Conditions: Hereditary Angioedema
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 44
Healthy volunteers: no

Brief summary:
This is a multicenter, randomized, placebo-controlled, parallel-arm, phase 2 study to investigate the clinical efficacy, pharmacokinetics, and safety of CSL312 as prophylaxis to prevent attacks in subjects with HAE.

Detailed description:

Arms:
arm 1: Subjects with C1-INH HAE receiving buffer only arm 2: Subjects with C1-INH HAE receiving low dose CSL312 arm 3: Subjects with C1-INH HAE receiving medium dose CSL312 arm 4: Subjects with C1-INH HAE receiving high dose CSL312 arm 5: Subjects with C1-INH HAE receiving medium/high dose CSL312

Interventions: intervention 1: Factor XIIa antagonist monoclonal antibody intervention 2: Placebo
Intervention descriptions: intervention 1: Factor XIIa antagonist monoclonal antibody for intravenous and subcutaneous use intervention 2: Buffer without active ingredient

Protocol document:
Prot_000.pdf: 
 
 
 
Protocol version: Amendment 2 Final  
 
Page 1 of 126 
Date: 20 March 2020 
 
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Confidential 
CLINICAL STUDY PROTOCOL 
 
A multicenter, randomized, placebo-controlled, parallel-arm study to investigate 
the efficacy, pharmacokinetics, and safety of CSL312 
in subjects with hereditary angioedema 
Study Number: 
CSL312_2001 
Study Product: 
CSL312 (Factor XIIa Antagonist Monoclonal Antibody) 
Development Phase: 
Phase 2 
Sponsor: 
CSL Behring LLC 
1020 First Avenue 
King of Prussia, Pennsylvania 
19406 
United States of America 
Protocol Version: 
Amendment 2  
EudraCT Number: 
2018-000605-24 
Protocol Date: 
20 March 2020 
Compliance: 
This study will be conducted in accordance with standards of 
Good Clinical Practice (as defined by the International 
Conference on 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. 
 


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List of Personnel and Organizations Responsible for Conduct of the Study 
A list of personnel and organizations responsible for the conduct of the study will be supplied 
to study sites as part of the Investigator’s Study File. This list will be updated by CSL (or 
delegate) and provided to the study sites as needed.  
  
 


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Revision History 
Date 
Version  
Summary of Changes 
30 May 2018 
Original 
Not applicable 
18 December 
2018 
Amendment 1 
• Frequency of pregnancy testing was 
increased in Treatment Period 2. 
• Urine testing for pregnancy was added 
as an alternative to serum testing. 
• Acceptable methods of contraception 
were updated. 
• The requirement that pregnancy test 
results obtained outside of the study site 
will be documented and tracked was 
added. 
• The duration of the Follow-up Period 
was extended to 95 days. 
• Activities related to the accessibility 
and accountability of CSL312 were 
clarified, in the case that Treatment 
Period 2 is extended. 
• Acceptable use of routine (long-term) 
HAE prophylaxis during the study was 
clarified. 
• Clarification to the laboratory values 
that are to be documented in the 
medical history page of the eCRF. 
• Clarifications to statistical methods. 
20 March 2020 
Amendment 2 
• For hereditary angioedema subjects 
with C1-esterase inhibitor deficiency 
(C1-INH HAE) receiving the 
 mg 
dose in Treatment Period 2, the dose 
will be decreased to 
 mg. 
• Edits were made to the Statistical 
Analysis and Methods section. 
• Administrative clarifications for 
accuracy, grammar, formatting, and 
consistency. 
 
 
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CSL312 (Factor XIIa Antagonist Monoclonal Antibody) 
Protocol version:  Amendment 2 Final 
 
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Protocol Synopsis 
Title 
A multicenter, randomized, placebo-controlled, parallel-arm study 
to investigate the efficacy, pharmacokinetics, and safety of CSL312 
in subjects with hereditary angioedema 
Study Number 
CSL312_2001 
Sponsor 
CSL Behring LLC (CSL) 
Development Phase 
Phase 2 
Study Product 
CSL312 (Factor XIIa Antagonist Monoclonal Antibody) 
Indication 
Hereditary angioedema 
Study Summary 
and Overview 
This is a multicenter, randomized, placebo-controlled, parallel-arm, 
phase 2 study to investigate the clinical efficacy, pharmacokinetics, 
and safety of CSL312 as prophylaxis to prevent hereditary 
angioedema (HAE). The study consists of a Screening Period, a 
Run-in Period, 2 treatment periods, and a Follow-up Period.  


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An overview of the study design is presented in the following 
schematic: 
Abbreviations presented in the study schematic: C1-INH HAE = HAE with C1-esterase 
inhibitor deficiency; FXII/PLG HAE = HAE with normal C1-esterase inhibitor and factor 
XII or plasminogen gene mutation; HAE = hereditary angioedema; q2wk = administered 
every 2 weeks; q4wk = administered every 4 weeks. 
a All C1-INH HAE subjects receiving the 
 mg dose will have their dose reduced to 
mg q4wk SC at their next scheduled study visit. 
Run-in Period 
After Screening, eligible subjects will enter into an initial Run-in 
Period lasting at least 4 and up to 8 weeks to confirm their underlying 
disease status and to assess their eligibility for participation in 
Treatment Period 1. The first day of the Run-in Period may occur on 
the same day as Screening. Subjects may stop participation in the 
Run-in Period and begin Treatment Period 1when they have met 
pre-specified criteria, including: 
1. For subjects with hereditary angioedema with C1-esterase
inhibitor deficiency (C1-INH HAE), subjects must have
experienced ≥ 2 HAE attacks within a consecutive 4-week period
during the Run-in Period.
2. For subjects with FXII/PLG HAE, subjects must have
experienced ≥ 1 HAE attack during the Run-in Period.
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Treatment Period 1 
Investigators will assess and document the occurrence of HAE attacks 
based on data reported by subjects in an eDiary. Safety and 
pharmacokinetic (PK) / 
 parameters, and use 
of on-demand HAE medication will also be assessed.  
The first 32 subjects with C1-INH HAE who are eligible to 
participate in Treatment Period 1 will be randomly assigned to receive 
treatment with investigational product in a 1:1:1:1 ratio 
(
 mg CSL312 administered every 4 weeks [q4wk] subcutaneously 
[SC]; 
 mg CSL312 q4wk SC; 
 mg CSL312 q4wk SC; placebo 
q4wk SC) during Treatment Period 1. Treatment in each of these arms 
will begin with an intravenous (IV) loading dose of CSL312 or 
placebo. For these C1-INH HAE subjects, Treatment Period 1 will be 
conducted in a blinded manner.  
After the first 32 subjects with C1-INH HAE are randomly assigned 
to treatment, up to an additional 8 subjects will be assigned to receive 
 mg CSL312 administered every 2 weeks (q2wk) SC. 
 
. For 
these C1-INH HAE subjects, Treatment Period 1 will be conducted in 
an open-label manner.  
Up to 10 eligible subjects with FXII/PLG HAE will be assigned to 
receive 
 mg CSL312 q4wk SC. Treatment in this arm will begin 
with an IV loading dose of CSL312. For these FXII/PLG HAE 
subjects, Treatment Period 1 will be conducted in an open-label 
manner.  
Treatment Period 2 
C1-INH HAE subjects who continue to participate in Treatment 
Period 2 will be receiving CSL312 
 mg or 
 mg q4wk SC at the 
beginning of Treatment Period 2. Effective with Amendment 2, all 
C1-INH HAE subjects receiving the 
 mg dose will have their dose 
reduced to 
 mg q4wk SC at their next scheduled study visit. 
FXII/PLG HAE subjects will be maintained on the 
 mg q4wk SC 
dose. Investigators will continue to assess and document the 
occurrence of HAE attacks based on data reported by subjects in an 
eDiary. Safety and PK / 
 parameters, and use of on-demand HAE 
medication will also continue to be assessed. Treatment Period 2 will 
be conducted in an open-label manner for all subjects. 
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Post-treatment Follow-up 
All subjects, including those who discontinue participation, will 
attend a Follow-up Visit ~14 weeks after each subject’s final visit in 
Treatment Period 1 or Treatment Period 2.
Primary Objective 
The primary objective of this study is to evaluate the efficacy of 
CSL312 in the prevention of HAE attacks in subjects with 
C1-INH HAE. 
Primary Endpoint 
The primary endpoint is the time-normalized number of HAE attacks. 
Secondary 
Objective(s) 
The secondary objectives of the study are: 
1. To further evaluate the efficacy of CSL312 in subjects
with C1-INH HAE.
2. To evaluate the PK of CSL312 in subjects with C1-INH HAE.
3. To evaluate the safety and tolerability of CSL312 in subjects with
C1-INH HAE.
Secondary 
Endpoint(s) 
The secondary endpoints of the study are: 
1. Responder subjects.
2. HAE attack-free subjects.
3. HAE attacks.
4. HAE attacks treated with on-demand HAE medication.
5. CSL312 PK in plasma:
•
Maximum concentration (Cmax).
•
Area under the concentration-time curve in 1 dosing interval
(AUC0-tau).
•
Time of maximum concentration (Tmax).
•
Terminal elimination half-life (T1/2).
•
Total systemic clearance (CLtot).
•
Volume of distribution during the elimination phase (Vz).
6. Subjects experiencing the following safety events:
•
Adverse events.
•
Serious adverse events.
•
Adverse events of special interest (ie, anaphylaxis,
thromboembolic events, and bleeding events).
•
Injection site reactions.


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•
Inhibitory antibodies to CSL312.
•
Clinically significant abnormalities in laboratory assessment
that are reported as adverse events.
Number of Subjects Up to 50 subjects are planned to be assigned to treatment with 
investigational product in Treatment Period 1, including: 
•
8 subjects with C1-INH HAE who will be assigned to receive
placebo q4wk.
•
8 subjects with C1-INH HAE who will be assigned to receive
 mg CSL312 q4wk. 
•
8 subjects with C1-INH HAE who will be assigned to receive
 mg CSL312 q4wk. 
•
8 subjects with C1-INH HAE who will be assigned to receive
 mg CSL312 q4wk. 
•
Up to 8 subjects with C1-INH HAE who will be assigned to
receive 
 mg CSL312 q2wk. 
•
Up to 10 subjects with FXII/PLG HAE who will be assigned to
receive 
 mg CSL312 q4wk. 
Study Duration 
The duration of the study for an individual subject who participates in 
Treatment Period 1and Treatment Period 2 is up to approximately 
83 weeks if the duration of Treatment Period 2 is not extended. This 
estimation is based on: 
•
A Screening Period of up to 4 weeks.
•
A Run-in Period of up to 8 weeks.
•
A treatment period of ~13 weeks (Treatment Period 1).
•
A treatment period of ~44 weeks (Treatment Period 2).
•
A Follow-up Period of ~14 weeks.
Treatment Period 2 will extend until another CSL312 study is opened 
for subjects to join, or until the current study is discontinued. 
Study Population 
and Main Criteria 
for Eligibility 
To enter the Run-in Period, subjects must meet all of the 
following inclusion criteria: 
1. Male or female.
2. Aged ≥ 18 to ≤ 65 years at the time of providing written informed
consent.
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3. A diagnosis of C1-INH HAE or FXII/PLG HAE:
•
For C1-INH HAE (type 1): Documented clinical history
consistent with HAE (subcutaneous or mucosal, non-pruritic
swelling episodes without accompanying urticaria);
 < 50% of the lower limit of the reference 
range, as documented in the subject’s medical record; 
 below the lower 
limit of the reference range, as documented in the subject’s 
medical record. 
•
For C1-INH HAE (type 2): Documented clinical history
consistent with HAE (subcutaneous or mucosal, non-pruritic
swelling episodes without accompanying urticaria); 
< 50% of the lower limit of the reference
range, as documented in the subject’s medical record; 
below the lower limit of the reference
range, as documented in the subject’s medical record.
•
For FXII/PLG HAE: Documented clinical history consistent
with HAE (subcutaneous or mucosal, non-pruritic swelling
episodes without accompanying urticaria); an HAE-associated
FXII gene mutation [eg, FXII point mutation Thr328Lys or
Thr328Arg, or deletion of 72 base pairs (c.971_1018 +
24del72), or duplication of 18 base pairs (c.892-909dup)], as
documented in the subject’s medical record, OR an
HAE-associated PLG gene mutation (eg, PLG point mutation
Lys330Glu), as documented in the subject’s medical record;
70 -120 % of the normal level, as documented in the subject’s
medical record.
4. For subjects with C1-INH HAE: ≥ 4 HAE attacks over a
consecutive 2-month period during the 3 months before
Screening, as documented in the subject’s medical record.
Note: For subjects taking any prophylactic HAE therapy during
the 3 months before Screening, ≥ 4 HAE attacks may be
documented over any consecutive 2-month period during the
3 months before commencing the prophylactic therapy.
5. For subjects with FXII/PLG HAE: ≥ 1 HAE attack during the
3 months before Screening, as documented in the subject’s
medical record. Note: For subjects taking any prophylactic HAE
therapy during the 3 months before Screening, 1 HAE attack may
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be documented during the 3 months before commencing the 
prophylactic therapy. 
6. Willing to cease the use of any medications for routine
prophylaxis against HAE attacks (eg, C1-INH, androgens,
antifibrinolytics) on the first day of the Run-in Period, after being
assessed by the investigator to be able to adequately manage
on-demand treatments of HAE attacks without assistance.
Subjects must not enter the Run-in Period if they meet any of the 
following exclusion criteria: 
1. History of clinically significant arterial or venous thrombosis, or
current clinically significant prothrombotic risk, including
presence of a central venous access device.
2. History of an uncontrolled, abnormal bleeding event due to a
coagulopathy, or a current clinically significant coagulopathy or
clinically significant risks for bleeding events.
3. Any pre-planned surgeries during the trial that have an inherent
clinically significant risk for thrombotic events or bleeding.
4. Any previous treatment with any monoclonal antibody,
recombinant protein bearing an Fc domain, ribonucleic acid
(RNA) silencing, or gene transfer technologies.
5. Pregnant or nursing mother.
6. Known or suspected hypersensitivity to the investigational
product or to any excipients of the investigational product.
Subjects will be eligible to exit the Run-in Period and begin 
Treatment Period 1 if they meet the following criteria: 
1. Subject participated in the Run-in Period for at least 4 weeks
(28 days).
2. A diagnosis of C1-INH HAE, confirmation of diagnosis by central
laboratory testing:
a.
For subjects with C1-INH HAE (type 1):
 < 50% of the lower limit 
of the reference range; 
 below the 
lower limit of the reference range 
b. For subjects with C1-INH HAE (type 2):
 < 50% of the lower limit of the reference range; 
 below the lower limit of the 
reference range. 
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3. For subjects with C1-INH HAE: the occurrence of ≥ 2 HAE
attacks within any consecutive 4-week period during the Run-in
Period.
4. For subjects with FXII/PLG HAE: the occurrence of ≥ 1 HAE
attack during the Run-in Period.
5. Do not have any clinical abnormalities assessed as clinically
significant by the investigator in results of hematology, chemistry,
or urinalysis assessments performed during Screening.
Investigational 
Product Dose, 
Dosing Regimen, 
and Administration 
Treatment Period 1 
The first 32 subjects with C1-INH HAE who are eligible to 
participate in Treatment Period 1 will be randomly assigned to receive 
1 of the following treatment regimens in a blinded manner: 
•
A single loading dose of
 mg CSL312 IV followed ~1 week 
later by 
 mg CSL312 q4wk SC; 
•
A single loading dose of 
 mg CSL312 IV followed ~1 week 
later by 
 mg CSL312 q4wk SC; 
•
A single loading dose of 
 mg CSL312 IV followed ~1 week 
later by 
 mg CSL312 q4wk SC; 
•
A single loading dose of placebo IV followed ~1 week later by
placebo q4wk SC.
After the first 32 subjects with C1-INH HAE are randomly assigned 
to treatment (as above), up to an additional 8 subjects will be assigned 
in an open-label manner to receive 
 mg CSL312 q2wk SC. 
. 
Up to 10 eligible subjects with FXII/PLG HAE will be assigned in an 
open-label manner to receive a loading dose of 
 mg CSL312 IV 
followed ~1 week later by 
 mg CSL312 q4wk SC. 
All IV loading doses of investigational product (ie, CSL312 or 
placebo) will be administered by the investigator or delegate at the 
study site. All SC doses of investigational product will be self-
administered under supervision of the investigator or delegate at the 
study site. 
Treatment Period 2 
C1-INH HAE subjects who continue to participate in Treatment 
Period 2 will be receiving CSL312 
 mg or 
 mg q4wk SC at the 
beginning of Treatment Period 2. Effective with Amendment 2, all 
C1-INH HAE subjects receiving the 
 mg dose will have their dose 
reduced to 
 mg q4wk SC at their next scheduled study visit. 
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FXII/PLG HAE subjects will be maintained on the 
 mg q4wk SC 
dose. The first dose of CSL312 in Treatment Period 2 will be 
administered at the Week 13 (Day 91) Visit and at the Week 13 (Day 
85) Visit for subjects who administer investigational product q4wk
and q2wk in Treatment Period 1, respectively. Administration of
CSL312 at the Week 13 (Day 85 / 91) Visit, the Week 17 (Day 119)
Visit, and the Week 21 (Day 147) Visit will be self-administered
under supervision of the investigator or delegate at the study site.
After administration of CSL312 at the Week 21 (Day 147) Visit, all
subsequent doses of CSL312 will be self-administered SC every 28
days (± 2 days) by the subject at home or at the study site.
Efficacy 
Assessments 
Investigators will assess and document the occurrence of HAE attacks 
based on subject eDiary data. The following information will be 
documented in the subject eDiary: 
•
Date and time of HAE symptom onset and resolution.
•
Location of HAE symptom(s).
•
Interference of symptom(s) with the subject’s daily activities.
•
On-demand medication used to treat HAE symptoms.
•
Assistance by a healthcare professional during HAE symptoms.
Safety Assessments 
The safety and tolerability of CSL312 will be assessed based on: 
•
Adverse events.
•
Vital signs.
•
Physical examinations.
•
Clinical laboratory assessments:
•
Urinalysis.
•
Hematology.
•
Biochemistry.
•
Coagulation.
•
Immunogenicity.
In addition, a blood sample will be retained for potential assessment 
of viral serology. 
Pharmacokinetics 
Blood samples will be collected for assessment of CSL312 PK in 
plasma. 
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Statistical Analyses 
Sample Size 
Overall, up to 50 subjects will be assigned to treatment in Treatment 
Period 1. 
• Seven subjects assigned to placebo, and
 mg and 
 mg 
CSL312 q4wk are needed to reach power of ~82% for the 
comparisons of 
 mg CSL312 q4wk versus placebo q4wk and 
 mg CSL312 q4wk versus placebo q4wk in Treatment Period 1. 
An additional subject will be added to each of these treatment arms 
to account for drop outs during Treatment Period 1, resulting in 
8 subjects in each of these treatment arms (ie, 24 subjects total).  
• Seven subjects will be assigned to receive 
 mg CSL312 q4wk. 
The sample size for this arm is not driven by an efficacy 
comparison, but instead, by consistency with other treatment arms 
and for maintenance of blinding of the study. No testing for 
efficacy of 
 mg CSL312 against placebo will be performed and 
no power calculation has been done. An additional subject will be 
added to the treatment arm to account for drop outs during 
Treatment Period 1, resulting in 8 subjects in the treatment arm. 
• Up to 7 subjects with C1-INH HAE will be assigned to receive
 mg CSL312 q2wk. This arm is included for informational 
purposes, and therefore no testing against placebo is planned and 
no power calculation has been done. An additional subject may be 
added to the treatment arm to account for drop outs during 
Treatment Period 1, resulting in up to 8 subjects in the treatment 
arm. 
• Up to 10 subjects with FXII/PLG HAE will take part in the study.
Data Analysis
The data from Treatment Period 1 and Treatment Period 2 will be 
analyzed separately. In addition, Treatment Period 1 and Treatment 
Period 2 will be analyzed together for subjects who are being 
continuously administered the same dose of CSL312 during both 
treatment periods, unless otherwise specified.  
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Subjects with C1-INH HAE who are treated with placebo or 
 mg, 
 mg, or 
 mg CSL312 q4wk will be analyzed separately from 
subjects with C1-INH HAE who are treated with 
 mg CSL312 
q2wk. Subjects with FXII/PLG HAE will be analyzed separately from 
subjects with C1-INH HAE. 
Continuous variables will be described by using mean values with 
their respective 95% confidence intervals; standard deviation; range; 
25th, 50th (median), and 75th percentiles; and counts of missing and 
non-missing values. The geometric coefficient of variation will be 
expressed as a percentage for PK and 
 data. The geometric mean 
and its respective 90% confidence interval will be calculated for PK 
and 
 data. Categorical values will be described using counts and 
percentages.  
All data will be displayed in by-subject listings. The listings will be 
sorted by treatment, study site, subject, time point, and item number 
(if applicable). 
Primary Endpoint Analysis 
For subjects with C1-INH HAE who were treated with placebo, or 
 mg, 
 mg, or 
 mg CSL312 q4wk during Treatment Period 1: 
To test for a difference in the primary efficacy endpoint between 
 
mg CSL312 q4wk or 
 mg CSL312 q4wk and placebo, pairwise 
comparisons will be performed by testing the hypotheses using a two-
sided Mann-Whitney Test. To account for multiple testing, the alpha 
level of 5% will be evenly split between the hypotheses tested. 
Therefore, the 
 mg CSL312 q4wk or 
 mg CSL312 q4wk 
CSL312 doses (in subjects with C1-INH HAE) will each be evaluated 
against placebo at alpha = 0.025 for each test. The time-normalized 
number of HAE attacks will be summarized descriptively by 
treatment. There will be no testing of the 
 mg CSL312 q4wk dose 
against placebo. The time-normalized number of HAE attacks will be 
presented descriptively (only). 
For all other subjects: There will be no testing of the of 
 mg 
CSL312 q2wk dose against placebo for subjects with C1-INH HAE 
or the 
 mg CSL312 q4wk dose against placebo for subjects with 
FXII/PLG HAE. 
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Schedule of Assessments: Screening and Run-in Period [All Subjects] 
Study Period 
Screening 
Run-in Period a 
Week 
-4 to -1
1 
3 
5 
7 
9 b 
Day 
-28 to -1
1 
15 
29 
43 
57 
Window (Days) 
± 3 
± 3 
± 3 
± 3 
Study center visit 
X c 
Telephone contact 
X 
X 
X 
X 
X 
Written informed consent d 
X 
Medical history / demographics 
X 
Inclusion / exclusion criteria 
X 
Physical examination e 
X 
Vital signs including height and body weight 
X 
Urine collection for urinalysis 
X 
Blood 
Draws 
Hematology / Biochemistry / Coagulation 
X 
Pregnancy g 
X 
Confirmation of FXII or PLG mutation h 
X 
Individual acute action plan i 
X 
eDiary training 
X 
Open eDiary access / review eDiary instructions with subject 
X 
Review eDiary data and assess / document HAE attacks 
X 
X 
X 
X 
Confirm access to on-demand HAE medication j 
X 
X 
X 
X 
X 
Close eDiary access 
X k 
Prior / concomitant medications and therapies 
Adverse events 
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Abbreviations: 
; C1-INH HAE = hereditary angioedema with C1-esterase inhibitor deficiency; C4 = complement C4; 
eDiary = electronic diary; FXII = factor XII; FXII/PLG HAE = Hereditary angioedema with normal C1-esterase inhibitor and factor XII or plasminogen gene 
mutation; HAE = hereditary angioedema; 
; PLG = plasminogen.  
Footnotes to the Schedule of Assessments: Screening and Run-in Period [All Subjects] 
a Subjects must participate in the Run-in Period for at least 4 weeks (see Section 8.5.1.2.2). Subjects may stop participation in the Run-in Period and begin 
Treatment Period 1 when they have met the criteria specified in Section 4.1.3, including: 
• For subjects with C1-INH HAE, subjects must have experienced ≥ 2 HAE attacks within a consecutive 4-week period during the Run-in Period.
• For subjects with FXII/PLG HAE, subjects must have experienced ≥ 1 HAE attacks during the Run-in Period.
b Subjects should enter Treatment Period 1 no later than 14 days after the Week 9 (Day 57) Telephone Contact. If a subject is unable to enter Treatment Period 1 
within the 14 days after the Week 9 (Day 57) Telephone Contact, then CSL approval is required for the subject to enter into Treatment Period 1. The Week 9 
(Day 57) Telephone Contact will conclude the Run-in Period for a subject who has entered the Run-in Period and is subsequently not eligible to be assigned to 
treatment with investigational product in Treatment Period 1.  
c Screening may occur on the same day as the first day of the Run-in Period.  
d Written informed consent must be provided before any study-specific assessments or procedures are performed. 
e 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. 
g The test for beta-human chorionic gonadotropin will be performed for women of childbearing potential (only). A serum or urine pregnancy test may be used. A 
serum pregnancy test will be performed by the site if urine result is inconclusive. 
h Confirmation of the FXII or PLG gene mutation will be based on the subject’s medical record. 
i An individual acute action plan is developed by the investigator to ensure that participating subjects are capable of managing their HAE attacks during the 
study. The action plan will be reviewed with subjects. 
j Subjects may use the on-demand medication of their choice to treat HAE attacks experienced during the study if that medication has previously been shown to 
be effective (see Section 7.2). 
k Access to the eDiary should be closed within 14 days after the Week 9 Telephone Contact for subjects who will not participate in Treatment Period 1. 
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Schedule of Assessments: Treatment Period 1 [C1-INH HAE and FXII/PLG HAE Subjects Receiving 
Investigational Product Every 4 Weeks] 
Study Period 
Treatment Period 1 
Follow-
up b 
Visit Week 
1 
5 
9 
10 
11 
12 
13 a 
26 b 
Visit Day 
1 
6 
35 
63 
66 
70 
77 
84 
91 a 
186 b 
Visit Window (Days) 
± 2 
± 2 
± 2 
± 1 
± 2 
± 2 
± 2 
± 2 
± 3 
Time (Hours) 
Pre-dose 
0.5 
4.0 c 
8.0 c 
Time window (Minutes) 
± 15 
± 60 
± 120 
Study center visit 
X 
X 
X 
X d 
X d 
X d 
X 
X 
X 
X l 
Confirm eligibility for Treatment Period 1 e 
X 
Assignment to treatment via IRT 
X 
Physical examination f, g 
X 
X 
X 
X 
X 
Vital signs including body weight g 
X 
X 
X 
X 
X 
Urine collection for urinalysis g 
X 
X 
X 
X 
Blood 
Draws g 
Hematology / Biochemistry / Coagulation 
X 
X 
X 
X 
Retention sample for viral serology 
X 
X 
Pharmacokinetics / 
X 
X 
X c 
X c 
X 
X 
X d 
X d 
X d 
X 
X 
X 
X l 
Immunogenicity 
X 
X 
Pregnancy h 
X 
X 
X 
X 
Review of eDiary instructions with subject 
X 
Review eDiary data and assess / document HAE attacks 
X 
X 
X 
X 
X 
X 
Close eDiary access 
X 
Confirm access to on-demand HAE medication i 
X 
X 
X 
X 
Dispense and administer investigational product j 
X 
X 
X 
X k 
Accountability of investigational product 
X 
X 
X 
X 
Concomitant medications and therapies 
Adverse events 
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CSL312_2001 
CSL312 (Factor XIIa Antagonist Monoclonal Antibody) 
Protocol version:  Amendment 2 Final 
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Abbreviations: 
; 
; C1-INH HAE = hereditary angioedema with C1-esterase inhibitor 
deficiency; C4 = complement C4; eDiary = electronic diary; FXII = factor XII; FXII/PLG HAE = Hereditary angioedema with normal C1-esterase inhibitor and 
factor XII or plasminogen gene mutation; HAE = hereditary angioedema; 
; IRT = interactive 
responses technology; IV = intravenous; 
; PK = pharmacokinetic; PLG = plasminogen; SC = subcutaneous; 
; 
. 
Footnotes to the Schedule of Assessments: Treatment Period 1 [C1-INH HAE and FXII/PLG HAE Subjects Receiving Investigational Product Every 
4 Weeks] 
a For subjects who are taking part in Treatment Period 2, the Week 13 (Day 91) Visit is the first study visit in Treatment Period 2; refer to the 
Schedule of Events: Treatment Period 2 [All Subjects]. If a subject is discontinued from the study before completing Treatment Period 1, the subject will 
undergo the assessments scheduled for the Week 13 (Day 91) Visit and then attend the Treatment Period 1 Follow-up Visit ~14 weeks later. 
b If a subject participates in Treatment Period 2, then the subject will not attend the Treatment Period 1 Follow-up Visit. Refer to the 
Schedule of Events: Treatment Period 2 [All Subjects] for the visit schedule for subjects who participate in Treatment Period 2. 
c The PK / 
 blood draws at 4.0 hours (± 60 minutes) post-dose and 8.0 hours (± 120 minutes) post-dose at the Week 1 (Day 1) Visit should occur 
≥ 120 minutes apart. 
d The Week 9 (Day 63) and Week 9 (Day 66) Visits and corresponding PK / 
 blood draws should each occur at least 24 hours apart. The Week 9 (Day 66) 
and Week 10 (Day 70) Visits and corresponding PK / 
 blood draws should each occur at least 72 hours apart. 
e Subjects may stop participation in the Run-in Period and begin Treatment Period 1 when they have met the criteria specified in Section 4.1.3, including: 
• For subjects with C1-INH HAE, subjects must have experienced ≥ 2 HAE attacks within a consecutive 4-week period during the Run-in Period.
• For subjects with FXII/PLG HAE, subjects must have experienced ≥ 1 HAE attacks during the Run-in Period.
f 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. 
g At visits where physical examinations, vital signs, urine collection, and blood draws are scheduled to occur on the same day as administration of the 
investigational product, administration of investigational product will occur after these assessments have been completed. 
h The test for beta-human chorionic gonadotropin will be performed for women of childbearing potential (only). A serum or urine pregnancy test may be used. A 
serum pregnancy test will be performed by the site if urine result is inconclusive. 
i Subjects may use the on-demand medication of their choice to treat HAE attacks experienced during the study if that medication has previously been shown to 
be effective (see Section 7.2). 
j Investigational product will be administered IV by the investigator or delegate at the study site during the Week 1 (Day 1) Visit, and will be self-administered 
SC by the subject under supervision of the investigator or delegate at the study site during the Week 1 (Day 6) Visit, the Week 5 (Day 35) Visit, and the Week 
9 (Day 63) Visit. 
k For subjects who do not participate in Treatment Period 2, the final dose of investigational product will be administered at the Week 9 (Day 63) Visit. 
l The Treatment Period 1 Follow-up Visit may be waived in place of a telephone contact. If the Treatment Period 1 Follow-up is conducted as a visit, then a
blood draw for assessment of PK / 
 should occur.
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CSL312_2001 
CSL312 (Factor XIIa Antagonist Monoclonal Antibody) 
Protocol version:  Amendment 2 Final 
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Date: 20 March 2020 
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Confidential 
Schedule of Assessments: Treatment Period 1 [C1-INH HAE Subjects Receiving Investigational Product 
Every 2 Weeks] 
Study Period 
Treatment Period 1 
Follow-up b 
Visit Week 
1 
3 
5 
7 
9 
10 
11 
12 
13 a 
25 b 
Visit Day 
1 
15 
29 
43 
57 
64 
71 
77 
85 a 
180 b 
Visit Window (Days) 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 3 
Study center visit 
X 
X 
X 
X 
X 
X c 
X 
X d 
X 
X l 
Confirm eligibility for Treatment Period 1 e 
X 
Assignment to treatment via IRT 
X 
Physical examination f, g 
X 
X 
X 
X 
Vital signs including body weight g 
X 
X 
X 
X 
Urine collection for urinalysis g 
X 
X 
X 
X 
Blood 
Draws g 
Hematology / Biochemistry / Coagulation 
X 
X 
X 
X 
Retention sample for viral serology 
X 
X 
Pharmacokinetics / 
X 
X 
X 
X 
X 
X c 
X 
X d 
X 
X l 
Immunogenicity 
X 
X 
Pregnancy h 
X 
X 
X 
X 
Review of eDiary instructions with subject 
X 
Review eDiary data and assess / document HAE attacks 
X 
X 
X 
X 
X 
X 
X 
X 
Close eDiary access 
X 
Confirm access to on-demand HAE medication i 
X 
X 
X 
X 
X 
X 
X 
Dispense and administer investigational product j 
X 
X 
X 
X 
X 
X k 
Accountability of investigational product 
X 
X 
X 
X 
X 
X 
Concomitant medications and therapies 
Adverse events 
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CSL312_2001 
CSL312 (Factor XIIa Antagonist Monoclonal Antibody) 
Protocol version:  Amendment 2 Final 
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Abbreviations: 
; 
; C1-INH HAE = hereditary angioedema with C1-esterase inhibitor 
deficiency; C4 = complement C4; eDiary = electronic diary; HAE = hereditary angioedema; 
; 
IRT = interactive responses technology; 
; PK = pharmacokinetic; SC = subcutaneous; 
; 
. 
Footnotes to the Schedule of Assessments: Treatment Period 1 [C1-INH HAE Subjects Receiving Investigational Product Every 2 Weeks] 
a For subjects who are taking part in Treatment Period 2, the Week 13 (Day 85) Visit is the first study visit in Treatment Period 2; refer to the 
Schedule of Events: Treatment Period 2 [All Subjects]. If a subject is discontinued from the study before completing Treatment Period 1, the subject will 
undergo the assessments scheduled for the Week 13 (Day 85) Visit and then attend the Treatment Period 1 Follow-up Visit ~14 weeks later. 
b If a subject participates in Treatment Period 2, then the subject will not attend the Treatment Period 1 Follow-up Visit. Refer to the 
Schedule of Events: Treatment Period 2 [All Subjects] for the visit schedule for subjects who participate in Treatment Period 2. 
c The Week 10 (Day 64) Visit is optional, and blood for assessment of PK / 
 may be collected off-site. 
d Blood for assessment of PK / 
 may be collected off-site. If blood is collected off-site, then a study visit is not required. 
e Subjects may stop participation in the Run-in Period and begin Treatment Period 1 when they have met the criteria specified in Section 4.1.3, including: 
• For subjects with C1-INH HAE, subjects must have experienced ≥ 2 HAE attacks within a consecutive 4-week period during the Run-in Period.
f 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. 
g At visits where physical examinations, vital signs, urine collection, and blood draws are scheduled to occur on the same day as administration of the 
investigational product, administration of investigational product will occur after these assessments have been completed. 
h The test for beta-human chorionic gonadotropin will be performed for women of childbearing potential (only). A serum or urine pregnancy test may be used. A 
serum test will be performed by the site if result from urine test is inconclusive. 
i Subjects may use the on-demand medication of their choice to treat HAE attacks experienced during the study if that medication has previously been shown to 
be effective (see Section 7.2). 
j Investigational product will be self-administered SC by the subject under the supervision of the investigator or delegate at designated study visits. 
k For subjects who do not participate in Treatment Period 2, the final dose of investigational product will be administered at the Week 11 (Day 71) Visit. 
l The Treatment Period 1 Follow-up Visit may be waived in place of a telephone contact. If the Treatment Period 1 Follow-up is conducted as a visit, then a
blood draw for assessment of PK / 
 should occur. 
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CSL312_2001 
CSL312 (Factor XIIa Antagonist Monoclonal Antibody) 
Protocol version:  Amendment 2 Final 
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Date: 20 March 2020 
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Schedule of Assessments: Treatment Period 2 [All Subjects] 
Study Period 
Treatment Period 2 
Follow
-up
Visit Week 
13 
17 
21 
25 
29 
33 
37 
41 
45 
49 
53 
57 b 
70 
Visit Day 
85 / 91 a 
119 
147 
175 
203 
231 
259 
287 
315 
343 
371 
399 b 
494 
Visit Window (Days) 
± 2 
± 2 
± 2 
± 10 
± 10 
± 2 
± 10 
± 10 
± 2 
± 10 
± 10 
± 2 
± 3 
Study center visit 
X 
X 
X 
X c
X c
X 
X c 
X c 
X 
X c 
X c 
X 
X i 
Assignment to treatment via IRT 
X 
Physical examination d, e 
X 
X 
X 
X 
X 
X 
Vital signs including body weight e 
X 
X 
X 
X 
X 
X 
Urine collection for urinalysis e 
X 
X 
X 
X 
X 
X 
Blood 
Draws e 
Hematology / Biochemistry / Coagulation 
X 
X 
X 
X 
X 
X 
Retention sample for viral serology 
X 
X 
Pharmacokinetics / 
X 
X 
X 
X 
X 
X 
X i 
Immunogenicity 
X 
X 
Pregnancy f 
X 
X 
X 
X c
X c
X 
X c
X c
X 
X c
X c
X 
Review eDiary data and assess / document HAE attacks 
X 
X 
X 
X 
X 
X 
X 
Close eDiary access 
X 
Confirm access to on-demand HAE medication g 
X 
X 
X 
X 
X 
X 
Administer investigational product h 
X 
X 
X 
Dispense investigational product 
X 
X 
X 
X 
X 
X j 
Accountability of investigational product 
X 
X 
X 
X 
X 
X j 
Concomitant medications and therapies 
Adverse events 
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CSL312_2001 
CSL312 (Factor XIIa Antagonist Monoclonal Antibody) 
Protocol version:  Amendment 2 Final 
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Abbreviations: 
; 
; C1-INH HAE = hereditary angioedema with C1-esterase inhibitor 
deficiency; C4 = complement C4; FXII = factor XII; FXII/PLG HAE = Hereditary angioedema with normal C1-esterase inhibitor and factor XII or plasminogen 
gene mutation; eDiary = electronic diary; HAE = hereditary angioedema; 
; IRT = interactive 
responses technology; PK = pharmacokinetics; 
; PLG = plasminogen; q2wk = administered every 2 weeks; q4wk = administered every 
4 weeks; SC = subcutaneous; 
; 
. 
Note: Treatment Period 2 will extend until another CSL312 study is opened for enrollment, or until the current study is discontinued. If Treatment Period 2 is 
extended, procedures from the Week 45 (Day 315) Visit will be repeated approximately every 12 weeks starting 12 weeks after all listed assessments are 
completed at the Week 57 (Day 399) Visit. If Treatment Period 2 is extended, then all assessments scheduled for the Week 57 (Day 399) Visit will be repeated at 
each subject’s final Treatment Period 2 visit. A Follow-up Visit will occur ~14 weeks after each subject’s final Treatment Period 2 visit.  
Footnotes to the Schedule of Assessments: Treatment Period 2 [All Subjects] 
a The Week 13 (Day 91) Visit will be the first visit in Treatment Period 2 for C1-INH HAE subjects receiving placebo, 
 mg, 
 mg, or 
 mg CSL312 
q4wk, and FXII/PLG HAE subjects receiving 
 mg CSL312 q4wk in Treatment Period 1. The Week 13 (Day 85) Visit will be the first visit in Treatment 
Period 2 for C1-INH HAE subjects receiving 
 mg CSL312 q2wk in Treatment Period 1. 
b If a subject is discontinued from the study before completing Treatment Period 2, the subject will undergo the assessments scheduled for the 
Week 57 (Day 399) Visit in Treatment Period 2, and will then attend the Treatment Period 2 Follow-up Visit ~14 weeks later.  
c Pregnancy testing is mandatory. However, site visits for pregnancy tests are optional. Documentation and tracking of pregnancy testing must be conducted by 
the site. 
d 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. 
e At visits where physical examinations, vital signs, urine collection, and blood draws are scheduled to occur on the same day as administration of CSL312, 
administration of CSL312 will occur after these assessments have been completed. 
f The test for beta-human chorionic gonadotropin will be performed for women of childbearing potential (only). A serum or urine pregnancy test may be used. A 
serum pregnancy test will be performed by the site if urine result is inconclusive. 
g Subjects may use the on-demand medication of their choice to treat HAE attacks experienced during the study if that medication has previously been shown to 
be effective (see Section 7.2). 
h The first administration of investigational product in Treatment Period 2 will occur at the Week 13 (Day 85 / 91) Visit. Investigational product will be self-
administered by the subject under the supervision of the investigator or delegate at the Week 13 (Day 85 / 91) Visit, the Week 17 (Day 119) Visit, and the 
Week 21 (Day 147) Visit. After administration of the investigational product at the Week 21 (Day 147) Visit, all subsequent doses of investigational product 
will be self-administered SC every 28 days (± 2 days) by the subject at home or at the study site. 
i The Treatment Period 2 Follow-up Visit may be waived in place of a telephone contact. If the Treatment Period 2 Follow-up is conducted as a visit, then a 
blood draw for assessment of PK / 
 should occur. 
j Investigational product will be dispensed and accountability will be conducted only if Treatment Period 2 is extended beyond the subject’s Week 57 (Day 399) 
Visit (see Section 8.5.4.14). 
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CSL312_2001 
CSL312 (Factor XIIa Antagonist Monoclonal Antibody) 
Protocol version: Amendment 2 Final 
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Table of Contents 
List of Personnel and Organizations Responsible for Conduct of the Study ............................. 2
Revision History ........................................................................................................................ 3
Protocol Synopsis ...................................................................................................................... 4
Schedule of Assessments: Screening and Run-in Period [All Subjects] ................................. 15
Schedule of Assessments: Treatment Period 1 [C1-INH HAE and FXII/PLG HAE Subjects 
Receiving Investigational Product Every 4 Weeks] ............................................. 17
Schedule of Assessments: Treatment Period 1 [C1-INH HAE Subjects Receiving 
Investigational Product Every 2 Weeks] ............................................................... 19
Schedule of Assessments: Treatment Period 2 [All Subjects] ................................................. 21
Table of Contents ..................................................................................................................... 23
List of Tables............................................................................................................................ 28
List of Figures .......................................................................................................................... 28
List of Appendices ................................................................................................................... 28
List of Abbreviations ............................................................................................................... 29
List of Conventions .................................................................................................................. 31
1
Introduction .......................................................................................................... 32
1.1
Background ...................................................................................................... 32
1.1.1
Factor XII ..................................................................................................... 32
1.1.2
Factor XII and the Kallikrein-kinin Pathway ............................................... 32
1.1.3
Hereditary Angioedema ................................................................................ 32
1.1.4
Treatment of Hereditary Angioedema .......................................................... 34
1.2
Background Information on CSL312 ............................................................... 35
1.2.1
Overview ...................................................................................................... 35
1.2.2
Nonclinical Evaluation ................................................................................. 35
1.2.3
Clinical Experience ...................................................................................... 35
1.3
Study Overview ................................................................................................ 36
1.4
Potential Risks and Benefits ............................................................................. 36
2
Study Objectives and Endpoints ........................................................................... 38
2.1
Primary Objective and Endpoint ...................................................................... 38
2.1.1
Primary Objective ......................................................................................... 38


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2.1.2
Primary Endpoints ........................................................................................ 39
2.2
Secondary Objectives and Endpoints ............................................................... 39
2.2.1
Secondary Objectives ................................................................................... 39
2.2.2
Secondary Endpoints .................................................................................... 39
2.3
2.3.1
2.3.2
3
Study Overview .................................................................................................... 43
3.1
Study Design .................................................................................................... 43
3.1.1
Screening ...................................................................................................... 44
3.1.2
Run-in Period ............................................................................................... 44
3.1.3
Treatment Period 1 ....................................................................................... 45
3.1.4
Treatment Period 2 ....................................................................................... 46
3.1.5
Post-Treatment Follow-up Period ................................................................ 46
3.2
Dose and Dosing Regimen ............................................................................... 47
3.2.1
Treatment Period 1 ....................................................................................... 47
3.2.2
Treatment Period 2 ....................................................................................... 48
3.3
Scientific Rationale .......................................................................................... 48
3.3.1
Study Design Rationale ................................................................................ 48
3.3.2
Dose Rationale ............................................................................................. 48
3.4
Planned Study Duration ................................................................................... 50
3.5
Planned Number of Subjects ............................................................................ 50
3.6
Definition of End of the Clinical Study ........................................................... 51
3.7
Study Oversight ................................................................................................ 51
3.7.1
Independent Data Monitoring Committee .................................................... 51
3.7.2
Other Monitoring Committees ..................................................................... 51
4
Selection and Withdrawal of Subjects .................................................................. 51
4.1
Eligibility Criteria ............................................................................................ 51
4.1.1
Inclusion Criteria for Entry into the Run-in Period ...................................... 52
4.1.2
Exclusion Criteria for Entry into the Run-in Period ..................................... 53
4.1.3
Criteria for Entry into Treatment Period 1 ................................................... 54
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.......................................................... 56
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4.2.3
Replacement Policy ...................................................................................... 56
5
Study Interventions ............................................................................................... 56
5.1
Description of Investigational Product ............................................................. 56
5.1.1
CSL312 ......................................................................................................... 56
5.1.2
Placebo ......................................................................................................... 57
5.1.3
CSL312 Diluent ............................................................................................ 57
5.2
Packaging, Labeling, Supply and Storage ........................................................ 57
5.2.1
Packaging and Labeling ............................................................................... 57
5.2.2
Supply and Storage ....................................................................................... 57
5.3
Accountability and Destruction ........................................................................ 58
5.4
On-demand HAE Therapy................................................................................ 59
5.5
Dose Modification ............................................................................................ 59
6
Allocation, Dosing, and Administration ............................................................... 59
6.1
Allocation to Treatment .................................................................................... 59
6.1.1
Subject Assignment ...................................................................................... 59
6.1.2
Randomization Procedures ........................................................................... 59
6.1.3
Blinding Procedures ..................................................................................... 61
6.2
Dosing and Administration ............................................................................... 62
6.3
Treatment Compliance ..................................................................................... 64
7
Contraindications, Permitted Therapies and Prohibited Therapies ...................... 64
7.1
Contraindications and Precautions to Further Dosing ...................................... 64
7.2
Permitted Therapies .......................................................................................... 64
7.3
Prohibited Therapies......................................................................................... 65
7.4
Lifestyle Restrictions ........................................................................................ 66
7.5
Overdose ........................................................................................................... 67
8
Study Procedures and Visit Schedule ................................................................... 67
8.1
Clinical Procedures .......................................................................................... 67
8.1.1
Demographics and Safety Assessments ....................................................... 67
8.1.2
Pharmacokinetic and 
 Assessments ................................ 69
8.1.3
Efficacy Assessments ................................................................................... 70
8.1.4
Other Assessments ........................................................................................ 70
8.2
Blood Samples .................................................................................................. 72
8.3
Retention of Samples ....................................................................................... 72
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8.4
Prior and Concomitant Medications and Therapies ......................................... 73
8.5
Visit Schedule ................................................................................................... 73
8.5.1
Screening / Run-in Period Visits .................................................................. 73
8.5.2
Treatment Period 1 for C1-INH HAE and FXII/PLG HAE Subjects 
Receiving Investigational Product Every 4 Weeks ....................................... 76
8.5.3
Treatment Period 1 for C1-INH HAE Subjects Receiving Investigational 
Product Every 2 Weeks ................................................................................. 82
8.5.4
Treatment Period 2 ....................................................................................... 88
8.5.5
Subject Withdrawal / Discontinuation .......................................................... 95
9
Adverse Events ..................................................................................................... 96
9.1
Definitions ........................................................................................................ 96
9.1.1
Adverse Event .............................................................................................. 96
9.1.2
Adverse Event of Special Interest ................................................................ 97
9.1.3
Serious Adverse Event .................................................................................. 97
9.2
Severity of Adverse Events .............................................................................. 98
9.3
Causality of Adverse Events ............................................................................ 99
9.4
Observation Period for Adverse Events ........................................................... 99
9.5
Follow-up of Adverse Events ......................................................................... 100
9.6
Adverse Event Reporting ............................................................................... 100
9.6.1
Adverse Events ........................................................................................... 100
9.6.2
Adverse Events of Special Interest ............................................................. 100
9.6.3
Serious Adverse Event Reporting ............................................................... 101
9.6.4
Abnormal Laboratory Values ..................................................................... 102
9.6.5
Overdose ..................................................................................................... 103
9.6.6
Pregnancy and Breastfeeding ..................................................................... 103
9.7
IRB / IEC Reporting Requirements ............................................................... 103
10
Statistics .............................................................................................................. 104
10.1
Sample Size Estimation .................................................................................. 104
10.2
Description of Study Analysis Populations .................................................... 105
10.2.1
Screening Population .................................................................................. 105
10.2.2
Intent-to-Treat Population .......................................................................... 105
10.2.3
Per Protocol Population .............................................................................. 105
10.2.4
Safety Population ....................................................................................... 105
10.2.5
Pharmacokinetic Population ....................................................................... 105
10.2.6
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10.3
Statistical Analyses and Methods ................................................................... 106
10.3.1
Subject Disposition and Characteristics ..................................................... 108
10.3.2
Efficacy Analyses ....................................................................................... 109
10.3.3
Safety Analyses .......................................................................................... 112
10.3.4
Pharmacokinetic Analyses .......................................................................... 114
10.3.5
10.3.6
Pharmacokinetic / 
 Relationships ................................. 114
10.3.7
Other Analyses ........................................................................................... 114
10.3.8
Interim Analysis ......................................................................................... 114
11
Quality Assurance ............................................................................................... 115
12
Regulatory and Ethics Considerations ................................................................ 115
12.1
Regulatory Considerations ............................................................................. 115
12.2
Institutional Review Board / Independent Ethics Committee ........................ 116
12.3
Subject Information and Informed Consent ................................................... 116
12.4
Subject Confidentiality ................................................................................... 116
12.5
Indemnity and Compensation ......................................................................... 117
13
Administrative Considerations ........................................................................... 117
13.1
Clinical Trial Agreement ................................................................................ 117
13.2
Clinical Study Registration and Results Disclosure ....................................... 117
13.3
Implementation of the Protocol / Protocol Amendment(s) ............................ 117
13.4
Protocol Deviations ........................................................................................ 118
13.5
Documentation and Record Keeping ............................................................. 118
13.5.1
Data Collection ........................................................................................... 118
13.5.2
Data Quality Assurance .............................................................................. 119
13.5.3
Record Retention ........................................................................................ 119
13.6
Study and Site Closure ................................................................................... 119
13.7
Clinical Study Report ..................................................................................... 120
13.8
Use of Data and Publications ......................................................................... 120
14
References .......................................................................................................... 121
15
Appendices ......................................................................................................... 125
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List of Tables 
Table 1
Primary Endpoint ............................................................................................. 39
Table 2
Secondary Endpoints ....................................................................................... 39
Table 3
Description of CSL312 .................................................................................... 56
Table 4
Description of Placebo ..................................................................................... 57
Table 5
Investigational Product Dosing Characteristics ............................................... 63
Table 6
Study Procedures: Demographics and Safety Assessments ............................. 68
Table 7
Pharmacokinetic and 
 Analytes .......................................... 69
List of Figures 
Figure 1
Study Overview ............................................................................................... 43
List of Appendices 
Appendix 1
Signature on Behalf of Sponsor ..................................................................... 125
Appendix 2
Signature of Principal Investigator ................................................................ 126
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List of Abbreviations 
Abbreviation 
Term 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
AUC0-tau 
Area under the concentration curve in 1 dosing interval 
BK 
Bradykinin 
C1-INH 
C1-esterase inhibitor 
C1-INH HAE 
Hereditary angioedema with C1-esterase inhibitor deficiency 
C4 
Complement C4 
CI 
Confidence interval 
CL/F 
Apparent clearance 
CLtot 
Total systemic clearance 
Cmax 
Maximum concentration 
CSL312 
Factor XIIa antagonist monoclonal antibody 
CSL 
CSL Behring LLC 
CVAD 
Central venous access device 
eCRF 
Electronic case report form 
eDiary 
Electronic diary 
FXII 
Factor XII 
FXII/PLG HAE 
Hereditary angioedema with normal C1-esterase inhibitor and 
factor XII or plasminogen gene mutation 
FXIIa 
Activated factor XII 
GCP 
Good Clinical Practice 
HAE 
Hereditary angioedema 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
IDMC 
Independent data monitoring committee 
IEC 
Independent ethics committee 
IRB 
Institutional review board 
IRT 
Interactive response technology 
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Abbreviation 
Term 
ISR 
Injection site reaction 
ITT 
Intent-to-Treat 
IV 
Intravenous(ly) 
nC1-INH 
Normal C1-esterase inhibitor 
PK 
Pharmacokinetic 
PP 
Per-Protocol 
PT 
Prothrombin time 
q2wk 
Administered every 2 weeks 
q4wk 
Administered every 4 weeks 
RNA 
Ribonucleic acid 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SC 
Subcutaneous(ly) 
SOC 
System Organ Class 
Study 1001 
Study CSL312_1001 
TEE 
Thromboembolic event 
T1/2 
Terminal elimination half-life 
Tmax 
Time to reach the maximum concentration in plasma 
Vd/F 
Apparent volume of distribution 
Vz 
Volume of distribution during the elimination phase 
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List of Conventions 
•
The abbreviation “C1-INH HAE” is used in this clinical study protocol to include
hereditary angioedema type 1 (quantitative decrease in C1-esterase inhibitor plasma
concentrations) and hereditary angioedema type 2 (dysfunctional C1-esterase inhibitor
present in normal or high plasma concentrations).
•
The abbreviation “FXII/PLG HAE” is used in this clinical study protocol to include
hereditary angioedema with normal C1-esterase inhibitor and factor XII or plasminogen
gene mutation.
•
In some sections of the protocol, dosing regimens are identified without reference to the
initial intravenously administered loading dose that some subjects are required to receive.
This approach has been taken to streamline presentation of protocol text and is not
intended to indicate that the loading dose is optional. Full details for dosing and
administration are presented in Section 3.2, with supportive information presented in
Section 5.5 and Section 6.2.
•
For subjects who administer investigational product subcutaneously every 4 weeks in
Treatment Period 1, the first dose of CSL312 in Treatment Period 2 will be administered
at the Week 13 (Day 91) Visit. For subjects who administer investigational product
subcutaneously every 2 weeks in Treatment Period 1, the first dose of CSL312 in
Treatment Period 2 will be administered at the Week 13 (Day 85) Visit. Within the body
of the protocol, these visits are presented together as “the Week 13 (Day 85 / 91) Visit”.


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1 Introduction 
1.1 Background 
1.1.1 
Factor XII 
Factor XII (Hageman factor, FXII) is produced in the liver and is secreted into the plasma; 
the glycosylated 80 kilodalton (kDa) zymogen circulates with a concentration of ~30 µg / mL 
and a half-life of 50 to 70 hours [Björkqvist et al, 2014].  
Factor XII is the principal initiator of the plasma contact system [Renné et al, 2012]. The 
contact system is a protease cascade involving the proteins FXII, factor XI (FXI), plasma 
prekallikrein, and the nonenzymatic cofactor 
 (
). 
Upon contact with a negatively-charged surface FXII is converted to activated FXII (FXIIa). 
Several biologic substances have been shown to support FXII activation in vivo, including 
heparin released from mast cells, misfolded protein aggregates, ribonucleic acid, and platelet 
polyphosphates [Kenne et al, 2015]. FXIIa triggers fibrin formation through activation of 
FXI, and also leads to the production of the inflammatory mediator bradykinin (BK) through 
the kallikrein-kinin pathway. Further cleavage of FXIIa releases the 30 kDa light chain 
containing the catalytic domain (βFXIIa), which can activate the classical complement 
pathway. Thus, activated forms of FXII have proinflammatory and procoagulant activities. 
1.1.2 
Factor XII and the Kallikrein-kinin Pathway 
Activation of FXII (to FXIIa) also leads to the production of BK through the kallikrein-kinin 
pathway. In this pathway prekallikrein is converted to kallikrein by FXIIa. Kallikrein plays a 
number of roles. First, it activates FXII zymogens by a positive feedback mechanism to 
amplify the cascade. Second, kallikrein cleaves 
 to release the potent inflammatory 
mediator BK. The binding of BK to BK type 2 (B2) receptors activates various intracellular 
signaling pathways that dilate vessels, induce chemotaxis of neutrophils, and increase 
vascular permeability and fluid efflux [Björkqvist et al, 2013]. Bradykinin production is 
increased during acute hereditary angioedema (HAE) attacks and is the mediator of swelling 
in HAE [Nussberger et al, 1998; Nussberger et al, 1999].  
1.1.3 
Hereditary Angioedema 
Hereditary angioedema is a rare genetic disorder classified into 3 disease types [Rosen et al, 
1965; Bork et al, 2000], including HAE type 1, HAE type 2, and HAE with normal 
C1-esterase inhibitor (nC1-INH). 
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HAE type 1 and type 2 are caused by mutations of the SERPING1 gene, and are 
characterized by a quantitative decrease in C1-esterase inhibitor (C1-INH) plasma 
concentrations (type 1) and dysfunctional C1-INH present in normal plasma concentrations 
(type 2) [Zuraw, 2010; Cicardi, 2014]. Together, HAE type 1 and type 2 are grouped as HAE 
with C1-INH deficiency (C1-INH HAE). 
A large number of different SERPING1 mutations have been associated with HAE type 1, 
including missense, nonsense, frameshift, deletion, and insertion mutations [Kalmar et al, 
2005]. In general, HAE type 1 is caused by mutations in the C1-INH gene that results in 
either truncated or misfolded proteins that cannot be secreted [Verpy et al, 1995]. In HAE 
type 1, an impaired synthesis of normal and functionally active C1-INH occurs, causing a 
reduction in the availability of functionally active C1-INH levels to as low as between 5% 
and 30% of normal [Rosen et al, 1965]. Approximately 85% of subjects with C1-INH HAE 
have HAE type 1 [Longhurst and Bork, 2006].  
Most SERPING1 mutations associated with HAE type 2 involve residues at or near the active 
site on the reactive mobile loop of the C1-INH protein that result in a protein that is secreted 
but is dysfunctional [Wagenaar-Bos et al, 2006]. In HAE type 2, normal levels of a 
functionally impaired C1-INH molecule are synthesized, but the normal form of C1-INH is 
considerably reduced in the circulation [Rosen et al, 1965]. Approximately 15% of subjects 
with C1-INH HAE have HAE type 2 [Longhurst and Bork, 2006].  
C1-esterase inhibitor is a serine protease inhibitor that regulates the generation of BK by the 
plasma contact system, and is the major inhibitor of a number of plasma contact system 
proteases including FXII and kallikrein [Davis et al, 2010]. Excessive BK formation due to 
pathological activation of the factor XII (FXII)-driven plasma contact system is a consistent 
finding in acute episodes of HAE [Björkqvist, 2013].  
HAE with normal C1-INH (nC1-INH) is an inherited disorder not associated with C1-INH 
deficiency but missense mutations, deletions or insertions of base pairs of the FXII gene 
[Cicardi et al, 2014], a missense mutation of the plasminogen gene [Bork et al, 2018], 
[Dewald, 2018], or caused by an unknown genetic defect [Cicardi, 2014]. A defective mucin-
type Thr309-linked glycosylation may lead to increased contact-mediated autoactivation of 
zymogen FXII, resulting in excessive activation of the BK-forming kallikrein-kinin pathway 
[Björkqvist, 2015]. A Lys311Glu substitution is a disease-causing plasminogen mutation 
which may cause an irregular cleavage by activated factor XII and kallikrein, the serine 


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proteases of the kinin-forming cascade [Dewald, 2018]. For other forms of HAE with nC1-
INH, the underlying pathophysiology is poorly understood [Bork et al, 2000].  
Clinically, HAE attacks occurring in patients with C1-INH HAE and HAE with nC1-INH are 
characterized by local swelling of the skin (ie, edema of the extremities, facial edema, and 
edema of the genitals), abdominal pain, and, occasionally, life-threatening attacks of 
laryngeal edema [Bork, 2008]. The estimated prevalence of C1-INH HAE is commonly 
reported as 1:50,000, while the prevalence of nC1-INH HAE is unknown [Cicardi et al, 
2010b; Nasr et al, 2016]. 
1.1.4 
Treatment of Hereditary Angioedema 
Current treatment options for HAE can be subdivided into the acute treatment of attacks and 
prophylaxis. The treatment of choice in the event of an acute HAE attack is the rapid 
intravenous (IV) administration of C1-INH concentrate [Bork 2008; Gompels et al, 2005; 
Longhurst 2005]. Recently, compounds including a kallikrein inhibitor and a BK receptor 
antagonist have been added to the spectrum of medications available to treat acute HAE 
attacks [Cicardi et al, 2010a; Cicardi et al, 2010b].  
Despite a number of treatment options for acute HAE attacks, the prophylactic treatment of 
HAE remains an area of unmet medical need. Limitations of current prophylactic therapies 
are an unfavorable side effect profile (androgens), a lack of effect (antifibrinolytics), or the 
frequency of administration (IV or subcutaneous [SC] C1-INH). Although emerging therapies 
are providing improved prophylactic clinical outcomes, there is a need for further modalities 
in the prophylactic management of HAE, especially those targeting novel pharmacological 
pathways. 
Acute and prophylactic treatments for HAE are based on blocking BK production through 
targeting different proteins in the kallikrein-kinin pathway. Plasma levels of FXIIa have been 
shown to increase in patients during acute HAE attacks compared to during remission 
[Csuka et al, 2015; Cugno et al, 1996]. Given the importance of FXIIa in the initiation of the 
plasma contact system it is a novel target for the inhibition of the kallikrein-kinin pathway 
and the excessive production of BK detected during HAE attacks. 


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1.2 Background Information on CSL312 
1.2.1 
Overview 
CSL312 (factor XIIa antagonist monoclonal antibody) is a fully human IgG4 / lambda 
recombinant monoclonal antibody which specifically binds to the catalytic domain of FXIIa 
and potently inhibits its catalytic activity. CSL312 is an affinity-matured variant of the 
parental antibody 3F7, which was isolated following screening against the active catalytic 
fragment of FXII (βFXIIa). CSL312 is produced in Chinese hamster ovary cells that have 
been characterized according to applicable international guidelines. 
1.2.2 
Nonclinical Evaluation 
The non-clinical program conducted to support development of CSL312 included 
pharmacological, pharmacokinetic (PK), and toxicological studies performed in 
pharmacologically relevant species that are described in the CSL312 investigator’s brochure. 
1.2.3 
Clinical Experience 
1.2.3.1 
Healthy Subjects 
Previous clinical experience with CSL312 is limited to a single, randomized, double-blind, 
placebo-controlled, single ascending dose, phase 1 study. During this study, the safety and 
tolerability, and PK of escalating doses of CSL312 were assessed after single IV or SC 
injections of up to 10 mg / kg in healthy male subjects. CSL312 had an acceptable safety and 
tolerability profile. During the study there were no serious adverse events (SAEs); no 
withdrawals due to adverse events (AEs); no thromboembolic events (TEEs), bleeding 
events, or cases of anaphylaxis; no clinically significant abnormal trends in hematology or 
clinical chemistry assessments. The majority of all AEs were of mild intensity. Injection site 
reactions (ISRs) were more common with SC CSL312 than SC placebo, but there was no 
apparent dose dependence. Additionally, CSL312 exhibited linear PK behavior with a half-
life ~19 days. The study results are described in greater detail in the CSL312 investigator’s 
brochure. 
1.2.3.2 
Subjects with Hereditary Angioedema 
No clinical studies with CSL312 have been conducted in subjects with HAE. 


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1.3 Study Overview 
This is a multicenter, randomized, placebo-controlled, parallel-arm, phase 2 study to 
investigate the clinical efficacy, PK, and safety of CSL312 as prophylaxis to prevent HAE 
attacks in subjects with C1-INH HAE or FXII/PLG HAE. Section 3.1 presents a detailed 
overview of the study. 
1.4 Potential Risks and Benefits 
CSL312 is a fully human monoclonal antibody that inhibits factor XIIa activity. CSL312 is 
being developed for routine prophylaxis to prevent angioedema attacks in patients with 
C1-INH HAE or FXII/PLG HAE. In the current study, CSL312 will be administered to 
subjects experiencing recurrent HAE attacks for the first time.  
CSL312 is currently only administered in the clinical trial setting in accordance with the 
study protocol. The maximum dose and the predicted corresponding maximum concentration 
(Cmax) in this study is lower than the highest administered dose and its corresponding Cmax 
observed in the phase 1 study CSL312_1001 (Study 1001). Each subject who participated in 
Study 1001 received a single dose of CSL312 as a part of Study 1001; however, each subject 
who participates in the current study will receive multiple doses of CSL312 to produce target 
trough levels for up to 12 weeks or longer. 
Benefits 
A potential benefit of this study is the prevention of attacks in subjects with HAE type 1 and 
2 or normal C1-INH with known mutation in the FXII or Plasminogen gene by inhibiting the 
attack-causing defective pathways. CSL312 acts as an antagonist to FXIIa, affecting the 
regulation of BK formation via the kallikrein-kinin pathway. In Study 1001, a dose-
dependent inhibition of 
 was observed after single-dose IV 
or SC administration of CSL312 with near complete inhibition at the 3 and 10 mg / kg IV and 
SC Cohorts. Because FXIIa is an inherent part in the kallikrein-kinin cascade, its inhibition is 
expected to prevent the excessive BK generation, and with that, the occurrence of HAE 
attacks. This is supported by preclinical data in disease related models and the understanding 
that the major inhibitor of FXIIa is C1-INH. 
The lack of sufficient functional C1-INH leads to recurring HAE attacks in HAE type 1 and 2 
patients, and the administration of C1-INH prevents HAE attacks almost completely. In 
contrast, patients with normal C1-INH but mutations in the FXII or plasminogen gene are 
symptomatic despite the presence of sufficient C1-INH protein. Mutated FXII may be 
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susceptible to an increased activation of FXII, whereas the plasminogen mutation may lead to 
a dysregulation between the plasminogen / plasmin system and the kinin pathway, both 
resulting in an over activated kallikrein-kinin pathway. There is currently no licensed 
treatment available for HAE subjects with a known mutation in the FXII or Plasminogen 
gene.  
Risks 
The following risks were not observed in the phase 1 Study 1001, but are potential risks 
based on the drug class and mechanism of action of CSL312: 
•
Hypersensitivity / Anaphylactic-type Reactions: Administration of therapeutic proteins
including monoclonal antibodies such as CSL312 is associated with the risk of
hypersensitivity and anaphylactic reactions, some of which can be serious and life-
threatening. Appropriate precautions will be taken when CSL312 is administered at the
study site, with vigilant monitoring for potential anaphylactic reactions. The initial
administrations of CSL312 will be performed under medical supervision with immediate
access to emergency equipment and medication for treatment of adverse reactions.
Subjects who self-administer CSL312 outside of the study site will be informed of the
early signs of hypersensitivity reactions including hives, generalized urticaria, tightness
of the chest, wheezing, hypotension, and anaphylaxis. Patients should be advised to
discontinue use of CSL312 if hypersensitivity reactions occur and to seek immediate
medical assistance.
•
Thromboembolic Events and Bleeding: By blocking FXIIa with CSL312, there may be
a potential risk of bleeding or TEEs due to altered haemostasis, unstable clot formation,
or impaired clot breakdown. Subjects will be monitored carefully for signs of thrombosis
or bleeding during the study. Also, because of the pharmacological action of CSL312, a
prolonged of 
 is expected to be observed in a
concentration-dependent manner. However, no effect on prothrombin time (PT) was seen
in the phase 1 Study 1001. This is consistent with the observation that patients who have
congenital deficiency of FXII do not exhibit a bleeding phenotype, despite having a
prolonged 
 [Lammle et al, 1991; Ratnoff and Colopy, 1955]. In addition, nonclinical
studies in mice and rabbits showed no impairment in haemostasis following inhibition of
FXIIa [Larsson et al, 2014]. Coagulation parameters, including 
 and PT will be
monitored throughout the study.
•
Immunogenicity (Anti-drug Antibodies): All protein therapeutics are potentially
immunogenic. Because CSL312 is a protein it has the potential to cause the development
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of neutralizing and non-neutralizing anti-drug antibodies. Subjects will be monitored for 
the development of anti-drug antibodies throughout the study. 
During Study 1001, CSL312 was administered as a single IV or SC dose up to 10 mg / kg to 
healthy male subjects, it was safe and well tolerated. No dose dependent trends were seen in 
treatment emergent AE frequency or severity. No deaths, SAEs, or AEs leading to 
discontinuation were reported. The majority of all treatment emergent AEs were mild. There 
were no TEEs, bleeding, or anaphylaxis events. No clinically relevant changes in laboratory 
parameters, vital signs, or electrocardiograms were observed. No anti-CSL312 antibodies 
were detected in any subject at baseline or at any time point during the study. 
Subjects randomized to placebo, and not participating in an optional open-label extension 
period, will have no benefits. 
Given the potential benefit of CSL312 for HAE patients, the acceptable safety data for 
CSL312 from Study 1001, and the implementation of study procedures in the current study 
(Study 2001) that will closely monitor the safety of study subjects, the associated benefit-risk 
assessment is considered acceptable for subjects who participate in the study. Additional 
information on CSL312 can be found in the CSL312 investigator’s brochure. 
2 Study Objectives and Endpoints 
Primary, secondary, and some 
 will be analyzed for subjects with 
C1-INH HAE, as indicated.  
Other 
 will be analyzed for subjects with FXII/PLG HAE, as indicated. 
2.1 Primary Objective and Endpoint 
2.1.1 
Primary Objective 
The primary objective of this study is to evaluate the efficacy of CSL312 in the prevention of 
HAE attacks in subjects with C1-INH HAE. 
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2.1.2 
Primary Endpoints 
Table 1 
Primary Endpoint 
Primary Endpoint 
Summary Measure 
Time-normalized number of HAE attacks. 
The time-normalized number (per month) of 
HAE attacks in subjects with C1-INH HAE 
on treatment with CSL312 (
 mg, or 
 
mg administered every 4 weeks [q4wk]) 
compared to placebo q4wk during 
Treatment Period 1. 
Abbreviations: HAE = hereditary angioedema; C1-INH HAE = Hereditary angioedema with C1-esterase 
inhibitor deficiency; q4wk = administered every 4 weeks. 
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 CSL312 in subjects with C1-INH HAE.
2. To evaluate the PK of CSL312 in subjects with C1-INH HAE.
3. To evaluate the safety and tolerability of CSL312 in subjects with C1-INH HAE.
2.2.2 
Secondary Endpoints 
Table 2 
Secondary Endpoints 
Secondary 
Objective 
Secondary Endpoints 
Summary Measure(s) 
1 
Responder subjects. 
The number and percentage of 
subjects with C1-INH HAE who 
respond to treatment with CSL312 
or placebo during Treatment Period 
1, where “response” is defined as a 
≥ 50% relative reduction in the 
time-normalized number of HAE 
attacks (per month) compared to 
each subject’s time-normalized 
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Secondary 
Objective 
Secondary Endpoints 
Summary Measure(s) 
number of HAE attacks (per 
month) during the Run-in Period. 
1 
HAE attack-free subjects. 
The number and percentage of 
subjects with C1-INH HAE who 
do not experience an HAE attack 
on treatment with CSL312 or 
placebo during Treatment Period 1. 
1 
HAE attacks. 
The number, time-normalized 
number (per month), and 
percentage of mild, moderate, or 
severe HAE attacks in subjects 
with C1-INH HAE on treatment 
with CSL312 or placebo during 
Treatment Period 1. 
1 
HAE attacks treated with on-demand 
HAE medication. 
The number, time-normalized 
number (per month), and 
percentage of mild, moderate, or 
severe HAE attacks in subjects 
with C1-INH HAE treated with on-
demand HAE medication on 
treatment with CSL312 or placebo 
during Treatment Period 1. 
2 
CSL312 PK in plasma: 
• Maximum concentration (Cmax).
• Area under the concentration-time
curve in 1 dosing interval (AUC0-tau).
• Time of maximum concentration
(Tmax).
• Terminal elimination half-life (T1/2).
• Total systemic clearance (CLtot).
CSL312 concentration in plasma in 
subjects with C1-INH HAE during 
treatment with CSL312 or placebo 
at specified time points during 
Treatment Period 1. 


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Secondary 
Objective 
Secondary Endpoints 
Summary Measure(s) 
• Volume of distribution during the
elimination phase (Vz).
3 
Subjects experiencing: 
• AEs.
• SAEs.
• AEs of special interest
(ie, anaphylaxis, TEEs, and bleeding
events).
• ISRs.
• Inhibitory antibodies to CSL312.
• Clinically significant abnormalities in
laboratory assessment that are
reported as AEs.
The number and percentage of 
subjects with C1-INH HAE 
experiencing the specified safety 
events on treatment with CSL312 
or placebo during Treatment Period 
1. 
Abbreviations: AEs = adverse events; HAE = hereditary angioedema; C1-INH HAE = Hereditary 
angioedema with C1-esterase inhibitor deficiency; ISRs = injection site reactions; SAEs = serious adverse 
events; TEEs = thromboembolic events. 
2.3
2.3.1
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2.3.2
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3 Study Overview 
3.1 Study Design 
This is a multicenter, randomized, placebo-controlled, parallel-arm, phase 2 study to 
investigate the clinical efficacy, pharmacokinetics, and safety of CSL312 as prophylaxis to 
prevent HAE attacks in subjects with C1-INH HAE or FXII/PLG HAE. As presented in 
Figure 1, the study consists of a Screening Period, a Run-in Period, 2 treatment periods, and a 
Follow-up Period.  
Figure 1 
Study Overview 
Abbreviations: C1-INH HAE = HAE with C1-esterase inhibitor deficiency; FXII/PLG HAE = HAE with normal 
C1-esterase inhibitor and factor XII or plasminogen gene mutation; HAE = hereditary angioedema; q2wk = administered 
every 2 weeks; q4wk = administered every 4 weeks. 
Footnotes: 
a An overview of the Run-in Period is presented in Section 3.1.2. 
b An overview of Treatment Period 1 is presented in Section 3.1.3. 
c An overview of Treatment Period 2 is presented in Section 3.1.4. 
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d An overview of the Follow-up Period is presented in Section 3.1.5. 
e Subjects may use the medication of their choice to treat HAE attacks experienced during the study if that 
medication has previously been shown to be effective (Section 7.2). Investigators should ensure that 
participating subjects are capable of managing their HAE attacks.
f C1-INH HAE subjects will be assigned to receive 
 mg CSL312 q2wk, only after 32 subjects with C1-INH 
HAE are first randomly assigned to receive placebo or 
 mg, 
 mg, or 
 mg CSL312 q4wk. 
g Subjects will receive treatment with investigational product in a blinded manner (Section 6.1.3). These 
subjects will receive an initial IV loading dose of investigational product in Treatment Period 1 before 
receiving investigational product q4wk (Section 3.2). 
h Subjects will receive treatment with CSL312 in an open-label manner (Section 6.1.3). 
i Subjects will receive treatment with CSL312 in an open-label manner (Section 6.1.3). These subjects will 
receive an initial IV loading dose of investigational product in Treatment Period 1 before receiving 
investigational product q4wk (Section 3.2). 
j All C1-INH HAE subjects receiving the 
 mg dose will have their dose reduced to 
 mg q4wk SC at their 
next scheduled study visit. 
3.1.1 
Screening 
Subjects who provide written informed consent will be screened for their eligibility to enter 
the Run-in Period. Screening will be completed within 28 days before the first day of the 
Run-in Period.  
3.1.2 
Run-in Period 
After Screening, eligible subjects will enter into an initial Run-in Period lasting at least 
4 and up to 8 weeks to confirm their underlying disease status and to assess their eligibility 
for participation in Treatment Period 1. The first day of the Run-in Period may occur on the 
same day as Screening. 
Subjects are not permitted to use routine prophylaxis to prevent HAE attacks during the Run-
in Period (Section 7.3); however, subjects may use on-demand HAE therapy to treat 
emerging HAE attacks if that medication has previously been shown to be effective 
(Section 7.2). 
Subjects may stop participation in the Run-in Period and begin Treatment Period 1 when they 
have met the criteria specified in Section 4.1.3, including: 
•
For subjects with C1-INH HAE, subjects must have experienced ≥ 2 HAE attacks within
a consecutive 4-week period during the Run-in Period.
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•
For subjects with FXII/PLG HAE, subjects must have experienced ≥ 1 HAE attack
during the Run-in Period.
3.1.3 
Treatment Period 1 
Subjects should enter Treatment Period 1 no later than 14 days after the Week 9 (Day 57) 
Telephone Contact of the Run-in Period. If a subject is unable to enter Treatment Period 1 
within the 14 days after the Week 9 (Day 57) Telephone Contact, then CSL approval is 
required for the subject to enter into Treatment Period 1. 
Treatment Period 1 will last for ~ 13 weeks, during which time investigators will assess and 
document the occurrence of HAE attacks based on data reported by subjects in an electronic 
diary (eDiary). 
Subjects with C1-INH HAE 
The first 32 subjects with C1-INH HAE who are eligible to participate in Treatment Period 1 
will be randomly assigned to receive treatment with investigational product in a 1:1:1:1 ratio 
(a loading dose of 
 mg CSL312 IV followed by 
 mg CSL312 q4wk SC; a loading dose 
of 
 mg CSL312 IV followed by 
 mg CSL312 q4wk SC; a loading dose of 
 mg 
CSL312 IV followed by 
 mg CSL312 q4wk SC; a loading dose of placebo IV followed 
by placebo q4wk SC) during Treatment Period 1 (see Section 3.2.1). For these C1-INH HAE 
subjects, Treatment Period 1 will be conducted in a blinded manner. In order to maintain the 
blind, investigational product will be volume-normalized (Section 6.1.3.1). 
After the first 32 subjects with C1-INH HAE are randomly assigned to treatment, up to an 
additional 8 subjects will be assigned to receive 
 mg CSL312 administered every 2 weeks 
(q2wk) SC. 
. For these 
C1-INH HAE subjects, Treatment Period 1 will be conducted in an open-label manner and 
will not be volume-normalized. 
Subjects with FXII/PLG HAE 
Up to 10 eligible subjects with FXII/PLG HAE will be assigned to receive a loading dose of 
 mg CSL312 IV followed by 
 mg CSL312 q4wk SC. For these FXII/PLG HAE 
subjects, Treatment Period 1 will be conducted in an open-label manner and will not be 
volume normalized. 
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3.1.4 
Treatment Period 2 
All subjects who participated in Treatment Period 1 may participate in Treatment Period 2. 
Treatment Period 2 will last for at least 44 weeks, or until another CSL312 study is opened 
for subjects to join, or until the current study is discontinued. During Treatment Period 2 
investigators will continue to assess and document the occurrence of HAE attacks based on 
data reported by subjects in an eDiary. Treatment Period 2 will be conducted in an open-label 
manner for all subjects. 
•
Subjects with C1-INH HAE who received placebo or
 mg CSL312 q4wk in Treatment 
Period 1 will be randomly assigned to receive either
 mg or 
 mg CSL312 q4wk SC 
in a 1:1 ratio in Treatment Period 2.
•
Subjects with C1-INH HAE who received
 mg CSL312 q4wk in Treatment Period 1 
will continue to receive 
 mg CSL312 q4wk SC in Treatment Period 2. 
•
Subjects with C1-INH HAE who received
 mg CSL312 q4wk in Treatment Period 1 
will continue to receive 
 mg CSL312 q4wk SC in Treatment Period 2. 
•
Subjects with C1-INH HAE who received
 mg CSL312 q2wk in Treatment Period 1 
will be randomly assigned to receive either
 mg or 
 mg CSL312 q4wk SC in a 1:1 
ratio in Treatment Period 2.
•
Subjects with FXII/PLG HAE will continue to receive
 mg CSL312 q4w SC in 
Treatment Period 2.
Dose modification details for Treatment Period◦2 are presented in◦Section 5.5. All C1-INH 
HAE subjects receiving the 
 mg dose will have their dose reduced to 
 mg q4wk SC at 
their next scheduled study visit, effective with Amendment 2. 
3.1.5 
Post-Treatment Follow-up Period 
Subjects will attend a Follow-up Visit ~14 weeks after each subject’s final treatment period 
visit; however, the Follow-up Visit may be waived in place of a telephone contact, at the 
discretion of the investigator.  
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3.2 Dose and Dosing Regimen 
3.2.1 
Treatment Period 1  
The first 32 subjects with C1-INH HAE who are eligible to participate in Treatment Period 1 
will be randomly assigned to receive 1 of the following treatment regimens in a blinded 
manner: 
•
A single loading dose of
 mg CSL312 IV followed ~1 week later by 
 mg CSL312 q4wk SC. 
•
A single loading dose of
 mg CSL312 IV followed ~1 week later by 
 mg CSL312 q4wk SC. 
•
A single loading dose of
 mg CSL312 IV followed ~1 week later by 
 mg CSL312 q4wk SC. 
•
A single loading dose of placebo IV followed ~1 week later by placebo q4wk SC.
After the first 32 subjects with C1-INH HAE are randomly assigned to treatment (as above), 
up to an additional 8 subjects will be assigned in an open-label manner to receive 
 mg CSL312 q2wk SC. 
. 
Up to 10 eligible subjects with FXII/PLG HAE will be assigned in an open-label manner to 
receive a loading dose of 
 mg CSL312 IV followed ~1 week later by 
 mg CSL312 
q4wk SC. 
All IV loading doses of investigational product (ie, CSL312 or placebo) will be administered 
by the investigator or delegate at the study site. All SC doses of investigational product will 
be self-administered under supervision of the investigator or delegate at the study site.  
Subjects should remain on site for at least 30 minutes after the investigational product is 
administered. 
Dose modification is NOT permitted in Treatment Period 1, and additional details are 
presented in Section 5.5. 
Additional information related to dosing and administration of investigational product is 
presented in Section 6.2. 
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3.2.2 
Treatment Period 2 
C1-INH HAE subjects who continue to participate in Treatment Period 2 will be receiving 
CSL312 
 mg or 
 mg q4wk SC at the beginning of Treatment Period 2. Effective with 
Amendment 2, all C1-INH HAE subjects receiving the 
 mg dose will have their dose 
reduced to 
 mg q4wk SC at their next scheduled study visit. FXII/PLG HAE subjects will 
be maintained on the 
 mg q4wk SC dose. The first dose of CSL312 in Treatment Period 2 
will be administered at the Week 13 (Day 91) Visit and at the Week 13 (Day 85) Visit for 
subjects who administer investigational product q4wk and q2wk in Treatment Period 1, 
respectively. Administration of CSL312 at the Week 13 (Day 85 / 91) Visit, the Week 17 (Day 
119) Visit, and the Week 21 (Day 147) Visit will be self-administered under supervision of
the investigator or delegate at the study site. After administration of the CSL312 at the Week
21 (Day 147) Visit, all subsequent doses of CSL312 will be self-administered SC every 28
days (± 2 days) by the subject at home or at the study site.
Subjects should remain at the study site for at least 30 minutes after any CSL312 
administration that occurs at the study site.  
Dose modification details for Treatment Period◦2 are presented in Section 5.5. 
Additional information related to dosing and administration of investigational product is 
presented in Section 6.2. 
3.3 Scientific Rationale 
3.3.1 
Study Design Rationale 
The present phase 2 study will evaluate the efficacy, safety, tolerability, and PK profile of 
multiple subcutaneous administrations of CSL312 across a range of doses in subjects with 
C1-INH HAE or FXII/PLG HAE. The study consists of a Screening Period to assess subject 
eligibility, a Run-in Period to assess underlying disease activity, and 2 treatment periods to 
assess initial and long-term (respectively) safety, tolerability, and efficacy. The data from this 
study will be used to select dose(s) for a potential phase 3 study. 
3.3.2 
Dose Rationale 
Dose selection was based on the safety, PK and 
 data obtained in the phase 1 single 
ascending dose study (Study 1001) after administration of single IV and SC doses ranging 
from 0.1 to 10 mg / kg (7.75 to 1015 mg) in healthy volunteers. The key 
 endpoint used 
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for dose selection was 
 It is hypothesized that inhibiting 
 consistently to a particular % target inhibition is expected 
to provide protection from HAE attacks. The exact % target 
 to prevent HAE attacks is unknown and will be evaluated in this study in HAE 
patients. 
A PK / 
 model was developed to quantify the relationship between CSL312 plasma 
concentrations and 
 from the IV and SC cohorts in 
Study 1001. The modeled relationship showed an increase in inhibition of 
 with increasing concentrations of CSL312. The IC50 was estimated to be 
14.9 µg / mL. 
Based on the relationship between CSL312 plasma concentration and 
 the % target inhibition levels that were chosen included ≥ 30, ≥ 50, and 
≥ 90% (corresponding to doses that would result in inhibition below the IC50, at the 
inflection point and at the maximum effect of the curve), which would provide information 
along the entire spectrum of the curve allowing for a robust assessment of doses in this study. 
Simulations using the final PK / 
 model determined that fixed doses of 
 mg, 
 mg, 
and 
 mg administered every 4 weeks would result in at least 75% of the patients reaching 
a % target inhibition of 
 of ≥ 30, ≥ 50, and ≥ 90%, 
respectively. 
The dosing interval of every 4 weeks was selected based on the calculated half-life of 
CSL312 of ~19 days in the phase 1 single ascending dose study (Study 1001). The interval 
between the IV loading dose and the SC maintenance doses was chosen such that the CSL312 
plasma trough concentration after the IV loading dose would be within 20% of the trough 
concentration at steady-state after SC doses given every 4 weeks. The IV route of 
administration was selected for the loading dose as CSL312 plasma concentrations higher 
than the trough concentrations observed at steady state after SC doses given every 4 weeks 
are expected to be achieved instantaneously. The IV loading doses selected for this study are 
expected to result in exposures that are similar to the exposures after SC doses given the 
~50% bioavailability of CSL312 when administered SC based on the results from phase 1 
single ascending dose study (Study 1001).  
A dose of 
 mg q2wk for subjects with C1-INH HAE in the open-label arm of the study 
was selected to explore a dosing interval of 2 weeks. This dosing regimen was chosen to 
target a % inhibition of ≥ 90% of the 
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A dose of 
 mg q4wk was selected for subjects with FXII/PLG HAE to provide the 
maximum potential benefit of treatment with a target of ≥ 90% inhibition of their 
. 
The maximum dose (IV or SC) and the predicted corresponding Cmax in this study is lower 
than the highest administered dose (IV or SC) and its corresponding Cmax observed in the 
phase 1 study, which were associated with acceptable safety findings.  
3.4 Planned Study Duration 
The duration of the study for an individual subject who participates in Treatment Period 1 
and Treatment Period 2 is up to approximately 83 weeks if the duration of Treatment Period 2 
is not extended (see Section 8.5.4.14). 
This estimation is based on: 
•
A Screening Period of up to 4 weeks.
•
A Run-in Period of up to 8 weeks.
•
A treatment period of ~13 weeks (Treatment Period 1).
•
A treatment period of at least ~44 weeks (Treatment Period 2).
•
A Follow-up Period of ~14 weeks.
The overall study duration (ie, first subject’s Screening Visit to last subject’s final visit) is 
estimated to be 119 weeks, if Treatment Period 2 is not extended (see Section 8.5.4.14). 
Treatment Period 2 will extend until another CSL312 study is opened for subjects to join, or 
until the current study is discontinued. 
3.5 Planned Number of Subjects 
Up to 50 subjects are planned to be assigned to treatment with investigational product in 
Treatment Period 1, including: 
•
8 subjects with C1-INH HAE who will be assigned to receive placebo q4wk.
•
8 subjects with C1-INH HAE who will be assigned to receive
 mg CSL312 q4wk. 
•
8 subjects with C1-INH HAE who will be assigned to receive
 mg CSL312 q4wk. 
•
8 subjects with C1-INH HAE who will be assigned to receive
 mg CSL312 q4wk. 
•
Up to 8 subjects with C1-INH HAE who will be assigned to receive
 mg CSL312 q2wk. 
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•
Up to 10 subjects with FXII/PLG HAE who will be assigned to receive
 mg CSL312 q4wk. 
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 study visit with the last subject at their Follow-up Visit 
(eg, Week 70 [Day 494] Visit if Treatment Period 2 is not extended [see Section 8.5.4.14]). 
3.7 Study Oversight 
3.7.1 
Independent Data Monitoring Committee 
An independent data monitoring committee (IDMC) will be established to monitor the 
critical efficacy and safety data generated during the study. The IDMC will consist of 
independent clinical specialists in HAE, who also have experience in clinical trials. The 
IDMC will review accumulating data from the ongoing study in an unblinded manner. Based 
on these reviews, the IDMC will advise on the further conduct of the study. No success or 
futility thresholds will be set for the IDMC reviews. CSL will continue the study unless a 
safety issue (including lack of efficacy) is confirmed that warrants study termination. The 
composition, activities, analyses, responsibilities, and timing of meetings of the IDMC will 
be described in the IDMC charter. 
3.7.2 
Other Monitoring Committees 
Not applicable 
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 should meet all of the inclusion criteria and 
none of the exclusion criteria for this study. Subject eligibility should be reviewed and 
documented by an appropriately medically qualified member of the investigator’s study team 
before subjects are included in the study. 
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4.1.1 
Inclusion Criteria for Entry into the Run-in Period 
To enter the Run-in Period, subjects must meet all of the following inclusion criteria: 
1. Provides written informed consent.
2. Male or female.
3. Aged ≥ 18 to ≤ 65 years at the time of providing written informed consent.
4. A diagnosis of C1-INH HAE or FXII/PLG HAE:
•
Clinical diagnosis of C1-INH HAE, based on the following criteria:
o
For C1-INH HAE (type 1):
-
Documented clinical history consistent with HAE (subcutaneous or mucosal,
non-pruritic swelling episodes without accompanying urticaria).
- 
 < 50% of the lower limit 
of the reference range, as documented in the subject’s medical record.  
- 
 below the lower limit of the reference range, as 
documented in the subject’s medical record. 
o
For C1-INH HAE (type 2):
-
Documented clinical history consistent with HAE (subcutaneous or mucosal,
non-pruritic swelling episodes without accompanying urticaria).
-
 < 50% of the lower limit of the reference range, as 
documented in the subject’s medical record. 
-
 below the lower limit of the reference range, as 
documented in the subject’s medical record. 
•
Clinical diagnosis of FXII/PLG HAE, based on the following criteria:
o
Documented clinical history consistent with HAE (subcutaneous or mucosal,
non-pruritic swelling episodes without accompanying urticaria).
o
An HAE-associated FXII gene mutation (eg, FXII point mutation Thr328Lys or
Thr328Arg, or deletion of 72 base pairs [c.971_1018 + 24del72], or duplication of
18 base pairs [c.892-909dup]), as documented in the subject’s medical record, OR
an HAE-associated PLG gene mutation (eg, PLG point mutation Lys330Glu), as
documented in the subject’s medical record.
o 
 70 – 120 % of the normal 
level, as documented in the subject’s medical record. 
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5. For subjects with C1-INH HAE: ≥ 4 HAE attacks over a consecutive 2-month period
during the 3 months before Screening, as documented in the subject’s medical record.
Note: For subjects taking any prophylactic HAE therapy during the 3 months before
Screening, ≥ 4 HAE attacks may be documented over any consecutive 2-month period
during the 3 months before commencing the prophylactic therapy.
6. For subjects with FXII/PLG HAE: ≥ 1 HAE attack during the 3 months before Screening,
as documented in the subject’s medical record. Note: For subjects taking any
prophylactic HAE therapy during the 3 months before Screening, 1 HAE attack may be
documented during the 3 months before commencing the prophylactic therapy.
7. Willing to cease the use of C1-INH products, androgens or antifibrinolytics for routine
prophylaxis against HAE attacks on the first day of the Run-in Period, after being
assessed by the investigator to be able to adequately manage on-demand treatments of
HAE attacks without assistance. Please see Section 7.3 for guidance.
8. Investigator believes that the subject understands the nature, scope and possible
consequences of the study.
4.1.2 
Exclusion Criteria for Entry into the Run-in Period 
Subjects must not enter the Run-in Period if they meet any of the following exclusion 
criteria: 
1. History of clinically significant arterial or venous thrombosis, or current clinically
significant prothrombotic risk (including presence of a central venous access device
[CVAD]).
2. History of an uncontrolled, abnormal bleeding event due to a coagulopathy, or a current
clinically significant coagulopathy or clinically significant risks for bleeding events.
3. Any pre-planned surgeries during the trial that have an inherent clinically significant risk
for thrombotic events or bleeding.
4. Known incurable malignancies at the time of Screening.
5. For subjects with a clinical diagnosis of C1-INH HAE, a clinically significant history of
poor response to C1-INH therapy for the management of HAE.
6. Female subjects with C1-INH HAE who started taking or changed dose of any hormonal
contraceptive regimen or hormone replacement therapy (ie, estrogen / progesterone
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7. Participation in another interventional clinical study during the 30 days before Screening
or within 5 half-lives of the final dose of the investigational product administered during
the previous interventional study, whichever is longer.
8. Any previous treatment with any monoclonal antibody, recombinant protein bearing an
Fc domain, ribonucleic acid (RNA) silencing, or gene transfer technologies.
9. Receiving any other therapy not permitted during the study at the time of Screening.
Note: Prohibited therapies are described in Section 7.3.
10. Male or female subject of childbearing potential either not using or not willing to use a
highly-effective method of contraception or not sexually abstinent at any time during
Treatment Period 1 or Treatment Period 2 and during the Follow-up Period, or not
surgically sterile. Note: Childbearing potential and the acceptable methods of
contraception are defined in Section 7.4.
11. Intention to become pregnant or to father a child at any time during the study.
12. Pregnant or nursing mother.
13. Known or suspected hypersensitivity to the investigational product or to any excipients of
the investigational product.
14. Employee of the study site, or spouse / partner or relative of the investigator or any
sub-investigator.
15. Any other issue that, in the opinion of the investigator, would render the subject
unsuitable for participation in the study.
4.1.3 
Criteria for Entry into Treatment Period 1 
Subjects will be eligible to exit the Run-in Period and begin Treatment Period 1 if they meet 
the following criteria: 
1. Subject participated in the Run-in Period for at least 4 weeks (28 days).
2. For subjects with C1-INH HAE, confirmation of diagnosis by central laboratory testing:
•
For subjects with C1-INH HAE (type 1):
- 
 < 50% of the lower limit of the 
reference range. 
- 
 below the lower limit of the reference range 
•
For subjects with C1-INH HAE (type 2):
- 
 < 50% of the lower limit of the reference range. 
- 
 below the lower limit of the reference range. 
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3. For subjects with C1-INH HAE: the occurrence of ≥ 2 HAE attacks within any
consecutive 4-week period during the Run-in Period.
4. For subjects with FXII/PLG HAE: the occurrence of ≥ 1 HAE attack during the Run-in
Period.
5. Do not have any clinical abnormalities assessed as clinically significant by the
investigator in results of hematology, chemistry, or urinalysis assessments performed
during Screening. Note: Subjects with ≥ 2 times the upper limit of normal for aspartate
aminotransferase (AST) and / or alanine aminotransferase (ALT) may be eligible for
participation if there is an explanation for this laboratory result and if the results are not
clinically significant.
Note: Subjects should enter Treatment Period 1 no later than 14 days after the 
Week 9 (Day 57) Telephone Contact of the Run-in Period. If a subject is unable to enter 
Treatment Period 1 within the 14 days after the Week 9 (Day 57) Telephone Contact, then 
CSL approval is required for the subject to enter into Treatment Period 1. 
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 terminated by CSL).  
In accordance with International Conference on Harmonization (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 
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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 8.5.5. 
If the subject is discontinued or 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 the subject discontinues or 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. 
4.2.3 
Replacement Policy 
Subjects who discontinue or are withdrawn from the study will not be replaced. 
5 Study Interventions 
5.1 Description of Investigational Product 
5.1.1 
CSL312 
CSL312 will be supplied (  mL per vial) as a sterile, preservative-free solution for injection, 
at pH 
 CSL312 is formulated in buffer containing 
Table 3 
Description of CSL312 
Substance number 
CSL312 
Active substance 
Factor XIIa antagonist monoclonal antibody 
Trade name 
Not applicable 
Dosage form 
Solution for injection 
Mode of administration 
Intravenous and subcutaneous injection 
CSL312 will be manufactured in accordance with ICH Good Manufacturing Practice 
guidelines and local regulatory requirements. 
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Additional details related to the dosing and administration of the investigational product 
(ie, CSL312 or placebo) is presented in Section 6.2. 
5.1.2 
Placebo 
The placebo will be supplied (  mL per vial) as a sterile, preservative-free solution for 
injection. The placebo is the same as the CSL312 formulation buffer, but does not contain the 
active substance (ie, factor XIIa antagonist monoclonal antibody). 
Table 4 
Description of Placebo 
Substance number 
Not applicable 
Substance 
Placebo 
Trade name 
Not applicable 
Dosage form 
Solution for injection 
Mode of administration 
Intravenous and subcutaneous injection 
The placebo will be manufactured in accordance with ICH Good Manufacturing Practice 
guidelines and local regulatory requirements. 
Additional details related to the dosing and administration of the investigational product 
(ie, CSL312 or placebo) is presented in Section 6.2. 
5.1.3 
CSL312 Diluent 
The CSL312 diluent is identical to placebo (see Section 5.1.2). 
5.2 Packaging, Labeling, Supply and Storage 
5.2.1 
Packaging and Labeling 
Investigational product will be packaged and labeled according to current ICH Good 
Manufacturing Practice and GCP guidelines, and national legal requirements. 
5.2.2 
Supply and Storage 
Investigational product will be supplied to the study sites or to a subject’s home by CSL or 
delegate. 
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At the study site, investigational product must be stored under temperature-controlled and 
monitored conditions from +2°C to +8°C in a secure storage area as specified in the site 
investigational product manual. 
In cases where investigational product is stored at a subject’s home, detailed storage 
instructions will be provided in a separate manual. 
5.3 Accountability and Destruction 
Investigational product must be used only as directed in the clinical study protocol. 
The unblinded pharmacist or delegate will confirm receipt of all shipments of investigational 
product (ie, CSL312 and placebo) in the interactive response technology (IRT) system. 
All supplies of investigational product must be accounted for throughout the study in the IRT 
system. 
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 unblinded pharmacist or delegate using the appropriate 
form or the IRT system. 
The unblinded pharmacist or delegate must provide reasons for any discrepancies in records 
of drug accountability. 
Any unused vials of investigational product must not be destroyed until the drug 
accountability documentation has been checked by the study monitor, and any necessary 
permission for destruction has been given by CSL. Any destruction of investigational product 
must be documented and certification 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 manual. 


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5.4 On-demand HAE Therapy 
Subjects must be assessed by an investigator to be capable of managing their HAE attacks 
during participation in the study. This must be documented by the investigator in an 
individual acute action plan.  
Subjects may use the on-demand medication of their choice to treat HAE attacks experienced 
during the study as described in Section 7.2. 
5.5 Dose Modification 
No modification of dose is planned in Treatment Period 1. 
Subjects in Treatment Period 2 at a dose of 
 mg CSL312 q4wk who experience ≥ 3 HAE 
attacks within an 8-week period are eligible to have their CSL312 dose increased to 
 mg 
CSL312 q4wk. All CSL312 dose increases will be made in eligible subjects at the discretion 
of the investigator in consultation with CSL. All C1-INH HAE subjects receiving the 
 mg 
dose will have their dose reduced to 
 mg q4wk SC at their next scheduled study visit. 
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 by the IRT. 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 
Randomization will be conducted using an IRT. The investigator will be supplied with a user 
guide for the IRT. The randomization list will be generated according to the approved 
randomization specifications. The IRT service provider will keep the randomization code on 
file.  
Treatment Period 1 
In Treatment Period 1, subjects will be randomized using block randomization with fixed 
block size by means of centralized IRT to 1 of 4 blinded treatment arms: 
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•
The first 32 subjects with C1-INH HAE who are assigned to treatment in Treatment
Period 1 will be randomized in a 1:1:1:1 ratio to receive placebo, 
 mg CSL312,
 mg CSL312, or 
 mg CSL312 q4wk SC. 
Up to 8 additional subjects with C1-INH HAE who are assigned to treatment in Treatment 
Period 1 after the first 32 subjects (above) will receive 
 mg CSL312 q2wk SC. 
Subjects with FXII/PLG HAE who are assigned to treatment in Treatment Period 1 will 
receive 
 mg CSL312 q4wk SC.  
Treatment Period 1 will be conducted in a blinded manner for C1-INH HAE subjects who 
receive placebo, 
 mg CSL312, 
 mg CSL312, or 
 mg CSL312 q4wk. Emergency 
unblinding will be performed in the IRT (Section 6.1.3.2).  
Treatment Period 1 will be conducted in an open-label manner for C1-INH HAE subjects 
who receive 
 mg CSL312 q2wk and for FXII/PLG HAE subjects who receive 
 mg 
CSL312 q4wk. 
Treatment Period 2 
In Treatment Period 2, subjects will be re-randomized using block randomization with fixed 
block size by means of a centralized IRT to receive either 
 mg or 
 mg CSL312 q4wk. 
•
For subjects with C1-INH HAE, randomization will be stratified by Treatment Period 1
treatment assignments: subjects on placebo q4wk; subjects on 
 mg CSL312 q4wk;
subjects on 
 mg CSL312 q2wk.
o
Subjects on placebo q4wk in Treatment Period 1 will be randomized in a 1:1 ratio to
receive either 
 mg CSL312 q4wk or 
 mg CSL312 q4wk in Treatment Period 2. 
o
Subjects on 
 mg CSL312 q4wk in Treatment Period 1, will be randomized in a 1:1 
ratio to receive either 
 mg CSL312 q4wk or 
 mg CSL312 q4wk in Treatment 
Period 2.  
o
Subjects on 
 mg CSL312 q2wk in Treatment Period 1 will be randomized in a 1:1 
ratio to receive either 
 mg CSL312 q4wk or 
 mg CSL312 q4wk in Treatment 
Period 2. 
•
Subjects with C1-INH HAE on
 mg CSL312 q4wk in Treatment Period 1 will 
continue to receive 
 mg CSL312 q4wk in Treatment Period 2. 
•
Subjects with C1-INH HAE on
 mg CSL312 q4wk in Treatment Period 1 will 
continue to receive 
 mg CSL312 q4wk in Treatment Period 2. 
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•
Subjects with FXII/PLG HAE will continue to receive
 mg CSL312 q4wk in 
Treatment Period 2.
Treatment Period 2 will be conducted in an open-label manner. 
6.1.3 
Blinding Procedures 
6.1.3.1 
Blinding Method 
Treatment Period 1 
Treatment Period 1 will be conducted in a blinded manner for subjects with C1-INH HAE 
who receive placebo, or 
 mg, 
 mg, or 
 mg CSL312 q4wk SC. 
•
For these treatments, all C1-INH HAE subjects will be blinded to their treatment
assignment in Treatment Period 1.
•
Except for the unblinded pharmacist or delegate, all investigational site staff (including
the investigator) will also be blinded to the treatment assignment of subjects with C1-INH
HAE in Treatment Period 1. The unblinded pharmacist or delegate will be responsible for
the preparation of the investigational product, but will not administer the investigational
product or assess subjects.
•
Representatives from CSL and their delegates who have direct interaction with the study
sites and / or subjects will be blinded to treatment assignment throughout Treatment
Period 1. Adequate procedures are in place to ensure the integrity of the blinded data
within CSL for those representatives who are blinded.
In order to maintain the blind, all doses of investigational product administered during 
Treatment Period 1 will be volume normalized (see Section 6.2). Volume normalization will 
permit administration of the same volume of investigational product to be administered to 
each subject, regardless of their treatment assignment.  
•
The unblinded pharmacist or delegate will dilute the assigned IV loading doses of
CSL312 so that each is the same volume for administration as a dose of
 mg CSL312 (ie,  mL). 
•
The unblinded pharmacist or delegate will dilute the assigned SC doses of CSL312 so
that each is the same volume for administration as a dose of 
 mg CSL312 (ie,  mL). 
After preparation of the investigational product and before the investigational product is 
delivered to the subject for administration, a physical blind (eg, opaque or colored syringe) 
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will be employed so that other site staff and study subjects are unable to detect any 
differences between CSL312 or placebo. 
In addition, results from assessment of 
 will not be available to subjects, study site 
personnel, or CSL and their delegates who are blinded to treatment assignment 
Treatment Period 1 will be conducted in an open-label manner for subjects with 
C1-INH HAE who receive 
 mg CSL312 q2wk SC. Investigational product will not be 
volume normalized for these subjects. 
Treatment Period 1 will be conducted in an open-label manner for subjects with 
FXII/PLG HAE. Investigational product will not be volume normalized for these subjects. 
Treatment Period 2 
Treatment Period 2 will be conducted in an open-label manner for all subjects. 
6.1.3.2 
Breaking the Blind for an Emergency 
The randomization code for all or individual subjects may be unblinded to a site using the 
IRT during the study in emergency situations for reasons of subject safety if knowing 
treatment assignment will change subject management. Whenever possible, the investigator 
should consult with the Medical Monitor before unblinding the randomization code. The 
reason for unblinding the randomization code must be fully documented and the investigator 
must follow the defined procedures provided in the study manual. 
Additional details are presented in the IRT Manual. 
6.2 Dosing and Administration 
The investigator (or delegate) will only administer or dispense the investigational product to 
subjects included in this study following the procedures set out in this study protocol. 
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Table 5 
Investigational Product Dosing Characteristics 
Investigational product 
CSL312 
Placebo 
Route 
Intravenous 
infusion 
Subcutaneous 
injection 
Intravenous 
infusion 
Subcutaneous 
injection 
Preferred anatomic location for 
administration 
Arm 
Abdomen a 
Arm 
Abdomen a 
Total administration volume, 
Treatment Period 1 
 mL b 
 mL c 
 mL b 
 mL c 
Total administration volume, 
Treatment Period 2 
Not applicable 
 mg CSL312 
=  mL; 
 mg CSL312 
=  mL 
Not applicable 
Not applicable 
Recommended duration of 
administration 
~ 1 mL / min 
Maximum 
fixed rate of 
approximately 
1 mL / min d 
~ 1 mL / min 
Maximum 
fixed rate of 
approximately 
1 mL / min d 
Abbreviations: min = minute 
a Another anatomic location may be used, at the discretion of the investigator. 
b  In order to maintain the blind, 
 mg and 
 mg CSL312 will be volume normalized to a total administration 
volume that is equivalent to a dose of 
 mg CSL312. 
c  In order to maintain the blind, 
 mg and 
 mg CSL312 will be volume normalized to a total administration 
volume that is equivalent to a dose of 
 mg CSL312. 
d  The rate of administration may be adapted to the comfort level of the subject. 
Additional information related to the dose and dosing regimen of investigational product is 
presented in Section 3.2.  
Additional information related to modification of the dose of investigational product is 
presented in Section 5.5. 
Additional information related to the volume normalization of investigational product in 
Treatment Period 1 is presented in Section 6.1.3.1. 
Detailed investigational product preparation and administration instructions will be provided 
in the Investigational Medicinal Product Manual.  
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6.3 Treatment Compliance 
For investigational product that is administered in Treatment Period 1, treatment compliance 
will be assessed using the administration details entered into the eCRF. For investigational 
product that is administered in Treatment Period 2, compliance will be assessed using the 
administration details entered into the eDiary. 
7 Contraindications, Permitted Therapies and Prohibited Therapies 
7.1 Contraindications and Precautions to Further Dosing 
The following are considered contraindications for further administration of the 
investigational product for an individual subject: 
• Anaphylaxis or severe and clinically significant allergic reaction that is causally related to 
the investigational product active substance or excipients. 
• Α diagnosis of a TEE (other than superficial thrombophlebitis and catheter-related 
thromboses), irrespective of causal relationship to the investigational product. 
• A clinically significant, abnormal bleeding event, irrespective of causal relationship to the 
investigational product. 
• The subject has been administered a prohibited therapy or has a prohibited change in 
concomitant therapy, at the discretion of the investigator in consultation with CSL. 
• Any event that is considered by the investigator and / or CSL to be serious and clinically 
significant, and that would suggest significant hazard to the subject following further 
administration of the investigational product. 
7.2 Permitted Therapies 
The following medications and therapies are PERMITTED at any time during the study: 
• Prescribed medication(s) required for the management of acute or chronic medical 
conditions, except those described in Section 7.3. 
• Therapies to treat any AEs the subject experiences during the study, including non-
prophylactic aspirin (eg, to treat a headache). 
For C1-INH HAE subjects, estrogen-containing medications with systemic absorption (such 
as oral contraceptives or hormonal replacement therapy) are PERMITTED if taken at a stable 
dose during the 3 months before Screening with no plans to change the dose during the study. 


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For FXII/PLG HAE subjects, estrogen-containing medications with systemic absorption 
(such as oral contraceptives or hormonal replacement therapy) are PERMITTED without 
restriction.  
The following on-demand HAE therapy is PERMITTED at any time during the study for the 
treatment of HAE attacks if that medication has previously been shown to be effective and if 
it used according to the product label or with deviations from the label as directed by a health 
care provider: 
• Plasma-derived or recombinant C1-INH (eg, Berinert, Cinryze, Ruconest). 
• Firazyr (icatibant). 
• Kalbitor (ecallantide). 
The use of medications (eg, IV C1-INH) for the pre-procedure prevention of HAE attacks is 
PERMITTED at any time during the study (not to exceed 1 dose prior to each procedure). 
The use of androgens is PERMITTED during the 3 months before the first day of the Run-in 
Period, but it is preferred that androgens are used only if at a stable dose OR if medically 
indicated for emergent medical conditions during this time. 
Routine (long-term) prophylaxis to prevent HAE attacks, including the use of C1-INH 
products, androgens, or antifibrinolytics is PERMITTED during the Follow-up Period.  
7.3 Prohibited Therapies 
Routine (long-term) prophylaxis to prevent HAE attacks with the use of C1-INH products or 
antifibrinolytics is PROHIBITED during the Run-in Period and at any time during Treatment 
Period 1 and/or Treatment Period 2. 
The use of androgens (eg, stanozolol, danazol, oxandrolone, methyltestosterone, testosterone) 
is PROHIBITED during the Run-in Period and at any time during Treatment Period 1 and/or 
Treatment Period 2. 
The following medications / therapies are PROHIBITED during the 3 months before 
Screening and at any time during the study: 
• Angiotensin-converting enzyme (ACE) inhibitors. 
• Any anticoagulant or antiplatelet therapy, including low-dose aspirin therapy taken 
prophylactically. 


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The use of any investigational drug or device is PROHIBITED during the study and during 
the 30 days before Screening or within 5 half-lives of the final dose of the investigational 
product administered during the previous interventional study, whichever is longer. 
The use of any therapeutic antibody other than CSL312 is PROHIBITED at any time during 
the study. 
7.4 Lifestyle Restrictions  
Subjects receiving investigational product will be provided with a wallet card specifying that 
their treatment may result in a prolonged 
 test result and that if assessment of 
 is 
required as a part of medical treatment then the subject’s investigator should be contacted. 
Subjects are expected to carry this wallet card during participation in the study. 
Female subjects of childbearing potential and all male subjects must use highly-effective 
methods of contraception from the first dose of investigational product and at any time during 
Treatment Period 1 or Treatment Period 2 and during the Follow-up Period. 
Childbearing potential is assumed in all female subjects except: 
• Female subjects aged > 45 years with amenorrhea for ≥ 12 months without an alternative 
medical cause. 
• Female subjects who are surgically sterile for at least 3 months before providing informed 
consent. 
Acceptable, highly-effective 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. 
• Hormonal methods that are associated with inhibition of ovulation if used at a stable dose 
during the 3 months before Screening with no plans to change dose during the study; 
acceptable hormonal methods include: oral contraceptives, contraceptive medication 
patch, contraceptive medication injection, estrogen / progestin vaginal ring, or 
contraceptive medication implant. 
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• 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 infusion or ingestion of any dose (single or cumulative) of a 
product that is considered excessive. The effects of any potential overdose with CSL312 have 
not been studied. In case of overdose, the subject should be closely monitored, and 
supportive treatment should be administered, as needed. 
See Section 9.6.5 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 Run-in Period [All Subjects] 
• Schedule of Assessments: Treatment Period 1 [C1-INH HAE and FXII/PLG HAE 
Subjects Receiving Investigational Product Every 4 Weeks] 
• Schedule of Assessments: Treatment Period 1 [C1-INH HAE Subjects Receiving 
Investigational Product Every 2 Weeks] 
• Schedule of Assessments: Treatment Period 2 [All Subjects] 
More frequent evaluations may be performed, if clinically indicated, at the discretion of the 
investigator.  
8.1.1 
Demographics and Safety Assessments 
The clinical procedures to be conducted during this study related to the evaluation of 
population demographics and safety are provided in Table 6. All assessments are to be 
performed at time points as detailed in the schedules of assessments. 
 


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Table 6 
Study Procedures: Demographics and Safety Assessments 
Assessment 
Description 
Demographics 
• Year of birth / age 
• Sex 
• Race and ethnicity 
Medical history 
• Relevant medical history, including HAE attack frequency and HAE diagnosis 
(C1-INH HAE or FXII/PLG HAE) 
• Contraception method 
• Prior (within 6 before Screening) / concomitant medications and therapies 
Pregnancy test 
• Serum a or urine test for Choriogonadotropin Beta (beta-human chorionic 
gonadotropin), for women of childbearing potential. A serum pregnancy test will be 
performed by the site if the result from urine testing is inconclusive. 
Physical 
examination 
• As per the investigator’s standard procedure, including assessment of unilateral pain 
and / or swelling of the lower extremities for the purpose of screening for deep vein 
thrombosis 
Adverse events 
• Refer to Section 9. 
Vital signs 
• Blood pressure (systolic and diastolic) 
• Respiratory rate 
• Pulse rate 
• Temperature 
• Height and body weight 
Urinalysis a 
• Bilirubin 
• Occult blood 
• Erythrocytes  
• Glucose 
• Ketones 
• Leukocyte esterase  
• Nitrite 
• pH 
• Protein 
• Specific gravity 
• Urobilinogen 
 
Hematology a 
• Hemoglobin 
• Hematocrit 
• Erythrocytes (red blood cell count) 
• Mean corpuscular volume 
• Mean corpuscular hemoglobin 
• Mean corpuscular hemoglobin concentration 
• Leukocytes (white blood cell count) 
• Neutrophils, % and absolute 
• Lymphocytes, % and absolute 
• Monocytes, % and absolute 
• Eosinophils, % and absolute 
• Basophils, % and absolute 
• Platelet count 
 
Biochemistry a 
• Sodium 
• Potassium 
• Chloride 
• Carbon dioxide 
• Albumin 
• Alkaline phosphatase (ALP) 
• Direct Bilirubin 
• Bilirubin, total 
• Aspartate aminotransferase (AST) 
• Protein – total 
• Calcium 
• Alanine aminotransferase (ALT) 
• Creatinine 
• Phosphate 
• Blood urea nitrogen (BUN) 
• Glucose 
 
 
Coagulation a 
• 
 
• 
 
• 
 
• 
 
• 
 
Viral serology a 
• A blood sample will be retained for potential assessment of viral serology 
Immunogenicity a • Binding antibodies (inhibitory and non-inhibitory) specific to FXIIa antagonist 
monoclonal antibody. 
Abbreviations: 
; C1-INH HAE = Hereditary angioedema with C1-esterase 
inhibitor deficiency; FXIIa = activated factor XII; FXII/PLG HAE = Hereditary angioedema with normal C1-esterase 
inhibitor and factor XII or plasminogen gene mutation; HAE = hereditary angioedema. 
Footnotes: 
a Analysis will be conducted at a central laboratory. Additional details are provided in the Laboratory Manual. 
b 
 will be measured as a part of the coagulation panel for assessment of safety, but will also be analyzed 
as 
 (Table 7). 
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Laboratory Parameters 
Details related to the collection, preparation, and transfer of blood and urine samples for 
laboratory assessments will be provided in the Laboratory Manual. 
Refer to Section 9.6.4 for assessment of abnormal laboratory values. Tests resulting in 
abnormal laboratory values during the study period that have been classified by the 
investigator as clinically significant should be repeated as soon as possible after receiving the 
laboratory report to rule out laboratory error. 
Vital Signs 
Blood pressure and heart rate will be measured with the subject in a supine or seated position 
after resting for at least 5 minutes. Body temperature will be measured either sublingually or 
tympanically, and the method of measurement should be consistent throughout the study for a 
given subject. 
8.1.2 
Pharmacokinetic and 
 Assessments 
Pharmacokinetic and 
 analytes to be assessed during the study are provided in Table 7. 
Details related to the collection, preparation and transfer of PK / 
 samples will be provided 
in the laboratory manual. 
Table 7 
Pharmacokinetic and 
 Analytes 
Assessment 
Description 
Pharmacokinetic evaluations 
• CSL312 concentration 
 evaluations 
• 
 
• 
 
• 
 
• 
 
• 
 
• 
 
Abbreviations: 
; 
; 
; 
; 
; 
. 
Note: 
 will be measured as a part of the coagulation panel (Table 6) for assessment of safety, 
but will also be analyzed as 
. 
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8.1.3 
Efficacy Assessments 
At each subject visit, investigators will assess and document the occurrence of HAE attacks 
based on subject eDiary data. The following information will be documented in the subject 
eDiary: 
• Date and time of HAE symptom onset. 
• Date and time of HAE symptom resolution. 
• Location of HAE symptom(s). 
• Interference of symptom(s) with the subject’s daily activities (yes / no). 
• On-demand medication used to treat HAE symptoms (yes / no). 
• Assistance by a healthcare professional during HAE symptoms (yes / no). 
• If medication was needed to treat HAE symptoms: 
o On-demand HAE medication used (Berinert or other on-demand HAE medication 
[Kalbitor (ecallintide), Firazyr (icatibant), C1-INH other than Berinert, or other]). 
o Dose administered. 
o Date and time started. 
8.1.4 
Other Assessments  
8.1.4.1 
 
 
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8.1.4.2 
 
8.1.4.3 
  
 
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8.1.4.4 
 
 
8.2 Blood Samples 
During the study, blood will be taken from each subject for laboratory safety assessments and 
PK / 
 evaluations. Detailed information on the volume of blood to be sampled for each 
assessment will be available in the laboratory manual. 
Repeat or unscheduled blood samples may be taken for safety reasons or for technical issues 
with the samples. 
Refer to the Laboratory Manual for details about the collection, storage, handling and 
processing of blood samples. 
8.3 Retention of Samples 
Refer to the Laboratory Manual for further details about the collection, storage, and 
destruction of retention samples. 
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Retention Sample for Viral Serology 
Blood samples for potential future assessment of viral serology will be obtained during 
Treatment Period 1 and Treatment Period 2. These samples will be shipped to CSL and stored 
at -70°C for potential testing of viral markers, and will be destroyed within 5 years after 
completion of the study.  
Retention Samples for Non-genetic Testing Related to HAE 
Informed consent / assent (as appropriate), independent to that for participating in the study, 
will be requested from subjects to allow left-over samples of their blood to be retained for up 
to 5 years after the end of the study for future, non-genetic research related to HAE. This 
consent / assent will not be valid for future research that involves genetic analysis of the 
retained samples or research that is unrelated to HAE. 
8.4 Prior and Concomitant Medications and Therapies 
Both pharmacological (eg, prescription and over-the-counter medications, and herbal and 
vitamin supplements) and nonpharmacological (eg, any surgical or diagnostic procedures) 
will be reported. 
All medications and therapies that have been administered to a subject within 6 months 
before signing informed consent are regarded as prior medications and therapies, and must be 
documented as such in the eCRF. 
All medications and therapies being administered to a subject at the time of the first 
administration of the investigational product, and which continue to be taken in addition to 
the investigational product during the study, are regarded as concomitant medications and 
therapies, and must be documented as such in the eCRF.  
8.5 Visit Schedule 
8.5.1 
Screening / Run-in Period Visits 
8.5.1.1 
Screening 
All subjects must provide written informed consent before any study-specific assessments or 
procedures are performed. Written informed consent is not required for assessments or 
procedures performed according to standard of care (eg, for diagnosis or treatment), and 
results from such assessments may be used in the determination of study eligibility. 


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The following procedures will be conducted at Screening: 
• Written informed consent. 
• Demographics. 
• Medical history (including HAE attack frequency and HAE diagnosis). 
• Physical examination. 
• Vital signs, including height and body weight. 
• Collection of urine for urinalysis. 
• Collection of urine or blood for pregnancy test (for women of childbearing potential). A 
serum pregnancy test will be performed by the site if urine result is inconclusive. 
• Collection of blood to assess: 
o Hematology. 
o Biochemistry. 
o Coagulation. 
o 
.  
Note: If a subject requires the use of on-demand medication to treat an HAE attack 
within 120 hours (ie, 5 days) before Screening, then that subject may return to 
the study site within the first 2 weeks of the Run-in Period for a second blood 
draw 
 (
 
). 
• Confirm FXII or PLG mutation, based on the subject’s medical record.  
• Development of an individual acute action plan, including assessment of subject’s ability 
to manage HAE attacks and confirmation of subject’s access to on-demand HAE 
medication to treat HAE attacks. 
• Train subject on the use of the eDiary.  
• Prior and concomitant medications and therapies. 
• Begin to monitor AEs. 
• Inclusion / exclusion criteria. 
Screen Failure: If a subject is not eligible for entry into the Run-in Period, the primary 
reason for screen failure must be documented. 
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Re-screening: If a potential subject is not eligible for entry into the Run-in Period within 
28 days after providing informed consent, then the subjects may re-consent and may be 
screened again (for a maximum of 2 Screening Periods per subject). In the event that a 
potential subject is screened twice, all Screening assessments must be repeated during the 
second Screening Period, except for confirmation of FXII or PLG gene mutation in subjects 
with FXII/PLG HAE. 
8.5.1.2 
Run-in Period 
8.5.1.2.1 Week 1 Telephone Contact  
The first day of the Run-in Period and Screening may occur on the same day. If the Run-in 
Period begins after Screening, then the first day of the Run-in Period begins with a telephone 
contact. 
The following procedures will be conducted: 
• Open subject access to eDiary and review instructions with subject. 
• Confirm access to on-demand HAE medication. 
• Prior and Concomitant medications and therapies. 
• Adverse events. 
8.5.1.2.2 
Week 3, Week 5, Week 7, and Week 9 Telephone Contacts 
The following procedures will be conducted at the Week 3, Week 5, Week 7, and Week 9 
Run-in Period Telephone Contacts for all subjects: 
• Review eDiary data and assess / document HAE attacks. 
• Confirm access to on-demand HAE medication. 
• Concomitant medications and therapies 
• Adverse Events. 
Note 1: Subjects should enter Treatment Period 1 no later than 14 days after the Week 9 
Telephone Contact. If a subject is unable to enter Treatment Period 1 within the 14 days after 
the Week 9 Telephone Contact, then CSL approval is required for the subject to enter into 
Treatment Period 1. 
Note 2: Access to the eDiary should be closed within 14 days after the Week 9 Telephone 
Contact for subjects who will not participate in Treatment Period 1. 


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Note 3: Subjects who enter the Run-in Period, but are not eligible to enter Treatment Period 1 
are considered screen failures. If a subject is not eligible to enter Treatment Period 1, the 
primary reason for screen failure must be documented. These subjects may not be re-
screened. 
8.5.2 
Treatment Period 1 for C1-INH HAE and FXII/PLG HAE Subjects 
Receiving Investigational Product Every 4 Weeks 
All subjects should remain at the study site for at least 30 minutes after the administration of 
investigational product when administered at the study site. 
8.5.2.1 
Week 1 (Day 1) Visit 
The following procedures will be conducted at the Week 1 (Day 1) Visit: 
• Confirm eligibility for entry into Treatment Period 1. 
• Assignment to treatment with the investigational product. 
• Physical examination.  
• Vital signs, including weight. 
• 
 
• 
 
• Collection of urine for urinalysis. 
• Collection of urine or blood for pregnancy test (for women of childbearing potential). A 
serum pregnancy test will be performed by the site if urine result is inconclusive.  
• Collection of blood to assess: 
o Hematology. 
o Biochemistry. 
o Coagulation. 
o Viral serology (retention sample). 
o PK / 
 (pre-dose and 0.5, 4.0, and 8.0 hours post-dose). 
o Immunogenicity. 
• Review eDiary instructions with subject. 
• Review eDiary data, including investigator assessment of HAE symptoms and 
documentation of HAE attacks.  
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• Confirm access to on-demand HAE medication. 
• Intravenous administration of investigational product by investigator or delegate. 
• Accountability of investigational product. 
• Concomitant medications and therapies. 
• Adverse events. 
Note 1: The physical examinations, vital signs, weight measurement, and collection of blood 
and urine for laboratory assessments must occur before administration of the investigational 
product. 
Note 2: The PK / 
 blood draws at 4.0 hours (± 60 minutes) post-dose and 8.0 hours 
(± 120 minutes) post-dose at the Week 1 (Day 1) Visit should occur ≥ 120 minutes apart. 
8.5.2.2 
Week 1 (Day 6) Visit 
The following procedures will be conducted at the Week 1 (Day 6) Visit: 
• Physical examination.  
• Vital signs, including weight.  
• Collection of blood to assess PK / 
 
• Review eDiary data, including investigator assessment of HAE symptoms and 
documentation of HAE attacks.  
• Confirm access to on-demand HAE medication. 
• Supervise subject self-administration of investigational product (SC). 
• Accountability of investigational product. 
• Concomitant medications and therapies. 
• Adverse events. 
Note: The physical examinations, vital signs, weight measurement, and collection of blood 
and urine for laboratory assessments must occur before administration of the investigational 
product. 
8.5.2.3 
Week 5 (Day 35) Visit 
The following procedures will be conducted at the Week 5 (Day 35) Visit: 
• Physical examination.  
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• Vital signs, including weight.  
• Collection of urine for urinalysis. 
• Collection of urine or blood for pregnancy test (for women of childbearing potential). A 
serum pregnancy test will be performed by the site if urine result is inconclusive. 
• Collection of blood to assess: 
o Hematology. 
o Biochemistry. 
o Coagulation. 
o PK / 
 
• Review eDiary data, including investigator assessment of HAE symptoms and 
documentation of HAE attacks.  
• Confirm access to on-demand HAE medication. 
• Supervise subject self-administration of investigational product (SC). 
• Accountability of investigational product. 
• Concomitant medications and therapies. 
• Adverse events. 
Note: The physical examinations, vital signs, weight measurement, and collection of blood 
and urine for laboratory assessments must occur before administration of the investigational 
product. 
8.5.2.4 
Week 9 (Day 63) Visit 
The following procedures will be conducted at the Week 9 (Day 63) Visit: 
• Physical examination.  
• Vital signs, including weight.  
• Collection of urine for urinalysis. 
• Collection of urine or blood for pregnancy test (for women of childbearing potential). A 
serum pregnancy test will be performed by the site if urine result is inconclusive. 
• Collection of blood to assess: 
o Hematology. 
o Biochemistry. 
o Coagulation. 
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o PK / 
 
Note: The Week 9 (Day 63) and Week 9 (Day 66) Visits and corresponding PK / 
 
blood draws should each occur at least 24 hours apart. 
• Review eDiary data, including investigator assessment of HAE symptoms and 
documentation of HAE attacks.  
• Confirm access to on-demand HAE medication. 
• Supervise subject self-administration of investigational product (SC). 
Note: For subjects who do not participate in Treatment Period 2, this is the final dose of 
investigational product. 
• Accountability of investigational product. 
• Concomitant medications and therapies. 
• Adverse events. 
Note: The physical examinations, vital signs, weight measurement, and collection of blood 
and urine for laboratory assessments must occur before administration of the investigational 
product. 
8.5.2.5 
Week 9 (Day 66) Visit 
The following procedures will be conducted at the Week 9 (Day 66) Visit: 
• Collection of blood to assess PK / 
 
Note: The Week 9 (Day 63) and Week 9 (Day 66) Visits and corresponding PK / 
 
blood draws should each occur at least 24 hours apart. The Week 9 (Day 66) and 
Week 10 (Day 70) Visits and corresponding PK / 
 blood draws should each 
occur at least 72 hours apart. 
• Concomitant medications and therapies. 
• Adverse events. 
8.5.2.6 
Week 10 (Day 70) Visit 
The following procedures will be conducted at the Week 10 (Day 70) Visit: 
• Collection of blood to assess PK / 
 
Note: The Week 9 (Day 66) and Week 10 (Day 70) Visits and corresponding PK / 
 
blood draws should each occur at least 72 hours apart. 
• Concomitant medications and therapies. 
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• Adverse events. 
8.5.2.7 
Week 11 (Day 77) Visit 
The following procedures will be conducted at the Week 11 (Day 77) Visit: 
• Collection of blood to assess PK / 
 
• Concomitant medications and therapies. 
• Adverse events. 
8.5.2.8 
Week 12 (Day 84) Visit 
The following procedures will be conducted at the Week 12 (Day 84) Visit: 
• Collection of blood to assess PK / 
 
• Concomitant medications and therapies. 
• Adverse events. 
8.5.2.9 
Week 13 (Day 91) Visit 
The following procedures will be conducted at the Week 13 (Day 91) Visit: 
• Physical examination. 
• Vital signs, including weight. 
• 
 
• 
 
• 
 
• 
 
• Collection of urine for urinalysis.  
• Collection of urine or blood for pregnancy test (for women of childbearing potential). A 
serum pregnancy test will be performed by the site if urine result is inconclusive. 
• Collection of blood to assess: 
o Hematology. 
o Biochemistry. 
o Coagulation. 
o Retention Sample for viral serology. 
o PK / 
 
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o Immunogenicity. 
• Review eDiary data, including investigator assessment of HAE symptoms and 
documentation of HAE attacks.  
• Concomitant medications and therapies. 
• Adverse events. 
Note: For subjects who are taking part in Treatment Period 2, the Week 13 (Day 91) Visit is 
the first study visit in Treatment Period 2; refer to the Schedule of Events: Treatment Period 2 
[All Subjects] and Section 8.5.4. If a subject is discontinued from the study before 
completing Treatment Period 1, the subject will undergo the assessments scheduled for the 
Week 13 (Day 91) Visit and then attend the Treatment Period 1 Follow-up Visit ~14 weeks 
later. 
8.5.2.10 Treatment Period 1 Follow-up Visit  
Subjects who do not participate in Treatment Period 2 will attend a Follow-up Visit at 
Week 26 (Day 186 ± 3 days). 
The following procedures will be conducted at the Week 26 (Day 186) Treatment Period 1 
Follow-up Visit: 
• Collection of blood to assess PK / 
  
• Review eDiary data, including investigator assessment of HAE symptoms and 
documentation of HAE attacks. 
• Concomitant medications and therapies. 
• Adverse events. 
• Close eDiary access (for subjects who will not participate in Treatment Period 2). 
Note 1: If a subject participates in Treatment Period 2, then the subject will not attend the 
Treatment Period 1 Follow-up Visit.  
Note 2: The Treatment Period 1 Follow-up Visit may be waived in place of a telephone 
contact. If Treatment Period 1 Follow-up is not conducted as a visit, then the blood draw for 
assessment of PK / 
 is not required. 
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8.5.3 
Treatment Period 1 for C1-INH HAE Subjects Receiving 
Investigational Product Every 2 Weeks 
All subjects should remain at the study site for at least 30 minutes after the administration of 
investigational product when administered at the study site. 
8.5.3.1 
Week 1 (Day 1) Visit 
The following procedures will be conducted at the Week 1 (Day 1) Visit: 
• Confirm eligibility for entry into Treatment Period 1. 
• Assignment to treatment with the investigational product. 
• Physical examination. 
• Vital signs, including weight. 
• 
 
• 
 
• Collection of urine for urinalysis. 
• Collection of urine or blood for pregnancy test (for women of childbearing potential). A 
serum pregnancy test will be performed by the site if urine result is inconclusive. 
• Collection of blood to assess: 
o Hematology. 
o Biochemistry. 
o Coagulation. 
o Viral serology (retention sample). 
o PK / 
 
o Immunogenicity. 
• Review eDiary instructions with subject. 
• Review eDiary data, including investigator assessment of HAE symptoms and 
documentation of HAE attacks. 
• Confirm access to on-demand HAE medication. 
• Supervise subject self-administration of investigational product (SC). 
• Accountability of investigational product. 
• Concomitant medications and therapies. 
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• Adverse events. 
Note: The physical examinations, vital signs, weight measurement, and collection of blood 
and urine for laboratory assessments must occur before administration of the investigational 
product. 
8.5.3.2 
Week 3 (Day 15) Visit 
The following procedures will be conducted at the Week 3 (Day 15) Visit: 
• Collection of blood for PK / 
 analysis 
• Review eDiary data, including investigator assessment of HAE symptoms and 
documentation of HAE attacks.  
• Confirm access to on-demand HAE medication. 
• Supervise subject self-administration of investigational product (SC). 
• Accountability of investigational product. 
• Concomitant medications and therapies. 
• Adverse events. 
Note: The physical examinations, vital signs, weight measurement, and collection of blood 
and urine for laboratory assessments must occur before administration of the investigational 
product. 
8.5.3.3 
Week 5 (Day 29) Visit 
The following procedures will be conducted at the Week 5 (Day 29) Visit: 
• Physical examination.  
• Vital signs, including weight.  
• Collection of urine for urinalysis. 
• Collection of urine or blood for pregnancy test (for women of childbearing potential). A 
serum pregnancy test will be performed by the site if urine result is inconclusive. 
• Collection of blood to assess: 
o Hematology. 
o Biochemistry. 
o Coagulation. 
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o PK / 
 
• Review eDiary data, including investigator assessment of HAE symptoms and 
documentation of HAE attacks Confirm access to on-demand HAE medication. 
• Confirm access to on-demand HAE medication. 
• Supervise subject self-administration of investigational product (SC). 
• Accountability of investigational product. 
• Concomitant medications and therapies. 
• Adverse events. 
Note: The physical examinations, vital signs, weight measurement, and collection of blood 
and urine for laboratory assessments must occur before administration of the investigational 
product. 
8.5.3.4 
Week 7 (Day 43) Visit 
The following procedures will be conducted at the Week 7 (Day 43) Visit: 
• Collection of blood for PK / 
 analysis. 
• Review eDiary data, including investigator assessment of HAE symptoms and 
documentation of HAE attacks.  
• Confirm access to on-demand HAE medication. 
• Supervise subject self-administration of investigational product (SC). 
• Accountability of investigational product. 
• Concomitant medications and therapies. 
• Adverse events. 
Note: The physical examinations, vital signs, weight measurement, and collection of blood 
and urine for laboratory assessments must occur before administration of the investigational 
product. 
8.5.3.5 
Week 9 (Day 57) Visit 
The following procedures will be conducted at the Week 9 (Day 57) Visit: 
• Physical examination.  
• Vital signs, including weight.  
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• Collection of urine for urinalysis.  
• Collection of urine or blood for pregnancy test (for women of childbearing potential). A 
serum pregnancy test will be performed by the site if urine result is inconclusive. 
• Collection of blood to assess: 
o Hematology. 
o Biochemistry. 
o Coagulation. 
o PK / 
 
• Review eDiary data, including investigator assessment of HAE symptoms and 
documentation of HAE attacks Confirm access to on-demand HAE medication. 
• Confirm access to on-demand HAE medication. 
• Supervise subject self-administration of investigational product (SC). 
• Accountability of investigational product. 
• Concomitant medications and therapies. 
• Adverse events. 
Note: The physical examinations, vital signs, weight measurement, and collection of blood 
and urine for laboratory assessments must occur before administration of the investigational 
product. 
8.5.3.6 
Week 10 (Day 64) Visit (Optional) 
The following procedures will be conducted at the Week 10 (Day 64) Visit: 
• Collection of blood for PK / 
 analysis. 
• Concomitant medications and therapies. 
• Adverse events. 
Note: The Week 10 (Day 64) Visit is optional, and blood for PK / 
 analysis may be 
collected off site. 
8.5.3.7 
Week 11 (Day 71) Visit  
The following procedures will be conducted at the Week 11 (Day 71) Visit: 
• Collection of blood for PK / 
 analysis. 
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• Review eDiary data, including investigator assessment of HAE symptoms and 
documentation of HAE attacks. 
• Confirm access to on-demand HAE medication. 
• Supervise subject self-administration of investigational product (SC). 
Note: For subjects who do not participate in Treatment Period 2, this is the final dose of 
investigational product. 
• Accountability of investigational product. 
• Concomitant medications and therapies. 
• Adverse events. 
Note: For subjects who do not participate in Treatment Period 2, this is the final dose of 
investigational product. 
8.5.3.8 
Week 12 (Day 77) Visit  
The following procedures will be conducted at the Week 12 (Day 77) Visit: 
• Collection of blood for PK / 
 analysis. 
• Concomitant medications and therapies. 
• Adverse events. 
Note: Blood for PK / 
 analysis may be collected off-site. If blood is collected off-site, then 
a study visit is not required. 
8.5.3.9 
Week 13 (Day 85) Visit 
The following procedures will be conducted at the Week 13 (Day 85) Visit: 
• Physical examination.  
• Vital signs, including weight.  
• 
 
• 
 
• 
 
• 
 
• Collection of urine for urinalysis.  
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• Collection of urine or blood for pregnancy test (for women of childbearing potential). A 
serum pregnancy test will be performed by the site if urine result is inconclusive. 
• Collection of blood to assess: 
o Hematology. 
o Biochemistry. 
o Coagulation. 
o Viral serology (retention sample). 
o PK / 
 
o Immunogenicity. 
• Review eDiary data, including investigator assessment of HAE symptoms and 
documentation of HAE attacks.  
• Confirm access to on-demand HAE medication. 
• Concomitant medications and therapies. 
• Adverse events. 
Note: For subjects who are taking part in Treatment Period 2, the Week 13 (Day 85) Visit is 
the first study visit in Treatment Period 2; refer to the Schedule of Events: Treatment Period 2 
[All Subjects] and Section 8.5.4. If a subject is discontinued from the study before 
completing Treatment Period 1, the subject will undergo the assessments scheduled for the 
Week 13 (Day 85) Visit and then attend the Treatment Period 1 Follow-up Visit ~14 weeks 
later. 
8.5.3.10 Treatment Period 1 Follow-up Visit  
Subjects who do not participate in Treatment Period 2 will attend a Follow-up Visit at 
Week 25 (Day 180 ± 3 days). 
The following procedures will be conducted at the Week 25 (Day 180) Treatment Period 1 
Follow-up Visit: 
• Collection of blood to assess PK / 
  
• Review eDiary data, including investigator assessment of HAE symptoms and 
documentation of HAE attacks. 
• Concomitant medications and therapies. 
• Adverse events. 
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• Close eDiary access (for subjects who will not participate in Treatment Period 2). 
Note 1: If a subject participates in Treatment Period 2, then the subject will not attend the 
Treatment Period 1 Follow-up Visit.  
Note 2: The Treatment Period 1 Follow-up Visit may be waived in place of a telephone 
contact. If Treatment Period 1 Follow-up is not conducted as a visit, then the blood draw for 
assessment of PK / 
 is not required. 
8.5.4 
Treatment Period 2 
All subjects should remain at the study site for at least 30 minutes after the administration of 
investigational product when administered at study visits. 
8.5.4.1 
Week 13 (Day 85 / 91) Visit 
For subjects who are participating in Treatment Period 2, the following procedures will be 
conducted at the Week 13 (Day 85 / 91) Visit: 
• Assignment to treatment with CSL312. 
• Physical examination. 
• Vital signs, including weight. 
• 
 
• 
 
• 
 
• 
 
• Collection of urine for urinalysis 
• Collection of urine or blood for pregnancy test (for women of childbearing potential). A 
serum pregnancy test will be performed by the site if urine result is inconclusive. 
• Collection of blood to assess: 
o Hematology. 
o Biochemistry. 
o Coagulation. 
o Viral serology (retention sample). 
o PK / 
 
o Immunogenicity. 
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• Review eDiary data, including investigator assessment of HAE symptoms and 
documentation of HAE attacks. 
• Confirm access to on-demand HAE medication. 
• Supervise subject self-administration CSL312 (SC). 
• Dispense CSL312. 
• Accountability of CSL312. 
• Concomitant medications and therapies. 
• Adverse events. 
Note: The physical examinations, vital signs, weight measurement, and collection of blood 
and urine for laboratory assessments must occur before administration of the investigational 
product. 
8.5.4.2 
Week 17 (Day 119) Visit 
The following procedures will be conducted at the Week 17 (Day 119) Visit: 
• Physical examination. 
• Vital signs, including weight. 
• Collection of urine for urinalysis. 
• Collection of urine or blood for pregnancy test (for women of childbearing potential). A 
serum pregnancy test will be performed by the site if urine result is inconclusive. 
• Collection of blood to assess: 
o Hematology. 
o Biochemistry. 
o Coagulation. 
o PK / 
 
• Review eDiary data, including investigator assessment of HAE symptoms and 
documentation of HAE attacks. 
• Confirm access to on-demand HAE medication. 
• Supervise subject self-administration CSL312 (SC). 
• Dispense CSL312. 
• Accountability of CSL312. 
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• Concomitant medications and therapies. 
• Adverse events. 
Note: The physical examinations, vital signs, weight measurement, and collection of blood 
and urine for laboratory assessments must occur before administration of the investigational 
product. 
8.5.4.3 
Week 21 (Day 147) Visit 
The following procedures will be conducted at the Week 21 (Day 147) Visit: 
• Physical examination. 
• Vital signs, including weight. 
• Collection of urine for urinalysis. 
• Collection of urine or blood for pregnancy test (for women of childbearing potential). A 
serum pregnancy test will be performed by the site if urine result is inconclusive. 
• Collection of blood to assess: 
o Hematology. 
o Biochemistry. 
o Coagulation. 
o PK / 
 
• Review eDiary data, including investigator assessment of HAE symptoms and 
documentation of HAE attacks. 
• Confirm access to on-demand HAE medication. 
• Supervise subject self-administration CSL312 (SC). 
• Dispense CSL312. 
• Accountability of CSL312. 
• Concomitant medications and therapies. 
• Adverse events. 
Note: The physical examinations, vital signs, weight measurement, and collection of blood 
and urine for laboratory assessments must occur before administration of the investigational 
product. 
 
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8.5.4.4 
Week 25 (Day 175) Activity  
The following procedures will be conducted at approximately Week 25 (day 175): 
• The test for beta-human chorionic gonadotropin will be performed for women of 
childbearing potential (only). A serum or urine pregnancy test may be used. A serum 
pregnancy test will be performed by the site if urine result is inconclusive. 
Documentation and tracking of pregnancy testing must be conducted by the site. 
8.5.4.5 
Week 29 (Day 203) Activity 
The following procedures will be conducted at approximately Week 29 (Day 203): 
• The test for beta-human chorionic gonadotropin will be performed for women of 
childbearing potential (only). A serum or urine pregnancy test may be used. A serum 
pregnancy test will be performed by the site if urine result is inconclusive. 
Documentation and tracking of pregnancy testing must be conducted by the site. 
8.5.4.6 
Week 33 (Day 231) Visit 
The following procedures will be conducted at the Week 33 (Day 231) Visit: 
• Physical examination. 
• Vital signs, including weight. 
• Collection of urine for urinalysis. 
• Collection of urine or blood for pregnancy test (for women of childbearing potential). A 
serum pregnancy test will be performed by the site if urine result is inconclusive.  
• Collection of blood to assess: 
o Hematology. 
o Biochemistry. 
o Coagulation. 
o PK / 
 
o Review eDiary data, including investigator assessment of HAE symptoms and 
documentation of HAE attacks. 
• Confirm access to on-demand HAE medication. 
• Dispense CSL312. 
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• Accountability of CSL312. 
• Concomitant medications and therapies. 
• Adverse events. 
Note: The physical examinations, vital signs, weight measurement, and collection of blood 
and urine for laboratory assessments must occur before administration of the investigational 
product. 
8.5.4.7 
Week 37 (Day 259) Activity 
The following procedures will be conducted at approximately Week 37 (Day 259): 
• The test for beta-human chorionic gonadotropin will be performed for women of 
childbearing potential (only). A serum or urine pregnancy test may be used. A serum 
pregnancy test will be performed by the site if urine result is inconclusive. 
Documentation and tracking of pregnancy testing must be conducted by the site. 
8.5.4.8 
Week 41 (Day 287) Activity 
The following procedures will be conducted at approximately Week 41 (Day 287): 
• The test for beta-human chorionic gonadotropin will be performed for women of 
childbearing potential (only). A serum or urine pregnancy test may be used. A serum 
pregnancy test will be performed by the site if urine result is inconclusive. 
Documentation and tracking of pregnancy testing must be conducted by the site. 
8.5.4.9 
Week 45 (Day 315) Visit 
The following procedures will be conducted at the Week 45 (Day 315) Visit: 
• Physical examination. 
• Vital signs, including weight. 
• Collection of urine for urinalysis. 
• Collection of urine or blood for pregnancy test (for women of childbearing potential). A 
serum pregnancy test will be performed by the site if urine result is inconclusive. 
• Collection of blood to assess: 
o Hematology. 
o Biochemistry. 


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o Coagulation. 
o PK / 
. 
• Review eDiary data, including investigator assessment of HAE symptoms and 
documentation of HAE attacks. 
• Confirm access to on-demand HAE medication. 
• Dispense CSL312. 
• Accountability of CSL312. 
• Concomitant medications and therapies. 
• Adverse events. 
Note: The physical examinations, vital signs, weight measurement, and collection of blood 
and urine for laboratory assessments must occur before administration of the investigational 
product. 
8.5.4.10 Week 49 (Day 343) Activity 
The following procedures will be conducted at approximately Week 49 (Day 343): 
• The test for beta-human chorionic gonadotropin will be performed for women of 
childbearing potential (only). A serum or urine pregnancy test may be used. A serum 
pregnancy test will be performed by the site if urine result is inconclusive. 
Documentation and tracking of pregnancy testing must be conducted by the site. 
8.5.4.11 Week 53 (Day 371) Activity 
The following procedures will be conducted at approximately Week 53 (Day 371): 
• The test for beta-human chorionic gonadotropin will be performed for women of 
childbearing potential (only). A serum or urine pregnancy test may be used. A serum 
pregnancy test will be performed by the site if urine result is inconclusive. 
Documentation and tracking of pregnancy testing must be conducted by the site. 
8.5.4.12 Week 57 (Day 399) Visit 
The following procedures will be conducted at the Week 57 (Day 399) Visit: 
• Physical examination. 
• Vital signs, including weight. 
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• 
 
• 
 
• 
 
• 
 
• Collection of urine for urinalysis. 
• Collection of urine or blood for pregnancy test (for women of childbearing potential). A 
serum pregnancy test will be performed by the site if urine result is inconclusive. 
• Collection of blood to assess: 
o Hematology. 
o Biochemistry. 
o Coagulation. 
o Viral serology (retention sample). 
o PK / 
. 
o Immunogenicity. 
• Review eDiary data, including investigator assessment of HAE symptoms and 
documentation of HAE attacks. 
• Confirm access to on-demand HAE medication. 
• Dispense CSL312 (only if Treatment Period 2 is extended). 
• Accountability of CSL312 (only if Treatment Period 2 is extended). 
• Concomitant medications and therapies. 
• Adverse events. 
Note: If a subject is discontinued from the study before completing Treatment Period 2, the 
subject will undergo the assessments scheduled for the Week 57 (Day 399) Visit in Treatment 
Period 2, and will then attend the Treatment Period 2 Follow-up Visit ~14 weeks later.  
8.5.4.13 Treatment Period 2 Follow-up Visit 
The Treatment Period 2 Follow-up Visit will be conducted ~14 weeks after the final visit in 
Treatment Period 2. If Treatment Period 2 is not extended, then Treatment Period 2 Follow-
up will be conducted at the Week 70 (Day 494) Visit. 
The following procedures will be conducted at the Treatment Period 2 Follow-up Visit: 
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• Collection of blood to assess PK / 
.  
• Review eDiary data, including investigator assessment of HAE symptoms and 
documentation of HAE attacks. 
• Concomitant medications and therapies. 
• Adverse events. 
• Close eDiary access. 
Note: The Treatment Period 2 Follow-up Visit may be waived in place of a telephone contact. 
If Treatment Period 2 Follow-up is not conducted as a visit, then the blood draw for 
assessment of PK / 
 is not required.  
8.5.4.14 Extension of Treatment Period 2 
Treatment Period 2 will extend until another CSL312 study is opened for enrollment, or until 
the current study is discontinued. If Treatment Period 2 is extended, procedures from the 
Week 45 (Day 315) Visit will be repeated approximately every 12 weeks starting 12 weeks 
after all listed assessments are completed at the Week 57 (Day 399) Visit. In the instance of 
an extension of Treatment Period 2, investigational product will be dispensed and 
accountability of investigational product will be conducted at the Week 57 (Day 399) Visit. If 
Treatment Period 2 is extended, then all assessments scheduled for the Week 57 (Day 399) 
Visit will be repeated at each subject’s final Treatment Period 2 visit (approximately 4 weeks 
after the last dose of study treatment). The Follow-up Visit will occur ~14 weeks after each 
subject’s final Treatment Period 2 visit. 
8.5.5 
Subject Withdrawal / Discontinuation 
If a subject declines further participation or is withdrawn from the study for any reason, 
attempts will be made to complete and document all scheduled assessments: 
• Any subjects who discontinue or are withdrawn during the Run-in Period should 
complete assessments scheduled for the Week 9 Telephone Contact of the Run-in Period.  
• C1-INH HAE subjects who received placebo, 
 mg, 
 mg, or 
 mg CSL312 q4wk 
during Treatment Period 1, and who discontinue or are withdrawn during Treatment 
Period 1 should complete assessments for the Week 13 (Day 91) Visit of Treatment 
Period 1, and then attend a Treatment Period 1 Follow-up Visit ~14 weeks later. 
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• FXII/PLG HAE subjects who discontinue or are withdrawn during Treatment Period 1 
should complete assessments for the Week 13 (Day 91) Visit of Treatment Period 1, and 
then attend a Treatment Period 1 Follow-up Visit ~14 weeks later. 
• C1-INH HAE subjects who received 
 mg CSL312 q2wk during Treatment Period 1, 
and who discontinue or are withdrawn during Treatment Period 1 should complete 
assessments for the Week 13 (Day 85) Visit of Treatment Period 1, and then attend a 
Treatment Period 1 Follow-up Visit ~14 weeks later. 
• Any subjects who discontinue or are withdrawn during Treatment Period 2 should 
complete assessments for the Week 57 (Day 399) Visit of Treatment Period 2, and then 
attend a Treatment Period 2 Follow-up Visit ~14 weeks later. 
9 Adverse Events 
9.1 Definitions 
9.1.1 
Adverse Event 
As per the ICH guidelines, an AE is any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have a causal relationship with this treatment. An AE can, therefore, be any unfavorable and 
unintended sign (including an abnormal, clinically significant laboratory finding), symptom, 
or disease temporally associated with the use of a medicinal (investigational) product, 
whether or not considered related to the medicinal (investigational) product.  
The period of observation for AEs extends from the time the subject gives informed consent 
until the end of study (see Section 9.4 for further details). 
 Adverse events may include: 
• Exacerbation (ie, an increase in the frequency or severity) of a pre-existing condition. 
Illness present before study entry should be recorded in the medical history section of the 
eCRF and only be reported as an AE if there is an increase in the frequency or severity of 
the condition during the study.  
• A clinical event occurring after consent but before investigational product administration. 
• Intercurrent illnesses with an onset after administration of investigational product. 
Adverse events do not include: 
• Events identified at Screening that meet exclusion criteria. 
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• Medical or surgical procedures (the condition that leads to the procedure is the AE). 
• Situations where an untoward medical occurrence has not taken place.  
• 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). 
• Overdose of investigational product or any concomitant therapy that does not result in 
any adverse signs or symptoms.  
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 CSL312.  
The following events will be considered AEs of special interest: 
• Disorders of coagulation: 
o 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 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. 
o Bleeding events.  
▪ All bleeding events that are abnormal in the opinion of the investigator are 
considered SAEs and should be reported as such. Additionally, any bleeding event 
not considered abnormal that meets the criteria for an SAE must be reported as an 
SAE. 
• Anaphylaxis.  
o All events of anaphylaxis are considered SAEs and should be reported as such. 
9.1.3 
Serious Adverse Event 
A serious adverse event (SAE) is defined as any untoward medical occurrence that at any 
dose: 


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• 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 1 
of the above outcomes listed as an SAE criterion. 
Adverse events that do not fall into the above categories are defined as nonserious AEs. 
9.2 Severity of Adverse Events 
The severity of each AE (ie, non-serious and serious AEs) is to be assessed by the 
investigator as follows: 
Severity 
Definition 
Mild 
A type of AE that is usually transient and may require only minimal 
treatment or therapeutic intervention. The event does not generally interfere 
with usual activities of daily living. 
Moderate 
A type of AE that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, 
causing discomfort but poses no significant or permanent risk of harm to the 
subject. 
Severe 
A type of AE that interrupts usual activities of daily living, or significantly 
affects clinical status, or may require intensive therapeutic intervention. 
Source: CDISC SDTM Severity Intensity Scale for Adverse Event Terminology. 


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9.3 Causality of Adverse Events 
The causal relationship of an AE to investigational product must always be assessed by the 
investigator. All AEs will be classified as either related or not related to investigational 
product. If a causality assessment is not provided for an AE (including an SAE), that AE will 
be considered related to the investigational product.  
The degree of certainty with which an AE is attributed to the investigational product 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). 
9.4 Observation Period for Adverse Events 
The observation period for AE (and SAE) reporting for an individual subject will start at the 
time of giving written informed consent for participation in the current study and finish at the 
subject’s final study visit: 
• The Week 9 Telephone Contact for any subject who enters the Run-in Period and does 
not participate in Treatment Period 1. 
• Follow-up at the Week 26 (Day 186) Visit for C1-INH HAE subjects who are assigned to 
receive placebo, 
 mg, 
 mg, or 
 mg CSL312 q4wk during Treatment Period 1. 
• Follow-up at the Week 26 (Day 186) Visit for FXII/PLG HAE subjects who take part in 
Treatment Period 1. 
• Follow-up at the Week 25 (Day 180) Visit for C1-INH HAE subjects who are assigned to 
receive 
 mg CSL312 q2wk during Treatment Period 1. 
• Follow-up at the Week 70 (Day 494) Visit for subjects taking part in Treatment Period 1 
and Treatment Period 2, if Treatment Period 2 is not extended. 
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• Follow-up at the Treatment Period 2 Follow-up Visit taking place ~14 weeks (ie, 95 days 
[± 3 days]) after each subject’s final Treatment Period 2 study visit for subjects taking 
part in Treatment Period 1 and Treatment Period 2, if Treatment Period 2 is extended. 
If the investigator becomes aware of an SAE 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 9.6.3). 
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 page of the eCRF. If known, the medical 
diagnosis of an AE should be recorded in preference to the listing of individual signs and 
symptoms. The investigator must follow up on the course of an AE until resolution or 
stabilization. If an AE is ongoing after the final 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. 
9.6.2 
Adverse Events of Special Interest 
In order to guarantee the rapid communication of AESIs from investigator to CSL, 
information relating to any AESI must be entered into the eCRF within 24 hours. 
If an AESI is considered serious, the event must be reported to CSL as described in 
Section 9.6.3 (Serious Adverse Event Reporting).  


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9.6.3 
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. 
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 immediately (within 
24 hours of the investigator becoming aware of the event). An assessment of causality to 
the investigational product must be included. 
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 final study visit 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 (Note: the reporting source must be medically qualified). 
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: 
• Report all SAEs to the relevant Institutional Review Board (IRB) / Independent Ethics 
Committee (IEC) during 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. 


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• 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). 
9.6.4 
Abnormal Laboratory Values 
During Screening, any laboratory values that deviate from the reference ranges and are 
considered clinically significant by the investigator must be documented on the medical 
history page of the eCRF. 
For laboratory safety parameters, any instances of absolute values being outside the reference 
range and/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: 
• Increases in 
 will not be classified as AEs because CSL312 is expected to cause 
increase in this parameter. 
• Laboratory parameters already beyond the reference range at Screening, unless a further 
increase / decrease can be considered an exacerbation of a pre-existing condition. 
• Abnormal laboratory parameters caused by mechanical or physical influences on the 
blood sample (eg, in vitro hemolysis) and flagged as such by the laboratory in the 
laboratory report. 
• Abnormal parameters that are obviously biologically implausible (eg, values that are 
incompatible with life or outside the measuring range). 
• An abnormal laboratory value that cannot be confirmed after repeat analysis, preferably 
in the same laboratory (ie, the previous result could be marked as not valid and should not 
necessarily be reported as an AE). 
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9.6.5 
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 9.6.3). 
Details (eg, volume, location of infusions, infusion rate) 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. 
9.6.6 
Pregnancy and Breastfeeding  
A female subject or female partner of a male subject who becomes pregnant while 
participating in the study must notify the investigator immediately and at any time during the 
study (see Section 9.4). 
If a female subject becomes pregnant, she must discontinue treatment with the investigational 
product immediately, her participation will be discontinued, and the procedure for 
discontinuation of a subject will be followed, as described in Section 4.2. 
During the study, CSL must be notified within 5 days of the investigator becoming aware of 
the pregnancy (by entry of appropriate data into the eCRF). 
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. 


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10 Statistics 
10.1 Sample Size Estimation 
Subjects with C1-INH HAE 
Seven subjects assigned to each treatment (Placebo, or 
 mg, 
 mg, or 
 mg CSL312 
q4wk) are needed to reach power of ~82% for the comparisons of 
 mg CSL312 q4wk 
versus placebo q4wk and 
 mg CSL312 q4wk versus placebo q4wk in Treatment Period 1. 
This is based on the following assumptions: 
• The time-normalized number of HAE attacks is 2.9 attacks per month during treatment 
with placebo. This number was derived from CSL study CSL830_3001, using the lower 
bound of the distribution-free 95% confidence interval for the median of the first placebo 
treatment period. 
• The time-normalized number of HAE attacks is 0.6 attacks per month during treatment 
with 
 mg CSL312 q4wk or 
 mg CSL312 q4wk. The number was derived from 
CSL study CSL830_3001, using the upper bound of the distribution-free 95% confidence 
interval for the median of the combined active treatment periods. 
• Alpha is 2.5% for each of the 2 two-sided Mann-Whitney Tests of 
 mg CSL312 q4wk 
or 
 mg CSL312 q4wk against placebo. 
 
. The sample size of 7 subjects for this arm is not driven by an 
efficacy comparison, but instead, by consistency with other treatment arms and for 
maintenance of blinding of the study. No testing for efficacy of the 
 mg CSL312 dose 
against placebo is planned and no power calculation has been done. An additional subject 
may be added to each of these 4 treatment arms to account for drop outs during Treatment 
Period 1, resulting in 8 subjects in each treatment arm. 
Up to 7 subjects with C1-INH HAE will be assigned to receive 
 mg CSL312 q2wk. This 
arm is included for informational purposes, and therefore no testing against placebo is 
planned and no power calculation has been done. An additional subject may be added to this 
arm to account for drop outs during Treatment Period 1, resulting in up to 8 subjects in this 
treatment arm. 
Overall, a total of up to 40 subjects with C1-INH HAE will be assigned to treatment in 
Treatment Period 1. 
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Subjects with FXII/PLG HAE 
Up to 10 subjects with FXII/PLG HAE will take part in the study. 
10.2 Description of Study Analysis Populations 
10.2.1 Screening Population 
The Screening population will consist of all subjects who provide written informed consent 
and who undergo any study screening procedure.  
10.2.2 Intent-to-Treat Population 
The Intent-to-Treat (ITT) population will consist of all subjects who provide informed 
consent, undergo any study screening procedure, and who are assigned to treatment in 
Treatment Period 1 or to treatment in Treatment Period 2, regardless of whether they receive 
the investigational product. The ITT population will be analyzed using the treatment to which 
the subject was assigned at Treatment Period 1, at Treatment Period 2 Week 13, or 
 mg 
after dose reduction from 
 mg in Treatment Period 2 (only applicable for C1-INH HAE 
subjects), regardless of the actual treatment received. 
10.2.3 Per Protocol Population 
The per protocol (PP) population will consist of all subjects in the ITT population, excluding 
subjects who have a significant protocol violation. Protocol violations which will lead to 
exclusion from the PP population will be reviewed and agreed prior to conducting interim 
analyses and before database lock. 
10.2.4 Safety Population 
The Safety population will consist of all subjects who provide informed consent, are assigned 
to treatment in Treatment Period 1 or to treatment in Treatment Period 2, and receive at least 
1 dose or partial dose of the investigational product and will be based on the actual treatment 
received. 
10.2.5 Pharmacokinetic Population 
The PK population will consist of all subjects in the Safety population for whom at least 
1 measurable concentration of CSL312 is reported. 
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10.2.6 
 
 
10.3 Statistical Analyses and Methods 
The data from Treatment Period 1 and Treatment Period 2 will be analyzed separately. 
In addition, Treatment Period 1 and Treatment Period 2 will be analyzed together for subjects 
who are being continuously administered the same dose of CSL312 in both treatment periods, 
unless otherwise specified. For C1-INH subjects having a dose reduction from 
 mg to 
 
mg in Treatment Period 2, only data until the date and time of the dose reduction will be 
included. 
Subjects with C1-INH HAE who are treated with placebo or 
 mg, 
 mg, or 
 mg 
CSL312 q4wk will be analyzed separately from subjects with C1-INH HAE who are treated 
with 
 mg CSL312 q2wk. Subjects with FXII/PLG HAE will be analyzed separately from 
subjects with C1-INH HAE. 
Subject disposition will be summarized using all Subjects. Demographic and subject 
characteristics will be summarized using the ITT and PP populations. Safety data will be 
summarized using the Safety population. The primary efficacy endpoint will be summarized 
using the ITT and PP populations. 
 
. Pharmacokinetic data will be summarized using 
the PK population. 
 
Continuous variables will be described by using mean values with their respective 95% 
confidence intervals (CI); standard deviation; range; 25th, 50th (median), and 75th 
percentiles; and counts of missing and non-missing values. The geometric coefficient of 
variation will be expressed as a percentage for PK and 
 data. The geometric mean and its 
respective 90% CI will be calculated for PK and 
 data. The 90% CI for the geometric 
mean will be calculated by log transforming the data, calculating the lower and upper limits 
of the 90% CI of the mean of the log-transformed data, and subsequently back transforming 
the lower and upper limits. Categorical values will be described using counts and 
percentages. 
All data will be displayed in by-subject listings. The listings will be sorted by treatment, 
study site, subject, time point, and item number (if applicable). 
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The evaluation periods for assessment of efficacy will be: 
• The Run-in Period (all subjects): From Week 1 (Day 1) of the Run-in Period until the 
date / time of the first administration of investigational product in Treatment Period 1 
(ie, at the Week 1 [Day 1] Visit of Treatment Period 1). 
• Treatment Period 1 (subjects who receive an IV loading dose of investigational 
product and who participate in Treatment Period 2): From the date / time of the first 
SC administration of investigational product in Treatment Period 1 (ie, at the Week 1 
[Day 6] Visit) until the date / time of the first administration of investigational product in 
Treatment Period 2 (ie, at the Week 13 [Day 91] Visit). 
• Treatment Period 1 (subjects who receive an IV loading dose of investigational 
product and who do NOT participate in Treatment Period 2): From the date / time of 
the first SC administration of investigational product in Treatment Period 1 (ie, at the 
Week 1 [Day 6] Visit) until the Week 13 (Day 91) Visit date and time. 
• Treatment Period 1 (
 
): From the date / 
time of the second SC administration of investigational product in Treatment Period 1 
(ie, at the Week 3 [Day 15] Visit) until the date / time of the first administration of 
investigational product in Treatment Period 2 (ie, at the Week 13 [Day 85] Visit). 
• Treatment Period 1 (
 
): From the 
date / time of the second SC administration of investigational product in Treatment 
Period 1 (ie, at the Week 3 [Day 15] Visit) until the Week 13 (Day 85) Visit date and time. 
• Treatment Period 2 (subjects assigned to 
 mg): From the date / time of the third 
administration of investigational product in Treatment Period 2 (ie, at the 
Week 21 [Day 147] Visit) until the Week 57 (Day 399) Visit date and time. 
• Treatment Period 2 (subjects assigned to 
 mg): 
o From the date / time of the third administration of investigational product in 
Treatment Period 2 (ie, at the Week 21 [Day 147] Visit) until the Week 57 (Day 399) 
Visit date and time OR time point of planned switch to 
 mg (per protocol 
Amendment 2), whatever occurs first OR  
o From the date / time of planned switch to 
 mg (per protocol Amendment 2) until 
the Week 57 (Day 399) Visit date and time. 
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The evaluation period for assessment of efficacy in Treatment Period 2 will be extended to 
the subject’s final Treatment Period 2 visit for subjects who are in the Extended Treatment 
Period 2. 
Hereditary angioedema attacks with a start date between the first and second administrations 
of the investigational product in Treatment Period 1 will not be included in the analyses of 
efficacy, but will be presented in a listing (only). 
A complete description of the statistical analyses and methods will be available in a statistical 
analysis plan (SAP). The SAP will be finalized within 2 months after the first subject is 
entered into the Run-in Period. 
10.3.1 Subject Disposition and Characteristics 
10.3.1.1 Subject Disposition 
The following will be presented in summary tables for all subjects who have provided 
informed consent / assent (as appropriate) by treatment and overall: 
• The number of subjects who provide informed consent. 
• The number of subjects who undergo Screening. 
• The number of subjects who enter the Run-in Period. 
• The number of subjects who are not assigned to treatment. 
• The number of subjects who are assigned to treatment in Treatment Period 1. 
• The number of subjects who are assigned to treatment in Treatment Period 2. 
• The number of subjects who have a dose reduction from 
 mg to 
 mg in Treatment 
Period 2 (per protocol Amendment 2). 
• The number of subjects who complete Treatment Period 1. 
• The number of subjects who complete Treatment Period 2. 
• The number of subjects who completed the study. 
• The number of subjects who discontinued participation in the study (overall and for 
Treatment Period 1 and Treatment Period 2; including the reason for discontinuation). 
The number of subjects in each analysis population will be summarized by treatment and 
overall. 
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Subjects with C1-INH HAE and subjects with FXII/PLG HAE will be presented combined 
and separately. 
Reasons for discontinuations / withdrawals will be listed by subject. 
10.3.1.2 Subject Characteristics 
All demographic and subject characteristics will be summarized by treatment and overall for 
the ITT Population and Per Protocol Population. These will include: 
• Demographics (age, sex, race, ethnicity, height, body weight, body mass index). 
• Medical history. 
• HAE history (including confirmation of HAE diagnosis, identification of HAE type, and 
number of HAE attacks in the 3 months before Screening). 
10.3.2 Efficacy Analyses 
10.3.2.1 Primary Efficacy Analysis 
10.3.2.1.1 The Primary Analysis 
The primary endpoint (time-normalized number of HAE attacks) will be analyzed using the 
ITT and PP Populations. The ITT population will be used for the primary analysis and the PP 
will be used as the secondary analysis. 
The evaluation periods for efficacy, including for the time-normalized number of HAE 
attacks are specified in Section 10.3. For the primary analysis, only the efficacy period for 
Treatment Period 1 and subjects with q4wk dosing, as defined in Section 10.3, is applicable.  
Subjects are to enter HAE symptoms into their eDiary. HAE attacks are based upon review of 
patient diaries and review of relevant interim medical history by the investigator, including 
hospital / medical records and any information provided by the subject. Using medical 
judgment, the investigator is to determine the occurrence of an HAE attack. 
The time-normalized number of HAE attacks per month during treatment is calculated per 
subject as: [the number of HAE attacks / length of subject treatment in days] * 30.4375, 
where the length of subject treatment is calculated for Treatment Period 1 as: [the date / time 
of the first SC dose of investigational product in Treatment Period 2 – the date / time of the 
first SC dose of investigational product in Treatment Period 1]. 


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The time-normalized number of HAE attacks will be summarized descriptively by median 
(primary) and mean (secondary) with corresponding 95% CIs by treatment (ie, placebo, or 
 
mg, 
 mg, or 
 mg CSL312 q4wk).  
To test for a difference in the primary efficacy endpoint between 
 mg CSL312 q4wk 
or 
 mg CSL312 q4wk and placebo, pairwise comparisons will be performed by testing the 
hypotheses using a two-sided Mann-Whitney Test.  
To account for multiple testing, the alpha level of 5% will be evenly split between the 
hypotheses tested. Therefore, the 
 mg CSL312 q4wk or 
 mg CSL312 q4wk CSL312 
doses (in subjects with C1-INH HAE) will each be evaluated against placebo at alpha = 0.025 
for each test:  
H01: a1 = 0 vs H11: a1 ≠ 0  
and  
H02: a2 = 0 vs H12: a2 ≠ 0  
In the above hypotheses, the term “a1” is the shift between the 2 distributions of 
 mg 
CSL312 q4wk and placebo and the term “a2” is the shift between the distributions of 
 mg 
CSL312 q4wk and placebo, respectively. 
There will be no testing of the 
 mg CSL312 q4wk dose against placebo. The time-
normalized number of HAE attacks will be presented descriptively (only). 
There will be no testing of the of 
 mg CSL312 q2wk dose against placebo for subjects 
with C1-INH HAE or the 
 mg CSL312 q4wk dose against placebo for subjects with 
FXII/PLG HAE. 
10.3.2.1.2 Supportive Analyses 
The primary endpoint (the time-normalized number of HAE attacks) will also be summarized 
descriptively for the 
 mg CSL312 q2wk regimen (for subjects with C1-INH HAE) and the 
 mg CSL312 q4wk regimen (for subjects with FXII/PLG HAE) for the evaluation period 
of Treatment Period 1. 
The primary endpoint will also be summarized descriptively for the CSL312 q4wk regimens 
for the following (see Section 10.3): 
• Treatment Period 2 evaluation period (alone). 
• Treatment Period 1 and Treatment Period 2 evaluation periods (combined). 
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For the difference in the primary endpoint between the 2 treatments 
 mg and 
 mg 
CSL312 q4wk in Treatment Period 1, a comparison will be performed as an 
 
 using a two-sided Mann Whitney test at alpha = 0.05: [H01: a3 = 0 vs H11: a3 ≠ 0] 
(
 mg tested against 
 mg CSL312 q4wk) where the term “a3” is the shift in the 2 
distributions of the 2 CSL312 doses compared against each other. 
. 
There will be no testing of the of 
 mg CSL312 q2wk dose for subjects with C1-INH HAE 
or the 
 mg CSL312 q4wk dose against placebo for subjects with FXII/PLG HAE. 
10.3.2.2 Secondary Efficacy Analyses 
Secondary efficacy endpoints will be analyzed for Treatment Period 1 and Treatment Period 2 
separately. In addition, Treatment Period 1 and Treatment Period 2 will be analyzed together 
for subjects who are being continuously administered the same dose of CSL312 during both 
treatment periods. For C1-INH subjects having a dose reduction from 
 mg to 
 mg in 
Treatment Period 2, only data until the date and time of the dose reduction will be included. 
Subjects with C1-INH HAE who are treated with placebo or 
 mg, 
 mg, or 
 mg 
CSL312 q4wk, will be analyzed separately from subject with C1-INH HAE who are treated 
with 
 mg q2wk. Subjects with FXII/PLG HAE will be analyzed separately from subjects 
with C1-INH HAE. 
The number and percentage of responders and non-responders will be presented by treatment 
and for all CSL312 doses combined with corresponding 95% CI. A subject is classified as a 
responder if the percentage reduction in HAE attacks is ≥ 50%. The percentage reduction in 
the time-normalized number of HAE attacks per subject is calculated within a subject as: 
100% * [1 – (the time-normalized number of HAE attacks with CSL312 per month) / 
(the time-normalized number of HAE attacks per month during the Run-in Period)]. 
 
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The number and percentage of subjects who do not experience an HAE attack will be 
presented by treatment and for all CSL312 doses combined. Additionally, the median time, 
the 25th percentile of time, and the 75th percentile of time of the subjects being attack-free 
will be calculated for each treatment. 
The total number and percentage of mild, moderate, or severe HAE attacks as well as the 
time-normalized number per month will be presented by treatment. The number of subjects 
having at least 1 mild, moderate, or severe HAE attacks will also be presented. 
The number, the time-normalized number, and the percentage of treated and untreated attacks 
overall and by severity will be presented by treatment. The above will also be presented as 
rate per month. A treated HAE attack will be defined as a treatment-emergent HAE attack 
during which on-demand medication to treat HAE attacks was taken. The number and 
percentage of subjects with at least 1 treated attack, the number and percentage of subjects 
with only treated attacks, the number and percentage of subjects with attacks but without 
treated attacks, and the number and percentage of subjects with no attacks at all will be 
presented by treatment. These analyses will be repeated including moderate or severe attacks 
only. The above will also be presented as rate per month. 
10.3.3 Safety Analyses 
AEs with a start date and time on or after the first injection date and time of investigational 
product are considered treatment-emergent AEs. AEs with missing or partial start date or time 
will also be considered treatment-emergent following the worst case principle, unless the 
partial date clearly indicates that the AE started before first injection date and time. 
Adverse events with a start date occurring after administration of IV investigational product 
and occurring before the first administration of SC investigational product will be analyzed 
separately from AEs with a start date occurring after the first administration of SC 
investigational product. 
Only treatment-emergent AEs will be included in analyses, although all AEs will be listed. 
The following tables will be presented for AEs occurring at any dose: 
• Summary of subjects with AEs (number with any AE, with AEs occurring within 
24 hours of investigational product injection, with SAE, with related AE, with AEs 
leading to study discontinuation, with each intensity, and with each outcome). 


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• Summary of subjects with SAEs (number with any SAE, with SAEs occurring within 
24 hours of investigational product injection, with related SAE, with SAEs leading to 
study discontinuation, with each intensity, and with each outcome). 
• Incidence of subjects with AEs by system organ class (SOC) and preferred term. 
• Incidence of subjects with SAEs by SOC and preferred term. 
• Incidence of subjects with AEs by severity and SOC and preferred term.  
• Incidence of subjects with AEs by relationship to investigational product and SOC and 
preferred term. 
• Incidence of subjects with AEs leading to discontinuation by SOC and preferred term. 
• Incidence of subjects with TEEs by SOC and preferred term. 
• Incidence of subjects with bleeding events by SOC and preferred term. 
• Incidence of subjects with anaphylaxis by SOC and preferred term. 
• The number of subjects experiencing AEs which occur in at least 1 treatment in at least 
1, 2, 3, 4 and 5% of events will also be presented. 
Summaries will include the number and percentage of subjects, the number of AEs, and the 
number of AEs per injection and per subject year (where applicable). 
A summary of non-serious AEs only will be presented by treatment and also by SOC, preferred 
term, and treatment.  
Summaries of ISRs will be presented by treatment and also by MedDRA System Organ Class 
and Preferred Term, and treatment, with relationship to investigational product and with 
severity. 
A subject with more than 1 occurrence of the same AE will be counted only once in the total 
of those experiencing that adverse event. Similarly, a subject with 1 or more AEs in a particular 
SOC will be counted only once in the total of those experiencing AEs in that particular SOC. 
Adverse events, SAEs, AEs leading to study discontinuation and deaths will be listed. 


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10.3.4 Pharmacokinetic Analyses 
PK parameters for CSL312 in plasma will be derived using non-compartmental analyses, and 
will include: 
• Maximum concentration (Cmax). 
• Time to reach Cmax in plasma (Tmax). 
• Area under the concentration-time curve in 1 dosing interval (AUC0-tau). 
• Total systemic clearance (CLtot). 
• Apparent clearance (CL/F).  
• Apparent volume of distribution (Vd/F). 
• Volume of distribution during the elimination phase (Vz). 
• Terminal elimination half-life (T1/2). 
All PK values will be listed by individual subject and summarized descriptively by time point 
and treatment. 
10.3.5 
 
 
10.3.6 Pharmacokinetic / 
 Relationships 
Additional PK / 
 analyses may be conducted, and the relevant details will be provided in 
the SAP. 
10.3.7 Other Analyses 
Analyses of 
 will be described in the SAP. 
10.3.8 Interim Analysis 
An interim analysis of data from Treatment Period 1 will be conducted after all C1-INH HAE 
subjects who received placebo or 
 mg, 
 mg, 
 mg CSL312 q4wk complete Treatment 
Period 1. 
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An interim analysis of data from subjects with FXII/PLG HAE will be conducted after 
subjects with FXII/PLG HAE complete Treatment Period 1. 
Additional interim analyses may be conducted, as outlined in the SAP. 
Additional details regarding planned interim analyses will be provided in supporting 
documents (eg, SAP, IDMC charter). 
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, United States Food and Drug 
Administration). 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 a Food and Drug Administration Investigational New 
Drug application and will be 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. 


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12.2 Institutional Review Board / Independent Ethics Committee 
The protocol and informed consent forms (ICFs) must be submitted 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. 
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 must be given ample opportunity to inquire about details of the study. 
The subject 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), then 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. 


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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. 
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 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. Clinical trial 
agreements may be executed by electronic signature (current provider DocuSign) in 
compliance with 21 CFR Part 11 and simple or advanced electronic signature according to 
EU Regulation No 910 / 2014 – eIDAS. 
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.  


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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. 
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 the investigational product and 
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 who takes part in 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 who take part 
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 


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requirements. Source data must be completed legibly for each subject who takes part in 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.  
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 
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 


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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, if applicable, a nominated coordinating investigator (or 
delegate). In this case, 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 
Björkqvist J, Jämsä A, and Renné T. Plasma kallikrein: the bradykinin-producing enzyme. 
Thrombosis and Haemostasis. 2013;110(3):399-407. 
Björkqvist J, Nickel KF, Stavrou E, Renné T. In vivo activation and functions of the protease 
factor XII. Thrombosis and Haemostasis. 2014;112(5):868-75. 
Björkqvist J, de Maat S, Lewandrowski U, Di Gennaro A, Oschatz C, Schonig K, et al. 
Defective glycosylation of coagulation factor XII underlies hereditary angioedema type III. 
Journal of Clinical Investigation. 2015;125(8):3132. 
Bork K, Barnstedt SE, Koch P, Traupe H. Hereditary angioedema with normal C1-inhibitor 
activity in women. Lancet. 2000;356(9225):213-7.  
Bork K. Pasteurized C1 inhibitor concentrate in hereditary angioedema: pharmacology, 
safety, efficacy and future directions. Expert Reviews in Clinical Immunology. 2008;4(1):13-
20. 
Bork K, Wulff K, Steinmüller-Magin L, Braenne I, Staubach-Renz P, Witzke G, Hardt J. 
Hereditary angioedema with a mutation in the plasminogen gene. Allergy. 2018 
Feb;73(2):442-450. doi: 10.1111 / all.13270. Epub 2017 Sep 7. 
Cicardi M, Banerji A, Bracho F, Malbran A, Rosenkranz B, Riedl M, et al. Icatibant, a new 
bradykinin-receptor antagonist, in hereditary angioedema. New England Journal of Medicine. 
2010a; 363(6):532- 41. 
Cicardi M, Levy RJ, McNeil DL, Li HH, Sheffer AL, Campion M, et al. Ecallantide for the 
treatment of acute attacks in hereditary angioedema. New England Journal of Medicine. 
2010b;363(6):523-31. 
Cicardi M, Aberer W, Banerji A, Bas M, Bernstein JA, Bork K, Caballero T, Farkas H, 
Grumach A, Kaplan AP, Riedl MA, Triggiani M, Zanichelli A, Zuraw B; HAWK under the 
patronage of EAACI (European Academy of Allergy and Clinical Immunology). 
Classification, diagnosis, and approach to treatment for angioedema: consensus report from 
the Hereditary Angioedema International Working Group. Allergy. 2014 May;69(5):602-16. 


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Csuka D, Veszeli N, Imreh É, Zotter Z, Skopál J, Prohászka Z, Varga L, Farkas H. 
Comprehensive study into the activation of the plasma enzyme systems during attacks of 
hereditary angioedema due to C1-inhibitor deficiency. Orphanet Journal of Rare Diseases. 
2015;10:132. 
Cugno M, Cicardi M, Coppola R, Agostoni A. Activation of factor XII and cleavage of high 
molecular weight kininogen during acute attacks in hereditary and acquired C1-inhibitor 
deficiencies. Immunopharmacology. 1996;33(1-3):361-4. 
Davis AE, Lu F, and Mejia P. C1 inhibitor, a multi-functional serine protease inhibitor. 
Thrombosis and Haemostasis. 2010; 104(5): 886-893. 
Dewald G. A missense mutation in the plasminogen gene, within the plasminogen kringle 3 
domain, in hereditary angioedema with normal C1 inhibitor. Biochem Biophys Res Commun. 
2018 Mar 25;498(1):193-198. 
Gompels MM, Lock RJ, Abinun M, Bethune CA, Davies G, Grattan C, et al. C1 inhibitor 
deficiency: consensus document. Clinical and Experimental Immunology. 2005;139(3):379-
94. 
Kalmar L, Hegedus T, Farkas H, et al. HAEdb: a novel interactive, locus-specific 
mutation database for the C1 inhibitor gene. Hum Mutat. 2005; 25(1): 1-5. 
Kenne E, Nickel KF, Long AT, Fuchs TA, Stavrou EX, Stahl FR, Renné T. Factor XII: a 
novel target for safe prevention of thrombosis and inflammation. Journal of Internal 
Medicine. 2015;278(6):571-85. 
Lämmle B, Wuillemin WA, Huber I, Krauskopf M, Zürcher C, Pflugshaupt R, Furlan M. 
Thromboembolism and bleeding tendency in congenital factor XII deficiency—a study on 74 
subjects from 14 Swiss families. Thromb Haemost. 1991 Feb 12;65(2):117-21. 
Larsson M, Rayzman V, Nolte MW, Nickel KF, Björkqvist J, Jämsä A, Hardy MP, Fries M, 
Schmidbauer S, Hedenqvist P, Broomé M, Pragst I, Dickneite G, Wilson MJ, Nash AD, 
Panousis C, Renné T. A factor XIIa inhibitory antibody provides thromboprotection in 
extracorporeal circulation without increasing bleeding risk. Sci Transl Med. 2014 Feb 
5;6(222):222ra17. 


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Longhurst HJ. Emergency treatment of acute attacks in hereditary angioedema due to C1 
inhibitor deficiency: what is the evidence? International Journal of Clinical Practice. 
2005;59(5):594-9. 
Longhurst HJ, Bork K. Hereditary angioedema: causes, manifestations and treatment. Br J 
Hosp Med (Lond). 2006 Dec;67(12):654-7. 
Nasr IH, Manson AL, Al Wahshi HA, Longhurst HJ. Optimizing hereditary angioedema 
management through tailored treatment approaches. Expert Rev Clin Immunol. 
2016;12(1):19-31. 
Nussberger J, Cugno M, Amstutz C, Cicardi M, Pellacani A, Agostoni A. Plasma bradykinin 
in angio-oedema. Lancet. 1998;351(9117):1693-7. 
Nussberger J, Cugno M, Cicardi M, Agostoni A. Local bradykinin generation in hereditary 
angioedema. Journal of Allergy and Clinical Immunology. 1999;104(6):1321-2. 
Ratnoff OD, Colopy JE. A familial hemorrhagic trait associated with a deficiency of a clot-
promoting fraction of plasma. J Clin Invest. 1955 Apr;34(4):602-13. 
Reilly MC, Zbrozek AS, Dukes EM. The validity and reproducibility of a work productivity 
and activity impairment instrument. Pharmacoeconomics. 1993 Nov;4(5):353-65. 
Renné T, Schmaier AH, Nickel KF, Blombäck M, and Maas C. In vivo roles of factor XII. 
Blood. 2012;120(22):4296-4303. 
Rosen FS, Pensky J, Donaldson V, Charache P. Hereditary Angioneurotic Edema: Two 
Genetic Variants. Science. 1965;148:957-8. 
Verpy E, Couture-Tosi E, Eldering E, Lopez-Trascasa M, Späth P, Meo T, Tosi M. Crucial 
residues in the carboxy-terminal end of C1 inhibitor revealed by pathogenic mutants impaired 
in secretion or function. J Clin Invest. 1995 Jan;95(1):350-9. 
Wagenaar-Bos IG, Hack CE. Structure and function of C1-inhibitor. Immunol Allergy Clin 
North Am. 2006 Nov;26(4):615-32. 
Weller K, Groffik A, Magerl M, Tohme N, Martus P, Krause K, Metz M, Staubach P, 
Maurer M. Development and construct validation of the angioedema quality of life 
questionnaire. Allergy. 2012 Oct;67(10):1289-98. 


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Zuraw BL, Busse PJ, White M, Jacobs J, Lumry W, Baker J, Craig T, Grant JA, Hurewitz D, 
Bielory L, Cartwright WE, Koleilat M, Ryan W, Schaefer O, Manning M, Patel P, Bernstein 
JA, Friedman RA, Wilkinson R, Tanner D, Kohler G, Gunther G, Levy R, McClellan J, 
Redhead J, Guss D, Heyman E, Blumenstein BA, Kalfus I, Frank MM. Nanofiltered C1 
inhibitor concentrate for treatment of hereditary angioedema. N Engl J Med. 2010 Aug 
5;363(6):513-22. 
 


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CSL312 (Factor XJJa Antagonist Monoclonal Antibody) 
15 Appendices 
Appendix 1 
Study Title: 
Protocol 
Number: 
Signature on Behalf of Sponsor 
A multicenter, randomized, placebo-controlled, parallel-arm study 
to investigate the efficacy, pharmacokinetics, and safety of CSL3 12 
in subjects with hereditary angioedema 
CSL3J2 2001 
I have read the Clinical Study Protocol titled ''A multicenter, randomized, placebo-controlled, 
parallel-arm study to investigate the efficacy, pharmacokinetics, and safety of CSL312 
in subjects with hereditary angioedema" and confirm that, to the best of my knowledge, the 
protocol accurately describes the design and conduct of the study. 
 
Protocol version: Amendment 2 Final 
Date: 20 March 2020 
Confidential 
Date 
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Appendix 2 
Signature of Principal Investigator 
 
Study Title: 
A multicenter, randomized, placebo-controlled, parallel-arm study 
to investigate the efficacy, pharmacokinetics, and safety of CSL312 
in subjects with hereditary angioedema 
Protocol 
Number: 
CSL312_2001 
Site Number: 
 
I have read the Clinical Study Protocol titled “A multicenter, randomized, placebo-controlled, 
parallel-arm study to investigate the efficacy, pharmacokinetics, and safety of CSL312 
in subjects with hereditary angioedema”. 
By signing this Clinical Study Protocol, I agree to conduct the clinical study, after approval 
by an Institutional Review Board or Independent Ethics Committee (as appropriate), in 
accordance with the Clinical Study Protocol, the standards of Good Clinical Practice (as 
defined by the International Conference on Harmonisation) and applicable regulatory 
requirements. 
Changes to the Clinical Study Protocol will only be implemented after written approval is 
received from CSL Behring and the Institutional Review Board or Independent Ethics 
Committee (as appropriate) with the exception of medical emergencies. 
I will ensure that study staff fully understand and follow the Clinical Study Protocol. 
 
 
 
(Signature) 
 
 
Date (DD MMM YYYY) 
(Printed name) 
 
 
 
(Title) 
 
 
 


Version: 1.0
Signature Page 1 of 1
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glbdctmp
Print Date: 04-Mar-2022 08:58:29 GMT-05:00
Signature Page
CSL312_2001 - Protocol Amendment - 2 - 20Mar2020
Signed By
Date (GMT)
Approved-
 Approval
25-Mar-2020 15:19:13
Approved-Clinical Safety Physician Approval
25-Mar-2020 17:02:23
Approved-
 Approval
25-Mar-2020 17:34:15
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SAP_001.pdf: 
CONFIDENTIAL 
 Page 1 of 71 
STATISTICAL ANALYSIS PLAN 
Study Title:  A multicenter, randomized, placebo-controlled, parallel-arm study to 
investigate the efficacy, pharmacokinetics, and safety of CSL312 in subjects with 
hereditary angioedema 
Investigational Medicinal Product:  CSL312 (Factor XIIa Antagonist Monoclonal 
Antibody) 
Protocol Number:  CSL312_2001 
Version:  2.0 FINAL 
Version Date:  19-JUN-2020 
Sponsor: 
CSL Behring LLC 
1020 First Avenue 
King of Prussia, Pennsylvania 
19406 
United States of America 
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. 


CSL Behring 
Statistical Analysis Plan 
Protocol Number: CSL312_2001 
Product Name: CSL312 
CONFIDENTIAL 
 Page 2 of 71 
Table of Contents 
Table of Contents ....................................................................................................................... 2 
1 
Modification History ........................................................................................................... 6 
2 
List of Abbreviations ........................................................................................................... 7 
3 
Purpose ................................................................................................................................ 9 
4 
Study Design ....................................................................................................................... 9 
4.1 
Study Design ................................................................................................................... 9 
Figure 1 Study Overview ......................................................................................................... 11 
Run-in Period ............................................................................................................ 12 
Treatment Period 1 .................................................................................................... 12 
Treatment Period 2 .................................................................................................... 13 
Post-Treatment Follow-up Period ............................................................................. 13 
4.2 
Objectives and Endpoints .............................................................................................. 14 
Primary Study Hypothesis ......................................................................................... 17 
4.3 
Study Treatments ........................................................................................................... 17 
On-demand HAE Therapy ......................................................................................... 17 
Dose Modification ..................................................................................................... 17 
4.4 
Randomization Procedures and Blinding ...................................................................... 18 
4.5 
Determination of the Sample Size ................................................................................. 20 
4.6 
Planned Interim Analyses and Reviews ........................................................................ 21 
Interim Analyses ........................................................................................................ 21 
IDMC Reviews .......................................................................................................... 24 
5 
Changes in the Conduct of Planned Analyses ................................................................... 25 
6 
Study Analysis Populations ............................................................................................... 25 
6.1 
Screening Population ..................................................................................................... 25 
6.2 
Intent-to-Treat Population ............................................................................................. 26 
6.3 
Safety Population .......................................................................................................... 26 
6.4 
Per-Protocol Population ................................................................................................ 26 
6.5 
Pharmacokinetic Population .......................................................................................... 26 
6.6 
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7 
General Considerations...................................................................................................... 27 
7.1 
Multicenter Studies........................................................................................................ 30 
7.2 
Treatment Descriptors ................................................................................................... 30 
7.3 
Multiple Comparisons and Multiplicity ........................................................................ 31 
8 
Data Handling Conventions .............................................................................................. 31 
8.1 
Missing Data.................................................................................................................. 31 
Imputation of Non-Date Missing Data ...................................................................... 31 
Imputation of Partial Dates ........................................................................................ 32 
8.2 
Derived Variables .......................................................................................................... 32 
Reference Dates ......................................................................................................... 32 
Study Day for Safety and Efficacy Measures............................................................ 32 
Durations ................................................................................................................... 33 
Baseline Definition .................................................................................................... 33 
Change from Baseline ............................................................................................... 33 
Multiple Assessments ................................................................................................ 33 
Actual Treatment ....................................................................................................... 34 
Study Periods Relative to Treatment ......................................................................... 34 
8.3 
Laboratory Parameters .................................................................................................. 39 
9 
Study Population ............................................................................................................... 39 
9.1 
Disposition of Subjects .................................................................................................. 39 
9.2 
Protocol Violations ........................................................................................................ 40 
9.3 
Demographic and Baseline Characteristics ................................................................... 42 
9.4 
Concomitant Medications.............................................................................................. 43 
10 Efficacy .............................................................................................................................. 46 
10.1 Primary Efficacy: Analysis of Time-Normalized Number of HAE Attacks in Treatment 
Period 1 (Blinded Part) .................................................................................................. 47 
Sensitivity Analysis for Primary Efficacy: Missing Values for the Time-normalized 
Number of HAE Attacks in Treatment Period 1........................................................ 49 
Supporting Analysis: Time-normalized Number of HAE Attacks in Treatment 
Period 1 and 2 (Open-label Part) ............................................................................... 49 
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Protocol Number: CSL312_2001 
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10.2 Secondary Efficacy ........................................................................................................ 52 
Analysis of Responders ............................................................................................. 52 
Analysis of Attack-free Subjects ............................................................................... 53 
Analysis of HAE Attacks .......................................................................................... 53 
Analysis of HAE Attacks Treated With On-demand HAE Medication .................... 54 
PK Analysis of CSL312 in Subjects With C1-INH ................................................... 54 
Analysis of Safety and Tolerability of CSL312 in Subjects With C1-INH ............... 54 
10.3 
Analyses of Time-normalized Uses of On-demand HAE Medication per Month .... 55 
10.4 Treatment Compliance .................................................................................................. 57 
11 Safety Analyses ................................................................................................................. 59 
11.1 Extent of Exposure ........................................................................................................ 59 
11.2 Dose Modification ......................................................................................................... 59 
11.3 Adverse Events .............................................................................................................. 60 
11.4 Adverse Events of Special Interest ................................................................................ 63 
11.5 Deaths and Serious Adverse Events .............................................................................. 63 
11.6 Adverse Events Leading to Discontinuation of Study Treatment, Withdrawal from the 
Study, and Other Significant Adverse Events ............................................................... 64 
11.7 Adverse Drug Reactions ................................................................................................ 64 
11.8 Public Disclosure of Clinical Trials Requirements ....................................................... 65 
11.9 Pregnancies .................................................................................................................... 65 
11.10 Clinical Laboratory Evaluations .................................................................................... 65 
11.11 Other Safety Measures .................................................................................................. 67 
Vital Signs ................................................................................................................. 67 
12 Pharmacokinetic Analyses ................................................................................................. 67 
12.1 Plasma PK Endpoints .................................................................................................... 68 
12.2 Summary of CSL312 Plasma Concentrations ............................................................... 68 
12.3 Summary of CSL312 Pharmacokinetic Parameters ...................................................... 69 
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Protocol Number: CSL312_2001 
Product Name: CSL312 
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13 
13.1 
13.2 
14 Pharmacokinetic - 
 Analyses ................................................................ 71 
15 References ......................................................................................................................... 71 
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1 Modification History 
Version 
Effective Date 
Author of 
Modification 
Reason for Change 
1.0 
01/APR/2020 
N/A – First Version 
2.0 
19/JUN/2020 
Incorporation of Protocol 
Amendment 2; 
Assignment of concomitant 
medication; 
COVID-19 related modifications; 
combination of 2nd and 3rd interim 
analysis; 
editorial changes. 
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2 List of Abbreviations 
Abbreviation 
Definition 
AE 
Adverse Event 
AESI 
AE of Special Interest 
ATC 
Anatomical Therapeutic Chemical 
AUC0-tau 
Area under the concentration-time curve in one dosing interval 
BMI 
Body Mass Index 
C4 
Complement Component 4 
CDISC 
Clinical Data Interchange Standards Consortium 
CLtot 
Total Systemic Clearance 
Cmax 
Maximum Concentration 
COVID-19 
Corona Virus Disease 2019 
CI 
Confidence Interval 
CSR 
Clinical Study Report 
EMA 
European Medicines Agency 
ESP 
External Service Provider 
eCRF 
Electronic Case Report Form 
FDA 
Food and Drug Administration 
FXII(a) 
(Activated) Factor XII 
HAE 
Hereditary Angioedema 
ICH 
International Conference on Harmonisation 
IDMC 
Independent Data Monitoring Committee 
IRT 
Interactive Response Technology 
ISR 
Injection Site Reaction 
ITT 
Intent-to-Treat Population 
IV 
Intravenous(ly) 
MCMC 
Markov-Chain Monte Carlo 
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Statistical Analysis Plan 
Protocol Number: CSL312_2001 
Product Name: CSL312 
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Abbreviation 
Definition 
MedDRA 
Medical Dictionary for Regulatory Activities 
PK 
Pharmacokinetic 
PP 
Per-Protocol Population 
PT 
Preferred Term 
q2wk 
Administered Every 2 Weeks 
q4wk 
Administered Every 4 Weeks 
SAE 
Serious AE 
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous(ly) 
SD 
Standard Deviation 
SOC 
System Organ Class 
T1/2 
Terminal Elimination Half-Life 
TEAE 
Treatment-Emergent Adverse Event 
TEE 
Thromboembolic Event 
TFL 
Tables, Figures, and Listings 
Tmax 
Time of Cmax 
Vz 
Volume of Distribution During the Elimination Phase 
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Protocol Number: CSL312_2001 
Product Name: CSL312 
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3 Purpose 
This SAP provides a detailed and complete description of the planned statistical analyses for 
the Independent Data Monitoring Committee (IDMC), the interim, and final analysis of the 
study CSL312_2001 to support the Clinical Study Report (CSR). Mock tables, figures, and 
listings (TFL) shells will be provided in separate supporting document. 
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 
following study documents: 
•
Study Protocol Amendment 2 (dated 20 March 2020);
•
Electronic Case Report Form (eCRF) (dated 11 May 2020).
The "Guideline on Missing Data in Confirmatory Clinical Trials" (European Medicines 
Agency [EMA] dated 2 Jul 2010) is relevant for analysis methodologies for missing data for 
the primary efficacy comparison. 
Further detailed Pharmacokinetic (PK)-
 analyses will be described in 
the Modeling and Simulation Analysis Plan. 
All decisions regarding the IDMC, interim, and final analysis of the study results, as defined 
in SAP 1.0 document, have been made within 2 months after the first subject will be entered 
the Run-in period. 
SAP 2.0 was issued following Protocol Amendment 2. 
4 Study Design 
4.1 Study Design 
This is a multicenter, randomized, placebo-controlled, parallel-arm, phase 2 study to 
investigate the clinical efficacy, PK, and safety of CSL312 as prophylaxis to prevent 
hereditary angioedema (HAE) attacks in subjects with C1-esterase inhibitor (C1-INH) 
deficiency HAE or HAE with normal C1-INH and factor XII or plasminogen gene mutation 
(FXII/PLG). As presented in Figure 1, the study consists of a Screening Period, a Run-in 
Period, 2 treatment periods, and a Follow-up Period. 
The following interim analyses are planned, with the sequence depending on subject 
recruitment: 
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Statistical Analysis Plan 
Protocol Number: CSL312_2001 
Product Name: CSL312 
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 Page 10 of 71 
•
after the last C1-INH subject who participated in the blinded part of the study has
completed Treatment Period 1;
•
after the last C1-INH subject who participated in the open-label part receiving 
 mg 
CSL312 and the last FXII/PLG subjects of the study have completed Treatment
Period 1
All available data will be reported in each of the interim analyses. For details on the interim 
analyses see Section 4.6.1. 
Three IDMC analyses are planned around following time points: 
•
First IDMC: December 2018;
•
Second IDMC: end of February 2019;
•
Third IDMC: end of May 2019 or beginning of June 2019.
Further IDMC analyses during Treatment Period 2 will be conducted with the first one 
planned after the last subject will have entered Treatment Period 2 and will have completed 3 
months in Treatment Period 2. Subsequent IDMC analyses will be planned around every 4 
months.  
The IDMC intervals may be adjusted during the study depending on the enrolment rate. 
IDMC meetings may also be conducted upon request. 
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Protocol Number: CSL312_2001 
Product Name: CSL312 
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Figure 1 Study Overview 
Abbreviations: q2wk = administered every 2 weeks; q4wk = administered every 4 weeks. 
Footnotes: 
a An overview of the Run-in Period is presented in protocol section 3.1.2. 
b An overview of Treatment Period 1 is presented in protocol section 3.1.3. 
c An overview of Treatment Period 2 is presented in protocol section 3.1.4. 
d An overview of the Follow-up Period is presented in protocol section 3.1.5. 
e Subjects may use the medication of their choice to treat HAE attacks experienced during the study if that medication has previously been 
shown to be effective. Investigators should ensure that participating subjects are capable of managing their HAE attacks. 
f C1-INH HAE subjects will be assigned to receive 
 mg CSL312 q2wk, only after 32 subjects with C1-INH HAE are first randomly 
assigned to receive placebo or 
 mg, 
 mg, or 
 mg CSL312 q4wk. 
g Subjects will receive treatment with investigational product in a blinded manner. These subjects will receive an initial intravenous (IV) 
loading dose of investigational product in Treatment Period 1 before receiving investigational product q4wk. 
h Subjects will receive treatment with CSL312 in an open-label manner. 
I Subjects will receive treatment with CSL312 in an open-label manner. These subjects will receive an initial IV loading dose of 
investigational product in Treatment Period 1 before receiving investigational product q4wk. 
j All C1-INH HAE subjects receiving the 
 mg dose will have their dose reduced to 
 mg q4wk SC at their next scheduled study visit. 
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Statistical Analysis Plan 
Protocol Number: CSL312_2001 
Product Name: CSL312 
CONFIDENTIAL 
 Page 12 of 71 
Run-in Period 
After Screening, eligible subjects will enter the Run-in Period which will last at least 4 and 
up to 8 weeks. The HAE attacks recorded during Run-in will serve as subject’s comparator to 
the number of attacks which occur under treatment. 
Subjects are not permitted to use routine prophylaxis to prevent HAE attacks during the 
Run-in Period; however, subjects may use on-demand HAE therapy to treat emerging HAE 
attacks if that medication has previously been shown to be effective. 
To enter Treatment Period 1 subjects must have participated in the Run-in period for a 
minimum of 4 weeks, and among other inclusion and exclusion criteria (see Protocol section 
4.1.3) during that time: 
•
experienced ≥ 2 HAE attacks within a consecutive 4-weeks period during Run-in
(subjects with C1-INH HAE);
•
experienced ≥ 1 HAE attack during Run-in (subjects with FXII/PLG HAE).
Treatment Period 1
Subjects who are eligible should enter Treatment Period 1 no later than 14 days after Week 9 
(Day 57) of the Run-in Period.  
Treatment Period 1 will last for around 13 weeks. Subjects may complete the study after 
Treatment Period 1. 
Subjects with C1-INH HAE 
The first 32 eligible subjects with C1-INH HAE will be randomly assigned to receive 
treatment (
 mg CSL312 q4wk; 
 mg CSL312 q4wk; 
 mg CSL312 q4wk; placebo 
q4wk) with investigational product in a ratio of 1:1:1:1 during Treatment Period 1 as 
described in detail in Section 4.4. Subjects will receive a single intravenous (IV) loading dose 
of investigational product followed by three subcutaneous (SC) doses, depending on the 
randomized treatment arm in the following way: 
•
A single loading dose of 
 mg CSL312 IV followed by 
 mg CSL312 administered 
every 4 weeks (q4wk) (SC). 
•
A single loading dose of
 mg CSL312 IV followed by 
 mg CSL312 q4wk SC. 
•
A single loading dose of
 mg CSL312 IV followed by 
 mg CSL312 q4wk SC. 
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•
A single loading dose of placebo IV followed by placebo q4wk SC.
For these first 32 subjects with C1-INH HAE, Treatment Period 1 will be conducted in a 
blinded manner, and the investigational product will be volume-normalized to maintain the 
blind.  
After the first 32 subjects with C1-INH HAE are randomly assigned to study treatment, up to 
an additional 8 subjects with C1-INH HAE will be assigned to receive 
 mg CSL312 
administered every 2 weeks (q2wk). 
. For these C1-INH HAE subjects, Treatment Period 1 will be conducted in an 
open-label manner and the investigational product will not be volume-normalized. 
Subjects with FXII/PLG HAE 
Up to 10 eligible subjects with FXII/PLG HAE will be assigned to receive a single loading 
dose of 
 mg CSL312 IV followed by 
 mg CSL312 q4wk. For these FXII/PLG 
subjects, Treatment Period 1 will be conducted in an open-label manner and the 
investigational product will not be volume-normalized. 
Treatment Period 2 
All subjects who participated in Treatment Period 1 may participate in Treatment Period 2. 
Treatment Period 2 will last for at least 44 weeks, or until another CSL312 study is opened 
for subjects to join, or until the current study is discontinued. Treatment Period 2 will be 
conducted in an open-label manner for all subjects. Subjects will be re-randomized or 
continue the treatment received in Treatment Period 1 as described in detail in Section 4.4. 
Dose modification details for Treatment Period 2 are presented in Section 4.3.2. All C1-INH 
HAE subjects receiving the 
 mg dose will have their dose reduced to 
 mg q4wk SC at 
their next scheduled study visit, effective with Amendment 2. 
Post-Treatment Follow-up Period 
Subjects will attend a Follow-up Visit ~2 weeks after each subject’s final treatment period 
visit; however, the Follow-up Visit may be waived in place of a telephone contact, at the 
discretion of the investigator. 
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4.2 Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
The primary objective of this study is to 
evaluate the efficacy of CSL312 in the 
prevention of HAE attacks in subjects with 
C1-INH HAE. 
Time-normalized number of HAE attacks. 
Secondary 
1. To further evaluate the efficacy of
CSL312 in subjects with C1-INH HAE.
2. To evaluate the PK of CSL312 in
subjects with C1-INH HAE.
3. To evaluate the safety and tolerability of
CSL312 in subjects with C1-INH HAE.
1. Responder subjects;
HAE attack-free subjects;
HAE attacks;
HAE attacks treated with on-demand
HAE medication.
2. CSL312 PK in plasma:
•
Maximum concentration (Cmax);
•
Area under the concentration-time
curve in 1 dosing interval
(AUC0-tau);
•
Time of maximum concentration
(Tmax);
•
Terminal elimination half-life (T1/2);
•
Total systemic clearance (CLtot);
•
Volume of distribution during the
elimination phase (Vz).
3. Subjects experiencing:
•
Adverse events (AEs);
•
Serious AEs (SAEs);
•
AEs of special interest (AESIs), (i.e.
anaphylaxis, thromboembolic events
[TEEs], and bleeding events);
•
Injection site reactions (ISRs);
•
Inhibitory antibodies to CSL312;
•
Clinically significant abnormalities
in laboratory assessments reported
as AEs.


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Protocol Number: CSL312_2001 
Product Name: CSL312 
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 Page 15 of 71 
Objectives 
Endpoints 
The time-normalized number of uses of 
on-demand HAE medication per month. 
• 
• 
(
); 
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Product Name: CSL312 
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Objectives 
Endpoints 
The endpoints will be evaluated separately for Treatment Period 1 and 2. Treatment Period 1 
and Treatment Period 2 will be analyzed together for subjects who receive continuously the 
same dose of CSL312 during both treatment periods. For C1-INH subjects having a planned 
dose reduction from 
 mg to 
 mg in Treatment Period 2, only data until the date and 
time of the planned dose reduction will be included. 
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Product Name: CSL312 
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Primary Study Hypothesis 
To test for a difference in the primary efficacy endpoint between 
 mg CSL312 q4wk or 
 mg CSL312 q4wk and placebo q4wk, pairwise comparisons will be performed by testing 
the hypotheses using a two-sided Mann-Whitney test. 
To account for multiple testing, the alpha level of 5% will be evenly split between the two 
hypotheses tested. Details are given in Section 10.1. 
4.3 Study Treatments 
CSL312 will be supplied as a sterile, preservation-free solution for injection (  mL per vial 
with a concentration of 
 mg per  mL). The active substance is FXIIa antagonist 
monoclonal antibody. The mode of administration is IV or SC. CSL312 will be manufactured 
in accordance with ICH Good Manufacturing Practice guidelines and local regulatory 
requirements. 
The placebo will be the same as the CSL312 formulation buffer and supplied in the same way 
as CSL312 but will not contain the active substance (FXIIa antagonist monoclonal antibody). 
All study administration for the blinded part in Treatment Period 1 will be 
volume-normalized by diluting them to the volume of the 
 mg dose as further explained 
below in Section 4.4. 
On-demand HAE Therapy 
Subjects must be assessed by an investigator to be capable of managing their HAE attacks 
during participation in the study. This must be documented by the investigator in an 
individual acute action plan. 
Subjects may use the on-demand medication of their choice that has previously been shown 
to be effective to treat HAE attacks experienced during the study. 
Dose Modification 
No dose modification is planned in Treatment Period 1. 
Subjects in Treatment Period 2 at dose of 
 mg CSL312 q4wk who experience ≥ 3 HAE 
attacks within an 8-week period are eligible to have their CSL312 dose increased to 
 mg 
CSL312 q4wk. All CSL312 dose increases will be made in eligible subjects at the discretion 
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Protocol Number: CSL312_2001 
Product Name: CSL312 
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of the investigator in consultation with CSL. All C1-INH HAE subjects receiving the 
 mg 
dose will have their dose reduced to 
 mg q4wk SC at their next scheduled study visit, 
after the subject has signed informed consent to Amendment 2. 
4.4 Randomization Procedures and Blinding 
Randomization will be conducted using an interactive response technology (IRT). 
Treatment Period 1 
In Treatment Period 1, subjects will be randomized using block randomization with fixed 
block size by means of centralized IRT to 1 of 4 blinded treatment arms: 
•
The first 32 subjects with C1-INH HAE who are assigned to treatment in Treatment
Period 1 will be randomized in a 1:1:1:1 ratio to receive placebo, 
 mg CSL312,
 mg CSL312, or 
 mg CSL312 q4wk. 
For the four blinded treatments above, the 32 C1-INH HAE subjects will be blinded to their 
treatment assignment. Except for the unblinded pharmacist (or delegate), all investigational 
site staff including the investigator will also be blinded to the treatment assignment of the 32 
subjects with C1-INH HAE in Treatment Period 1. The unblinded personnel will prepare the 
investigational product but will not administer it to the subjects or assess the subjects. 
Representatives from CSL (or their delegates) with direct interaction with the study sites or 
subjects will be blinded to treatment assignment throughout Treatment Period 1. A physical 
blind (
) will be employed so that blinded study personnel or subjects are 
unable to detect any difference between CSL312 or placebo. Furthermore, the IV and SC 
doses will be volume-normalized so that irrespective of the randomized dose, the same 
volume will be infused or injected to each subject. The assigned IV loading doses will be 
diluted so that each is the same volume for administration as a dose of 
 mg (i.e.,  mL). 
The assigned SC doses of CSL312 will be diluted so that each is the same volume for 
administration as a dose of 
 mg (i.e.,  mL). 
In addition, laboratory results which may reveal the treatment allocation will not be available 
to subjects, study site personnel, or CSL (and delegates) blinded to treatment assignment. 
The following laboratory tests may reveal the treatment allocation: 
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Product Name: CSL312 
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Laboratory 
Category 
Laboratory Test 
Comments 
Coagulation 
Blinded in eCRF 
Blinded in eCRF 
Immunogenicity 
Inhibitory and non-inhibitory 
antibodies specific to FXIIa antagonist 
monoclonal antibody 
PK 
CSL312 concentration 
Up to 8 additional subjects with C1-INH HAE who are assigned to treatment in Treatment 
Period 1 after the first 32 subjects (above) will receive 
 mg CSL312 q2wk in an unblinded 
open-label manner. 
Up to 10 subjects with FXII/PLG HAE who are assigned to treatment in Treatment Period 1 
will receive 
 mg CSL312 q4wk in an unblinded open-label manner. 
Treatment Period 2 
In Treatment Period 2, subjects will be re-randomized using block randomization with fixed 
block size by means of a centralized IRT to receive either 
 mg or 
 mg CSL312 q4wk. 
•
For subjects with C1-INH HAE, randomization will be stratified by Treatment
Period 1 treatment assignment: subjects on placebo q4wk, subjects on 
 mg CSL312 
q4wk, and subjects on 
 mg CSL312 q2wk: 
o
Subjects on placebo q4wk and subjects on
 mg CSL312 q4wk will be 
randomized in a 1:1 ratio to receive either 
 mg CSL312 q4wk or 
 mg 
CSL312 q4wk in Treatment Period 2. 
o
Subjects on 
 mg CSL312 q2wk will be randomized in a 1:1 ratio to receive 
either 
 mg CSL312 q4wk or 
 mg CSL312 q4wk in Treatment Period 2. 
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Statistical Analysis Plan 
Protocol Number: CSL312_2001 
Product Name: CSL312 
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 Page 20 of 71 
•
Subjects with C1-INH HAE on
 mg CSL312 q4wk in Treatment Period 1 will 
continue to receive 
 mg CSL312 q4wk in Treatment Period 2. 
•
Subjects with C1-INH HAE on 
 mg CSL312 q4wk in Treatment Period 1 will 
continue to receive 
 mg CSL312 q4wk in Treatment Period 2. 
•
Subjects with FXII/PLG HAE will continue to receive
 mg CSL312 q4wk in 
Treatment Period 2. 
Treatment Period 2 will be conducted in an open-label manner. 
4.5 Determination of the Sample Size 
Subjects with C1-INH HAE 
Seven subjects assigned to each treatment (placebo, or 
 mg, or 
 mg CSL312 q4wk) are 
needed to reach a power of ~82% for the comparisons of 
 mg CSL312 q4wk against 
placebo q4wk and 
 mg CSL312 q4wk against placebo q4wk in Treatment Period 1. 
This is based on the following assumptions: 
•
Alpha is 2.5% for each of the 2 two-sided Mann-Whitney tests of
 mg CSL312 
q4wk or 
 mg CSL312 q4wk against placebo q4wk.
•
The time-normalized number of HAE attacks is 2.9 attacks per month during treatment
with placebo. This number was derived from CSL study CSL830_3001, using the lower
bound of the distribution-free 95% confidence interval (CI) for the median of the first
placebo treatment period.
•
The time-normalized number of HAE attacks is 0.6 attacks per month during treatment
with 
 mg or 
 mg CSL312 q4wk. The number was derived from CSL study
CSL830_3001, using the upper bound of the distribution-free 95% CI for the median
of the combined active treatment periods.
•
For the time-normalized number of HAE attacks during CSL321 treatment and placebo
a Poisson distribution is assumed. The lower bound and the upper bound, respectively,
of the CIs for the medians are chosen for the rate parameters.
•
Randomization allocation between CSL321 treatment and placebo which are compared
are equal.
. The sample size of 7 subjects for this arm is not driven by an 
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Statistical Analysis Plan 
Protocol Number: CSL312_2001 
Product Name: CSL312 
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 Page 21 of 71 
efficacy comparison, but instead, by consistency with other treatment arms and for 
maintenance of the blinding of the study. No testing for efficacy of the 
 mg CSL312 dose 
against placebo is planned and no power calculation has been done. 
An additional subject will be added to each of these 4 treatment arms to account for dropouts 
during Treatment Period 1, resulting in 8 subjects required in each treatment arm. 
Up to 7 subjects with C1-INH HAE will be assigned to receive 
 mg CSL312 q2wk. This 
arm is included for informational purposes, and therefore no testing against placebo is planned 
and no power calculation has been done. An additional subject will be added to this arm to 
account for dropouts during Treatment Period 1, resulting in up to 8 subjects in this treatment 
arm. 
Overall, a total of up to 40 subjects with C1-INH HAE will be assigned to treatment in 
Treatment Period 1. 
Subjects with FXII/PLG HAE 
Up to 10 subjects with FXII/PLG HAE will take part in the study. The sample size for this arm 
is not driven by statistical considerations, but instead, by the expectations what number of 
subjects with FXII/PLG HAE is feasible to be enrolled in the study. 
4.6 Planned Interim Analyses and Reviews 
Interim Analyses 
A first interim analysis will be conducted after all C1-INH HAE subjects who received placebo 
or 
 mg, 
 mg, or 
 mg CSL312 q4wk have completed Treatment Period 1 using data 
from all subjects available at this time. The confirmatory test of 
 mg or 
 mg CSL312 
q4wk against placebo q4wk will not be performed for any dry run. It will only be performed 
for the interim analysis. 
A second interim analysis will be conducted after all subjects with C1-INH HAE who received 
 mg CSL312 q2wk and subjects with FXII/PLG HAE have completed Treatment Period 1 
using data from all subjects available at this time. This interim analysis will include subjects 
with C1-INH HAE  and with FXII/PLG HAE with all available data collected up to this time 
point. 
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Statistical Analysis Plan 
Protocol Number: CSL312_2001 
Product Name: CSL312 
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 Page 22 of 71 
No separate interim analysis will be conducted after subjects with FXII/PLG HAE have 
completed Treatment Period 1. 
The interim analyses should provide information about the efficacy, safety and PK/
 of 
 mg, 
 mg, and 
 mg CSL312 q4wk (
) and 
 mg CSL312 q2wk. 
Each interim analysis will be presented as outlined in Section 7 and will include the following 
analyses: 
•
The time-normalized number of HAE attacks presented descriptively by treatment.
•
Pairwise comparisons by using a two-sided Mann-Whitney test for a difference in the
time-normalized number of HAE attacks between 
 mg CSL312 or 
 mg CSL312
q4wk for subjects with C1-INH HAE and placebo q4wk (the test will only be applied
to the interim analysis after all subjects completed the blinded part of Treatment
Period 1).
•
Mann-Whitney test for the difference in the time-normalized number of HAE attacks
between the 2 treatments 
 mg and 
 mg CSL312 q4wk for subjects with C1-INH
HAE (the test will only be applied to the interim analysis after all subjects completed
the blinded part of Treatment Period 1).
•
By-subject listing for primary efficacy.
• 
. 
•
The number and percentage of responders and non-responders with corresponding 95%
CI and corresponding by-subject listing.
• 
• The number and percentage, and the fraction of subjects who do not experience a HAE 
attack at certain time points as well as the median time of being attack-free and 
corresponding by-subject listing. 
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Statistical Analysis Plan 
Protocol Number: CSL312_2001 
Product Name: CSL312 
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 Page 23 of 71 
•
The total number and percentage of mild, moderate, or severe HAE attacks as well as
the time-normalized number per month and the number of subjects having at least 1
mild, moderate, or severe HAE attack and corresponding by-subject listing.
•
The number, the time-normalized number, and the percentage of treated and untreated
attacks overall and by severity. The number and percentage of subjects with at least 1
treated attack, the number and percentage of subjects with only treated attacks, the
number and percentage of subjects with attacks but without treated attacks, the number
and percentage of subjects with no attacks at all, and the number and percentage of
attacks treated per subject and corresponding by-subject listing.
•
Summary of subjects with AEs (number with any AE, with AEs occurring within 24
hours of investigational product injection, with SAE, with related AEs, with AEs
leading to study discontinuation, AEs within each of the intensity categories, and AEs
within each of the outcome categories).
•
Summary of subjects with SAEs (number with any SAE, with SAEs occurring within
24 hours of investigational product injection, with related SAE, with SAEs leading to
study discontinuation, SAEs within each of the intensity categories, and SAEs within
each of the outcome categories).
•
Incidence of subjects with AEs  by system organ class (SOC) and preferred term (PT)
•
Incidence of subjects with TEEs by SOC and PT.
•
Incidence of subjects with bleeding events by SOC and PT.
•
Incidence of subjects with anaphylaxis by SOC and PT.
•
By-subject listings of TEAEs, SAEs, AESIs
•
Summary of CSL312 concentrations by planned time point and corresponding
by-subject listing showing individual CSL312 concentrations by actual sampling time.
•
Summary of PK parameters and corresponding by-subject listing.
• 
Further details to the analysis above can be found in the corresponding sections (Section 10.1, 
11.2, 12.2, 0, 13.1, 13.2). 
Further interim analyses may be conducted on an as-needed basis to support regulatory 
activities. 
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Protocol Number: CSL312_2001 
Product Name: CSL312 
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IDMC Reviews 
Output provided for the IDMCs will be unblinded and will be distributed only to IDMC 
members and unblinded CSL personnel. The outputs will be stored in access restricted folders 
to which only unblinded CSL personnel will have access (see further details to unblinded CSL 
personnel in the IRT Project Communication Plan). The output will be presented in the format 
as described in Section 7. 
The IDMC will monitor safety, efficacy, and PK/
 at regular intervals. The following outputs 
will be provided for the IDMCs: 
First IDMC Review: Overview of Study Initiation Visits, Health Authorities feedback, 
number of subjects screened, enrolled, and entered Run-In Period. No analysis outputs will be 
produced. 
Second IDMC Review: The following outputs as specified in this SAP will be produced: 
•
Subject Disposition (table);
•
HAE History (table);
•
Overall AE Summary (table);
•
Overall SAE Summary (table)
•
Treatment-emergent AE (TEAE) Summary by SOC and PT (table);
•
Subject profiles showing HAE attacks and treatments on a timeline (figure).
•
Listings:
o
SAEs;
o 
o 
. 
Third IDMC review: The following outputs as specified in this SAP will be produced: 
•
Outputs listed above for the second IDMC review;
•
Tables of
o
Time-normalized Number of HAE Attacks;
o
Responder Subjects;
o
HAE Attack-free Subjects;
o
HAE Attacks;
o
HAE Attacks Treated With On-demand HAE Medication;
o 
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Product Name: CSL312 
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o 
; 
o
;
o 
; 
o 
; 
o 
; 
o
;
o
.
5 Changes in the Conduct of Planned Analyses 
Changes after finalization of this SAP will either be described in a protocol amendment or in 
an update to the SAP. They will be clearly indicated in the CSR. 
Changes in the analysis following Amendment 2 are as follows: 
Efficacy analysis: the planned treatment for the efficacy analysis is the randomized treatment. 
Following Amendment 2, for subjects randomized to 
 mg CSL312 q4wk in Treatment 
Period 2 their planned treatment will be reduced to 
 mg CSL312 q4wk. The subjects will 
be reported under this treatment after the planned dose reduction. For subjects who receive 
continuously the same dose of CSL312 during both treatment periods, data will be included in 
the analysis until the planned dose reduction following Amendment 2. 
Safety analysis: the actual treatment will be used for the Safety analysis. Subjects with planned 
or unplanned dose reduction or allowed dose increase will be reported under the treatment they 
actually received. For subjects who receive continuously the same dose of CSL312 during both 
treatment periods, data will be included in the analysis until any dose change. 
The second and third interim analysis will be combined into one. 
6 Study Analysis Populations 
6.1 Screening Population 
The Screening population will consist of all subjects who provide written informed consent 
and who undergo any study screening procedure. 
Technical Note: Subjects with informed consent date available and any assessments labelled as 
Screening Visit available will be included. 
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Protocol Number: CSL312_2001 
Product Name: CSL312 
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6.2 Intent-to-Treat Population 
The Intent-to-Treat (ITT) population will consist of all subjects who provide informed consent, 
undergo any study screening procedure, and who are assigned to treatment in Treatment 
Period 1 or to treatment in Treatment Period 2, regardless of whether they receive the 
investigational product. The ITT population will be analyzed using the treatment to which the 
subject was assigned in Treatment Period 1, in Treatment Period 2 at Week 13, or 
 mg after 
dose reduction from 
 mg following Amendment 2 in Treatment Period 2 (only applicable 
for C1-INH HAE subjects), regardless of the actual treatment received. 
Technical Note: Subjects who belong to the Screening population and have randomization date 
available for Treatment Period 1 or Treatment Period 2 will be included for the corresponding 
Treatment Periods. Thus, the ITT will be assigned within treatment period. 
6.3 Safety Population 
The Safety population will consist of all subjects who provide informed consent, are assigned 
to treatment in Treatment Period 1 or to treatment in Treatment Period 2 and receive at least1 
dose or partial dose of the investigational product and will be based on the actual treatment 
received. 
Technical Note: Subjects who belong to the ITT population and have at least one non-missing 
volume of study medication entered in the eCRF will be included. 
6.4 Per-Protocol Population 
The per-protocol (PP) population will consist of all subjects in the ITT population, excluding 
subjects who have a significant protocol violation. Protocol violations which will lead to 
exclusion from the PP population will be reviewed and agreed prior to conducting each of the 
interim analyses and before database lock. 
Technical Note: Subjects who belong to the ITT population and who do not have significant 
protocol violations which lead to exclusion from PP as decided during the Data Review 
Meeting will be included. 
6.5 Pharmacokinetic Population 
The PK population will consist of all subjects in the Safety population for whom at least 1 
measurable concentration of CSL312 is reported. 
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Product Name: CSL312 
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6.6 
7 General Considerations 
Analysis datasets will be created according to Clinical Data Interchange Standards Consortium 
(CDISC) standards, and data will be displayed according to reporting standards in this SAP 
and TFL formats.  
SAS version 9.3 or higher will be used to perform all data analyses and to generate TFLs. 
All ICH required data in the database will be presented in data listings. 
Depending on the analysis populations defined, all data from a subject or a subset of data may 
be excluded from certain analyses (e.g., analyses based on the PP population) as defined in 
Section 6. 
Continuous variables will be described by the number of observations, mean values with their 
95% CIs, standard deviation (SD), 25th percentile, median (50th percentile), 75% percentile, 
and range (minimum to maximum). The geometric coefficient of variation will be expressed 
as a percentage for PK and 
 data and will be calculated as 100*sqrt(exp(SDlog2)-1). The 
geometric mean and its 90% CI will be calculated for PK and 
 data. The geometric mean 
and its 90% CI will be calculated by log-transforming the data, calculating the mean and the 
lower and upper limits of the 90% CI of the log-transformed data, and subsequently back 
transforming the mean and the lower and upper limits. Categorical variables will be 
summarized using frequency counts and percentages. Analyses that use other descriptive 
statistics will have the specific descriptive statistics required identified with the analysis in the 
applicable SAP section. 
Summary statistics of location parameters (mean, median, quartiles) will be reported to one 
more decimal place than the collected data. Summary statistics of variability (SD) will be 
reported to one more decimal place than the commensurate location parameter. For example, 
the mean and median for age will be reported to one decimal place because it is collected in 
full years. The SD of age will then be reported to 2 decimal places. Descriptive percentages 
and proportions will be displayed to one decimal place. Percentages and proportions to be 
tested will be calculated to 4 decimal places. Durations will be display to 1 decimal place. 
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Product Name: CSL312 
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The data from Treatment Period 1 and Treatment Period 2 will be analyzed separately. For 
subjects who received continuously the same dose of CSL312 during both treatment periods, 
the two treatment periods will also be analyzed together. For C1-INH subjects having a dose 
change in Treatment Period 2, only data until the date and time of the dose change will be 
included in these summaries over both treatment periods for the safety analyses. For efficacy 
analyses, data until the date and time of the planned dose reduction will be included in these 
summaries over both treatment periods. 
In Treatment Period 1, subjects with C1-INH HAE who are treated with placebo, 
 mg, 
 mg, or 
 mg CSL312 q4wk will be analyzed separately from subjects with C1-INH HAE 
who are treated with 
 mg CSL312 q2wk. In both treatment periods, subjects with FXII/PLG 
HAE will be analyzed separately from subjects with C1-INH HAE. 
Summaries will be reported by treatment period and treatment in the following order: 
• Treatment Period 1 FXII/PLG HAE: 
 mg CSL312 q4wk; 
• Treatment Period 2 FXII/PLG HAE: 
 mg CSL312 q4wk; 
• Treatment Period 1 & 2 FXII/PLG HAE:
 mg CSL312 q4wk; 
• Treatment Period 1 C1-INH HAE: placebo, 
 mg, 
 mg, and 
 mg CSL312 
q4wk, Total Blinded Part and Total CSL312 (no totals will be populated for efficacy; 
for PK, 
 only Total CSL312); 
•
Treatment Period 1 C1-INH HAE: 
 mg CSL312 q2wk; 
•
Treatment Period 2 C1-INH HAE: 
 mg (initial and after down-titration), [
 mg in 
the Safety analysis], 
 mg CSL312 q4wk, and Total (no total will be populated for 
efficacy); 
•
Treatment Period 1 & 2 C1-INH HAE: 
 mg, 
 mg CSL312 q4wk, and Total (no 
total will be populated for efficacy) – only data included until dose change (Safety 
analysis) or planned dose reduction (Efficacy analysis). 
The by-subject listings will include treatment period, treatment, subject number, and basic 
demographics (sex, age, body mass index [BMI]), and the information specific to that listing. 
The laboratory normal reference ranges will be provided and clinical laboratory test results 
outside the normal reference range will be flagged in the laboratory data listings. 
The by-subject listings will be sorted by the treatment which the subjects will be assigned to 
in Treatment Period 1 in combination with the treatment they will be assigned to in Treatment 
Period 2, subject number, and then by visit / date and time. The planned dose reduction 
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following Amendment 2 or dose increase according to the protocol and any unplanned dose 
reductions will happen on an individual base and will be reported in the listings. The dose 
changes will not affect the treatment sequences. The treatment sequences for sorting will be 
as follows: 
Treatment Period 1 
Treatment Period 2 
Subjects With C1-INH HAE 
Placebo q4wk 
none 
Placebo q4wk 
 mg CSL312 q4wk 
Placebo q4wk 
 mg CSL312 q4wk 
 mg CSL312 q4wk 
none 
 mg CSL312 q4wk 
 mg CSL312 q4wk 
 mg CSL312 q4wk 
 mg CSL312 q4wk 
 mg CSL312 q4wk 
none 
 mg CSL312 q4wk 
 mg CSL312 q4wk 
 mg CSL312 q4wk 
none 
 mg CSL312 q4wk 
 mg CSL312 q4wk 
 mg CSL312 q2wk 
none 
 mg CSL312 q2wk 
 mg CSL312 q4wk 
 mg CSL312 q2wk 
 mg CSL312 q4wk 
Subjects With FXII/PLG HAE 
 mg CSL312 q4wk 
none 
 mg CSL312 q4wk 
 mg CSL312 q4wk 
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Formatting for dates and times will be: 
•
Dates only – ddmmmyyyy;
•
Times only – hh:mm or hh:mm:ss (as appropriate);
•
Dates and times – ddmmmyyyy hh:mm or ddmmmyyyy hh:mm:ss (as appropriate).
Generally, only pre-specified planned times will be used in the summaries, statistical 
analyses, and calculations of any derived parameters; unscheduled assessments will be 
included in the listings. 
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. 
Assessment windows will not be defined for classifying measurements obtained outside 
scheduled assessment times. 
7.1 Multicenter Studies 
Data from all participating sites will be pooled prior to analysis. The site identifier will be 
populated in the listings along with the subject number. 
7.2 Treatment Descriptors 
C1-INH HAE: Treatment Period 1 Blinded 
Placebo q4wk 
 mg CSL312 q4wk 
 mg CSL312 q4wk 
 mg CSL312 q4wk 
C1-INH HAE Treatment Period 1 Open-label 
 mg CSL312 q2wk 
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C1-INH HAE: Treatment Period 2 Open-label 
 mg 
CSL312 q4wk 
 mg 
CSL312 q4wk 
 mg 
CSL312 q4wk 
 mg CSL312 will be included only for the Safety analysis; 
 mg will include planned 
(for Efficacy and Safety analysis) and unplanned dose reduction for Safety analysis. 
FXII/PLG HAE: Treatment Period 2 Open-label 
 mg CSL312 q4wk 
7.3 Multiple Comparisons and Multiplicity 
See Section 10.1 for details. 
8 Data Handling Conventions 
8.1 Missing Data 
Imputation of Non-Date 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 using 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. 
Only missing values for the primary efficacy endpoint (i.e., time-normalized number of HAE 
attacks) during Treatment Period 1 will have an impact on the analyses of the pairwise 
comparison between 
 mg CSL312 q4wk versus placebo q4wk and 
 mg CSL312 q4wk 
versus placebo q4wk in Treatment Period 1. The time-normalized number of HAE attacks 
will only be missing for subjects receiving investigational product q4wk and q2wk who drop 
out before Day 6 and Day 15, respectively, of Treatment Period 1. 
Imputation methods based on Markov-Chain Monte Carlo (MCMC) techniques assume a 
certain distribution of the data and sample from this distribution values which are imputed to 
replace the missing values. With only 8 subjects per treatment, MCMC methods are not 
expected to yield reliable estimates. Instead a systematic approach (Enhanced Tipping Point 
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analysis [Liublinska and Rubin, 2014]) will be applied to investigate the robustness of the 
study’s conclusion to the assumed missingness pattern. For details see Section 10.1.1. 
Subjects with the assessment of treatment relationship for AEs and SAEs missing will have 
the worst case assumed to impute the relationship: if relationship to study treatment is 
missing and the event started on or after the first administration of study treatment it will be 
assumed to be “Yes”. There will be no other imputation for missing data. 
Imputation of Partial Dates 
If the start or end date of an event is missing, then the duration of the event will naturally also 
be missing. 
There will be no imputation of partially or completely missing dates. See Section 11.2 for the 
handling of partially or completely missing AE start dates. See Section 0 for the handling of 
partially or completely missing start and end dates of concomitant medication. 
8.2 Derived Variables 
The following sections provide a general description of the derived variables for data 
analyses. Analysis dataset specifications in a separate document will provide full details on 
data derivations and transformations. 
Reference Dates 
Reference dates are used to assign study periods relative to treatment. 
Because age is an eligibility criterion, the reference date for age will be the date of Screening. 
The safety reference date will be the treatment start date and will be used to calculate study 
day for safety measurements. 
The efficacy reference date will be the start date of the efficacy evaluation period. 
Study Day for Safety and Efficacy Measures 
If the date of interest occurs on or after the safety or efficacy reference date, then the study 
day will be calculated as (date of interest – safety or efficacy reference date) + 1. If the date 
of interest occurs before the safety or efficacy reference date, then the study day will be 
calculated as (date of interest – safety or efficacy reference date). There will be no Day 0. 


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Durations 
Durations (e.g., the duration of an AE) will be calculated in days: 
•
End date and time (if available) – start date and time (if available) + 1.
To transform durations or 
 which are calculated in days into months, divide the 
number of days by 30.4375; to transform to weeks divide the number of days by 7; to 
transform to years divide the number of days by 365.25. These algorithms 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. 
Age will be taken from the data base. 
Baseline Definition 
Baseline is defined as the most recent, non-missing value prior to or on the first study 
treatment dose date. 
Change from Baseline 
Change from baseline can only be calculated for measures that have baseline and 
post-baseline records and will be calculated as: 
•
Value at respective visit – baseline value.
Percentage change from baseline will be calculated as: 
•
(change from baseline / baseline value) * 100
If either the baseline or the visit value is missing, the change from baseline and percentage 
change from baseline will be missing as well. 
Multiple Assessments 
All data will be reported according to the nominal visit date at which it was assessed (that is, 
no visit windows will be applied during dataset creation and the visit will not be re-allocated 
if the actual visit date deviates from the planned date according to the visit schedule in the 
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protocol). 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 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. 
Actual Treatment 
The subject’s actual treatment will be derived from exposure data. If a subject is either 
up-titrated or down-titrated during Treatment Period 2, the actual treatment will be the initial 
treatment until dose change and the modified treatment after dose change. The subject will be 
reported in the initial treatment until dose change and in the modified treatment beginning 
with the dose change. If a subject receives a treatment different from the planned it will be 
decided during the Data Review Meeting on an individual base what is considered the actual 
treatment. 
Study Periods Relative to Treatment 
The following definitions for the evaluation periods of efficacy and safety will be used to 
define the durations used in the denominator of the time-normalized endpoints and safety 
endpoints such as exposure and subject-years. It is not intended to re-assign assessments 
made during scheduled visits based on these definitions. Scheduled visits will not be 
re-labelled based on subject’s study days irrespective of whether the visit takes place in the 
planned time window. 
The Study Completion Date Visit in this study is at the end of Treatment Period 1 or 
Treatment Period 2 or at the time of premature study discontinuation. This visit is followed 
by the Follow-up Visit which may be waived in place of a telephone contact. 
Efficacy Analysis: The evaluation periods will be: 
Run-in Period (all subjects): From Week 1 Day 1 of the Run-in Period until the date / time 
of the Week 1 Day 1 Visit of Treatment Period 1 (the date / time of the first administration of 


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investigational product in Treatment Period 1) or the Study Completion Visit date and time 
(whichever occurs earlier). The duration (days) of the Run-in period will be: 
Week 1 Day 1 Visit date and time of Treatment Period 1 or Study Completion Visit date and 
time – Week 1 Day 1 Visit date and time of Run-in + 1. 
Treatment Period 1 (subjects who receive an IV loading dose of investigational 
product): From Week 1 Day 6 Visit of Treatment Period 1 (the date / time of the first SC 
administration of investigational product in Treatment Period 1) until the date / time of the 
Week 13 Day 91 Visit (the date / time of the first administration of investigational product in 
Treatment Period 2) or the Study Completion Visit date and time (whichever occurs earlier). 
The duration (days) of the efficacy evaluation period for Treatment Period 1 will be: 
Week 13 Day 91 Visit date and time or Study Completion Visit date and time – Week 1 Day 6 
Visit date and time + 1. 
Treatment Period 1 (
): From Week 3 Day 15 Visit of Treatment Period 1 (the date / time of the second SC 
administration of investigational product in Treatment Period 1) until the date / time of the 
Week 13 Day 85 Visit (the date / time of the first administration of investigational product in 
Treatment Period 2) or the Study Completion Visit date and time (whichever occurs earlier). 
The duration (days) of the efficacy evaluation period for Treatment Period 1 will be: 
Week 13 Day 85 Visit date and time or Study Completion Visit date and time – Week 3 
Day 15 Visit date and time + 1. 
Treatment Period 2 (subjects assigned to 
 mg CSL312 and FXII/PLG HAE 
subjects): Treatment Period 2 will start after it is assumed that all subjects have achieved 
steady-state under CSL312. From Week 21 Day 147 Visit of Treatment Period 2 (the date / 
time of the third administration of investigational product in Treatment Period 2) until the 
date / time of the Study Completion Visit. The duration (days) of the efficacy evaluation 
period for Treatment Period 2 will be: 
Study Completion Visit date and time – Week 21 Day 147 Visit date and time + 1. 
Treatment Period 2 (C1-INH HAE subjects assigned to 
 mg CSL312): Treatment 
Period 2 will start after it is assumed that all subjects have achieved steady-state under 
CSL312. 
o 
 mg portion: From Week 21 Day 147 Visit of Treatment Period 2 (the date / time 
of the third administration of investigational product in Treatment Period 2) until the 
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date / time of the Study Completion Visit OR the date / time of the planned dose 
reduction to 
 mg (following Amendment 2), whatever occurs first. The duration 
(days) of the efficacy evaluation period for 
 mg in Treatment Period 2 will be: 
(Study Completion Visit date and time or Date and time of planned dose reduction, 
whichever occurs first) – Week 21 Day 147 Visit date and time + 1; 
o 
 mg portion: From the date / time of the planned dose reduction to 
 mg 
(following Amendment 2) until the Study Completion Visit date / time. The duration 
(days) of the efficacy evaluation period for 
 mg in Treatment Period 2 will be: 
Study Completion Visit date and time – Date and time of planned dose reduction. 
Treatment Period 1 and 2 (subjects who receive an IV loading dose of investigational 
product and who participate in Treatment Period 2): From Week 1 Day 6 Visit of 
Treatment Period 1 (the date / time of the first SC administration of investigational product in 
Treatment Period 1) until the date / time of the Study Completion Visit or the date / time of 
planned dose reduction, whichever occurs first. The duration (days) of the efficacy evaluation 
period for Treatment Period 1 and 2 will be: 
Study Completion Visit date and time or Date and time of planned dose reduction, whichever 
occurs first – Week 1 Day 6 Visit date and time + 1. 
After planned dose reduction, data will not be included in the summary tables. 
HAE attacks with start dates outside the above specified efficacy evaluation periods will not 
be included in the efficacy analysis but will only be listed: 
•
HAE attacks with a start date between the first and second administrations of the
investigational product in Treatment Period 1,
•
HAE attacks with a start date between Week 13 Day 85/91 and Week 21 Day 147,
•
HAE attacks with start date between date of last treatment period visit and Follow-up.
Safety Analysis Exposure: The duration in days of the evaluation periods will be: 
Treatment Period 1 (subjects who participate in Treatment Period 2): 
Week 13 Day 85/91 Visit date and time – 1 – date and time of first administration of 
study treatment + 1. 
Treatment Period 1 (subjects who do NOT participate in Treatment Period 2): 
Study Completion Visit date and time – date and time of first administration of study 
treatment + 1. 
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Treatment Period 2 (subjects without dose change): 
Study Completion Visit date and time –Week 13 Day 85/91 Visit date and time  + 1. 
Treatment Period 2 (subjects with dose change): 
Portion before dose change: 
Date and time of dose change – Week 13 Day 85/91 Visit date and time + 1. 
Portion after dose change: 
Study Completion Visit date and time – Date and time of dose change. 
Treatment Period 1 and 2 (subjects without dose change): 
Study Completion Visit date and time – date and time of first administration of study 
treatment + 1. 
Treatment Period 1 and 2 (subjects with dose change): 
Portion before dose change: 
Date and time of dose change – date and time of first administration of study treatment + 1. 
Portion after dose change: 
Data will not be included in the summary tables. 
Safety Analysis AEs: The duration in days of the evaluation periods will be: 
Treatment Period 1 (subjects who receive an IV loading dose of investigational product 
and who participate in Treatment Period 2): 
Week 13 Day 91 Visit date and time – 1 – Week 1 Day 6 Visit of Treatment Period 1 
date and time (the date / time of the first SC administration of investigational product 
in Treatment Period 1) + 1. 
Treatment Period 1 (subjects who receive an IV loading dose of investigational product 
and who do NOT participate in Treatment Period 2): 
Follow-up or Study Completion Visit date and time (whichever occurs later) – Week 1 
Day 6 Visit of Treatment Period 1 date and time (the date / time of the first SC 
administration of investigational product in Treatment Period 1) + 1. 
Treatment Period 1 (
): 
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Week 13 Day 85 Visit date and time – 1 – Week 1 Day 1 Visit of Treatment Period 1 
date and time (the date / time of first SC administration of investigational product in 
Treatment Period 1) + 1. 
Treatment Period 1 (
): 
Follow-up or Study Completion Visit date and time (whichever occurs later) – Week 1 
Day 1 Visit of Treatment Period 1 date and time (the date / time of first SC 
administration of investigational product in Treatment Period 1) + 1. 
Treatment Period 2 (subjects without dose change): 
Follow-up or Study Completion Visit date and time (whichever occurs later) –
Week 13 Day 85/91 Visit date and time + 1. 
Treatment Period 2 (subjects with dose change): 
Portion before dose change: 
Date and time of dose change – Week 13 Day 85/91 Visit date and time + 1. 
Portion after dose change: 
Follow-up or Study Completion Visit date and time (whichever occurs later) – Date 
and time of dose change. 
Treatment Period 1 and 2 (subjects without dose change): 
Follow-up or Study Completion Visit date and time (whichever occurs later) – date and time 
of first SC administration of study treatment + 1. 
Treatment Period 1 and 2 (subjects with dose change): 
Portion before dose change: 
Date and time of dose change – date and time of first SC administration of study treatment 
+ 1.
Portion after dose change: 
Data will not be included in the summary tables. 
Date and time of first SC administration of study treatment is Week 1 Day 6 or Week 1 Day 1 
for those with 
 an IV loading dose, respectively.  
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8.3 Laboratory Parameters 
A laboratory value that is outside the reference range is either high abnormal (value above the 
upper limit of the normal reference range) or low abnormal (value below the lower limit of 
the normal reference range). An abnormal laboratory value is not necessarily of potential 
clinical interest. 
For laboratory safety parameters, any instances of absolute values being outside the reference 
range or changes at any visit after study start that are considered by the investigator as 
clinically significant must be recorded in the eCRF as AEs. In addition, at the investigator’s 
discretion, any changes or trends over time in laboratory parameters can be recorded in the 
eCRF as AEs if such changes or trends are clinically relevant, even if the absolute values are 
within the reference range. 
9 Study Population 
9.1 Disposition of Subjects 
Subject disposition will be summarized using all subjects who provided informed consent. 
The following will be presented in summary tables by treatment as specified in Section 7. 
The results will be presented over all subjects and for subjects with C1-INH and FXII/PLG 
HAE. Percentages will be based on the Screening population: 
•
Number of subjects who provided informed consent;
•
Number and percentage of subjects who underwent Screening;
•
Number and percentage of subjects who entered the Run-in Period;
•
Number and percentage of subjects still in the Run-in Period (only for interim
analysis);
•
Number and percentage of subjects who were not assigned to study treatment;
•
Number and percentage of subjects who were assigned to study treatment in
Treatment Period 1;
•
Number and percentage of subjects who were assigned to study treatment in
Treatment Period 2;
•
Number and percentage of subjects still in Treatment Period 1 (only for interim
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•
Number and percentage of subjects still in Treatment Period 2 (only for interim
analysis);
•
Number and percentage of subjects who have a planned dose reduction from 
 mg 
to 
 mg in Treatment Period 2 (following Amendment 2);
•
Number and percentage of subjects who completed Treatment Period 1;
•
Number and percentage of subjects who completed Treatment Period 2;
•
Number and percentage of subjects still in the study (only for interim analysis);
•
Number and percentage of subjects who completed the study;
•
Number and percentage of subjects who discontinued the study in the Run-in Period
with reason for discontinuation (percentages based on the number who discontinued);
•
Number and percentage of subjects who discontinued the study in Treatment Period 1
with reason for discontinuation (percentages based on the number who discontinued);
•
Number and percentage of subjects who discontinued the study in Treatment Period 2
with reason for discontinuation (percentages based on the number who discontinued);
•
Number and percentage of subjects who discontinued the study in any period with
reason for discontinuation (percentages based on the number who discontinued).
A by-subject listing for all available data with the information as described in Section 7 and 
in addition screening status (failed or qualified), reason for screening failure (in- or exclusion 
criterion numbers), date and time of informed consent, date of eligibility for Run-in, reasons 
for non-eligibility for Run-in, date of eligibility for Treatment Period 1, date and time of 
randomization, reason for non-eligibility for randomization, date and time of first IV, first SC, 
and last treatment, date of study completion or discontinuation, and reason for study 
discontinuation will be presented. Another listing for all available data will present the 
individual visit dates for all visits (scheduled and unscheduled) which the subject attended. 
9.2 Protocol Violations 
Protocol violations are those protocol deviations which may identify subjects who should be 
excluded from one or more analysis population(s). Listings showing subjects with protocol 
deviations will be generated prior to each interim and the final analysis to identify subjects 
who may have these protocol violations. During the Data Review Meetings, the subject 
assignment to analysis populations will be discussed in detail based on the consolidated 
protocol deviations from the 
 along with the listings of the potential 
protocol violations specified below. It cannot be ruled out that during the discussion of 
protocol deviations, additional violations which are not listed below will be considered to 
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have a significant impact and will thus lead to exclusion of subjects from analysis 
population(s). The decisions made during the Data Review Meetings will be documented in 
detail in the Data Review Meeting minutes and may modify the specifications in the list 
below. The Data Review Meeting minutes will be agreed upon prior to each interim and final 
analysis. 
Potential Protocol Violations 
Potential Exclusion From 
Analysis Population 
Subject did not provide informed consent 
(informed consent date missing) 
Screening, Safety, ITT, PP, PK, 
Subject randomized but not treated with study 
treatment 
Safety, PP, PK, 
Subjects treated with incorrect study treatment 
PP, potentially PK, 
Subject randomized and treated but does not 
have at least one measurable PK concentration 
PK 
Subject randomized and treated but does not 
have at least one 
 measurement 
Subject randomized and treated but without 
primary efficacy assessment 
PP 
Subject randomized and treated but violated 
inclusion or exclusion criteria 
PP, potentially also PK, 
Subject randomized and treated but compliance 
outside 80-120% 
PP, potentially also PK, 
Subject randomized and treated but received 
prohibited concomitant medication 
PP, potentially also PK, 
Protocol deviations caused by the Corona Virus Disease 2019 (COVID-19) pandemic will be 
documented throughout the entire study. They will be assigned as a separate protocol 
deviation category “COVID-19”, will be listed, and discussed during the Data Review 
Meetings. They will be summarized separately from the other protocol deviations and will 
also be discussed in the CSR. 
Prior to each Data Review Meeting, a list of concomitant medications used in the study will 
be provided to CSL as an Excel file in the same format as the corresponding listing of 
concomitant medications in the TFL shells. This Excel file will be reviewed by CSL and 
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concomitant medication potentially interfering with the PK/
 analysis or with the efficacy 
analysis will be flagged. 
A summary table with the number and percentages of subjects with  
•
Inclusion and exclusion protocol violations;
•
All significant protocol violations including inclusion and exclusion violations
will be provided. Number and percentage of subjects in the Screening, Safety, ITT, PP, PK, 
and 
 population will be provided. 
The following by-subject listings for all available data with the information as described in 
Section 7 and in addition information as listed below will be provided: 
•
Randomized and actual treatment;
•
All inclusion and exclusion protocol deviations;
•
All other protocol deviations with an indication whether this is a significant violation
or minor deviation and from which analysis population the subject will be excluded;
•
COVID-19 protocol deviations.
9.3 Demographic and Baseline Characteristics 
Demographic and baseline subject characteristics will be summarized for the ITT and PP 
populations. 
BMI will be defined as body weight [kg]/height [m2] 
The following summaries will be provided: 
•
Demographic characteristics: sex, race, ethnicity, age, height and body weight at
Screening, and BMI. As only adults will be included, no age groups will be formed.
•
HAE history: HAE type (C1-INH Type I, C1-INH Type 2, FXII HAE, PLG HAE),
number of HAE attacks before Screening for subjects without prophylactic HAE therapy
(C1-INH HAE: over a consecutive 2-month period during the 3 months before Screening;
FXII/PLG HAE: during the 3 months before Screening), number and percentage of
subjects who took prophylactic HAE therapy, number of HAE attacks before the start of
prophylactic therapy (C1-INH: over any consecutive 2-months period during 3 months
before the start of prophylactic HAE therapy; FXII/PLG: during the 3 months before the
start of prophylactic therapy).
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•
Medical history will be presented by SOC and PT – include medical history terms with
end date / evidence for end date prior to informed consent date.
•
Concomitant diseases will be presented by SOC and PT – include medical history terms
with end date / evidence for end date after informed consent date or flagged “Ongoing” or
end date missing.
Medical history and concomitant diseases will be coded by Medical Dictionary for 
Regulatory Activities (MedDRA). There will be periodic updates of the MedDRA version. 
The latest licensed version will be used, and version updates will be implemented upon 
availability.  
By-subject listings for all available data with the information as described in Section 7 will be 
provided for: 
•
Demographic data (sex, age, race, ethnicity, height at Screening, body weight at
Screening, and BMI);
•
Disease characteristics (HAE type, number of HAE attacks before Screening,
prophylactic HAE therapy [Yes, No], number of HAE attacks before the start of
prophylactic HAE therapy);
•
Medical history and concomitant diseases (medical history term, SOC, PT, start and end
date or ongoing flag);
•
Reproductive system findings (childbearing potential, method of birth control, date and
time of pregnancy test, and pregnancy test result).
9.4 Concomitant Medications 
Prior and concomitant medication will be summarized for the Safety population. On-demand 
HAE medication will be summarized as separate block within the summaries of prior and 
concomitant medication (as a “virtual” ATC class ”On-demand HAE Medication”). The 
on-demand HAE medication will also be reported in their original ATC class. For the “Any 
Medication” entry, the virtual ATC class “On-demand HAE Medication” will be excluded to 
avoid counting the medication twice. 
Concomitant medications will be coded using World Health Organization Drug Dictionary 
Enhanced (WHO-DDE) B3 version March 2018 or more recent. The summary of 
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concomitant medications by Anatomical Therapeutic Chemical (ATC) class and PT. ATC 
Level 4 will be used for the summary tables and listing unless coding is not available at level 
4. In these cases, level 3 ATC name will be used. Similarly, if the level 3 ATC name is not
available then the level 2 ATC name will be used and if the level 2 ATC name is not available
then the level 1 ATC name will be used. These replacements will only be made for missing
ATC level 4. ATC Level 1 information will be included in the dataset created but will not
appear in the listing or summary except when all other levels are not available.
The following classification of concomitant medication related to start date of study 
treatment in each treatment period will be applied: 
•
Assign to ‘Prior Only’ if the concomitant medication start date and end date is prior to
study treatment start date of the respective treatment period; if the subject has not taken
any study treatment; or the concomitant medication start date is missing and the
concomitant medication end date is before the study treatment start date of the respective
treatment period;
•
Assign to ‘Prior and Concomitant’ if the concomitant medication start date is prior to
study treatment start date of the respective treatment period and the concomitant
medication end date is on or after study treatment start date of the respective treatment
period or ongoing treatment;
•
Assign to ‘Concomitant Only’ if the concomitant medication start date is on or after the
study treatment start date of the respective treatment period.
If medication start and/or stop dates are partially or completely missing, medications will be 
assumed to be ‘Concomitant Only’, unless there is clear evidence (through comparison of 
partial dates) to suggest that the medication started prior to the date of the first administration 
of study treatment of the respective treatment period. If there is clear evidence to suggest that 
the medication started prior to the date of first administration of study treatment of the 
respective treatment period (the available parts of the date are prior to the corresponding parts 
of the date of first administration of study treatment of the respective treatment period), the 
medication will be assumed to be ‘Prior and Concomitant’, unless there is clear evidence to 
suggest that the medication stopped prior to the date of the first administration of study 
treatment of the respective treatment period (the available parts of the medication end date 
are prior to the corresponding parts of the date of first administration of study treatment of 
the respective treatment period). If this is the case, the medication will be considered ‘Prior 
Only’. 


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For medications which are considered ‘Prior and Concomitant’ or ‘Concomitant Only’ in 
Treatment Period 2 or in both treatment periods, the dose change needs to be considered. It 
should be noted that the medication flags will no longer be exclusive. The same medication 
may be “Concomitant Only” for Treatment Period 1 and for both treatment periods, but 
“Prior Only” for Treatment Period 2. 
The following flags will be assigned: 
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Product Name: CSL312 
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In the summary of concomitant medications, each subject will be counted once within each 
PT (Any Medication, ATC Class, and PT). For example, if a subject takes Amoxycillin on 
two separate occasions, the subject will be counted only once under the medication 
“Amoxycillin”, once in the corresponding ATC class, and once for “Any Medication”. The 
number and percentages of subjects based on the Safety population along with the number of 
reports will be presented for ‘Prior’. For ‘Prior and Concomitant’ the number and percentage 
of subjects will be presented together with ‘Concomitant Only’ medications. 
A by-subject listing for all available data with the information as described in Section 7 and 
in addition medication/treatment, start and end date or ongoing, dose, route, frequency, 
primary indication for the concomitant medication, AE identifier if applicable, medical 
history identifier if applicable, and concomitant medication flag (Prior Only [P1, P2], Prior 
and Concomitant [PC1, PC2, PC2_after, PC12], Concomitant Only [C1, C2, C2_after, C12]) 
will be provided. 
10 Efficacy 
The primary efficacy endpoint will be summarized for the ITT and PP populations. 
Tables will be presented by treatment as described in Section 7.2 and treatment period. The 
planned treatment will be used. This is the randomized treatment before planned dose 
reduction following Amendment 2. After planned dose reduction following Amendment 2, 
the planned treatment is the reduced dose (
 mg) for the C1-INH HAE subjects 
randomized to 
 mg in Treatment Period 2. Unplanned dose reductions or dose increase to 
 mg CSL312 q4wk will not be considered for the Efficacy analysis. 
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10.1 Primary Efficacy: Analysis of Time-Normalized Number of HAE 
Attacks in Treatment Period 1 (Blinded Part) 
The ITT population will be used for the primary analysis and the PP will be used as the 
secondary. 
As outlined in Section 8.2.8, HAE attacks with a start date not falling into the efficacy 
evaluation period will not be included in the analyses of efficacy but will be presented in a 
listing only. 
Subjects will enter HAE symptoms into their eDiary and the start and end date and time, the 
interference of HAE symptom(s) with daily activities, and location(s) of the HAE 
symptom(s). Investigator-reported HAE attacks will be based upon review of subject diaries, 
relevant interval medical history, and physician judgment. The investigator may ask 
clarifying questions to assist in his/her assessment of whether or not an HAE attack occurred. 
If an attack occurred, then the investigator will record an attack in the eCRF, the start/end 
date, the attack location(s), and the severity of the attack based on the most severe symptoms. 
For every visit, the Investigator will report all HAE attacks that have occurred in the interim 
since the last visit the subject attended. 
For the analyses, a HAE attack is defined based on the HAE attacks reported by the 
investigator using the HAE attack eCRF. 
In the primary analysis, only subjects with C1-INH HAE who receive q4wk SC dosing (after 
an IV loading dose) in a blinded manner will be included. The evaluation periods are defined 
in Section 8.2.8. 
The time-normalized number of HAE attacks per month during Treatment Period 1 for a 
subject will be calculated as:  
(number of HAE attacks / length of subject’s evaluation period in days) * 30.4375 
where the length of subject’s evaluation period is defined in Section 8.2.8. 
The time-normalized number of HAE attacks per month will be summarized descriptively 
including median (primary) and mean (secondary) with corresponding 95% CIs by blinded 
treatment (i.e., placebo, or 
 mg, 
 mg, or 
 mg CSL312 q4wk). 
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Protocol Number: CSL312_2001 
Product Name: CSL312 
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 Page 48 of 71 
To test for a difference in the primary efficacy endpoint between 
 mg CSL312 q4wk or 
 mg CSL312 q4wk and placebo q4wk, pairwise comparisons will be performed by testing 
the hypotheses using a two-sided Mann-Whitney test. 
To account for multiple testing, the alpha level of 5% will be evenly split between the 
hypotheses tested. Therefore, the 
 mg CSL312 q4wk or 
 mg CSL312 q4wk CSL312 
doses will each be evaluated against placebo q4wk at alpha = 0.025: 
H01: a1 = 0 
versus 
H11: a1 ≠ 0 
and 
H02: a2 = 0 
versus 
H12: a2 ≠ 0 
In the above hypotheses, the term “a1” is the shift between the 2 distributions of 
 mg 
CSL312 q4wk and placebo q4wk and the term “a2” is the shift between the distributions of 
 mg CSL312 q4wk and placebo q4wk, respectively. 
For the difference in the primary endpoint between the 2 treatments 
 mg and 
 mg 
CSL312 q4wk in Treatment Period 1, a comparison will be performed as an 
 using a two-sided Mann-Whitney test at alpha = 0.05: 
H03: a3 = 0 
versus 
H13: a3 ≠ 0 
where the term “a3” is the shift in the 2 distributions of the 2 CSL312 doses compared against 
each other. 
There will be no testing of the 
 mg CSL312 q4wk dose against placebo q4wk. The 
time-normalized number of HAE attacks will be presented descriptively only. 
A by-subject listing will be generated as specified in Section 7 and in addition showing the 
subject reported HAE symptoms, the HAE attack identifier as entered by the investigator with 
start and end date and time and duration (days), HAE attack location(s), and severity. HAE 
attacks with a start date falling into the efficacy evaluation period and HAE attacks treated with 
on-demand treatment for HAE attacks will be flagged. Details of the on-demand treatment will 
be provided in another by-subject listing. Derived efficacy variables such as number of HAE 
attacks and the time-normalized number of HAE attacks per month for each treatment period 
and for both treatment periods for subjects who received the same dose will be presented in 
another by-subject listing. 
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Protocol Number: CSL312_2001 
Product Name: CSL312 
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Sensitivity Analysis for Primary Efficacy: Missing Values for the 
Time-normalized Number of HAE Attacks in Treatment Period 1 
To assess the impact of missing data for the primary efficacy variable a systematic approach 
will be applied. Imputation techniques based on MCMC methodology are considered 
inappropriate for this study with very small sample size.  
For each treatment (i.e., placebo q4wk, 
 mg, or 
 mg CSL312 q4wk), a range of values 
for the number of time-normalized HAE attacks per month from 0 to 6 subdivided into 9 
increments between two consecutive integer values will be generated. For the two 
comparisons of active treatment versus placebo all possible combinations from the 
subdivided ranges will be imputed to replace the missing values and the data will be analyzed 
using the Mann-Whitney test. Results will be classified into negative (i.e., placebo 
significantly better), neutral (i.e., no significant difference) and positive (i.e., active treatment 
significantly better) and depicted in a table and 2 graphs where the x-axis presents the 
subdivided range for placebo and the y-axis the subdivided range for the active treatment. 
The different outcomes will be distinguished by different symbols. This will only be applied 
to the ITT population. 
Supporting Analysis: Time-normalized Number of HAE Attacks in 
Treatment Period 1 and 2 (Open-label Part) 
In addition to the primary analysis, the time-normalized number of HAE attacks per month will 
also be summarized descriptively for the 
 mg and 
 mg CSL312 q4wk regimens for the 
following: 
•
Treatment Period 2 evaluation period (alone).
•
Treatment Period 1 and Treatment Period 2 evaluation periods (combined) for subjects
who received the same dose continuously during both treatment periods (data will only
be included until the date of the planned dose reduction following Amendment 2 in
Treatment Period 2).
The time-normalized number of HAE attacks per month will also be summarized descriptively 
for the 
 mg CSL312 q2wk regimen for subjects with C1-INH HAE for the efficacy 
evaluation period of Treatment Period 1 and for the 
 mg CSL312 q4wk regimen for subjects 
with FXII/PLG HAE for the efficacy evaluation periods of Treatment Period 1, Treatment 
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Protocol Number: CSL312_2001 
Product Name: CSL312 
CONFIDENTIAL 
 Page 50 of 71 
Period 2, and combined Treatment Period 1 and Treatment Period 2 (only applicable for 
subjects with FXII/PLG HAE). 
The efficacy evaluation periods are defined in Section 8.2.8. 
There will be no testing of the of 
 mg CSL312 q2wk dose against placebo q4wk or the 
 mg CSL312 q4wk dose against placebo q4wk for subjects with FXII/PLG HAE. 
Subjects profiles will be generated for each subject. Subjects will be grouped by treatment 
sequence as for the by-subject listings as described in Section 7. The x-axis will show the 
Run-in Period, Treatment Period 1 and Treatment Period 2. The different subject IDs will be 
plotted on the y-axis. For each subject, a horizontal bar will show the duration of his/her study 
participation; the planned treatment, dots at the respective position of the x-axis will symbolize 
a mild (white dot), moderate (gray dot), and severe (black dot) HAE attack; an arrow above the 
bar at a certain position of the x-axis will show the time point when the subject took rescue 
Subject profiles will be reviewed to detect possible patterns of missing values due to drop-outs, 
e.g., due to many attacks.
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10.2 Secondary Efficacy 
Secondary efficacy endpoints will be analyzed for Treatment Period 1 and Treatment Period 2 
separately. In addition, both treatment periods will be analyzed together for subjects who 
received the same dose continuously during both treatment periods (data will only be 
included until the date of the planned dose reduction following Amendment 2 in Treatment 
Period 2). The evaluation periods are defined in Section 8.2.8. 
Analysis of Responders 
A subject is classified as a responder if the percentage reduction in time-normalized number 
of HAE attacks per month is ≥ 50% as compared to the Run-in Period. The percentage 
reduction is calculated within a subject as: 
100 * [1 – (TNA CSL312 / TNA Run-in)] 
where TNA CSL312 is the time-normalized number of HAE attacks per month during 
treatment with CSL312 and TNA Run-in is the time-normalized number of HAE attacks per 
month during the Run-in Period. 
The number and percentage of subjects classified as responders and non-responders will be 
presented along with 95% CI. 
In Treatment Period 2, the comparison between 
 mg and 
 mg CSL312 q4wk will only 
include data collected prior to the planned dose reduction following Amendment 2. 
A by-subject listing will be provided as specified in Section 7 with the response classification 
and the degree of reduction in time-normalized number of HAE attacks per month. 
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Product Name: CSL312 
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 Page 53 of 71 
Analysis of Attack-free Subjects 
The number and percentage of subjects who do not experience a HAE attack will be 
presented. 
Analysis of HAE Attacks 
The number and percentage of mild, moderate, and severe HAE attacks will be presented as 
well as the time-normalized number of mild, moderate, and severe HAE attacks per month. 
The number and percentage of subjects experiencing at least 1 mild, moderate, or severe 
HAE attack will also be presented. 
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Product Name: CSL312 
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The severity of HAE attacks will be included in the by-subject listing (see Section 10.1). 
Analysis of HAE Attacks Treated With On-demand HAE 
Medication 
A treated HAE attack is defined as a HAE attack which started during the corresponding 
evaluation period for Treatment Period 1 or 2 and during which (start and end date including) 
on-demand medication to treat HAE attacks was taken (i.e., has been started). 
The number and percentage and the time-normalized number of treated and untreated HAE 
attacks per month overall and by severity will be presented. A summary table will be 
provided with 
•
Number and percentage of subjects with at least 1 treated HAE attack;
•
Number and percentage of subjects with only treated HAE attacks;
•
Number and percentage of subjects with HAE attacks but without treated attacks;
•
Number and percentage of subjects with no attacks at all (attack-free subjects);
•
Descriptive statistics for the number and percentage of treated attacks per subject.
This analysis will be repeated for moderate or severe HAE attacks only. 
A by-subject listing will be provided as specified in Section 7 and with the additional 
information of type of on-demand HAE medication (Berinert, Firazyr, Ruconest, Kalbitor, 
Cinryze, or Other), start date and time of the on-demand HAE medication, dose (unit), route, 
frequency, the date and dose of the last and next CSL312 (or placebo) administration, HAE 
attack identifier, start and end date and time of the HAE attack, location(s), and severity. 
PK Analysis of CSL312 in Subjects With C1-INH 
Please refer to Section 12. 
Analysis of Safety and Tolerability of CSL312 in Subjects With 
C1-INH 
Please refer to Sections 11.3, 11.4, 11.5, 11.6, 11.7, 11.8. 


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Product Name: CSL312 
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10.3 
Analyses of Time-normalized Uses of On-demand HAE Medication 
per Month 
Only for subjects with C1-INH HAE, the time-normalized number of uses of on-demand 
HAE medication per month will be summarized descriptively. 
On the “Acute HAE Treatment” eCRF page, it will be entered if on-demand treatment for a 
HAE attack is needed and if so, what medication was used (Berinert, Firazyr, Ruconest, 
Kalbitor, Cinryze, or Other), the dose, route, and frequency administered, and the start date 
and time as well as the HAE attack identifier.  
On-demand medications for treatment of a HAE attack during the efficacy evaluation period 
which will be administered during a HAE attack, will be included in the calculation of the 
time-normalized number of uses of on-demand medication for the treatment of a HAE attack. 
The start date and time of the administration of the on-demand medications will be compared 
with the start and end dates of the HAE attacks described in Section 10.1. Only if the date of 
an administration of an on-demand medication is between the start (including) and end date 
(including) of a HAE attack, the on-demand medication will be included in the calculation of 
the time-normalized number of uses of on-demand HAE medication per month. 
The time-normalized number of uses of on-demand HAE medication per month will be 
calculated as: 
(number of uses of on-demand HAE medication / length of subject’s evaluation period) * 
30.4375 
where the length of subject’s evaluation period is defined in Section 8.2.8. 
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• 
; 
• 
; 
• 
; 
• 
; 
• 
; 
• 
; 
•
;
•
.
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Product Name: CSL312 
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10.4 Treatment Compliance 
Compliance will be summarized for the ITT population for the SC injections in each 
treatment period and both periods together for subjects who received the same dose 
continuously during both treatment periods (data will only be included until the date of the 
planned dose reduction following Amendment 2 in Treatment Period 2). The IV infusions 
will not be included in the compliance analysis. The administered volume of each injection 
will be taken from the data base. The study medication has a concentration of 
 mg per 
 mL. To maintain the blind, the doses in the blinded part of Treatment Period 1 will be 
volume-normalized. It is planned that all SC injections will contain  mL. If in the blinded 
study part, the subject is randomized to 
 mg CSL312, the  mL injection will contain 
purely the study medication. For the 
 mg and the 
 mg CSL312 group, the study 
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Product Name: CSL312 
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medication will be diluted in a 
 and 
 ratio, respectively. For the derivation of the actual 
dose, it is assumed that the dilution will take place as planned. For the open-label part, the 
study medication is not diluted. 
From the actual volume of an injection as in the database and considering the randomized 
dose, the actual dose will be derived as: 
Actual dose (mg) = (actual volume [mL] / K [mL/mg]) * 100, 
where K = 
 or  mL/mg for 
 mg, 
 mg, or 
 mg CSL312 q4wk in the blinded arm 
and  for the open-label arms. 
Compliance for dose (mg) will be calculated as 
Compliance (%) = [total cumulative actual dose / total planned dose)]*100, 
where the total planned dose will be derived from the subject’s exposure and planned 
treatment schedule (q2wk or q4wk) as 
 (duration of exposure in days / (7 * X)) * planned dose + planned dose 
where (duration of exposure in days) is rounded down to the nearest integer which can be 
divided by 7 and X = 2 or 4 corresponds to q2wk or q4wk, respectively. 
Only the administered doses will be considered for the total cumulative actual dose which are 
identical to the planned treatment. The planned treatment is the randomized treatment in 
Treatment Period 1 and in Treatment Period 2 prior to the planned dose reduction following 
Amendment 2. For C1-INH HAE subjects randomized to 
 mg CSL312 in Treatment 
Period 2, the planned treatment after dose reduction changes to 
 mg CSL312. Exposure 
duration will depend on the treatment period and subject’s course of the study. Definitions are 
provided in Section 8.2.8. 
The following summaries will be provided: 
•
Descriptive statistics for compliance (%) over the entire treatment period, for
Treatment Period 1 plus the first three doses of Treatment Period 2 (administration on
site), and for Treatment Period 2 after the first three doses (administration at home);
•
Number and percentage of subjects in the compliance categories < 80%, 80 – 120%,
and > 120% and < 90%, 90 - 110%, and > 110% for the periods specified above.
A by-subject listing as specified in Section 7 and with the following additional information 
will be provided: 
•
Randomized, planned and actual treatments;
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Product Name: CSL312 
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•
Compliance in Treatment Period 1 plus the first three doses of Treatment Period 2,
after the first three doses in Treatment Period 2, and over the entire study.
11 Safety Analyses 
Safety data will be summarized using the Safety population. Evaluation periods for the Safety 
analysis are defined in Section 8.2.8. 
The summary tables will be presented by actual treatment. Due to the dose increase allowed 
in Treatment Period 2 for subjects randomized to 
 mg CSL312, the unplanned dose 
reduction, and the planned dose reduction for C1-INH HAE subjects randomized to 
 mg 
CSL312 following Amendment 2, the same subject may occur in different dose groups in 
Treatment Period 2. The Total column will report each subject only once. Thus, the treatment 
columns will no longer sum up to the Total column. This applies to all Safety summary 
tables. 
11.1 Extent of Exposure 
Duration of exposure (days) will be calculated as specified in Section 8.2.8 for the duration of 
the safety evaluation periods. Descriptive statistics will be provided for each treatment period 
in which a subject participated and for the subject’s exposure over the entire study. 
Number  and percentages of subjects who received 0 or 1 IV infusions and descriptive 
statistics for the number of SC injections will also be presented. 
A by-subject listing will be provided as specified in Section 7 and with the following 
additional information: 
•
Duration of exposure (days) for each treatment period in which the subject
participated and subject’s exposure over the entire study;
•
Number of IV infusions and SC injections;
•
Time point and level of dose modifications.
11.2 Dose Modification 
The number and percentage of subjects (based on the Safety population) with dose change in 
Treatment Period 2 will be summarized. It will be differentiated between subjects randomized 
to 
 mg or 
 mg CSL312 and planned or unplanned dose changes. A by-subject listing 
will be provided as specified in Section 7 and with date and level of dose change. 
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Product Name: CSL312 
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11.3 Adverse Events 
TEAEs are AEs which start on or after the date and time of the first administration of study 
treatment. TEAEs with a start date and time on or after the administration of the IV loading 
dose and before the first administration of SC investigational product will be analyzed 
separately from TEAEs with start date and time on or after the first administration of SC 
investigational product. 
AEs with completely or partially missing date or time will be considered treatment-emergent 
following the worst-case principle, unless the partial date clearly indicates that the AE started 
before the first administration of study treatment. AEs with completely missing start dates 
will be considered treatment-emergent. If only the day is missing, and the start month and 
year of the AE is before the start month and year of the first administration of study 
treatment, the AE will be considered non-treatment-emergent. If day and month are missing 
and the start year of the AE is before the year of the first administration of study treatment, 
the AE will be considered non-treatment-emergent. 
AEs will be coded by MedDRA. There will be periodic updates of the MedDRA version. The 
latest licensed version will be used, and version updates will be implemented upon 
availability. AEs will be primarily classified by MedDRA PT. Analyses will be performed by 
SOC and PT. Aggregated incidences at SOC level and Any TEAE will also be provided. 
TEAEs occurring until the Follow-up Visit will be summarized. All AEs regardless of when 
they were reported will be listed. 
Summaries of TEAEs will count the number of subjects, that is, subjects with multiple 
occurrences of the same TEAE will be counted once in the total of those experiencing this 
PT. Similarly, a subject with 1 or more PT in a SOC will be counted once in the total of those 
experiencing PTs in that SOC. Percentages for subject incidence rates will be based on the 
Safety population. 
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. The MedDRA SOCs and PTs will be presented in 
descending frequency of the overall CSL312 category. Within the same frequency, SOCs and 
PTs will be ordered alphabetically. 
The tables referring to TEAEs on or after first SC injection will comprise two parts: one – 
indicated in the numbering by x.1 – containing the number of subjects, percentage of 
subjects, and number of events, and the other – indicated in the numbering by x.2 – 
containing the event rates per administration and per subject year. The tables referring to 
TEAEs on or after the IV loading dose and before the first SC injection will comprise only 
the first part (number and percentage of subjects and number of events) as described above 
and no rates. 
AE rates per SC injection for each safety evaluation period will be calculated as follows: 
•
AE Rate per SC Injection = 
Number of events for a particular PT
Number of SC injections
where number of SC injections will be the sum of the SC injections that subjects received 
during the respective safety evaluation period. 
•
AE Rate per Subject SC Year = 
Number of events for a particular PT
Subject SC years 
where subject SC years will be the sum of the time in years that subjects were exposed to 
study treatment administered by SC injections during the respective safety evaluation period 
(sum of the duration after SC injections of the respective safety evaluation period in years). 
The safety evaluation periods (Treatment Period 1, Treatment Period 2, and overall) are 
defined for the Safety analysis in Section 8.2.8. 
For TEAEs which started on or after the IV loading dose but before the first SC dose, a 
summary table as described below will be provided and a table of TEAEs by SOC and PT as 
described below. 
An overview summary of TEAEs will be provided as specified in Section 7 for:  
•
Any TEAE;
•
Any SAEs;
•
Any SAEs caused by COVID-19;
•
Any deaths;
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•
Any deaths caused by COVID-19;
•
TEAEs occurring within 24 hours of investigational product administration;
•
Relates TEAEs;
•
TEAEs leading to study discontinuation;
•
TEAEs leading to study discontinuation caused by COVID-19;
•
TEAEs in each intensity category;
•
TEAEs in each outcome category;
•
TEAEs not resolved or resolved with sequelae caused by COVID-19.
The following summary tables will be provided as specified in Section 7 for: 
•
TEAEs by SOC and PT;
•
TEAEs by intensity, SOC, and PT;
•
Related TEAEs by SOC and PT;
•
TEAEs leading to study discontinuation by SOC and PT;
•
Non-serious TEAEs by SOC and PT;
•
Laboratory Findings reported as AEs.
The relationship between MedDRA SOC, PT, and Verbatim Text will be listed. 
TEAEs will be listed for the Safety population. AEs without specification for 
treatment-emergency will be listed for all data available. The listings will include the 
variables as specified in Section 7 and in addition MedDRA SOC, PT, and the verbatim, AE 
start and end date and time if available, duration of AE in days, intensity, serious (yes or no), 
relationship to treatment (yes or no), outcome, action taken, and AE flags (TEAE, SAE, 
temporal relationship within 24 hours, laboratory finding, AESI).  
The following listings will be provided: 
•
Non-TEAEs – all data available;
•
TEAEs on or after IV loading dose and before first SC dose – Safety population;
•
TEAEs on or after first SC dose – Safety population;
•
AEs related to laboratory findings – all data available;
•
AEs caused by COVID-19;
•
MedDRA SOC and PT with all AE verbatim – all data available.


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11.4 Adverse Events of Special Interest 
The AESIs are: 
•
TEE –Embolic and thrombotic events (Standardized MedDRA Query [SMQ]);
•
Bleeding events –Haemorrhages (SMQ);
•
Anaphylactic reaction–Anaphylactic reaction (SMQ)(broad).
Summaries by SOC and PT for each AESI will be provided separately.  
In addition, AESIs will be listed separately in the format specified in Section 11.3. 
CSL will provide 
 with the MedDRA SMQs. 
11.5 Deaths and Serious Adverse Events 
There will be an entry in the overall summary table showing the number of subjects with 
treatment-emergent SAEs and the number of events. Another entry will show the number of 
treatment-emergent deaths. Treatment-emergent SAEs and deaths will be differentiated for 
caused by COVID-19. 
An overview summary of treatment-emergent SAEs, including counts and percentages of 
subjects as well as the number of events, will be provided for:  
•
any treatment-emergent SAE;
•
treatment-emergent SAEs caused by COVID-19;
•
any treatment-emergent death;
•
treatment-emergent death caused by COVID-19;
•
treatment-emergent SAEs occurring within 24 hours of investigational product
administration;
•
Relates treatment-emergent SAEs;
•
treatment-emergent SAEs leading to study discontinuation;
•
treatment-emergent SAEs leading to study discontinuation caused by COVID-19;
•
treatment-emergent SAEs in each intensity category;
•
treatment-emergent SAEs in each outcome category;
•
treatment-emergent SAEs not resolved or resolved with sequelae caused by
COVID-19.
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For treatment-emergent SAEs a summary table by SOC and PT as specified in Section 11.3 
will be provided. 
Deaths will be listed for all available data. An additional by-subject listing for SAEs 
(including deaths) will be produced for all available data which will contain the information 
as specified in Section 7 and in addition information for criteria for SAE, hospitalization 
admission and discharge date, alternative cause for SAE not related to study treatment. SAEs 
and deaths caused by COVID-19 will be flagged. 
11.6 Adverse Events Leading to Discontinuation of Study Treatment, 
Withdrawal from the Study, and Other Significant Adverse Events 
For AEs leading to study discontinuation, a summary table by SOC and PT as specified in 
Section 11.3 will be provided. AEs leading to study discontinuation will also be listed. AEs 
leading to study discontinuation caused by COVID-19 will be flagged and displayed 
separately. 
11.7 Adverse Drug Reactions 
An adverse drug reaction is defined as either: 
a.
A TEAE, including local tolerability events, that began during or within 1 hour of the
start of an administration, or
b. A TEAE reported as causally related to the administration of study treatment, or which
the sponsor determined to be causally related to the administration of study treatment, or
c.
A TEAE for which the investigator's causality assessment is missing or indeterminate, or
d. All TEAEs for which the exposure-adjusted incidence rate in an active treatment arm
exceeds the exposure-adjusted incidence rate in the placebo arm by 30% or more,
provided the difference in exposure-adjusted incidence rates is 1% or more. This bullet
point is only applicable for Treatment Period 1 (blinded and open-label part).
A summary table for adverse drug reactions by SOC and PT will be provided as well as a 
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11.8 Public Disclosure of Clinical Trials Requirements 
To support public disclosure requirements for clinical study, a summary of treatment-related 
SAEs will be provided. 
Additionally, a summary of non-serious TEAEs by SOC and PT will be produced. A 
summary of the number of subjects with non-serious TEAEs that occurred at a frequency of 
more than 1%, 2%, 3%, 4%, and 5% will be produced following these steps for each 
frequency: 
•
Determine which subjects experienced any non-serious TEAE that occurred at a
frequency higher than the frequency of interest.
•
From that subset of subjects, sum the subjects who experienced at least one of the
non-serious TEAEs that occurred at a frequency higher than the frequency of interest. Do
not double count subjects who experienced 2 or more of those non-serious TEAEs.
11.9 Pregnancies 
If a female subject becomes pregnant, she must discontinue treatment with the investigational 
product immediately, her participation in the study will be discontinued, and the procedure 
for discontinuation of a subject will be followed, as described in protocol Section 4.2. 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy for medical reasons will be recorded as an AE or SAE as 
described in the protocol. If any subject becomes pregnant while on the study, the information 
will be included in the narratives and no separate table or listing will be produced. 
11.10 Clinical Laboratory Evaluations 
Laboratory tests will be summarized descriptively by scheduled visit as specified in Section 
7. For laboratory test with continuous values, descriptive statistics for the measured values
and for change from baseline will be presented. Definition of the baseline assessment can be
found in Section 8.2.4. Laboratory tests with categorical values will be summarized by
number and percentage of subjects in the respective categories (based on subjects of the
Safety population with non-missing values at this time point). Summary tables will be
provided for hematology, biochemistry, coagulation, and immunogenicity (inhibitory and
non-inhibitory antibodies). All laboratory tests (scheduled and unscheduled) will be listed.
The listings will include the variables as specified in Section 7 and in addition the laboratory


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test name and unit along with normal range, the sampling date and time, the test result, an 
assessment whether the result is high (above normal range) or low (below normal range). Any 
comments to the laboratory test will be provided in a separate listing. 
A by-subject listing for laboratory abnormalities will be provided in the same format as the 
laboratory listings described above but only containing information about abnormal 
laboratory results. 
The number and percentage of subjects who experience antibodies (inhibitory and 
non-inhibitory) specific to FXIIa will be summarized as a secondary (for subjects with 
C1-INH HAE) and 
 in this study. 
Percentages will be based on subjects of the Safety population with non-missing values at 
each time point. 
The number and percentage of subjects with abnormal laboratory values reported as AEs will 
be summarized by laboratory test and visit and for all laboratory tests combined as a further 
secondary (for subjects with C1-INH HAE) and 
. The laboratory findings reported as AEs will be identified through the eCRF. 
Percentages will be based on subjects of the Safety population with non-missing values at 
each time point. 
The laboratory tests will be presented in the following grouping and sequence as specified in 
Table 6 of the protocol. The test names used in the TFLs may differ depending on the 
terminology used by the central laboratory. The test names and units as provided in the 
laboratory data transfer will be used. 
Hematology: Hemoglobin, Hematocrit, Erythrocytes (red blood cell count), Mean 
corpuscular volume, Mean corpuscular hemoglobin, Mean corpuscular hemoglobin 
concentration, Leukocytes (white blood cell count), Neutrophils (% and absolute), 
Lymphocytes (% and absolute), Monocytes (% and absolute), Eosinophils (% and absolute), 
Basophils (% and absolute), and Platelet count. 
Biochemistry: Sodium, Potassium, Chloride, Carbon dioxide, Albumin, Alkaline 
phosphatase, Direct bilirubin, Total bilirubin, Aspartate aminotransferase, Total protein, 
Calcium, Alanine aminotransferase, Creatinine, Phosphate, Blood urea nitrogen, Glucose. 
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Coagulation: 
. 
Immunogenicity: Binding antibodies (inhibitory and non-inhibitory) specific to FXIIa 
antagonist monoclonal antibody. 
Urinalysis: Bilirubin, Occult blood, Erythrocytes, Glucose, Ketones, Leukocyte esterase, 
Nitrite, pH, Protein, Specific gravity, Urobilinogen. 
11.11 Other Safety Measures 
The denominator in percentage calculation at each scheduled visit will be based on the 
number of subjects of the Safety population with non-missing value at each visit. 
 Vital Signs 
Systolic and diastolic blood pressure, respiratory rate, pulse rate, temperature, and body 
weight will be collected as vital signs. 
The following summaries of descriptive statistics will be provided for scheduled visits as 
specified in Section 7: 
•
Measured values of vital signs by scheduled visit;
•
Change from baseline by scheduled visit.
A by-subject listing will also be provided. The listing will also include unscheduled 
assessments. 
12 Pharmacokinetic Analyses 
The PK analysis will be performed using the PK population. 
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Protocol Number: CSL312_2001 
Product Name: CSL312 
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 will produce the TFLs for the CSL312 plasma concentrations and the PK 
parameters as specified below. 
Derivation of PK parameters will be conducted using actual infusion durations, actual doses 
administered and actual sampling times relative to the start of the dose infusion. 
12.1 Plasma PK Endpoints 
The PK parameters derived by 
 will include 
•
Cmax;
•
AUC0-tau;
•
Tmax;
•
T1/2;
•
CLtot;
•
Vz.
The PK parameter derivation including imputation of the values below the lower limit of 
quantification (BLQ) and missing data will be conducted in accordance to PK-GDL-01 which 
gives guidance on how to derive PK parameters in the presence of missing data. 
12.2 Summary of CSL312 Plasma Concentrations 
The handling and imputation of BLQ values for PK parameter derivation is described in PK-
GDL-01. The imputation rules below will be used for summary statistics of CSL312 plasma 
concentrations. The summaries will be given by sampling time point (planned time points) 
and treatment group. 
•
The sampling time of pre-dose samples relative to start of the dose infusion will be
treated as zero;
•
Concentration values below BLQ in pre-dose samples and in samples taken before the
time of the first quantifiable concentration will be treated as zero;
•
Post-dose one or more consecutive BLQ concentrations flanked by quantifiable
concentrations will be set to missing;
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Protocol Number: CSL312_2001 
Product Name: CSL312 
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•
Post-dose BLQ concentrations after the last quantifiable point will be set to missing
for mean presentations of plasma concentrations.
•
The mean/median value at a time-point where one or more samples have BLQ values
will be reported (in tabular or graphical fashion) even if the mean/median value is
below the lower limit of quantification (BLQ) of the assay;
•
Zero mean or median values will be included in summary tables.
It should be noted that a high proportion of BLQ values may affect the SD; if more than 50% 
of the values are imputed (i.e., BLQ), then the SD will not be displayed. 
Summary statistics for concentration-time data will include the percentage of BLQ values 
relative to the total number of observations 
%BLQ = 100 * (number of subjects who have BLQ values / total number of subjects 
within each treatment group at each time point) 
and the coefficient of variation (CV) % in addition to the statistic parameters outlined in 
Section 7. 
Two mean plots for CSL312 plasma concentrations (one on linear and one on log-linear 
scale) versus nominal (planned) time will be provided. All CSL312 treatment groups will be 
overlaid in each mean plot. Error bars on mean values within the plot will represent +/- SD 
values. The plasma concentration for subjects who are down-titrated from 
 mg to 
 mg 
will stop for the 
 mg group when down-titration occurs. The plasma concentrations after 
down-titration will be included in the 
 mg group starting at the time point of 
down-titration. 
Individual PK plots (one linear and one log-linear scale) for all subjects within the same 
active treatment (with dose level specified) combined on one graph and plotted versus actual 
time of the samples will be provided. For subjects who are down-titrated, a vertical line will 
indicate the time point when the 
 mg dose was administered. 
A by-subject listing of CSL312 plasma concentrations with the concentrations flagged that 
have been excluded from the derivation of the PK parameters will support the summaries. 
12.3 Summary of CSL312 Pharmacokinetic Parameters 
PK parameters will be summarized by treatment group. 
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Variable 
Statistical Parameters: 
Cmax, AUC0-tau, CLtot and Vz n, arithmetic mean, SD, CV%, minimum, median, 
maximum, geometric mean, and geometric CV% 
T1/2 
n, arithmetic mean, SD, CV%, minimum, median, and 
maximum 
Tmax 
n, minimum,Q1, median, Q3, and maximum 
A by-subject listing of CSL312 PK parameters will be provided. 
13 
13.1 
13.2 
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14 Pharmacokinetic - 
 Analyses 
A population PK-
 analysis using the 
 population will be conducted by Clinical 
Pharmacology at CSL. 
. This work will be presented in a separate analysis plan 
and report. 
15 References 
Liublinska, V and Rubin, DB (2014) Sensitivity analysis for a partially missing binary 
outcome in a two-arm randomized clinical trial, Statistics in Medicine Vol 33 (24) 4170-
4185. 
PK-GDL-01, Guideline on the Conduct of Non-compartmental Pharmacokinetic Analyses, 
CSL Behring. 
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CSL312_2001 - Statistical Analysis Plan - V2.0 - 19Jun2020
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