Procedures 
All subjects will receive open-label C1-INH during TP1. Subjects who are eligible for TP2 
(ie, responder subjects, as defined in Section 8.1.3.2) will be assigned to either continued 
C1-INH or matched placebo in accordance with a computer-generated randomization list. 
Investigational product assigned in TP2 will be allocated on a 1:1 ratio. The randomization 
(permuted block) will be stratified on the following factors:  


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 DSA: sensitized prior to transplantation versus de novo; de novo is defined as the 
development of DSA after transplantation. In the case of both sensitized and de novo, 
the subject will be considered sensitized for stratification purposes. 
 AMR severity: severe versus non-severe (ie, all other severities); severe is defined as 
new onset oliguria (<400 cc/24 hours) or anuria with the current episode of AMR. 
Treatment assignment will be determined centrally. The randomization list will be generated 
and managed by the study’s IRT external service provider. A detailed user guide for the IRT 
will be available. 
6.1.3 
Blinding Procedures 
Treatment Period 1 is open-label.  
Treatment Period 2 is double-blind. The blind will be maintained during TP2 for 
investigational site staff, including investigators, and subjects, and CSL. 
The blind will be maintained for investigational site staff, including investigators, and 
subjects during the Responder Follow-up Period, and any Retreatment Periods. 
6.1.3.1 
Blinding Method 
Vials of investigational product (ie, either C1-INH or placebo) will be packaged identically 
and individual packages may be identified only by the kit number.  
Investigational product vials will be fully covered to avoid visual inspection of the contents 
by the subjects and study personnel. A standard procedure will be followed to completely 
reconstitute the lyophilized product to make up the solution. The solution will then be 
withdrawn through a filter and will be inspected in the syringe prior to administration. 
C1-INH or placebo will be administered in a blinded manner. 
A dose of 60 IU/kg C1-INH is equivalent to a volume of 0.12 mL/kg. In order to maintain the 
blind in TP2, the same volume of investigational product (ie, 0.12 mL/kg, rounded to the 
lowest mL) will be administered to all subjects regardless of treatment assignment. 
6.1.3.2 
Breaking the Blind for an Emergency 
In emergency situations involving the safety of the subject, the Investigator may break the 
blind using the IRT system. The reason for unblinding the randomization code must be fully 


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documented. Emergency unblinding will be performed using the IRT. Steps for navigating the 
IRT for emergency unblinding are defined in the IRT Manual. 
6.2 Dosing and Administration 
A description of the dose and dosing regimen of the investigational product can be found in 
Section 3.2. 
A description of the investigational product can be found in Section 5.1.  
6.3 Treatment Compliance 
Treatment compliance will be assessed using data captured in the eCRF including the date 
and time of the injection of investigational product (C1-INH or placebo) and the volume of 
investigational product that is administered. 
7 Contraindications, Permitted Therapies, and Prohibited Therapies 
7.1 Contraindications and Precautions to Further Dosing 
The investigational product is contraindicated in individuals who have manifested severe 
immediate hypersensitivity reactions, including anaphylaxis to C1-INH, albumin, or to any of 
the excipients of the investigational product (ie, C1-INH or placebo). 
7.2 Permitted Therapies 
The following therapies are PERMITTED during the study (note, this list is not intended to 
be all inclusive): 
 Maintenance immune suppression, steroid therapy, and anti-lymphocyte therapy licensed 
for clinical use, unless specifically prohibited in Section 7.3. 
 Prophylactic antibacterial, antifungal, and antiviral agents. 
 Prescribed medication(s) required for the management of chronic medical conditions. 
 Over the counter medications and dietary supplements.  
 Plasmapheresis, as described in Section 5.4.2. 
7.3 Prohibited Therapies 
The following therapies are NOT PERMITTED during TP1, TP2, and the Retreatment 
Period: 


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 Other C1-esterase inhibitor products (eg, Berinert, Cinryze). 
 Other complement inhibitors, including eculizumab. 
 Proteasome inhibitors, including but not limited to bortezomib, carfilzomib, and 
ixazomib. 
 Any immune suppression agent used to treat AMR that is not licensed for clinical use. 
 Administration of any other investigational agent during the study. 
Subjects are not to be enrolled into the study if they receive any prohibited therapy or any 
therapy in a prohibited dosage that cannot be discontinued or reduced to a permitted dose 
before enrollment.  
If administration of any prohibited therapy becomes necessary during the study for medical 
reasons, the subject may be withdrawn from further study participation. 
Subjects are not permitted to receive any prohibited therapies between the time of signing 
informed consent and the time of completing participation in the study. 
7.4 Lifestyle Restrictions  
Female subjects of childbearing potential and all male subjects must use medically reliable 
methods of contraception from the first dose of investigational product in any treatment 
period until 1 month after the last dose of investigational product in the same treatment 
period. 
Childbearing potential is assumed in all female subjects except: 
 Female subjects aged > 60 years. 
 Female subjects aged 45 to 60 years (inclusive) with amenorrhea for ≥ 1 year. 
 Female subjects who are surgically sterile for at least 3 months before providing informed 
consent. 
Acceptable methods of contraception are:  
 Abstinence, where abstinence is the preferred and usual lifestyle of the subject, including 
refraining from heterosexual intercourse during the entire period of risk associated with 
the investigational product. Periodic abstinence (calendar, symptothermal, postovulation 
methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhoea 
method are not acceptable definitions of abstinence. 


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 Hormonal methods; acceptable hormonal methods include: oral contraceptives, 
contraceptive medication patch, contraceptive medication injection, estrogen/progestin 
vaginal ring, or contraceptive medication implant. 
 2 barrier methods; acceptable barrier methods include: female or male condoms, with 
spermicidal foam or spermicidal jelly, or diaphragm, with spermicidal foam or 
spermicidal jelly. The female condom and male condom should not be used together. 
 Use of intrauterine device (placed more than 3 months before providing informed 
consent). 
 Surgical sterilization (more than 3 months before providing informed consent) of subject 
or subject's partner. 
7.5 Overdose 
Overdose is defined as the accidental or intentional infusion or ingestion of any dose of the 
investigation product that is higher than the dose established in this protocol. In a previous 
study of subjects with HAE, doses up to 6000 IU (up to approximately 120 IU/kg) were 
administered twice weekly for 4 weeks without any safety issues [C1-INH (500 IU/mL) 
Investigator’s Brochure, 2019].  
The effects of any potential overdose with C1-INH have not been otherwise studied. The 
development of thrombosis has been reported after IV administration of C1-INH doses up to 
500 IU/kg body weight when used off label in newborns and young children with congenital 
heart anomalies during or after cardiac surgery under extracorporeal circulation [Arzteblatt, 
2000]. 
In case of overdose, the subject should be closely monitored, and supportive treatment should 
be administered, as needed. See Section 9.6.4 for overdose reporting requirements. 
8 Study Procedures and Visit Schedule 
8.1 Clinical Procedures 
The timing and frequency of the clinical procedures described in the following sections are 
detailed in the following Schedules of Assessments: 
 Schedule of Assessments: Screening and Open-label Treatment Period 1 
 Schedule of Assessments: Blinded Treatment Period 2 
 Schedule of Assessments: Responder Follow-up 


C S L Be hri n g L L C  
C S L 8 4 2 _ 3 0 0 1  
C 1 -ester ase I n hi bit or, H u m a n ( 5 0 0 I U/ m L)  
S u bsta ntial A me n d me nt 3  
 
Pa ge 6 5  of 1 3 1  
Date: 3 1 Ja n 2 0 2 0  
C o nfi d e ntial 
 Sc he d ule of Assess me nts: N o n -res p o n der F oll o w-u p Peri o d  
 Sc he d ule of Assess me nts: Bli n de d Retreat me nt  Peri o d   
 Sc he d ule of Assess me nts: Se q ue ntial P har mac o ki netic / 
 Sa m pli n g 
C o n d ucte d i n a S u bset of S u bjects   
M ore fre q ue nt e val uati o ns ma y be perf or me d, if cli nicall y i n dicate d, at t he discreti o n of t he 
i n vesti gat or at u nsc he d ule d st u d y visits. T he s pecific pr oce d ures perf or me d at a n y 
u nsc he d ule d st u d y visit are at t he discreti o n of t he i n vesti gat or a n d are t o be ca pt ure d i n t he 
e C R F, i ncl u di n g re prese ntati ve all o graft bi o psies.  
8. 1. 1  De m o gr a p hics a n d S afet y Assess me nts  
T he cli nical pr oce d ures t o be c o n d ucte d d uri n g t his  st u d y relate d t o t he e val uati o n of 
p o p ulati o n de m o gra p hics a n d safet y are pr o vi de d i n  Ta ble 1 3 . Cli nical la b orat or y 
assess me nts are t o be perf or me d at ti me p oi nts as detaile d i n t he sc he d ule of assess me nts. 
T he ti me wi n d o ws f or eac h t y pe of assess me nt are detaile d i n Secti o n 8. 5. 1 . 
Ta ble 1 3   
St u d y Pr oce d ures: De m o gr a p hics a n d S afet y Assess me nts  
Assess me nt  
Descri pti o n  
De m o gra p hics  
 Date of birt h  
 Se x  
 Race  
 Et h nicit y  
Me dical hist or y  
 Rele va nt me dical hist or y wit hi n 6 m o nt hs bef ore i nf or me d c o nse nt  
 D oc u me ntati o n of date of bi o ps y  
 All o graft d o n or i nf or mati o n  
 Dia g n osis a n d disease stat us:  
o  
Tra ns pla nt hist or y  
o  
Pre vi o us e pis o des of rejecti o n  
o  
D oc u me ntati o n of t hr o m b otic micr oa n gi o pat h y a n d Ba nff cate g or y sc ores fr o m 
t he bi o ps y use d t o q ualif y f or e nr oll me nt 
o  
Ser u m creati ni ne dra w n at t he ti me of i ncl usi o n bi o ps y ( ± 2 wee ks)  
 Pri or t hera pies wit hi n 3 m o nt hs bef ore i nf or me d c o nse nt  
 C urre nt/c o nc o mita nt t hera pies  
Pr e g na nc y test  
 Uri ne or bl o o d test f or c h ori o g o na d otr o pi n beta, as i n dicate d f or w o me n of 
c hil d beari n g p ote ntial. 
P h ysical e xa mi nati o n   As per t he i n vesti gat or’s sta n dar d pr oce d ure, a n d i ncl u di n g assess me nt of u nilateral 
pai n a n d/ or s welli n g of t he l o wer e x tre mities 
A d verse e ve nts  
 Refer t o Secti o n 9  
C CI


C S L Be hri n g L L C  
C S L 8 4 2 _ 3 0 0 1  
C 1 -ester ase I n hi bit or, H u m a n ( 5 0 0 I U/ m L)  
S u bsta ntial A me n d me nt 3  
 
Pa ge 6 6  of 1 3 1  
Date: 3 1 Ja n 2 0 2 0  
C o nfi d e ntial 
Assess me nt  
Descri pti o n  
Vital si g ns  
 Bl o o d press ure (s yst olic a n d diast olic)  
 P ulse rate ( per mi n ute)  
 B o d y te m perat ure  
 B o d y wei g ht  
 B o d y hei g ht ( Scree ni n g o nl y)  
He mat ol o g y  
 He m o gl o bi n  
 He mat ocrit  
 Re d bl o o d cell i n dices: mea n c or p usc ular he m o gl o bi n, mea n c or p usc ular he m o gl o bi n 
c o nce ntrati o n, mea n c or p usc ular v ol u me (if a n y a vaila ble)  
 Bl o o d cell c o u nts: bas o p hils, e osi n o p hils, er yt hr oc ytes, le u k oc ytes, l y m p h oc ytes, 
m o n oc ytes, ne utr o p hils, n e utr o p hil ba n d f or ms (if a vaila ble), platelets, retic ul oc ytes 
(if a vaila ble) 
Ser u m bi oc he mistr y 
pa nel  
 Al b u mi n  
 Bl o o d urea nitr o ge n ( or Urea)  
 Al kali ne p h os p hatase  
 Calci u m  
 Gl uc ose  
 Ala ni ne a mi n otra nsferase  
 Car b o n di o xi de  
 P otassi u m  
 As partate a mi n otra nsf erase 
 C hl ori de  
 S o di u m  
 Bilir u bi n (t otal)  
 Creati ni ne  
 Pr otei n (t otal)  
 
N ote:  Creati ni ne will be meas ure d b y t he ce ntral  la b orat or y a n d as a part of t he ser u m 
bi oc he mistr y pa nel b y t he l ocal  la b orat or y. 
 
 
 
Vir us testi n g  
 He patitis pa nel  
o  
He patitis B c ore a nti b o d y (I g M)  
o  
He patitis B s urface a nti ge n wit h n ucleic aci d testi n g c o nfir mati o n  
o  
He patitis C a nti b o d y wit h n ucleic aci d testi n g c o nfir mati o n  
 Rete nti o n sa m ples ma y be teste d f or tra ns missi ble i nfecti o us a ge nts  
. 
8. 1. 2  P h ar m ac o ki netic a n d 
 Assess me nts 
P har mac o ki netic a n d  
 e val uati o ns will be c o n d ucte d d uri n g t he st u d y. Ta ble 1 4  prese nts a 
descri pti o n of t he a nal ytes t hat will be meas ure d. Ta ble 1 , Ta ble 2 , a n d Ta ble  3  prese nt t he 
ti mi n g of meas ure me nt f or eac h a nal yte.  
C CI
C CI
C CI
C CI


C S L Be hri n g L L C  
C S L 8 4 2 _ 3 0 0 1  
C 1 -ester ase I n hi bit or, H u m a n ( 5 0 0 I U/ m L)  
S u bsta ntial A me n d me nt 3  
 
Pa ge 6 7  of 1 3 1  
Date: 3 1 Ja n 2 0 2 0  
C o nfi d e ntial 
Ta ble 1 4  
P h ar m ac o ki netic a n d 
 A n al ytes 
Assess me nt  
Descri pti o n  
C 1 -esterase i n hi bit or acti vit y/a nti ge n  
 C 1 -esterase i n hi bit or a nti ge n c o nce ntrati o n.  
 C 1 -esterase i n hi bit or f u ncti o nal acti vit y.  
I m m u n o gl o b uli n c o nce ntrati o n 
 I m m u n o gl o b uli n c o nce ntrati o n. 
 
 
. 
 
. 
 
. 
 
. 
 
. 
 
8. 1. 3  Effic ac y Assess me nts  
Efficac y assess me nts c o n d ucte d d uri n g t he st u d y will i ncl u de:  
 e G F R.  
 Res p o n de r stat us (ie, res p o nse/l oss-of -res p o nse). 
 Bi o ps y hist o pat h ol o g y.  
 S ple nect o m y.  
 D S A . 
 
 
 All o graft fail ure.  
 S u bject s ur vi val.  
 
 
 De vel o p me nt of rec urre nt/ persiste nt A M R . 
8. 1. 3. 1  
Esti m ate d Gl o mer ul ar Filtr ati o n R ate (e G F R)  
Creati ni ne will be assesse d as a part of t he ser u m bi oc he mistr y pa nel or as a n i n de pe n de nt 
assess me nt. Creati ni ne meas ure me nts, i n a d diti o n t o w hat is pre -s pecifie d per pr ot oc ol, ma y 
be perf or me d as a part of sta n dar d of care.  
F or t he p ur p oses of deter mi ni n g e G F R f or t he pri mar y e n d p oi nt, creati ni ne will be meas ure d 
i n a ce ntral la b orat or y. Creati ni ne will be meas ure d usi n g a sta n dar dize d creati ni ne assa y 
cali brate d t o be tracea ble t o a n is ot o pe dil uti o n mass s pectr o metr y refere nce meas ure me nt 
pr oce d ure.  
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI


CSL Behring LLC 
CSL842_3001 
C1-esterase Inhibitor, Human (500 IU/mL) 
Substantial Amendment 3 
 
Page 68 of 131 
Date: 31 Jan 2020 
Confidential 
For purposes of determining eGFR at the time of inclusion biopsy and in non-responders 
during the Non-responder Follow-up Period prior to Amendment 3, creatinine measurements 
that are performed as part of clinical standard of care may be abstracted from the medical 
record.  
In addition, creatinine will also be measured in the local laboratory as part of the serum 
biochemistry panel or additionally at the discretion of the physician. If it is measured in the 
local laboratory, then the results should be documented in the eCRF.  
In all cases, eGFR will be calculated using the following MDRD formula [Levey et al, 2008]: 
eGFR =  [(175) x (standardized Scr-1.154) x (age-0.203) x (1.212, if black) x (0.742, if female)], 
where Scr is expressed as mg/dL 
Additional details regarding the assessment of eGFR will be presented in the laboratory 
manual. 
8.1.3.2 
Responder Status and Loss-of-Response 
Responder status in TP1 is determined at the Week 13 Visit to randomize subjects into the 
double-blind TP2. Only responders in TP1 are randomized.  
Responder status and loss-of-response at the End-of-TP2 are defined in Section 10.3.1.  
Central laboratory measurements of creatinine will be used for calculation of eGFR, except 
for creatinine values collected from the medical record (Section 8.1.3.1). Response and loss-
of-response will be determined by CSL. 


CSL Behring LLC 
CSL842_3001 
C1-esterase Inhibitor, Human (500 IU/mL) 
Substantial Amendment 3 
Page 69 of 131 
Date: 31 Jan 2020 
Confidential 
8.1.3.3 
Renal Allograft Biopsy 
Inclusion Biopsy 
The renal allograft biopsy used to determine inclusion into the study will have been 
performed as standard of care within 90 days before the Day 1 Visit. The diagnosis of AMR 
can be made > 90 days before Day 1 as long as the inclusion biopsy establishes that AMR is 
ongoing within 90 days of Day 1. Slides stained with hematoxylin and eosin stain, periodic 
acid-Schiff, trichrome stain, and silver stain or will be provided to the central histopathologist 
for evaluation as the baseline for comparison with the Week 38 biopsy. 
Week 38 Biopsy 
A biopsy will be performed at Week 38 (ie, the End-of-TP2), and will be compared to the 
inclusion biopsy to assess changes in histopathology. Where possible, a biopsy should also be 
performed for subjects who discontinue treatment before the Week 38 Visit. The central 
histopathologist will be blinded to treatment assignment beginning with TP2.  
Biopsy during the Responder Follow-up Period 
Subjects may have additional biopsies as part of their local standard of care treatment at any 
point during the study, including during the Responder Follow-up Period. A biopsy at the 
Week 38 Visit or during the Responder Follow-up Period that shows evidence of infiltrating 
neutrophils and/or monocytes with or without the presence of C4d (g > 0, v > 0, and/or ptc 
> 0; if C4d is negative, g + ptc ≥ 2) will qualify as an episode of acute AMR (see Appendix
3). A subject with a biopsy-proven persistent or recurrent episode of AMR may receive 
additional treatment according to their previous randomization (C1-INH or placebo) in 
addition to monthly IVIg (2 grams/kg) (Table 5). Slides of any biopsy taken during the 
Responder Follow-up Period documenting a persistent or recurrent episode of AMR will be 
provided to the central histopathologist. 
Histopathology 
Representative histopathology sections from each renal allograft biopsy will be processed 
with hematoxylin and eosin stain, periodic acid-Schiff, trichrome stain, and silver stain. In 
addition, frozen or formalin fixed biopsy sections will be processed for the presence of C4d 
by any immunoassay.  


C S L Be hri n g L L C  
C S L 8 4 2 _ 3 0 0 1  
C 1 -ester ase I n hi bit or, H u m a n ( 5 0 0 I U/ m L)  
S u bsta ntial A me n d me nt 3  
 
Pa ge 7 0  of 1 3 1  
Date: 3 1 Ja n 2 0 2 0  
C o nfi d e ntial 
I n a d diti o n, a n y electr o n micr o gra p h i ma ges (if a vaila ble) fr o m re prese ntati ve all o graft 
bi o psies s h o ul d be se nt t o t he ce ntral re p osit or y f or t he st u d y pat h ol o gist.  
Bi o ps y hist o p at h ol o g y will be assesse d b y a ce ntral st u d y pat h ol o gist f or  
 
 a n d Ba nff cate g or y sc ori n g (see A p pe n di x 3 ). Bi o ps y hist o pat h ol o g y will be 
rec or de d i n t he e C R F.  
A d diti o nal details re gar di n g  t he pr ocessi n g of bi o ps y secti o ns a n d assess me nt of 
hist o pat h ol o g y will be prese nte d i n t he la b orat or y ma n ual.  
8. 1. 3. 4  
S ple nect o m y  
If a s ple nect o m y ( or t otal s ple nic irra diati o n) is perf or me d f or a n y reas o n, t he n t he date a n d 
reas o n will be rec or de d i n t he e C R F.  
8. 1. 3. 5  
D o n or -s pecific A nti b o d y ( D S A) 
D o n or -s pecific a nti b o d y i de ntificati o n a n d s pecificit y will be perf or me d usi n g a tiere d 
a p pr oac h. D S A t o H L A Class I a n d Class II a nti ge ns will be i de ntifie d b y t he L u mi ne x 
s oli d-p hase si n gle -bea d a nti ge n i m m u n oassa y. If a n y D S A is ≥ 5 0 0 0 M FI o n a neat ser u m 
sa m ple, t he n dil uti o n testi n g of 1: 1 6 s h o ul d be perf or me d t o deter mi ne if t he D S A dr o ps t o 
bel o w 2 0 0 0 M FI or re mai ns str o n g ( ≥ 5 0 0 0 M FI). A d diti o nal titers ma y be teste d at t he 
discreti o n of t he i n vesti gat or. L ocal D S A  results will n ot be rec or de d i n t he e C R F s. 
Decisi o ns re gar di n g t he c o n d uct of plas ma p heresis will be base d o n l ocal la b orat or y a nal ysis 
of D S A, as o utli ne d i n Secti o n 5. 4. 2 . Sa m ples will als o be se nt f or ce ntral la b orat or y testi n g. 
Ce ntral la b orat or y res ults will be use d f or a nal yses.  
A d diti o nal details re gar di n g t he assess me nt of D S A will be prese nte d i n t he la b orat or y 
ma n ual.  
8. 1. 3. 6  
 
8. 1. 3. 7  
All o gr aft F ail ure  
A ll o graft fail ure is defi ne d as 1 of t he f oll o wi n g, w hic he ver occ urs first: 
C CI
C CI
C CI


C S L Be hri n g L L C  
C S L 8 4 2 _ 3 0 0 1  
C 1 -ester ase I n hi bit or, H u m a n ( 5 0 0 I U/ m L)  
S u bsta ntial A me n d me nt 3  
 
Pa ge 7 1  of 1 3 1  
Date: 3 1 Ja n 2 0 2 0  
C o nfi d e ntial 
 All o graft ne p hrect o m y.  
 I nstit uti o n of per ma ne nt dial ysis; per mane nt dial ysis is defi ne d as dial ysis o n g oi n g f or 
≥ 3 0 da ys.  
 Ret ur n t o t he tra ns pla nt waitlist f or re nal tra ns pla nt.  
T he date a n d ca use of t he first fail ure e ve nt will be rec or de d i n t he e C R F (if k n o w n).  
8. 1. 3. 8  
S u bject S ur vi v al  
S u bject s ur vi val ( yes/ n o) will be deter mi ne d b y site visits or p h o ne call. T he date of eac h 
assess me nt will be rec or de d i n t he e C R F. I n t he case of s u bject deat h, t he date a n d ca use of 
deat h, a n d all o graft stat us at ti me of deat h will be rec or de d i n t he e C R F (if k n o w n).  
8. 1. 3. 9  
  
8. 1. 4  He alt h -rel ate d Q u alit y of Life Assess me nts  
T he E Q -5 D -3 L pr o vi des a si m ple descri pti ve pr ofile of t he s u bject ’s healt h state a n d a si n gle 
vis ual a nal o g ue scale i n de x val ue f or o verall healt h t hat ca n be use d i n t he c li nical a n d 
ec o n o mic e val uati o n of healt h care as well as i n p o p ulati o n healt h s ur ve ys [ D ola n, 1 9 9 7 ; 
Clee m p ut et al, 2 0 0 4 ]. It will be perf or me d i n c o u ntries w here vali date d la n g ua ge versi o ns of 
t he q uesti o n naires are a vaila ble. 
T he E Q -5 D -3 L descri pti ve pr ofile of healt h state c o nsists of t he f oll o wi n g 5 di me nsi o ns: 
m o bilit y, self -care, us ual acti vities, pai n/ disc o mf ort, a n d a n xiet y/ de pressi o n. T he s u bject rates 
C CI
C CI


C S L Be hri n g L L C  
C S L 8 4 2 _ 3 0 0 1  
C 1 -ester ase I n hi bit or, H u m a n ( 5 0 0 I U/ m L)  
S u bsta ntial A me n d me nt 3  
 
Pa ge 7 2  of 1 3 1  
Date: 3 1 Ja n 2 0 2 0  
C o nfi d e ntial 
8. 2  Bl o o d S a m ples  
D uri n g t he st u d y, bl o o d will  be ta ke n fr o m eac h s u bject f or la b orat or y safet y assess me nts a n d 
P K/ 
 e val uati o ns.  
T he I n vesti gat or m ust re vie w t he la b orat or y re p ort a n d e val uate a n y res ults ( ot her t ha n re nal 
f u ncti o n tests) t hat are o utsi de t he n or mal ra n ge a n d deter mi ne cli nical si gnifica nce.  
All a b n or mal la b orat or y val ues will be e ntere d o n t he e C R F wit h a c o m me nt.   T he f oll o wi n g 
c o des s h o ul d be use d t o a d d a c o m me nt o n t he res pecti ve e C R F:  
 
Err or ( E R; e. g., la b orat or y err or, i m pr o per sa m ple pre parati o n, he m ol ysis, 
dela ye d tra nsit t o la b orat or y, etc.).  
 
A b n or mal, n ot cli nicall y si g nifica nt ( A N C S).  
 
A b n or mal, cli nicall y si g nifica nt ( A C S).  
Re peat or u nsc he d ule d bl o o d sa m ples ma y be ta ke n f or safet y reas o ns or f or tec h nical iss ues 
wit h t he sa m ples.  
Refer t o t he La b orat or y Ma n ual f or detai ls a b o ut t he c ollecti o n (i ncl u di n g v ol u me of bl o o d 
sa m ple), st ora ge, ha n dli n g a n d pr ocessi n g of bl o o d sa m ples. 
8. 3  Rete nti o n of S a m ples  
Bl o o d sa m ples f or rete nti o n will be o btai ne d at t he Da y 1 Visit ( pri or t o t he first d ose of 
C 1 -I N H i n T P 1 ) a n d Wee k 1 2 d uri n g  T P 1 a n d at t he Wee k 3 8 Visit d uri n g T P 2. S u bjects w h o 
wit h dra w bef ore c o m pleti n g T P 1 a n d T P 2 will be as ke d t o c o m plete sc he d ule d bl o o d dra w 
f or rete nti o n sa m ples. 
F or s u bjects w h o partici pate i n a Retreat me nt Peri o d, bl o o d sa m ples f or rete nti o n will be 
o btai ne d at t he Da y 1 Retreat me nt Visit ( pri or t o t he first d ose of C 1 -I N H i n a Retreat me nt 
Peri o d) a n d at t he Wee k 2 6 Retreat me nt Visit.  
Rete nti o n sa m ples will be s hi p pe d t o C S L a n d st ore d at -7 0° C f or p ote ntial testi n g of viral 
mar kers, a n d will be destr o ye d wit hi n 5 years after c o m pleti o n of t he st u d y. Refer t o t he 
La b orat or y Ma n ual f or f urt her details a b o ut t he st ora ge a n d destr ucti o n of rete nti o n sa m ples.  
C CI
C CI


C S L Be hri n g L L C  
C S L 8 4 2 _ 3 0 0 1  
C 1 -ester ase I n hi bit or, H u m a n ( 5 0 0 I U/ m L)  
S u bsta ntial A me n d me nt 3  
 
Pa ge 7 3  of 1 3 1  
Date: 3 1 Ja n 2 0 2 0  
C o nfi d e ntial 
8. 4  Pri or a n d C o nc o mit a nt T her a pies  
All t hera pies (e g, me dicati o ns a n d/ or pr oce d ures) t hat ha ve bee n a d mi nistere d t o a s u bject 
wit hi n 3 m o nt hs of si g ni n g i nf or me d c o nse nt are re gar de d as pri or t hera pies a n d m ust be 
d oc u me nte d as s uc h i n t he e C R F.  
All t hera pies (e g, me dicati o ns a n d/ or pr oce d ures) bei n g a d mi nistere d t o a s u bject at t he ti me 
of si g ni n g i nf or me d c o nse nt, a n d w hic h c o nti n ue t o be ta ke n i n a d diti o n t o i n vesti gati o nal 
pr o d uct d uri n g t he st u d y, are re gar de d as c o nc o mita nt t hera pies a n d m ust be d oc u me nte d as 
s uc h i n t he e C R F. 
8. 5  Visit Sc he d ule  
8. 5. 1  Assess me nt Ti me Wi n d o ws  
T he ti me wi n d o ws ass ociate d wit h all  visits a n d assess me nts are pr o vi de d i n t he f oll o wi n g 
Sc he d ules of Assess me nts:  
 Sc he d ule of Assess me nts: Scree ni n g a n d O pe n -la bel Treat me nt Peri o d 1 
 Sc he d ule of Assess me nts: Bli n de d Treat me nt Peri o d 2  
 Sc he d ule of Assess me nts: Res p o n der  F oll o w -u p   
 Sc he d ule of Assess me nts: N o n -res p o n der F oll o w-u p Peri o d  
 Sc he d ule of Assess me nts: Bli n de d Retreat me nt  Peri o d  
 Sc he d ule of Assess me nts: Se q ue ntial P har mac o ki netic / 
 Sa m pli n g 
C o n d ucte d i n a S u bset of  S u bjects   
8. 5. 2  Scree ni n g  
All s u bjects m ust pr o vi de writte n i nf or me d c o nse nt bef ore a n y st u d y -s pecific assess me nts or 
pr oce d ures are perf or me d. Writte n i nf or me d c o nse nt is n ot re q uire d f or assess me nts or 
pr oce d ures perf or me d acc or di n g t o sta n dar d of care (e g, f or dia g n osis or treat me nt); res ults 
fr o m s uc h assess me nts ma y be use d i n t he deter mi nati o n of st u d y eli gi bilit y. 
Scree ni n g s h o ul d be c o m plete d wit hi n 1 4 da ys bef ore t he i nte n de d date of t he first 
a d mi nistrati o n of C 1 -I N H at t he Da y 1 Visit. T he pr oce d ures sc he d ule d f or Scree ni n g ma y be 
c o n d ucte d o ver m ore t ha n a si n gle da y, w he n necessar y.  
C CI


C S L Be hri n g L L C  
C S L 8 4 2 _ 3 0 0 1  
C 1 -ester ase I n hi bit or, H u m a n ( 5 0 0 I U/ m L)  
S u bsta ntial A me n d me nt 3  
 
Pa ge 7 4  of 1 3 1  
Date: 3 1 Ja n 2 0 2 0  
C o nfi d e ntial 
F or all s u bjec ts w h o ha d t he Scree ni n g Visit pri or t o A me n d me nt 3, creati ni ne meas ure me nt 
at t he ti me of t he i ncl usi o n bi o ps y ( ± 2 wee ks) will be c ollecte d retr os pecti vel y b y wa y of 
me dical hist or y rec or ds.  
T he f oll o wi n g pr oce d ures will be c o n d ucte d a n d d oc u me nte d at Sc ree ni n g: 
 Writte n i nf or me d c o nse nt.  
 Re gistrati o n of t he s u bject via I R T.  
 De m o gra p hics.  
 Me dical hist or y, i ncl u di n g creati ni ne meas ure me nt at t he ti me of t he i ncl usi o n bi o ps y.  
 P h ysical e xa mi nati o n.  
 Vital si g ns.  
 
 
 
 Bl o o d dra ws:  
 Ser u m pre g na nc y test (f or fe male s u bjects of c hil d beari n g p ote ntial).  
 H B V a n d H C V test.  
 Rete nti o n sa m ple f or viral ser ol o g y.  
 Creati ni ne.  
 Ser u m bi o c he mistr y pa nel.  
 He mat ol o g y.  
 A d verse e ve nts.  
 Pri or a n d c o nc o mita nt t hera pies.  
 I ncl usi o n a n d e xcl usi o n criteria. 
Scree n F ail ure: If t he s u bject is n ot eli gi ble f or t he st u d y, t he pri mar y reas o n f or scree n 
fail ure m ust be e ntere d i n t he e CR F.  
Re -scree ni n g after scree n f ail ure: If a p ote ntial s u bject was n ot e nr olle d i nt o t he st u d y 
wit hi n 1 4 da ys after pr o vi di n g i nf or me d c o nse nt, t he n p ote ntial s u bjects ma y re -c o nse nt a n d 
ma y be scree ne d a gai n; h o we ver, o nl y pre g na nc y testi n g, creati ni ne, a n d a n y assess me nts f or 
w hic h t he s u bject faile d o n t he first scree ni n g nee d t o be c o n d ucte d. I n t he e ve nt t hat a 
p ote ntial s u bject has scree ni n g assess me nts ≥ 6 0 da ys pri or t o e nteri n g t he st u d y, all 
scree ni n g assess me nts m ust be re peate d.  
C CI


C S L Be hri n g L L C  
C S L 8 4 2 _ 3 0 0 1  
C 1 -ester ase I n hi bit or, H u m a n ( 5 0 0 I U/ m L)  
S u bsta ntial A me n d me nt 3  
 
Pa ge 7 5  of 1 3 1  
Date: 3 1 Ja n 2 0 2 0  
C o nfi d e ntial 
8. 5. 3  Tre at me nt Peri o d 1  
8. 5. 3. 1  
D a y 1 Visit  
T he f oll o wi n g pr oce d ures will be c o n d ucte d at t he Da y 1 Visit:  
 P h ysical e xa mi nati o n.  
 Vital si g ns.  
 Ser u m pre g na nc y test (f or fe male s u bj ects of c hil d beari n g p ote ntial) if t he scree ni n g 
pre g na nc y test was > 2 4 h o urs bef ore t he Da y 1 Visit.  
 E Q -5 D -3 L q uesti o n naire.  
 Bl o o d dra ws:  
 Creati ni ne.  
 Ser u m bi oc he mistr y pa nel.  
 He mat ol o g y.  
 
 
 D S A.  
 C 1 -esterase i n hi bit or acti vit y/a nti ge n.  
 I m m u n o gl o b uli n c o nce ntrati o n. 
 
 
 
 
N O T E:  All bl o o d dra ws s h o ul d be c o m plete d bef ore a d mi nistrati o n of C 1 -I N H a n d I VI g.  
 I ntra ve n o us a d mi nistrati o n of C 1 -I N H ( 6 0 I U/ k g, d ose r o u n de d t o t he l o west 1 m L).  
 I VI g be gi ns ( 2 gra ms/ k g t otal d ose; t he d ose m ust be a d mi nistere d o ver a mi ni m u m 
peri o d of at least 2 da ys, a n d ma y be a d mi nistere d o ver a peri o d of u p t o 5 da ys).  
N O T E:   See Secti o n 5. 4. 1  f or details. 
 A d verse e ve nts.  
 C o n c o mita nt t hera pies.  
 Sc he d ule ne xt visit.  
C CI
C CI
C CI


C S L Be hri n g L L C  
C S L 8 4 2 _ 3 0 0 1  
C 1 -ester ase I n hi bit or, H u m a n ( 5 0 0 I U/ m L)  
S u bsta ntial A me n d me nt 3  
 
Pa ge 7 6  of 1 3 1  
Date: 3 1 Ja n 2 0 2 0  
C o nfi d e ntial 
8. 5. 3. 2  
D a y 4 Visit  
T he f oll o wi n g pr oce d ures will be c o n d ucte d at t he Da y 4 Visit:  
 I ntra ve n o us a d mi nistrati o n of C 1 -I N H ( 6 0 I U/ k g, d ose r o u n de d t o t he l o west 1 m L).  
 A d verse e ve nts.  
 C o nc o mita nt t hera pies.  
 C 1 -esterase i n hi bit or acti vit y/a nti ge n.  
 Sc he d ule ne xt visit.  
8. 5. 3. 3  
D a y 7 Visit  
T he f oll o wi n g pr oce d ures will be c o n d ucte d at t he Da y 7 Visit:  
 P h ysical e xa mi nati o n.  
 Vital si g ns.  
 Bl o o d dra ws:  
 Creati ni ne.  
 Ser u m bi oc he mistr y pa nel.  
 He mat ol o g y.  
 C 1 -esterase i n hi bit or acti vit y/a nti ge n.  
N O T E:  All bl o o d dra ws s h o ul d be c o m plete d bef ore a d mi nistrati o n of C 1 -I N H. 
 I ntra ve n o us a d mi nistrati o n of C 1 -I N H ( 6 0 I U/ k g, d ose r o u n de d t o t he l o west 1 m L).  
 A d verse e ve nts.  
 C o nc o mita nt t hera pies.  
 Sc he d ule ne xt visit.  
8. 5. 3. 4  
D a y 1 0 Visit  
T he f oll o wi n g pr oce d ures wi ll be c o n d ucte d at t he Da y 1 0 Visit: 
 Bl o o d dra ws:  
 C 1 -esterase i n hi bit or acti vit y/a nti ge n.  
 
 
N O T E:  T he bl o o d dra w s h o ul d be c o m plete d bef ore a d mi nistrati o n of C 1 -I N H. 
 I ntra ve n o us a d mi nistrati o n of C 1 -I N H ( 6 0 I U/ k g, d ose r o u nde d t o t he l o west 1  m L).  
C CI


C S L Be hri n g L L C  
C S L 8 4 2 _ 3 0 0 1  
C 1 -ester ase I n hi bit or, H u m a n ( 5 0 0 I U/ m L)  
S u bsta ntial A me n d me nt 3  
 
Pa ge 7 7  of 1 3 1  
Date: 3 1 Ja n 2 0 2 0  
C o nfi d e ntial 
 A d verse e ve nts.  
 C o nc o mita nt t hera pies.  
 Sc he d ule ne xt visit.  
S u bjects w h o are a part of t he 
 will u n der g o pr oce d ures as prese nte d 
a b o ve, b ut will als o ha ve a d diti o nal bl o o d dra ws, as prese nte d i n Ta ble 6 .  
8. 5. 3. 5  
D a y 1 3 Visit  
T he f oll o wi n g pr oce d ures will be c o n d ucte d at t he Da y 1 3 Visit:  
 I ntra ve n o us a d mi nistrati o n of C 1 -I N H ( 6 0 I U/ k g, d ose r o u n de d t o t he l o west 1 m L).  
N O T E:  T his is t he fi nal I V d ose of C 1 -I N H.  
 A d verse e ve nts.  
 C o nc o mita nt t hera pies.  
 Sc he d ule ne xt visit.  
8. 5. 3. 6  
D a y 1 4 Visit  
T he f oll o wi n g pr oce d ures will be c o n d ucte d at t he Da y 1 4 Visit:  
 P h ysical e xa mi nati o n.  
 Vital Si g ns.  
 Bl o o d dra ws:  
 Creati ni ne.  
 Ser u m bi oc he mistr y pa nel.  
 He mat ol o g y.  
 C 1 -esterase i n hi bit or acti vit y/a nti ge n.  
 
 
N O T E:  All bl o o d dra ws s h o ul d be c o m plete d bef ore a d mi nistrati o n of C 1 -I N H. 
 S u bc uta ne o us a d mi nistrati o n of C 1 -I N H ( 6 0 I U/ k g, d ose r o u n de d t o t he l o west 1 m L).  
N O T E S:  
 T his is t he first S C d ose of C 1 -I N H. 
 T his a d mi nistrat i o n of C 1 -I N H s h o ul d be ti me d t o occ ur 2 4 t o 4 8 h o urs after t he fi nal 
I V d ose of C 1 -I N H. 
C CI
C CI


C S L Be hri n g L L C  
C S L 8 4 2 _ 3 0 0 1  
C 1 -ester ase I n hi bit or, H u m a n ( 5 0 0 I U/ m L)  
S u bsta ntial A me n d me nt 3  
 
Pa ge 7 8  of 1 3 1  
Date: 3 1 Ja n 2 0 2 0  
C o nfi d e ntial 
 S u bse q ue nt a d mi nistrati o ns of t he i n vesti gati o nal pr o d uct s h o ul d occ ur e ver y 3 or 4 
da ys (ie,  t wice wee kl y). 
 I n vesti gati o nal pr o d uct dis pe nse, if a p plica ble. 
 A d verse e ve nts.  
 C o nc o mita nt t hera pies.  
 Sc he d ule ne xt visit.  
8. 5. 3. 7  
Wee k 3 Visit  
T he f oll o wi n g pr oce d ures will be c o n d ucte d at t he Wee k 3 Visit:  
 Bl o o d dra ws:  
 Creati ni ne.  
 Ser u m bi oc he mistr y pa nel.  
N O T E:  All bl o o d dra ws s h o ul d be c o m plete d bef ore a d mi nistrati o n of C 1 -I N H. 
 S u bc uta ne o us a d mi nistrati o n of C 1 -I N H ( 6 0 I U/ k g, d ose r o u n de d t o t he l o west 1 m L).  
 I n vesti gati o nal pr o d uct dis pe nse, if a p plica ble. 
 I n vesti gati o nal pr o d uct vial ret ur n, if a p plica ble. 
 A d verse e ve nts.  
 C o nc o mita nt t hera pies.  
 Sc he d ule ne xt visit.  
8. 5. 3. 8  
Wee k 4 Visit  
T he f oll o wi n g pr oce d ures will be c o n d ucte d at t he Wee k 4 Visit:  
 P h ysical e xa mi nati o n.  
 Vital si g ns.  
 Uri ne or ser u m pre g na nc y test (f or fe male s u bjects of c hil d beari n g p ote ntial).  
 Bl o o d dra ws:  
 Creati ni ne.  
 Ser u m bi oc he mistr y pa nel.  
 
 
 D S A.  
C CI


C S L Be hri n g L L C  
C S L 8 4 2 _ 3 0 0 1  
C 1 -ester ase I n hi bit or, H u m a n ( 5 0 0 I U/ m L)  
S u bsta ntial A me n d me nt 3  
 
Pa ge 7 9  of 1 3 1  
Date: 3 1 Ja n 2 0 2 0  
C o nfi d e ntial 
 C 1 -esterase i n hi bit or acti vit y/a nti ge n.  
 I m m u n o gl o b uli n c o nce ntrati o n. 
 
 
N O T E:  All bl o o d dra ws s h o ul d be c o m plete d bef ore a d mi nistrati o n of C 1 -I N H a n d I VI g.  
 A d verse e ve nts.  
 C o nc o mita nt t hera pies.  
 S u bc uta ne o us a d mi nistrati o n of C 1 -I N H ( 6 0 I U/ k g, d ose r o u n de d t o t he l o west 1 m L).  
 I n vesti gati o nal pr o d uct dis pe nse, if a p plica ble. 
 I n vesti gati o nal pr o d uct vial ret ur n, if a p plica ble. 
 I VI g be gi ns ( 2 gra ms/ k g t otal d ose; t he d ose m ust be a d mi nistere d o ver a mi ni m u m 
peri o d of at least 2 da ys, a n d ma y be a d mi nistere d o ver a peri o d of u p t o 5 da ys).  
N O T E:  See Secti o n 5. 4. 1  f or details. 
 A d verse e ve nts.  
 C o nc o mita nt t hera pies.  
 Sc he d ule ne xt visit.  
8. 5. 3. 9  
Wee k 5, Wee k 6, a n d Wee k 7 Visits  
T he f oll o wi n g pr oce d ures will be c o n d ucte d  at t he Wee k 5, 6, a n d 7 Visits:  
 Bl o o d dra ws:  
 Creati ni ne.  
 Ser u m bi oc he mistr y pa nel.  
N O T E:  All bl o o d dra ws s h o ul d be c o m plete d bef ore a d mi nistrati o n of C 1 -I N H. 
 S u bc uta ne o us a d mi nistrati o n of C 1 -I N H ( 6 0 I U/ k g, d ose r o u n de d t o t he l o west 1 m L).  
 I n vesti gati o nal pr o d uct dis pe nse, if a p plica ble. 
 I n vesti gati o nal pr o d uct vial ret ur n, if a p plica ble. 
 A d verse e ve nts.  
 C o nc o mita nt t hera pies.  
 Sc he d ule ne xt visit.  
C CI


C S L Be hri n g L L C  
C S L 8 4 2 _ 3 0 0 1  
C 1 -ester ase I n hi bit or, H u m a n ( 5 0 0 I U/ m L)  
S u bsta ntial A me n d me nt 3  
 
Pa ge 8 0  of 1 3 1  
Date: 3 1 Ja n 2 0 2 0  
C o nfi d e ntial 
8. 5. 3. 1 0  Wee k 8 Visit  
T he f oll o wi n g pr oce d ures will be c o n d ucte d at t he Wee k 8 Visit:  
 P h ysical e xa mi nati o n.  
 Vital Si g n s. 
 Uri ne or ser u m pre g na nc y test (f or fe male s u bjects of c hil d beari n g p ote ntial).  
 Bl o o d dra ws:  
 Creati ni ne.  
 Ser u m bi oc he mistr y pa nel.  
 
 
 D S A.  
 C 1 -esterase i n hi bit or acti vit y/a nti ge n.  
 I m m u n o gl o b uli n c o nce ntrati o n. 
 
 
N O T E:  All bl o o d dra ws s h o ul d be c o m plete d bef ore a d mi nistrati o n of C 1 -I N H a n d I VI g.  
 S u bc uta ne o us a d mi nistrati o n of C 1 -I N H ( 6 0 I U/ k g, d ose r o u n de d t o t he l o west 1 m L).  
 I n vesti gati o nal pr o d uct dis pe nse, if a p plica ble. 
 I n vesti gati o nal pr o d uct vial ret ur n, if a p plica ble. 
 I VI g be gi ns ( 2 gra ms/ k g t otal d ose; t he d ose m ust be a d mi nistere d o ver a mi ni m u m 
peri o d of at least 2 da ys, a n d ma y be a d mi nistere d o ver a peri o d of u p t o 5 da ys).  
 A d verse e ve nts.  
 C o nc o mita nt t hera pies.  
 Sc he d ule ne xt visit.  
8. 5. 3. 1 1  Wee k 9 a n d Wee k 1 0 Visits  
T he f oll o wi n g pr oce d ures will be c o n d ucte d at t he Wee k 9 a n d 1 0 Visits:  
 Bl o o d dra ws:  
 Creati ni ne.  
 Ser u m bi oc he mistr y pa nel.  
 C 1 -esterase i n hi bit or acti vit y/a nti ge n ( Wee k 1 0 o nl y).  
N O T E:  All bl o o d dra ws s h o ul d be c o m plete d bef ore a d mi nistrati o n of C 1 -IN H . 
C CI
C CI


C S L Be hri n g L L C  
C S L 8 4 2 _ 3 0 0 1  
C 1 -ester ase I n hi bit or, H u m a n ( 5 0 0 I U/ m L)  
S u bsta ntial A me n d me nt 3  
 
Pa ge 8 1  of 1 3 1  
Date: 3 1 Ja n 2 0 2 0  
C o nfi d e ntial 
 S u bc uta ne o us a d mi nistrati o n of C 1 -I N H ( 6 0 I U/ k g, d ose r o u n de d t o t he l o west 1 m L).  
 I n vesti gati o nal pr o d uct dis pe nse, if a p plica ble. 
 I n vesti gati o nal pr o d uct vial ret ur n, if a p plica ble. 
 A d verse e ve nts.  
 C o nc o mita nt t hera pies.  
 Sc he d ule ne xt visit.  
8. 5. 3. 1 2  Wee k 11 Visit  
T he f oll o wi n g pr oce d ures will be c o n d ucte d at t he Wee k 1 1 Visit:  
 Bl o o d dra ws:  
 Creati ni ne.  
 Ser u m bi oc he mistr y pa nel.  
N O T E:  All bl o o d dra ws s h o ul d be c o m plete d bef ore a d mi nistrati o n of C 1 -I N H. 
 S u bc uta ne o us a d mi nistrati o n of C 1 -I N H ( 6 0 I U/ k g, d ose r o u n de d t o t he l o west 1  m L).  
 I n vesti gati o nal pr o d uct dis pe nse, if a p plica ble. 
 I n vesti gati o nal pr o d uct vial ret ur n, if a p plica ble. 
 A d verse e ve nts.  
 C o nc o mita nt t hera pies.  
 Sc he d ule ne xt visit.  
S u bjects w h o are a part of t he 
 will u n der g o pr oced ures as prese nte d 
a b o ve, b ut will als o ha ve a d diti o nal bl o o d dra ws, as prese nte d i n Ta ble 6 .  
 
 
8. 5. 3. 1 3  Wee k 1 2 Visit  
T he f oll o wi n g pr oce d ures will be c o n d ucte d at t he Wee k 1 2 Visit:  
 E Q -5 D -3 L q uesti o n naire.  
 Bl o o d dra ws:  
 Creati ni ne.  
C CI
C CI


C S L Be hri n g L L C  
C S L 8 4 2 _ 3 0 0 1  
C 1 -ester ase I n hi bit or, H u m a n ( 5 0 0 I U/ m L)  
S u bsta ntial A me n d me nt 3  
 
Pa ge 8 2  of 1 3 1  
Date: 3 1 Ja n 2 0 2 0  
C o nfi d e ntial 
 Ser u m pre g na nc y test (f or fe male s u bjects of c hil d beari n g p ote ntial).  
 Ser u m bi oc he mistr y pa nel.  
 He mat ol o g y.  
 
 
 D S A.  
 C 1 -esterase i n hi bit or acti vit y/a nti ge n.  
 I m m u n o gl o b uli n c o nce ntrati o n. 
 
 
 
. 
 Rete nti o n sa m ple f or viral ser ol o g y.  
N O T E:  All bl o o d dra ws s h o ul d be c o m plete d bef ore a d mi nistrati o n of C 1 -I N H a n d I VI g.  
 S u bc uta ne o us a d mi nistrati o n of C 1 -I N H ( 6 0 I U/ k g, d ose r o u n de d t o t he l o west 1 m L).  
 I n vesti gati o nal pr o d uct dis pe nse, if a p plica ble. 
 I n vesti gati o nal pr o d uct vial ret ur n, if a p plica ble. 
 I VI g be gi ns ( 2 gra ms/k g t otal d ose; t he d ose m ust be a d mi nistere d o ver a mi ni m u m 
peri o d of at least 2 da ys, a n d ma y be a d mi nistere d o ver a peri o d of u p t o 5 da ys).  
 A d verse e ve nts.  
 C o nc o mita nt t hera pies.  
 Sc he d ule ne xt visit.  
8. 5. 3. 1 4  Wee k 1 3 Visit/ E n d of Tre at me nt Peri o d 1 f or 
N o n -res po n ders/ St art of Tre at me nt Peri o d 2 f or Res p o n ders  
T he f oll o wi n g pr oce d ures will be c o n d ucte d at t he Wee k 1 3 Visit, or if a s u bject 
wit h dra ws/ disc o nti n ues fr o m t he st u d y d uri n g T P 1 : 
 P h ysical e xa mi nati o n.  
 Vital Si g ns.  
 A d verse e ve nts.  
 C o nc o mita nt t hera pies.  
 R es p o n der stat us, as deter mi ne d b y C S L.  
C CI
C CI
C CI


C S L Be hri n g L L C  
C S L 8 4 2 _ 3 0 0 1  
C 1 -ester ase I n hi bit or, H u m a n ( 5 0 0 I U/ m L)  
S u bsta ntial A me n d me nt 3  
 
Pa ge 8 3  of 1 3 1  
Date: 3 1 Ja n 2 0 2 0  
C o nfi d e ntial 
 Ra n d o mizati o n of res p o n ders t o treat me nt wit h bli n de d i n vesti gati o nal pr o d uct (eit her 
C 1 -I N H or p lace b o) i n T P 2.  
 I n vesti gati o nal pr o d uct dis pe nse, if a p plica ble. 
 S u bc uta ne o us a d mi nistrati o n of C 1 -I N H/ place b o ( 6 0 I U/ k g, d ose r o u n de d t o t he l o west 
1  m L) f or res p o n ders.  
 I n vesti gati o nal pr o d uct vial ret ur n, if a p plica ble. 
 Sc he d ule ne xt visit.  
E arl y Wit h dr a w al D uri n g Tre at me nt Peri o d 1  
I n a d diti o n, f or s u bjects w h o wit h dra w/ disc o nti n ue fr o m t he st u d y d uri n g T P 1 , t he f oll o win g 
bl o o d dra ws s h o ul d als o be c ollecte d:  
 Creati ni ne.  
 Ser u m bi oc he mistr y pa nel.  
 He mat ol o g y.  
 
 
 D S A.  
 C 1 -esterase i n hi bit or acti vit y/a nti ge n.  
 I m m u n o gl o b uli n c o nce ntrati o n. 
 
 
 
 
 Rete n ti o n sa m ple f or viral ser ol o g y. 
 Ser u m pre g na nc y test (f or fe male s u bjects of c hil d beari n g p ote ntial).  
8. 5. 4  Tre at me nt Peri o d 2  
Be gi n ni n g at t he fi nal visit i n Treat me nt Peri o d 1 (ie, t he Wee k 1 3 Visit), a n d t hr o u g h o ut 
T P 2:  
 Be gi n ni n g d uri n g T P 2, a bl o o d sa m ple f o r creati ni ne meas ure me nt will be dra w n o nce 
e ver y 1 4  da ys  ( ± 7  da ys) at t he st u d y site, at h o me b y a me dical pr ofessi o nal. T he 
fre q ue nc y of bl o o d dra w f or creati ni ne meas ure me nt ma y occ ur m ore fre q ue ntl y  at t he 
i n vesti gat or’s discreti o n.  
 S u bc uta ne o us i n ves ti gati o nal pr o d uct (ie, C 1 -I N H or place b o) will be a d mi nistere d e ver y 
3  or 4 da ys (ie, t wice wee kl y), as per t he ra n d o mizati o n sc he d ule.  
C CI
C CI
C CI


C S L Be hri n g L L C  
C S L 8 4 2 _ 3 0 0 1  
C 1 -ester ase I n hi bit or, H u m a n ( 5 0 0 I U/ m L)  
S u bsta ntial A me n d me nt 3  
 
Pa ge 8 4  of 1 3 1  
Date: 3 1 Ja n 2 0 2 0  
C o nfi d e ntial 
8. 5. 4. 1  
Wee k 1 6 Visit  
T he f oll o wi n g pr oce d ures will be c o n d ucte d at t he Wee k 1 6 Visit:  
 Bl o o d dra ws:  
 Creati ni ne.  
 Ser u m pre g na nc y  test (f or fe male s u bjects of c hil d beari n g p ote ntial). 
 
 
 D S A.  
 C 1 -esterase i n hi bit or acti vit y/a nti ge n.  
 
 
N O T E:  All bl o o d dra ws s h o ul d be c o m plete d bef ore a d mi nistrati o n of i n vesti gati o nal 
pr o d uct a n d I VI g.  
 S u bc uta ne o us a d mi nistrati o n of bli n de d i n vesti gati o nal pr o d uct ( C 1 -I N H [ 6 0 I U/ k g] or 
place b o, d ose r o u n de d t o t he l o west 1 m L).  
 I n vesti gati o nal pr o d uct dis pe nse, if a p plica ble. 
 I n vesti gati o nal pr o d uct vial ret ur n, if a p plica ble. 
 I VI g ma y be gi n if D S A is ≥ 2 0 0 0 M F I ( 2 gra ms/ k g t otal d ose; t he d ose m ust be 
a d mi nistere d o ver a mi ni m u m peri o d of at least 2 da ys, a n d ma y be a d mi nistere d o ver a 
peri o d of u p t o 5 da ys).  
 A d verse e ve nts.  
 C o nc o mita nt t hera pies.  
 Sc he d ule ne xt visit.  
8. 5. 4. 2  
Wee k 2 0 Visit  
T he f oll o wi n g pr oce d ures wi ll be c o n d ucte d at t he Wee k 2 0 Visit: 
 Uri ne or ser u m pre g na nc y test (f or fe male s u bjects of c hil d beari n g p ote ntial).  
 Bl o o d dra ws:  
 Creati ni ne.  
 Ser u m Bi oc he mistr y pa nel.  
 He mat ol o g y.  
 
 
C CI
C CI
C CI


C S L Be hri n g L L C  
C S L 8 4 2 _ 3 0 0 1  
C 1 -ester ase I n hi bit or, H u m a n ( 5 0 0 I U/ m L)  
S u bsta ntial A me n d me nt 3  
 
Pa ge 8 5  of 1 3 1  
Date: 3 1 Ja n 2 0 2 0  
C o nfi d e ntial 
 D S A.  
N O T E:  All bl o o d dra ws s h o ul d be c o m plete d bef ore a d mi nistr ati o n of i n vesti gati o nal 
pr o d uct a n d I VI g.  
 S u bc uta ne o us a d mi nistrati o n of bli n de d i n vesti gati o nal pr o d uct ( C 1 -I N H [ 6 0 I U/ k g] or 
place b o, d ose r o u n de d t o t he l o west 1 m L).  
 I n vesti gati o nal pr o d uct dis pe nse, if a p plica ble. 
 I n vesti gati o nal pr o d uct vial ret ur n, if a p plica ble. 
 I VI g ma y be gi n if D S A is ≥ 2 0 0 0 M FI ( 2 gra ms/ k g t otal d ose; t he d ose m ust be 
a d mi nistere d o ver a mi ni m u m peri o d of at least 2 da ys, a n d ma y be a d mi nistere d o ver a 
peri o d of u p t o 5 da ys).  
 A d verse e ve nts.  
 C o nc o mita nt t hera pies.  
 Sc he d ule ne x t visit. 
8. 5. 4. 3  
Wee k 2 4 Visit  
T he f oll o wi n g pr oce d ures will be c o n d ucte d at t he Wee k 2 4 Visit:  
 P h ysical E xa mi nati o n.  
 Vital Si g ns.  
 Uri ne or ser u m pre g na nc y test (f or fe male s u bjects of c hil d beari n g p ote ntial).  
 Bl o o d dra ws:  
 Creati ni ne.  
 
 
 D S A.  
N O T E:  T he b l o o d dra w s h o ul d be c o m plete d bef ore a d mi nistrati o n of i n vesti gati o nal 
pr o d uct a n d I VI g.  
 S u bc uta ne o us a d mi nistrati o n of bli n de d i n vesti gati o nal pr o d uct ( C 1 -I N H [ 6 0 I U/ k g] or 
place b o, d ose r o u n de d t o t he l o west 1 m L).  
 I n vesti gati o nal pr o d uct dis pe nse, if a pplica ble.  
 I n vesti gati o nal pr o d uct vial ret ur n, if a p plica ble. 
C CI


C S L Be hri n g L L C  
C S L 8 4 2 _ 3 0 0 1  
C 1 -ester ase I n hi bit or, H u m a n ( 5 0 0 I U/ m L)  
S u bsta ntial A me n d me nt 3  
 
Pa ge 8 6  of 1 3 1  
Date: 3 1 Ja n 2 0 2 0  
C o nfi d e ntial 
 I VI g ma y be gi n if D S A is ≥ 2 0 0 0 M FI ( 2 gra ms/ k g t otal d ose; t he d ose m ust be 
a d mi nistere d o ver a mi ni m u m peri o d of at least 2 da ys, a n d ma y be a d mi nistere d o ver a 
peri o d of u p t o 5 da ys).  
 A d ver se e ve nts. 
 C o nc o mita nt t hera pies.  
 Sc he d ule ne xt visit.  
8. 5. 4. 4  
Wee k 2 8 Visit  
T he f oll o wi n g pr oce d ures will be c o n d ucte d at t he Wee k 2 8 Visit:  
 Uri ne or ser u m pre g na nc y test (f or fe male s u bjects of c hil d beari n g p ote ntial).  
 Bl o o d dra ws:  
 Creati ni ne.  
 Ser u m Bi oc he mistr y  pa nel.  
 He mat ol o g y.  
 
 
 D S A.  
N O T E:  All bl o o d dra ws s h o ul d be c o m plete d bef ore a d mi nistrati o n of i n vesti gati o nal 
pr o d uct a n d I VI g.  
 S u bc uta ne o us a d mi nistrati o n of bli n de d i n vesti gati o nal pr o d uct ( C 1 -I N H [ 6 0 I U/ k g] or 
place b o, d ose r o u n de d t o t he l o w est 1 m L).  
 I n vesti gati o nal pr o d uct dis pe nse, if a p plica ble. 
 I n vesti gati o nal pr o d uct vial ret ur n, if a p plica ble. 
 I VI g ma y be gi n if D S A is ≥ 2 0 0 0 M FI ( 2 gra ms/ k g t otal d ose; t he d ose m ust be 
a d mi nistere d o ver a mi ni m u m peri o d of at least 2 da ys, a n d ma y be a d mi nistere d o ver a 
peri o d of u p t o 5 da ys).  
 A d verse e ve nts.  
 C o nc o mita nt t hera pies.  
 Sc he d ule ne xt visit.  
8. 5. 4. 5  
Wee k 3 2 Visit  
T he f oll o wi n g pr oce d ures will be c o n d ucte d at t he Wee k 3 2 Visit:  
C CI


C S L Be hri n g L L C  
C S L 8 4 2 _ 3 0 0 1  
C 1 -ester ase I n hi bit or, H u m a n ( 5 0 0 I U/ m L)  
S u bsta ntial A me n d me nt 3  
 
Pa ge 8 7  of 1 3 1  
Date: 3 1 Ja n 2 0 2 0  
C o nfi d e ntial 
 Uri ne or ser u m pre g na nc y test (f or fe male s u bjects of c hil d beari n g p ote n tial). 
 Bl o o d dra ws:  
 Creati ni ne.  
 
 
 D S A.  
 C 1 -esterase i n hi bit or acti vit y/a nti ge n.  
 I m m u n o gl o b uli n c o nce ntrati o n. 
N O T E:  All bl o o d dra ws s h o ul d be c o m plete d bef ore a d mi nistrati o n of i n vesti gati o nal 
pr o d uct a n d I VI g.  
 S u bc uta ne o us a d mi nistrati o n of bli n de d i n vesti gati o nal pr o d uct ( C 1 -I N H [ 6 0 I U/ k g] or 
place b o, d ose r o u n de d t o t he l o west 1 m L).  
 I n vesti gati o nal pr o d uct dis pe nse, if a p plica ble. 
 I n vesti gati o nal pr o d uct vial ret ur n, if a p plica ble. 
 I VI g ma y be gi n if D S A is ≥ 2 0 0 0 M FI ( 2 gra ms/ k g t otal d ose; t h e d ose m ust be 
a d mi nistere d o ver a mi ni m u m peri o d of at least 2 da ys, a n d ma y be a d mi nistere d o ver a 
peri o d of u p t o 5 da ys).  
 A d verse e ve nts.  
 C o nc o mita nt t hera pies.  
 Sc he d ule ne xt visit.  
8. 5. 4. 6  
Wee k 3 8 Visit / E n d of Tre at me nt Peri o d 2 Visit 
T he f oll o wi n g pr oce d ure s will be c o n d ucte d at t he Wee k 3 8 Visit: 
 E Q -5 D -3 L q uesti o n naire.  
 P h ysical e xa mi nati o n.  
 Vital Si g ns.  
 Pre g na nc y test (f or fe male s u bjects of c hil d beari n g p ote ntial).  
 Bl o o d dra ws:  
o  Creati ni ne.  
o  Ser u m pre g na nc y test (f or fe male s u bjects of c hil d beari n g p ote nt ial). 
 Ser u m bi oc he mistr y pa nel.  
 He mat ol o g y.  
C CI


C S L Be hri n g L L C  
C S L 8 4 2 _ 3 0 0 1  
C 1 -ester ase I n hi bit or, H u m a n ( 5 0 0 I U/ m L)  
S u bsta ntial A me n d me nt 3  
 
Pa ge 8 8  of 1 3 1  
Date: 3 1 Ja n 2 0 2 0  
C o nfi d e ntial 
 
 
 D S A.  
 C 1 -esterase i n hi bit or acti vit y/a nti ge n.  
 
 
 Rete nti o n sa m ple f or viral ser ol o g y.  
 
. 
N O T E:  All bl o o d dra ws s h o ul d be c o m plete d bef ore a d mi nistrati o n of i n vesti gati o nal 
pr o d uct.  
 
 
 
 Bi o ps y of ki d ne y all o graft.  
 S u bc uta ne o us a d mi nistrati o n of bli n de d i n vesti gati o nal pr o d uct ( C 1 -I N H [ 6 0 I U/ k g] or 
place b o, d ose r o u n de d t o t he l o west 1 m L).  
 N O T E:  T his is t he fi nal d ose of bli n de d i n vesti gati o nal pr o d uct a d mi nistere d as a part of 
T P 2 . 
 I n vesti gati o nal pr o d uct vial ret ur n, if a p plica ble. 
 A d vers e e ve nts. 
 C o nc o mita nt t hera pies.  
 Sc he d ule ne xt visit.  
8. 5. 5  Res p o n der F oll o w -u p Peri o d  
T hr o u g h o ut t he Res p o n der F oll o w -u p Peri o d:  
 Assess me nt of D S A a n d/ or all o graft bi o ps y will be c o n d ucte d as per l ocal sta n dar d of 
care. If t he i n vesti gat or bec o mes a ware of a n A E t hat has starte d after t he o bser vati o n 
peri o d has fi nis he d, a n d t here is at least a p ossi ble ca usal relati o ns hi p t o t he 
i n vesti gati o nal pr o d uct, t he e ve nt m ust be re p orte d t o C S L (see Secti o n 9. 4 ). 
8. 5. 5. 1  
M o nt h 1 2 Vi sit 
T he f oll o wi n g pr oce d ures will be c o n d ucte d at t he M o nt h 1 2 Visit:  
 E Q -5 D -3 L q uesti o n naire.  
 Bl o o d dra ws:  
C CI
C CI
C CI
C CI


C S L Be hri n g L L C  
C S L 8 4 2 _ 3 0 0 1  
C 1 -ester ase I n hi bit or, H u m a n ( 5 0 0 I U/ m L)  
S u bsta ntial A me n d me nt 3  
 
Pa ge 8 9  of 1 3 1  
Date: 3 1 Ja n 2 0 2 0  
C o nfi d e ntial 
 Creati ni ne.  
 
. 
 C 1 -esterase i n hi bit or acti vit y/a nti ge n.  
 
 
 All o graft fail ure ( yes/ n o).  
 S u bject s u r vi val ( yes/ n o). 
 De vel o p me nt of bi o ps y -c o nfir me d A M R si nce t he last visit ( yes/ n o).  
 Sc he d ule ne xt visit.  
8. 5. 5. 2  
M o nt h 1 8, M o nt h 2 4, M o nt h 3 0, M o nt h 3 6, a n d M o nt h  4 2  Visits  
T he f oll o wi n g pr oce d ures will be c o n d ucte d at t he M o nt h 1 8, 2 4, 3 0, 3 6, a n d 4 2 Visits:  
 E Q -5 D -3 L q uesti o n naire ( M o nt h 2 4 a n d 3 6 Visits o nl y).  
 Bl o o d dra ws:  
 Creati ni ne.  
 All o graft fail ure ( yes/ n o).  
 S u bject s ur vi val ( yes/ n o).  
 De vel o p me nt of bi o ps y -c o nfir me d A M R si nce t he last visit ( yes/ n o).  
 Sc he d ule ne xt visit.  
8. 5. 5. 3  
M o nt h 4 8 Visit/ E n d of St u d y Visit  
T he  f oll o wi n g pr oce d ures will be c o n d ucte d at t he M o nt h 4 8 Visit, or if a s u bject wit h dra ws 
fr o m t he st u d y d uri n g t he Res p o n der F oll o w -u p Peri o d:  
 E Q -5 D -3 L q uesti o n naire  
 Bl o o d dra ws:  
 Creati ni ne.  
 
. 
 All o graft fail ure ( yes/ n o).  
 S u bject s ur vi val ( yes/ n o).  
 De vel o p me nt of bi o ps y -c o nfir me d A M R si nce t he last visit ( yes/ n o).  
 Seri o us A d verse E ve nts.  
C CI
C CI
C CI


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8.5.6 
Retreatment Period(s) 
 Subjects may undergo retreatment during the Responder Follow-up Period with the 
blinded investigational product to which they were randomized in TP2. Retreatment may 
occur following a diagnosis of persistent or recurrent AMR by biopsy, evidenced by 
infiltrating neutrophils and/or monocytes with or without the presence of C4d (g > 0, v > 
0, and/or ptc > 0; if C4d is negative, g + ptc ≥ 2).    
 Retreatment may start at any time during the Responder Follow-up Period, and will last 
for 25 weeks or until the Month 48 Visit, whichever occurs first. The Retreatment Period 
may also be shorter than 25 weeks at the investigator’s discretion. 
 If retreatment is stopped prior to completing the entire Retreatment Period, the 
procedures at the Retreatment Week 26 visit should replace the procedures at the 
scheduled monthly visit. 
 Subcutaneous investigational product (ie, C1-INH or placebo) will be administered every 
3 or 4 days (ie, twice weekly) during a Retreatment Period. 
 Assessment of DSA will be conducted as per local standard of care.  
8.5.6.1 
Retreatment Day 1 Visit 
The following procedures will be conducted at the Retreatment Day 1 Visit: 
 Confirmation of recurrent, acute AMR, as shown by biopsy. 
 Physical examination. 
 Vital signs. 
 Blood draws: 
 Creatinine. 
 Serum pregnancy test (for female subjects of childbearing potential). 
 Retention sample for viral serology. 
NOTE: All blood draws should be completed before administration of C1-INH and IVIg. 
 Subcutaneous administration of blinded investigational product (C1-INH [60 IU/kg] or 
placebo, dose rounded to the lowest 1 mL). 
 Investigational product dispense, if applicable. 
 IVIg may begin if DSA is ≥ 2000 MFI (2 grams/kg total dose; the dose must be 
administered over a minimum period of at least 2 days, and may be administered over a 
period of up to 5 days). 


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 Adverse events. 
 Concomitant therapies. 
 Schedule next visit. 
8.5.6.2 
Retreatment Day 7 Visit 
The following procedures will be conducted at the Retreatment Day 7 Visit: 
 Blood draws: 
 Creatinine. 
NOTE: The blood draw should be completed before administration of C1-INH. 
 Subcutaneous administration of blinded investigational product (C1-INH [60 IU/kg] or 
placebo, dose rounded to the lowest 1 mL). 
 Investigational product dispense, if applicable. 
 Investigational product vial return, if applicable. 
 Adverse events. 
 Concomitant therapies. 
 Schedule next visit. 
8.5.6.3 
Retreatment Week 4 and Week 8 Visits 
The following procedures will be conducted at the Retreatment Week 4 and Week 8 Visits: 
 Urine or serum pregnancy test (for female subjects of childbearing potential). 
 Blood draws: 
 Creatinine. 
NOTE: The blood draw should be completed before administration of C1-INH and IVIg. 
 Subcutaneous administration of blinded investigational product (C1-INH [60 IU/kg] or 
placebo, dose rounded to the lowest 1 mL). 
 Investigational product dispense, if applicable. 
 Investigational product vial return, if applicable. 
 IVIg may begin if DSA is ≥ 2000 MFI (2 grams/kg total dose; the dose must be 
administered over a minimum period of at least 2 days, and may be administered over a 
period of up to 5 days). 
 Adverse events. 


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Substantial Amendment 3 
 
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Confidential 
 Concomitant therapies. 
 Schedule next visit. 
8.5.6.4 
Retreatment Week 12 Visit 
The following procedures will be conducted at the Retreatment Week 12 Visit: 
 Physical examination. 
 Vital signs. 
 Urine or serum pregnancy test (for female subjects of childbearing potential). 
 Blood draws: 
 Creatinine. 
NOTE: The blood draw should be completed before administration of C1-INH and IVIg. 
 Subcutaneous administration of blinded investigational product (C1-INH [60 IU/kg] or 
placebo, dose rounded to the lowest 1 mL). 
 Investigational product dispense, if applicable. 
 Investigational product vial return, if applicable. 
 IVIg may begin if DSA is ≥ 2000 MFI (2 grams/kg total dose; the dose must be 
administered over a minimum period of at least 2 days, and may be administered over a 
period of up to 5 days). 
 Adverse events. 
 Concomitant therapies. 
 Schedule next visit. 
8.5.6.5 
Retreatment Week 16 and Week 22 Visits 
The following procedures will be conducted at the Retreatment Week 16 and Week 22 Visits: 
 Urine or serum pregnancy test (for female subjects of childbearing potential). 
 Blood draws: 
 Creatinine. 
NOTE: The blood draw should be completed before administration of C1-INH and IVIg. 
 Subcutaneous administration of blinded investigational product (C1-INH [60 IU/kg] or 
placebo, dose rounded to the lowest 1 mL). 
 Investigational product dispense, if applicable. 


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 Investigational product vial return, if applicable. 
 IVIg may begin if DSA is ≥ 2000 MFI (2 grams/kg total dose; the dose must be 
administered over a minimum period of at least 2 days, and may be administered over a 
period of up to 5 days). 
 Adverse events. 
 Concomitant therapies. 
 Schedule next visit. 
8.5.6.6 
Retreatment Week 26 Visit 
The following procedures will be conducted at the Retreatment Week 26 Visit: 
 Physical examination. 
 Vital signs. 
 Blood draws: 
 Creatinine. 
 Retention sample for viral serology. 
 Serum pregnancy test (for female subjects of childbearing potential). 
NOTE: All blood draws should be completed before administration of C1-INH. 
 Subcutaneous administration of blinded investigational product (C1-INH [60 IU/kg] or 
placebo, dose rounded to the lowest 1 mL). 
 Investigational product vial return, if applicable. 
 Adverse events. 
 Concomitant therapies. 
 Schedule next visit. 
8.5.7 
Non-responder Follow-up Period 
The following will be collected during the Non-responder Follow-up Period at 3 months 
(± 2 days) following the Week 13 Visit, then every 6 months (± 28 days) until the end of the 
Non-responder Follow-up Period: 
 Graft failure (yes/no, date of failure if available) 
 Subject survival (yes/no) 


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 Development of biopsy-confirmed AMR (yes/no) 
 Creatinine measurement 
Creatinine will be measured by the central laboratory for prospectively collected samples 
from subjects who enter the Non-responder Follow-up Period after Amendment 3. 
Creatinine values may be obtained retrospectively from medical records if samples 
cannot be drawn prospectively. 
 EQ-5D-3L (Months 12, 24, 36, and 48) 
8.5.8 
Subject Withdrawal/Discontinuation 
8.5.8.1 
Withdrawal/Discontinuation during Treatment Period 1 
If a subject is withdrawn/discontinued from the study for any reason during TP1, then the 
investigator should make every effort to perform the assessments scheduled for the 
Week 13 Visit. In addition, investigators should contact these subjects by telephone 
approximately 30 days after the Week 13 Visit (ie, End-of-TP1 Visit) to collect follow-up 
safety information.  
8.5.8.2 
Withdrawal/Discontinuation during Treatment Period 2 
If a subject is withdrawn from the study for any reason during TP2, the investigator should 
make every effort to perform the assessments scheduled for the Week 38 Visit. In addition, 
investigators should contact these subjects by telephone approximately 30 days after the 
Week 38 Visit (ie, End-of-TP2 Visit) to collect follow-up safety information. 
8.5.8.3 
Withdrawal/Discontinuation during any Retreatment Period 
If a subject is withdrawn from the study for any reason during a Retreatment Period, the 
investigator should make every effort to perform the assessments scheduled for the 
Retreatment Week 26 Visit. In addition, investigators should contact these subjects by 
telephone approximately 30 days after the Retreatment Week 26 Visit (ie, the End of 
Retreatment Period Visit) to collect follow-up safety information. 
8.5.8.4 
Withdrawal/Discontinuation during the Follow-up Period 
If a subject is withdrawn from the study for any reason during the Follow-up Period, the 
investigator should make every effort to perform the assessments scheduled for the 
Month 48 Visit. 


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Substantial Amendment 3 
 
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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 product (eg, the investigational 
product), whether or not considered related to the medicinal product (eg, the investigational 
product).  
The period of observation for AEs extends from the time the subject gives informed consent 
until 30 days after the last administration of any investigational product (see Section 9.4 for 
further details). 
 Adverse events may include: 
 A clinical event occurring after written informed consent but before administration of the 
investigational product.  
 Exacerbation (ie, an increase in the frequency or severity) of a pre-existing condition. 
Illness present before study entry should be recorded in the medical history section of the 
eCRF and only be reported as an AE if there is an increase in the frequency or severity of 
the condition during the study.  
 Intercurrent illnesses with an onset after administration of investigational product. 
Adverse events do not include: 
 Events identified at Screening that meet exclusion criteria. 
 Medical or surgical procedures (the condition that leads to the procedure is the AE). 
 Situations where an untoward medical occurrence has not taken place, including: 
 Planned hospitalizations due to pre-existing conditions, which have not worsened. 
 Hospitalizations that occur for procedures not due to an AE (eg, cosmetic surgery). 
 Hospitalizations for a diagnostic procedure where the hospital stay is less than 
24 hours in duration or for normal management procedures (eg, chemotherapy). 


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 Overdose of investigational product or any concomitant therapy that does not result in 
any adverse signs or symptoms.  
 Selected endpoints and transplant-related disease events, including: 
 Elevated creatinine. 
 Worsening of renal function and related laboratory changes. 
 Hospitalization for per protocol IVIg administration or other immune suppressive 
therapy. 
 Hospitalization for per protocol plasmapheresis. 
 Allograft failure. 
For laboratory safety parameters, any instances of absolute values being outside the reference 
range or changes at any visit after study start that are considered by the investigator as 
clinically significant must recorded in the eCRF as AEs. In addition, at the investigator’s 
discretion, any changes or trends over time in laboratory parameters can be recorded in the 
eCRF as AEs if such changes or trends are considered to be clinically relevant, even if the 
absolute values are within the reference range. 
Laboratory findings do not need to be reported as AEs in the following cases: 
 Laboratory parameters already beyond the reference range at 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).  
9.1.2 
Adverse Event of Special Interest 
There are several AEs that will be monitored as AEs of special interest to enable an adequate 
risk-benefit evaluation of the C1-INH.  
The following events will be considered AEs of special interest: 


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 Thromboembolic events (TEEs). 
 Any systemic TEE is considered an SAE and should be reported as such. 
Additionally, any non-systemic TEE (eg, a TEE associated with dialysis access or 
other vascular access) that meets the serious criteria must be reported as an SAE. 
 Any non-serious access-related thrombosis should be entered as an AE on the eCRF 
and will be part of the regular review of AEs of special interest by the IDMC. 
 Anaphylaxis.  
 All events of anaphylaxis are considered SAEs and should be reported as such. 
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. Transmission of an infectious agent 
may be considered medically significant. 
Additionally, AEs of special interest may be considered SAEs (see Section 9.1.2).  
Adverse events that do not fall into the above categories are defined as non-serious AEs. 


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9.2 Severity of Adverse Events 
The severity of each AE (ie, non-serious and serious AEs) is to be assessed by the 
investigator as described in Table 15. 
Table 15 
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. 
Source: CDISC SDTM Severity Intensity Scale for Adverse Event Terminology. 
9.3 Causality of Adverse Events 
The causal relationship of an AE to the investigational product must always be assessed by 
the investigator. All AEs will be classified as either related or not related to the 
investigational product. If a causality assessment is not provided for an AE (including an 
SAE), then that AE will be considered related to the investigational product.  
The degree of certainty with which an AE is attributed to the investigational product 
(ie, C1-INH or placebo) 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 the investigational product. 
 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 the investigational product, drug 
withdrawal or reproduced on rechallenge). 


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9.4 Observation Period for Adverse Events 
For TP1 and TP2, the observation period for AEs and SAEs reporting for an individual 
subject will start at the time of giving written informed consent for participation in the 
current study and finish 30 days after the last administration of any investigational product as 
a part of TP1 and TP2. 
Throughout the Responder Follow-up Period, if the investigator becomes aware of an AE that 
has started after the observation period has finished, and there is at least a possible causal 
relationship to the investigational product, the event must be reported to CSL (see 
Section 9.6). 
If a subject participates in a Retreatment Period, the observation period for AEs and SAEs 
reporting for an individual subject will start at the Retreatment Day 1 Visit and finish 30 days 
after the last administration of any investigational product as a part of Retreatment Period. 
9.5 Follow-up of Adverse Events 
Every effort should be made to follow AEs until resolution or stabilization. Ongoing, 
non-serious AEs that have not resolved or stabilized will be followed until the subject 
completes the study. Serious adverse events will be followed until the AE resolves, stabilizes, 
or the subject is lost to follow-up.  
9.6 Adverse Event Reporting 
9.6.1 
Adverse Events 
At each clinical evaluation, the investigator (or delegate) will determine whether any AEs 
have occurred. AEs will be recorded in the AE/SAE 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 the subject is lost to follow-up. 
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 eCRF. 


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9.6.2 
Serious Adverse Event Reporting 
This study will comply with all applicable regulatory requirements and adhere to the full 
requirements of ICH Topic E2A (Clinical Safety Data Management: Definitions and 
Standards for Expedited Reporting). 
For SAEs occurring during the study, the investigator or delegate will enter all relevant 
information in the eCRF. 
An electronic document containing the AE page and other applicable pages of the eCRF must 
be sent (via facsimile or email) to CSL 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 
the investigational product, must be entered into the eCRF and CSL notified 
immediately (within 24 hours of the investigator becoming aware of the event). 
Adverse events occurring in the period between the time the subject gave written informed 
consent and the first exposure to the investigational product that meet 1 or more of the 
seriousness criteria be entered into the eCRF in the same manner as other SAEs and will be 
included in the clinical study database.  
Any SAE that occurs after the Week 38 Visit or during the Responder Follow-up Period that 
is considered to be causally related to the investigational product must be reported 
immediately (ie, within 24 hours of the investigator becoming aware of the event) to CSL.  
The minimum reporting requirements for reporting of SAEs include: 
 Subject identification number. 
 Suspected medicinal product and/or procedure. 
 Event term. 
 Reporting source identification. 
If the minimum requirements for reporting are fulfilled, the investigator should not wait to 
receive additional information to fully document the event.  
In addition, the investigator must: 


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 Report all SAEs to the relevant Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC) within the timeframe specified by the IRB/IEC. 
 Enter follow-up information in the eCRF 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. 
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). 
9.6.3 
Other Significant Event Reporting 
Adverse events of special interest (see Section 9.1.2) that are considered SAEs should be 
reported accordingly (see Section 9.6.2) 
9.6.4 
Overdose 
Any overdose that occurs in association with an adverse sign or symptom must be entered 
into the eCRF as an AE; if the AE meets any seriousness criteria, the event must be reported 
as an SAE (see Section 9.6.2).  
Details of overdose of the investigational product (defined in Section 7.5) must be recorded 
in the study treatment administration eCRF. Details of overdose of any concomitant therapy 
must be recorded in the Concomitant Medication eCRF. 
9.6.5 
Pregnancy and Breastfeeding  
A female subject or female partner of a male subject who becomes pregnant while 
participating in the study, or up to and including 30 days after the last dose of the 
investigational product, must notify the investigator immediately.  
If a female subject becomes pregnant, she must discontinue treatment with the investigational 
product immediately, but may continue other study procedures at the discretion of the 
investigator. If the female subject is in the active treatment period of the study, her 
participation will be discontinued and the procedure for discontinuation of a subject will be 
followed, as described in Section 4.2). 
CSL must be notified within 5 days of the investigator becoming aware of the pregnancy (by 
entry of appropriate data into the eCRF).  


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Whenever possible, a pregnancy in a subject or in a female partner of a male subject exposed 
to the investigational product 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.  
9.7 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. 
10 Statistics 
10.1 Sample Size Estimation 
10.1.1 Sample Size Based on the Primary Efficacy Endpoint 
The sample size is based on the primary efficacy endpoint of loss-of-response status (binary 
endpoint of loss-of-response or not), at the End-of-TP2 (ie, within 25 weeks after 
randomization). The null hypothesis is that there is no difference between C1-INH and 
placebo with respect to the proportion of subjects with loss-of-response at the End-of-TP2.  
Let p0 and p1 be the expected proportion of subjects with loss-of-response in TP2 in the 
placebo and C1-INH treatment groups, respectively. The alternative is that there is a 
difference between the treatment groups. That is, H0: p0 = p1 versus H1: p0 ≠ p1.   
The power procedure in SAS STAT software (Cary, NC SAS Institute Inc.) was used to 
estimate the sample size, based on the likelihood ratio chi-square test. Determination of the 
sample size was based on the following assumptions: 
 The proportions of subjects experiencing loss-of-response at the End-of-TP2 will be 0.75 
with placebo and 0.30 with C1-INH. 
 There will be at least 90% power to detect a statistically significant effect with two-sided 
test with alpha = 0.05. 
 Logistic regression model with treatment effect will be used for the primary efficacy 
analysis. Wald test statistic for treatment effect from Logistic regression has 
approximately same distribution as chi-square [Fleiss et al, 2003].  Therefore, the sample 


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size calculation based on chi-square test is used to ensure similar power for hypothesis 
testing. 
 Treatment allocation will be 1:1. 
 The planned interim analysis for futility will not impact the type 1 error for the final 
analysis. 
Under these assumptions, a total of 60 subjects (30 randomized to C1-INH and 30 
randomized to placebo) will provide approximately 95% power. The study will enroll a 
sufficient number of subjects to ensure that 60 subjects are randomized. 
The assumptions above are based on a prospective single-arm pilot study to investigate the 
C1-INH added to high-dose IVIG for the treatment of acute AMR non-responsive to 
conventional therapy [Viglietti et al, 2016a]. A total of 6 subjects received C1-INH and IVIg 
for 6 months. The primary endpoint was change in eGFR. These were compared to a 
historical control of 21 subjects who received IVIg. In the prospectively treated C1-INH 
group, 0/6 subjects experienced decline in eGFR at 6 months (0; 95% confidence interval 
[CI], 0 to 46%); and 4/6 subjects had a greater than 20% increase in eGFR (67%; 95% CI, 
22% to 96%). In the historical control group, 15/21 subjects (71%; 95% CI, 48% to 89%) 
experienced decline in eGFR during a comparable 6 month period. 
10.1.2 Power for Allograft Survival  
Allograft survival status (or all-cause allograft failure) at the end of 48 months after 
enrollment represents clinical confirmation of the effect on the allograft of improving eGFR.  
The primary comparison of the proportion of subjects with allograft survival will be between 
the subjects randomized to placebo or C1-INH. It is anticipated that very few subjects will be 
lost to follow-up as standard of care mandates close follow up by the transplanting center. 
This endpoint will be analyzed after all subjects have been followed for 4 years after 
enrollment.  
The power for hypothesis testing of this endpoint was estimated using the power procedure in 
SAS STAT under the following assumptions: 
 The proportions of subjects with allografts surviving at 4 years after enrollment will be 
0.25 with the placebo cohort and 0.75 in the C1-INH cohort. 
 
Alpha = 0.05 (two-sided test). 


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 
Logistic regression model with treatment effect will be used for the primary efficacy 
analysis.  Wald test statistic for treatment effect from Logistic regression has 
approximately same distribution as chi-square [Fleiss et al, 2003].  Therefore, the sample 
size calculation based on chi-square test is used to ensure similar power for hypothesis 
testing. 
 Approximately 30 subjects in each randomized treatment groups. 
There is greater than 90% power to detect the specified target difference between C1-INH 
and placebo groups based on sample size of 60 (approximately 30 in the C1-INH cohort and 
approximately 30 in the placebo cohort). 
The 4-year graft survival for placebo of 25% is based on data presented at the American 
Transplant Congress in Boston [Viglietti et al, 2016b]. This study involved follow-up of 
kidney transplant recipients with biopsy-proven active AMR diagnosed between 2007 and 
2013. Among the subjects who have not responded to standard of care, the 4-year graft 
survival ranged from approximately 10% to 40% for subjects with high and intermediate risk 
scores, respectively. The 4-year graft survival for C1-INH of 75% represents what would be 
expected for subjects who are successfully treated. 
10.1.3 Sample Size Re-estimation 
Data on which to estimate the effect size for the primary endpoint is limited. Because of the 
relatively high degree of uncertainty surrounding the true treatment effect, an unblinded 
sample size re-estimation is planned.  
The interim analysis and sample size re-estimation will be performed by the independent 
Statistical Data Analysis Center supporting the IDMC. In order to maintain study integrity, 
the results of the interim analysis will not be revealed to CSL or otherwise made public. The 
sample size will not be reduced based on sample size re-estimation. The details of sample 
size re-estimation will be provided in an independent charter for IDMC. The 
recommendations from IDMC to CSL will be non-binding as a guideline to aid 
decision-making rather than a definitive rule. 


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10.2 Description of Study Analysis Sets 
10.2.1 Screened Analysis Set 
The Screened analysis set comprises all subjects who provided written informed consent and 
who undergo study screening procedures. 
10.2.2 Enrolled Analysis Set 
The Enrolled analysis set comprises all subjects in the Screened analysis set who do not fail 
screening.  
10.2.3 Intent-to-Treat Analysis Set 
The Intent-to-treat (ITT) analysis set comprises all subjects who were randomized. Subjects 
will be analyzed according to the investigational product to which they were assigned 
(ie, continued C1-INH or placebo) regardless of what was actually received. Any subject who 
receives a randomization identification number will be considered to have been randomized. 
10.2.4 Modified Intent-to-Treat Analysis Set 
All subjects randomized under the original protocol and under all protocol amendments will 
be included in this population except the subjects randomized prior to amendment 3 who do 
not satisfy the criteria in amendment 3.  This modified ITT set will be the primary analysis 
set for the analysis of efficacy data.  
10.2.5 Safety Analysis Sets 
10.2.5.1 Run-in Safety Analysis Set 
The Run-in Safety (RiS) analysis set will include all subjects who received at least one dose 
of C1-INH during TP1. 


C S L Be hri n g L L C  
C S L 8 4 2 _ 3 0 0 1  
C 1 -ester ase I n hi bit or, H u m a n ( 5 0 0 I U/ m L)  
S u bsta ntial A me n d me nt 3  
 
Pa ge 1 0 6  of 1 3 1  
Date: 3 1 Ja n 2 0 2 0  
C o nfi d e ntial 
1 0. 2. 5. 2  R a n d o mize d Wit h dr a w al S afet y A n al ysis Set  
T he Ra n d o mize d Wit h dra wal Safet y ( R W S) a nal ysis set will i ncl u de all s u bjects i n t he I T T 
a nal ysis set w h o recei ve d at least o ne d ose of t he i n vesti gati o nal pr o d uct after ra n d o mizati o n 
d uri n g T P 2. T he R W S a nal ysis set will be base d o n t he i n vesti gati o nal pr o d uct act uall y 
recei ve d (ie, c o nti n ue d C 1 -I N H or p lace b o) d uri n g T P 2.  
1 0. 2. 6  P h ar m ac o ki netic A n al ys is Set 
T he P K a nal ysis set will c o m prise all s u bjects w h o recei ve ≥ 1 d ose of C 1 -I N H a n d w h o ha ve 
≥ 1 meas ura ble le vel of C 1 -esterase i n hi bit or f u ncti o nal acti vit y or C 1 -esterase i n hi bit or 
a nti ge n c o nce ntrati o n.  
1 0. 2. 7  
 
 
 
. 
1 0. 3  St atistic al A n al yses a n d Met h o ds  
A c o m plete descri pti o n of t he statistical a nal yses a n d met h o ds will be a va ila ble i n a statistical 
a nal ysis pla n , w hic h will be fi nalize d bef ore t he data base is l oc ke d. 
U nless ot her wise state d, efficac y a nal yses will be base d o n  t he m o difie d I T T a nal ysis set f or 
a nal yses of e n d p oi nts defi ne d i n T P 2 . Se nsiti vit y a nal yses will be b ase d o n t he I T T set.  
E nr olle d a nal ysis set will be use d f or t he a nal ysis of e n d p oi nts defi ne d o ver t he e ntire st u d y. 
Se nsiti vit y a nal yses of t hese  e n d p oi nts will be d o ne wit h I T T a n d m o difie d I T T sets. 
 
Safet y will be s u m marize d o ver t he e ntire st u d y, a n d acc or di n g t o treat me nt peri o d. Safet y 
will be a nal yze d f or eit her t he Ri S a nal ysis set or t he R W S a nal ysis set, as a p pr o priate.  
All data will be s u m mari ze d i n ta bles or fi g ures a n d all I C H -re q uire d data i n t he data base will 
be liste d. U nless ot her wise s pec ifie d, c o nti n u o us varia bles will be s u m marize d b y prese nti n g 
t he n u m ber of n o n-missi n g o bser vati o ns, mea n, sta n dar d de viati o n, me dia n, mi ni m u m a n d 
ma xi m u m. Ot her descri pti ve statistics (e g, 2 5t h a n d 7 5t h perce ntile, c oefficie nt of variati o n) 
will be re p ort e d w he n a p pr o priate. Cate g orical varia bles will be s u m mari ze d b y prese nti n g 
t he n u m ber of s u bjects a n d perce nta ge f or eac h cate g or y. 
C CI
C CI


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Unless otherwise stated, the statistical model on which inference is based will contain terms 
for the randomization strata as well as treatment. It is anticipated that subject accrual will be 
spread thinly across the centers. There will be no pooling of centers for purposes of analysis. 
Therefore, investigation of center-by-treatment interaction will not be possible. 
Unless otherwise specified, all confidence intervals and P-values will be two-sided. From a 
formal inferential perspective, the type I error will be fully allocated to the analysis of the 
primary efficacy variable, and the selected secondary efficacy variable (ie, all-cause allograft 
failure after randomization into TP2 and through the Responder Follow-up Period). A serial 
gatekeeper hierarchical testing strategy will be used to protect the overall type I error rate of 
0.050 (two-sided). Statistical significance will be claimed only when the results of the two-
sided test favor C1-INH. 
Supportive and secondary analyses will be inspected for consistency and directionality. 
P-values for supportive and/or secondary analyses will be used to provide guidance on the 
weight of evidence for any observed effects. P-values for supportive and/or secondary 
analyses will not be adjusted for multiplicity. 
10.3.1 Definitions 
Baseline 
Baseline eGFR measurements are the nadir of the eGFR of the measurements on the 
Screening and Day 1 Visits for those subjects who entered prior to Amendment 1 and the 
mean of these values for subjects who entered post Amendment 1. 
 
Day 1 is the baseline for vital signs, laboratory values, and other measures unless otherwise 
specified. 
Responder Status 
Responders are defined as subjects whose End-of-TP1 (the mean of Week 11 and Week 12) 
eGFR ≥ 90% of baseline and ≥ 20 mL/min/1.73 m2. The baseline eGFR is defined as the 
mean of the eGFR values obtained during Screening and the Day 1 Visit. 
Loss-of-response at the End-of-TP2 is defined as any 1 of the following 3 conditions:  
 End-of-TP2 eGFR (mean of Week 36 and Week 38 eGFR) that is not stable, defined as: 


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o End-of-TP2 eGFR that is < 90% of the End-of-TP1 eGFR for subjects whose End-of-
TP1 eGFR (mean of Week 11 and Week 12 eGFR) is ≥ 100% of baseline; 
o End-of-TP2 eGFR that is < 90% of baseline for subjects whose End-of-TP1 eGFR is 
≥ 90% of baseline and < 100% of baseline. 
 Allograft failure (defined by allograft nephrectomy, or institution of permanent dialysis, 
or return to the transplant waitlist for renal transplant, whichever occurs first) 
 Subject death by any cause. 
 
10.3.2 Subject Disposition and Characteristics 
10.3.2.1 Subject Disposition 
The following summaries will be provided: 
 The number of subjects in each of the analysis sets defined for this study. 
 Subject status, including subjects ongoing, subjects completed, and subjects withdrawn 
from the study, and primary reason for withdrawal. 
 Investigation product status, including premature discontinuation of the investigational 
product and primary reason for premature discontinuation. 
10.3.2.2 Subject Characteristics 
The following will be summarized using descriptive statistics or frequency counts, as 
appropriate: 
 Demographic characteristics. 
 Relevant medical history. 
 Allograft/allograft donor characteristics. 
 Diagnosis and disease characteristics. 
 Prior and concomitant therapies. 
10.3.3 Efficacy Analyses 
All efficacy endpoints will be analyzed based on Modified-ITT analysis set. Sensitivity 
analyses for efficacy endpoints will be based on ITT set. 


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10.3.3.1 Primary Efficacy Analysis 
The primary analysis of the primary efficacy endpoint of loss-of-response at the End-of-TP2, 
will be based on a logistic regression model. The randomized treatment groups, C1-INH and 
placebo, will be compared based on the logistic model. 
Subjects will be considered to have lost response if they drop-out or are lost to follow-up 
before the response status at the End-of-TP2 could be determined.   
If  is the probability that an individual in a given treatment group will have a loss-of-
response at the End-of-TP2, the logistic model assumes that in each treatment group,  binary 
outcome of response status can be described by a model which assumes independence 
between subjects. Also, the model assumes that all subjects with the same covariate values 
have the same probability, such that the logit of π is a linear function of the regression 
coefficients particular to that individual:  
                                         Logit() = log ( π/1-π)  =   + T XT,      
where XT is the indicator variable for treatment (C1-INH=1, placebo = 0).  
Please note the stratification factors for randomization are not included in this model as 
difference in efficacy is not expected based on these strata.  However, subjects have been 
randomized based on these strata of DSA sensitized versus DSA de novo and AMR severity 
(severe versus all other severities) to ensure balance among these strata. 
The odds ratio for C1-INH versus placebo is exp(T) based on this model for primary 
efficacy analysis. The primary hypothesis to be tested is H0: βT = 0 vs H1:βT ≠ 0. This will be 
tested using the Wald statistic derived from maximum likelihood estimation of the logistic 
model. If this hypothesis is rejected at the 0.05 level of significance and the point estimate of 
βT is positive, efficacy will be declared.  The logistic model will be used to provide point 
estimates of the odds ratio and risk difference, with 95% confidence intervals by treatment 
groups.   Summary statistics of proportion of subjects with loss-of-response will also be 
presented by treatment. If maximum likelihood estimation of the logistic model fails to 
converge then exact methods for logistic regression will be used for hypothesis and 
estimation. 
Components of loss-of-response at the End-of-TP2 will be summarized by treatment groups 
in terms of the proportion of subjects with: 


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 End-of-TP2 eGFR (mean of Week 36 and Week 38 eGFR values) that is not stable, 
defined as: 
o End-of-TP2 eGFR that is < 90% of the End-of-TP1 eGFR for subjects whose End-of-
TP1 eGFR is ≥ 100% of baseline,   
o End-of-TP2 eGFR that is < 90% of baseline for subjects whose End-of-TP1 eGFR is 
≥  90% of baseline and < 100% of baseline 
 All-cause allograft failure (ie, allograft nephrectomy, or institution of permanent dialysis, 
or return to the transplant waitlist for renal transplant). 
 Death by any cause. 
Sensitivity analysis of loss-of-response at the End-of-TP2 
A sensitivity analysis will be performed to access the possible effect of other factors on the 
analysis by performing the logistic regression including the stratification variables DSA 
(sensitized versus de novo) and AMR severity (severe versus all other severities), and 
possibly other key variables, as covariates in the model. If maximum likelihood estimation of 
the logistic model fails to converge subgroup analyses determined by the above factors will 
be performed using exact methods for logistic regression. Summary statistics by covariate 
levels will also be presented. 
Further details of the sensitivity analyses will be specified in the SAP. 
10.3.3.2 Secondary Analyses 
Analysis of key secondary endpoint of proportion of all-cause allograft failure at the end of 
48 months after enrollment 
The primary comparison for the proportion of subjects with all-cause allograft failure at the 
end of 48 months after enrollment will be based on a logistic regression model. The 
randomized treatment groups, C1-INH and placebo, will be compared based on the logistic 
model. 
The same logistic model as described for the primary endpoint will also be used for this 
analysis. 
Analysis of components of all-cause allograft failure after enrollment into TP1 through the 
Responder Follow-up Period (ie, within 48 months after enrollment) will be summarized for 
the randomized treatment groups and also the non-responder subjects who were not 
randomized in TP2.  The summary will be based on the proportion of subjects with: 


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 Any event (ie, all-cause allograft failure or death by any cause). 
 All-cause allograft failure (defined by allograft nephrectomy, or institution of permanent 
dialysis, or return to the transplant waitlist for renal transplant);  
 Surviving allografts 
 Death by any cause 
 
Proportion of subjects with all cause allograft failure will be also summarized by treatment 
groups at 1 year, 2 years, and 3years since enrollment. 
 
Analysis of key secondary endpoint of time to all-cause allograft failure through 
48 months after enrollment 
Treatment group differences will be analyzed with a Cox proportional hazards regression 
model with randomization strata as covariates.  This model will be used to estimate the 
C1-INH /placebo hazard ratio and two-sided 95% confidence interval. Kaplan-Meier plots of 
time to failure through the Responder Follow-up Period will be produced.  
 
Subgroup analysis of loss-of-response at the End-of-TP2 
Details of subgroup analyses will be provided in the SAP.  
The following subgroups, and possibly others to be described in the SAP, will be summarized 
by treatment group with respect to the proportion of loss-of-response: 
 Geographic region: USA, non-USA. 
 DSA by randomization strata: sensitized, de novo. 
 DSA by classification: HLA class I, HLA class II, both HLA class I and II. 
 AMR severity: severe, non-severe (all other severities). 
 Type of donor: deceased, living. 
 Recipient race: Black, non-Black. 
 Recipient sex: male, female. 
 Recipient age: < 65 years, ≥ 65 years. 
Subgroup analysis of all-cause allograft failure at the end of 48 months after enrollment 
Subject Proportions by treatment group for components of all-cause allograft failure will be 
presented for similar subgroups as described above 


C S L Be hri n g L L C  
C S L 8 4 2 _ 3 0 0 1  
C 1 -ester ase I n hi bit or, H u m a n ( 5 0 0 I U/ m L)  
S u bsta ntial A me n d me nt 3  
 
Pa ge 1 1 2  of 1 3 1  
Date: 3 1 Ja n 2 0 2 0  
C o nfi d e ntial 
A n alysis of res p o n ders at t he E n d -of -T P 1   
T he pr o p orti o n of res p o n ders at t he E n d -of -T P 1  will be prese nte d t o get her wit h a n e xact 9 5 % 
c o nfi de nce i nter v al. To calc ulate t his pr o p orti o n, t he de n o mi nat or will i ncl u de all s u bjects i n 
t he E nr olle d a nal ysis set, a n d t he n u merat or will i ncl u de all s u bjects meeti n g t he defi niti o n of 
res p o nse (Secti o n 8. 1. 3. 2 ). 
T he e G F Rs d uri n g T P 1 (ie, wit h o pe n-la bel C 1 -I N H) will be s u m marize d b y sc he d ule d visit 
usi n g descri pti ve statistics, as will t he a bs ol ute a n d perce nt c ha n ges fr o m baseli ne. T he 
descri pti ve statistics will use a vaila ble data fr o m t he E nr olle d a nal ysis set (ie,  mi ssi n g data 
will be n ot i m p ute d).  
 
 
. 
 
 
 
 
. . 
Ne w or w orse ni n g c hr o nic active A M R  
T he pr o p orti o n of s u bjects wit h ne w or w orse ni n g c hr o nic acti ve A M R d uri n g T P 2, as 
defi ne d b y t he Ba nff 2 0 1 5 Criteria [ L o u p y et al, 2 0 1 7 ], will be a nal yze d usi n g t he l o gistic 
m o del as descri be d f or t he pri mar y efficac y e n d p oi nt a n d als o wit h t his m o del stratifie d b y 
t he ra n d o mizati o n strata, f or t he I T T a nal ysis set. 
S ple nect o my  
T he pr o p orti o n of s u bjects wit h s ple nect o m y d uri n g T P 1 will be s u m mari ze d. Descri pti ve 
statistics of ti me fr o m first d ose of C 1 -I N H will be prese nte d. S ple nect o m y d uri n g T P 1  will 
be s u m mari ze d f or t he E nr olle d a nal ysis set.  
T he pr o p orti o ns of s u bjects wit h s ple nect o m y d uri n g T P 2 will be s u m mari ze d b y treat me nt 
gr o u p. Descri pti ve statistics f or ti me fr o m first d ose of C 1 -I N H, a n d ti me fr o m last d ose of 
C 1 -I N H will be prese nte d. S ple nect o m y d uri n g T P 2 will be s u m marize d f or t he I T T a na l ysis 
set.  
C CI
C CI
C CI


C S L Be hri n g L L C  
C S L 8 4 2 _ 3 0 0 1  
C 1 -ester ase I n hi bit or, H u m a n ( 5 0 0 I U/ m L)  
S u bsta ntial A me n d me nt 3  
 
Pa ge 1 1 3  of 1 3 1  
Date: 3 1 Ja n 2 0 2 0  
C o nfi d e ntial 
C 1 -ester ase i n hi bit or f u ncti o n al activity  
C 1 -esterase i n hi bit or f u ncti o nal acti vit y at t he desi g nate d ti me p oi nts will be s u m mari ze d 
usi n g descri pti ve statistics.  
1 0. 3. 3. 3  
  
 
1 0. 3. 4  S afet y A n al yses  
T he e xte nt of e x p os ure t o o pe n -la bel C 1 -I N H; a n d t o d o u ble-bli n d C 1 -I N H or place b o will be 
s u m marize d usi n g descri pti ve statistics. 
1 0. 3. 4. 1  A d verse e ve nts  
A d verse e ve nts will be c o de d usi n g t he Me dical Dicti o nar y f or Re g ulat or y Aff airs 
( Me d D R A) dicti o nar y. T he n u m ber a n d perce nta ge of s u bjects wit h A Es will be re p orte d. 
Fre q ue nc y c o u nts a n d perce nta ges will als o be prese nte d f or s u bjects wit h S A Es, A Es lea di n g 
t o wit h dra wal, A Es b y se verit y, a n d A Es b y relati o ns hi p t o i n vesti gati o nal pr o d uct.  A d verse 
e ve nts will be prese nte d f or T P 1  a n d T P 2.  
1 0. 3. 4. 2  Ot her s afet y e v al u ati o ns  
Cli nical la b orat or y para meters f or t his st u d y will be s u m mari ze d b y sc he d ule d visit usi n g 
descri pti ve statistics or fre q ue nc y c o u nts a n d perce nta ges, as a p pr o priate. Vi tal si g ns will be 
s u m marize d si milarl y. 
1 0. 3. 5  P h ar m ac o ki netics A n al yses  
Bl o o d sa m ples will be c ollecte d f or t he assess me nt of C 1 -esterase i n hi bit or  a nti ge n 
c o nce ntrati o ns a n d C 1 -esterase i n hi bit or  f u ncti o nal acti vit y at desi g nate d ti me p oi nts. 
C 1 -esterase i n hi bit or  f u ncti o nal acti vit y will be deter mi ne d b y a vali date d assa y. 
T he o bser ve d C 1 -esterase i n hi bit or a nti ge n c o nce ntrati o ns a n d f u ncti o nal acti vit y  will be 
s u m marize d b y ti me, r o ute of a d mi nistrati o n, a n d treat me nt s u b gr o u p ( place b o vs C 1 -I N H). 
T he para meter s A U C0 -t a n d C ma x  will be esti mate d, if feasi ble, usi n g n o n -c o m part me ntal P K 
a nal yses i n t he s u bset of ~ 2 0 s u bjects w h o ha ve m ore fre q ue nt, se q ue ntial P K sa m pli n g at t he 
Da y 1 0 Visit a n d t he Wee k 1 1 Visit.  
C CI
C CI


C S L Be hri n g L L C  
C S L 8 4 2 _ 3 0 0 1  
C 1 -ester ase I n hi bit or, H u m a n ( 5 0 0 I U/ m L)  
S u bsta ntial A me n d me nt 3  
 
Pa ge 1 1 4  of 1 3 1  
Date: 3 1 Ja n 2 0 2 0  
C o nfi d e ntial 
I n a d diti o n, p o p ulati o n P K a nal yses ma y als o be c on d ucte d a n d re p orte d se paratel y.  
1 0. 3. 6  
 
 
. 
1 0. 3. 7  
 
1 0. 3. 8  Ot her A n al yses  
Healt h -relate d q ualit y of life will be assesse d usi n g t he E Q-5 D -3 L wit h c o u ntr y s pecific 
val ue sets t o assess t he dis utilit y ass ociate d wit h A M R refract or y t o treat me nt [ D ola n, 1 9 9 7 ; 
Clee m p ut et al, 2 0 0 4 ]. 
1 0. 3. 9  I nteri m A n al ysis 
T w o u n bli n de d a nal yses of t he pri mar y e n d p oi nt are pla n ne d: o ne i nteri m a nal ysis a n d a fi nal 
a nal ysis. T he i nter i m a nal ysis will occ ur w he n 5 0 % of ra n d o mize d s u bjects (ie, 3 0 s u bjects) 
ha ve bee n f oll o we d f or 2 5 wee ks. T he fi nal pri mar y efficac y e n d p oi nt a nal ysis will ta ke place 
after all ra n d o mize d s u bjects ha ve bee n f oll o we d f or 2 5 wee ks after ra n d o mizati o n. T he fi nal 
a nal ysis f or t he st u d y (ie, t he a nal ysis ass ociate d wit h t he st u d y c o m pleti o n date) will ta ke 
place after all ra n d o mize d s u bjects ha ve bee n f oll o we d f or 4 8 m o nt hs  after e nr oll me nt.  
T he i nteri m a nal ysis of t he pri mar y e n d p oi nt will be perf or me d f or p ur p oses of sa m ple size 
re-esti mati o n a n d f or f utilit y m o nit ori n g. Sa m ple size re -esti mati o n is a d dresse d i n 
Secti o n  1 0. 1. 3 .  
To pr otect t he i nte grit y of t he st u d y, res ults of i nteri m efficac y of t he pri mar y e n d p oi n t will 
o nl y be k n o w n t o t he I D M C. T hese res ults will n ot be ma de p u blic. F ull details of t he f utilit y 
a nal ysis a n d w h o will ha ve access t o w hat data/i nf or mati o n a n d w he n t he y will ha ve access 
will be s pecifie d i n t he I D M C C harter. Alt h o u g h statistical st o p pi n g g ui deli nes will be 
pr o vi di n g i n t he c harter , a n u m ber of fact ors m ust be c o nsi dere d t h or o u g hl y as part of t he 
C CI
C CI
C CI
C CI


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decision to modify or terminate the trial [Pocock, 1993]. A recommendation to modify or 
terminate the trial will not be based solely on statistical grounds.  
11 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 
notify the investigator of any 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. 
12 Regulatory and Ethics Considerations 
12.1 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 an FDA Investigational New Drug Application 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. 
12.2 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. 


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12.3 Subject Information and Informed Consent 
Informed consent of study subjects according to the standards of GCP must be implemented 
in this clinical study before protocol-specified procedures are carried out. Information should 
be given in both oral and written form and should be 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. 
The subject (or if necessary, legally acceptable representatives) must be provided with a copy 
of the signed informed consent form. 
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. Subjects must be informed of the change and they must sign 
the amended ICF indicating that they re-consent to participate in the study. 
12.4 Subject 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. 
12.5 Indemnity and Compensation 
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. 


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Other details regarding compensation and the obligations of the investigator/CSL are 
provided in the Clinical Trial Agreement for the study (see Section 13.1). 
13 Administrative Considerations 
13.1 Clinical Trial Research 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.  
13.2 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. 
13.3 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 
or designee and the IRB/IEC. In the event of a medical emergency, the investigator at the 
study site will institute any medical procedures deemed appropriate. However, all such 
procedures must be promptly reported to the CSL Medical Monitor and the IRB/IEC.  
Modifications to the protocol that may affect subject safety or the way the study is to be 
conducted will be documented in a protocol amendment, which must be approved by the 
IRB/IEC.  
Administrative changes to the protocol, defined as minor corrections and/or clarifications that 
have no effect on the way the study is to be conducted, will not require IRB/IEC approval, 
but will be submitted to the IRB/IEC for their information. 


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13.4 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 either subjects who have been 
entered in the study and/or the study sites 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.  
13.5 Documentation and Record Keeping  
13.5.1 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 investigational product or concomitant 
therapy, any AEs experienced, and other notes as appropriate. These records (electronic or 
paper) constitute source data.  
Electronic CRF entries will be considered source data if the eCRF is the site of the original 
recordings (ie, there is no other written or electronic record of the 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 the eCRF is 
considered 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). 
13.5.2 Data Quality Assurance 
Data generated throughout the study will be monitored and the eCRFs checked against the 
subject records for completeness and accuracy. The investigator must provide direct access to 
source data documents. CSL’s study monitor will perform this function.  


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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). 
13.5.3 Record Retention 
The investigator must follow the principles for record retention outlined in the Clinical Trial 
Research Agreement. 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 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.  
13.6 Study and Site Closure 
CSL reserves the right to prematurely discontinue or suspend the study either at a particular 
site or at all study sites at any time and for any reason. If such action is taken, the CSL Study 
Monitor (or delegate) will discuss this with the investigator at each study site at that time and 
notify the investigators in writing. If the study is suspended or terminated for safety reasons, 
then all investigators and the relevant regulatory agencies will be immediately notified of the 
action, as well as the reason for the suspension/termination. The investigator at each study 
site will advise their IRB/IEC overseeing the study of the suspension/termination. 
13.7 Clinical Study Report 
A 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 


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coordinating investigator (or delegate). It is required by CSL that the coordinating 
investigator will sign the clinical study report.  
Progress reports may be provided to the relevant regulatory bodies in accordance with their 
requirements. 
13.8 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. 


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14 References 
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Thrombenbildung nach Berinert HS. Dtsch Arztebl. 2000; 97: A-1016. 
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Glotz D, Legendre C, Delahousse M, Shah N, Sis B, Campbell P, Mengel M, Jouven X, Van 
Huyen JD, Lefaucheur C, Loupy A. Archetype analysis identifies distinct profiles in renal 
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Burns JM, Cornell LD, Perry DK, Pollinger HS, Gloor JM, Kremers WK, Gandhi MJ, Dean 
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C1-esterase Inhibitor, Human (500 IU/mL) Investigator’s Brochure. CSL Behring. 
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Emonds MP, Herman J, Dendievel J, Waer M, Van Damme-Lombaerts R. Evaluation of anti-
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retransplantation in children. J Pediatr. 1979; 95:244-248. 
Fleiss JL, Levin B, Paik MC. Statistical methods for rates and proportions. 3rd rev. ed. New 
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Grafals M, Akalin E. The Highly Sensitized Renal Transplant Recipient. Neph Rounds. 2009; 
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Gulleroglu K, Fidan K, Hancer VS, Bayrakci U, Baskin E, Soylemezoglu O. Neurologic 
involvement in atypical hemolytic uremic syndrome and successful treatment with 
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Kittleson MM, Kobashigawa JA. Antibody-mediated rejection. Curr Opin Organ Transplant. 
2012; 17:551-557. 
Lefaucheur C, Loupy A, Hill GS, Andrade J, Nochy D, Antoine C, Gautreau C, Charron D, 
Glotz D, Suberbielle-Boissel C. Preexisting donor-specific HLA antibodies predict outcome 
in kidney transplantation. J Am Soc Nephrol. 2010; 21:1398-1406. 
Levey AS, Coresh J, Greene T, Stevens LA, Zhang YL, Hendriksen S, Kusek JW, 
Van Lente F; Chronic Kidney Disease Epidemiology Collaboration. Using standardized 
serum creatinine values in the modification of diet in renal disease study equation for 
estimating glomerular filtration rate. Ann Intern Med. 2006 Aug 15;145(4):247-54. Erratum 
in: Ann Intern Med. 2008 Oct 7;149(7):519. 
Loupy A, Haas M, Solez K, Racusen L, Glotz D, Seron D, Nankivell BJ, Colvin RB, 
Afrouzian M, Akalin E, Alachkar N, Bagnasco S, Becker JU, Cornell L, Drachenberg C, 
Dragun D, de Kort H, Gibson IW, Kraus ES, Lefaucheur C, Legendre C, Liapis H, 
Muthukumar T, Nickeleit V, Orandi B, Park W, Rabant M, Randhawa P, Reed EF, Roufosse 
C, Seshan SV, Sis B, Singh HK, Schinstock C, Tambur A, Zeevi A, Mengel M. The Banff 
2015 Kidney Meeting Report: Current Challenges in Rejection Classification and Prospects 
for Adopting Molecular Pathology. Am J Transplant.2017 Jan;17(1):28-41. 
Loupy A, Lefaucheur C. Anti-body mediated rejection of solid-organ allografts. N Engl J 
Med. 2018;379:1150-60. 
Miller GG, Destarac L, Zeevi A, Girnita A, McCurry K, Iacono A, Murray JJ, Crowe D, 
Johnson JE, Ninan M, Milstone AP. Acute humoral rejection of human lung allografts and 
elevation of C4d in bronchoalveolar lavage fluid. Am J Transplant. 2004; 4:1323-1330. 
Montgomery RA, Cozzi E, West LJ, Warren DS. Humoral immunity and antibody-mediated 
rejection in solid organ transplantation. Semin Immunol. 2011a; 23:224-234. 
Montgomery RA, Lonze BE, King KE, Kraus ES, Kucirka LM, Locke JE, Warren DS, 
Simpkins CE, Dagher NN, Singer AL, Zachary AA, Segev DL. Desensitization in HLA-
incompatible kidney recipients and survival. N Engl J Med. 2011b; 365:318-326. 


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Substantial Amendment 3 
 
Page 124 of 131 
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Confidential 
Montgomery RA, Orandi BJ, Racusen L, Jackson AM, Garonzik-Wang JM, Shah T, Woodle 
ES, Sommerer C, Fitts D, Rockich K, Zhang P, Uknis ME. Plasma-Derived C1 Esterase 
Inhibitor for Acute Antibody Mediated Rejection Following Kidney Transplantation: Results 
of a Randomized, Double-Blind, Placebo-Controlled Pilot Study. Am J Transplant. 2016 May 
16. [Epub ahead of print]. 
Nankivell BJ, Alexander SI. Rejection of the kidney allograft. N Engl J Med. 2010; 
363:1451-1462. 
Nguyen S, Butani L. Treatment Options for Pediatric Renal Transplant Recipients with Acute 
Antibody-Mediated Rejection. Ann Pediatr Child Health. 2013; 1:1003. 
Pascual J, Samaniego MD, Torrealba JR, Odorico JS, Djamali A, Becker YT, Voss B, 
Leverson GE, Knechtle SJ, Sollinger HW, Pirsch JD. Antibody-mediated rejection of the 
kidney after simultaneous pancreas-kidney transplantation. J Am Soc Nephrol. 2008; 19: 
812-824. 
Pocock SJ. Statistical and ethical issues in monitoring clinical trials. Statistics in Medicine. 
1993; 12: 1459-1469. 
Stegall MD, Chedid MF, Cornell LD. The role of complement in antibody-mediated rejection 
in kidney transplantation. Nat Rev Nephrol. 2012; 8: 670-678. 
Stegall MD, Diwan T, Raghavaiah S, Cornell LD, Burns J, Dean PG, Cosio FG, Gandhi MJ, 
Kremers W, Gloor JM. Terminal complement inhibition decreases antibody-mediated 
rejection in sensitized renal transplant recipients. Am J Transplant. 2011; 11: 2405-2413. 
Stites E, Le Quintrec M, Thurman JM. The Complement System and Antibody-Mediated 
Transplant Rejection. J Immunol. 2015; 195: 5525-5531. 
Takemoto SK, Zeevi A, Feng S, Colvin RB, Jordan S, Kobashigawa J, Kupiec-Weglinski J, 
Matas A, Montgomery RA, Nickerson P, Platt JL, Rabb H, Thistlethwaite R, Tyan D, 
Delmonico FL. National conference to assess antibody-mediated rejection in solid organ 
transplantation. Am J Transplant. 2004; 4: 1033-1041. 
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May Be Unreliable: a comparison to modification of diet in renal disease in renal transplant 
patients. American Transplant Congress, May 18–23, 2013, in Seattle, WA. 


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Viglietti D, Gosset C, Loupy A, Deville L, Verine J, Zeevi A, Glotz D, Lefaucheur C. 
C1-inhibitor in Acute Antibody-mediated Rejection Nonresponsive to Conventional Therapy 
in Kidney Transplant Recipients: A Pilot Study. Am J Transplant. 2016a; 16: 1596-1603. 
Viglietti D, Loupy A, Duong Van Huyen J, Verine J, Zeevi A, Legendre C, Glotz D, 
Lefaucheur C. Composite Score to Define the Risk of Allograft Loss After Standard-of-Care 
Treatment of Antibody-Mediated Rejection in Kidney Transplantation. Am J Transplant. 
2016b; 16 (Suppl 3). 
Viglietti D, Loupy A, Auburt O, Bestard O, Van Huyen JD, Taupin JL, Glotz D, Legendre C, 
Jouven X, Delahousse M, Kamar N, Lefaucheur C. Dynamic prognostic score to predict 
kidney allograft survival in patients with antibody-mediated rejection. J Am Soc Nephrol. 
2018; 29(2):606-19. 
Vo AA, Zeevi A, Choi J, Cisneros K, Toyoda M, Kahwaji J, Peng A, Villicana R, Puliyanda 
D, Reinsmoen N, Haas M, Jordan SC. A phase I/II placebo-controlled trial of C1-inhibitor for 
prevention of antibody-mediated rejection in HLA sensitized patients. Transplantation. 2015; 
99: 299-308. 


C S L B e h ri n g L L C 
C S L 8 4 2 _ 3 0 0 1 
Cl- est e r as e I n hi bit o r, H u m a n ( 5 0 0 I U/ m L) 
1 5 A p p e n di c es 
A p p e n di x 1 
St u d y Title: 
Si g n at u r e o n B e h alf of S p o ns o r 
A D o u bl e- bli n d , R a n d o mi z e d- wit h dr a w al , Pl a c e b o- c o ntr oll e d St u d y t o 
E v al u at e t he Effi c a c y a n d Safet y of H u m a n Pl as m a- d eri v e d Cl-
est er as e I n hi bit or as A d d- o n t o St a n d ar d of C ar e f or t h e Tr e at m e nt of 
R efr a ct or y A nti b o d y M e di at e d R ej e cti o n i n A d ult R e n al Tr a ns pl a nt 
R e ci pi e nts 
P r ot o c ol N u m b e r: 
C S L 8 4 2 3 0 0 1 
I h a v e r e a d t h e Cli ni c al St u d y Pr ot o c ol titl e d " A D o u bl e- bli n d, R a n d o mi z e d- wit h dr a w al, 
Pl a c e b o- c o ntr oll e d St u d y t o E v al u at e t h e Effi c a c y a n d Safet y of H u m a n Pl as m a- d eri v e d Cl-
est er as e I n hi bit or as A d d- o n t o St a n d ar d of C ar e f or t he Tr e at m e nt of R efr a ct or y A nti b o d y 
M e di at e d R ej e cti o n i n A d ult Re nal Tr a ns pl a nt R e ci pi e nts" a n d c o nfir m t h at, t o t h e b est of m y 
k n o wl e d g e, t h e pr ot o c ol a c c ur at el y d es cri b es t h e d esi g n a n d c o n d u ct of t h e st u d y. 
( Si g n at u r e) 
 M D 
( P ri nt e d n a m e) 
 
( Titl e) 
S u bst a nti al A m e n d m e nt 3 
D at e : 3 1 J a n 2 0 2 0 
D at e ( D D M M M Y Y Y Y) 
P a g e 1 2 6 of 1 3 1 
C o nfi d e nti al 
P P D
P P D
P P D
P P D


CSL Behring LLC 
CSL842_3001 
C1-esterase Inhibitor, Human (500 IU/mL) 
Substantial Amendment 3 
 
Page 127 of 131 
Date: 31 Jan 2020 
Confidential 
Appendix 2 
Signature of Principal Investigator 
Study Title: 
A Double-blind, Randomized-withdrawal, Placebo-controlled Study to 
Evaluate the Efficacy and Safety of Human Plasma-derived C1-esterase 
Inhibitor as Add-on to Standard of Care for the Treatment of Refractory 
Antibody Mediated Rejection in Adult Renal Transplant Recipients 
Protocol Number: 
CSL842_3001 
Site Number: 
 
I have read the Clinical Study Protocol titled “A Double-blind, Randomized-withdrawal, 
Placebo-controlled Study to Evaluate the Efficacy and Safety of Human Plasma-derived C1-
esterase Inhibitor as Add-on to Standard of Care for the Treatment of Refractory Antibody 
Mediated Rejection in Adult Renal Transplant Recipients”. 
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 Council for Harmonisation) and applicable regulatory 
requirements. 
Changes to the Clinical Study Protocol will only be implemented after written approval is 
received from CSL Behring LLC (CSL) and the Institutional Review Board or Independent 
Ethics Committee (as appropriate) with the exception of medical emergencies. 
I will ensure that study staff fully understand and follow the Clinical Study Protocol. 
 
 
 
(Signature) 
 
 
Date (DD MMM YYYY) 
(Printed name) 
 
 
 
(Title) 
 
 


CSL Behring LLC 
CSL842_3001 
C1-esterase Inhibitor, Human (500 IU/mL) 
Substantial Amendment 3 
 
Page 128 of 131 
Date: 31 Jan 2020 
Confidential 
Appendix 3 
Banff 2015 Scoring System for Antibody-mediated Rejection [Loupy et al, 2017] 
Score 
Description 
i: inflammation 
0 
No inflammation or in < 10% of unscarred cortical parenchyma 
1 
Inflammation in 10 to25% of unscarred cortical parenchyma 
2 
Inflammation in 26 to 50% of unscarred cortical parenchyma 
3 
Inflammation in > 50% of unscarred cortical parenchyma 
t: tubulitis 
0 
No mononuclear leukocytes in tubules 
1 
Foci with 1 to 4 leukocytes per tubular cross-section (or 10 tubular cells) 
2 
Foci with 5 to 10 leukocytes per tubular cross-section (or 10 tubular cells) 
3 
Foci with >10 leukocytes per tubular cross-section or the presence of two or more areas of tubular basement membrane destruction accompanied by 
i2/i3 inflammation and t2 elsewhere 
v: intimal arteritis 
0 
No arteritis 
1 
Mild to moderate intimal arteritis in at least one arterial cross-section 
2 
Severe intimal arteritis with at least 25% luminal area lost in at least one arterial cross-section 
3 
Transmural arteritis and/or arterial fibrinoid change and medial smooth muscle necrosis with lymphocytic infiltrate in vessel 
g: glomerulitis  
0 
No glomerulitis 
1 
Glomerulitis in < 25% of glomeruli 
2 
Segmental or global glomerulitis in 25 to 75% of glomeruli 
3 
Glomerulitis in > 75% of glomeruli 


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Confidential 
Score 
Description 
ptc: peritubular capillaritis 
0 
≥ 1 leukocyte in < 10% of cortical PTCs and/or maximum number of leukocytes < 3 
1 
≥ 1 leukocyte cell in ≥ 10% of cortical PTCs with 3 or 4 leukocytes in most severely involved PTC 
2 
≥ 1 leukocyte in ≥ 10% of cortical PTCs with 5 to 10 leukocytes in most severely involved PTC 
3 
≥ 1 leukocyte in ≥ 10% of cortical PTCs with > 10 leukocytes in most severely involved PTC 
ti: total inflammation  
0 
No or trivial interstitial inflammation (<10% of total cortical parenchyma) 
1 
10–25% of total cortical parenchyma inflamed 
2 
26–50% of total cortical parenchyma inflamed 
3 
>50% of total cortical parenchyma inflamed 
i-IFTA: inflammation in area of interstitial fibrosis and tubular atrophy  
0 
No inflammation or <10% of scarred cortical parenchyma 
1 
Inflammation in 10–25% of scarred cortical parenchyma 
2 
Inflammation in 26–50% of scarred cortical parenchyma 
3 
Inflammation in >50% of scarred cortical parenchyma 
C4d  
0 
No staining of peritubular capillaries (0%) 
1 
Minimal C4d staining; > 0 to < 10% of peritubular capillaries 
2 
Focal C4d staining; 10 to 50% of peritubular capillaries 
3 
Diffuse C4d staining; > 50% of peritubular capillaries 
cg: glomerular double contours 
0 
No GBM double contours by light microscopy or EM 


CSL Behring LLC 
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Page 130 of 131 
Date: 31 Jan 2020 
Confidential 
Score 
Description 
1a 
No GBM double contours by light microscopy but GBM double contours (incomplete or circumferential) in at least three glomerular capillaries by EM 
1b 
Double contours of the GBM in 1 to 25% of capillary loops in the most affected nonsclerotic glomerulus by light microscopy 
2 
Double contours affecting 26 to 50% of peripheral capillary loops in the most affected glomerulus 
3 
Double contours affecting > 50% of peripheral capillary loops in the most affected glomerulus 
mm: mesangial matrix expansion 
0 
No more than mild mesangial matrix increase in any glomerulus 
1 
At least moderate mesangial matrix increase in up to 25% of nonsclerotic glomeruli 
2 
At least moderate mesangial matrix increase in 26–50% of nonsclerotic glomeruli 
3 
At least moderate mesangial matrix increase in >50% of nonsclerotic glomeruli 
ah: arteriolar hyalinosis 
0 
No PAS-positive hyaline arteriolar thickening 
1 
Mild to moderate PAS-positive hyaline thickening in at least one arteriole 
2 
Moderate to severe PAS-positive hyaline thickening in more than one arteriole 
3 
Severe PAS-positive hyaline thickening in many arterioles 
aah: hyaline arteriolar thickening 
0 
No typical lesions of calcineurin inhibitor–related arteriolopathy 
1 
Replacement of degenerated smooth muscle cells by hyaline deposits in only one arteriole, without circumferential involvement 
2 
Replacement of degenerated smooth muscle cells by hyaline deposits in more than one arteriole, without circumferential involvement 
3 
Replacement of degenerated smooth muscle cells by hyaline deposits with circumferential involvement, independent of the number of arterioles 
involved 


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C1-esterase Inhibitor, Human (500 IU/mL) 
Substantial Amendment 3 
 
Page 131 of 131 
Date: 31 Jan 2020 
Confidential 
Score 
Description 
cv: vascular fibrous intimal thickening 
0 
No chronic vascular changes 
1 
Vascular narrowing of up to 25% luminal area by fibrointimal thickening 
2 
Vascular narrowing of 26–50% luminal area by fibrointimal thickening 
3 
Vascular narrowing of >50% luminal area by fibrointimal thickening 
ci: interstitial fibrosis 
0 
Interstitial fibrosis in ≤ 5% of cortical area 
1 
Interstitial fibrosis in 6 to 25% of cortical area 
2 
Interstitial fibrosis in 26 to 50% of cortical area 
3 
Interstitial fibrosis in > 50% of cortical area 
ct: tubular atrophy 
0 
No tubular atrophy 
1 
Tubular atrophy involving up to 25% of the area of cortical tubules (mild tubular atrophy) 
2 
Tubular atrophy involving 26 to 50% of the area of cortical tubules (moderate tubular atrophy) 
3 
Tubular atrophy involving in > 50% of the area of cortical tubules (severe tubular atrophy) 
ah = arteriorlar hyalinosis; cg = glomerular double contours; ci = interstitial fibrosis; ct = tubular atrophy; cv = arterial fibrointimal thickening; EM = electron 
microscopy; g = glomerulitis; GBM = glomerular basement membrane; i = inflammation; PAS = periodic acid–Schiff; ptc = peritubular capillaritis; 
PTC = peritubular capillary; t = tubulitis; v = intimal arteritis. 
 
 


V er si o n: 1. 0
Si g n at ur e P a g e 1  of 1
--- D o N ot D et a c h T hi s Si g n at ur e P a g e ---
gl b d ct m p
Pri nt D at e: 1 8- A u g- 2 0 2 1 0 9: 5 0: 4 2 G M T- 0 4: 0 0
Si g n at ur e P a g e
C S L 8 4 2 _ 3 0 0 1 - Pr ot o c ol A m e n d m e nt - 3 - 3 1 J a n 2 0 2 0
Si g n e d B y
D at e ( G M T)
A p pr o v e d-
 A p pr o v al
0 7- F e b- 2 0 2 0 1 9: 2 5: 4 1
A p pr o v e d-
 A p pr o v al
1 0- F e b- 2 0 2 0 0 0: 1 0: 1 9
A p pr o v e d- Cli ni c al S af et y P h y si ci a n A p pr o v al
1 0- F e b- 2 0 2 0 0 8: 2 0: 2 5
P P D
P P D
P P D
P P D
P P D

SAP_001.pdf: 
CSL Behring 
Statistical Analysis Plan 
Protocol Number: CSL842_3001 
Product Name: C1-esterase 
Inhibitor, Human (500 IU/mL) 
 
 
CONFIDENTIAL 
 
 
 Page 1 of 73 
 
STATISTICAL ANALYSIS PLAN (SAP) 
 
Study Title: A Double-blind, Randomized-withdrawal, Placebo-controlled Study 
to Evaluate the Efficacy and Safety of Human Plasma-derived C1-esterase 
Inhibitor as Add-on to Standard of Care for the Treatment of Refractory Antibody 
Mediated Rejection in Adult Renal Transplant Recipients 
Investigational Medicinal Product: C1-INH (C1-esterase Inhibitor, Human) 
Protocol Number: CSL842_3001 
Version: FINAL 1.0 
Version Date: 10-Dec-2020 
 
Sponsor: 
 
CSL Behring LLC 
1020 First Avenue 
King of Prussia, PA 19406 
United States 
 
This document includes information and data that contain trade secrets and privileged or confidential 
information which is the property of CSL Behring LLC and/or its affiliates (“CSL”). This information 
must not be made public without written permission from CSL. These restrictions on disclosure will 
apply equally to all future information supplied to you. 
 
 


C S L Be hri n g  
Statistical A nal ysis Pla n  
Pr ot oc ol N u m ber: C S L 8 4 2 _ 3 0 0 1  
Pr o d uct Na me: C 1 -esterase 
I n hi bit or, H u ma n ( 5 0 0 I U/ m L) 
 
 
C O N FI D E N TI A L  
 
 
 Pa g e 2 of 7 3  
Si g n at ure P a ge s 
A ut h ors:   
 
C S L Be hri n g St u d y 
St atistici a n  
N a m e  
Si g n at ure  
D ate ( d d/ m m m/yyyy) 
A ut h or:  
 
 
 
Title:  
 
C o m p a n y:  
C S L Be hri n g L L C  
 
 
E S P Le a d 
St atistici a n  
N a m e  
Si g n at ure  
D ate ( d d/ m m m/yyyy) 
A ut h or:  
 
 
 
Title:  
 
C o m p a n y:  
 
 
 
 
P P D
P P D
P P D
P P D
P P D


C S L Be hri n g  
Statistical A nal ysis Pla n  
Pr ot oc ol N u m ber: C S L 8 4 2 _ 3 0 0 1  
Pr o d uct Na me: C 1 -esterase 
I n hi bit or, H u ma n ( 5 0 0 I U/ m L) 
 
 
C O N FI D E N TI A L  
 
 
 Pa g e 3 of 7 3  
A p pr o vers:  
B y si g ni n g bel o w, I a p pr o ve of t his versi o n of t he Statistical A nal ysis Pla n. 
 
N a me  
Si g n at ure  
D ate ( d d/ m m m/yyyy) 
A p pr o ve d b y:  
 
, P h D 
 
 
Title:  
 
C o m p a n y:  
C S L Be hri n g L L C  
 
 
N a me  
Si g n at ure  
D ate ( d d/ m m m/yyyy) 
A p pr o ve d b y:  
, M D 
 
 
Title:  
 
C o m p a n y:  
C S L Be hri n g L L C  
 
 
 
P P D
P P D
P P D
P P D


C S L Be hri n g  
Statistical A nal ysis Pla n  
Pr ot oc ol N u m ber: C S L 8 4 2 _ 3 0 0 1  
Pr o d uct Na me: C 1 -esterase 
I n hi bit or, H u ma n ( 5 0 0 I U/ m L) 
 
 
C O N FI D E N TI A L  
 
 
 Pa g e 4 of 7 3  
Ta ble of C o nte nts  
 
Ta ble of C o nte nts ............................................................................................................................ 4 
List of Ta bles  ................................................................................................................................... 7 
List of Fi g ures ................................................................................................................................. 8 
1  M o dificati o n Hist or y  ................................................................................................................ 9 
2  List of A b bre viati o ns  .............................................................................................................. 1 0 
3  P ur p ose .................................................................................................................................... 1 1  
4  St u d y Desi g n ............................................................................................................................ 1 1  
4. 1  
St u d y Desi g n ....................................................................................................................... 1 1  
4. 2  
St u d y O bjecti ves a n d E n d p oi nts ......................................................................................... 1 3  
4. 2. 1  
Pri mar y O bjecti ve a n d E n d p oi nt .................................................................................... 1 3  
4. 2. 2  
Sec o n dar y O bj ecti ves a n d E n d p oi nts ............................................................................. 1 5  
4. 3  
St u d y Treat me nts  ................................................................................................................ 1 8 
4. 4  
Ra n d o mizati o n Pr oce d ur es a n d Bli n di n g ........................................................................... 2 1  
4. 5  
Deter mi nati o n of t he Sa m ple Size  ...................................................................................... 2 2 
4. 6  
Pla n ne d I nteri m A n al yses a n d Re vie ws ............................................................................. 2 5  
5  C ha n ges i n t he C o n d uct of Pla n ne d A n al yses ........................................................................ 2 5  
6  St u d y A nal ysis Sets  ................................................................................................................ 2 6 
6. 1  
Scree ne d A n al ysis Set ......................................................................................................... 2 6  
6. 2  
E nr olle d A nal ysis Set  ......................................................................................................... 2 6 
6. 3  
I nte nt-t o-Treat A nal ysis Set  ................................................................................................ 2 6 
6. 4  
M o difie d I nte nt- t o-Treat A nal ysis Set  ................................................................................ 2 7 
6. 5  
Safet y A n al ysis Sets  ........................................................................................................... 2 7 
6. 6  
P har mac o ki netic A nal ysis Set  ............................................................................................ 2 7 
6. 7  
 
7  Ge ner al C o nsi derati o ns ........................................................................................................... 2 8  
7. 1  
M ult ice nter St u dies ............................................................................................................. 2 9 
7. 2  
Treat me nt Descri pt ors  ........................................................................................................ 2 9 
C CI


CSL Behring 
Statistical Analysis Plan 
Protocol Number: CSL842_3001 
Product Name: C1-esterase 
Inhibitor, Human (500 IU/mL) 
 
 
CONFIDENTIAL 
 
 
 Page 5 of 73 
7.3 
Multiple Comparisons and Multiplicity ............................................................................. 29 
8 
Data Handling Conventions .................................................................................................... 30 
8.1 
Missing Data ....................................................................................................................... 30 
8.1.1 
Imputation of Non-Date Missing Data ........................................................................... 30 
8.1.2 
Imputation of Partial Dates ............................................................................................. 30 
8.2 
Derived Variables ............................................................................................................... 33 
8.2.1 
Reference Dates .............................................................................................................. 33 
8.2.2 
Study Day for Safety Measures ...................................................................................... 34 
8.2.3 
Study Day for Efficacy ................................................................................................... 34 
8.2.4 
Durations ........................................................................................................................ 34 
8.2.5 
Baseline Definition ......................................................................................................... 34 
8.2.6 
Change From Baseline ................................................................................................... 35 
8.2.7 
Multiple Assessments ..................................................................................................... 35 
8.2.8 
Actual Treatment ............................................................................................................ 36 
8.2.9 
Derived Variables ........................................................................................................... 36 
8.3 
Study Periods Relative to Treatment .................................................................................. 38 
8.3.1 
Time in Relation to Treatment ........................................................................................ 38 
8.3.2 
Study Time Periods for AEs ........................................................................................... 38 
8.3.3 
Study Time Periods for Prior and Concomitant Medications ......................................... 39 
9 
Study Population ..................................................................................................................... 39 
9.1 
Disposition of Subjects ....................................................................................................... 39 
9.2 
Protocol Deviations ............................................................................................................ 40 
9.3 
Demographic and Baseline Characteristics ........................................................................ 40 
9.3.1 
Demographics ................................................................................................................. 41 
9.3.2 
Baseline Characteristics .................................................................................................. 41 
9.4 
Prior and Concomitant Medications ................................................................................... 42 
9.5 
Medical History .................................................................................................................. 43 
10 Efficacy ................................................................................................................................... 43 
10.1 Analysis of Proportion of Subjects With Loss of Response at the End-of-TP2 ................. 43 
10.1.1 
Subgroup Analyses of Proportion of Subjects With Loss of Response at the End-of-TP2
 ........................................................................................................................................ 44 
10.2 Analysis of key Secondary Endpoint Proportion of Subjects With All-Cause Allograft 
Failure Through the Responder Follow-up Period (ie, Within 48 Months After Enrollment)
 ............................................................................................................................................ 45 


C S L Be hri n g  
Statistical A nal ysis Pla n  
Pr ot oc ol N u m ber: C S L 8 4 2 _ 3 0 0 1  
Pr o d uct Na me: C 1 -esterase 
I n hi bit or, H u ma n ( 5 0 0 I U/ m L) 
 
 
C O N FI D E N TI A L  
 
 
 Pa g e 6 of 7 3  
1 0. 3  A nal ysis of Ti me t o All -Ca use All o graft Fail ure T hr o u g h 4 8 M o nt hs After E nr oll me nt... 4 5  
1 0. 4  A nal ysis of t he C ha n ge i n e G F R Fr o m Baseli ne t o E n d- of- T P 1  ....................................... 4 5 
1 0. 5  A nal ysis of Res p o n ders at t he E n d- of- T P 1  ........................................................................ 4 5 
1 0. 6  A nal ysis of t he C ha n ge i n e G F R Fr o m E n d- of- T P 1 t o t he E n d- of- T P 2  ............................ 4 5 
1 0. 7  A nal ysis of t he Rate of C ha n ge of e G F R i n Treat me nt Peri o d 2 ....................................... 4 5  
1 0. 8  
1 0. 9  
 
1 0. 1 0  A nal ysis of C 1- I N H F u n cti o nal Acti vit y ............................................................................ 4 6 
1 0. 1 1  
 
1 0. 1 2  A nal ysis of Plas ma p heresis Sessi o ns ................................................................................. 4 6  
1 0. 1 3  
 
1 0. 1 4  
 
1 0. 1 5  
 
1 0. 1 6  
 
 
1 0. 1 7  
 
1 0. 1 8  Tr o u g h I VI g C o nce ntr ati o ns at Desi g nate d Ti me P oi nts .................................................... 4 7  
1 0. 1 9  
 
1 0. 2 0  Treat me nt C o m plia nce  ....................................................................................................... 4 8 
1 1  Safet y A n al yses  ....................................................................................................................... 4 9 
1 1. 1  E xte nt of E x p os ure ............................................................................................................. 4 9  
1 1. 2  A d verse E v e nts  ................................................................................................................... 5 0 
1 1. 3  A d verse E v e nts of S peci al I nterest ( A E SI)  ........................................................................ 5 1 
1 1. 4  Deat hs a n d Seri o us A d verse E ve nts ................................................................................... 5 1  
1 1. 5  A d verse E v e nts Lea di n g t o Disc o nti n uati o n of St u d y Treat me nt, Wit h dra wal fr o m t he 
St u d y, a n d Ot her Si g nifica nt A d verse E ve nts ..................................................................... 5 2  
1 1. 6  Pre g na ncies  ......................................................................................................................... 5 2 
1 1. 7  Cli nical La b orat or y E val uati o ns ......................................................................................... 5 2  
1 1. 7. 1  
Cli nical c he mistr y  ........................................................................................................... 5 2 
1 1. 7. 2  
He mat ol o g y .................................................................................................................... 5 3  
C CI
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C S L Be hri n g  
Statistical A nal ysis Pla n  
Pr ot oc ol N u m ber: C S L 8 4 2 _ 3 0 0 1  
Pr o d uct Na me: C 1 -esterase 
I n hi bit or, H u ma n ( 5 0 0 I U/ m L) 
 
 
C O N FI D E N TI A L  
 
 
 Pa g e 7 of 7 3  
1 1. 8  Ot her Safet y M eas ur es  ....................................................................................................... 5 3 
1 1. 8. 1  
Vital Si g ns  ...................................................................................................................... 5 3 
1 2  P har mac o ki netics  .................................................................................................................... 5 3 
1 2. 1  P K Sa m pli n g Sc he d ule ....................................................................................................... 5 4  
1 2. 2  Plas ma P K E n d p oi nts ......................................................................................................... 5 4  
1 2. 3  S u m mar y of C 1- I N H A nti ge n a n d F u ncti o nal Acti vit y Plas ma C o nce ntrati o ns ................ 5 5 
1 2. 4  S u m mar y of C 1 -I N H P K Para meters  ................................................................................. 5 5 
1 2. 5  P har mac o ki netic A nal ysis Data Fl o w  ................................................................................. 5 6 
1 3  
 
1 4  
 
1 5  Refere n ces ............................................................................................................................... 5 6 
1 6  A p pe n dices ............................................................................................................................. 5 8  
1 6. 1  Sta n dar dize d Me d D R A Q uer y f or E m b olic a n d T hr o m b otic E ve nts ( Narr o w) ( S M Q C o de: 
2 0 0 0 0 0 8 1) ........................................................................................................................... 5 8  
1 6. 2  Sta n dar dize d Me d D R A Q uer y - A na p h yl actic Reacti o n ( Br oa d) ( S M Q C o de: 2 0 0 0 0 0 2 1) 6 9 
 
List of Ta bles  
Ta ble 1  
Pri mar y E n d p oi nt .................................................................................................. 1 4  
Ta ble 2  
Sec o n dar y E n d p oi nts ............................................................................................ 1 5  
Ta ble 3  
 
Ta ble 4  
S u m mar y of d ose a n d d osi n g re gi me .................................................................... 1 8  
Ta ble 5  
Descri pti o n of C 1- I N H ......................................................................................... 2 0 
Ta ble 6  
Descri pti o n of Place b o  .......................................................................................... 2 1 
 
 
 
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CSL Behring 
Statistical Analysis Plan 
Protocol Number: CSL842_3001 
Product Name: C1-esterase 
Inhibitor, Human (500 IU/mL) 
 
 
CONFIDENTIAL 
 
 
 Page 8 of 73 
 
List of Figures 
Figure 1 
Study Overview .................................................................................................... 12 
Figure 2 
Individual variations of eGFR in C1-INH patients ............................................... 23 
Figure 3 
Stratification of Graft Survival After ABMR Therapy Based on Prognostic 
Scoring .................................................................................................................. 25 
 
 
 


C S L Be hri n g  
Statistical A nal ysis Pla n  
Pr ot oc ol N u m ber: C S L 8 4 2 _ 3 0 0 1  
Pr o d uct Na me: C 1 -esterase 
I n hi bit or, H u ma n ( 5 0 0 I U/ m L) 
 
 
C O N FI D E N TI A L  
 
 
 Pa g e 9 of 7 3  
1  M o dific ati o n Hist or y  
 
Versi o n  
Effecti ve 
D ate  
A ut h or of 
M o dific ati o n  
Re as o n f or C h a n ge  
0. 2 ( mislea di n g 
versi o n 
n u m beri n g, ha d 
be e n versi o n 1. 0) 
2 1 /J u n/ 2 0 18  
 
N/ A –  First Versi o n  
1. 0  
1 3/ Dec/ 2 0 1 8  
 
I m ple me ntati o n of s p o ns or 
c o m me nts 
2. 0  
2 7 N o v 2 0 2 0  
 
 
 
 
U p date d d oc u me nt f oll o wi n g st u d y 
ter mi nati o n decisi o n b y s p o ns or 
3. 0  
0 8 Dec 2 0 2 0  
 
I m ple me ntati o n of s p o ns or re vie w 
c o m me nts 
Fi nal 1 . 0 
1 0 Dec 2 0 2 0  
 
N A  
 
 
 
P P D
P P D
P P D
P P D
P P D


C S L Be hri n g  
Statistical A nal ysis Pla n  
Pr ot oc ol N u m ber: C S L 8 4 2 _ 3 0 0 1  
Pr o d uct Na me: C 1 -esterase 
I n hi bit or, H u ma n ( 5 0 0 I U/ m L) 
 
 
C O N FI D E N TI A L  
 
 
 Pa g e 1 0  of 7 3  
2  List of A b bre vi ati o ns  
A b bre vi ati o n  
Ter m  
A B M R  
 A nti b o d y -Me diate d Rejecti o n  
A E  
A d verse E ve nt  
A M R  
A nti b o d y -me diate d Rejecti o n  
A Da M  
A nal ysis Data M o del  
C DI S C  
Cli nical Data I nterc ha n ge Sta n dar ds C o ns orti u m  
C 1 -I N H 
C 1 -esterase  I n hi bit or 
C g  
C hr o nic Gl o mer ul o pat h y  
C P  
C o n diti o nal P o wer  
C S L  
C S L Be hri n g L L C  
D G F  
Dela ye d Graft F u ncti o n  
D S A  
D o n or -s pecific A nti b o d y  
D V T  
Dee p Vei n T hr o m b osis  
e C R F  
Electr o nic Case Re p ort F or m  
e G F R  
Esti mate d Gl o mer ular Filtrati o n Rate  
G C P  
G o o d Cli nical Practice  
G F R  
Gl o mer ular Filtrati o n Rate  
H R  
Hazar d Rati o  
I C H 
I nter nati o nal C o nfere nce o n Har m o nizati o n 
I M P 
I n vesti gati o nal Me dici nal Pr o d uct 
I D M C 
I n de pe n de nt Data M o nit ori n g C o m mittee 
I R T 
I nteracti ve Res p o nse Tec h n ol o g y  
I T T 
I nte nt-t o-Treat  
I V 
I ntra ve n o us 
I VI g 
I ntra ve n o us I m m u n o gl o b uli n 
P K  
P har mac o ki netic  
RI S  
R u n -i n Safet y 
R W S  
Ra n d o mize d Wit h dra wal Safet y  
S A E  
Seri o us A d verse E ve nt  
S A P  
Statistical A nal ysis Pla n  
S C  
S u bc uta ne o us  
S cr 
Ser u m Creati ni ne  
T E E  
T hr o m b oe m b olic E ve nts  
 
 
 
 
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CSL Behring 
Statistical Analysis Plan 
Protocol Number: CSL842_3001 
Product Name: C1-esterase 
Inhibitor, Human (500 IU/mL) 
 
 
CONFIDENTIAL 
 
 
 Page 11 of 73 
3 Purpose 
This is the statistical analysis plan (SAP) for the Clinical Study Report for study CSL842_3001. 
This SAP provides details of the planned statistical analyses of the primary and relevant 
secondary endpoints for which data are available. This study was terminated by the sponsor on 
September 15, 2020 for administrative reasons. At the time of termination, 13 subjects were 
randomized and 2 subjects were still in treatment (1 subject in TP2 and another subject in re-
treatment). The study database will be locked after the completion of the dosing regimens of 
these 2 subjects.  Based n the termination of the study, many analysis discussed in the protocol 
will not be able to be performed (for example, all 4 year endpoints are unattainable). 
This SAP complies with the International Conference on Harmonisation (ICH) Harmonised 
Tripartite Guideline Topic E9, Statistical Principles for Clinical Trials. It is based upon the 
Clinical Study Protocol (dated 01-March-2017) and Study Protocol Amendment Version 1.0 
(dated 30-August-2017), Study Protocol Amendment Version 2.0 (dated 23-January 2019), and 
Study Protocol Amendment Version 3.0 (dated 31-January 2020). 
4 Study Design 
4.1 
Study Design 
Study CSL842_3001 is a randomized withdrawal, double-blind, placebo-controlled, multi-center 
study. A schematic of the design is shown in Figure 1. Full details may be found in Section 3 of 
the Clinical Study Protocol. 
 
 


CSL Behring 
Statistical Analysis Plan 
Protocol Number: CSL842_3001 
Product Name: C1-esterase 
Inhibitor, Human (500 IU/mL) 
 
 
CONFIDENTIAL 
 
 
 Page 12 of 73 
Figure 1 
Study Overview 
 
AMR = antibody-mediated rejection; C1-INH = C1-esterase inhibitor; human; IVIg = intravenous immunoglobulin; MFI = 
mean fluorescence intensity; TP1 = Treatment Period 1; Treatment Period 2 
Note: Post-treatment Follow-up Period is for responders. 
a Intravenous immunoglobulin (IVIg) will be administered every 4 weeks to all subjects at a dose of 2 grams/kg. The dose must 
be administered over a minimum period of at least 2 days, and may be administered over a period of up to 5 days. 
Plasmapheresis may be administered based on local DSA results and Principal Investigator’s judgement. 
b Intravenous (IV) C1-INH (60 IU/kg) will be administered to each subject over the first 13 days of TP1for a total of 5 doses. 
Thereafter, subcutaneous (SC) C1-INH (60 IU/kg twice weekly) will be administered to each subject for the remainder of 
TP1. 
c If DSA ≥ 2000 MFI in local lab in TP2 or Retreatment Period, IVIg may be administered to subjects at a dose of 2 grams/kg 
every 4 weeks. The dose must be administered over a minimum period of at least 2 days, and may be administered over a 
period of up to 5 days. Plasmapheresis may be administered based on local DSA results and Principal Investigator’s 
judgement (Section 5.4.2 of the protocol). 
d During the TP2, eligible subjects will be randomized 1:1 to receive treatment with investigational product (C1-INH [60 
IU/kg] or placebo) subcutaneously twice weekly.  
e Retreatment Period(s) are blinded and subjects will receive the same investigational product treatment assignment as received 
during Treatment Period 2. 
f Response is defined as an End-of-TP1 eGFR (mean of Week 11 and Week 12 eGFR) that is ≥ 20 mL/min/1.73 m2 and ≥ 90% 
of the baseline eGFR (mean of Screening and the Day 1 eGFR)).  
g AMR Recurrence or persistence in Responder Follow-up Period is proven by biopsy, evidenced by infiltrating neutrophils 
and/or monocytes with or without the presence of C4d (g > 0, v > 0, and/or ptc > 0 (if C4d is negative, g + ptc ≥ 2, (Section 
8.1.3.3 of the protocol). 
 
 
IVIg c + C1-INH d
IVIg c + Placebo d
IVIg a
+ 
C1-INH b
1º endpoint
assessed
Open-label
Treatment Period 1: 
13 weeks
Double-blind
Treatment Period 2: 
25 weeks
Post-treatment 
Follow-up Period:
39 months
End of 
Study
Non-responsef
Responsef
Non-responder follow-up until graft failure or up to 48 months
Retreatment Periodc,e
AMR 
Recurrence g
Re-enter 
Follow-up 
Period


CSL Behring 
Statistical Analysis Plan 
Protocol Number: CSL842_3001 
Product Name: C1-esterase 
Inhibitor, Human (500 IU/mL) 
 
 
CONFIDENTIAL 
 
 
 Page 13 of 73 
• During open-label TP1, all eligible subjects will receive treatment with C1-INH (60 IU/kg) in 
combination with standard of care for 13 weeks. At the conclusion of TP1, subjects who 
demonstrate a treatment response (see Section 8.2.9) will be randomized to continue in the 
study in TP2. Subjects who are considered non-responders will enter the Non-responder 
Follow-up Period during which they will be followed for up to 48 months. 
• During the blinded TP2, randomized subjects will either continue treatment with C1-INH (60 
IU/kg) or begin treatment with placebo (both in combination with IVIg and plasmapheresis) 
for 25 weeks, according to the randomization schedule.  
• At the conclusion of TP2, randomized subjects will enter the Responder Follow-up Period, 
where they will be observed for approximately 39 months until Study Month 48. 
Randomized subjects who experience a biopsy-proven AMR recurrence or who have persistent 
AMR during the Responder Follow-up will be permitted to undergo blinded retreatment with 
either C1-INH or placebo (both in combination with standard of care treatment). Subjects who 
participate in a Retreatment Period will receive blinded investigational product (C1-INH or 
placebo) according to their TP2 treatment assignment, in combination with standard of care. 
4.2 
Study Objectives and Endpoints 
4.2.1 
Primary Objective and Endpoint 
4.2.1.1 
Primary Objective 
The primary objective of the study is to evaluate the efficacy of C1-INH in the treatment of 
refractory AMR in renal allograft recipients. 
 
 


CSL Behring 
Statistical Analysis Plan 
Protocol Number: CSL842_3001 
Product Name: C1-esterase 
Inhibitor, Human (500 IU/mL) 
 
 
CONFIDENTIAL 
 
 
 Page 14 of 73 
4.2.1.2 
Primary Endpoint 
Table 1 
Primary Endpoint 
Endpoint 
Summary Measure 
Loss-of-response 
during TP2. 
Proportion of subjects with loss-of-response at the End-of-TP2.  
Loss-of-response at the End-of-TP2 is defined as any 1 of the 
following 3 conditions: 
• End-of-TP2 eGFR (mean of Week 36 and Week 38 eGFR) 
that is not stable, defined as: 
o End-of-TP2 eGFR that is < 90% of the End-of-TP1 
eGFR for subjects whose End-of-TP1 eGFR (mean of 
Week 11 and Week 12 eGFR) is ≥ 100% of baseline, 
o End-of-TP2 eGFR that is < 90% of baseline for subjects 
whose end-of- TP1 eGFR is ≥ 90% of baseline and 
<100% of baseline, 
• Allograft failure (defined by allograft nephrectomy, or 
institution of permanent dialysis, or return to the transplant 
waitlist for renal transplant, whichever occurs first), 
• Subject death by any cause. 
eGFR = estimated glomerular filtration rate; TP1= Treatment Period 1; TP2 = Treatment Period 2 
4.2.1.3 
Intended Primary Study Hypothesis 
Corresponding to the primary objective, the superiority of C1-INH relative to placebo are 
measured by the primary endpoint, proportion of subjects with loss of response at the End-of-
TP2, based on the Modified Intent-to-Treat analysis. The null hypothesis was to be tested using 
the Wald statistic derived from maximum likelihood estimation of the logistic model with a Type 
I error rate of 0.05 (two-sided test). Symbolically, the null and alternative hypotheses are 
expressed as follows: 
H0: βT = 0 vs H1:βT ≠ 0  
where βT is the coefficient of treatment in the logistic regression model. 
Since the study terminated early, there will be no formal hypothesis testing for any endpoints. 
 
 


CSL Behring 
Statistical Analysis Plan 
Protocol Number: CSL842_3001 
Product Name: C1-esterase 
Inhibitor, Human (500 IU/mL) 
 
 
CONFIDENTIAL 
 
 
 Page 15 of 73 
4.2.2 
Secondary Objectives and Endpoints 
4.2.2.1 
Secondary Objectives 
The secondary objectives of the study are: 
1. To further evaluate the efficacy of C1-INH in the treatment of refractory AMR in renal 
allograft recipients. 
2. To evaluate the safety of C1-INH in the treatment of refractory AMR in renal allograft 
recipients. 
3. To evaluate the pharmacokinetics (PK) of C1-INH during the treatment of refractory AMR in 
renal allograft recipients. 
4.2.2.2 
Secondary Endpoints 
Table 2 
Secondary Endpoints 
Secondary 
Objective 
Endpoints 
Summary Measure 
1 
All-cause 
allograft failure 
through the 
Responder 
Follow-up Period  
Proportion of subjects with all-cause allograft failure 
through the Responder Follow-up Period (ie, within 48 
months after enrollment). Allograft failure is defined as 1 
of the following:  
• Allograft nephrectomy, institution of permanent 
dialysis, or return to the transplant waitlist for renal 
transplant, whichever occurs first, OR  
• Subject death by any cause. 
1 
Change in eGFR 
from baseline to 
TP1 
The difference between the End-of-TP1 eGFR and 
baseline eGFR. 
1 
Change in eGFR 
from TP1 to the 
End-of -TP2. 
The difference between the End-of-TP2 eGFR and the 
End-of-TP1 eGFR. 
1 
The rate of 
change of eGFR. 
The rate of change of eGFR during TP2 as defined by the 
slope of the mean regression of eGFR over time in TP2. 
1 
Time (weeks) to 
all-cause allograft 
failure through the 
Responder 
Follow-up Period  
Time (weeks) to all-cause allograft failure through the 
Responder Follow-up Period (ie, within 48 months after 
enrollment).  


CSL Behring 
Statistical Analysis Plan 
Protocol Number: CSL842_3001 
Product Name: C1-esterase 
Inhibitor, Human (500 IU/mL) 
 
 
CONFIDENTIAL 
 
 
 Page 16 of 73 
Secondary 
Objective 
Endpoints 
Summary Measure 
1 
Responder status 
at the End-of-
TP1. 
Proportion of responders at the End-of-TP1. Response is 
defined as End-of-TP1 eGFR that is ≥ 20 mL/min/1.73 
m2 and ≥ 90% of the baseline eGFR. 
1 
Subject death 
through the 
Responder 
Follow-up Period. 
Proportion of subjects surviving through the Responder 
Follow-up Period. 
2 
Any AE assessed 
as related to 
investigational 
product during 
TP1 and during 
TP2. 
Proportion of subjects with any AE assessed as related to 
investigational product. 
3 
Pre-dose C1-
esterase inhibitor 
functional activity 
at Day 1, Week 
12, and Week 38. 
Mean pre-dose C1-esterase inhibitor functional activity 
at Day 1, Week 12, and Week 38. 
3 
For the subset of 
subjects with 
sequential PK 
sampling, C1-
esterase inhibitor 
functional activity 
Cmax, and AUC0-t 
after IV and/or SC 
administration of 
C1-INH. 
C1-esterase inhibitor functional activity Cmax and AUC0-t 
for IV and SC administration. 
AE = adverse event; AUC0-t = area under the plasma-concentration time curve 0 to a definite time; Cmax = maximum 
concentration; eGFR = estimated glomerular filtration rate; IV = intravenous; PK = pharmacokinetic; SC = 
subcutaneous; TP1 = Treatment Period 1; TP2 = Treatment Period 2 
 


C S L Be hri n g  
Statistical A nal ysis Pla n  
Pr ot oc ol N u m ber: C S L 8 4 2 _ 3 0 0 1  
Pr o d uct Na me: C 1 -esterase 
I n hi bit or, H u ma n ( 5 0 0 I U/ m L) 
C O N FI D E N TI A L  
 Pa g e 1 7  of 7 3  
4. 2. 2. 3  
 
4. 2. 2. 4  
 
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C S L Be hri n g  
Statistical A nal ysis Pla n  
Pr ot oc ol N u m ber: C S L 8 4 2 _ 3 0 0 1  
Pr o d uct Na me: C 1 -esterase 
I n hi bit or, H u ma n ( 5 0 0 I U/ m L) 
 
C O N FI D E N TI A L  
 
 
 Pa g e 1 8  of 7 3  
4. 3  
St u d y Tre at me nts  
D ose a n d D osi n g Re gi me n 
A s u m mar y of d ose a n d d osi n g re gi me n is s h o w n i n  Ta ble 4 . 
Ta ble 4  
S u m m ar y of d ose a n d d osi n g re gi me 
Ti mefr a m e  
I ntr a ve n o us 
A d mi nistr ati o n  
S u bc ut a ne o us 
A d mi nistr ati o n  
Tre at m e nt Peri o d 1: T he Da y 1 Visit t o t he Da y 1 3 Visit a 
6 0 I U/ k g C 1 -I N H  
N ot a p plica ble  
Tre at m e nt Peri o d 1: T he Da y 1 4 Visit t o t he Wee k 1 2 2 n d 
Visit a  
N ot A p plica ble  
6 0 I U/ k g C 1 -I N H  
Tre at m e nt Peri o d 2: Wee k 1 3 t o t he Wee k 3 8 Visit
b  
N ot A p plica ble  
6 0 I U/ k g C 1 -I N H  
O R  
0. 1 2  m L/ k g  Place b o  
Re -tre at me nt Peri o d:  T he Retreat me nt Da y 1 Visit t o 
t he Retreat me nt Wee k 2 6 Visit. c 
N ot A p plica ble  
6 0 I U/ k g C 1 -I N H  
O R  
0. 1 2  m L/ k g  Place b o  
I V = i ntra ve n o us; S C = s u b c uta n e o us 
a   Trea tme n t Peri o d 1 i s o p e n -la b el a n d each s u bject will recei ve C 1-IN H . C 1-IN H  ( 6 0 I U/ k g) will be a d mi nistered I V t o each 
s u bject o ve r t h e first 1 3 d a y s of Trea tme n t Peri o d 1 f or a t otal of 5 d oses. T h ereaf ter, C 1-IN H  ( 6 0 I U/ kg t wic e wee kl y ) will be 
a d mi nistered S C t o  each s u bjects f or t h e re mai n d er of Trea tme n t Peri o d 1.  T h e first d ose of ra n d o mize d i n v esti g ati o n al pr o d uct 
will be a d mi nistere d t o res p o n d ers at t h e Wee k 1 3 Visit.  
b    Trea tme n t Peri o d 2 i s bl i n d ed a n d s u bjects will b e ra n d o mized 1 : 1 t o treatme n t wit h i n v esti g ati o n al pr o d u c t ( C 1-IN H [ 6 0 
I U/k g ] or place b o)  s u b c uta n e o usly t wice wee kl y . 
c    Retreatme n t Peri o d(s) are bli n d ed a n d s u bjects will recei v e t h e sa me i n v esti g ati o n al pr o d u c t treatme n t assi g n me n t as recei ved 
d uri n g Trea tme n t Peri o d 2. 
N ote: Wee k 1 3 is t h e fi n al visit of Treat me nt Peri o d 1 f or n o n -res p o n d ers a n d t h e first visit of Treat me nt Peri o d 2 f or res p o n ders. 
 
 
C CI


CSL Behring 
Statistical Analysis Plan 
Protocol Number: CSL842_3001 
Product Name: C1-esterase 
Inhibitor, Human (500 IU/mL) 
 
 
CONFIDENTIAL 
 
 
 Page 19 of 73 
Treatment Period 1 
C1-INH will be administered to all subjects during Treatment Period 1 in an open-label manner. 
Five doses of C1-INH will be administered intravenously to subjects at the Day 1, 4, 7, 10, and 
13 Visits. Intravenous C1-INH will be administered at the study site during site visits. 
Subcutaneous C1-INH will be administered every 3 to 4 days (ie, twice weekly) beginning at the 
Day 14 Visit and for the remainder of Treatment Period 1. Subcutaneous C1-INH is required to 
be administered at the study site during site visits, but at other times may instead be administered 
at home by a medical professional ((eg, a home visit nurse) or by the subject under the 
supervision of a medical professional. 
Treatment Period 2 
Investigational product (ie, C1-INH or placebo) will be administered to all subjects during 
Treatment Period 2 in a double-blind manner. Subcutaneous investigational product will be 
administered every 3 to 4 days (ie, twice weekly) during Treatment Period 2. Subcutaneous C1-
INH is required to be administered at the study site during site visits, but at other times may 
instead be administered at home by a medical professional (eg, a home visit nurse) or by the 
subject under the supervision of a medical professional. 
Retreatment Period 
Subjects may undergo retreatment during the Responder Follow-up Period with the blinded 
investigational product to which they were randomized in TP2. Retreatment may occur following 
a diagnosis of recurrent or persistent AMR by biopsy, evidenced by infiltrating neutrophils 
and/or monocytes with or without the presence of C4d (glomerulitis [g] > 0, intimal 
arteritis  [v]   > 0, and/or peritubular capillaritis [ptc] > 0; if C4d is negative, g+ptc ≥ 2). 
Retreatment may start at any time during the Responder Follow-up Period, and will last for 
26  weeks or until the Month 48 Visit, whichever occurs first. The Retreatment Period may also 
be shorter than 26  weeks at the investigator’s discretion. 
During the Retreatment Period, SC investigational product will be administered twice weekly 
(approximately every 3 to 4 days). During the Retreatment Period (if needed), SC C1-INH will 
be administered either at the site or may be dispensed to the subject and administered SC at 
home either by a medical professional or by the subject under the supervision of a medical 
professional. 
 
 


CSL Behring 
Statistical Analysis Plan 
Protocol Number: CSL842_3001 
Product Name: C1-esterase 
Inhibitor, Human (500 IU/mL) 
 
 
CONFIDENTIAL 
 
 
 Page 20 of 73 
Subcutaneous Administration of the Investigational Product 
Subcutaneous administration of the investigational product should be via a single SC injection in 
the abdomen, thigh, upper arm, or other appropriate location. The twice weekly administration of 
investigational product beginning at the Day 14 Visit and during any Retreatment Period (if 
applicable). The suggested interval between each administration of investigational product is 3 or 
4 days (ie, twice weekly). In addition, the investigational product should ideally be administered 
at approximately the same time on each day. A missed injection should be administered as soon 
as possible, unless within 24 hours of the next scheduled injection; in this situation, the missed 
injection should be omitted, and the administration of investigational product should occur at the 
next scheduled day and time. The volume of investigational product to be administered will be 
based on each subject’s body weight (from the Screening physical examination) and will not be 
adjusted during the study. 
Description of Investigational Products 
The investigational products for this study are C1-INH and placebo. A description of C1-INH 
and Placebo and given in Table 5 and Table 6 respectively. 
Table 5 
Description of C1-INH 
Substance name 
C1-esterase Inhibitor, Human (500 IU/mL)  
Active substance 
C1-esterase inhibitor (human) 
Trade name 
Not applicable 
Dosage form 
Lyophilized powder for reconstitution; 1500 IU C1-INH per 
single-use vial. 
Dose 
60 IU/kg  
Mode of administration 
Intravenous / subcutaneous injection 
Before use, each vial of C1-INH is reconstituted with 3 mL water for injection. 60 IU/kg C1-INH 
is equivalent to a volume of 0.12 mL/kg. 


CSL Behring 
Statistical Analysis Plan 
Protocol Number: CSL842_3001 
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Table 6 
Description of Placebo 
Substance number 
Not applicable 
Substance 
Excipients of C1-INH plus albumin 
Trade name 
Not applicable 
Dosage form 
Lyophilized powder for reconstitution 
Dose 
0.12 mL/kg 
Mode of administration 
Subcutaneous injection 
Before use, each vial of placebo is reconstituted with 3 mL water for injection. 
The volume of placebo will be based on the body weight obtained with vital signs assessment at 
the Screening Visit, and will not be changed through the study. The actual dose of placebo will 
be rounded to the lowest 1 mL as if the subject receiving C1-INH. 
4.4 
Randomization Procedures and Blinding 
Randomization Procedures 
All subjects will receive open-label C1-INH during Treatment Period 1. Subjects who are 
eligible for Treatment Period 2 will be assigned to either continued C1-INH or matched placebo 
in accordance with a computer-generated randomization list. Investigational product assigned in 
Treatment Period 2 will be allocated on a 1:1 ratio. The randomization will be stratified on the 
following 2 factors:  
• Donor Specific Antibodies (DSA): sensitized prior to transplantation versus de novo. 
De  novo is defined as the development of DSA after transplantation. In the case of both 
sensitized and de novo, the subject will be considered sensitized for stratification purposes. 
• AMR severity: severe versus non-severe (ie all other severities). Severe AMR is defined as 
new onset oliguria (< 400 cc / 24 hours) or anuria with the current episode of AMR. 
Therefore, there will be a total of 4 strata (2 factors, 2 levels per factor).  The randomization will 
be permuted block within each stratum. Treatment assignment will be determined centrally. The 
randomization list will be generated and managed by the study’s interactive response technology 
(IRT) external service provider. 
The study database will be locked once all the randomized subjects currently in the study 
complete week 38 visit and re-treatment period as described in Section 3. The study will be 
unblinded for final analysis of the primary efficacy endpoint. 


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Maintaining the Blind 
Treatment Period 1 is open-label. Treatment Period 2 is double-blind. During Treatment Period 
2, the blind will be maintained for investigational site staff, including investigators, subjects, and 
CSL. 
Emergency Unblinding 
In emergency situations involving the safety of the subject, the investigator may break the blind 
using the IRT system. The reason for unblinding the randomization code must be fully 
documented. Emergency unblinding will be performed using the IRT. Steps for navigating the 
IRT for emergency unblinding are defined in the IRT manual. 
4.5 
Determination of the Sample Size 
Sample Size Based on the Primary Efficacy Endpoint 
The sample size is based on the primary efficacy endpoint of loss-of-response status (binary 
endpoint of loss-of-response or not), at the End-of-TP2 (ie, within 25 weeks after 
randomization). The null hypothesis is that there is no difference between C1-INH and placebo 
with respect to the proportion of subjects with loss-of-response at the End-of-TP2. Let p0 and p1 
be the expected proportion of subjects with loss-of-response in TP2 in the placebo and C1-INH 
treatment groups, respectively. The alternative is that there is a difference between the treatment 
groups. That is, H0: p0 = p1 versus H1: p0 ≠ p1.  
The power procedure in SAS STAT software (Cary, NC SAS Institute Inc.) was used to estimate 
the sample size, based on the likelihood ratio chi-square test. Determination of the sample size 
was based on the following assumptions: 
• The proportions of subjects experiencing loss-of-response at the End-of-TP2 will be 0.75 
with placebo and 0.30 with C1-INH. 
• There will be at least 90% power to detect a statistically significant effect with two-sided test 
with alpha = 0.05. 
• Logistic regression model with treatment effect will be used for the primary efficacy 
analysis. Wald test statistic for treatment effect from Logistic regression has approximately 
same distribution as chi-square [Fleiss et al, 2003]. Therefore, the sample size calculation 
based on chi-square test is used to ensure similar power for hypothesis testing. 
• Treatment allocation will be 1:1. 


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• The planned interim analysis for futility will not impact the type 1 error for the final analysis. 
Under these assumptions, a total of 60 subjects (30 randomized to C1-INH and 30 randomized to 
placebo) will provide approximately 95% power. The study was planned to enroll a sufficient 
number of subjects (up to 175) to ensure that 60 subjects are randomized. 
The assumptions above are based on a prospective single-arm pilot study to investigate the 
C1- INH added to high-dose IVIG for the treatment of acute AMR non-responsive to 
conventional therapy [Viglietti et al, 2016a]. A total of 6 subjects received C1-INH and IVIg for 
6 months. The primary endpoint was change in eGFR. These were compared to a historical 
control of 21 subjects who received IVIg. In the prospectively treated C1-INH group, 0/6 
subjects experienced decline in eGFR at 6 months (0; 95% confidence interval [CI], 0 to 46%); 
and 4/6 subjects had a greater than 20% increase in eGFR (67%; 95% CI, 22% to 96%). In the 
historical control group, 15/21 subjects (71%; 95% CI, 48% to 89%) experienced decline in 
eGFR during a comparable 6-month period. The results are presented in Figure 2. 
Figure 2 
Individual variations of eGFR in C1-INH patients 
    
 
Left: Distributions of eGFR at time of initial diagnosis (M-3), at the end of first line treatment (SOC; M0) and at the end of C1-
INH treatment (M+6) in 6 patients. Right: Individual variations in eGFR between M0 and M+6 in C1-INH patients (green) and 
historical controls (red). From Viglietti et al. (Viglietti et al, 2016b) 
 
 


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Power for the analysis of all-cause allograft failure 
Allograft survival status (or all-cause allograft failure) at the end of 48 months after enrollment 
represents clinical confirmation of the effect on the allograft of improving eGFR.  
The primary comparison of the proportion of subjects with allograft survival will be between the 
subjects randomized to placebo or C1-INH. It is anticipated that very few subjects will be lost to 
follow-up as standard of care mandates close follow up by the transplanting center. This endpoint 
will be analyzed after all subjects have been followed for 4 years after enrollment.  
The power for hypothesis testing of this endpoint was estimated using the power procedure in 
SAS STAT under the following assumptions: 
• The proportions of subjects with allografts surviving at 4 years after enrollment will be 0.25 
with the placebo cohort and 0.75 in the C1-INH cohort. 
• 
Alpha = 0.05 (two-sided test). 
• 
Logistic regression model with treatment effect will be used for the primary efficacy 
analysis. Wald test statistic for treatment effect from Logistic regression has approximately 
same distribution as chi-square [Fleiss et al, 2003]. Therefore, the sample size calculation 
based on chi-square test is used to ensure similar power for hypothesis testing. 
• Approximately 30 subjects in each randomized treatment groups. 
There is greater than 90% power to detect the specified target difference between C1-INH and 
placebo groups based on sample size of 60 (approximately 30 in the C1-INH cohort and 
approximately 30 in the placebo cohort). 
The 4-year graft survival for placebo of 25% is based on data presented at the American 
Transplant Congress in Boston [Viglietti et al, 2016b], as shown in Figure 3. This study involved 
follow-up of kidney transplant recipients with biopsy-proven active AMR diagnosed between 
2007 and 2013. Among the subjects who have not responded to standard of care, the 4-year graft 
survival ranged from approximately 10% to 40% for subjects with high and intermediate risk 
scores, respectively. The 4-year graft survival for C1-INH of 75% represents what would be 
expected for subjects who are successfully treated. 


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Figure 3 
Stratification of Graft Survival After ABMR Therapy Based on Prognostic 
Scoring 
 
Source: Viglietti et al, 2016b American Transplant Congress Abstract #198 
4.6 
Planned Interim Analyses and Reviews 
The study will be monitored by an Independent Data Monitoring Committee (IDMC). The 
meeting frequency, specific responsibilities, and composition of the IDMC will be outlined in a 
separate document, the IDMC charter. 
The study was terminated by the sponsor on 15 September 2020, therefore, no interim analysis 
will be conducted. 
5 Changes in the Conduct of Planned Analyses 
There are changes in the planned analyses (from those specified in the protocol) following the 
sponsor’s decision to terminate the study. There will be no analysis of the endpoints below Data 
from these endpoints will be presented only in subject listings.: 


C S L Be hri n g  
Statistical A nal ysis Pla n  
Pr ot oc ol N u m ber: C S L 8 4 2 _ 3 0 0 1  
Pr o d uct Na me: C 1 -esterase 
I n hi bit or, H u ma n ( 5 0 0 I U/ m L) 
 
 
C O N FI D E N TI A L  
 
 
 Pa g e 2 6  of 7 3  
•  Sec o n dar y e n d p oi nt of pr o p orti o n of s u bjects wit h all-ca use all o graft fail ure t hr o u g h t he 
Res p o n der F oll o w- u p Peri o d, 
•  Ti me t o all -ca use all o graft fail ure t hr o u g h 4 8 m o nt hs after e nr oll me nt, 
•  C ha n ge i n e G F R fr o m E n d- of- T P 1 t o t h e E n d- of-T P 2 , 
•  Rate of c ha n g e of e G F R i n Treat me nt Peri o d 2 , 
•  
, 
•  Plas ma p heresis sessi o ns , 
•  
 
, 
•  
 
, 
•  
, 
•  Tr o u g h I VI g c o n ce ntrati o ns at d esi g nate d ti me p oi nts , 
•  
, 
F or ot her e n d p oi nts t he statistical a nal ysis was re d uce d as des cri be d i n t he s ecti o ns of t his S A P. 
6  St u d y A n al ysis Sets  
6. 1  
Scree ne d A n al ysis Set  
T he Scree ne d a n al ysis will c o m prise all s u bjects w h o pr o vi de d writte n i nf or me d c o nse nt a n d 
w h o u n der w e nt  st u d y scr ee ni n g pr oce d ures. 
6. 2  
E nr olle d A n al ysis Set  
T he E nr olle d A nal ysis Set  will c o m prise all s u bjects i n t he Scree ne d A nal ysis Set  w h o di d n ot 
fail scree ni n g. 
6. 3  
I nte nt-t o-Tre at A n al ysis Set  
T he I nte nt- t o-Treat (I T T) a nal ysis will c o m prise all s u bjects w h o were ra n d o mize d. S u bjects will 
be classifie d acc or di n g t o t he i n vesti gati o nal pr o d uct t o w hic h t he y were assi g ne d ( ie, c o nti n ue d 
C 1 -I N H or p lace b o) re gar dless of w hat w as act u all y recei ve d. T his will be t he pri mar y a n al ysis 
C CI
C CI
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set for the analysis of efficacy data. Any subject who received a randomization identification 
number will be considered to have been randomized. 
6.4 
Modified Intent-to-Treat Analysis Set 
All subjects randomized under the original protocol and under all protocol amendments will be 
included in the Modified ITT (mITT) population except the subjects randomized prior to 
Amendment 3 who did not satisfy the eligibility criteria updated in Amendment 3. The mITT 
Analysis Set will be the primary analysis set for the analysis of efficacy data. 
6.5 
Safety Analysis Sets 
Run-in Safety Analysis Set 
The Run-in Safety (RiS) Analysis Set will comprise all subjects who received at least one dose of 
C1-INH during Treatment Period 1. 
Randomized Withdrawal Safety Analysis Set 
The Randomized Withdrawal Safety (RWS) Analysis Set will include all subjects in the ITT 
Analysis Set who received at least one dose of the investigational product after randomization 
during Treatment Period 2. The RWS Analysis Set will be based on the investigational product 
actually received (ie, continued C1-INH or placebo) during Treatment Period 2. If a C1-INH 
treatment subject receives one or two doses of placebo and then this is corrected for all 
subsequent doses they will be classified in the C1-INH treatment group. 
6.6 
Pharmacokinetic Analysis Set 
The Pharmacokinetic (PK) Analysis Set will comprise all subjects who received ≥ 1 dose of 
C1- INH and who have ≥ 1 measurable level of C1-INH functional activity or C1-INH antigen 
concentration. 
 
 


C S L Be hri n g  
Statistical A nal ysis Pla n  
Pr ot oc ol N u m ber: C S L 8 4 2 _ 3 0 0 1  
Pr o d uct Na me: C 1 -esterase 
I n hi bit or, H u ma n ( 5 0 0 I U/ m L) 
 
 
C O N FI D E N TI A L  
 
 
 Pa g e 2 8  of 7 3  
6. 7  
 
 
 
 
7  Ge ner al C o nsi der ati o ns  
A nal ysis datasets will be creat e d acc or di n g t o C DI S C  sta n dar ds, a n d data will be dis pla ye d 
acc or di n g  t o r e p orti n g sta n dar ds i n t his S A P a n d ta bles, fi g ures a n d listi n gs (T F L ) f or mats.  
S A S versi o n 9. 3 or hi g her will be use d t o perf or m all data a nal yses a n d t o g e nerat e T F Ls . 
All I C H re q uire d d ata i n t he data base will be pres e nte d i n data listi n gs.  
C o nti n u o us varia bles will be s u m marize d i n ter ms of t he n u m ber of o bs er v ati o ns, mea n, sta n dar d 
de viati o n, me dia n, Q 1, Q 3, mi ni m u m a n d ma xi m u m. Ot her descri pti ve statistics ( e g, q uartiles, 
c oefficie nt of variati o n) ma y be re p orte d w he n a p pr o priate. Cate g orical var ia bles will be 
s u m marize d usi n g fre q u e nc y c o u nts a n d perce nt a g es. A nal ys es t hat use ot her descri pti ve 
statistics will ha ve t he s pecific des cri pti ve statistics re q uire d i de ntifie d wit h t he a nal ysis i n t he 
a p plica ble S A P secti o n.  
All listi n gs will i ncl u de s u bject n u m ber, treat me nt gr o u p. T he la b orat or y n or mal refere n ce ra n ges 
will be pr o vi de d a n d cli nical la b orat or y test res ults o utsi de t he n or mal refere nce ra n ge will be 
fla g ge d i n t he la b or at or y data listi n gs. 
S u m mar y statistics of ce ntral te n de nc y will be r e p orte d t o o ne m ore d eci mal place t ha n t he 
c ollecte d data. S u m mar y statistics of varia bilit y will be re p orte d t o o ne m ore deci mal place t ha n 
t he c o m me ns urate m eas ure of ce ntral te n d e nc y. F or e xa m ple, t he mea n a n d me dia n f or a g e will 
be re p ort e d t o o ne deci mal place b eca us e it is c ollecte d i n f ull years. T he st a n dar d de vi ati o n of 
a ge will t he n be r e p orte d t o 2 deci mal places.  
F or matti n g f or dates a n d ti mes will be: descri pti ve perce nt a ges a n d pr o p orti o ns will be dis pla ye d 
t o o ne deci mal place. Per ce nta ges a nd pr o p orti o ns t o be teste d will be calc ulate d t o 4 deci mal 
places. D ur ati o ns f or e v e nts will be dis pla y t o 1 deci mal place. 
 
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• Dates only – ddmmmyyyy 
• Times only – hh:mm or hh:mm.ss 
• Dates and times – ddmmmyyyy hh:mm or ddmmmyyyy hh:mm:ss 
In general, only scheduled visits will be included in by-visit summaries. However, worst-case or 
best-case values (as appropriate) will be derived using both scheduled and unscheduled visits. In 
general, assessment windows will not be defined for the purpose of classifying measurements 
obtained outside scheduled assessment times, other than those indicated in the Schedule of 
Assessments. However, exceptions may apply for creatinine / eGFR. 
Actual rather than planned sampling times will be used in the derivation of PK parameters and in 
the individual concentration-time plots and listing of PK concentration data. Planned times will 
be used in the descriptive summaries and in mean and median plots. Concentration-time data will 
be listed according to actual sampling times relative to dosing time. 
Deviations from the analyses in this SAP will be identified in the CSR. 
7.1 
Multicenter Studies 
Data from all participating sites will be pooled prior to analysis. 
7.2 
Treatment Descriptors  
The following treatment group descriptor will be used on all applicable displays: 
Treatment Group 
Order of Treatment 
Groups 
Code 
Description 
A 
Placebo 
1 
B 
C1-INH  
2 
 
7.3 
Multiple Comparisons and Multiplicity 
No formal hypothesis testing is planned due to small number of subjects randomized in this 
study when the study was terminated by the sponsor. Hence multiplicity is not applicable. 


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8 Data Handling Conventions 
8.1 
Missing Data 
Missing data occurs when any requested data is not provided, leading to blank fields on the 
collection instrument. These data will be indicated by the use of a “blank” in subject listing 
displays. Answers such as “Not applicable” and “Not evaluable” are not considered to be missing 
data and should be displayed as such provided in the collection instrument. 
8.1.1 
Imputation of Non-Date Missing Data 
Non-date Clinical Data 
All available data will be analyzed using suitable statistical methods. For analysis of percent 
responders, all subjects in the appropriate analysis set (ITT Analysis Set or mITT Analysis Set) 
will be included in the denominator when calculating the percentages; any subject who drops out 
of the study at any time after randomization will be defined for the purpose of analysis as a non-
responder.  
Subjects with the designation of treatment relationship for adverse events (AEs) and serious 
adverse events (SAEs) missing will have the worst case assumed to impute the relationship: if 
relationship to study treatment is missing it will be assumed to be “Yes”. 
In summaries of absolute values and change from baseline, subjects with missing baseline values 
will not be included in baseline rows or in the change from baseline summary statistics. 
8.1.2 
Imputation of Partial Dates 
Imputed dates will not be used to derive study day, duration (eg, duration of adverse events), or 
elapsed time variables. In addition, imputed dates are not used for deriving the last contact date 
for overall survival. Imputed dates will be displayed in listings and identified as imputed. 
Partial date imputation will follow Analysis Data Model (ADaM) conventions. The ADaM 
approach is to populate the numeric date variables with the imputed date and add a flag variable 
to the dataset that indicates the level of imputation. 
The flag variable can contain the values: blank, 'D', 'M', 'Y'. 
blank: indicates that no imputation was done 
D = 'Day': indicates that the day portion of the date is imputed 


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M = 'Month': indicates that the month and day portions of the date are imputed 
Y = 'Year': indicates that the entire date (year, month, and day) is imputed 
Algorithms for imputing partial dates for AE and concomitant medications are below. 
Imputations in the adverse events dataset are used for slotting events to the appropriate study 
time periods and for sorting in data listings. They will not be used to calculate duration of AEs. If 
an AE start or end date is missing, then the duration of the AE will be set to missing. 
Adverse Events 
Impute start and end dates for use to derive the reference variables for adverse event start relative 
to treatment; include any imputed dates in analysis datasets with an identifier as imputed. The 
reference variables will be used to differentiate as Before-therapy, On-Therapy and Follow-up 
for AEs (see Section 8.3.2). 
Date 
Missing Element 
Rule 
Start Date 
day, month, and 
year 
Do not impute completely missing AE start dates, AE will 
be assumed as treatment emergent 
 
day and month 
• 
If the onset year is after the year of the first dose of study 
drug, then the AE is treatment-emergent. 
• 
If the onset year is the same as the year of the first dose of 
study drug and the end date is not before the first dose of 
study drug, then the AE is treatment-emergent. 
• 
If the onset year is the same as the year of the first dose of 
study drug and the end date is before the first dose of study 
drug, then the AE is not treatment-emergent. 
• 
If the onset year is before the year of the first dose of study 
drug, then the AE is not treatment-emergent. 
 
 


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Date 
Missing Element 
Rule 
 
day only 
• 
If the start yyyy-mm is after the yyyy-mm of first dose of 
study drug, then the AE is treatment-emergent. 
• 
If the start yyyy-mm is the same as the yyyy-mm of the first 
dose of study drug and the end date is not before the first 
dose of study drug, then the AE is treatment-emergent. 
• 
If the start yyyy-mm is the same as the yyyy-mm of the first 
dose of study drug and the end date is before the first dose of 
study drug, then the AE is not treatment-emergent. 
• 
If the onset yyyy-mm is before the yyyy-mm of the first dose 
of study drug, then the AE is not treatment-emergent. 
End Date 
any date element 
No imputation for completely or partially missing AE end 
dates; as applicable, report the AE as ongoing and the AE 
duration as missing. 
Concomitant Medication 
Impute start and end dates for use to derive the reference variables for concomitant medication 
start and end relative to treatment; include any imputed dates in analysis datasets with an 
identifier as imputed. The reference variables will be used to differentiate before, during and 
after treatment for the concomitant medication. 
Date 
Missing Element 
Rule 
Start Date 
day, month, and year 
Do not impute completely missing concomitant 
medication start dates. 
 
day and month 
• 
If the onset year is after the year of the first dose of 
study drug, then the CM is concomitant. 
• 
If the onset year is the same as the year of the first dose 
of study drug and the end date is not before the first 
dose of study drug, then the CM is concomitant. 
• 
If the onset year is the same as the year of the first dose 
of study drug and the end date is before the first dose 
of study drug, then the CM is prior. 
• 
If the onset year is before the year of the first dose of 
study drug, then the CM is prior. 
 
 


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Date 
Missing Element 
Rule 
 
day only 
• 
If the start yyyy-mm is after the yyyy-mm of first dose 
of study drug, then the CM is concomitant. 
• 
If the start yyyy-mm is the same as the yyyy-mm of the 
first dose of study drug and the end date is not before 
the first dose of study drug, then the CM is 
concomitant. 
• 
If the start yyyy-mm is the same as the yyyy-mm of the 
first dose of study drug and the end date is before the 
first dose of study drug, then the CM is prior. 
• 
If the onset yyyy-mm is before the yyyy-mm of the 
first dose of study drug, then the CM is prior. 
Date of Birth 
Imputation for birth date is only needed if age is missing on eCRF and needs to be recalculated. 
An incomplete birth date will be imputed as follows: 
If only the day is missing – the missing day will be imputed as 15th of the month. 
If day and month is missing – missing day and month will be imputed by 1st of July. 
A completely missing birth date will not be imputed. 
8.2 
Derived Variables 
The following sections provide a general description of the derived variables for data analyses. 
8.2.1 
Reference Dates  
Reference dates are used to assign study periods relative to treatment. 
There are three reference dates: 
• Because age is an eligibility requirement, the reference date for age is the date of 
screening. 
• The safety reference date is the date of first C1-INH dosing in Treatment Period 1 and 
will be used to calculate study day for safety measures. 
• The reference date for efficacy endpoints is the date of first intake of randomized study 
treatment in Treatment Period 2 and will be used to calculate study day for efficacy 
measures. 


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8.2.2 
Study Day for Safety Measures 
If the date of interest occurs on or after the safety reference date, then the safety study day will 
be calculated as (date of interest - safety reference date) + 1. If the date of interest occurs before 
the safety reference date, then the safety study day will be calculated as (date of interest – safety 
reference date). There is no safety study day 0. 
8.2.3 
Study Day for Efficacy 
The study day for efficacy will be calculated in the same manner as the study day for safety 
measures but will consider the reference date for efficacy. There is no efficacy Study Day 0. 
Timings for safety events and interventions 
Safety events and interventions will be classified as follows: 
Before-treatment: Date is strictly prior to the first administration of open-label C1-INH. 
Treatment-emergent or On-Treatment: Date is between the first administration of open-label 
C1-INH and 30 days after the investigational product stop date. 
Post-treatment: Date is strictly more than 30 days after the investigational product stop date. 
8.2.4 
Durations 
Durations (eg, the duration of an adverse event) and elapsed time will be calculated in days using 
the SAS DATDIF function. 
When reporting durations which are calculated in months, divide the number of days by 30.4375; 
to report in weeks divide the number of days by 7; to report in years divide the number of days 
by 365.25. These algorithms for time to event return decimal numbers, and ignore the actual 
numbers of days in the months or years between start date and stop date. The "year" used in these 
algorithms is 365.25 days long, and the "month" is one twelfth of that year. 
8.2.5 
Baseline Definition 
Baseline for non-laboratory and laboratory data (except creatinine for eGFR) is defined as the 
most recent, non-missing value prior to or on the first study treatment dose date/time in 
Treatment Period 1 (for non-laboratory it is referred to eCRF data and for laboratory data it is 
referred to local laboratory data). 


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For subjects who did not receive study treatment during the study, a baseline value will not be 
calculated. The most recent, non-missing value prior to or on the study treatment dose date / time 
is based on scheduled assessments only. 
Baseline eGFR has been defined as follows in original protocol and amendments: 
• For subjects randomized prior to Protocol Amendment 1, dated November 28, 2017, the 
nadir (minimum) of the eGFR values from screening and Day 1 will be used as the 
baseline. 
• For subjects randomized after Protocol Amendment 1 the mean of the screening and Day 
1 values will be used as the baseline. 
For the purpose of analysis, baseline eGFR is defined as the mean of the screening and Day 1 
values. 
Note that a set of vital signs or laboratory values may have different dates for baseline values. 
8.2.6 
Change From Baseline 
Change from baseline will only be calculated for measures that have post-baseline records. 
Change from baseline will be calculated as: 
• visit value – baseline value. 
Percentage change from baseline will be calculated as: 
• (change from baseline / baseline value) * 100 
8.2.7 
Multiple Assessments 
All data will be reported according to the nominal visit date/time for which it was assessed (that 
is, no visit windows will be applied during dataset creation). 
If multiple assessments for the same visit occur, it will be distinguished why this is the case. If a 
laboratory sample was repeated due to technical problems the results from the valid sample(s) for 
this visit – the non-missing results – will be used in the analysis. If a laboratory sample was 
repeated as safety follow-up to monitor abnormal values of the initial sample, the initial sample 
(revealing the abnormal values) of this visit will be used in the analysis. 
Data from all assessments (scheduled and unscheduled), including multiple assessments, will be 
included in listings. 


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8.2.8 
Actual Treatment 
The subjects’ actual treatment will be derived from exposure data. If a subject’s actual treatment 
is the same as the assigned treatment, then actual treatment is the assigned treatment. If a subject 
receives a study treatment that is different from the assigned treatment for the entire time of 
treatment, then actual treatment is the different treatment (the treatment actually received). 
8.2.9 
Derived Variables 
Start and End of Retreatment Periods 
Neither the start and end date of optional Retreatment Period(s) nor the number of individual 
Retreatment Period(s) will be explicitly recorded in the eCRF. So, the start date of a Retreatment 
Period will be derived by using the visit date associated with the label of first visit in a 
Retreatment Period, ie using a visit label of “RT – Day 1 (x)”, x – counter of individual 
Retreatment Period. The end date of a Retreatment Period will be derived in the same way by 
using the last available date in a chronological order of visit labels in a Retreatment Period, ie 
using a visit label of “RT – Day 182 (x)”, x – counter of individual Retreatment Period. The 
individual number of Retreatment Period will be derived from the counter (in brackets) given in 
the visit label of Retreatment Periods. 
For analysis purpose, a Retreatment Period will start with the first documented study drug intake 
on or after first retreatment visit which was identified via the visit label. The end of the 
Retreatment Period will be identified in a similar way. It will be the last intake of study drug 
before or on the last retreatment visit which was identified via the visit label. 
Demographics 
Years of Age 
Years of age will be derived as the number of complete years between a subject's birth date and 
the date of informed consent.  
Body mass index 
Body mass index (BMI) will be derived using the following formula: 
BMI (kg/m2) = Weight (kg) / [Height (m)]2 


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The height at Screening and the dry weight obtained from the medical history will be used. If the 
dry weight is missing, the weight at Screening will be used. If the weight at Screening is missing, 
the Day 1 weight will be used. 
Efficacy 
Estimated glomerular filtration rate (eGFR) 
eGFR will be derived using the following MDRD formula [Levey et al, 2008]: 
eGFR (mL/min/1.73m2) = [(175) x (standardized Scr-1.154) x (age-0.203) x 
(1.212, if black) x (0.742, if female)] 
The serum creatinine (Scr) is expressed as mg/dL. The years of age will be derived based on the 
subject birth date and the date that the Scr sample was taken. 
eGFR at the End of Treatment Period 1 (End-of-TP1) 
The mean of Week 11 and Week 12 eGFR measurements. If one of the measurements is missing 
it is then the non-missing value. 
eGFR at the End of Treatment Period 2 (End-of-TP2) 
The mean of Week 36 and Week 38 eGFR measurements. If one of the measurements is missing 
it is then the non-missing value. 
Response to Open-Label C1-INH at End of Treatment Period 1 (End-of-TP1) 
Responders are defined as subjects whose End-of-TP1 (the mean of Week 11 and Week 12) 
eGFR ≥ 90% of baseline and ≥ 20 mL/min/1.73 m2. The baseline eGFR is defined as the mean of 
the screening and Day 1 values in Section 8.2.5. 
Loss of Response During Treatment Period 2 
Loss-of-response at the End-of-TP2 is defined as any 1 of the following 3 conditions: 
• End-of-TP2 eGFR (mean of Week 36 and Week 38 eGFR) that is not stable, defined as: 
o End-of-TP2 eGFR that is < 90% of the End-of-TP1 eGFR for subjects whose End-of-TP1 
eGFR (mean of Week 11 and Week 12 eGFR) is ≥ 100% of baseline; 


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o End-of-TP2 eGFR that is < 90% of baseline for subjects whose End-of-TP1 eGFR is 
≥ 90% of baseline and < 100% of baseline. 
• Allograft failure (defined by allograft nephrectomy, or institution of permanent dialysis, or 
return to the transplant waitlist for renal transplant, whichever occurs first) 
• Subject death by any cause. 
All-Cause Allograft Failure 
All-cause allograft failure within 48 months after enrollment is defined as 1 of the following, 
whichever occurs first:  
• Allograft failure (defined by allograft nephrectomy, or institution of permanent dialysis, or 
return to the transplant waitlist for renal transplant, whichever occurs first), OR  
• Subject death by any cause. 
No subject has reached 48 months after enrollment due to study termination.  
8.3 
Study Periods Relative to Treatment 
8.3.1 
Time in Relation to Treatment 
Safety data (AEs and concomitant medications) will be assigned to the study time periods 
defined below (refer to Section 8.1.2 for imputation of incomplete or missing dates). 
Before-therapy is defined as the date/time prior to the first start of subject’s infusion with study 
treatment. 
On-therapy is defined as the time from the first start of an infusion of study treatment in 
Treatment Period 1 up to 30 days after last study drug administration in Treatment Period 2. If a 
subject had a Retreatment Period, the time still on drug in Retreatment Period (extended to +30 
days after last drug in Retreatment Period) will be accounted as On-therapy. In case a subject has 
more than one Retreatment Periods, the time between Retreatment Periods will be accounted for 
Follow-up. 
Follow-up is defined as any time after last study drug administration in Treatment Period 2 plus 
30 days. Time of Retreatment Periods are to be excluded from Follow-up, please refer to On-
therapy. 
8.3.2 
Study Time Periods for AEs 
AEs occurring On-Therapy or during Follow-up will be handled as treatment-emergent AEs. 


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8.3.3 
Study Time Periods for Prior and Concomitant Medications 
Prior medications are those ending in the before-therapy period. 
Concomitant medications include those that start during the before-therapy period and continue 
into the on-therapy and Follow-up periods as well as those that start during the on-therapy and 
Follow-up time periods. Therapies that start during the before-therapy period and have a missing 
end date will be assumed to continue into the on-therapy period and, therefore, will also be 
considered concomitant medications. 
9 Study Population 
Only data of subjects who provided informed consent (informed consent date available in the 
database) will be included in the statistical analysis. 
Unless otherwise stated, all tables and listings in this section will be based on the mITT and / or 
Safety Analysis Set, and all summaries and data listings will use treatment descriptors as 
specified in Section 7.2. 
9.1 
Disposition of Subjects 
The following summaries will be provided by treatment group and for the Screened Analysis Set, 
as appropriate: 
Subject disposition presenting the number and percentages of: 
• subjects screened, 
• subjects ineligible/failed screening, 
• reason for screening failure, 
• subjects eligible for Treatment Period 1, 
• subjects treated with open-label study medication in Treatment Period 1, 
• subjects completed Treatment Period 1, 
• subjects discontinued during Treatment Period 1 (before Week 13) and reasons for 
discontinuation, 
• subjects eligible for randomization in Treatment Period 2 (subjects reached week 13 and 
responded to treatment in Treatment Period 1), 
• subjects randomized, 
• subjects treated with blinded study medication during Treatment Period 2, 
• subjects completed Treatment Period 2, 


C S L Be hri n g  
Statistical A nal ysis Pla n  
Pr ot oc ol N u m ber: C S L 8 4 2 _ 3 0 0 1  
Pr o d uct Na me: C 1 -esterase 
I n hi bit or, H u ma n ( 5 0 0 I U/ m L) 
 
 
C O N FI D E N TI A L  
 
 
 Pa g e 4 0  of 7 3  
•  s u bjects disc o nti n ue d d uri n g Treat me nt Peri o d 2 ( bef ore Wee k 3 8) a n d reas o ns f or 
disc o nti n uati o n, 
•  S u bjects disc o nti n ue d fr o m st u d y bef ore w ee k 2 0 8, 
•  s u bjects a vaila ble b y visit ( Treat me nt Peri o d 1, Treat me nt Peri o d 2), a s u bj ect will be 
c o nsi dere d t o ha v e atte n d e d a visit if a visit date is rec or d e d ( pr o vi d e d f or Ri S A nal ysis 
Set a n d R W S A nal ysis S et) . 
N u m ber a n d p erce nta ge of s u bjects i n t he f oll o wi n g a nal ysis sets will be prese nte d: 
•  Scree ne d A n al ysis Set , 
•  E nr olle d A nal ysis Set , 
•  Ri S A nal ysis Set , 
•  R W S A nal ysis Set , 
•  m I T T A n al ysis Set, 
•  P K  A nal ysis Set , 
•  
. 
N u m ber a n d p erce nta ge of s u bjects i n t he f oll o wi n g cate g ories  will be pres e nte d:  
•  S u bjects a p plica ble t o ori gi nal pr ot oc ol, 
•  S u bjects a p plica ble t o a me n d me nt 1, 
•  S u bjects a p plica ble t o a me n d me nt 2, 
•  S u bjects a p plica ble t o a me n d me nt 3. 
Reas o ns f or st u d y wit h dr a wal will be pres e nte d i n t he or der t he y are dis pla ye d i n t he e C R F. 
A listi n g will be pr o vi de d i ncl u di n g date of i nf or m e d c o nse nt, date of ra n d o mizati o n, date of first 
treat me nt ( Treat me nt Peri o d 1, Treat me nt Peri o d 2, Retreat me nt Peri o d[s]), st u d y c o m pleti o n, 
reas o n if n ot c o m plete d, a n d assi g n me nt t o a nal ysis sets. 
9. 2  
Pr ot oc ol De vi ati o ns  
T he f oll o wi n g listi n gs will be pr o vi de d f or t he E nr olle d  A nal ysis Set : 
•  All i ncl usi o n / e xcl usi o n a n d maj or pr ot oc ol de vi ati o ns. 
•  All ot her pr ot oc ol de viati o ns. 
9. 3  
De m o gr a p hic a n d B aseli ne C h ar acteristics  
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9.3.1 
Demographics 
The following demographic characteristics will be summarized using descriptive statistics or 
frequency counts, as appropriate: 
• Age, 
• Age group (< 65 years and ≥65 years), 
• Sex, 
• Ethnicity, 
• Race and racial combinations, 
• Height, 
• Weight, 
• BMI, 
• Diagnosis of HIV, 
• Diagnosis of HBV, 
• Diagnosis of HCV. 
The weight to be summarized as part of demographics will be the dry weight based on medical 
history. If the dry weight is missing, the weight at Screening will be used. If the weight at 
Screening is missing, the Day 1 weight will be used. Demographics will be summarized for the 
RWS Analysis Set and overall and for RiS Analysis Set. 
9.3.2 
Baseline Characteristics 
The following will be summarized using descriptive statistics or frequency counts, as 
appropriate: 
• Allograft / allograft donor characteristics, 
• Diagnosis and disease characteristics. 
Baseline characteristics will be summarized for the RWS Analysis Set and overall and for RiS 
Analysis Set. 
• Allograft / allograft donor characteristics: age, sex, ethnicity, race, biological relative, 
blood group, status at time of donation (alive, dead), deceased donor donation type 
(donation after brain death, donation after circulatory death), deceased donor criteria 
(kidney standard criteria donor, kidney expanded criteria donor), Kidney Donor Profile 


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Index (KDPI score), Human Immunodeficiency Virus (HIV) (yes, no), Hepatitis B Virus 
(HBV) (yes, no), Hepatitis C Virus (HCV) (yes, no), 
• Diagnosis and disease characteristics: time since most recent renal transplant, time since 
AMR diagnosis, time since most recent rejection episode, severity of current AMR 
episode, total number of renal transplants, primary reason for kidney transplant (diabetes 
[type 1 and 2], hypertension, polycystic kidney disease, drug toxicity [non-steroidal anti-
inflammatory drugs or others], IgA nephropathy, rapidly progressive neuropathy, 
membranous glomerulopathy, other nephritides, renal artery stenosis, other infectious 
diseases [HIV; hepatitis; endotoxin], congenital nephropathy [primary NOS], stone 
disease, renal cancer, other), delayed graft function (yes, no), dialysis within 14 days after 
most recent transplant (yes, no), presence of DSA prior to kidney transplant (yes, no), 
de  novo DSA post-transplant (yes, no). 
The following listings will be provided for RWS Analysis Set and overall and for RiS Analysis 
Set: 
• Demographic characteristics, 
• Allograft / allograft donor characteristics, 
• Diagnosis and disease characteristics. 
9.4 
Prior and Concomitant Medications 
Prior and Concomitant medications will be coded using CSL Behring Drug coding dictionary 
(WHO-DDE Enhanced 2016MAR, B2 Format), summarized, and listed. The summary of prior 
and concomitant medications will show the number and percentage of subjects taking 
prior/concomitant medications. Anatomical Therapeutic Chemical (ATC) classification Level 1 
(Body System) information will be included in the dataset created but will not appear on the 
listing or summary. ATC Level 4 and preferred term of prior/concomitant medications will be 
used for summaries and listings. If the ATC Level 4 coding is not available for a preferred term, 
the next available lower level ATC code will be used. The summary will be provided by 
treatment group for RWS Analysis Set and overall for the RiS Analysis Set. 
Concomitant medication start and end dates relative to treatment start and end dates are used to 
select data to include in summaries as follows: 
• Summary of Concomitant Medications: This summary will contain medications with start 
dates relative to treatment assigned to ('BEFORE', 'DURING') and end dates relative to 
treatment assigned to ('DURING', 'AFTER'). 


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• Summary of Concomitant Medications with On-Therapy Onset: This summary will contain 
medications with start dates relative to treatment assigned ('DURING') and end dates relative 
to treatment assigned to ('DURING', 'AFTER'). 
In the summary of concomitant medications, each subject is counted once within each unique 
term. For example, if a subject takes Amoxycillin on two separate occasions, the subject is 
counted only once under the ingredient “Amoxycillin”. 
Concomitant medications will be summarized separately for medications with onset date within 
the on-therapy period and for medications with onset date within the before-therapy period. 
Note: In order to be considered a concomitant medication, the concomitant medication must have 
been taken at some point during the on-therapy window. 
Concomitant medications will be summarized for the RWS Analysis Set and overall and for RiS 
Analysis Set. 
9.5 
Medical History 
Medical history by body system will be summarized in a frequency table by treatment group for 
RWS Analysis Set and overall and for RiS Analysis Set. 
Medical history will also be presented in a by-subject listing for RiS Analysis Set. 
10 Efficacy 
All efficacy summary will be based on mITT Analysis Set of subjects for Period 2 unless 
otherwise specified. All efficacy summary will be based on RiS Analysis Set for Period 1 unless 
otherwise specified. 
Subject listings will be provided for the efficacy information based on the mITT Analysis Set. 
10.1 
Analysis of Proportion of Subjects With Loss of Response at the End-
of-TP2 
The number and proportion of subjects with loss of response at the End-of-TP2 will be presented 
by treatment group along with the confidence interval for the difference between the two groups. 
Subjects will be considered to have lost response if they drop-out or are lost to follow-up before 
the response status at the End-of-TP2 could be determined. 


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Components of loss-of-response at the End-of-TP2 will be summarized by treatment groups in 
terms of the proportion of subjects with: 
• End-of-TP2 eGFR (mean of Week 36 and Week 38 eGFR values) that is not stable, defined 
as: 
o End-of-TP2 eGFR that is < 90% of the End-of-TP1 eGFR for subjects whose End-of-TP1 
eGFR is ≥ 100% of baseline, 
o End-of-TP2 eGFR that is < 90% of baseline for subjects whose End-of-TP1 eGFR is 
≥90% of baseline and < 100% of baseline, 
• All-cause allograft failure (ie, allograft nephrectomy, or institution of permanent dialysis, or 
return to the transplant waitlist for renal transplant), 
• Death by any cause. 
The primary efficacy analysis will be conducted for the mITT Analysis Set. 
10.1.1 Subgroup Analyses of Proportion of Subjects With Loss of Response at 
the End-of-TP2 
The proportion of subjects with loss of response at the End-of-TP2 will be summarized by the 
treatment group for the following subgroups based on the following subgroup analyses outlined 
below will be conducted for the mITT Analysis Set. 
The following subgroups, and possibly others to be described in the SAP, will be summarized by 
treatment group with respect to the proportion of loss-of-response: 
• Geographic region: USA, non-USA, 
• DSA by randomization strata: sensitized, de novo, 
• DSA by classification: HLA class I, HLA class II, both HLA class I and II, 
• AMR severity: severe, non-severe (all other severities), 
• Type of donor: deceased, living, 
• Recipient race: Black, non-Black, 
• Recipient sex: Male, Female, 
• Recipient age: < 65 years, ≥ 65 years. 
The difference in the proportion of response along with the 95% confidence interval will be also 
presented for each subgroup. 


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10.2 
Analysis of key Secondary Endpoint Proportion of Subjects With All-
Cause Allograft Failure Through the Responder Follow-up Period (ie, 
Within 48 Months After Enrollment) 
No subject will complete the follow-up period of 48 months after enrollment. Therefore, this key 
secondary analyses cannot be conducted. 
10.3 
Analysis of Time to All-Cause Allograft Failure Through 48 Months 
After Enrollment 
No formal analysis will be conducted for time to all-cause allograft failure since no subject will 
complete 48 months after enrollment. 
A by-listing of all-cause allograft failure information will be provided for the mITT Analysis Set. 
10.4 
Analysis of the Change in eGFR From Baseline to End-of-TP1 
This analysis will be based on the RiS Analysis Set. 
The eGFRs during Treatment Period 1 (ie with open-label C1-INH ) will be summarized by 
scheduled visit using descriptive statistics for the observed values, and changes from baseline (ie 
missing data will be not imputed). 
10.5 
Analysis of Responders at the End-of-TP1 
This analysis will be based on the RiS Analysis Set. 
The proportion of responders at the End-of-TP1 will be presented together with an exact 95% 
confidence interval. Definition of response at End-of-TP1 is given in Section 8.2.9. 
10.6 
Analysis of the Change in eGFR From End-of-TP1 to the End-of-TP2 
No formal analysis for the change in eGFR from End-of-TP1 to the End-of-TP2 will be 
conducted. 
A by-listing for eGFR of all individual values will be provided. for the mITT Analysis Set. 
10.7 
Analysis of the Rate of Change of eGFR in Treatment Period 2 


C S L Be hri n g  
Statistical A nal ysis Pla n  
Pr ot oc ol N u m ber: C S L 8 4 2 _ 3 0 0 1  
Pr o d uct Na me: C 1 -esterase 
I n hi bit or, H u ma n ( 5 0 0 I U/ m L) 
 
 
C O N FI D E N TI A L  
 
 
 Pa g e 4 6  of 7 3  
N o f or mal a n al ysis of t he rate of c ha n ge of e G F R i n Treat me nt Peri o d 2  will be c o n d ucte d d u e t o 
t he s mall n u m ber of s u bjects c o m pleti n g T P 2. Mea n p l ot f or t he c h a n ge i n e G F R fr o m baseli ne 
i n Treat me nt Peri o d 2  will be pr o vi de d f or t he s u bj ects i n t he mI T T A nal ysis Set . 
1 0. 8  
 
 
. 
 
 
 
. 
 
 
. 
1 0. 9  
 
 
. 
1 0. 1 0  A n al ysis of C 1 -I N H F u ncti o n al A cti vit y 
P K para meter of C ma x  a n d A U C 0-t f or C 1-I N H f u n cti o nal acti vit y will be prese nte d i n  a b y-
s u bject listi n g f or t he P K A nal ysis Set  (see Secti o n 1 2 ). 
1 0. 1 1  
 
 
 
 
 
1 0. 1 2  A n al ysis of P l as m a p heresis S essi o ns 
T he t otal n u m ber plas ma p heresis sessi o ns will be deri ve d f or eac h s u bject a n d pr o vi de d i n a b y-
listi n g f or t he mI T T A nal ysis Set . 
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C S L Be hri n g  
Statistical A nal ysis Pla n  
Pr ot oc ol N u m ber: C S L 8 4 2 _ 3 0 0 1  
Pr o d uct Na me: C 1 -esterase 
I n hi bit or, H u ma n ( 5 0 0 I U/ m L) 
 
 
C O N FI D E N TI A L  
 
 
 Pa g e 4 7  of 7 3  
1 0. 1 3  
 
 
1 0. 1 4  
 
 
 
1 0. 1 5  
 
 
 
 
. 
. 
1 0. 1 6  
 
 
 
. 
1 0. 1 7  
 
 
 
. 
1 0. 1 8  Tr o u g h I VI g C o nce ntr ati o ns at D esi g n ate d T i me P oi nts  
A b y -listi n g of tr o u g h I VI g c o nce ntrati o ns at will be prese nt e d f or t he Ri S A nal ysis Set  at Wee k 
1 2 a n d f or t he mI T T A n al ysis Set  at Wee k 3 2.  
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C S L Be hri n g  
Statistical A nal ysis Pla n  
Pr ot oc ol N u m ber: C S L 8 4 2 _ 3 0 0 1  
Pr o d uct Na me: C 1 -esterase 
I n hi bit or, H u ma n ( 5 0 0 I U/ m L) 
 
 
C O N FI D E N TI A L  
 
 
 Pa g e 4 8  of 7 3  
1 0. 1 9  
 
 
. 
1 0. 2 0  Tre at me nt C o m pli a nce  
Perce nta g e c o m plia nce will be a f u ncti o n of t he a m o u nt of I M P ta ke n, ie, t he act ual c u m ulati ve 
a d mi nistere d v ol u me ( m L), a n d t he a m o u nt of I M P prescri be d, i e, t he c u m ulati ve pla n ne d 
v ol u me ( m L). 
Perce nta g e c o m plia nce t o I M P will be calc ulate d as:  
c o m plia nce ( %) = (c u m ulati ve a d mi nistere d v ol u me / c u m ulati ve pla n ne d v ol u me) * 1 0 0. 
Perce nta g e  c o m plia nce will be s u m marize d b y fre q ue ncies of < 8 0 %, 8 0 % – 1 2 0 %, > 1 2 0 %. 
Perce nta g e c o m plia nce will be s u m marize d f or t he Ri S A nal ysis Set  f or Treat me nt Peri o d 1 a n d 
b y treat me nt gr o u p f or t he m I T T A nal ysis Set  f or Treat me nt Peri o d 2. Perce nta ge c o m plia nce 
will be  als o s u m marize d f or t he e ntire st u d y f or t h e mI T T s u bjects ra n d o mize d t o C 1-I N H i n 
peri o d 2. Als o, c o m plia n ce will be s u m marize d base d o n i ntra ve n o us deli ver y a n d s u bc uta n e o us 
deli ver y of C 1- I N H d uri n g Treat me nt Peri o d 1. 
S u bjects ma y u n der g o r etreat me nt d uri n g t he p ost- treat me nt F oll o w- u p Peri o d wit h t he bli n de d 
i n vesti gati o nal pr o d uct t o w hic h t he y were ra n d o mize d i n Treat me nt Peri o d 2. 
T he f oll o wi n g listi n gs will be pr o vi de d: 
•  Ra n d o mize d a n d act ual treat me nts , 
•  Dr u g acc o u nta bilit y data ( dis pe nse d a n d ret ur ne d), 
•  O verall c o m plia nce . 
A b y -s u bject listi n g will be pr o vi de d i ncl u di n g c o m plia nce b y treat me nt p eri o d, b y deli ver y 
s yste m (i ntra ve n o us a n d s u bc uta ne o us), ra n d o mize d a n d act ual treat me nts.  
Calc ulati o n of c o m plia nce a n d e xte n d of e x p os ure (s ee Secti o n 1 1. 1 ) will be base d o n dr u g 
acc o u nta bilit y data c ollecte d b y I R T s yste m ( or R A V E) as t he e C R F d oes n ot c o ntai n a n y s uc h 
relate d dat a fiel ds. Dr u g acc o u nta bilit y data will b e part of fi n al st u d y data base. 
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11 Safety Analyses 
Open-label safety events and findings will be defined as those with an onset date prior to the 
randomization date. Double-blind safety events and findings will be defined as those with an 
onset date on or after the randomization date. 
The RiS Analysis Set will be used for analysis of safety for open label TP1. The RWS Analysis 
Set will be used for analysis of safety during the double-blind period; summaries will be 
presented by treatment group and total number of subjects in RWS Analysis Set. Also, safety of 
RWS subjects randomized to C1-INH will be summarized over the study including periods 1 and 
2 and follow-up. 
11.1 
Extent of Exposure 
The extent of exposure to C1-INH in open-label and in double-blind period and to placebo in 
double-blind period will be summarized using descriptive statistics. Extent of exposure will be 
described in terms of the following (including intravenous administration and subcutaneous 
administrations): 
• Cumulative administered volume (mL), calculated as sum of single administered volumes 
in treatment periods, 
• Cumulative planned volume (mL), calculated as sum of single planned volumes in 
treatment periods (planned administration at days 1, 4, 7, 10, and 13 and twice weekly 
dosing beginning at the day 14 visit in Treatment Period 1 and twice weekly dosing in 
Treatment Period 2; dosing scheme must be taken into account for cumulative planned 
dose depending on subjects time in study; the number of administrations in period of 
twice weekly dosing will be calculated as: ((date of end of twice weekly dosing - date of 
start of twice weekly dosing +1) / 7) *2, 
• Days on treatment, calculated as days between first and last dose in treatment periods; 
• Average daily dose, calculated as cumulative administered dose divided by days on 
treatment for each treatment period, 
• For subjects continuing C1-INH in Treatment Period 2 cumulative administered dose, 
cumulative planned dose, days on treatment and average daily dose will be summarized 
for the whole C1-INH treatment period. 
Extent of exposure for Retreatment Periods will be summarized separately.  


CSL Behring 
Statistical Analysis Plan 
Protocol Number: CSL842_3001 
Product Name: C1-esterase 
Inhibitor, Human (500 IU/mL) 
 
 
CONFIDENTIAL 
 
 
 Page 50 of 73 
For summaries of Treatment Period 1 the RiS Analysis Set will be used. Summaries for 
Treatment Period 2 will be based on the RWS Analysis Set. Also, exposure summary will be 
presented for the RWS subjects receiving C1-INH during the entire study (Treatment Period 1 
and Treatment Period 2 combined). 
A by-subject listing will be provided including treatment period (including re-treatment), 
cumulative administered volume, cumulative planned volume, days on treatment and average 
daily dose. 
11.2 
Adverse Events 
Adverse events will be coded to the Preferred Term (PT) level using the Medical Dictionary for 
Regulatory Affairs (MedDRA dictionary), version 23.0 or higher. Treatment-emergent AEs 
(TEAEs) are defined as AEs reported at or after the start of the first infusion. All AEs regardless 
of when they were reported will be listed. 
Summaries of TEAEs will count the number of subjects, not the number of events, that is, 
subjects with multiple occurrences of the same TEAE will be counted once. 
The number and percentage of subjects with TEAEs will be reported. Also, the number and 
percentage of subjects with serious TEAEs, TEAEs by severity, and serious TEAEs related to 
investigational product will be presented. Adverse events will be presented for Treatment Period 
1 and RiS Analysis Set. For Treatment Period 2 summaries will be presented for the RWS 
Analysis Set. In addition, the summaries will be given for C1-INH over the whole study for RWS 
Analysis Set and a summary across the whole study will be given for the RiS Analysis Set. 
A summary of number and percentage of subjects with any TEAE by maximum severity or grade 
will be produced. TEAEs will be sorted by System Organ Class (SOC) and PT in descending 
order of incidence overall treatment arms. The summary will report the number of subjects with 
at least one TEAE, counted for the maximum severity and, for each PT reported, the number of 
subjects for each, counted for the maximum severity. 
In addition, the frequency and percentage of TEAEs will be summarized and displayed in two 
ways: 1) in descending order of incidence in whole study for RiS Analysis Set by PT only and 2) 
in descending order of incidence whole study for RiS Analysis Set by SOC and PT. In the SOC 
row, the number of subjects with multiple events under the same system organ class will be 
counted once. 


CSL Behring 
Statistical Analysis Plan 
Protocol Number: CSL842_3001 
Product Name: C1-esterase 
Inhibitor, Human (500 IU/mL) 
CONFIDENTIAL 
 Page 51 of 73 
A separate summary will be provided for study treatment-related serious TEAEs. Missing 
relationship to study treatment will be imputed as described in Section 8.1.2; this summary will 
also include the number and percentage of TEAEs with a missing relationship to aid in 
interpretation of the results. 
By-subject listings will also be provided with detailed information to support the different AE 
summaries. 
11.3 
Adverse Events of Special Interest (AESI) 
Adverse events of special interest of Treatment Period 2 will be presented for the RWS Analysis 
Set. In addition, adverse events of special interest will be summarized for C1-INH over the 
whole study for RWS Analysis Set and a summary across the whole study will be given for the 
RiS Analysis Set. 
•
Thromboembolic events
o
Systemic thrombotic or thromboembolic events not including catheter or
dialysis related clots are of interest. Identification will be based on the
Standardized MedDRA Query (SMQ) Embolic and thrombotic events
(narrow),
•
Anaphylaxis
o
Anaphylaxis will be identified using the SMQ - Anaphylactic reaction (broad).
Treatment-emergent adverse events of special interest will be summarized by SOC and PT. 
A separate by-subject listing will be produced for all treatment-emergent adverse events of 
special interest based on RiS Analysis Set. A listing of terms included in each SMQ can be found 
in Section 16.1 and 16.2. 
11.4 
Deaths and Serious Adverse Events 
A by-listing will be generated to provide subject-specific details on subjects who died. 
The following summaries will be provided for Treatment Period 2 and the RWS Analysis Set. In 
addition, a summary for C1-INH over the whole study for RWS Analysis Set and a summary 
across the whole study will be given for the RiS Analysis Set: 
•
Serious TEAEs,


C S L Be hri n g  
Statistical A nal ysis Pla n  
Pr ot oc ol N u m ber: C S L 8 4 2 _ 3 0 0 1  
Pr o d uct Na me: C 1 -esterase 
I n hi bit or, H u ma n ( 5 0 0 I U/ m L) 
 
 
C O N FI D E N TI A L  
 
 
 Pa g e 5 2  of 7 3  
•  Seri o us T E A Es relat e d t o St u d y Treat me nt . 
T he f oll o wi n g listi n gs will be pr o vi de d f or Ri S A n al ysis Set : 
•  Seri o us N o n- T E A Es,  
•  Seri o us T E A Es,  
•  T E A Es res ulti n g i n deat h. 
1 1. 5  
A d verse E ve nts Le a di n g t o Disc o nti n u ati o n of St u d y Tre at m e nt, 
Wit h dr a w al fr o m t he St u d y, a n d Ot her Si g nific a nt A d verse E ve nts  
T he f oll o wi n g listi n gs will be pr o vi de d base d o n Ri S A nal ysis Set : 
•  T E A Es Lea di n g t o Disc o nti n uati o n of St u d y Treat me nt, 
•  N o n -T E A Es lea di n g t o Wit h dra wal fr o m t he St u d y, 
•  T E A Es lea di n g t o Wit h dr a wal fr o m t he St u d y. 
1 1. 6  
Pre g n a ncies  
W hile pre g na n c y itself is n ot c o nsi dere d t o be a n A E or S A E, a n y pre g na n c y c o m plicati o n or 
electi ve ter mi nati o n of a pre g na nc y f or me dical reas o ns will be rec or de d as a n A E or S A E as 
descri be d i n t he pr ot o c ol. If a n y s u bject O R a n y s u bject or s u bject’s part n er bec o mes pre g na nt 
w hile o n t he st u d y, t he i nf or mati o n will be i ncl u de d i n t he narrati ves a n d n o se parat e ta ble or 
listi n g will be pr o d uce d. 
1 1. 7  
Cli nic al L a b or at or y E v al u ati o ns  
1 1. 7. 1  Cli nic al c he mistr y  
All cli nical c he mistr y par a meters f or t his st u d y will be s u m marize d b y sc h e d ule d visit usi n g 
descri pti ve statistics. All u nsc he d ule d visits will be e xcl u de d fr o m t hese b y -visit s u m maries.  
O pe n -la bel cli nical c he mistr y data f or Peri o d 1 a n d t hat f or t he e ntire st u d y will be s u m marize d 
f or t he Ri S A nal ysis Set . D o u ble-bli n d cli nical c he mistr y data f or Peri o d 2 will be s u m marize d 
f or t he R W S A nal ysis Set b y treat me nt.  
T he esti mate d a n d  
 e G F R will be s u m marize d as p art of efficac y, a n d n ot part of safet y.  
C CI


CSL Behring 
Statistical Analysis Plan 
Protocol Number: CSL842_3001 
Product Name: C1-esterase 
Inhibitor, Human (500 IU/mL) 
 
 
CONFIDENTIAL 
 
 
 Page 53 of 73 
Clinical Chemistry parameter to be summarized: Albumin, alkaline phosphatase, ALT, AST, 
total bilirubin, BUN, calcium, carbon dioxide, chloride, creatinine, glucose, potassium, sodium, 
and protein (total). 
11.7.2 Hematology 
All hematology parameters for this study will be summarized by scheduled visit using 
descriptive statistics. All unscheduled visits will be excluded from these by-visit summaries. 
Open-label hematology data and that for the entire study will be summarized for the RiS 
Analysis Set. 
Double-blind hematology data will be summarized for the RWS Analysis Set by treatment. 
Hematology parameter to be summarized: Hemoglobin, hematocrit, red blood cell indices: 
mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, mean corpuscular 
volume, blood cell counts: basophils, eosinophils, erythrocytes, leukocytes, lymphocytes, 
monocytes, neutrophils, neutrophil band forms, platelets, and reticulocytes. 
DSA: will be included as efficacy endpoint and will therefore be summarized for efficacy. 
11.8 
Other Safety Measures 
11.8.1 Vital Signs 
Systolic blood pressure, diastolic blood pressure, heart rate, and weight will be summarized for 
each scheduled visit using descriptive statistics or frequency counts as appropriate. 
Vital signs during Treatment Period 1 will be summarized for the RiS Analysis Set. Vital signs 
for the entire study will be summarized for the RWS Analysis Set by treatment. 
12 Pharmacokinetics 
All non-compartmental analyses for the derivation of PK parameters will be performed 
according to CSL SOP PK-GDL-01 and will be performed by CSL Behring Clinical 
Pharmacology & Pharmacometrics or their designate by using WinNonlin® version 8.1 or later. 
All analyses in this section will be based on the PK population, unless otherwise stated. 
The merge of PK concentration data and CRF data to generate a dataset with actual blood 
sampling times, nominal sampling times, actual time relative to dosing, and PK concentrations of 


C S L Be hri n g  
Statistical A nal ysis Pla n  
Pr ot oc ol N u m ber: C S L 8 4 2 _ 3 0 0 1  
Pr o d uct Na me: C 1 -esterase 
I n hi bit or, H u ma n ( 5 0 0 I U/ m L) 
 
 
C O N FI D E N TI A L  
 
 
 Pa g e 5 4  of 7 3  
C 1 -I N H a nti ge n c o nce ntr ati o ns a n d C 1 -I N H f u n cti o nal acti vit y will be perf or me d after data b ase 
l oc k b y  
 a n d is s pecifie d i n Secti o n 1 2. 5 . 
1 2. 1  P K S a m pli n g S c he d ule 
Bl o o d sa m ples will be ta ke n f or meas ure me nt of C 1 -I N H a nti ge n c o nce ntrati o ns a n d C 1 -I N H 
f u ncti o nal acti vit y at t he f oll o wi n g ti me p oi nts of Da y 1 0 of Treat me nt Peri o d 1: pre - d ose, 0 
mi n utes (start of C 1 -I N H i nf usi o n), 1 5 mi n utes, 3, 8, 2 4, a n d 7 2 h o urs aft er start of i nf usi o n a n d 
at Wee k 1 1 visit ( Treat m e nt Peri o d 1) at ti me p oi nts  of:  pre - d ose, 0 mi n utes (ti me of C 1-I N H 
i njecti o n), 2 4, 4 8, a n d 7 2 h o urs after i njecti o n. P K sa m ples will be dra w n i n a s u bset of s u bjects. 
S u m mar y statistic s will be pr o vi de d b y n o mi nal ( pla n ne d) ti me p oi nts. 
C o nce ntrati o n data e xcl u de d fr o m t he deri vati o n of P K para met ers will  be o mitte d fr o m 
s u m maries a n d will be fl a g ge d wit h a n asteris k i n t he rele va nt d ata listi n gs, wit h a f o ot n ote t o 
i n dicate t hat t hese val u es ha ve bee n o mitte d fr o m s u bse q ue nt a nal yses. 
1 2. 2  Pl as m a P K E n d p oi nts  
T he P K para m eters bas e d o n data c ollecte d o n Da y 1 0 f oll o wi n g I V a d mi nistrati o n a n d Wee k 1 0 
f oll o wi n g S C a d mi nistrati o n will be deri ve d , usi n g P h oe ni x Wi n N o nli n, Versi o n 8. 1 or hi g her. 
T he P K para m eter deri vati o n is base d o n act ual sa m pli n g ti mes a n d i ncl u des i m p utati o n of t he 
val ues bel o w t he l o wer li mit of q ua ntificati o n ( B L Q) a n d missi n g data will be c o n d ucte d i n 
acc or d a nce t o C S L S O P P K -G D L - 0 1, G ui deli ne o n t he C o n d uct of N o n-c o m part me ntal 
P har mac o ki netic A nal yses, C S L Be hri n g w hic h gi ves g ui da nce o n h o w t o deri ve P K para meters 
i n t he prese nce of missi n g data. 
Defi niti o n of deri ve d P K Para meter : 
Ter m  
Defi niti o n  
A U C 0-t 
Area u n d er t he c o nce ntrati o n ti me c ur ve fr o m ti me p oi nt zer o t o t he 
last q ua ntifia ble ti me p oi nt. 
C ma x  
T he ma xi m u m ( pea k) o bser ve d C 1 -I N H le vel. 
T ma x  
T he ti me t o reac h C ma x . 
P P D


CSL Behring 
Statistical Analysis Plan 
Protocol Number: CSL842_3001 
Product Name: C1-esterase 
Inhibitor, Human (500 IU/mL) 
 
 
CONFIDENTIAL 
 
 
 Page 55 of 73 
Term 
Definition 
Ctrough 
Trough C1-INH, collected prior to the next infusion. 
 
12.3 Summary of C1-INH Antigen and Functional Activity Plasma 
Concentrations 
The handling and imputation of BLQ values for PK parameters derivation is described in PK-
GDL-01, Guideline on the Conduct of Non-compartmental Pharmacokinetic Analyses, CSL 
Behring. The imputation rules below will be used for summary statistics of C1-INH antigen and 
functional activity plasma concentrations. The summaries will be given by sampling time point 
(planned time points) and treatment group for the PK Analysis Set. 
• The sampling time of pre-dose samples relative to dosing will be set to zero. 
• Any BLQ in the listing of individual concentrations will be set to missing. 
• Set any pre-dose BLQ to zero for summaries. 
• Set any BLQ occurring in the profile or at the end of the profile to missing and exclude 
missing values from the calculation of the means. 
• Calculate mean concentrations at any individual time point if at least 50% of the 
individual values are available (ie are quantifiable and not missing) at this time point 
otherwise report as “not calculated (NC)”. 
Summary statistics for concentration-time data will include  number of observations, mean, 
standard deviation, coefficient of variation (CV)%, minimum, median and maximum. 
A by-subject listing of C1-INH antigen and functional activity plasma concentration data will 
support the summaries. 
12.4 Summary of C1-INH PK Parameters 
PK parameters of Cmax, AUC0-t, Ctrough and for C1-INH antigen and functional activity will be 
summarized by treatment group for the PK Analysis Set by descriptive statistics with parameter 
of n, arithmetic mean, SD, CV% (CV% = 100* standard deviation / mean), minimum, Q25, 
median, Q75, and maximum. 
Tmax will be summarized by descriptive statistics with parameter of n, minimum, Q25, median, 
Q75, and maximum. 


C S L Be hri n g  
Statistical A nal ysis Pla n  
Pr ot oc ol N u m ber: C S L 8 4 2 _ 3 0 0 1  
Pr o d uct Na me: C 1 -esterase 
I n hi bit or, H u ma n ( 5 0 0 I U/ m L) 
 
 
C O N FI D E N TI A L  
 
 
 Pa g e 5 6  of 7 3  
A b y -s u bject listi n g of C 1-I N H P K p ara meters will be pr o vi de d. 
1 2. 5  P h ar m ac o ki netic A n al ysi s D at a Fl o w  
After dat a base l oc k,  
 will pr o d uce t h e S D T M d o mai ns. D o mai n P C will c o ntai n t he 
C 1 -I N H a nti ge n c o nce ntr ati o ns a n d C 1 -I N H f u n cti o nal acti vit y c o nce ntrati o ns. T he P C d o mai n 
al o n g wit h d o mai ns V S, D M a n d E X will be pr o vi de d b y  
.  
 Earl y P hase 
Ser vices  will deri ve t he P K para met ers a n d pr o d uce t he P K para m eter d atas et i n E xcel f or mat. 
Fr o m t his,  
 will pr o d uce t he S D T M d o mai n P P a n d e ve nt uall y t he a nal ysis dataset. 
Bef ore dat a base l o c k,  
 will use d u m m y data f or t he P K p ara met ers i n d o mai n P P t o be 
a ble t o pre- pr o gra m t he pla n ne d o ut p ut. 
1 3  
 
 
1 4  
 
 
 
1 5  Refere nces  
Fleiss J L, Le vi n B, Pai k M C. Statistical met h o ds f or rates a n d pr o p orti o ns. 3r d re v. e d. N e w 
Yor k: Wile y; 2 0 0 3.  
Le ve y A S, C ores h J, Gree ne T, Ste ve ns L A, Z h a n g Y L, He n dri kse n S, K use k J W, Va n L e nte  F; 
C hr o nic Ki d ne y Diseas e E pi de mi ol o g y C olla b orati o n. Usi n g sta n dar dize d s er u m creati ni ne 
val ues i n t he m o dificati o n of diet i n re nal diseas e st u d y e q uati o n f or esti mati n g gl o mer ular 
filtrati o n rate. A n n I nt er n Me d. 2 0 0 6 A u g 1 5; 1 4 5( 4): 2 4 7- 5 4. Errat u m i n: A n n I nter n Me d. 2 0 0 8 
Oct 7; 1 4 9( 7): 5 1 9. 
C CI
P P D
P P D
P P D
P P D
P P D
C CI
C CI
C CI


CSL Behring 
Statistical Analysis Plan 
Protocol Number: CSL842_3001 
Product Name: C1-esterase 
Inhibitor, Human (500 IU/mL) 
 
 
CONFIDENTIAL 
 
 
 Page 57 of 73 
Loupy A, Haas M, Solez K, Racusen L, Glotz D, Seron D, Nankivell BJ, Colvin RB, Afrouzian 
M, Akalin E, Alachkar N, Bagnasco S, Becker JU, Cornell L, Drachenberg C, Dragun D, de Kort 
H, Gibson IW, Kraus ES, Lefaucheur C, Legendre C, Liapis H, Muthukumar T, Nickeleit V, 
Orandi B, Park W, Rabant M, Randhawa P, Reed EF, Roufosse C, Seshan SV, Sis B, Singh HK, 
Schinstock C, Tambur A, Zeevi A, Mengel M. The Banff 2015 Kidney Meeting Report: Current 
Challenges in Rejection Classification and Prospects for Adopting Molecular Pathology. Am J 
Transplant.2017 Jan;17(1):28-41. 
Viglietti D, Gosset C, Loupy A, Deville L, Verine J, Zeevi A, Glotz D, Lefaucheur C. 
C1-inhibitor in Acute Antibody-mediated Rejection Nonresponsive to Conventional Therapy in 
Kidney Transplant Recipients: A Pilot Study. Am J Transplant. 2016; 16: 1596-1603. 
Viglietti D, Loupy A, Duong Van Huyen J, Verine J, Zeevi A, Legendre C, Glotz D, Lefaucheur 
C. Composite Score to Define the Risk of Allograft Loss After Standard-of-Care Treatement of 
Antibody-Mediated Rejection in Kidney Transplantation. Am J Transplant. 2016; 16 (Suppl 3). 
Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0, U.S. DEPARTMENT 
OF HEALTH AND HUMAN SERVICES, Published: November 27, 2017. 
PK-GDL-01, Guideline on the Conduct of Non-compartmental Pharmacokinetic Analyses, CSL 
Behring. 
 
 


CSL Behring 
Statistical Analysis Plan 
Protocol Number: CSL842_3001 
Product Name: C1-esterase 
Inhibitor, Human (500 IU/mL) 
 
 
CONFIDENTIAL 
 
 
 Page 58 of 73 
16 Appendices 
16.1 
Standardized MedDRA Query for Embolic and Thrombotic Events 
(Narrow) (SMQ Code: 20000081) 
 
SMQ Name: Embolic and thrombotic events, arterial (SMQ)                 SMQ Code:20000082 
Preferred Term 
Code 
Level 
Scope 
Category 
Acute aortic syndrome 
10074337 PT 
Narrow 
A 
Acute myocardial infarction 
10000891 PT 
Narrow 
A 
Amaurosis 
10001902 PT 
Narrow 
A 
Amaurosis fugax 
10001903 PT 
Narrow 
A 
Angioplasty 
10002475 PT 
Narrow 
A 
Aortic bypass 
10057617 PT 
Narrow 
A 
Aortic embolus 
10002897 PT 
Narrow 
A 
Aortic surgery 
10061651 PT 
Narrow 
A 
Aortic thrombosis 
10002910 PT 
Narrow 
A 
Aortogram abnormal 
10057794 PT 
Narrow 
A 
Arterectomy 
10071026 PT 
Narrow 
A 
Arterectomy with graft replacement 
10003140 PT 
Narrow 
A 
Arterial angioplasty 
10081731 PT 
Narrow 
A 
Arterial bypass occlusion 
10077766 PT 
Narrow 
A 
Arterial bypass operation 
10056418 PT 
Narrow 
A 
Arterial bypass thrombosis 
10077765 PT 
Narrow 
A 
Arterial graft 
10061655 PT 
Narrow 
A 
Arterial occlusive disease 
10062599 PT 
Narrow 
A 
Arterial revascularisation 
10084482 PT 
Narrow 
A 
Arterial stent insertion 
10061657 PT 
Narrow 
A 
Arterial therapeutic procedure 
10052949 PT 
Narrow 
A 
Arterial thrombosis 
10003178 PT 
Narrow 
A 
Arteriogram abnormal 
10061659 PT 
Narrow 
A 
Arteriogram carotid abnormal 
10003195 PT 
Narrow 
A 
Arteriotomy 
10078636 PT 
Narrow 
A 
Atherectomy 
10063025 PT 
Narrow 
A 
Atherosclerotic plaque rupture 
10076604 PT 
Narrow 
A 
Atrial appendage closure 
10079735 PT 
Narrow 
A 
Atrial appendage resection 
10080843 PT 
Narrow 
A 
Basal ganglia infarction 
10069020 PT 
Narrow 
A 
 
 


CSL Behring 
Statistical Analysis Plan 
Protocol Number: CSL842_3001 
Product Name: C1-esterase 
Inhibitor, Human (500 IU/mL) 
 
 
CONFIDENTIAL 
 
 
 Page 59 of 73 
Preferred Term 
Code 
Level 
Scope 
Category 
Basilar artery occlusion 
10048963 PT 
Narrow 
A 
Basilar artery thrombosis 
10063093 PT 
Narrow 
A 
Blindness transient 
10005184 PT 
Narrow 
A 
Brachiocephalic artery occlusion 
10069694 PT 
Narrow 
A 
Capsular warning syndrome 
10067744 PT 
Narrow 
A 
Carotid angioplasty 
10071260 PT 
Narrow 
A 
Carotid arterial embolus 
10007684 PT 
Narrow 
A 
Carotid artery bypass 
10053003 PT 
Narrow 
A 
Carotid artery occlusion 
10048964 PT 
Narrow 
A 
Carotid artery stent insertion 
10066102 PT 
Narrow 
A 
Carotid artery thrombosis 
10007688 PT 
Narrow 
A 
Carotid endarterectomy 
10007692 PT 
Narrow 
A 
Cerebellar artery occlusion 
10053633 PT 
Narrow 
A 
Cerebellar artery thrombosis 
10008023 PT 
Narrow 
A 
Cerebral artery embolism 
10008088 PT 
Narrow 
A 
Cerebral artery occlusion 
10008089 PT 
Narrow 
A 
Cerebral artery stent insertion 
10081893 PT 
Narrow 
A 
Cerebral artery thrombosis 
10008092 PT 
Narrow 
A 
Cerebral hypoperfusion 
10065384 PT 
Narrow 
A 
Cerebrovascular insufficiency 
10058842 PT 
Narrow 
A 
Cerebrovascular stenosis 
10061751 PT 
Narrow 
A 
Coeliac artery occlusion 
10069696 PT 
Narrow 
A 
Coronary angioplasty 
10050329 PT 
Narrow 
A 
Coronary arterial stent insertion 
10052086 PT 
Narrow 
A 
Coronary artery bypass 
10011077 PT 
Narrow 
A 
Coronary artery embolism 
10011084 PT 
Narrow 
A 
Coronary artery occlusion 
10011086 PT 
Narrow 
A 
Coronary artery reocclusion 
10053261 PT 
Narrow 
A 
Coronary artery surgery 
10011090 PT 
Narrow 
A 
Coronary artery thrombosis 
10011091 PT 
Narrow 
A 
Coronary endarterectomy 
10011101 PT 
Narrow 
A 
Coronary revascularisation 
10049887 PT 
Narrow 
A 
Coronary vascular graft occlusion 
10075162 PT 
Narrow 
A 
Embolia cutis medicamentosa 
10058729 PT 
Narrow 
A 
Embolism arterial 
10014513 PT 
Narrow 
A 
Endarterectomy 
10014648 PT 
Narrow 
A 
Femoral artery embolism 
10068365 PT 
Narrow 
A 
Hepatic artery embolism 
10019635 PT 
Narrow 
A 


CSL Behring 
Statistical Analysis Plan 
Protocol Number: CSL842_3001 
Product Name: C1-esterase 
Inhibitor, Human (500 IU/mL) 
 
 
CONFIDENTIAL 
 
 
 Page 60 of 73 
Preferred Term 
Code 
Level 
Scope 
Category 
Hepatic artery occlusion 
10051991 PT 
Narrow 
A 
Hepatic artery thrombosis 
10019636 PT 
Narrow 
A 
Hypothenar hammer syndrome 
10063518 PT 
Narrow 
A 
Iliac artery embolism 
10021338 PT 
Narrow 
A 
Iliac artery occlusion 
10064601 PT 
Narrow 
A 
Internal capsule infarction 
10083408 PT 
Narrow 
A 
Intra-aortic balloon placement 
10052989 PT 
Narrow 
A 
Intraoperative cerebral artery occlusion 
10056382 PT 
Narrow 
A 
Ischaemic cerebral infarction 
10060840 PT 
Narrow 
A 
Ischaemic stroke 
10061256 PT 
Narrow 
A 
Lacunar infarction 
10051078 PT 
Narrow 
A 
Leriche syndrome 
10024242 PT 
Narrow 
A 
Mesenteric arterial occlusion 
10027394 PT 
Narrow 
A 
Mesenteric arteriosclerosis 
10065560 PT 
Narrow 
A 
Mesenteric artery embolism 
10027395 PT 
Narrow 
A 
Mesenteric artery stenosis 
10027396 PT 
Narrow 
A 
Mesenteric artery stent insertion 
10071261 PT 
Narrow 
A 
Mesenteric artery thrombosis 
10027397 PT 
Narrow 
A 
Myocardial infarction 
10028596 PT 
Narrow 
A 
Myocardial necrosis 
10028602 PT 
Narrow 
A 
Ophthalmic artery thrombosis 
10081144 PT 
Narrow 
A 
Papillary muscle infarction 
10033697 PT 
Narrow 
A 
Penile artery occlusion 
10068035 PT 
Narrow 
A 
Percutaneous coronary intervention 
10065608 PT 
Narrow 
A 
Peripheral arterial occlusive disease 
10062585 PT 
Narrow 
A 
Peripheral arterial reocclusion 
10069379 PT 
Narrow 
A 
Peripheral artery angioplasty 
10057518 PT 
Narrow 
A 
Peripheral artery bypass 
10072561 PT 
Narrow 
A 
Peripheral artery occlusion 
10057525 PT 
Narrow 
A 
Peripheral artery stent insertion 
10072562 PT 
Narrow 
A 
Peripheral artery surgery 
10082470 PT 
Narrow 
A 
Peripheral artery thrombosis 
10072564 PT 
Narrow 
A 
Peripheral embolism 
10061340 PT 
Narrow 
A 
Peripheral endarterectomy 
10072560 PT 
Narrow 
A 
Popliteal artery entrapment syndrome 
10071642 PT 
Narrow 
A 
Post procedural myocardial infarction 
10066592 PT 
Narrow 
A 
Postinfarction angina 
10058144 PT 
Narrow 
A 
Precerebral artery occlusion 
10036511 PT 
Narrow 
A 


CSL Behring 
Statistical Analysis Plan 
Protocol Number: CSL842_3001 
Product Name: C1-esterase 
Inhibitor, Human (500 IU/mL) 
 
 
CONFIDENTIAL 
 
 
 Page 61 of 73 
Preferred Term 
Code 
Level 
Scope 
Category 
Precerebral artery thrombosis 
10074717 PT 
Narrow 
A 
Profundaplasty 
10078867 PT 
Narrow 
A 
Pulmonary artery occlusion 
10078201 PT 
Narrow 
A 
Pulmonary artery therapeutic procedure 
10063731 PT 
Narrow 
A 
Pulmonary artery thrombosis 
10037340 PT 
Narrow 
A 
Pulmonary endarterectomy 
10072893 PT 
Narrow 
A 
Pulmonary tumour thrombotic microangiopathy 
10079988 PT 
Narrow 
A 
Renal artery angioplasty 
10057493 PT 
Narrow 
A 
Renal artery occlusion 
10048988 PT 
Narrow 
A 
Renal artery thrombosis 
10038380 PT 
Narrow 
A 
Renal embolism 
10063544 PT 
Narrow 
A 
Retinal artery embolism 
10038826 PT 
Narrow 
A 
Retinal artery occlusion 
10038827 PT 
Narrow 
A 
Retinal artery thrombosis 
10038831 PT 
Narrow 
A 
Silent myocardial infarction 
10049768 PT 
Narrow 
A 
Spinal artery embolism 
10049440 PT 
Narrow 
A 
Spinal artery thrombosis 
10071316 PT 
Narrow 
A 
Splenic artery thrombosis 
10074600 PT 
Narrow 
A 
Splenic embolism 
10068677 PT 
Narrow 
A 
Stress cardiomyopathy 
10066286 PT 
Narrow 
A 
Subclavian artery embolism 
10042332 PT 
Narrow 
A 
Subclavian artery occlusion 
10069695 PT 
Narrow 
A 
Subclavian artery thrombosis 
10042334 PT 
Narrow 
A 
Thromboembolectomy 
10064958 PT 
Narrow 
A 
Thrombotic microangiopathy 
10043645 PT 
Narrow 
A 
Thrombotic thrombocytopenic purpura 
10043648 PT 
Narrow 
A 
Transient ischaemic attack 
10044390 PT 
Narrow 
A 
Truncus coeliacus thrombosis 
10062363 PT 
Narrow 
A 
Vascular pseudoaneurysm thrombosis 
10078269 PT 
Narrow 
A 
Vertebral artery occlusion 
10048965 PT 
Narrow 
A 
Vertebral artery thrombosis 
10057777 PT 
Narrow 
A 
Visual acuity reduced transiently 
10047532 PT 
Narrow 
A 
 
 


CSL Behring 
Statistical Analysis Plan 
Protocol Number: CSL842_3001 
Product Name: C1-esterase 
Inhibitor, Human (500 IU/mL) 
 
 
CONFIDENTIAL 
 
 
 Page 62 of 73 
SMQ Name: Embolic and thrombotic events, venous (SMQ)                SMQ Code:20000084 
Preferred Term 
Code 
Level 
Scope 
Category 
Aseptic cavernous sinus thrombosis 
10084527 PT 
Narrow 
A 
Axillary vein thrombosis 
10003880 PT 
Narrow 
A 
Brachiocephalic vein occlusion 
10076837 PT 
Narrow 
A 
Brachiocephalic vein thrombosis 
10063363 PT 
Narrow 
A 
Budd-Chiari syndrome 
10006537 PT 
Narrow 
A 
Catheterisation venous 
10052698 PT 
Narrow 
A 
Cavernous sinus thrombosis 
10007830 PT 
Narrow 
A 
Central venous catheterisation 
10053377 PT 
Narrow 
A 
Cerebral venous sinus thrombosis 
10083037 PT 
Narrow 
A 
Cerebral venous thrombosis 
10008138 PT 
Narrow 
A 
Compression garment application 
10079209 PT 
Narrow 
A 
Deep vein thrombosis 
10051055 PT 
Narrow 
A 
Deep vein thrombosis postoperative 
10066881 PT 
Narrow 
A 
Embolism venous 
10014522 PT 
Narrow 
A 
Hepatic vein embolism 
10078810 PT 
Narrow 
A 
Hepatic vein occlusion 
10058991 PT 
Narrow 
A 
Hepatic vein thrombosis 
10019713 PT 
Narrow 
A 
Homans' sign positive 
10051031 PT 
Narrow 
A 
Iliac vein occlusion 
10058992 PT 
Narrow 
A 
Inferior vena cava syndrome 
10070911 PT 
Narrow 
A 
Inferior vena caval occlusion 
10058987 PT 
Narrow 
A 
Jugular vein embolism 
10081850 PT 
Narrow 
A 
Jugular vein occlusion 
10076835 PT 
Narrow 
A 
Jugular vein thrombosis 
10023237 PT 
Narrow 
A 
Mahler sign 
10075428 PT 
Narrow 
A 
May-Thurner syndrome 
10069727 PT 
Narrow 
A 
Mesenteric vein thrombosis 
10027402 PT 
Narrow 
A 
Mesenteric venous occlusion 
10027403 PT 
Narrow 
A 
Obstetrical pulmonary embolism 
10029925 PT 
Narrow 
A 
Obstructive shock 
10073708 PT 
Narrow 
A 
Ophthalmic vein thrombosis 
10074349 PT 
Narrow 
A 
Ovarian vein thrombosis 
10072059 PT 
Narrow 
A 
Paget-Schroetter syndrome 
10050216 PT 
Narrow 
A 
Pelvic venous thrombosis 
10034272 PT 
Narrow 
A 
Penile vein thrombosis 
10034324 PT 
Narrow 
A 
Peripheral vein occlusion 
10083103 PT 
Narrow 
A 
Peripheral vein thrombus extension 
10082853 PT 
Narrow 
A 


CSL Behring 
Statistical Analysis Plan 
Protocol Number: CSL842_3001 
Product Name: C1-esterase 
Inhibitor, Human (500 IU/mL) 
 
 
CONFIDENTIAL 
 
 
 Page 63 of 73 
Preferred Term 
Code 
Level 
Scope 
Category 
Phlebectomy 
10048874 PT 
Narrow 
A 
Portal vein cavernous transformation 
10073979 PT 
Narrow 
A 
Portal vein embolism 
10082030 PT 
Narrow 
A 
Portal vein occlusion 
10058989 PT 
Narrow 
A 
Portal vein thrombosis 
10036206 PT 
Narrow 
A 
Portosplenomesenteric venous thrombosis 
10077623 PT 
Narrow 
A 
Post procedural pulmonary embolism 
10063909 PT 
Narrow 
A 
Post thrombotic syndrome 
10048591 PT 
Narrow 
A 
Postoperative thrombosis 
10050902 PT 
Narrow 
A 
Postpartum venous thrombosis 
10036300 PT 
Narrow 
A 
Pulmonary embolism 
10037377 PT 
Narrow 
A 
Pulmonary infarction 
10037410 PT 
Narrow 
A 
Pulmonary microemboli 
10037421 PT 
Narrow 
A 
Pulmonary thrombosis 
10037437 PT 
Narrow 
A 
Pulmonary vein occlusion 
10068690 PT 
Narrow 
A 
Pulmonary veno-occlusive disease 
10037458 PT 
Narrow 
A 
Pulmonary venous thrombosis 
10037459 PT 
Narrow 
A 
Renal vein embolism 
10038547 PT 
Narrow 
A 
Renal vein occlusion 
10056293 PT 
Narrow 
A 
Renal vein thrombosis 
10038548 PT 
Narrow 
A 
Retinal vein occlusion 
10038907 PT 
Narrow 
A 
Retinal vein thrombosis 
10038908 PT 
Narrow 
A 
Septic pulmonary embolism 
10083093 PT 
Narrow 
A 
SI QIII TIII pattern 
10068479 PT 
Narrow 
A 
Splenic vein occlusion 
10068122 PT 
Narrow 
A 
Splenic vein thrombosis 
10041659 PT 
Narrow 
A 
Subclavian vein occlusion 
10079164 PT 
Narrow 
A 
Subclavian vein thrombosis 
10049446 PT 
Narrow 
A 
Superior sagittal sinus thrombosis 
10042567 PT 
Narrow 
A 
Superior vena cava occlusion 
10058988 PT 
Narrow 
A 
Superior vena cava syndrome 
10042569 PT 
Narrow 
A 
Thrombophlebitis 
10043570 PT 
Narrow 
A 
Thrombophlebitis migrans 
10043581 PT 
Narrow 
A 
Thrombophlebitis neonatal 
10043586 PT 
Narrow 
A 
Thrombophlebitis superficial 
10043595 PT 
Narrow 
A 
Thrombosed varicose vein 
10043605 PT 
Narrow 
A 
Thrombosis corpora cavernosa 
10067270 PT 
Narrow 
A 
Transverse sinus thrombosis 
10044457 PT 
Narrow 
A 


CSL Behring 
Statistical Analysis Plan 
Protocol Number: CSL842_3001 
Product Name: C1-esterase 
Inhibitor, Human (500 IU/mL) 
 
 
CONFIDENTIAL 
 
 
 Page 64 of 73 
Preferred Term 
Code 
Level 
Scope 
Category 
Vena cava embolism 
10047193 PT 
Narrow 
A 
Vena cava filter insertion 
10048932 PT 
Narrow 
A 
Vena cava filter removal 
10074397 PT 
Narrow 
A 
Vena cava thrombosis 
10047195 PT 
Narrow 
A 
Venogram abnormal 
10047209 PT 
Narrow 
A 
Venoocclusive disease 
10062173 PT 
Narrow 
A 
Venoocclusive liver disease 
10047216 PT 
Narrow 
A 
Venous angioplasty 
10077826 PT 
Narrow 
A 
Venous occlusion 
10058990 PT 
Narrow 
A 
Venous operation 
10062175 PT 
Narrow 
A 
Venous recanalisation 
10068605 PT 
Narrow 
A 
Venous repair 
10052964 PT 
Narrow 
A 
Venous stent insertion 
10063389 PT 
Narrow 
A 
Venous thrombosis 
10047249 PT 
Narrow 
A 
Venous thrombosis in pregnancy 
10067030 PT 
Narrow 
A 
Venous thrombosis limb 
10061408 PT 
Narrow 
A 
Venous thrombosis neonatal 
10064602 PT 
Narrow 
A 
Visceral venous thrombosis 
10077829 PT 
Narrow 
A 
 
 


CSL Behring 
Statistical Analysis Plan 
Protocol Number: CSL842_3001 
Product Name: C1-esterase 
Inhibitor, Human (500 IU/mL) 
 
 
CONFIDENTIAL 
 
 
 Page 65 of 73 
SMQ Name: Embolic and thrombotic events, vessel type unspecified and mixed arterial and 
venous (SMQ)                                                                                                SMQ Code:20000083 
Preferred Term 
Code 
Level 
Scope 
Category 
Administration site thrombosis 
10075968 PT 
Narrow 
A 
Adrenal thrombosis 
10075178 PT 
Narrow 
A 
Angiogram abnormal 
10060956 PT 
Narrow 
A 
Angiogram cerebral abnormal 
10052906 PT 
Narrow 
A 
Angiogram peripheral abnormal 
10057517 PT 
Narrow 
A 
Antiphospholipid syndrome 
10002817 PT 
Narrow 
A 
Application site thrombosis 
10076026 PT 
Narrow 
A 
Arteriovenous fistula occlusion 
10058562 PT 
Narrow 
A 
Arteriovenous fistula thrombosis 
10003192 PT 
Narrow 
A 
Arteriovenous graft thrombosis 
10053182 PT 
Narrow 
A 
Artificial blood vessel occlusion 
10078895 PT 
Narrow 
A 
Atrial thrombosis 
10048632 PT 
Narrow 
A 
Basal ganglia stroke 
10071043 PT 
Narrow 
A 
Bone infarction 
10049824 PT 
Narrow 
A 
Brain stem embolism 
10074422 PT 
Narrow 
A 
Brain stem infarction 
10006147 PT 
Narrow 
A 
Brain stem stroke 
10068644 PT 
Narrow 
A 
Brain stem thrombosis 
10062573 PT 
Narrow 
A 
Cardiac ventricular thrombosis 
10053994 PT 
Narrow 
A 
Catheter site thrombosis 
10079523 PT 
Narrow 
A 
Cerebellar embolism 
10067167 PT 
Narrow 
A 
Cerebellar infarction 
10008034 PT 
Narrow 
A 
Cerebral congestion 
10076929 PT 
Narrow 
A 
Cerebral infarction 
10008118 PT 
Narrow 
A 
Cerebral infarction foetal 
10008119 PT 
Narrow 
A 
Cerebral ischaemia 
10008120 PT 
Narrow 
A 
Cerebral microembolism 
10078311 PT 
Narrow 
A 
Cerebral microinfarction 
10083668 PT 
Narrow 
A 
Cerebral septic infarct 
10070671 PT 
Narrow 
A 
Cerebral thrombosis 
10008132 PT 
Narrow 
A 
Cerebral vascular occlusion 
10076895 PT 
Narrow 
A 
Cerebrospinal thrombotic tamponade 
10052173 PT 
Narrow 
A 
Cerebrovascular accident 
10008190 PT 
Narrow 
A 
Cerebrovascular accident prophylaxis 
10049165 PT 
Narrow 
A 
Cerebrovascular disorder 
10008196 PT 
Narrow 
A 
Cerebrovascular operation 
10051902 PT 
Narrow 
A 


CSL Behring 
Statistical Analysis Plan 
Protocol Number: CSL842_3001 
Product Name: C1-esterase 
Inhibitor, Human (500 IU/mL) 
 
 
CONFIDENTIAL 
 
 
 Page 66 of 73 
Preferred Term 
Code 
Level 
Scope 
Category 
Choroidal infarction 
10057403 PT 
Narrow 
A 
Collateral circulation 
10069729 PT 
Narrow 
A 
Coronary bypass thrombosis 
10059025 PT 
Narrow 
A 
Device embolisation 
10074896 PT 
Narrow 
A 
Device occlusion 
10064685 PT 
Narrow 
A 
Device related thrombosis 
10077455 PT 
Narrow 
A 
Diplegia 
10013033 PT 
Narrow 
A 
Directional Doppler flow tests abnormal 
10013048 PT 
Narrow 
A 
Disseminated intravascular coagulation 
10013442 PT 
Narrow 
A 
Disseminated intravascular coagulation in newborn 10013443 PT 
Narrow 
A 
Embolic cerebellar infarction 
10084072 PT 
Narrow 
A 
Embolic cerebral infarction 
10060839 PT 
Narrow 
A 
Embolic pneumonia 
10065680 PT 
Narrow 
A 
Embolic stroke 
10014498 PT 
Narrow 
A 
Embolism 
10061169 PT 
Narrow 
A 
Eye infarction 
10083006 PT 
Narrow 
A 
Fluorescence angiogram abnormal 
10083087 PT 
Narrow 
A 
Foetal cerebrovascular disorder 
10053601 PT 
Narrow 
A 
Gastric infarction 
10084858 PT 
Narrow 
A 
Graft thrombosis 
10051269 PT 
Narrow 
A 
Haemorrhagic adrenal infarction 
10079902 PT 
Narrow 
A 
Haemorrhagic cerebral infarction 
10019005 PT 
Narrow 
A 
Haemorrhagic infarction 
10019013 PT 
Narrow 
A 
Haemorrhagic stroke 
10019016 PT 
Narrow 
A 
Haemorrhagic transformation stroke 
10055677 PT 
Narrow 
A 
Haemorrhoids thrombosed 
10019023 PT 
Narrow 
A 
Hemiparesis 
10019465 PT 
Narrow 
A 
Hemiplegia 
10019468 PT 
Narrow 
A 
Heparin-induced thrombocytopenia 
10062506 PT 
Narrow 
A 
Hepatic infarction 
10019680 PT 
Narrow 
A 
Hepatic vascular thrombosis 
10074494 PT 
Narrow 
A 
Implant site thrombosis 
10063868 PT 
Narrow 
A 
Incision site vessel occlusion 
10076839 PT 
Narrow 
A 
Infarction 
10061216 PT 
Narrow 
A 
Infusion site thrombosis 
10065489 PT 
Narrow 
A 
Injection site thrombosis 
10022104 PT 
Narrow 
A 
Inner ear infarction 
10070754 PT 
Narrow 
A 
Instillation site thrombosis 
10073625 PT 
Narrow 
A 


CSL Behring 
Statistical Analysis Plan 
Protocol Number: CSL842_3001 
Product Name: C1-esterase 
Inhibitor, Human (500 IU/mL) 
 
 
CONFIDENTIAL 
 
 
 Page 67 of 73 
Preferred Term 
Code 
Level 
Scope 
Category 
Intestinal infarction 
10022657 PT 
Narrow 
A 
Intracardiac mass 
10066087 PT 
Narrow 
A 
Intracardiac thrombus 
10048620 PT 
Narrow 
A 
Lambl's excrescences 
10083691 PT 
Narrow 
A 
Medical device site thrombosis 
10076145 PT 
Narrow 
A 
Mesenteric vascular insufficiency 
10027401 PT 
Narrow 
A 
Mesenteric vascular occlusion 
10074583 PT 
Narrow 
A 
Microembolism 
10073734 PT 
Narrow 
A 
Monoparesis 
10027925 PT 
Narrow 
A 
Monoplegia 
10027926 PT 
Narrow 
A 
Optic nerve infarction 
10030936 PT 
Narrow 
A 
Pancreatic infarction 
10068239 PT 
Narrow 
A 
Paradoxical embolism 
10066059 PT 
Narrow 
A 
Paraneoplastic thrombosis 
10079251 PT 
Narrow 
A 
Paraparesis 
10033885 PT 
Narrow 
A 
Paraplegia 
10033892 PT 
Narrow 
A 
Paresis 
10033985 PT 
Narrow 
A 
Peripheral revascularisation 
10053351 PT 
Narrow 
A 
Pituitary infarction 
10035092 PT 
Narrow 
A 
Placental infarction 
10064620 PT 
Narrow 
A 
Pneumatic compression therapy 
10059829 PT 
Narrow 
A 
Portal shunt procedure 
10077479 PT 
Narrow 
A 
Post procedural stroke 
10066591 PT 
Narrow 
A 
Postpartum thrombosis 
10077022 PT 
Narrow 
A 
Prosthetic cardiac valve thrombosis 
10063176 PT 
Narrow 
A 
Prosthetic vessel implantation 
10068628 PT 
Narrow 
A 
Quadriparesis 
10049680 PT 
Narrow 
A 
Quadriplegia 
10037714 PT 
Narrow 
A 
Renal infarct 
10038470 PT 
Narrow 
A 
Renal vascular thrombosis 
10072226 PT 
Narrow 
A 
Retinal infarction 
10051742 PT 
Narrow 
A 
Retinal vascular thrombosis 
10062108 PT 
Narrow 
A 
Revascularisation procedure 
10084091 PT 
Narrow 
A 
Shunt occlusion 
10040621 PT 
Narrow 
A 
Shunt thrombosis 
10059054 PT 
Narrow 
A 
Spinal cord infarction 
10058571 PT 
Narrow 
A 
Spinal stroke 
10082031 PT 
Narrow 
A 
Splenic infarction 
10041648 PT 
Narrow 
A 


CSL Behring 
Statistical Analysis Plan 
Protocol Number: CSL842_3001 
Product Name: C1-esterase 
Inhibitor, Human (500 IU/mL) 
 
 
CONFIDENTIAL 
 
 
 Page 68 of 73 
Preferred Term 
Code 
Level 
Scope 
Category 
Splenic thrombosis 
10074601 PT 
Narrow 
A 
Stoma site thrombosis 
10074515 PT 
Narrow 
A 
Stroke in evolution 
10059613 PT 
Narrow 
A 
Strokectomy 
10084735 PT 
Narrow 
A 
Surgical vascular shunt 
10058408 PT 
Narrow 
A 
Testicular infarction 
10043337 PT 
Narrow 
A 
Thalamic infarction 
10064961 PT 
Narrow 
A 
Thrombectomy 
10043530 PT 
Narrow 
A 
Thromboangiitis obliterans 
10043540 PT 
Narrow 
A 
Thrombolysis 
10043568 PT 
Narrow 
A 
Thrombosis 
10043607 PT 
Narrow 
A 
Thrombosis in device 
10062546 PT 
Narrow 
A 
Thrombosis mesenteric vessel 
10043626 PT 
Narrow 
A 
Thrombosis prophylaxis 
10043634 PT 
Narrow 
A 
Thrombotic cerebral infarction 
10067347 PT 
Narrow 
A 
Thrombotic stroke 
10043647 PT 
Narrow 
A 
Thyroid infarction 
10043742 PT 
Narrow 
A 
Tumour embolism 
10045168 PT 
Narrow 
A 
Tumour thrombectomy 
10081994 PT 
Narrow 
A 
Tumour thrombosis 
10068067 PT 
Narrow 
A 
Ultrasonic angiogram abnormal 
10061604 PT 
Narrow 
A 
Ultrasound Doppler abnormal 
10045413 PT 
Narrow 
A 
Umbilical cord occlusion 
10076714 PT 
Narrow 
A 
Umbilical cord thrombosis 
10071652 PT 
Narrow 
A 
Vaccination site thrombosis 
10076190 PT 
Narrow 
A 
Vascular access site thrombosis 
10078675 PT 
Narrow 
A 
Vascular device occlusion 
10080803 PT 
Narrow 
A 
Vascular graft 
10067740 PT 
Narrow 
A 
Vascular graft occlusion 
10049060 PT 
Narrow 
A 
Vascular graft thrombosis 
10069922 PT 
Narrow 
A 
Vascular operation 
10049071 PT 
Narrow 
A 
Vascular stent insertion 
10063382 PT 
Narrow 
A 
Vascular stent occlusion 
10077143 PT 
Narrow 
A 
Vascular stent thrombosis 
10063934 PT 
Narrow 
A 
 
 


CSL Behring 
Statistical Analysis Plan 
Protocol Number: CSL842_3001 
Product Name: C1-esterase 
Inhibitor, Human (500 IU/mL) 
 
 
CONFIDENTIAL 
 
 
 Page 69 of 73 
Preferred Term 
Code 
Level 
Scope 
Category 
Vasodilation procedure 
10058794 PT 
Narrow 
A 
Vessel puncture site occlusion 
10076838 PT 
Narrow 
A 
Vessel puncture site thrombosis 
10070649 PT 
Narrow 
A 
Visual midline shift syndrome 
10066856 PT 
Narrow 
A 
SMQ Export: 23.1 - English 2/12/2020 8:42:53 
PM 
  
  
  
  
 
16.2 
Standardized MedDRA Query - Anaphylactic Reaction (Broad) (SMQ 
Code: 20000021) 
 
SMQ Name: Anaphylactic reaction (SMQ)                                                   SMQ Code: 20000021 
Preferred term 
Code 
Level 
Scope 
Category 
Anaphylactic reaction 
10002198 
PT 
Narrow 
A 
Anaphylactic shock 
10002199 
PT 
Narrow 
A 
Anaphylactic transfusion reaction 
10067113 
PT 
Narrow 
A 
Anaphylactoid reaction 
10002216 
PT 
Narrow 
A 
Anaphylactoid shock 
10063119 
PT 
Narrow 
A 
Circulatory collapse 
10009192 
PT 
Narrow 
A 
Dialysis membrane reaction 
10076665 
PT 
Narrow 
A 
Kounis syndrome 
10069167 
PT 
Narrow 
A 
Procedural shock 
10080894 
PT 
Narrow 
A 
Shock 
10040560 
PT 
Narrow 
A 
Shock symptom 
10040581 
PT 
Narrow 
A 
Type I hypersensitivity 
10045240 
PT 
Narrow 
A 
Acute respiratory failure 
10001053 
PT 
Broad 
B 
Asthma 
10003553 
PT 
Broad 
B 
Bronchial oedema 
10056695 
PT 
Broad 
B 
Bronchospasm 
10006482 
PT 
Broad 
B 
Cardio-respiratory distress 
10049874 
PT 
Broad 
B 
Chest discomfort 
10008469 
PT 
Broad 
B 
Choking 
10008589 
PT 
Broad 
B 
Choking sensation 
10008590 
PT 
Broad 
B 
Circumoral oedema 
10052250 
PT 
Broad 
B 
Cough 
10011224 
PT 
Broad 
B 
Cough variant asthma 
10063076 
PT 
Broad 
B 


CSL Behring 
Statistical Analysis Plan 
Protocol Number: CSL842_3001 
Product Name: C1-esterase 
Inhibitor, Human (500 IU/mL) 
 
 
CONFIDENTIAL 
 
 
 Page 70 of 73 
 
 


CSL Behring 
Statistical Analysis Plan 
Protocol Number: CSL842_3001 
Product Name: C1-esterase 
Inhibitor, Human (500 IU/mL) 
 
 
CONFIDENTIAL 
 
 
 Page 71 of 73 
Preferred term 
Code 
Level 
Scope 
Category 
Cyanosis 
10011703 
PT 
Broad 
B 
Dyspnoea 
10013968 
PT 
Broad 
B 
Hyperventilation 
10020910 
PT 
Broad 
B 
Irregular breathing 
10076213 
PT 
Broad 
B 
Laryngeal dyspnoea 
10052390 
PT 
Broad 
B 
Laryngeal oedema 
10023845 
PT 
Broad 
B 
Laryngospasm 
10023891 
PT 
Broad 
B 
Laryngotracheal oedema 
10023893 
PT 
Broad 
B 
Mouth swelling 
10075203 
PT 
Broad 
B 
Nasal obstruction 
10028748 
PT 
Broad 
B 
Oedema mouth 
10030110 
PT 
Broad 
B 
Oropharyngeal oedema 
10078783 
PT 
Broad 
B 
Oropharyngeal spasm 
10031111 
PT 
Broad 
B 
Oropharyngeal swelling 
10031118 
PT 
Broad 
B 
Pharyngeal oedema 
10034829 
PT 
Broad 
B 
Pharyngeal swelling 
10082270 
PT 
Broad 
B 
Respiratory arrest 
10038669 
PT 
Broad 
B 
Respiratory distress 
10038687 
PT 
Broad 
B 
Respiratory failure 
10038695 
PT 
Broad 
B 
Reversible airways obstruction 
10062109 
PT 
Broad 
B 
Sensation of foreign body 
10061549 
PT 
Broad 
B 
Sneezing 
10041232 
PT 
Broad 
B 
Stridor 
10042241 
PT 
Broad 
B 
Swollen tongue 
10042727 
PT 
Broad 
B 
Tachypnoea 
10043089 
PT 
Broad 
B 
Throat tightness 
10043528 
PT 
Broad 
B 
Tongue oedema 
10043967 
PT 
Broad 
B 
Tracheal obstruction 
10044291 
PT 
Broad 
B 
Tracheal oedema 
10044296 
PT 
Broad 
B 
Upper airway obstruction 
10067775 
PT 
Broad 
B 
Wheezing 
10047924 
PT 
Broad 
B 
Acquired C1 inhibitor deficiency 
10081035 
PT 
Broad 
C 
Allergic oedema 
10060934 
PT 
Broad 
C 
Angioedema 
10002424 
PT 
Broad 
C 
Circumoral swelling 
10081703 
PT 
Broad 
C 
Erythema 
10015150 
PT 
Broad 
C 
Eye oedema 
10052139 
PT 
Broad 
C 


CSL Behring 
Statistical Analysis Plan 
Protocol Number: CSL842_3001 
Product Name: C1-esterase 
Inhibitor, Human (500 IU/mL) 
 
 
CONFIDENTIAL 
 
 
 Page 72 of 73 
Preferred term 
Code 
Level 
Scope 
Category 
Eye pruritus 
10052140 
PT 
Broad 
C 
Eye swelling 
10015967 
PT 
Broad 
C 
Eyelid oedema 
10015993 
PT 
Broad 
C 
Face oedema 
10016029 
PT 
Broad 
C 
Flushing 
10016825 
PT 
Broad 
C 
Hereditary angioedema with C1 esterase 
inhibitor deficiency 
10080955 
PT 
Broad 
C 
Injection site urticaria 
10022107 
PT 
Broad 
C 
Lip oedema 
10024558 
PT 
Broad 
C 
Lip swelling 
10024570 
PT 
Broad 
C 
Nodular rash 
10075807 
PT 
Broad 
C 
Ocular hyperaemia 
10030041 
PT 
Broad 
C 
Oedema 
10030095 
PT 
Broad 
C 
Oedema blister 
10080039 
PT 
Broad 
C 
Periorbital oedema 
10034545 
PT 
Broad 
C 
Periorbital swelling 
10056647 
PT 
Broad 
C 
Pruritus 
10037087 
PT 
Broad 
C 
Pruritus allergic 
10063438 
PT 
Broad 
C 
Rash 
10037844 
PT 
Broad 
C 
Rash erythematous 
10037855 
PT 
Broad 
C 
Rash pruritic 
10037884 
PT 
Broad 
C 
Skin swelling 
10053262 
PT 
Broad 
C 
Swelling 
10042674 
PT 
Broad 
C 
Swelling face 
10042682 
PT 
Broad 
C 
Swelling of eyelid 
10042690 
PT 
Broad 
C 
Urticaria 
10046735 
PT 
Broad 
C 
Urticaria papular 
10046750 
PT 
Broad 
C 
Blood pressure decreased 
10005734 
PT 
Broad 
D 
Blood pressure diastolic decreased 
10005737 
PT 
Broad 
D 
Blood pressure systolic decreased 
10005758 
PT 
Broad 
D 
Cardiac arrest 
10007515 
PT 
Broad 
D 
Cardio-respiratory arrest 
10007617 
PT 
Broad 
D 
Cardiovascular insufficiency 
10065929 
PT 
Broad 
D 
Diastolic hypotension 
10066077 
PT 
Broad 
D 
 
 


CSL Behring 
Statistical Analysis Plan 
Protocol Number: CSL842_3001 
Product Name: C1-esterase 
Inhibitor, Human (500 IU/mL) 
 
 
CONFIDENTIAL 
 
 
 Page 73 of 73 
Preferred term 
Code 
Level 
Scope 
Category 
Hypotension 
10021097 
PT 
Broad 
D 
Hypotensive crisis 
10083659 
PT 
Broad 
D 
Post procedural hypotension 
10084013 
PT 
Broad 
D 
SMQ Export: 23.1 - English (2/12/2020 
8:39:05 PM) 
 
 
 
 
 


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