Clinical trial NCT05130970
Conditions: Idiopathic Pulmonary Fibrosis
Sponsor: CSL Behring
Start date: 2022-02-03; Completion date: 2024-01-02
Enrollment: 81 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a prospective, phase 2a, multicenter, randomized, double-blind, placebo-controlled, parallel-group study to assess the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of garadacimab in subjects with idiopathic pulmonary fibrosis (IPF).

Detailed description:

Arms: arm 1: Administered IV and SC arm 2: Administered IV and SC
Interventions: intervention 1: Garadacimab intervention 2: Placebo
Intervention descriptions: intervention 1: Participants received garadacimab intravenous (IV) loading dose followed by 3 subcutaneous (SC) doses. intervention 2: Participants received a matching placebo IV loading dose, followed by 3 SC doses.

Protocol documents:
Prot_000.pdf: 
 
  
  
 
Protocol version: Amendment 3 
 
Page 1 of 107 
Date: 18 October 2022 
Confidential 
Template: CS-SOP-04-T02 Version 2.0 
 
 
Effective Date: Week commencing 25-June-2018 
CLINICAL STUDY PROTOCOL 
 
A Randomized, Double-blind, Placebo-controlled, Study to Investigate the Safety, 
Pharmacokinetics, and Pharmacodynamics of CSL312 in Subjects with Idiopathic 
Pulmonary Fibrosis 
Study Number: 
CSL312_2002 
Study Product: 
CSL312 
(Garadacimab, Factor XIIa Antagonist Monoclonal Antibody) 
Development Phase: 
Phase 2a 
Short Title: 
CSL312 Safety, Pharmacokinetics, and Pharmacodynamics in 
Idiopathic Pulmonary Fibrosis 
Sponsor: 
CSL Behring, LLC 
1020 First Avenue 
King of Prussia, Pennsylvania 19406 
United States of America 
Protocol Version: 
Amendment 3 
EudraCT Number: 
2021-003162-12 
IND Number: 
156 849 
Protocol Date: 
18 October 2022 
Compliance: 
This study will be conducted in accordance with standards of 
Good Clinical Practice (as defined by the International Council 
for Harmonisation) and all applicable national and local 
regulations. 
Commercial in Confidence. This document and the information contained herein are proprietary and 
confidential. This document and the contained information are intended for disclosure to and use by those 
personnel who are under an obligation of confidentiality by a signed agreement with the Sponsor 
(CSL Behring). This document and the contained information may be disclosed and used only to the extent 
necessary to conduct the clinical study. Reproduction or disclosure of this document or its contained 
information is forbidden unless at the express request or with the written consent of CSL Behring. 
 


CSL Behring 
Study Number: 
CSL312_2002 
 
Study Product: 
CSL312 
 
Protocol version: Amendment 3 
 
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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 Behring (or delegate) and provided to the study sites as needed. 
 


CSL Behring 
Study Number: 
CSL312_2002 
 
Study Product: 
CSL312 
 
Protocol version: Amendment 3 
 
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Revision History 
Date 
Version  
Summary of Changes 
07 June 2021 
Original 
Not applicable 
15 November 2021 Amendment 1 
For clarification regarding the process for 
breaking the blind in an emergency situation, 
the following statement has been removed from 
Section 6.3.2: “Whenever possible, the 
investigator should consult with CSL before 
unblinding the randomization code.” 
18 January 2022 
Amendment 2 
Removed the word “prolonged” from the 
individual subject halting criterion for 
symptoms of severe hypersensitivity in 
Section 3.9.1. 


CSL Behring 
Study Number: 
CSL312_2002 
 
Study Product: 
CSL312 
 
Protocol version: Amendment 3 
 
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Effective Date: Week commencing 25-June-2018 
18 October 2022 
Amendment 3 
1. Removed exclusion criterion #8 to allow 
administration of nonlive influenza virus 
vaccines or severe acute respiratory 
syndrome coronavirus-2 (SARS-CoV-2) 
vaccines before and during study 
participation. 
2. Updated the Schedule of Assessments and 
Sections 4.1.2, 8.1.1, and 8.1.4 to clarify 
that: 
• International normalized ratio (INR) will 
be measured only at Screening and 
Baseline at the local laboratory. 
• Prothrombin time (PT) will not be 
measured in the local laboratory. 
• Both PT and INR will be measured in 
the central laboratory. 
3. Revised wording in exclusion criterion #12 
to clarify that standard of care medication is 
also prohibited during the Treatment and 
Observation Period up to Day 92. 
4. Revised wording for subcutaneous (SC) 
administration regarding anatomical site of 
injection and the number of injections per 
dose. 
5. Added an additional citation and reference 
for diffusing capacity of the lungs for carbon 
monoxide (DLCO). 
6. Low-dose aspirin now specifically 
mentioned in table of permitted therapies. 
7. Revised wording on halting criteria due to 
electrocardiogram (ECG) prolongation for 
clarification. 
8. Minor corrections and clarifications, 
including word modifications and 
administrative changes. 
 


CSL Behring 
Study Number: 
CSL312_2002 
 
Study Product: 
CSL312 
 
Protocol version: Amendment 3 
 
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Clinical Study Protocol Synopsis 
Title 
A randomized, double-blind, placebo-controlled, study to 
investigate the safety, pharmacokinetics, and pharmacodynamics of 
CSL312 in subjects with idiopathic pulmonary fibrosis 
Study Number 
CSL312_2002 
Sponsor 
CSL Behring LLC 
1020 First Avenue 
King of Prussia, Pennsylvania 19406 
United States of America 
Development Phase Phase 2a 
Study Product 
CSL312 
(Garadacimab, factor XIIa antagonist monoclonal antibody) 
Indication 
For the treatment of idiopathic pulmonary fibrosis 
Study Summary 
and Overview 
This is a prospective, phase 2a, multicenter, randomized, 
double-blind, placebo-controlled, parallel-group study to assess the 
safety, pharmacokinetics (PK), and pharmacodynamics (PD) of 
CSL312 in subjects with idiopathic pulmonary fibrosis (IPF). 
For all enrolled subjects, informed consent must be obtained at the 
Screening Visit before any study-specific assessments are 
performed. Screening can occur between 1 and 28 days before 
Day 1. For this study, Baseline is defined as before dosing on 
Day 1. 
Eligible subjects will be randomized to enter the Treatment and 
Observation Period for 14 weeks, during which subjects will 
receive an intravenous (IV) loading dose of CSL312 or placebo 
followed by 3 subcutaneous (SC) doses of CSL312 or placebo. A 
total of 12 study visits are planned (1 Screening Visit and 11 visits 
during the Treatment and Observation Period). A final safety check 
will be conducted by telephone approximately 90 days after the last 
administration of investigational product. The study will end when 
the last subject has completed the 14-week Treatment and 
Observation Period and the Follow-up Visit (Telephone Call). 
Primary Objective 
The primary objective of this study is to investigate the safety of 
CSL312 in subjects with IPF. 


CSL Behring 
Study Number: 
CSL312_2002 
 
Study Product: 
CSL312 
 
Protocol version: Amendment 3 
 
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Primary Endpoint 
The primary endpoints of this study are the subjects experiencing 
treatment-emergent adverse events (TEAEs) including: 
• Serious adverse events (SAEs) 
• Adverse events of special interest (AESIs) 
• CSL312-induced anti-CSL312 antibodies 
• Clinically significant abnormalities in laboratory assessments 
that are reported as adverse events (AEs) 
Secondary 
Objectives 
The secondary objectives of the study are: 
• To characterize the systemic PK of CSL312 in patients with IPF 
• To investigate the PD activity of CSL312 in patients with IPF 
Secondary 
Endpoints 
• Plasma PK parameters after SC administration of CSL312 at 
each SC dosing interval: 
o Trough plasma concentration (Ctrough) 
o Maximum plasma concentration (Cmax) (last SC dosing 
interval only) 
o Time to maximum plasma concentration (Tmax) (last SC 
dosing interval only) 
o Area under the plasma concentration-time curve after 1 dose 
interval (AUC0-tau) (last SC dosing interval only) 
• Plasma PK parameters after the IV dose of CSL312: 
o Cmax 
o Tmax 
o Ctrough 
• Effect of treatment with CSL312 on FXIIa-mediated kallikrein 
activity 
Study Duration 
The duration of the study for an individual subject is expected to be 
approximately 6 months. This estimate is based on: 
• Screening / Washout Period of up 28 days 
• 14-week Treatment and Observation Period 
• Follow-up Telephone Call at 90 days after the last 
investigational product administration 
The overall study duration (ie, first subject’s Screening Visit to last 
subject’s Follow up Telephone call) will be approximately 17 to 
19 months. 


CSL Behring 
Study Number: 
CSL312_2002 
 
Study Product: 
CSL312 
 
Protocol version: Amendment 3 
 
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Effective Date: Week commencing 25-June-2018 
Number of 
Subjects 
This study will enroll approximately 80 subjects to achieve a total 
of 70 evaluable subjects by Week 14; 35 subjects in the CSL312 
group and 35 subjects in the placebo group. The estimated dropout 
rate is approximately 12%. 
Study Population 
and Main Criteria 
for Eligibility 
Inclusion criteria: 
1. Capable of providing written informed consent and willing and 
able to adhere to all protocol requirements. 
2. Male or female patients, ≥ 40 years of age at the time of 
providing written informed consent. 
3. Documented diagnosis of IPF according to the investigator 
using the criteria from the 2018 Clinical Practice Guideline of 
the American Thoracic Society (ATS) / European Respiratory 
Society (ERS) / Japanese Respiratory Society (JRS) / Latin 
American Thoracic Association (ALAT) for the diagnosis of IPF 
[Raghu et al, 2018] at the time of Screening. 
4. Forced vital capacity (FVC) ≥ 45% of predicted normal at 
Screening. 
5. Diffusing capacity of the lungs for carbon monoxide (DLCO, 
corrected for hemoglobin) ≥ 30% of predicted normal at 
Screening. 
6. Forced expiratory volume in 1 second (FEV1) / FVC ratio ≥ 0.7 
at Screening. 
7. Investigator believes that the subject (or the subject’s legally 
acceptable representative) understands the nature, scope, and 
possible consequences of the study. 


CSL Behring 
Study Number: 
CSL312_2002 
 
Study Product: 
CSL312 
 
Protocol version: Amendment 3 
 
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Exclusion criteria: 
1. History of clinically significant cardiovascular disease, 
including myocardial infarction, unstable ischemic heart 
disease, congestive heart failure, or angina during the 6 months 
before Screening. 
2. Resting pulse < 50 beats per minute, sinoatrial or 
atrioventricular block, uncontrolled hypertension, or QT interval 
corrected using the Fridericia formula (QTcF) 
> 450 milliseconds. 
3. Active bleeding or current clinically significant coagulopathy 
(eg, international normalized ratio [INR] > 1.5) or clinically 
significant risk for bleeding (eg, recent intracranial hemorrhage 
or bleeding peptic ulcer within the 4 weeks before Screening). 
4. History of venous thrombosis or cerebrovascular event within 
the 3 months before Screening, or a prothrombotic disorder 
(eg, antithrombin III, protein C, or protein S deficiency or 
antiphospholipid syndrome). 
5. Known or suspected severe infusion-related reaction or 
hypersensitivity to monoclonal antibody therapy, or 
hypersensitivity to the investigational product or any excipients 
of the investigational product. 
6. Major surgery scheduled to occur during the study or up to 
90 days after the last administration of investigational product. 
7. Lung transplantation anticipated during the study or within 
90 days after the last administration of investigational product. 
8. Removed per Amendment #3 
9. Any other condition which, in the opinion of the investigator, 
may pose an additional risk to the study participant after the 
administration of investigational product. 
10. Received any investigational therapy within 28 days, or 5 drug 
half-lives whichever is longer, before randomization or intends 
to take an investigation therapy other than CSL312 during the 
study. 
11. Previously administered CSL312 in another interventional 
clinical study. 
12. Use of nintedanib or pirfenidone within 28 days before 
randomization and during the 14-week Treatment and 
Observation Period up to and including the End of Treatment 
Visit (Day 92). 
13. Pregnant at Screening or breastfeeding at Screening and not 
willing to cease breastfeeding. 


CSL Behring 
Study Number: 
CSL312_2002 
 
Study Product: 
CSL312 
 
Protocol version: Amendment 3 
 
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14. Female subject of childbearing potential or fertile male subject 
either not using or unwilling to use an acceptable method of 
contraception to avoid pregnancy during the study and for up to 
90 days after the last administration of investigational product. 
Acceptable methods of contraception. 
All female subjects are assumed to be of childbearing potential 
except: 
• Subjects > 60 years of age. 
• Subjects between the ages of 45 to 60 years, inclusive, with 
amenorrhea for ≥ 1 year with documented evidence of 
follicle-stimulating hormone (FSH) level > 30 IU/L. If the 
FSH level is not available before randomization, a serum 
pregnancy test is required at Screening. Urine pregnancy 
tests will also be required at the time points indicated in the 
Schedule of Assessments. 
• Subjects who are surgically sterile for ≥ 3 months before 
providing informed consent. 
All male subjects are assumed fertile except subjects who are 
surgically sterile for ≥ 3 months before providing informed 
consent. 
15. Clinical evidence of active infection, including severe acute 
respiratory syndrome coronavirus-2 (SARS-CoV-2). 
16. Current alcohol, drug, or medication abuse. 
17. Currently receiving a therapy not permitted during the study. 
18. Involved in the planning and / or conduct of the study (applies 
to CSL staff, staff at the study site, and third-party vendors). 
Study Product 
Dose, Dosing 
Regimen and 
Administration  
CSL312 will be supplied as a sterile solution for injection 
containing 100 mg/mL of CSL312 in 2-mL vials. On Day 1, an IV 
loading dose of 300 mg will be administered in an infusion volume 
of 3 mL, by IV injection (ie, push over approximately 3 minutes). 
The second dose of 600 mg will be administered SC 7 days later. 
Doses 3 and 4 of 600 mg will be administered SC 28 days after 
doses 2 and 3, respectively. 
Comparator 
Product, Dose, 
Dosing Regimen 
and Administration 
Placebo will be supplied as a sterile, preservative free solution for 
injection in 2-mL vials. The placebo is the same as the CSL312 
formulation buffer, but does not contain the active substance 
(ie, CSL312). IV and SC administered placebo will match the 
volume used for CSL312 to maintain the blind. The first dose of 
placebo will be administered IV (on Day 1) and the other 3 doses 
will be administered SC using the same dosing regimen as for 
CSL312. 


CSL Behring 
Study Number: 
CSL312_2002 
 
Study Product: 
CSL312 
 
Protocol version: Amendment 3 
 
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Efficacy 
Assessments 
Efficacy will be assessed using spirometry. 
Safety Assessments 
Safety will be assessed through documentation of 
treatment-emergent adverse events, vital signs, physical 
examinations, respiratory parameters, clinical laboratory 
assessments, and antidrug antibodies (ADAs). 
Pharmacokinetics 
Blood samples will be collected for assessment of CSL312 PK in 
plasma. 
Pharmacodynamics Plasma samples will be collected and analyzed for the following 
parameters: 
• Activated factor XII (FXIIa)-mediated kallikrein activity 
• Factor XII (FXII) concentration 
• Activated partial thromboplastin time (aPTT) 


CSL Behring 
Study Number: 
CSL312_2002 
 
Study Product: 
CSL312 
 
Protocol version: Amendment 3 
 
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Biomarker 
Assessments 
Additional biomarkers will explore the proposed mechanism of 
action of CSL312 in IPF including biomarkers of coagulation, 
inflammation, tissue modeling, and fibrosis, together with disease 
biomarkers of alveolar epithelial cell damage. 
The following biomarkers will be measured: pF1+2, fibrinogen, D-
dimer, aPTT, high-sensitivity C-reactive protein (hs-CRP), and 
monocytes. Samples will be collected at Screening, before 
administration of the IV loading dose of investigational product on 
Day 1, and on Days 8, 36, 64, and 92. hs-CRP will be assessed at all 
study visits, including Screening, before administration of the IV 
loading dose investigational product and immediately after the end 
of the infusion (EOI) on Day 1. 
The following biomarkers will be measured at Screening, before 
administration of the IV loading dose of investigational product on 
Day 1, and on Days 8, 36, 64, and 92: FXII (free vs. total), C3a, 
C5a, interleukin (IL)-8, IL-10, C-C motif chemokine ligand 
(CCL)-2, C-X-C motif chemokine ligand (CXCL)-1, CCL-18, 
plasminogen activator inhibitor 1 (PAI-1), surfactant protein A 
(SP-A), surfactant protein D (SP-D), YKL-40, tenascin-C (TN-C), 
thrombospondin-1 (TSP-1), vascular endothelial growth factor 
(VEGF), neo-epitope of matrix metalloproteinase-mediated 
degradation of citrullinated vimentin (VICM), neo-epitope of 
matrix metalloproteinase-mediated degradation of C-reactive 
protein (CRPM), Pro-Fib (biomarker specifically targeting the 
thrombin-mediated conversion of fibrinogen into fibrin), 
neo-epitope of calprotectin generated by human neutrophil elastase 
(CPa9-HNE), and collagen synthetic and degradation neo-epitopes 
(pro-C3/4/6 and C1/3/4/6M). 
The following PD parameters and biomarkers will be assessed at all 
study visits at which PK is being assessed, including before 
administration of the IV loading dose of investigational product and 
immediately after the EOI on Day 1: FXIIa-mediated kallikrein 
activity, FXII concentration, IL-6, and hs-CRP. Additionally, 
hs-CRP will also be assessed at Screening. 
Blood transcriptomics: Blood will be collected for RNA 
sequencing to investigate changes in gene expression at Screening, 
before administration of the IV loading dose of investigational 
product on Day 1, and on Days 8, 36, 64, and 92. 
Proteomic analysis: Blood will be collected to characterize the 
plasma proteome at Screening, before administration of the IV 
loading dose of investigational product on Day 1, and on Days 8, 
36, 64, and 92. 


CSL Behring 
Study Number: 
CSL312_2002 
 
Study Product: 
CSL312 
 
Protocol version: Amendment 3 
 
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Statistical Analyses 
The sample size for this study was determined based on feasibility, 
not based on a power calculation. It was estimated that enrolling 
approximately 80 subjects (40 in each treatment group), and taking 
into account a 12% dropout rate, a total of 70 evaluable subjects 
(35 in each treatment group), would be considered sufficient for 
assessment of safety, PK, and biomarker profiles. 
The primary endpoints of this study are subjects experiencing 
TEAEs including SAEs, AESIs, CSL312-induced ADAs, and 
clinically significant abnormalities in laboratory assessments that 
are reported as AEs. The summary measures will be the number and 
proportion of subjects experiencing these safety events after 
treatment with investigational product (CSL312 or placebo). 
TEAEs will be summarized by the number and percentages of 
subjects experiencing ≥ 1 TEAE and the number of events. TEAEs 
will be summarized by system organ class and preferred term and 
also by causality and severity. 
More detailed information on the analyses of efficacy, safety, PK, 
PD, and biomarkers are provided in the full clinical study protocol. 
 
 


CSL Behring 
Study Number:  CSL312_2002 
 
Study Product: 
CSL312 
 
Protocol version: Amendment 3 
 
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Schedule of Assessments 
Study Period 
Screening/ 
Washout 
PeriodA 
Treatment and Observation Period 
FU 
Visit 
(Phone 
Call)B 
Study Week 
-4 
1 
2 
3 
6 
7 
10 
11 
12 
13 
EOT/EW 
14C 
22 
Study Day 
-28 
1 
8 
15 
36 
43 
64 
67 71 
78 
85 
92 
154 
Time (Hours)D 
 
Baseline 
Predose 
0 
EOID 
 
Visit Window (Days) 
 
 
±1 
±1 
±2 
±1 
±1 
±1 ±1 
±2 
±2 
±2 
±5 
Informed consentE 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion / exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history and demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization via IRT 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment assignment via IRT 
 
X 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 
Administration of investigational product 
 
 
IV 
 
SC 
 
SC 
 
SC 
 
 
 
 
 
 
12-lead ECG 
X 
X 
 
 
X 
 
X 
 
X 
 
 
 
 
X 
 
Pregnancy testF 
X 
X 
 
 
X 
 
X 
 
X 
 
 
 
 
X 
 
Physical examination 
X 
X 
 
 
X 
 
X 
 
X 
 
 
 
 
X 
 
Vital signsG 
X 
X 
 
 
X 
 
X 
 
X 
 
 
 
 
X 
 
Urine sample for urinalysis 
(central laboratory) 
X 
X 
 
 
X 
 
X 
 
X 
 
 
 
 
X 
 
Blood 
Samples 
(central 
laboratory) 
HematologyH, biochemistryI,J, 
and coagulationK 
X 
X 
 
 
X 
 
X 
 
X 
 
 
 
 
X 
 
Retention sample for virologyL 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
PD and biomarkersM,N,O 
XN 
XM,N,O 
 
XO 
XM,N,O XO XM,N,O XO XM,N,O XO XO 
XO 
XO 
XN,O 
 
PK 
 
XM 
 
X 
XM 
X 
XM 
X 
XM 
X 
X 
X 
X 
X 
 
RNA Seq / proteomics 
X 
XM 
 
 
XM 
 
XM 
 
XM 
 
 
 
 
X 
 
INR and D-dimer (local laboratory) 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Immunogenicity (ADAs; central laboratory)P 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
Spirometry at site (local laboratory)Q 
X 
X 
 
 
X 
 
X 
 
X 
 
 
 
 
X 
 
DLCO (local laboratory)Q 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
AEsR 
Prior / concomitant therapiesR 


CSL Behring 
Study Number:  CSL312_2002 
 
Study Product: 
CSL312 
 
Protocol version: Amendment 3 
 
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ADA = antidrug antibody; AE = adverse event; ALT= alanine aminotransferase; aPTT = activated partial thromboplastin time; AST = aspartate aminotransferase; BMI = body 
mass index; CCL = C-C motif chemokine ligand; CK = creatinine kinase; CPa9-HNE = neo-epitope of calprotectin generated by human neutrophil elastase; CPK = creatinine 
phosphokinase; CRPM = neo-epitope of matrix metalloproteinase-mediated degradation of C-reactive protein; CSL = CSL Behring; CXCL = C-X-C motif chemokine ligand; 
DLCO = diffusing capacity of the lungs for carbon monoxide; ECG = electrocardiogram; EOI = end of the infusion; EOT = end of treatment; EW = early withdrawal; FU = follow-
up; GGT = gamma glutamyltransferase; HDL = high-density lipoprotein; hs-CRP = high-sensitivity C-reactive protein; IPF = idiopathic pulmonary fibrosis; IL-interleukin; 
INR = international normalized ratio; IRT = interactive response technology; IV = intravenous; LDH= lactate dehydrogenase; LDL = low-density lipoprotein; MCH = mean 
corpuscular hemoglobin; MCHC = mean corpuscular hemoglobin concentration; MCV = mean corpuscular volume; PAI-1 = plasminogen activator inhibitor 1; 
PD = pharmacodynamic; pF1+2 = prothrombin fragment; PFT = pulmonary function test; PK = pharmacokinetic; Pro-Fib = biomarker specifically targeting the thrombin-
mediated conversion of fibrinogen into fibrin; PT = prothrombin time; RBC = red blood cell; RDW = red cell (erythrocyte) distribution width; RNA seq = ribonucleic acid 
sequencing; SC = subcutaneous; SP-A = surfactant protein A; SP-D = surfactant protein D; TN-C = tenascin-C; TSP-1 = thrombospondin 1; VEGF = vascular endothelial growth 
factor; VICM = neo-epitope of matrix metalloproteinase-mediated degradation of citrullinated vimentin; WBC = white blood cell. 
Notes for the Schedule of Assessments: 
A. Eligible subjects must discontinue all prohibited medications ≥ 28 days (or 5 half-lives) before randomization. 
B. The Follow-up Visit will be a telephone call conducted on Day 154 (± 5), approximately 90 days after the last administration of investigational product, to collect data on AEs 
(including acute exacerbations of IPF) and concomitant medications since the previous study visit. 
C. EOT / EW Visit. If a subject withdraws from the study before the Week 14 Visit, the subject will be asked to return to the study site to complete the EOT assessments. 
D. Postdose assessments should be performed immediately after the EOI of investigational product for the IV loading dose. Subjects should remain at the site for 15 to 30 minutes 
after the EOI for the IV loading dose of investigational product. 
E. For all potential subjects, informed consent must be obtained before performing any study-specific screening assessments. 
F. For female subjects of childbearing potential only: a serum pregnancy test will be performed at Screening (local laboratory). At all other time points, a urine pregnancy test will 
be used. If the results of the urine pregnancy test are inconclusive, a serum pregnancy test will be performed by the site (local laboratory). Urine pregnancy test kits will be 
provided by the Sponsor. 
G. Vital signs include supine systolic and diastolic blood pressure, heart rate, and respiratory rate after resting for 5 (± 3) minutes, as well as body temperature, height, body 
weight, and BMI. Height will only be measured and recorded at Screening. 
H. Hematology parameters: hematocrit, hemoglobin, platelets, reticulocytes, erythrocytes (RBC count), RBC indices (MCHC, MCH, MCV, RDW), leukocytes (WBC count), 
differential (percentage and absolute): neutrophils, neutrophil band forms, lymphocytes, monocytes, eosinophils, and basophils. 
I. Biochemistry parameters: sodium, potassium, chloride, bicarbonate, calcium, bun, urea, creatinine, glucose, protein – total, albumin, alkaline phosphatase, ALT, AST, LDH, 
GGT, bilirubin – total, direct bilirubin, magnesium, phosphate, hs-CRP, cholesterol – total, triglycerides, HDL cholesterol, LDL cholesterol, urate (uric acid), and CK / CPK. 
J. hs-CRP will be assessed at all study visits, including at Screening and before administration of the IV loading dose investigational product and immediately after the EOI 
on Day 1. 
K. Coagulation: aPTT, PT and INR, pF1+2, fibrinogen (Clauss assay), and D-dimer. 
L. An additional blood sample will be obtained on Day 1, before administration of investigational product, for potential virus testing in the future. This retention sample will be 
stored at the central laboratory and will be analyzed only if there is a suspicion of viral infection. 
M. On the days when investigational product is administered (Days 1, 8, 36, and 64), blood samples for PK and PD assessments, biomarker assessments, proteomics, and RNA 
sequencing should be collected before administration of investigational product. 
N. The following biomarkers will be measured at Screening, before administration of the IV loading dose of investigational product on Day 1, and on Days 8, 36, 64, and 92: 
FXII (free vs. total), C3a, C5a, IL-8, IL-10, CCL-2, CXCL-1, CCL-18, PAI-1, SP-A, SP-D, YKL-40, TN-C, TSP-1, VEGF, VICM, CRPM, Pro-Fib, CPa9-HNE, and collagen 
synthetic and degradation neo-epitopes (pro-C3/4/6 and C1/3/4/6M). 
O. The following PD parameters and biomarkers will be assessed at all study visits, except Screening, including before administration of the IV loading dose of investigational 
product and immediately after the EOI on Day 1: FXIIa-mediated kallikrein activity, FXII concentration, IL-6, and hs-CRP. Additionally, hs-CRP will also be assessed at 
Screening. 
P. Blood samples for assessment of ADAs will be obtained before administration of investigational product. 
Q. PFTs including spirometry and DLCO will be performed before administration of investigational product. Bronchodilator therapies, if used, must be washed out before PFTs are 
performed (8 hours for short-acting bronchodilators and 24 hours for long-acting bronchodilators). CSL will provide the device to be used for spirometry. 
R. For each study visit, the investigator (or delegate) will review AEs and concomitant medications with the subject, which can be done in person or by telephone. 
 


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Table of Contents 
Revision History ........................................................................................................................ 3 
Clinical Study Protocol Synopsis .............................................................................................. 5 
Schedule of Assessments ......................................................................................................... 13 
Table of Contents ..................................................................................................................... 15 
List of Abbreviations ............................................................................................................... 21 
1 
Introduction .......................................................................................................... 25 
1.1 
Background ...................................................................................................... 25 
1.2 
Information on CSL312 ................................................................................... 28 
1.2.1 
Overview ...................................................................................................... 28 
1.2.2 
Nonclinical Evaluation ................................................................................. 31 
1.2.3 
Clinical Experience ...................................................................................... 34 
1.3 
Study Overview ................................................................................................ 38 
1.4 
Potential Risks and Benefits ............................................................................. 38 
1.4.1 
Potential Benefits ......................................................................................... 38 
1.4.2 
Potential Risks .............................................................................................. 39 
2 
Study Objectives and Endpoints ........................................................................... 40 
2.1 
Primary Objective and Endpoint ...................................................................... 40 
2.1.1 
Primary Objective ......................................................................................... 40 
2.1.2 
Primary Endpoints ........................................................................................ 40 
2.2 
Secondary Objectives and Endpoints ............................................................... 40 
2.2.1 
Secondary Objectives ................................................................................... 40 
2.2.2 
Secondary Endpoints .................................................................................... 41 
2.3 
Exploratory Objectives and Endpoints ............................................................. 42 
2.3.1 
Exploratory Objectives ................................................................................. 42 
2.3.2 
Exploratory Endpoints .................................................................................. 42 
3 
Study Design and Oversight ................................................................................. 43 
3.1 
Overall Design .................................................................................................. 43 
3.2 
Dose and Dosing Regimen ............................................................................... 44 
3.3 
Scientific Rationale .......................................................................................... 45 
3.3.1 
Study Design Rationale ................................................................................ 45 
3.3.2 
Dose Rationale ............................................................................................. 45 


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3.4 
Planned Study Duration ................................................................................... 46 
3.5 
Planned Number of Subjects ............................................................................ 46 
3.6 
Definition of Start of the Clinical Study .......................................................... 47 
3.7 
Definition of End of the Clinical Study ........................................................... 47 
3.8 
Study Oversight ................................................................................................ 47 
3.8.1 
Independent Data Monitoring Committee .................................................... 47 
3.9 
Stopping / Halting Criteria ............................................................................... 47 
3.9.1 
Individual Subject Halting Criteria .............................................................. 48 
3.9.2 
Study Halting Criteria .................................................................................. 49 
4 
Selection and Withdrawal of Subjects .................................................................. 49 
4.1 
Eligibility Criteria ............................................................................................ 49 
4.1.1 
Inclusion Criteria .......................................................................................... 49 
4.1.2 
Exclusion Criteria ......................................................................................... 50 
4.2 
Screen Failures ................................................................................................. 52 
4.3 
Discontinuation of Study Treatment and Subject Withdrawal ......................... 53 
4.3.1 
Discontinuation of Study Treatment ............................................................. 53 
4.3.2 
Subject Withdrawal ...................................................................................... 53 
4.3.3 
Procedures for Handling Withdrawals.......................................................... 53 
4.3.4 
Subjects Lost to Follow-up ........................................................................... 54 
4.3.5 
Replacement Policy ...................................................................................... 54 
5 
Study Interventions ............................................................................................... 55 
5.1 
Investigational Products ................................................................................... 55 
5.1.1 
Description of CSL312 ................................................................................. 55 
5.1.2 
Description of Placebo ................................................................................. 56 
5.1.3 
Dosing and Administration of Investigational Product ................................ 57 
5.1.4 
Description of Investigational Medical Device Constituents ....................... 59 
5.1.5 
Packaging, Labeling, Supply and Storage .................................................... 59 
5.2 
Accountability and Destruction ........................................................................ 59 
5.3 
Treatment for Acute Exacerbation or Disease Progression .............................. 60 
6 
Allocation to Treatment ........................................................................................ 60 
6.1 
Subject Assignment .......................................................................................... 60 
6.2 
Randomization Procedures ............................................................................... 60 
6.3 
Blinding Procedures ......................................................................................... 61 


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6.3.1 
Blinding Method ........................................................................................... 61 
6.3.2 
Breaking the Blind for an Emergency .......................................................... 62 
6.3.3 
Planned Unblinding Procedures ................................................................... 62 
6.3.4 
Ad-hoc Safety Unbinding ............................................................................. 62 
7 
Contraindications, Permitted Therapies and Prohibited Therapies ...................... 63 
7.1 
Contraindications and Precautions to Further Dosing ...................................... 63 
7.2 
Permitted Therapies .......................................................................................... 64 
7.3 
Prohibited Therapies......................................................................................... 65 
7.4 
Lifestyle Restrictions ........................................................................................ 66 
8 
Study Procedures and Visit Schedule ................................................................... 66 
8.1 
Clinical Procedures .......................................................................................... 66 
8.1.1 
Demographics and Safety Assessments ....................................................... 67 
8.1.2 
Acute Exacerbation of Idiopathic Pulmonary Fibrosis ................................ 69 
8.1.3 
Pharmacokinetic and Pharmacodynamic Assessments ................................ 70 
8.1.4 
Biomarker Assessments ................................................................................ 70 
8.1.5 
Pulmonary Function Tests ............................................................................ 72 
8.2 
Blood Samples .................................................................................................. 73 
8.3 
Retention of Samples ....................................................................................... 73 
8.3.1 
Retention Samples for Exploratory Biomarkers........................................... 74 
8.4 
Concomitant Therapies..................................................................................... 74 
8.5 
Visit Schedule ................................................................................................... 74 
8.5.1 
Assessment Time Windows .......................................................................... 74 
8.5.2 
Screening Period ........................................................................................... 74 
8.5.3 
Treatment and Observation Period ............................................................... 75 
8.5.4 
Unscheduled Study Visit .............................................................................. 75 
8.5.5 
End-of-Treatment Visit ................................................................................. 75 
8.5.6 
Follow-up Telephone Call ............................................................................ 76 
8.5.7 
Withdrawal ................................................................................................... 76 
9 
Adverse Events ..................................................................................................... 76 
9.1 
Definitions ........................................................................................................ 76 
9.1.1 
Adverse Event .............................................................................................. 76 
9.1.2 
Serious Adverse Event .................................................................................. 78 
9.1.3 
Adverse Event of Special Interest ................................................................ 78 
9.2 
Severity of Adverse Events .............................................................................. 79 


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9.3 
Causality of Adverse Events ............................................................................ 79 
9.4 
Observation Period for Adverse Events ........................................................... 80 
9.5 
Follow-up of Adverse Events ........................................................................... 80 
9.6 
Adverse Event Reporting ................................................................................. 80 
9.6.1 
Adverse Events ............................................................................................. 80 
9.6.2 
Adverse Events of Special Interest ............................................................... 81 
9.6.3 
Serious Adverse Events ................................................................................ 81 
9.6.4 
Other Significant Events .............................................................................. 82 
9.6.5 
Overdose ....................................................................................................... 82 
9.6.6 
Pregnancy and Breastfeeding ....................................................................... 82 
9.7 
Institutional Review Board / Independent Ethics Committee Reporting 
Requirements .................................................................................................... 83 
10 
Statistics ................................................................................................................ 83 
10.1 
Sample Size Estimation .................................................................................... 83 
10.2 
Description of Study Analysis Sets .................................................................. 84 
10.2.1 
Screened Analysis Set .................................................................................. 84 
10.2.2 
Safety Analysis Set ....................................................................................... 84 
10.2.3 
Pharmacokinetic Analysis Set ...................................................................... 84 
10.2.4 
Pharmacodynamic Analysis Set ................................................................... 84 
10.3 
Statistical Analyses and Methods ..................................................................... 84 
10.3.1 
General Considerations ................................................................................ 84 
10.3.2 
Subject Disposition and Characteristics ....................................................... 85 
10.3.3 
Safety Analyses ............................................................................................ 85 
10.3.4 
Pharmacokinetics Analyses .......................................................................... 86 
10.3.5 
Pharmacodynamic Analyses ......................................................................... 87 
10.3.6 
Pharmacokinetic / Pharmacodynamic Relationships ................................... 88 
10.3.7 
Analysis of Exploratory Endpoints .............................................................. 88 
10.3.8 
Interim Analysis ........................................................................................... 89 
11 
Quality Assurance ................................................................................................. 89 
12 
Regulatory and Ethics Considerations .................................................................. 89 
12.1 
Regulatory Considerations ............................................................................... 89 
12.2 
Institutional Review Board / Independent Ethics Committee .......................... 90 
12.3 
Subject Information and Informed Consent ..................................................... 90 
12.4 
Subject Confidentiality ..................................................................................... 90 


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12.5 
Indemnity and Compensation ........................................................................... 91 
13 
Administrative Considerations ............................................................................. 91 
13.1 
Clinical Trial Research Agreement .................................................................. 91 
13.2 
Clinical Study Registration and Results Disclosure ......................................... 91 
13.3 
Implementation of the Clinical Study Protocol and Amendments ................... 92 
13.4 
Protocol Deviations .......................................................................................... 92 
13.5 
Documentation and Record Keeping ............................................................... 93 
13.5.1 
Data Collection ............................................................................................. 93 
13.5.2 
Data Quality Assurance ................................................................................ 93 
13.5.3 
Record Retention .......................................................................................... 94 
13.6 
Study and Site Closure ..................................................................................... 94 
13.7 
Clinical Study Report ....................................................................................... 94 
13.8 
Use of Data and Publications ........................................................................... 95 
14 
References ............................................................................................................ 96 
15 
Appendices ......................................................................................................... 106 
Appendix 1 
Signatures ....................................................................................................... 106 
 
List of Tables 
Table 1 
Overview of Study Design ............................................................................... 44 
Table 2 
Description of CSL312 .................................................................................... 55 
Table 3 
Description of Placebo (Formulation Buffer) .................................................. 56 
Table 4 
Investigational Product Dosing Characteristics ............................................... 58 
Table 5 
Permitted Medications / Therapies .................................................................. 64 
Table 6 
Prohibited Medications / Therapies ................................................................. 65 
Table 7 
Study Procedures: Demographics and Safety Assessments ............................. 67 
Table 8 
Clinical Procedures: Pharmacokinetic and Pharmacodynamic Assessments .. 70 
Table 9 
Severity of Adverse Events .............................................................................. 79 
 


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List of Figures 
Figure 1 
Study Design Schematic .................................................................................. 43 
 


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List of Abbreviations 
Abbreviation 
Term 
3F7 
Parental antibody to garadacimab 
%BLQ 
Percent below the limit of quantitation 
%CV 
Percent coefficient of variance 
β-FXIIa 
Activated coagulation factor XII beta 
ADA 
Antidrug antibody 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALAT 
Latin American Thoracic Society 
aPTT 
Activated partial thromboplastin time 
ATS 
American Thoracic Society 
AUC 
Area under the plasma concentration-time curve 
AUC0-tau 
Area under the concentration-time curve in 1 dosing interval 
BMI 
Body-mass index 
C1-INH 
C1-esterase inhibitor 
CCl4 
Carbon tetrachloride 
CCL 
C-C motif chemokine ligand (CCL-2, CCL-18) 
Cmax 
Maximum observed plasma concentration 
COVID-19 
Coronavirus disease 2019 
CPa9-HNE 
Neo-epitope of calprotectin generated by human neutrophil elastase 
CRPM 
Neo-epitope of matrix metalloproteinase-mediated degradation of 
C-reactive protein 
CSL 
CSL Behring 
CSL312 
Factor XIIa antagonist monoclonal antibody 
CSP 
Clinical study protocol 
CSR 
Clinical study report 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTRA 
Clinical Trial Research Agreement 
Ctrough 
Trough plasma concentration 
Ctrough,ss 
Trough plasma concentration at steady-state 
CXCL 
C-X-C motif chemokine ligand (CXCL-1, CXCL-5, CXCL-10) 


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Abbreviation 
Term 
DLCO 
Diffusing capacity of the lungs for carbon monoxide 
DVT 
Deep vein thrombosis 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EOI 
End of the infusion 
EOT 
End of treatment 
ERS 
European Respiratory Society 
EU 
European Union 
FDA 
Food and Drug Administration 
FEV1 
Forced expiratory volume in 1 second 
FSH 
Follicle-stimulating hormone 
FVC 
Forced vital capacity 
FVIII 
Coagulation factor VIII 
FXa 
Activated coagulation factor X 
FXII 
Coagulation factor XII 
FXIIa 
Activated coagulation factor XII 
GCP 
Good Clinical Practice 
GCSP 
Global Clinical Safety and Pharmacovigilance 
GERD 
Gastroesophageal reflux disease 
GMP 
Good Manufacturing Practice 
Gro-α 
Growth-regulated oncogene-alpha (same as CXCL-1) 
HAE 
Hereditary angioedema 
hs-CRP 
High-sensitivity C-reactive protein 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IDMC 
Independent data monitoring committee 
IEC 
Independent ethics committee 
IgG 
Immunoglobulin G 
IL 
Interleukin (IL-1β, IL-6, IL-8, IL-10) 
ILD 
Interstitial lung disease 
IMP 
Investigational medicinal product 
INR 
International normalized ratio 


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Abbreviation 
Term 
IP 
Investigational product 
IPF 
Idiopathic pulmonary fibrosis 
IRB 
Institutional review board 
IRT 
Interactive response technology 
IV 
Intravenous 
JRS 
Japanese Respiratory Society 
LIF 
Leukemia inhibitory factor 
MCP-1 
Monocyte chemoattractant protein 1 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMP 
Matrix metalloproteinase 
MMRM 
Mixed-model repeated measure 
mRNA 
Messenger ribonucleic acid 
PAI-1 
Plasminogen activator inhibitor 1 
PAR-1 
Protease activated receptor 1 
PD 
Pharmacodynamic 
pF1+2 
Prothrombin fragment 
PFT 
Pulmonary function test 
PK 
Pharmacokinetic 
Pro-Fib 
Biomarker specifically targeting the thrombin-mediated conversion of 
fibrinogen into fibrin 
PT 
Prothrombin time 
Q 
Quartile 
Q4W 
Every 4 weeks 
QTcF 
QT interval corrected using the Fridericia formula 
RNA 
Ribonucleic acid 
REML 
Restricted maximum likelihood 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus-2 
SC 
Subcutaneous 
SD 
Standard deviation 
SOP 
Standard operating procedure 
SP-A 
Surfactant protein A 


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Abbreviation 
Term 
SP-D 
Surfactant protein D 
SUSAR 
Suspected unexpected serious adverse reaction 
T1/2 
Terminal half-life 
TEAE 
Treatment-emergent adverse event 
TEE 
Thromboembolic event 
TGF-β 
Transforming growth factor-beta 
Tmax 
Time to reach maximum observed plasma concentration 
TNF 
Tumor necrosis factor 
TSP-1 
Thrombospondin-1 
USA 
United States of America 
VEGF 
Vascular endothelial growth factor 
VICM 
Neo-epitope of matrix metalloproteinase-mediated degradation of 
citrullinated vimentin 
 


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1 
Introduction 
1.1 
Background 
Idiopathic pulmonary fibrosis (IPF) is a form of chronic, progressive, fibrosing interstitial 
pneumonia of unknown etiology that occurs primarily in older adults and is limited to the 
lungs. IPF is associated with the histopathological and / or radiological pattern of usual 
interstitial pneumonia [Raghu et al, 2011; Raghu et al, 2018]. A pattern of usual interstitial 
pneumonia typically shows basal honeycombing as a distinguishing feature with or without 
peripheral traction bronchiectasis or bronchiolectasis. In addition, subpleural, 
basal-predominant reticular abnormalities and ground-glass opacification are often present 
[Raghu et al, 2018]. 
Previously, IPF was considered to be a predominantly an inflammatory disease [Scadding et 
al, 1967; Katzenstein et al, 1998; Crystal et al, 1984; Ryu et al, 1998]. However, recently 
there has been a shift in thinking regarding IPF pathogenesis from an inflammatory driven 
process to a primarily fibrotic one, in which fibrogenesis results from repetitive local 
micro-injuries to an aging alveolar epithelium. These micro-injuries initiate aberrant 
epithelial-fibroblast communication, the induction of matrix-producing myofibroblasts, and 
extracellular matrix accumulation and remodeling of the lung interstitium [Richeldi et al, 
2017; Sgalla et al, 2018; Martinez et al, 2017]. Nevertheless, inflammation appears to be a 
prominent feature in the lungs of patients with IPF [Bringardner et al, 2008] and may 
contribute the rate of disease progression [Balestro et al, 2016; Kahloon et al, 2013]. A severe 
innate and adaptive inflammatory infiltrate is observed in rapidly progressing patients with 
IPF that is markedly increased compared with slow progressors and is similar to that 
observed in patients experiencing an acute exacerbation [Balestro et al, 2016]. Differences in 
the expression of inflammatory markers and autoantibodies have been shown to be associated 
with different clinical outcomes in patients with IPF [Kahloon et al, 2013; Gilani et al, 2010; 
Prasse et al, 2009; Shinoda et al, 2009; Collard et al, 2007; dePianto et al, 2015; Nicholson et 
al, 2002; Moore et al, 2014; Taille et al, 2011]. 
IPF is one of the most common forms of idiopathic interstitial lung disease (ILD) [Kim et al, 
2015] and several genetic and environmental risk factors for the disease have been identified. 
These include male sex, older age, cigarette smoking, environmental exposures such as metal 
and wood dusts, gastroesophageal reflux disease (GERD), chronic viral infections such as 
Epstein-Barr virus and hepatitis C, and a family history of ILD [Raghu et al, 2011; Raghu et 
al, 2018; Sgalla et al, 2018]. 


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Patients with IPF typically present with nonspecific symptoms of exertional dyspnea with or 
without dry cough. On physical examination, fine, high-pitched bibasilar inspiratory crackles 
are usually heard, and digital clubbing is present in approximately 30% of patients [Richeldi 
et al, 2017; Raghu et al, 2018]. The natural history of IPF is highly variable and the course of 
disease in an individual patient is difficult to predict [Kim et al, 2015]. For some patients, 
disease progress occurs relatively slowly; others have a rapid decline in lung function leading 
to death; and a portion of patients suffer a stepwise loss of lung function with periods of 
relative stability [Kim et al, 2015]. Progression of IPF is characterized by a decline in lung 
function, worsening symptoms of dyspnea and cough, and deterioration in quality of life 
[Quinn et al, 2019]. For patients with IPF, acute exacerbations in respiratory function usually 
result in hospitalization and are associated with high mortality [Collard et al, 2016]. The 
evidence suggests that up to 46% of deaths in patients with IPF are preceded by an acute 
exacerbation, with a median survival of approximately 3 to 4 months in these patients 
[Collard et al, 2016]. Although the course of IPF may be variable, its overall prognosis is 
poor, with a median survival after diagnosis of only 3 to 4 years in patients who do not 
receive antifibrotic therapy or undergo lung transplant [Quinn et al, 2019]. 
Many patients with IPF have comorbid conditions including chronic obstructive pulmonary 
disease, lung cancer, pulmonary hypertension, obstructive sleep apnea, anxiety, depression, 
GERD, and ischemic heart disease [Caminati et al, 2019; Raghu et al, 2015a]. Comorbid 
conditions may affect the disease course in patients with IPF [Raghu et al, 2011], although in 
most of these patients the cause of death is IPF itself (ie, respiratory failure) [Kim et al, 
2015]. 
Two antifibrotic medications, nintedanib and pirfenidone, are approved in most countries for 
the treatment of IPF. These drugs received conditional recommendation for use in the latest 
international treatment guideline for IPF [Raghu et al, 2015b]. Both drugs reduce the rate of 
decline in forced vital capacity (FVC) compared with placebo over time, consistent with 
slowing the progression of the disease [Raghu et al, 2015a; Quinn et al, 2019]. However, 
neither drug significantly improves the patient’s quality of life [Quinn et al, 2019; Graney 
and Lee, 2018]. 


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Hypercoagulation coupled with decreased antifibrinolytic activities have been reported in IPF 
and other ILDs. This claim is supported by several studies reporting increased deposition of 
platelets, tissue factor, coagulation factor VIII (FVIII), and plasminogen activator inhibitor-1 
(PAI-1) within animal models of lung fibrosis and in patients with IPF [Fujimoto et al, 2003; 
Navaratnam et al, 2014; Crooks and Hart, 2015]. Significantly, patients with IPF who 
experience acute exacerbations have correlating elevated levels of D-dimer, fibrinogen, and 
homocysteine have been reported in both subjects with stable IPF and subjects with acute 
exacerbations of IPF compared with healthy control subjects [Bargagli et al, 2014]. 
Fibrin-rich wound clots are the result of the activated coagulation cascade. The clot can serve 
as a scaffold for fibroblast accumulation and synthesis of extracellular matrix [Schuliga et al, 
2018]. Furthermore, various proteins from the coagulant and fibrinolytic pathways have been 
implicated in the pathogenesis of pulmonary fibrosis. Procoagulant proteins, thrombin, and 
activated coagulation factor X (FXa) have direct profibrotic activities on lung fibroblasts 
through activation of protease activated receptor 1 (PAR-1) and direct inhibition of these 
proteins attenuated lung fibrosis in vivo [Howell et al, 2005; Chiu et al, 2008; Scotton et al, 
2009; Shea et al, 2017]. Dabigatran, the direct thrombin inhibitor, was able to inhibit 
fibroblast differentiation, profibrotic cytokine, collagen production [Bogatkevich et al, 2009]. 
It also ameliorated the development of bleomycin-induced pulmonary fibrosis in vivo and 
demonstrated a good safety profile in a phase 1 clinical study for patients with systemic 
sclerosis-interstitial lung disease [Bogatkevich et al, 2011; Silver et al, 2019]. In the 
fibrinolytic system, PAI-1 and plasmin drive excess fibrin accumulation and activation of 
profibrogenic actions of fibroblasts, respectively [Hattori et al, 2000; Senoo et al, 2010; 
Schuliga et al, 2017]. Overall, the evidence suggests that targeting the coagulation, 
inflammatory, and fibrinolytic pathways may be a potentially viable strategy for treating 
patients with IPF. 


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1.2 
Information on CSL312 
1.2.1 
Overview 
The coagulation factor XII (Hageman factor, FXII) is produced in the liver and is secreted 
into the plasma where the glycosylated 80 kDa zymogen circulates with a concentration of 
~30 µg/mL and a half-life of 50 to 70 hours [Bjorkqvist et al, 2014]. FXII can be activated to 
a 2-chain active form, FXIIa (also 80 kDa), following binding to negatively charged artificial 
or biologic surfaces [Maas and Renne, 2018]. Further cleavage of FXIIa releases the 30 kDa 
light chain containing the catalytic domain (FXIIa-β), which can activate the classical 
complement pathway [Ghebrehiwet et al, 1981]. FXIIa initiates coagulation via the 
fibrin-forming intrinsic pathway and promotes inflammation via the bradykinin-producing 
kallikrein-kinin system [Renne and Stavrou, 2019; Maas and Renne, 2018]. Binding of 
bradykinin to the kinin B2 receptor activates proinflammatory signaling pathways that dilate 
vessels, induce chemotaxis of neutrophils, and increase vascular permeability [Renne et al, 
2012]. FXIIa may also modulate components of the complement and fibrinolytic systems. 
However, to date, these activities have only been demonstrated in vitro [Renne and Stavrou, 
2019]. Studies have shown that FXII deficient animals are protected from thrombosis without 
impaired hemostasis [Renne et al, 2005; Kleinschnitz et al, 2006; Matafonov et al, 2014]. 
Similarly, pharmacological targeting of FXII or FXIIa provides protection from thrombosis 
without an increased incidence of bleeding [Larsson et al, 2014; Revenko et al, 2011]. 
CSL312, an affinity matured antibody targeting the catalytic domain of FXII, effectively 
reduced edema in in vivo models and prevented bradykinin formation following contact 
activation of normal and kallikrein-defective plasma samples [Cao et al, 2018]. 


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1.2.1.1 
Evidence for FXII and the Contact System in Lung Fibrosis 
Emerging evidence has shown an increased expression and local activation of FXII in the 
lungs of patients with IPF that is associated with fibroblasts / myofibroblasts [Wygrecka et al, 
2015]. FXII binds to lung fibroblast through heparan sulfate proteoglycan and induces 
proliferation, fibroblast differentiation and extracellular matrix production [Wujak et al, 
2015; Hess et al, 2017]. Moreover, transforming growth factor-beta (TGF-β) was found to 
induce p-JNK and translocation of SMAD-3 to the nucleus to upregulate FXII expression 
[Jablonska et al, 2010]. Genetic ablation or pharmacological blockade of FXII activity 
abrogated fibrogenesis in a bleomycin lung injury model in mice [Wygrecka et al, 2015]. 
FXII was reported to induce the production and release of interleukin (IL)-8, IL-1β, IL-6, 
leukemia inhibitory factor (LIF), CXCL motif chemokine ligand 5 (CXCL-5), and tumor 
necrosis factor (TNF) in human precision-cut lung slides in a kallikrein kinin-independent 
manner [Hess et al, 2017]. FXII also has direct effects on endothelial cell proliferation, 
vascular smooth muscle cells, neutrophil activation, monocyte / macrophage activation and 
associated M2 phenotype induction [Mahdi et al, 2002; Fernando et al, 2005; LaRusch et al, 
2010; Wang et al, 2010; Vorlova et al, 2017; Stavrou et al, 2018]. These cells types have been 
implicated in fibrogenesis. Lung epithelial cells support the assembly and activation of 
plasma kallikrein kinin system. The resulting bradykinin production may potentiate 
inflammation in lung disease [Varano Della Vergiliana et al, 2010]. Bradykinin can also 
induce fibroblast cytokine expression and activation [Hayashi et al, 2000; Sabatini et al, 
2013]. Thus, inhibition of FXII and the contact protein functions may have a therapeutic 
effect in IPF patients. 


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CSL312 is a fully human, recombinant, immunoglobulin G4 (IgG4) monoclonal antibody 
which binds to activated human FXII and potently inhibits its catalytic activity. CSL312 is an 
affinity-matured variant of the parental antibody 3F7, which was isolated from a Fab-based 
phage display library following screening against the active catalytic fragment of FXII 
(β-FXIIa). CSL312 is expressed in Chinese hamster ovary cells and has a structure typical of 
IgG4 monoclonal antibodies consisting of 2 heavy and 2 light chains, joined by disulphide 
bridges. CSL312 has a molecular weight of ~148 kDa. The CSL312 drug product is a sterile 
liquid formulation presented in 2-mL single-use glass vials, which is suitable for intravenous 
(IV) and subcutaneous (SC) administration to humans. CSL312 is manufactured according to 
Good Manufacturing Practice (GMP), in GMP-compliant facilities. A comprehensive 
manufacturing strategy that employs a combination of virus testing, the use of 
animal / human component-free growth media and excipients, and the incorporation of 
2 dedicated virus removal / inactivation steps, ensures that the final product has a high level 
of virus safety. 
A detailed description of the chemistry, pharmacology, efficacy, and safety of CSL312 is 
provided in the CSL312 Investigator’s Brochure (IB). 


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1.2.2 
Nonclinical Evaluation 
For the ILD / IPF indication, in vitro studies were performed to support the role of FXII in 
lung fibrogenesis. FXII protein levels were found to be elevated in the lungs of patients with 
IPF when compared with non-disease control lungs. Whole lung RNA sequencing and 
published single cell RNA sequencing datasets have confirmed that FXII is not made in the 
lungs or the lung fibroblasts. Collectively, these data suggest that FXII is not produced in the 
lungs and is found when the lung is damaged, causing activation of the pulmonary 
endothelium, increased vascular permeability and increased perfusion into the lung tissue. 
FXII was found to be significantly elevated the blood of a subset of patients with IPF 
displaying a progressive decline in lung function. IL-6 has been implicated in the 
pathogenesis of lung fibrosis [Saito et al, 2008; Le et al, 2014; Kobayashi et al, 2015]. 
Activated β-FXIIa-induced IL-6 mRNA expression and protein production from human lung 
fibroblasts and CSL312 inhibited this function in a dose-dependent manner [Wong et al, 
2017]. This process was found to be mediated through PAR-1 and NF-κB signalling 
pathways. Aside from IL-6, β-FXIIa also significantly increased the release of pro-fibrotic 
cytokines / chemokines (CXCL-1 / growth regulated oncogene-alpha [Gro-α], monocyte 
chemoattractant protein 1 [MCP-1 / C-C motif chemokine ligand (CCL-2)], IL-8, PAI-1, and 
latent TGF-β from lung fibroblasts a dose-dependent manner. Correspondingly, CSL312 
inhibited CXCL-1, MCP-1, IL-6, IL-8, and PAI-1. β-FXIIa significantly induced the 
proliferation of IPF fibroblasts. β-FXIIa induced the transition of primary M0 macrophages 
to an M2 phenotype, and IL-6 induced hyperpolarization of M2 macrophages and also 
stimulated Type II cytokine (CCL-18, IL-10, and vascular endothelial growth factor [VEGF]) 
release from naïve and M2 macrophages. Excessive M2-associated responses are an 
important part of many fibrotic diseases and are implicated in the aberrant wound-healing 
cascade during fibrosis [Zhang et al, 2018]. CSL312 inhibited the β-FXIIa-mediated 
migration of primary lung fibroblasts in a dose-dependent manner. 
Bradykinin, a downstream product of FXII activation is involved in vasodilation and 
inflammation during tissue injury. CSL312 can effectively inhibit bradykinin formation in 
human plasma following potent FXII activation. Preliminary studies have confirmed that 
bradykinin induces IL-6 in lung fibroblasts, which is mediated through the bradykinin 
receptor-2 subtype. 


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Bioinformatics methods utilizing the transcriptome of in vitro FXII and CSL312-stimulated 
fibroblasts revealed processes regulated by CSL312, leading to the identification of a 
FXII / CSL312 gene signature. Preliminary results demonstrate an enrichment of this gene 
signature in patient samples of several ILD subtypes (IPF, nonspecific interstitial pneumonia, 
systemic sclerosis-ILD, and hypersensitivity pneumonitis) when compared with 
healthy / non-fibrotic controls. Stratification of ILD patients based on the FXII signature and 
clinical data showed that it correlated with declining lung function (increased disease 
severity). These preliminary findings may provide the potential to guide selection and 
stratification of ILD patients for treatment with CSL312. Further work is underway to 
validate and refine the FXII gene signature, examine the signature enrichment in larger ILD 
cohorts, and evaluate whether it can be translated into blood to select for CSL312-responsive 
patients. 
In vivo evaluation of 3F7, the parental antibody to CSL312, was assessed in the murine 
bleomycin lung model of pulmonary fibrosis. The prophylactic or therapeutic administration 
of 3F7 significantly ameliorated bleomycin-induced pulmonary fibrosis, as evident by the 
preserved lung structure, improved lung function, and reduced expression extracellular 
matrix proteins. Additionally, 3F7 inhibited bleomycin-induced pulmonary fibrosis similarly 
to anti-TGF-β monoclonal antibody in benchmarking studies. 3F7 also significantly inhibited 
carbon tetrachloride (CCl4)-induced liver fibrosis and unilateral ureteral obstruction-induced 
renal fibrosis in these mouse models. 
Within the framework of the hereditary angioedema (HAE) project the pharmacology 
program was structured to characterize the interaction between CSL312 and FXII zymogen 
and its active forms, as well as the ability of CSL312 to specifically inhibit FXIIa-mediated 
biological activities both in vitro and in vivo using relevant animal species, ie, mice, rabbits 
and cynomolgus monkeys. 
The pharmacokinetic (PK) studies and the toxicology program supporting the clinical 
development of CSL312 in IPF were performed according to international standards outlined 
in International Council for Harmonisation (ICH) guidelines. 


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Two single-dose PK / pharmacodynamics (PD) studies with CSL312 after IV and / or SC 
administration in cynomolgus monkeys showed prolongation of activated partial 
thromboplastin time (aPTT) confirming pharmacological activity of CSL312. Throughout 
both studies, terminal half-life (T1/2) after IV administration was between 9 and 11 days. 
After SC administration, T1/2 was between 12 and 14 days and bioavailability was calculated 
to be approximately 66%. A single-dose PK study comparing formulations of 100 mg/mL and 
170 mg/mL of CSL312 in rabbits at a SC dose of 20 mg/kg demonstrated a similar PK profile 
for both formulations. 
The CSL312 safety pharmacology and toxicological program demonstrated that at doses of 
up to 100 mg/kg IV and 200 mg/kg SC, CSL312 was well tolerated and had no adverse 
treatment-related effects on safety in mice or cynomolgus monkeys at up to 26 weeks. In the 
4-week repeat-dose toxicity study in mice lower IV doses (3 to 30 mg/kg) revealed adverse 
treatment-related clinical signs and mortality after repeat dosing due to an immunological 
reaction to the human protein CSL312, which has limited predictive value for the clinical 
situation. In a local tolerance study in rabbits, CSL312 was well tolerated at the injection site. 
In addition, no adverse treatment-related effects were observed in the embryo-fetal 
development, in the fertility studies (1 study for each sex), and in a prenatal and postnatal 
development study in rabbits. Moreover, tissue cross-reactivity was observed on various 
human and cynomolgus monkey tissues; however, no related safety findings were observed 
in cynomolgus monkey repeat-dose toxicity studies. 
Carcinogenicity assessments based on abovementioned published literature and available 
nonclinical and clinical data concluded that CSL312 has no carcinogenic potential when 
administered to patients. 
In conclusion, nonclinical experiments demonstrate increased FXII protein expression in the 
damaged IPF lung and contribution to lung fibrogenesis by enhancing in vitro fibroblast 
proliferation, migratory capacity and pro-inflammatory / profibrotic cytokine / chemokine 
release. CSL312 inhibited these FXIIa-β-mediated processes. Anti-FXIIa monoclonal 
antibody 3F7 also demonstrated efficacy in ameliorating lung fibrosis in the murine 
bleomycin model of lung fibrosis in the prophylactic and therapeutic setting. CSL312 safety, 
PD, and toxicology studies demonstrated an adequate safety profile supporting a phase 2 
clinical study. Since immunological reactions are principally expected after repeat-dosing of 
heterologous proteins (ie, human proteins in animal species), respective findings observed in 


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repeat-dose toxicological studies are considered not predictive for the clinical situation, 
which is in line with the ICH S6(R1) guideline. 
Further details on nonclinical data for CSL312 are available in the CSL312 IB. 
1.2.3 
Clinical Experience 
CSL312 is currently being developed for 2 target indications: IPF and HAE. Additionally, 
CSL312 had been under evaluation for the prevention of respiratory failure in patients with 
Coronavirus disease 2019 (COVID-19), but based on the results from a proof-of-concept 
study, development was discontinued (refer to the CSL312 IB for additional details). 
1.2.3.1 
Healthy Subjects 
In healthy subjects, a phase 1 study has been completed and another is ongoing. 
Study CSL312_1001, a phase 1, randomized, double-blind, placebo-controlled, 
single-ascending dose study was conducted in healthy volunteers. During this study, the 
safety, 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. After SC doses, the time to 
reach maximum observed plasma concentration (Tmax) was approximately 7 days. The 
majority of the AEs were of mild severity. Injection site reactions were more common 
with SC CSL312 than SC placebo, but there was no apparent dose dependence. 
Additionally, CSL312 exhibited linear PK with a T1/2 of approximately 18 days after the 
SC injection. The study results are described in greater detail in the CSL312 IB. 
Additionally, a phase 1, single ascending dose study to investigate the PK, PD, safety, and 
tolerability of CSL312 in healthy Japanese and Caucasian subjects (CSL312_1003) is 
ongoing. Preliminary data from this study are not yet available. 


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1.2.3.2 
Subjects with Idiopathic Pulmonary Fibrosis 
Study CSL312_2002 will be the first CSL-sponsored clinical study evaluating CSL312 in 
patients with IPF. 
1.2.3.3 
Subjects with Hereditary Angioedema 
Three clinical studies assessing CSL312 are currently ongoing in subjects with HAE; 
one phase 2 study and two phase 3 studies. 
Study CSL312_2001 
CSL312_2001 is an ongoing multicenter, randomized, placebo-controlled, parallel-arm, 
phase 2 dose-ranging (75, 200, and 600 mg) study to investigate the efficacy, PK, and safety 
of CSL312 SC administered every 4 weeks (Q4W) as prophylaxis to prevent HAE attacks in 
subjects with C1-esterase inhibitor (C1-INH) HAE or FXII / plasminogen HAE. The study 
consists of a Screening Period, a Run-in Period, 2 treatment periods (Treatment Period 1 
[2 parts: 1 double-blind portion and 1 open-label portion] and open-label Treatment 
Period 2), and a Follow-up Period. After the Run-in Period, eligible subjects with C1-INH 
HAE were randomized to 1 of 4 treatment groups (placebo, or 75, 200, or 600 mg CSL312) 
in double-blind Treatment Period 1. Subjects received a single IV loading dose of 
investigational product followed 1 week later by a single SC injection of investigational 
product Q4W for 12 weeks (for a total of 13 weeks). In the open-label portion (Treatment 
Period 2), subjects receive a single SC injection of CSL312 at a dose of either 200 or 600 mg 
Q4W. The study is currently ongoing and the randomized, double-blinded portion of 
Treatment Period 1 has been completed. 
A total of 32 patients with C1-INH (type 1 or type 2) HAE were enrolled in the randomized 
double-blind treatment groups of Treatment Period 1 at 20 study sites across 5 countries. 
Interim results from Treatment Period 1 demonstrate that CSL312 is safe and well tolerated at 
all 3 doses and has an overall favorable safety profile. All 3 dosages of CSL312 SC Q4W 
achieved clinically meaningful reductions in the HAE attack rate compared with placebo. The 
most frequent AEs were nonserious injection site reactions (ie, injection site erythema, 
pruritus, swelling, and discomfort) that were mild or moderate in severity. No related SAEs 
or adverse events of special interest (AESIs; TEEs, abnormal bleeding, or severe 
hypersensitivity and anaphylaxis events) were reported. 


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No difference in the PK of CSL312 was noted between healthy subjects in 
Study CSL312_1001 and subjects with HAE in Study CSL312_2001. 
All subjects who successfully complete Study CSL312_2001 will be eligible to participate in 
the open-label, long-term safety study (CSL312_3002). 
Study CSL312_3001 
Study CSL312_3001 is a phase 3, multicenter, double-blind, randomized, placebo-controlled, 
parallel-group study designed to investigate the efficacy and safety of a single dose of 
CSL312 administered SC once a month as prophylaxis to prevent HAE attacks in adolescent 
(12 to 17 years, inclusive) and adult subjects with HAE. This study was recently initiated 
and, therefore no preliminary data from this study are available. 
Study CSL312_3002 
A multicenter, open-label study designed to investigate the long-term safety and efficacy of 
SC administered CSL312 in the prophylactic treatment of subjects with HAE is currently 
ongoing. Preliminary data from this study are not yet available. 
1.2.3.4 
Subjects with Coronavirus Disease 2019 
A phase 2, prospective, multicenter, randomized, double-blind, placebo-controlled, 
parallel-group study was conducted to assess the safety, PK, and efficacy of IV 
administration of CSL312, administered in combination with standard-of-care treatment in 
patients with COVID-19 (CSL312_COVID19). Of the 124 patients randomized, 117 subjects 
were administered a single IV dose of investigational product (CSL312 or placebo). 
The primary endpoint of the study was the incidence of progression to tracheal intubation or 
death prior to tracheal intubation. Although the incidence of progression to tracheal 
intubation or death prior to tracheal intubation was lower for subjects in the CSL312 group 
compared with the placebo group, the difference was not statistically significant (p = 0.274). 


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During the study, nearly two-thirds of subjects experienced ≥ 1 TEAE (64.1% 
[75 / 117] subjects, 303 events); a smaller percentage in the CSL312 group experienced 
TEAEs compared with the placebo group (60.3% vs. 67.8%). Few TEAEs were considered 
treatment-related (5 events in 4 subjects [3.4%]) and the percentages were similar for the 
CSL312 and placebo groups (3 events in 2 subjects [3.4%] vs. 2 events in 2 subjects [3.4%]). 
All 3 related TEAEs in the CSL312 group (1 patient experienced 2 AEs of ALT increased and 
AST increased and 1 patient experienced 1 AE of hemiparesis [left-sided weakness]) were 
non-serious, mild in intensity and resolved within one day after onset. 
One-third of subjects (33.3%; 39 /117) experienced SAEs (83 events). The percentage of 
subjects with SAEs was similar for the CSL312 and placebo groups (34.5% vs. 32.2%), 
although the number of reported SAEs was lower for the CSL312 group (38 vs. 45 events). 
Only 1 subject, who was in the placebo group, experienced a treatment-related SAE of 
bilateral deep vein thrombosis (DVTs) that was reported as a suspected unexpected serious 
adverse reaction (SUSAR) and also as an AESI. 
During the study, 11 subjects experienced a total of 19 AESIs; 10 subjects with 15 TEEs and 
1 subject with 4 bleeding events. A total of 4 bleeding events were reported for 1 subject, 
who was in the placebo group. The percentage of subjects with TEEs and number of events 
was similar for the CSL312 group (5 / 58 subjects [8.6%], 8 events) and the placebo group 
(5 / 59 subjects [8.5%], 7 events). All AESIs except the previously described SUSAR case 
were considered as not related to the investigational product. 
In total, 23 subjects had fatal TEAEs (23 / 117 subjects [19.7%]). The percentage of subjects 
with fatal events was similar for the CSL312 and placebo groups (20.7% vs. 18.6%). None of 
the deaths were considered related to investigational product. 
Only 1 subject, who was in the CSL312 group, discontinued study treatment because of a 
TEAE. 


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1.3 
Study Overview 
Study CSL312_2002 is designed to explore the treatment effect of CSL312 600 mg on safety, 
PK, and biomarkers in subjects with IPF over a 14-week Treatment and Observation Period. 
Subjects will be randomized to 1 of 2 treatment groups: 
• CSL312 600 mg SC Q4W 
• Placebo SC Q4W 
One week before the first SC dose of investigational product, an IV loading dose that is half 
of the SC maintenance dose will be administered and the date of the IV loading dose will be 
considered Day 1 of study. 
The overall objective of the study is to establish a proof of mechanism and generate 
additional human data to support decision-making for further development of CSL312 for the 
treatment of patients with IPF. 
The study has the following specific objectives: 
• To investigate the safety of CSL312 in patients with IPF 
• To characterize the systemic PK of CSL312 in patients with IPF 
• To investigate the effect of CSL312 on FXII-related pathways and on a validated 
clinical endpoint (FVC) in patients with IPF 
• To further investigate the association of FXII-related anti-fibrotic pathways 
(contact / coagulation, inflammation, and fibroblast function) with IPF clinical 
features and biomarkers of lung structural damage and IPF pathogenesis 
1.4 
Potential Risks and Benefits 
1.4.1 
Potential Benefits 
This is a 26-week clinical study that includes a 28-day Screening Period, a 14-week 
Treatment and Observation Period, and a Follow-up Telephone call at 90 days after the last 
administration of investigational product. The benefits of treatment with CSL312 in patients 
with IPF are unknown. Subjects randomly assigned to the placebo group are not expected to 
receive any benefits related to their IPF disease from participating in this study. 


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1.4.2 
Potential Risks 
Potential risks associated with CSL312 have been considered based on the anticipated effects 
of the proposed mechanism of action and known risks associated with drugs of the same or 
similar class. The following events constitute potentially important medical risks: 
• Severe hypersensitivity including anaphylaxis: Administration of therapeutic proteins 
including monoclonal antibodies such as CSL312 may be associated with the risk of 
hypersensitivity and anaphylactic reactions, some of which can be serious and 
life-threatening. To date, no severe hypersensitivity or anaphylactic-type reactions have 
been observed after repeated administration of CSL312 in the completed or ongoing 
clinical studies. Nevertheless, administration of CSL312 will be performed at the study 
site under medical supervision, with immediate access to emergency equipment and 
medication for the treatment of severe hypersensitivity, including anaphylaxis. Subjects 
will be informed of the early signs of hypersensitivity reactions including hives, 
generalized urticaria, tightness of the chest, wheezing, hypotension, and anaphylaxis, and 
will be encouraged to report any symptoms to site personnel. 
• Abnormal bleeding and thromboembolic events: By blocking FXIIa, CSL312 may be 
associated with a potential risk of bleeding or TEEs, due to altered hemostasis, unstable 
clot formation, or impaired clot breakdown. In addition, due to the pharmacological 
action of CSL312, a concentration-dependent prolongation of aPTT was observed with 
dosages similar to those proposed in this study. Clinical experience with CSL312 in study 
CSL312_1001 and CSL312_2001 did not show an effect on prothrombin time (PT). This 
is consistent with the observation that patients who have a congenital deficiency of FXII 
do not exhibit a bleeding phenotype, despite having a prolonged aPTT [Lammle et al, 
1991; Ratnoff and Colopy, 1955]. In addition, nonclinical studies in mice and rabbits 
showed no impairment in hemostasis after inhibition of FXIIa [Larsson et al, 2014]. 
Nevertheless, subjects will be monitored carefully for any signs of thrombosis or bleeding 
during 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 
of ADAs. During the study, investigators will monitor subjects for the development of 
ADAs for clinical evaluation of any signs of immunogenicity. 


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Given the acceptable safety profile of CSL312 observed in the phase 1 study (CSL312_1001) 
and the two phase 2 studies (CSL312_2001 and CSL312_COVID-19), and taking into 
account the implementation of procedures in the current study to closely monitor subject 
safety, the associated benefit-risk assessment is considered to be acceptable. Additional 
information on CSL312 can be found in the CSL312 IB. 
2 
Study Objectives and Endpoints 
2.1 
Primary Objective and Endpoint 
2.1.1 
Primary Objective 
The primary objective of this study is to investigate the safety of CSL312 in subjects with 
IPF. 
2.1.2 
Primary Endpoints 
Endpoints 
Summary Measure 
Subjects experiencing treatment-emergent 
adverse events (TEAEs) including: 
• SAEs 
• AESIs 
• CSL312-induced ADAs 
• Clinically significant abnormalities in 
laboratory assessments that are reported 
as AEs 
Number and proportion of subjects 
experiencing the specified safety events 
after treatment with investigational product 
(CSL312 or placebo) 
 
2.2 
Secondary Objectives and Endpoints 
2.2.1 
Secondary Objectives 
The secondary objectives of the study are: 
1. To characterize the systemic PK of CSL312 in patients with IPF. 
2. To investigate the pharmacodynamics (PD) activity of CSL312 in patients with IPF. 


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2.2.2 
Secondary Endpoints 
The secondary endpoints of the study are: 
Secondary 
Objective 
Endpoints 
Summary Measures 
1 
Plasma PK parameters after SC 
administration of CSL312 at each SC 
dosing interval: 
• Trough plasma concentration 
(Ctrough) 
• Maximum plasma concentration 
(Cmax) (last SC dosing interval 
only) 
• Tmax (last SC dosing interval 
only) 
• Area under the plasma 
concentration-time curve after the 
first dose interval (AUC0-tau) (last 
SC dosing interval only) 
• Mean (standard deviation [SD]) 
and geometric mean (geometric 
percent coefficient of variation 
[%CV]) for all PK parameters 
except for Tmax 
• Median (minimum, maximum) 
for Tmax 
1 
Plasma PK parameters after the IV 
dose of CSL312: 
• Cmax 
• Tmax 
• Ctrough 
• Mean (SD) and geometric mean 
(geometric %CV) for all PK 
parameters except for Tmax 
• Median (minimum, maximum) 
for Tmax 
2 
Effect of treatment with CSL312 on 
FXIIa-mediated kallikrein activity 
• Mean (SD) change from Baseline 
in FXIIa-mediated kallikrein 
activity by treatment 
• Mean percentage of Baseline in 
FXIIa-mediated kallikrein 
activity by treatment 
 


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2.3 
Exploratory Objectives and Endpoints 
2.3.1 
Exploratory Objectives 
The exploratory objectives of this study are: 
1. To investigate the potential effect of CSL312 on FXII-related pathways in patients 
with IPF 
2. To investigate the effect of CSL312 on lung function in patients with IPF 
2.3.2 
Exploratory Endpoints 
The exploratory endpoints of the study are: 
Exploratory 
Objective 
Endpoints 
Summary Measures 
1 
Concentration of PD and 
biomarkers in blood 
• Mean (SD) change from Baseline in PD 
and biomarkers by treatment 
• Mean percent change from Baseline in 
PD and biomarkers by treatment 
2 
Change in FVC 
• Absolute change from Baseline in FVC at 
14 weeks (expressed in mL) 
• Absolute change from Baseline in FVC 
percent predicted at 14 weeks 
• Number and proportion of subjects with 
≥ 5% or ≥ 10% absolute or relative 
decline in FVC percent predicted at 
14 weeks 
 


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3 
Study Design and Oversight 
3.1 
Overall Design 
This is a prospective, randomized, double-blind, placebo-controlled study to investigate the 
safety, PK, and PD of CSL312 in patients with IPF (Figure 1). Approximately 80 patients 
with a confirmed diagnosis of IPF will be enrolled and randomized to treatment in a 1:1 ratio; 
to achieve a total of 70 evaluable subjects by Week 14; 35 subjects in the CSL312 600 mg 
group and 35 subjects in the placebo group. 
Figure 1 
Study Design Schematic 
EOT = End-of-Treatment Visit; IPF = idiopathic pulmonary fibrosis; IV = intravenous; n = number of subjects 
in the treatment group; SC = subcutaneous. 
For all enrolled subjects, informed consent must be obtained at the Screening Visit before any 
study-specific assessments are performed. Screening can occur between 1 and 28 days before 
Day 1. For this study, Baseline is defined as before dosing on Day 1. 
Eligible subjects will be randomized to enter the Treatment and Observation Period for 
14 weeks, during which subjects will receive an IV loading dose of CSL312 or placebo 
followed by 3 SC doses of CSL312 or placebo. A total of 12 study visits are planned 
(1 Screening Visit and 11 visits during the Treatment and Observation Period). A final safety 
check will be conducted by telephone approximately 90 days after the last administration of 
investigational product (see the Schedule of Assessments). The study will end when the last 
subject has completed the 14-week Treatment and Observation Period and the Follow-up 
Visit (Telephone Call). 


CSL Behring 
Study Number: 
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Table 1 
Overview of Study Design 
Study Type: 
Prospective / Interventional 
Study Periods: 
The study will consist of a Screening / Washout Period, a 
Treatment and Observation Period, and a Follow-up Period 
Blinding Type: 
The study will be conducted in a double-blind manner 
Study Configuration: 
Parallel group 
Method of Assigning 
Subjects to Treatment: 
Eligible subjects will be randomized to treatment at the first 
study visit on Day 1 during the Treatment and Observation 
Period 
 
3.2 
Dose and Dosing Regimen 
Investigational product will be administered as an IV loading dose followed by 3 subsequent 
SC injections at the following doses based on treatment group: 
• CSL312 Group: IV loading dose of CSL312 at 300 mg followed by a second dose of 
600 mg administered SC 7 days later (Week 2). Doses 3 and 4 of 600 mg will be 
administered SC at Weeks 6 and 10, respectively. 
• Placebo Group: IV loading dose of placebo followed by a second dose of placebo 
(formulation buffer) administered SC 7 days later (Week 2). Doses 3 and 4 of placebo 
will be administered SC at Weeks 6 and 10, respectively. 
On Day 1, subjects will be asked to remain at the site for observation for 15 to 30 minutes 
after the end of the infusion (EOI) for the IV loading dose of investigational product. 


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3.3 
Scientific Rationale 
3.3.1 
Study Design Rationale 
Data have shown that FXII contributes to lung fibrosis by modulating markers that are 
implicated in the mechanistic pathways of IPF [Wong et al, 2017]. In vitro studies conducted 
in human lung fibroblasts showed that CSL312 inhibited β-FXIIa-mediated IL-6 production, 
fibroblast migration, and bradykinin generation at the highest concentration tested. 
Furthermore, repeat administration of 3F7, the parental antibody to CSL312, at 20 mg/kg as 
either a prophylactic or a therapeutic treatment regimen significantly ameliorated 
bleomycin-induced pulmonary fibrosis in mice. Taken together, these results support the 
rationale to develop CSL312 as a therapeutic option for the treatment of IPF. Although it is 
known that IPF is a multi-factorial disease, it is assumed that inhibiting FXIIa-mediated 
kallikrein activity to a particular percent target inhibition may inhibit inflammatory and 
fibrotic mediators involved in the disease process in IPF. 
3.3.2 
Dose Rationale 
The proposed dose of CSL312 to be administered in this study is 600 mg SC Q4W. One week 
before the first SC dose, an IV loading dose that is half of the SC maintenance dose will be 
administered. 
Dose selection was based on the safety, PK, and PD data obtained from the phase 1 study in 
healthy volunteers (CSL312_1001) and the phase 2 study in subjects with HAE 
(CSL312_2001). Results from previous clinical studies in healthy volunteers and subjects 
with HAE showed that a single administration of CSL312 at a dose of up to 10 mg/kg both 
IV and SC (CSL312_1001) and repeated SC administration of CSL312 at doses of up to 
600 mg (CSL312_2001) were safe and well tolerated. In Study CSL312_1001, CSL312 
exhibited linear PK when administered as a single IV infusion or SC injection with an 
absolute bioavailability of approximately 50%, and a T1/2 of approximately 18 days after the 
SC injection. Dose-dependent PK was observed in Cmax and area under the plasma 
concentration-time curve (AUC) after repeated SC administration in Study CSL312_2001. To 
date, no difference in the PK of CSL312 was noted between healthy volunteers and subjects 
with HAE. 


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A PK / PD model was developed to quantify the relationship between CSL312 plasma 
concentrations and FXIIa-mediated kallikrein activity from Studies CSL312_1001 (healthy 
volunteers) and CSL312_2001 (patients with HAE). The modeled relationship showed an 
increase in inhibition of FXIIa-mediated kallikrein activity with increasing concentrations of 
CSL312. 
The IV loading dose was considered for this study to immediately achieve and maintain 
approximate steady-state exposures (ie, Cmax, Ctrough, AUC) during the proposed 3-month 
Treatment and Observation Period. With an IV loading dose, 73% of patients are projected to 
be above the median steady-state Ctrough (Ctrough,ss) at the end of the first SC dosing interval. 
Simulations from the final healthy volunteer / HAE patient PK / PD model showed that a 
fixed dose of 600 mg SC Q4W would achieve a median percent inhibition of FXIIa-mediated 
kallikrein activity of ≥ 90% at the nadir during the SC dosing interval. 
3.4 
Planned Study Duration 
The duration of the study for an individual subject is expected to be up to 6 months. This 
estimate is based on: 
• Screening / Washout Period of up to 28 days 
• 14-week Treatment and Observation Period 
• Follow-up Telephone Call at 90 days after the last investigational product administration 
The overall study duration (ie, first subject’s Screening Visit to last subject’s Follow-up 
Telephone call) will be approximately 17 to 19 months. 
3.5 
Planned Number of Subjects 
The study will enroll approximately 80 subjects to achieve a total of 70 evaluable subjects by 
Week 14; 35 subjects in the CSL312 group and 35 subjects in the placebo group. The 
estimated dropout rate is approximately 12%. 
A subject is considered enrolled in the study once they have signed the informed consent and 
are considered eligible for the study (ie, have met all inclusion criteria and none of the 
exclusion criteria; see Section 4.1). 


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3.6 
Definition of Start of the Clinical Study 
The start of the clinical study is defined as the date of the first subject's signed consent form 
(ICF). 
3.7 
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 contact with the last subject. 
3.8 
Study Oversight 
3.8.1 
Independent Data Monitoring Committee 
An independent data monitoring committee (IDMC) will be established to monitor the 
critical safety data generated during the study. The IDMC will consist of at least 3 members 
including at least 1 independent clinical specialist in pulmonology, who also has experience 
in clinical studies. The IDMC will review accumulating safety data from the ongoing study in 
an unblinded manner. Based on these reviews, the IDMC will advise on further conduct of 
the study. CSL will continue the study unless a safety issue is confirmed that warrants study 
termination. 
Details on the composition, responsibilities, activities, timing of meetings, data required for 
each review, analyses, and the review and decision-making processes for the IDMC will be 
described in the IDMC charter. 
3.9 
Stopping / Halting Criteria 
For the purpose of this study, the study stopping criteria and study halting criteria are the 
same. 


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If any halting criteria are met and the study is halted per IDMC recommendation, the CSL 
Global Safety Committees will conduct a safety assessment to establish whether the study 
should be resumed or whether the temporary halt should continue. The study can be resumed 
on the recommendation of CSL’s Global Safety Committees, in agreement with the IDMC, if 
the safety assessment concludes that no further study modifications, protocol amendments, or 
risk mitigation measures are necessary, and that it is safe to resume the study. Regulatory 
authorities and the institutional review board (IRB) will be notified of the temporary halt and 
subsequent resumption of the study. A substantial protocol amendment will be submitted to 
the regulatory authorities and the IRB for approval if the safety assessment concludes that 
modifications to the clinical study protocol (CSP), including addition of new risk mitigation 
measures, are required to resume the study. If necessary, ad-hoc unblinding procedures may 
be initiated according to CSL’s standard operating procedures (SOPs) for further safety 
assessment. If the risk assessment concludes that continued dosing poses an unacceptable risk 
to subjects and no further risk mitigation steps can be applied, the CSL Global Safety 
Committees will be involved in recommending a study stop. Regulators and the independent 
ethics committee (IEC) will be notified of a study stop. 
3.9.1 
Individual Subject Halting Criteria 
If a subject meets any of the following criteria, then further administration of CSL312 to that 
subject will be halted (ie, temporarily paused) until an assessment of that subject’s safety is 
completed: 
• Symptoms of severe hypersensitivity considered by the investigator and / or CSL to 
be related to CSL312 administration. 
• Prolongation of the QT interval corrected using the Fridericia formula (QTcF) interval 
of > 500 milliseconds. 
• Prolongation of the QT interval corrected using the QTcF interval of 
> 60 milliseconds compared with the baseline measurement. 
• A confirmed diagnosis of TEE or a clinically significant abnormal bleeding event, 
irrespective of CSL312 causality. 
• Any event or laboratory abnormality that is considered by the investigator and / or 
CSL to pose an unacceptable risk to the subject in the study. 


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3.9.2 
Study Halting Criteria 
The study will be halted (no recruitment or further dosing), pending review, if any of the 
following criteria are met: 
• One subject develops an SAE that results in death and is considered by the 
investigator and / or CSL to be related to the administration of CSL312. 
• One subject develops any other serious event that is deemed to pose an unacceptable 
risk to other subjects in the study, and this event is considered by the investigator 
and / or CSL to be related to the administration of CSL312. 
• An overall pattern of symptomatic, clinical, or laboratory events develops that the 
medical monitor, CSL, or IDMC considers to be associated with CSL312 and that 
may appear minor in terms of individual events, but that collectively may represent a 
serious potential concern for safety. 
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. 
4.1.1 
Inclusion Criteria 
To be enrolled into the study, subjects must meet all of the following inclusion criteria: 
1. Capable of providing written informed consent and willing and able to adhere to all 
protocol requirements. 
2. Male or female patients, ≥ 40 years of age at the time of providing written informed 
consent. 


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3. Documented diagnosis of IPF according to the investigator using the criteria from the 
2018 Clinical Practice Guideline of the American Thoracic Society (ATS) / European 
Respiratory Society (ERS) / Japanese Respiratory Society (JRS) / Latin American 
Thoracic Association (ALAT) for the diagnosis of IPF [Raghu et al, 2018] at the time of 
Screening. 
4. FVC ≥ 45% of predicted normal at Screening. 
5. Diffusing capacity of the lungs for carbon monoxide (DLCO, corrected for hemoglobin) 
≥ 30% of predicted normal at Screening. 
6. Forced expiratory volume in 1 second (FEV1) / FVC ratio ≥ 0.7 at Screening. 
7. Investigator believes that the subject (or the subject’s legally acceptable representative) 
understands the nature, scope, and possible consequences of the study. 
4.1.2 
Exclusion Criteria 
Subjects must not be enrolled into the study if they meet any of the following exclusion 
criteria: 
1. History of clinically significant cardiovascular disease, including myocardial infarction 
unstable ischemic heart disease, congestive heart failure, or angina during the 6 months 
before Screening. 
2. Resting pulse < 50 beats per minute, sinoatrial or atrioventricular block, uncontrolled 
hypertension, or QTcF > 450 milliseconds. 
3. Active bleeding or current clinically significant coagulopathy (eg, international 
normalized ratio [INR] > 1.5) or clinically significant risk for bleeding (eg, recent 
intracranial hemorrhage or bleeding peptic ulcer within the 4 weeks before Screening). 
4. History of venous thrombosis or cerebrovascular event within the 3 months before 
Screening, or a prothrombotic disorder (eg, antithrombin III, protein C, or protein S 
deficiency or antiphospholipid syndrome). 
5. Known or suspected severe infusion-related reaction or hypersensitivity to monoclonal 
antibody therapy, or hypersensitivity to the investigational product or any excipients of 
the investigational product. 
6. Major surgery scheduled to occur during the study or up to 90 days after the last 
administration of investigational product. 


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7. Lung transplantation anticipated during the study or within 90 days after the last 
administration of investigational product. 
8. Removed per Amendment #3 
9. Any other condition which, in the opinion of the investigator, may pose an additional risk 
to the study participant after the administration of investigational product. 
10. Received any investigational therapy within 28 days, or 5 drug half-lives whichever is 
longer, before randomization or intends to take an investigation therapy other than 
CSL312 during the study. 
11. Previously administered CSL312 in another interventional clinical study. 
12. Use of nintedanib or pirfenidone within 28 days before randomization and during the 
14-week Treatment and Observation Period up to and including the End of Treatment 
Visit (Day 92). 
13. Pregnant at Screening or breastfeeding at Screening and not willing to cease 
breastfeeding. 
14. Female subject of childbearing potential or fertile male subject either not using or 
unwilling to use an acceptable method of contraception to avoid pregnancy during the 
study and for up to 90 days after the last administration of investigational product. 
Acceptable methods of contraception are defined in Section 7.4. 
All female subjects are assumed to be of childbearing potential except: 
• Subjects > 60 years of age. 
• Subjects between the ages of 45 to 60 years, inclusive, with amenorrhea for ≥ 1 year 
with documented evidence of follicle-stimulating hormone (FSH) level > 30 IU/L. If 
the FSH level is not available before randomization, a serum pregnancy test is 
required at Screening. Urine pregnancy tests will also be required at the time points 
indicated in the Schedule of Assessments. 
• Subjects who are surgically sterile for ≥ 3 months before providing informed consent. 
All male subjects are assumed fertile except subjects who are surgically sterile for 
≥ 3 months before providing informed consent. 
15. Clinical evidence of active infection, including severe acute respiratory syndrome 
coronavirus-2 (SARS-CoV-2). 


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16. Current alcohol, drug, or medication abuse. 
17. Currently receiving a therapy not permitted during the study, as defined in Section 7.3. 
18. Involved in the planning and / or conduct of the study (applies to CSL staff, staff at the 
study site, and third-party vendors). 
4.2 
Screen Failures 
Screen failures are defined as individuals who consent to participate in the clinical study but 
who do not meet the eligibility criteria for participation in the study (see Section 4.1). A 
minimal set of information including demography, eligibility criteria, laboratory results, 
screening failure details, and any SAE should be recorded for all individuals considered 
screen failures. 
Subjects who do not meet the inclusion / exclusion criteria within the specified time limit of 
28 days and fail to complete screening assessments, may be re-screened but only once, if 
approved by the Sponsor’s medical monitor. 
Subjects who are not eligible for enrollment because laboratory test results do not meet the 
inclusion / exclusion criteria may have laboratory testing repeated, but once only, if the 
results are thought to represent a laboratory error or a reversible or a clinically insignificant 
intermittent condition. If testing is repeated, all Screening assessments will need to be 
repeated with the exception the 12-lead ECG, which may be repeated separately from other 
assessments, as necessary. The Sponsor’s medical monitor may also grant permission for tests 
to be repeated separately from other tests as necessary. If inclusion / exclusion criteria are not 
met based on the results of the repeated tests, the subject should be considered a screen 
failure and not be enrolled in the study. Repeat tests should be conducted and the results 
available within 28 days before Baseline. 
If the subject is re-screened, the subject will be asked to sign a new ICF. 


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4.3 
Discontinuation of Study Treatment and Subject Withdrawal 
4.3.1 
Discontinuation of Study Treatment 
Subjects may discontinue study treatment with investigational product at any time at their 
own request, or at the discretion of the investigator or CSL for safety, behavioral, or 
administrative reasons. 
Subjects who discontinue treatment with investigational product but remain in the study, will 
be asked to complete additional follow-up assessments or allow data collection as detailed in 
the Schedule of Assessments. If a subject discontinues investigational product and declines 
further study procedures / visit participation, the subject will be withdrawn from the study, 
and attempts will be made to complete and document the Withdrawal Visit assessments. 
Refer to Section 4.3.2 and Section 4.3.3 for details on handling subject withdrawals. 
4.3.2 
Subject Withdrawal 
Subjects may 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, because of an 
AE, protocol deviation, loss to follow-up, subject noncompliance, study termination). 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. 
In accordance with the 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 
wellbeing 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. 
4.3.3 
Procedures for Handling Withdrawals 
If a subject is withdrawn from the study, attempts will be made to complete and document the 
End-of-Treatment (EOT) Visit assessments. If the subject is withdrawn from the study after 
receiving investigational product, every effort will be made to ensure that the relevant safety 
assessments are completed. The subject may also be asked by the investigator to complete 
other study assessments. 
If the subject withdraws from the study, and also withdraws consent for disclosure of future 
information, CSL may retain and continue to use any data collected before such withdrawal 
of consent. 


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Publicly available records will be used to establish the vital status of subjects who withdraw 
from the study and withdraw consent for disclosure of future information. 
4.3.4 
Subjects Lost to Follow-up 
If a subject repeatedly fails to return for scheduled visits, the site must attempt to contact the 
subject and counsel the subject on the importance of maintaining the assigned visit schedule 
and to ascertain whether or not the subject wishes to and / or should continue in the study. All 
attempts to contact the subject should be documented in the subject’s medical record. 
A subject will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. Subjects lost to follow-up 
will be considered to have withdrawn from the study. 
4.3.5 
Replacement Policy 
Subjects withdrawn from the study will not be replaced. 


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5 
Study Interventions 
5.1 
Investigational Products 
5.1.1 
Description of CSL312 
CSL312 will be supplied (2 mL per vial) as a sterile, preservative-free solution for injection 
at a pH of 6.1 (Table 2). CSL312 is formulated in a buffer containing 20 mM L-histidine, 
150 mM arginine monohydrochloride, 140 mM L-proline, and 0.02% w/w polysorbate 80. 
Each vial contains CSL312 at a concentration of 100 mg per 1 mL. 
Table 2 
Description of CSL312 
Substance name: 
CSL312 
Active substance: 
Fully human IgG4 / lambda recombinant monoclonal antibody 
that binds specifically to the catalytic domain of FXIIa 
INN: 
Garadacimab 
Trade name: 
Not applicable 
Dosage form: 
IV CSL312: Sterile solution for injection containing 
100 mg/mL of CSL312 in 2-mL vials 
SC CSL312: Sterile solution for injection containing 
100 mg/mL of CSL312 in 2-mL vials 
Dose: 
CSL312 300 mg IV; CSL312 600 mg SC 
Dosing regimen: 
The first dose of CSL312 will be administered as an IV 
loading dose of 300 mg. The second dose of 600 mg will be 
administered 7 days later by the SC route. Doses 3 and 4 of 
600 mg will be administered SC 28 days after doses 2 and 3, 
respectively. 
Injection volume: 
IV 3 mL; SC 6 mL 
Mode of administration: IV loading dose followed by 3 SC doses 
Anatomic location of 
administration: 
IV CSL312: Left or right arm contralateral to the PK / PD 
sampling site 
SC CSL312: Abdomen is the preferred site of injection. If 
injection into the abdomen is not possible, injection can be 
into the thigh.  
 
FXIIa = activated coagulation factor XII; IgG = immunoglobulin G; INN = international nonproprietary name; 
IV = intravenous; PD = pharmacodynamic; PK = pharmacokinetic; SC = subcutaneous. 
CSL312 will be manufactured by CSL in accordance with ICH GMP guidelines and local 
regulatory requirements. 


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5.1.2 
Description of Placebo 
The placebo (formulation buffer) will be supplied (2 mL per vial) as a sterile, 
preservative-free solution for injection (Table 3). The placebo is the same as the CSL312 
formulation buffer, but does not contain the active substance (ie, FXIIa antagonist 
monoclonal antibody). 
Table 3 
Description of Placebo (Formulation Buffer) 
Substance name: 
Placebo 
Active substance: 
NA 
INN: 
NA 
Trade name: 
NA 
Dosage form: 
IV placebo: formulation buffer in 2-mL vials 
SC placebo: formulation buffer in 2-mL vials 
Dose: 
NA 
Dosing regimen: 
IV and SC administered formulation buffer using the same 
dosing regimen as for CSL312 
Injection volume: 
IV and SC administered formulation buffer will match the 
volume used for CSL312 to maintain the blind 
Mode of 
administration: 
IV loading dose followed by 3 SC doses 
Anatomic location of 
administration: 
IV: Left or right arm contralateral to the PK / PD sampling site 
SC: Abdomen is the preferred site of injection. If injection into 
the abdomen is not possible, injection can be into the thigh.  
 
INN = international nonproprietary name; IV = intravenous; NA = not applicable; PD = pharmacodynamics; 
PK = pharmacokinetic; SC = subcutaneous. 
The placebo will be manufactured by CSL in accordance with ICH GMP guidelines and local 
regulatory requirements. 
Additional details related to the dosing and administration of the investigational product 
(CSL312 or placebo), as well as the procedure used to prepare the study treatment before 
administration, will be described in the Site Investigational Medicinal Product (IMP) manual. 


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5.1.3 
Dosing and Administration of Investigational Product 
The investigator (or delegate) will administer or dispense investigational product (CSL312 or 
placebo) only to subjects included in this study following the procedures set out in this CSP. 
Information on the dosing characteristics of investigational product is provided in Table 4. 
Investigational product (CSL312 or placebo) will be administered by the investigator at the 
study site during Week 1 (IV loading dose on Day 1) and SC maintenance dose at Week 2, 
Week 6, and Week 10 (see Schedule of Assessments). 


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Table 4 
Investigational Product Dosing Characteristics 
Administration Parameter 
CSL312 
Placebo 
Dose 
CSL312 300 mg IV; 
CSL312 600 mg SC 
NA 
Route 
IV loading dose followed by 
3 SC doses 
IV loading dose followed by 
3 SC doses 
Anatomic Location of 
Administration 
IV: Left or right arm 
contralateral to the PK / PD 
sampling site 
SC: Abdomen is the 
preferred site of injection. If 
injection into the abdomen is 
not possible, injection can be 
into the thigh. Note that if IP 
is being administered as 
2 injections of 3 mL each or 
3 injections of 2 mL each, 
then all injections must be 
administered to the same 
anatomical site in a given 
subject (ie, abdomen) 
IV: Left or right arm 
contralateral to the PK / PD 
sampling site 
SC: Abdomen is the 
preferred site of injection. If 
injection into the abdomen 
is not possible, injection can 
be into the thigh. Note that 
if IP is being administered 
as 2 injections of 3 mL each 
or 3 injections of 2 mL 
each, then all injections 
must be administered to the 
same anatomical site in a 
given subject (ie, abdomen) 
Total Infusion Volume 
IV 3 mL;  
SC 2 mL × 3 (6 mL) that 
may be administered as 
1 injection of 6 mL or 
2 injections of 3 mL each or 
3 injections of 2 mL each 
IV and SC administered 
formulation buffer using the 
same volume and number of 
injections as CSL312 
Infusion / Injection 
Duration 
Approximately 3 minutes 
Approximately 3 minutes 
IP = investigational product; IV = intravenous; NA = not applicable; PD = pharmacodynamic; 
PK = pharmacokinetic; SC = subcutaneous. 
Detailed information on the preparation and administration of the investigational product is 
provided in the Site IMP Manual. 
5.1.3.1 
Dosing Modification 
No dose modifications are permitted during the study. 


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5.1.3.2 
Treatment Compliance 
All doses of investigational product will be administered at the study site. Treatment 
compliance will be assessed using the administration details entered into the eCRF. 
5.1.3.3 
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 this study, excessive is defined as any dose greater than the planned 
dose. In case of overdose, the subject should be closely monitored, and supportive treatment 
should be administered. 
See Section 9.6.5 for overdose reporting requirements. 
5.1.4 
Description of Investigational Medical Device Constituents 
Not applicable. 
5.1.5 
Packaging, Labeling, Supply and Storage 
5.1.5.1 
Packaging and Labeling 
The investigational product will be packaged and labeled according to current ICH GMP and 
GCP guidelines, and national legal requirements.  
5.1.5.2 
Supply and Storage 
The investigational product (CSL312 and placebo) will be supplied to the study sites by CSL 
or delegate.  
The investigational product must be stored under temperature-controlled and access-
monitored conditions from +2°C to +8°C in a secure storage area as specified in the Site IMP 
Manual. 
5.2 
Accountability and Destruction 
The investigational product must be used only as directed in the CSP. 
The investigator or delegate will confirm receipt of all shipments of investigational product 
in the interactive response technology (IRT) system. 


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All supplies of investigational product must be accounted for throughout the study. 
Records for the delivery of investigational product to the study site, the inventory at the study 
site, the use by each subject, and the destruction or return of investigational product to CSL 
(or designee) must be maintained by the investigator (or delegate) using the IRT system. 
The investigator (or delegate) must provide reasons for any discrepancies in drug 
accountability in the IRT. 
Further details regarding receipt, packaging, and labeling, storage accountability and 
destruction of investigational product are provided in the Site IMP Manual. 
5.3 
Treatment for Acute Exacerbation or Disease Progression 
At each study visit, subjects will be evaluated for symptoms of acute IPF as defined in 
Section 8.1.2. 
If a subject experiences an acute IPF exacerbation or disease progression, medications or 
other therapy, including but not limited to antifibrotic agents (nintedanib or pirfenidone), may 
be administered at the investigator’s discretion, at any time during the study. 
6 
Allocation to Treatment 
6.1 
Subject Assignment 
After providing written informed consent, the subject will be issued with a study-level unique 
subject identification number using an IRT system. 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. 
6.2 
Randomization Procedures 
Subjects will be randomized in a ratio of 1:1 to either CSL312 600 mg or placebo group by 
means of the IRT. A centralized randomization schedule will be used. 
The IRT external service provider will prepare the study randomization code according to 
approved specifications. The IRT external service provider will keep the randomization code 
on file. 
At Screening, subjects will be assigned a unique subject number via the IRT system. 


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6.3 
Blinding Procedures 
6.3.1 
Blinding Method 
Investigational site staff, including the investigators, will be blinded to treatment allocation. 
Subjects and CSL staff / designates participating in the conduct of the study, with the 
exception of IRT and Clinical Trial Supply staff at CSL, will also be blinded to treatment 
allocation (double-blind). 
To maintain the blind, all doses of investigational product administered during the Treatment 
and Observation Period will be volume normalized (see Section 5). Volume normalization 
will permit administration of the same volume of investigational product to be administered 
to each subject, regardless of their treatment assignment. 
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) 
will be employed so that other site staff and study subjects are unable to detect any 
differences between CSL312 and placebo. 
Unblinded study site personnel delegated by the investigator will prepare the investigational 
product, as assigned by the IRT. The unblinded study site personnel will also ensure the 
contents remain blinded to the subject and the blinded study site personnel who will be 
conducting assessments. Unblinded study site personnel are not to administer the 
investigational product and will not be involved in conducting or recording any study 
assessment procedures (ie, in the care of the subject). 
All samples analyzed by the central laboratory will remain blinded until database lock. Blood 
samples analyzed by the local laboratory will be interpreted by personnel appointed by the 
investigator and defined in the site-specific blinding plan. 
Study unblinding will take place following locking of the study database except in the 
situations as outlined in Section 6.3.2, Section 6.3.3, and Section 6.3.4. 
Adequate procedures are in place to ensure the integrity of the blinded data within CSL. 
Study data will be provided to the IDMC as unblinded data, as requested. 
The bioanalyst and pharmacokineticist responsible for the sample analysis and 
pharmacokinetic evaluation will be unblinded. However, they will agree not to disclose the 
randomization schedule. 


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6.3.2 
Breaking the Blind for an Emergency 
The randomization code for individual subjects may be unblinded to a site during the study in 
emergency situations for reasons of subject safety, if knowing treatment assignment will 
change subject management. In case of an emergency situation for reasons of subject safety, 
the investigator should use the IRT to identify the treatment allocation for a subject. The 
reason for unblinding the randomization code must be fully recorded in the subject’s source 
documents, and the investigator must follow the defined procedures provided in the study 
reference manuals. The subject’s treatment allocation should not be recorded in the subject’s 
source document. 
6.3.3 
Planned Unblinding Procedures 
Periodic unblinded safety reviews are planned for this study for the purposes of safety 
monitoring activities by the IDMC. With authorization by CSL, the IRT will provide either 
the unblinded statistician performing analyses for the IDMC with the randomization code or 
an IRT user account to obtain the required information directly from the IRT. 
At the end of the study, CSL will authorize that the study be unblinded after database lock. 
The randomization codes will be provided to the study statistician (or delegate). 
6.3.4 
Ad-hoc Safety Unbinding 
CSL’s Global Clinical Safety and Pharmacovigilance (GCSP) personnel may, on an ad-hoc 
basis, unblind the randomization code directly in the IRT at any time during the study, 
because of a safety concern. The purpose of the unblinded data review is to determine if there 
is a risk to subject safety that would require further action either for the individual 
management of a study subject or for the ongoing conduct of the study. The need to unblind a 
subject or group of subjects may not necessarily arise because of an SAE. The need to 
unblind on an ad-hoc basis will be determined by CSL’s GCSP senior leadership. 


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7 
Contraindications, Permitted Therapies and Prohibited 
Therapies 
7.1 
Contraindications and Precautions to Further Dosing 
There are no contraindications or precautions associated with CSL312 administration. 
The administration of investigational product (CSL312 or placebo) to any subject not 
meeting the eligibility criteria for this study, or to any patient not enrolled in this study, is 
prohibited. 


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7.2 
Permitted Therapies 
The medications and therapies that are PERMITTED during participation in the study are 
detailed in Table 5. Note: This list is not intended to be all inclusive. 
Table 5 
Permitted Medications / Therapies 
Medication / Therapy 
Dose 
Permitted Period of Use 
Corticosteroids for 
acute exacerbations of 
IPF during study 
participation 
No dose 
restriction for 
IPF 
exacerbation 
Treatment duration for acute IPF exacerbation 
at the investigator’s discretion 
Antifibrotic therapy 
(pirfenidone or 
nintedanib) for disease 
progression during 
study participation 
According to 
approved 
prescribing 
information 
Antifibrotic therapy (pirfenidone or nintedanib) 
is not permitted during this study as per 
exclusion criterion #12. However, in the event 
of disease progression during the study and if, 
in the investigator’s judgment, the subject will 
benefit from this medication, the subject may 
receive antifibrotic treatment. 
Bronchodilators 
According to 
approved 
prescribing 
information 
Bronchodilator therapies must be washed out 
before all PFTs as follows: 
Short-acting bronchodilators: 
8 hours 
Long-acting bronchodilators: 
24 hours 
Anticoagulant therapy 
with LMWH 
According to 
approved 
prescribing 
information 
Treatment at the investigator’s discretion 
Low dose aspirin 
75 to 100 mg 
Treatment at the investigator’s discretion 
Nonlive influenza virus 
vaccines and 
SARS-CoV-2 vaccines 
According to 
prescribing 
information 
Administered at the discretion of the subject’s 
treating physician 
IPF = idiopathic pulmonary fibrosis; LMWH = low molecular-weight heparin; PFT = pulmonary function test; 
SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2. 


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7.3 
Prohibited Therapies 
The medications and therapies that are NOT PERMITTED during participation in the study 
are detailed in Table 6. Note: This list is not intended to be all inclusive. 
Table 6 
Prohibited Medications / Therapies 
Prohibited Medication / Therapy 
Prohibited Period of Use 
Cytotoxic, immunosuppressive, or 
cytokine-modulating medication 
(ie, cyclophosphamide, 
cyclosporine, methotrexate, 
etanercept, TNF inhibitors, iloprost, 
tacrolimus, mycophenolate mofetil) 
Within 28 days before randomization (at any time, 
for any duration, and for any reason) or during the 
14-week Treatment and Observation Period 
Antifibrotic therapy (nintedanib 
and pirfenidone) 
Within 28 days before randomization and during the 
14-week Treatment and Observation Period up to 
and including the End of Treatment Visit (Day 92) 
unless administered at the investigator’s discretion 
for disease progression 
Anticoagulant therapy other than 
LMWH 
Within 28 days before randomization and during the 
14-week Treatment and Observation Period up to 
and including the End of Treatment Visit (Day 92) 
Any investigational therapy other 
than investigational product 
Within 28 days before randomization, or 5 drug 
half-lives before randomization, whichever is longer 
During the 14-week Treatment and Observation 
Period 
During the 90 days after the last administration of 
investigational product 
Lung transplantation 
Planned to occur during study participation 
LMWH = low molecular-weight heparin; TNF = tumor necrosis factor. 
Subjects should not be enrolled into the study if they receive any prohibited therapy. 
If administration of any prohibited therapy becomes necessary during the study for medical 
reasons, the subject may be withdrawn from further study participation. 


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7.4 
Lifestyle Restrictions 
Female subjects of childbearing potential or male subjects must use a medically reliable form 
of contraception until 90 days after the last administration of the investigational product. 
Acceptable methods of contraception are: 
• Abstinence, where abstinence is the preferred and usual lifestyle of the subject, including 
refraining from heterosexual intercourse during the entire period of risk associated with 
the investigational product. Periodic abstinence (calendar, symptothermal, postovulation 
methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhea 
method are not acceptable definitions of abstinence. 
• Hormonal methods associated with inhibition of ovulation. Acceptable hormonal methods 
include: oral contraceptives, contraceptive medication patch, contraceptive medication 
injection, estrogen / progestin vaginal ring, or contraceptive medication implant. 
• Use of intrauterine device (placed > 3 months before providing informed consent). 
• Bilateral tubal occlusion of female subjects (≥ 3 months before providing informed 
consent). 
• Vasectomy of male subjects (≥ 3 months before providing informed consent). 
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 Schedule of Assessments. More frequent assessments may be performed, if 
clinically indicated, at the discretion of the investigator. Refer to the provided study manual 
for detailed instructions on how the assessments should be performed. 


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8.1.1 
Demographics and Safety Assessments 
Subject demographics and safety assessments to be conducted during this study are provided 
in Table 7. Clinical laboratory assessments are to be performed at the time points indicated in 
the Schedule of Assessments. 
Table 7 
Study Procedures: Demographics and Safety Assessments 
Assessment 
Description 
Demographics 
• Year of birth 
• Age 
• Sex 
• Race and ethnicity (where permitted) 
Medical history 
• Relevant medical history 
• Diagnosis and disease status 
• Contraception method (if relevant) 
• Previous (within 6 months before 
Screening) and concomitant 
medications and therapies 
Pregnancy test 
(local laboratory) 
A serum test for β-hCG will be performed for all female subjects of childbearing 
potential to rule out pregnancy at Screening. At all other study visits, a urine pregnancy 
test will be performed. If the results from the urine pregnancy test are inconclusive, the 
site will perform a serum pregnancy test. 
Physical 
examination 
As per the site’s standard procedure, including assessment of unilateral pain and / or 
swelling of the lower extremities for the purposes of screening for DVTs. 
12-lead ECG 
(Performed and 
analyzed locally) 
• Heart rate 
• QT interval 
• PR interval 
• QTcB interval 
• QRS duration 
• QTcF interval 
• Interpretation (investigator’s overall interpretation) 
PFTs 
• Spirometry including FVC and FEV1 
• DLCO 
AEs 
• Evaluation of all AEs (eg, causality / relatedness, severity, seriousness) 
• AESIs: 
o Abnormal bleeding events 
o TEEs 
o Severe hypersensitivity including anaphylaxis 
The description of AEs and reporting requirements are detailed in Section 9. 
Vital signs 
• Blood pressure (systolic and diastolic) 
• Body temperature 
• Respiratory rate 
• Height (Screening only) 
• Heart rate 
• Weight and BMI 
Urinalysis 
(dipstick) 
(central laboratory) 
• Specific gravity 
• Occult blood 
• pH 
• Leukocyte esterase 
• Nitrite 
• Erythrocytes 
• Ketones 
• Bilirubin 
• Protein 
• Urobilinogen 
• Glucose 
 


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Assessment 
Description 
Hematology 
(central laboratory) 
• Hematocrit 
• Hemoglobin 
• Platelets 
• Reticulocytes 
• Erythrocytes (RBC count) 
• Leukocytes (WBC count) 
• RBC indices (MCHC, MCH, MCV, 
RDW) 
• Differential (percentage and absolute): 
neutrophils, neutrophil band forms, 
lymphocytes, monocytes, eosinophils, 
basophils 
Biochemistry 
(central laboratory) 
• Sodium 
• LDH 
• Potassium 
• GGT 
• Chloride 
• Bilirubin – total 
• Bicarbonate 
• Direct bilirubin 
• Calcium 
• Magnesium 
• BUN 
• Phosphate 
• Urea 
• hs-CRP 
• Creatinine 
• Cholesterol – total 
• Glucose 
• Triglycerides 
• Protein – total 
• HDL cholesterol 
• Albumin 
• LDL cholesterol 
• Alkaline phosphatase 
• Urate (Uric Acid) 
• ALT 
• CK / CPK 
• AST 
 
Coagulation for 
safety assessments 
(local laboratory) 
• INR 
D-dimer 
Coagulation for 
biomarker 
assessments 
(central laboratory) 
• aPTT 
• PT and INR 
• pF1+2 
• Fibrinogen (Clauss assay) 
• D-dimer 
Immunogenicity 
(ADAs) 
(central laboratory) 
Plasma analyzed for the presence of binding antibodies (neutralizing and 
non-neutralizing) specific to FXIIa antagonist monoclonal antibody (anti-CSL312). 
β-hCG = beta-human chorionic gonadotropin; ADA = antidrug antibody; AE = adverse event; AESI = adverse 
event of special interest; ALT = alanine aminotransferase; aPTT = activated partial thromboplastin time; 
AST = aspartate aminotransferase; BMI = body mass index; BUN = blood urea nitrogen; CK = creatinine 
kinase; CPK = creatinine phosphokinase; DLCO = diffusing capacity of the lungs for carbon monoxide; 
DVT = deep vein thrombosis; ECG = electrocardiogram; FEV1 = Forced expiratory volume in 1 second; 
FVC = forced vital capacity; FXIIa = activated coagulation factor XII; GGT = gamma glutamyl transferase; 
HDL = high-density lipoprotein; hs-CRP = high-sensitivity C-reactive protein; INR = international normalized 
ratio; LDH = lactate dehydrogenase; LDL = low-density lipoprotein; MCH = mean corpuscular hemoglobin; 
MCHC = mean corpuscular hemoglobin concentration; MCV = mean corpuscular volume; pF1+2= prothrombin 
fragment; PFT = pulmonary function tests; PT = prothrombin time; QTcB = Bazett’s correction formula; 
QTcF = Fridericia's correction formula; RBC = red blood cell; RDW = red cell (erythrocyte) distribution width; 
TEE = thromboembolic event; WBC = white blood cell. 


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Results of laboratory tests (hematology, coagulation, biochemistry, and urinalysis) completed 
at the central laboratory should be signed and dated and retained at the study site as source 
data. The investigator should make an evaluation of the available safety-assessment results 
with regard to clinically relevant abnormalities. Refer to Section 9 for information on how 
AEs based on laboratory tests should be assessed and reported. 
Laboratory Parameters 
Details related to the collection, preparation, storage, and transfer of blood and urine samples 
for laboratory assessments will be provided in the Laboratory Manual. 
Refer to Section 9.1.1 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 followed up after receiving the laboratory 
report, and may include an unscheduled repeat safety sampling at the discretion of the 
investigator. 
Vital Signs 
Blood pressure and heart rate will be measured with the subject in a supine or seated position 
after resting for 5 (± 3) 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 
Acute Exacerbation of Idiopathic Pulmonary Fibrosis 
Data on acute exacerbations will be collected. An acute exacerbation of IPF is an acute, 
clinically significant respiratory deterioration characterized by evidence of new widespread 
alveolar abnormality [Collard et al, 2016]. The median survival of patients with IPF who 
experience an acute exacerbation is approximately 3 to 4 months [Collard et al, 2016]. Acute 
exacerbation has been shown to increase the risk of death more profoundly than an absolute 
decline in FVC percent predicted of ≥ 15% [Paterniti et al, 2017; Ley et al, 2017]. 
The diagnostic criteria for acute exacerbation of IPF in this study will be as follows 
[Collard et al, 2016]: 
• Previous or concurrent diagnosis of IPF 
• Acute worsening or development of dyspnea typically < 1 month in duration 


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• Computed tomography (CT) scan results with new bilateral ground-glass opacity and / or 
consolidation superimposed on a background pattern consistent with a pattern for usual 
interstitial pneumonia. (If no previous CT scan results are available, the qualifier “new” 
can be dropped) 
• Deterioration not fully explained by cardiac failure or fluid overload 
Note: Events that are clinically considered to meet the definition of acute exacerbation of IPF 
but fail to meet all 4 diagnostic criteria because of missing CT data should be termed 
“suspected acute exacerbations.” 
8.1.3 
Pharmacokinetic and Pharmacodynamic Assessments 
PK and PD assessments to be conducted during the study are provided in Table 8. Details 
related to the collection, preparation, and transfer of PK / PD samples will be provided in a 
Laboratory Manual. 
Table 8 
Clinical Procedures: Pharmacokinetic and Pharmacodynamic 
Assessments 
Procedure 
Description 
PK evaluations 
(central laboratory) 
Plasma samples will be collected for assessment of CSL312 concentration. 
PD evaluations 
(central laboratory) 
Plasma samples will be collected for assessment of the following 
parameters: 
• FXIIa-mediated kallikrein activity 
• FXII concentration 
• aPTT 
aPTT = activated partial thromboplastin time; FXII = factor XII; FXIIa = activated factor XII; 
PD = pharmacodynamic; PK= pharmacokinetic. 
8.1.4 
Biomarker Assessments 
The proposed mechanism of action of CSL312 in IPF will be explored using biomarkers of 
coagulation, inflammation, alveolar epithelial cell damage, tissue modeling, and fibrosis, 
such as but not limited to, those detailed below. 


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The following biomarkers will be measured: pF1+2, fibrinogen, D-dimer, aPTT, 
high-sensitivity C-reactive protein (hs-CRP), and monocytes. Samples will be collected at 
Screening, before administration of the IV loading dose of investigational product on Day 1, 
and on Days 8, 36, 64 and 92. hs-CRP will be assessed at all study visits, including 
Screening, before administration of the IV loading dose investigational product and 
immediately after the EOI on Day 1. 
The following biomarkers will be measured at Screening, before administration of the IV 
loading dose of investigational product on Day 1, and on Days 8, 36, 64, and 92: 
FXII (free vs. total), C3a, C5a, IL-8, IL-10, CCL-2, CXCL-1, CCL-18, PAI-1, surfactant 
protein A (SP-A), surfactant protein D (SP-D), YKL-40, tenascin-C (TN-C), 
thrombospondin-1 (TSP-1), VEGF, neo-epitope of matrix metalloproteinase-mediated 
degradation of citrullinated vimentin (VICM), neo-epitope of matrix 
metalloproteinase-mediated degradation of C-reactive protein (CRPM), pro-Fib, neo-epitope 
of calprotectin generated by human neutrophil elastase (CPa9-HNE), and collagen synthetic 
and degradation neo-epitopes (pro-C3/4/6 and C1/3/4/6M). 
The following PD parameters and biomarkers will be assessed at all study visits at which PK 
is being assessed, including before administration of the IV loading dose of investigational 
product and immediately after the EOI on Day 1: FXIIa-mediated kallikrein activity, FXII 
concentration, IL-6, and hs-CRP. Additionally, hs-CRP will also be assessed at Screening. 
Blood transcriptomics: Blood will be collected for RNA sequencing to investigate changes 
in gene expression at Screening, before administration of the IV loading dose of 
investigational product on Day 1, and on Days 8, 36, 64, and 92. 
Proteomic analysis: Blood will be collected to characterize the plasma proteome at 
Screening, before administration of the IV loading dose of investigational product on Day 1, 
and on Days 8, 36, 64, and 92. 
Details related to the collection, preparation, transfer, and storage of biomarker samples will 
be provided in the laboratory manual. Blood sampling time points for biomarker assessment 
are indicated in the Schedule of Assessments. 


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8.1.5 
Pulmonary Function Tests 
Pulmonary function tests (PFTs) will be performed at the time points indicated in the 
Schedule of Assessments. The time windows for each type of assessment are detailed in 
Section 8.5.1. 
PFTs, including spirometry and DLCO, will be performed at the study site by the investigator 
or qualified designee according to the site’s SOPs and conducted in accordance with criteria 
published by the American Thoracic Society (ATS) / ERS [Graham et al, 2017; Graham et al, 
2019]. FVC reference ranges will be those established by the Global Lung Function Initiative 
[Cooper et al, 2017; Quanjer et al, 2012]. 
Before spirometry and measurement of DLCO, long-acting bronchodilators must be washed 
out for 24 hours and short-acting bronchodilators for 8 hours. Approximately 1 in 10 patients 
with IPF shows physiological evidence of reversible airflow limitation, and bronchodilator 
use in these patients may improve the assessment of disease progression based on FVC 
change over time. Bronchodilator use does not appear to meaningfully affect the precision of 
FVC as an endpoint in clinical studies [Assayag et al, 2015]. 
The decline in FVC is an accepted measure of disease course and reliably predicts mortality 
in patients with IPF [Paterniti et al, 2017; Zappala et al, 2010; Flaherty et al, 2003; Collard et 
al, 2003; Quinn et al, 2019]. A decline in FVC of ≥ 10% has been correlated with worse 
survival time in patients with IPF [Paterniti et al, 2017; Zappala et al, 2010; Flaherty et al, 
2003; Collard et al, 2003] and recent evidence-based guidelines state that an absolute 
decrease in FVC of ≥ 10% over time is an acceptable method for assessing disease 
progression and estimate risk of future mortality in patients with IPF [Raghu et al, 2011]. 
Some studies suggest that an FVC decline ≥ 5% may also be clinically significant [Zappala et 
al, 2010; du Bois et al, 2011]. Using a relative (rather than an absolute) change in FVC has 
been shown to maximize the chance of identifying a ≥ 10% decline without sacrificing 
prognostic accuracy [Richeldi et al, 2012]. The change in FVC has been used as the primary 
endpoint in several randomized controlled studies in subjects with IPF [Raghu et al, 2008; 
Raghu et al, 2012] including those for the approved drugs nintedanib and pirfenidone 
[Richeldi et al, 2014; Noble et al, 2011]. 


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This study is a 14-week, placebo-controlled study. In both the INPULSIS studies and the 
INBUILD study with nintedanib in patients with IPF and progressive fibrosing interstitial 
lung diseases, respectively, a clear difference in the mean change in FVC from Baseline 
between the nintedanib groups and the placebo group is apparent at 12 weeks [Richeldi et al, 
2014 (INPULSIS 1 and INPULSIS 2); Flaherty et al, 2019 (INBUILD)]. Similarly, a 
treatment effect is evident at Week 13 in the ASCEND study with pirfenidone in patients with 
IPF [King et al, 2014]. This study will determine if the FVC is altered by treatment with 
CSL312 over a 14-week period in patients with IPF. 
As a safety parameter, single-breath DLCO will be assessed at Screening, before 
administration of investigational product on Day 1 (Baseline), and at Week 14 
(EOT / EW Visit). DLCO will be assessed at the study site by the investigator or a qualified 
designee according to the site’s SOPs, and conducted in accordance with criteria published by 
ATS / ERS [Graham et al, 2017]. The DLCO reference ranges used will be those established 
by the Global Lung Function Initiative [Stanojevic et al, 2017]. DLCO will be corrected for 
hemoglobin retrospectively using a blood sample collected on the same day as the DLCO 
measurement, if available. 
8.2 
Blood Samples 
During the study, blood will be taken from each subject for laboratory safety assessments, 
PK, and relevant PD and exploratory biomarkers. Repeat or unscheduled blood samples may 
be taken for safety reasons or for technical issues with the samples. 
Information on the volume of blood to be collected for each visit will be available in the 
informed consent form (ICF). 
Refer to the Laboratory Manual for details about the volume, collection, storage, handling 
and processing of blood samples. 
8.3 
Retention of Samples 
Refer to the Laboratory Manual for further details about the storage and destruction of 
retention samples. 


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8.3.1 
Retention Samples for Exploratory Biomarkers 
Residual blood samples from the exploratory biomarker samples obtained during the 
Treatment and Observation Period at the time points indicated in the Schedule of 
Assessments, including the EOT Visit (Day 92) will be stored for potential testing of IPF 
biomarker and assay development and will be destroyed within 15 years or according to 
regional or local regulatory requirements after the completion of the study. 
8.4 
Concomitant Therapies 
All drugs and procedures currently being administered to a subject at the time of signing 
informed consent, and which continue to be taken in addition to investigational product 
during study participation, are regarded as concomitant therapies. 
8.5 
Visit Schedule 
8.5.1 
Assessment Time Windows 
The timing and frequency of the study visits, as well as time windows, are described in the 
Schedule of Assessments. 
8.5.2 
Screening Period 
All subjects (or the subject’s authorized representative) must provide written informed 
consent before any study-specific assessments or procedures are performed. Written informed 
consent is not required for assessments or procedures performed according to standard of 
care (eg, for diagnosis or treatment); results from such assessments may be used in the 
determination of study eligibility. 
A screening examination should be performed within 28 days before the intended date of 
dosing (Day 1). If a potential subject was not enrolled into the study within 28 days of the 
first Screening Visit, the potential subject may attend a second Screening Visit (for a 
maximum of 2 Screening Visits per subject). In the event that a potential subject is screened 
twice, all screening assessments must be repeated at the second Screening Visit, with the 
exception the 12-lead ECG, which may be repeated separately from other assessments, as 
necessary. The Sponsor’s medical monitor may also grant permission for tests to be repeated 
separately from other tests as necessary. 


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If the subject is not eligible for the study (ie, the subject is a screen failure), all eligibility 
criteria that are not met will be recorded in the eCRF. 
8.5.3 
Treatment and Observation Period 
On Day 1 (Baseline), subjects who complete all screening assessments and who fulfill the 
eligibility criteria (ie, eligible subjects) will be enrolled into the study and randomized to 
investigational product on Day 1 (Baseline). 
Subjects will continue participation in the study for the 14-week Treatment and Observation 
Period. Subjects will be asked to return to the site for safety, PK, and efficacy assessments at 
the time points indicated in the Schedule of Assessments. Subjects will be contacted by 
telephone on Day 154 (± 5 days) for safety follow-up. 
An IV loading dose of investigational product (CSL312 or placebo) will be administered on 
Day 1. Subjects subsequently will receive 3 doses of investigational product administered 
SC. The first SC dose will be administered 7 days after the IV loading dose and the second 
and third SC doses will be administered every 4 weeks (Q4W; on Day 36 and Day 64). 
8.5.4 
Unscheduled Study Visit 
Unscheduled study visits are possible and all assessments performed should be documented 
in the unscheduled visit page in the eCRF. 
Additional data given to CSL may include any medical information from hospital records 
required by the study but not outlined in the study protocol. This information may be required 
to help scientific understanding of study data and might be collected even after the 
completion of the study 
8.5.5 
End-of-Treatment Visit 
The scheduled end of study participation for an individual subject occurs with completion of 
the EOT Visit on Day 92 ± 2 days, after which no further study-related procedures will be 
performed. 


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8.5.6 
Follow-up Telephone Call 
On Day 154 (± 5 days), the investigator (or delegate) will contact the subject by telephone to 
collect data on AEs (including acute exacerbation of IPF symptoms) and concomitant 
medications. The Follow-up Telephone Call should be scheduled to occur 90 days after the 
last administration of investigational product. 
8.5.7 
Withdrawal 
If a subject is withdrawn from the study before the Week 14 Visit (EOT Visit), the 
investigator should make every effort to perform the assessments during the subjects last 
study visit or, if possible, encourage the subject to return to the study site for EOT 
assessments. 
9 
Adverse Events 
9.1 
Definitions 
9.1.1 
Adverse Event 
As per the ICH Topic E2A (Clinical Safety Data Management: Definitions and Standards for 
Expedited Reporting), 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 it is considered related to the medicinal (investigational) product. 
The period of observation for AEs extends from the time the subject gives informed consent 
until the end of study (see Section 9.4 for further details). 
AEs may include: 
• Exacerbation (ie, an increase in the frequency or severity) of a pre-existing condition. 
Illness present before study entry should be recorded in the medical history section of the 
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. 


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AEs do not include: 
• Events identified at Screening that meet exclusion criteria 
• Medical or surgical procedures (the condition that leads to the procedure is the AE) 
• Situations where an untoward medical occurrence has not taken place. For example: 
o Planned hospitalizations due to pre-existing conditions that have not worsened. 
o Hospitalizations that occur for procedures not due to an AE (eg, cosmetic surgery). 
o Hospitalizations for a diagnostic procedure where the hospital stay is less than 
24 hours in duration or for normal management procedures (eg, chemotherapy). 
o Overdose of investigational product or any concomitant therapy that does not result in 
any adverse signs or symptoms. 
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 to be 
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 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 aPTT will not be classified as AEs because CSL312 is expected to cause 
increase in these parameters. 
• Laboratory parameters already beyond the reference range at screening, unless a further 
increase / decrease can be considered an exacerbation of a pre-existing condition. 
• Abnormal laboratory parameters caused by mechanical or physical influences on the 
blood sample (eg, in vitro hemolysis) and flagged as such by the laboratory in the 
laboratory report. 
• Abnormal parameters that are obviously biologically implausible (eg, values that are 
incompatible with life or outside the measuring range). 
• An abnormal laboratory value that cannot be confirmed after repeat analysis, preferably 
in the same laboratory (ie, the previous result could be marked as not valid and should not 
necessarily be reported as an AE). 


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9.1.2 
Serious Adverse Event 
An SAE is defined as any untoward medical occurrence that at any dose: 
• Results in death: The event must be the cause of death for the SAE to meet this serious 
criterion. 
• Is life-threatening: The term “life-threatening” refers to an event in which the subject 
was at risk of death at the time of the event; it does not refer to an event that 
hypothetically might have caused death if it had been more severe. 
• Requires in-patient hospitalization or prolongation of existing hospitalization: CSL 
considers “hospitalization or prolongation of existing hospitalization” for ≥ 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 defining criteria 
for SAEs. 
• Results in persistent or significant disability or incapacity. 
• Is a congenital anomaly or birth defect. 
• Is medically significant: A medically significant event is defined as an event that does 
not necessarily meet any of the SAE criteria, but which is judged by a physician to 
potentially jeopardize the subject or require medical or surgical intervention to prevent 
one of the above outcomes listed as an SAE criterion. 
AEs that do not fall into the above categories are defined as nonserious AEs. 
9.1.3 
Adverse Event of Special Interest 
There are several AEs that will be monitored closely as AEs of special interest (AESIs) to 
allow for an adequate risk-benefit evaluation of CSL312 during the study. Additional data 
may be requested for these events. 
The AESIs for this study are: 
• Bleeding events that are abnormal in the opinion of the investigator 
• TEEs 
o Non-systemic thrombosis (eg, localized thrombosis associated with vascular access) 
is not considered an AESI 
• Severe hypersensitivity including anaphylaxis 


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The reporting requirements for AESIs are detailed in Section 9.6.2 
9.2 
Severity of Adverse Events 
The severity of each AE (ie, nonserious and serious AEs) is to be assessed by the investigator 
as shown in Table 9. 
Table 9 
Severity of Adverse Events 
Severity 
Definition 
Mild 
A type of AE that is usually transient and may require only minimal 
treatment or therapeutic intervention. The event does not generally interfere 
with usual activities of daily living. 
Moderate 
A type of AE that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, 
causing discomfort but posing 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. 
AE = adverse event; CDISC SDTM Severity Intensity Scale for Adverse Event Terminology. 
9.3 
Causality of Adverse Events 
The causal relationship of an AE to the investigational product must always be assessed by 
the investigator. All AEs will be classified as either related or not related to the 
investigational product. If a causality assessment is not provided for an AE (including an 
SAE), that AE will be considered related to the investigational product. 
The degree of certainty with which an AE is attributed to 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 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). 


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• Plausibility supported by the temporal relationship (eg, the event being related by time to 
administration or termination of treatment with investigational product, drug withdrawal, 
or reproducible on rechallenge). 
9.4 
Observation Period for Adverse Events 
The observation period for the reporting of AEs and SAEs for an individual subject will start 
at the time at which written informed consent for participation in the current study is obtained 
and ends with the Follow-up Telephone Call. 
If the investigator becomes aware of an SAE that started after the observation period has 
finished, and there is at least a possible causal relationship with 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, 
nonserious AEs that have not resolved or stabilized will be followed until the subject 
completes the study. SAEs 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. All AEs are to be recorded in the eCRF. If known, the medical diagnosis of an 
AE should be recorded in preference to the listing of individual signs, laboratory findings, 
and / or symptoms. The investigator must follow up on the course of an AE until resolution or 
stabilization. If an AE is ongoing after the Follow-up Visit, the AE will continue to be 
followed until resolution, stabilization, or the subject is lost to follow-up. 
If, during the study period, a subject presents with a preexisting condition that was not noted 
at the time of study entry, the condition should be retrospectively recorded in the Medical 
History eCRF. 


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9.6.2 
Adverse Events of Special Interest 
Adverse event of special interest must be reported as AEs in the subject’s eCRF. Additional data 
may be requested in the eCRF for these events. Serious and nonserious AESIs must be reported 
following the procedures for expedited reporting as described for SAEs (see Section 9.6.3). 
9.6.3 
Serious Adverse Events 
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’s becoming aware of the event). Assessment of causality to 
the investigational product must be included. 
AEs occurring in the period between the time when the subject gave written informed 
consent and the first exposure to investigational product, and that meet 1 or more of the 
seriousness criteria, must 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 EOT Visit that is considered to be causally related to 
investigational product must be reported immediately (ie, within 24 hours of the 
investigator becoming aware of the event) to CSL. Such events are not entered into the 
eCRF. 
The minimum reporting requirements for reporting of SAEs include: 
• Subject identification number 
• Suspected medicinal product and / or procedure 
• Event term 
• Reporting source identification 


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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 IRB / IEC within the timeframe specified by the 
IRB / IEC 
• If the subject is an active participant in the study: 
o Enter follow-up information in the eCRF until the SAE has resolved, or, in the case of 
permanent impairment, until stabilized 
o Ensure that the causality assessment for all SAEs is entered in the eCRF 
• If the subject is no longer participating in the study, report the follow-up information to 
CSL 
In cases of death, the investigator should supply CSL and the IRB / IEC (as applicable) with 
any additional information as it becomes available (eg, autopsy reports and detailed medical 
reports). 
9.6.4 
Other Significant Events 
Not applicable. 
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 (ie, volume, location of infusions, infusion rate) of overdose of investigational 
product (defined in Section 5.1.3.3) 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, or up to and including 90 days after the last administration of 
investigational product, must notify the investigator immediately. 


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If a female subject becomes pregnant, she must discontinue treatment with investigational 
product, but may continue other study procedures at the discretion of the investigator. If the 
female subject is in the active treatment period of the study, her participation will be 
discontinued and the procedure for discontinuation of a subject will be followed, as described 
in Section 4.3). 
CSL must be notified within 5 days of the investigator becoming aware of the pregnancy. 
Whenever possible, a pregnancy in a subject or in a female partner of a male subject exposed 
to 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 
Institutional Review Board / Independent Ethics Committee 
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 health authorities. 
10 
Statistics 
10.1 
Sample Size Estimation 
The sample size for this study was determined based on feasibility, not based on a power 
calculation. It was estimated that enrolling approximately 80 subjects (40 in each treatment 
group), and taking into account a 12% dropout rate, a total of 70 evaluable subjects (35 in 
each treatment group), would be considered sufficient for assessment of safety, PK, and 
biomarker profiles. 


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10.2 
Description of Study Analysis Sets 
10.2.1 
Screened Analysis Set 
The Screened Analysis Set comprises all subjects who provide written informed consent and 
who complete all of the Screening procedures. 
10.2.2 
Safety Analysis Set 
The Safety Analysis Set comprises all subjects who receive any portion of an IV infusion or 
SC injection of CSL312 or placebo, and analyses will be based on the actual treatment 
received. 
10.2.3 
Pharmacokinetic Analysis Set 
The PK Analysis Set is defined as subjects in the Safety Analysis Set who receive ≥ 1 dose of 
CSL312 with ≥ 1 measurable concentration of CSL312 after administration. 
10.2.4 
Pharmacodynamic Analysis Set 
The PD Analysis Set is defined as subjects in the Safety Analysis Set for whom analysis 
results are obtained for ≥ 1 of the exploratory biomarkers of interest. 
10.3 
Statistical Analyses and Methods 
10.3.1 
General Considerations 
A complete description of the statistical analyses and methods will be provided in the 
statistical analysis plan (SAP), which will be finalized before database lock. In general, 
continuous variables will be summarized using descriptive statistics (number of observations 
[n], mean, SD, median, minimum and maximum. Categorical variables will be described 
using frequencies and percentages. For repeated observations of continuous variables, the 
change from Baseline will also be summarized. 
All statistical tests will be 2-sided and will be performed at the 5% level of significance. 
Since no type I error adjustment will be performed for this study, all p-values will be 
considered nominal. 
If not specified otherwise, Baseline refers to the last nonmissing measurement before the first 
administration of investigational product (CSL312 or placebo). 


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10.3.2 
Subject Disposition and Characteristics 
10.3.2.1 
Subject Disposition 
Summary tables by treatment group and total population will present: 
• The number of subjects enrolled into the study (ie, signed the ICF). 
• The number of subjects who prematurely discontinued investigational product. 
• The number of subjects who were withdrawn from the study. 
• The number of subjects who completed the study. 
Reasons for discontinuing the investigational product and withdrawing a subject from the 
study will be listed by subject. 
10.3.2.2 
Subject Characteristics 
At minimum, subject characteristics will be presented in summary tables. Descriptive 
statistics will be presented for continuous data and categorical data as described above. 
Age will be described as both a continuous and a discrete variable. Supportive data will be 
listed by subject. 
10.3.3 
Safety Analyses 
TEAEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
version 24.1 (or higher). A TEAE is defined as an AE reported at or after the start of the first 
administration of study treatment. Only TEAEs will be summarized. 
An overview summary of TEAEs, including counts and percentages of subjects with any of 
the following events, will be produced: 
• TEAEs 
• TEAEs related to study treatment 
• TEAEs leading to permanent discontinuation of study treatment 
• Serious TEAEs 
• Serious TEAEs related to study treatment 
• Fatal TEAEs 


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• Fatal TEAEs related to study treatment 
• TEAEs by severity 
• Treatment-emergent AESIs 
TEAEs will be summarized by system organ class and preferred term. TEAEs will also be 
summarized by causality and severity. All TEAE summaries will be provided for each 
treatment group and overall. 
The number and percentage of subjects with plasma anti-CSL312 antibodies will be 
summarized by treatment group and overall. 
Laboratory evaluations (hematology, biochemistry, and urinalysis) will be summarized 
descriptively by treatment group. 
Change from Baseline in DLCO will be summarized using descriptive statistics by treatment 
group. 
The Safety Analysis Set will be used for the safety analyses unless indicated otherwise. 
10.3.4 
Pharmacokinetics Analyses 
Plasma concentrations of CSL312 will be summarized by nominal time point. The following 
descriptive statistics will be presented for plasma concentration summaries: number of 
observations (n), arithmetic mean, SD, %CV, median, geometric mean, geometric CV, 
minimum, and maximum. 
The following PK parameters will be derived using non-compartmental PK analyses and will 
be summarized after SC administration of CSL312 at each SC dosing interval: 
• Ctrough 
• Cmax (last SC dosing interval only) 
• Tmax (last SC dosing interval only) 
• AUC0-tau (last SC dosing interval only) 


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The following PK parameters will be derived and summarized after the IV administration of 
CSL312: 
• Cmax 
• Tmax 
• Ctrough 
The following descriptive statistics will be presented for all PK parameters except Tmax: 
n, arithmetic mean, SD, %CV, median, geometric mean, geometric %CV, minimum, and 
maximum. For Tmax, n, median, minimum, and maximum will be summarized. 
The PK Analysis Set will be used for the PK analyses. 
Additional information on the analysis of PK parameters will be provided in the SAP. 
10.3.5 
Pharmacodynamic Analyses 
10.3.5.1 
FXIIa-mediated Kallikrein Activity 
Change from Baseline in FXIIa-mediated kallikrein activity over time will be calculated for 
each subject. The comparison of primary interest is the change from Baseline at Week 14. If 
the data are not normally distributed by visual inspection or statistical testing, an appropriate 
data transformation may be done. The data (or transformed data) will be compared between 
CSL312 and placebo using mixed-model repeated measure (MMRM), with treatment group 
and visit as fixed effects, and Baseline as a covariate. Analyses will be implemented using 
SAS PROC MIXED. Interactions with visit will be included for treatment group and 
Baseline. A restricted maximum likelihood (REML) approach will be used. An unstructured 
variance-covariance structure will be used to model the within-subject errors. This 
variance-covariance matrix will be estimated across treatment groups. If the model fails to 
converge, a heterogeneous Toeplitz structure (the TOEPH option in SAS PROC MIXED) will 
be used. The Kenward-Roger approximation will be used to estimate denominator degrees of 
freedom and adjust standard errors. 


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FXIIa-mediated kallikrein activity will be summarized by nominal time point with the 
following descriptive statistics: n, mean, SD, %CV, minimum, first quartile (Q1), median, 
third quartile (Q3), maximum, geometric mean, geometric %CV, and percent below the limit 
of quantitation (%BLQ). Individual FXIIa-mediated kallikrein activity-time profiles will be 
plotted using actual sampling times. Mean (± SD) FXIIa-mediated kallikrein activity profiles 
will also be plotted using nominal (planned) time points. 
Observed change from Baseline and percentage of Baseline values of FXIIa-mediated 
kallikrein activity over time will also be summarized using descriptive statistics and 
presented graphically by treatment group. 
A nonparametric Jonckheere-Terpstra test may be performed as appropriate to test the trend 
over time for each treatment group. 
The PD Analysis Set will be used for this analysis. Additional information on the analyses of 
FXIIa-mediated kallikrein activity will be provided in the SAP. 
10.3.6 
Pharmacokinetic / Pharmacodynamic Relationships 
Population PK and PK / PD modelling will be explored, as feasible, for further 
time-dependent characterization of PK versus PD endpoints and / or safety and efficacy 
endpoints. 
Population PK and PK / PD modeling will be specified in a separate PK modelling SAP and 
the results will be reported separately. 
10.3.7 
Analysis of Exploratory Endpoints 
10.3.7.1 
Biomarker Analyses 
All PD and biomarker data change from Baseline and percent change from Baseline in the 
blood will be analyzed using the same methodologies as described for FXIIa-mediated 
kallikrein activity (see Section 10.3.5.1). In addition, correlations between the change from 
Baseline for each PD and biomarker at Week 14 and each spirometry measurement of FVC 
(change from Baseline in FVC [mL] and in FVC percent predicted) measured at Week 14 
may be investigated using a scatter plot, Pearson correlation coefficient and Spearman 
correlation coefficient by treatment group. All PD and biomarker data will be summarized 
and analyzed using the PD Analysis Set. Additional information on PD analyses will be 
provided in the SAP. 


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Additional exploratory biomarker analyses will be reported separately from the clinical study 
report (CSR). 
10.3.7.2 
Pulmonary Function Data Analyses 
Change from Baseline including absolute and percent predicted in FVC over time will be 
summarized using the same MMRM, with treatment group, and visit as fixed effects, and 
Baseline as a covariate. Interactions with visit will be included for treatment group and 
Baseline. Mean difference and its 95% confidence interval will be provided at each time 
point, assuming that the data is normally distributed. A plot of these variables over time will 
also be provided by treatment group. The number and proportion of subjects with ≥ 5% or 
≥ 10% absolute or relative decline in FVC percent predicted at 14 weeks will be presented. 
The Safety Analysis Set will be used for this analysis. 
10.3.8 
Interim Analysis 
No interim analysis is planned for this study. 
11 
Quality Assurance 
The study may be subject to an audit by CSL, an authorized representative of CSL or 
inspections by an authorized health authority (eg, USA Food and Drug Administration 
[FDA]). Health 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 auditors. 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. 


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This study will be conducted under an FDA investigational new drug application as well as 
clinical trial applications in multiple countries and documented in accordance with the 
applicable regulatory guidelines and requirements. 
The procedures set out in this CSP are designed to ensure that CSL and the investigator abide 
by the principles of the current ICH GCP guideline on the conduct, evaluation and 
documentation of this study, as described in ICH Topic E6 (Guideline for GCP). The study 
will also be carried out according to all applicable international and national regulatory 
requirements. 
12.2 
Institutional Review Board / Independent Ethics Committee 
The investigator must submit the CSP and ICFs for review by an authorized and properly 
constituted (according to local guidelines) IRB / IEC. Written approval must be received 
from the IRB / IEC before commencement of the study. 
12.3 
Subject Information and Informed Consent 
Informed consent of study subjects according to the standards of GCP must be implemented 
in this clinical study before protocol-specified procedures are carried out. Information should 
be given in both oral and written form and should be deemed appropriate by the IRB / IEC. 
Subjects, their relatives (or if necessary, legally acceptable representatives) must be given 
ample opportunity to inquire about details of the study. 
The subject (or if necessary, legally acceptable representatives) must be provided with a copy 
of the signed informed consent form. 
Should there be any amendments to the CSP that would directly affect the subject’s 
participation in the study (eg, a change in any procedure), the ICF must be amended to 
incorporate this modification. Subjects must be informed of the change and they must sign 
the amended ICF indicating that they re-consent to participate in the study. 
12.4 
Subject Confidentiality 
All subject names and contact details will be kept confidential. Subjects will be identified 
throughout documentation and evaluation by the number allotted to them during the study. 
Each subject will be told that all study findings will be handled in the strictest confidence. 


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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 health authority or the IRB / IEC. 
All records accessed will be strictly confidential. Consent to participate in the study includes 
consent to these inspections / audits. 
12.5 
Indemnity and Compensation 
CSL has taken out insurance to cover its obligations under both the Indemnity and the 
Compensation guidelines for injury to subjects involved in the study. 
Other details regarding compensation and the obligations of the investigator / CSL are 
provided in the Clinical Trial Research Agreement (CTRA) for the study (see Section 13.1). 
13 
Administrative Considerations 
13.1 
Clinical Trial Research Agreement 
This study will be conducted under a CTRA between CSL (“Sponsor”) and the institutions 
representing the investigational study sites (“Authority”). Financial support to the 
investigational sites will be detailed in the CTRA. The CTRA 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. CTRAs may be executed by electronic signature (current provider DocuSign) 
in compliance with 21 Code of Federal Regulations Part 11 and simple or advanced 
electronic signature according to European Union (EU) Regulation No 910/2014 – eIDAS. 
13.2 
Clinical Study Registration and Results Disclosure  
CSL will provide the relevant CSP information in public databases before or at 
commencement of the study. CSL may also provide study information for inclusion in 
national registries according to local regulatory requirements. 


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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 CSP registration record. 
13.3 
Implementation of the Clinical Study Protocol and 
Amendments 
With the exception of medical emergencies, no changes or deviations in the conduct of the 
signed CSP will be permitted without documented approval of the CSL Medical Monitor or 
designee and the IRB / IEC. In the event of a medical emergency, the investigator at the study 
site will institute any medical procedures deemed appropriate. However, all such procedures 
must be promptly reported to the CSL Medical Monitor and the IRB / IEC. 
Modifications to the CSP 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 CSP, 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 CSP were not complied with will be tracked. 
Corresponding subjects may be withdrawn from the study at the discretion of the investigator 
and / or CSL. Protocol deviations arise when either subjects who have been entered in the 
study and / or the study sites deviate from the IRB / IEC-approved CSP. 
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. 


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13.5 
Documentation and Record Keeping  
13.5.1 
Data Collection 
The investigator (or delegate) will maintain individual records for each subject. These records 
should include dates when a subject visited the study site, records of vital signs, medical 
history, or physical examinations, administration of investigational product or concomitant 
therapy, any AEs experienced, and other notes as appropriate. These records (electronic or 
paper) constitute source data. 
Electronic CRF entries will be considered source data if the eCRF is the site of the original 
recordings (ie, there is no other written or electronic record of the data). 
An eCRF will be provided by CSL (or delegate) for each subject enrolled into the study. The 
investigator is responsible for ensuring accurate and proper completion of the eCRF in a 
timely manner so that it always reflects the latest observations on the subjects enrolled in the 
study. All entries on the eCRF must be backed up by source data unless the eCRF is 
considered source data. All source data will be kept according to all applicable regulatory 
requirements. Source data must be completed legibly for each subject enrolled into the study 
and signed by the investigator (or delegate). 
13.5.2 
Data Quality Assurance 
Data generated throughout the study will be monitored and the eCRFs checked against the 
subject records for completeness and accuracy. The investigator must provide direct access to 
source data documents. CSL’s study monitor will perform this function. 
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). 


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13.5.3 
Record Retention 
The investigator must follow the principles for record retention outlined in the Clinical Trial 
Research Agreement. An investigator study file prepared by CSL (or delegate), containing all 
applicable documents for use at the study site, will be made available to the investigator 
before the start of the study. All study documentation and materials maintained in the 
investigator study file must be kept in conformance with applicable national laws and 
regulations. 
All study documentation and materials maintained in the investigator study file at the study 
site must be available for inspection by CSL’s study monitor (or delegate) to determine that 
all required documentation is present and correct. 
The study may be audited or inspected by qualified delegates from CSL or a competent 
health authority. 
Following completion of the study, the investigator is responsible for archiving the 
investigator’s study file, the subject’s records and the source data according to applicable 
regulatory requirements. 
13.6 
Study and Site Closure 
CSL reserves the right to prematurely discontinue or suspend the study either at a particular 
site or at all study sites at any time and for any reason. If such action is taken, the CSL Study 
Monitor (or delegate) will discuss this with the investigator at each study site at that time and 
notify the investigators in writing. If the study is suspended or terminated for safety reasons, 
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 CSR will be written after the completion of the study. CSL or its agent will write the report 
in consultation with the investigator or, if applicable, a nominated coordinating investigator 
(or delegate). CSL requires that the coordinating investigator will sign the CSR. 
Progress reports may be provided to the relevant regulatory bodies in accordance with their 
requirements. 


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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 CTRA for the study. 
 


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14 
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Quinn C, Wisse A, Manns ST. Clinical course and management of idiopathic pulmonary 
fibrosis. Multidiscip Respir Med. 2019;14:35. doi: 10.1186/s40248-019-0197-0. 


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idiopathic pulmonary fibrosis with etanercept: an exploratory, placebo-controlled trial. Am J 
Respir Crit Care Med. 2008;178(9):948-955. doi: 10.1164/rccm.200709-1446OC. 
Raghu G, Collard HR, Egan JJ, Martinez FJ, Behr J, Brown KK, et al. An Official 
ATS/ERS/JRS/ALAT Statement: Idiopathic Pulmonary Fibrosis: Evidence-based Guidelines 
for Diagnosis and Management. Am J Respir Crit Care Med. 2011;183(6):788-824. 
doi: 10.1164/rccm.2009-040GL. 
Raghu G, Anstrom KJ, King TE Jr, Lasky JA, Martinez FJ. Idiopathic Pulmonary Fibrosis 
Clinical Research Network. Prednisone, azathioprine, and N-acetylcysteine for pulmonary 
fibrosis. N Engl J Med. 2012;366(21):1968-1977. doi: 10.1056/NEJMoa1113354. 
Raghu G, Amatto VC, Behr J, Stowasser S. Comorbidities in idiopathic pulmonary fibrosis 
patients: a systematic literature review. Eur Respir J. 2015a;46(4):1113-1130. 
doi: 10.1183/13993003.02316-2014. 
Raghu G, Rochwerg B, Zhang Y, Cuello Garcia CA, Azuma A, Behr J, et al. An Official 
ATS/ERS/JRS/ALAT Clinical Practice Guideline: Treatment of Idiopathic Pulmonary 
Fibrosis. An Update of the 2011 Clinical Practice Guideline. Am J Respir Crit Care Med. 
2015b;192(2)e3-e19. doi: 10.1164/rccm.201506-1063ST. 
Raghu G, Remy-Jardin M, Myers J, Richeldi L, Ryerson CJ, Lederer DJ, et al. Diagnosis of 
idiopathic pulmonary fibrosis. An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline. 
Am J Respir Crit Care Med. 2018;198(5):e44-e68. doi: 10.1164/rccm.201807-1255ST. 
Ratnoff OD, Colopy JE. A familial hemorrhagic trait associated with a deficiency of a clot-
promoting fraction of plasma. J Clin Invest. 1955;34(4):602-613. doi: 10.1172/JCI103109. 
Renne T, Pozgajová M, Grüner S, Schuh K, Pauer H-U, Burfeind P, et al. Defective thrombus 
formation in mice lacking coagulation factor XII. J Exp Med. 2005;202(2):271-281. 
doi: 10.1084/jem.20050664. 
Renne T, Schmaier AH, Nickel KF, Blomback M, Maas C. In vivo roles of factor XII. Blood 
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Renne T, Stavrou EX. Roles of factor XII in innate immunity. Front Immunol. 2019;10:2011. 
doi: 10.3389/fimmu.2019.02011.  


CSL Behring 
Study Number: 
CSL312_2002 
 
Study Product: 
CSL312 
 
Protocol version: Amendment 3 
 
 
Page 103 of 107 
Date: 18 October 2022 
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CS-SOP-04-T02 Version 2.0 
 
 
Effective Date: Week commencing 25-June-2018 
Revenko AS, Gao D, Crosby JR, Bhattacharjee G, Zhao C, May C, et al. Selective depletion 
of plasma prekallikrein or coagulation factor XII inhibits thrombosis in mice without 
increased risk of bleeding. Blood. 2011;118(19):5302-5311. doi: 10.1182/blood-2011-05-
355248. 
Richeldi L, Ryerson CJ, Lee JS, Wolters PJ, Koth LL, Ley B, et al. Relative versus absolute 
change in forced vital capacity in idiopathic pulmonary fibrosis. Thorax. 2012;67(5):407-411. 
doi: 10.1136/thoraxjnl-2011-201184. 
Richeldi L, du Bois RM, Raghu G, Azuma A, Brown KK, Costabel U, et al. Efficacy and 
safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med. 2014;370(22):2071-
2082. doi: 10.1056/NEJMoa1402584. 
Richeldi L, Collard HR, Jones MG. Idiopathic pulmonary fibrosis. Lancet. 
2017;389(10082):1941-1952. doi: 10.1016/S0140-6736(17)30866-8. 
Ryu JH, Colby TV, Hartman TE. Idiopathic pulmonary fibrosis: current concepts. Mayo Clin 
Proc. 1998;73(11):1085-1101. doi: 10.4065/73.11.1085. 
Sabatini F, Luppi F, Petecchia L, Di Stefano A, Longo AM, Eva A, et al. Bradykinin-induced 
asthmatic fibroblast/myofibroblast activities via bradykinin B2 receptor and different MAPK 
pathways. Eur J Pharmacol. 2013;710(1-3):100-109. doi: 10.1016/j.ejphar.2013.03.048. 
Saito F, Tasaka S, Inoue K, Miyamoto K, Nakano Y, Ogawa Y, et al. Role of interleukin-6 in 
bleomycin-induced lung inflammatory changes in mice. Am J Resp Cell Mol. 
2008;38(5):566-571. doi: 10.1165/rcmb.2007-0299oc. 
Scadding JG, Hinson KF. Diffuse fibrosing alveolitis (diffuse interstitial fibrosis of the 
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Schuliga M, Jaffar J, Harris T, Knight DA, Westall G, Stewart AG. The fibrogenic actions of 
lung fibroblast-derived urokinase: a potential drug target in IPF. Sci Rep. 2017;7:41770. 
doi: 10.1038/srep41770. 
Schuliga M, Grainge C, Westall G, Knight D. The fibrogenic actions of the coagulant and 
plasminogen activation systems in pulmonary fibrosis. Int J Biochem Cell Biol. 2018;97:108-
117. doi: 10.1016/j.biocel.2018.02.016. 


CSL Behring 
Study Number: 
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Study Product: 
CSL312 
 
Protocol version: Amendment 3 
 
 
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Effective Date: Week commencing 25-June-2018 
Scotton CJ, Krupiczojc MA, Konigshoff M, Mercer PF, Lee YC, Kaminski N, et al. Increased 
local expression of coagulation factor X contributes to the fibrotic response in human and 
murine lung injury. J Clin Invest. 2009;119(9):2550-2563. doi: 10.1172/jci33288. 
Senoo T, Hattori N, Tanimoto T, Furonaka M, Ishikawa N, Fujitaka K, et al. Suppression of 
plasminogen activator inhibitor-1 by RNA interference attenuates pulmonary fibrosis. 
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Sgalla G, Iovene B, Calvello M, Ori M, Varone F, Richeldi L. Idiopathic pulmonary fibrosis: 
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profibrotic and hemostatic effects of thrombin in lung fibrosis. JCI Insight. 
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Stavrou EX, Fang C, Bane KL, Long AT, Naudin C, Kucukal E, et al. Factor XII and uPAR 
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Taille C, Grootenboer-Mignot S, Boursier C, Michel L, Debray MP, Fagart J, et al. 
Identification of periplakin as a new target for autoreactivity in idiopathic pulmonary fibrosis. 
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CSL Behring 
Study Number: 
CSL312_2002 
 
Study Product: 
CSL312 
 
Protocol version: Amendment 3 
 
 
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Date: 18 October 2022 
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CS-SOP-04-T02 Version 2.0 
 
 
Effective Date: Week commencing 25-June-2018 
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Vorlova S, Koch M, Manthey HD, Cochain C, Busch M, Chaudhari SM, et al. Coagulation 
factor XII induces pro-inflammatory cytokine responses in macrophages and promotes 
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Wang R, Zhang T, MA Z, Wang Y, Cheng Z, Xu H, et al. The interaction of coagulation factor 
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Gynecol Oncol. 2010;117(3):460-466. doi: 10.1016/j.ygyno.2010.02.015. 
Wong M, Jaffar J, McMillan L, Wilson NJ, Wilson MJ, Westall G, et al. CSL312, a novel 
anti-FXII antibody, blocks FXII-induced IL-6 production from primary non-diseased and 
idiopathic pulmonary fibrosis fibroblasts. Abstract C75 Fibrosis: Current and Future 
Approaches 2017. [abstract]. 
Wujak L, Didiasova M, Zakrzewicz D, Frey H, Schaefer L, Wygrecka M. Heparan sulfate 
proteoglycans mediate factor XIIa binding to the cell surface. J Biol Chem. 
2015;290(11):7027-7039. doi: 10.1074/jbc.m114.606343. 
Wygrecka M, Jablonska E, Henneke I, Renne T, Panousis K, McKenzie B, et al. Coagulation 
factor XII mediates fibrotic response to lung injury. Pneumologie. 2015;69-P05. 
doi: 10.1055/s-0035-1551907. 
Zappala CJ, Latsi PI, Nicholson AG, Colby TV, Renzoni EA, Hansell DM, et al. Marginal 
decline in forced vital capacity is associated with a poor outcome in idiopathic pulmonary 
fibrosis. Eur Respir J. 2010;35(4):830-836. doi: 10.1183/09031936.00155108. 
Zhang L, Wang Y, Wu G, Xiong W, Gu W, Wang CY. Macrophages: friend or foe in 
idiopathic pulmonary fibrosis? Respir Res. 2018;19(1):170. doi: 10.1186/s12931-018-0864-2. 


CSL Behring 
15 
Appendices 
Appendix 1 
Signatures 
Study Number: 
CSL3 l 2 2002 
Study Product: 
CSL3 J 2 
Signature on Behalf of Sponsor 
Study Title: 
A Randomized, Double-blind, Placebo-controlled, Study to 
Investigate the Safety, Pharmacokinetics, and Pharmacodynamics of 
CSL312 in Subjects with Idiopathic Pulmonary Fibrosis 
Protocol Number: 
CSL312 2002 
1 have read the clinical study protocol titled "A Randomized, Double-blind, Placebo-
controlled, Study to Investigate the Safety, Pharmacokinetics, and Pharmacodynamics of 
CSL312 in Subjects with Idiopathic Pulmonary Fibrosis," dated 18 October 2022, and 
confirm that, to the best of my knowledge, the protocol accurately describes the design and 
conduct of the study. 
(Printed name) 
Date (DD MMM YYYY) 
(Title) 
Protocol version: Amendment 3 
Date: 18 October 2022 
Confidential 
Page 106 of 107 
CS-SOP-04-T02 Version 2.0 
Effective Date: Week commencing 25-June-2018 
PPD
PPD
PPD
PPD


CSL Behring 
Study Number: 
CSL312_2002 
 
Study Product: 
CSL312 
 
Protocol version: Amendment 3 
 
 
Page 107 of 107 
Date: 18 October 2022 
Confidential 
CS-SOP-04-T02 Version 2.0 
 
 
Effective Date: Week commencing 25-June-2018 
Signature of Principal Investigator 
 
Study Title: 
A Randomized, Double-blind, Placebo-controlled, Study to 
Investigate the Safety, Pharmacokinetics, and Pharmacodynamics of 
CSL312 in Subjects with Idiopathic Pulmonary Fibrosis 
Protocol 
Number: 
CSL312_2002 
Site Number: 
 
I have read the clinical study protocol titled “A Randomized, Double-blind, Placebo-
controlled, Study to Investigate the Safety, Pharmacokinetics, and Pharmacodynamics of 
CSL312 in Subjects with Idiopathic Pulmonary Fibrosis,” dated 18 October 2022. 
By signing this clinical study protocol, I agree to conduct the clinical study, after approval by 
an Institutional Review Board or Independent Ethics Committee (as appropriate), in 
accordance with the clinical study protocol, the standards of Good Clinical Practice (as 
defined by the International Council 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
--- Do Not Detach This Signature Page ---
glbdctmp
Print Date: 24-Jun-2024 10:10:44 GMT-04:00
Signature Page
CSL312_2002 - Protocol Amendment - 3 - 18Oct2022
Signed By
Date (GMT)
Approved-
 Approval
24-Oct-2022 16:29:28
Approved-
Approval
24-Oct-2022 17:21:52
Approved-
 Approval
24-Oct-2022 18:42:50
PPD
PPD
PPD
PPD
PPD
PPD

SAP_001.pdf: 
SAP version: Final 1.0 
 
Page 1 of 38 
Date: 28Apr2022 
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Parent Document: RnD-SOP-000204555
 
 
Template-Form: RnD-FORM-000204573, version6.0 
 
STATISTICAL ANALYSIS PLAN (SAP) 
 
 
A Randomized, Double-blind, Placebo-controlled, Study to Investigate the Safety, 
Pharmacokinetics, and Pharmacodynamics of CSL312 in Subjects with Idiopathic 
Pulmonary Fibrosis (IPF) 
Study Number: 
CSL312_2002 
Study Product: 
CSL312 
(Garadacimab, Factor XIIa Antagonist Monoclonal Antibody) 
Development Phase: 
Phase 2a 
Sponsor: 
CSL Behring, LLC 
1020 First Avenue 
King of Prussia, Pennsylvania 19406 
United States of America 
Version: 
Final 1.0 
Version Date: 
28Apr2022 
Compliance: 
This study will be conducted in accordance with standards of 
Good Clinical Practice (as defined by the International Council 
for Harmonisation) and all applicable national and local 
regulations.  
 
 
COMMERCIAL IN CONFIDENCE 
This document and the information contained herein are proprietary and confidential. This document 
and the contained information are intended for disclosure to and use by those personnel who are under 
an obligation of confidentiality by a signed agreement with the Sponsor CSL Behring. This document 
and the contained information may be disclosed and used only to the extent necessary to conduct the 
clinical study. Reproduction or disclosure of this document or its contained information is forbidden 
unless at the express request or with the written consent of CSL Behring 


CSL Behring  
Study Number: 
CSL312_2002 
 
Study Product: 
CSL312 
 
SAP version: Final 1.0 
 
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Table of Contents 
Table of Contents ....................................................................................................................... 2 
List of Tables .............................................................................................................................. 4 
List of Figures ............................................................................................................................ 4 
1 
Modification History .......................................................................................................... 5 
2 
List of Abbreviations .......................................................................................................... 6 
3 
Purpose ............................................................................................................................... 9 
4 
Study Design ....................................................................................................................... 9 
4.1 
Objectives and Endpoints ............................................................................................ 10 
4.1.1 
Primary Study Hypotheses ...................................................................................... 12 
4.2 
Study Treatments ......................................................................................................... 13 
4.3 
Randomization Procedures and Blinding..................................................................... 13 
4.4 
Determination of the Sample Size ............................................................................... 13 
4.5 
Planned Interim Analyses and Sample Size Re-estimation ......................................... 13 
4.5.1 
Independent Data Monitoring Committee .............................................................. 14 
5 
Changes from the Protocol Planned Analyses .................................................................. 14 
6 
Study Analysis Sets........................................................................................................... 14 
6.1 
Screened Analysis Set .................................................................................................. 14 
6.2 
Safety Analysis Set ...................................................................................................... 15 
6.3 
Pharmacokinetic Analysis Set ...................................................................................... 15 
6.4 
Pharmacodynamic Analysis Set ................................................................................... 15 
7 
General Considerations ..................................................................................................... 15 
7.1 
COVID-19 Impact ....................................................................................................... 15 
8 
Data Handling Conventions .............................................................................................. 18 
8.1 
Missing Data ................................................................................................................ 18 
8.2 
General Derived Variables ........................................................................................... 19 
8.2.1 
Reference Dates and Study Days ............................................................................ 19 
8.2.2 
Durations ................................................................................................................. 19 
8.2.3 
Baseline Definition.................................................................................................. 19 
8.2.4 
Change from Baseline ............................................................................................. 20 
8.2.5 
Multiple Assessments .............................................................................................. 20 


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8.2.6 
Actual Treatment ..................................................................................................... 20 
8.3 
Stratification ................................................................................................................. 20 
8.4 
Study Periods Relative to Treatment............................................................................ 21 
9 
Study Population ............................................................................................................... 21 
9.1 
Subject Disposition ...................................................................................................... 21 
9.2 
Protocol Deviations ...................................................................................................... 22 
9.3 
Demographic and Baseline Characteristics ................................................................. 23 
9.4 
Prior/Concomitant Medications ................................................................................... 23 
9.5 
Study Population - Derived Variables .......................................................................... 24 
10 Efficacy Analyses ............................................................................................................. 24 
10.1 
Treatment Compliance ................................................................................................. 25 
11 Safety Analyses ................................................................................................................. 25 
11.1 
Extent of Exposure ....................................................................................................... 25 
11.2 
Adverse Events ............................................................................................................ 26 
11.3 
Clinical Laboratory Evaluations .................................................................................. 29 
11.4 
Other Safety Measures ................................................................................................. 30 
11.4.1 
Vital Signs ............................................................................................................... 30 
11.4.2 
Electrocardiogram (ECG) ....................................................................................... 30 
11.4.3 
Diffusing Capacity of the Lungs for Carbon Monoxide (DLCO) ........................... 31 
11.4.4 
Physical Examination .............................................................................................. 31 
12 Pharmacokinetic Analyses ................................................................................................ 31 
12.1 
Drug Concentration Measures ..................................................................................... 32 
12.2 
Deriving and Summarizing Pharmacokinetic Parameters ........................................... 33 
13 Pharmacodynamic and Biomarkers Analyses ................................................................... 34 
13.1 
Pharmacodynamic Analyses ........................................................................................ 34 
13.2 
Biomarker Analyses ..................................................................................................... 35 
13.2.1 
Pulmonary Function Data Analyses ........................................................................ 36 
14 References ......................................................................................................................... 37 
15 Appendices ....................................................................................................................... 38 
15.1 
Pharmacokinetic Parameters ........................................................................................ 38 
 


CSL Behring  
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List of Tables 
Table 1 
Study Objectives and Endpoints ...................................................................... 11 
Table 2 
TEAE Assignment in Case of Missing AE Start Date Elements ..................... 26 
 
List of Figures 
Figure 1 
Study Design Schematic .................................................................................. 10 
 


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1 
Modification History 
 
Vers
ion 
Effective Date  
Author of 
Modification 
Summary of Change 
1.0 
28Apr2022 
 
N/A – First Version 
 
PPD


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2 
List of Abbreviations 
Abbreviation 
Term 
%CV 
Percent coefficient of variation 
ADA 
Antidrug antibody 
ADaM 
Analysis data model 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
AUC 
Area under the plasma concentration-time curve 
AUC0-tau 
Area under the plasma concentration-time curve during a dosing 
interval 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
ATC 
Anatomical therapeutic chemical 
BMI 
Body mass index 
BLQ 
Below the limit of quantification 
BUN 
Blood urea nitrogen 
C3M 
neo-epitope of MMP-9 mediated degradation of type III collagen 
C6M 
neo-epitope of MMP-2 mediated degradation of type VI collagen 
CCL-18 
C-C motif chemokine ligand 18 
CDG 
Customized drug grouping 
CDISC 
Clinical data interchange standards consortium 
Cmax 
Maximum plasma concentration 
CK 
Creatine kinase 
CMQ 
Custom MedDRA Query 
COVID-19 
Coronavirus disease 2019 
CPK 
Creatine phosphokinase 
eCRF 
Electronic case report form 
CSP 
Clinical study protocol 
CSR 
Clinical study report 
CTMS 
Clinical trial management system 
Ctrough 
Trough plasma concentration 
CV 
Coefficient of variation 
DBL 
Database lock 


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Abbreviation 
Term 
DLCO 
Diffusing capacity of the lungs for carbon monoxide 
ECG 
Electrocardiogram 
EOT 
End of treatment 
eCRF 
Electronic case report form 
FVC 
Forced vital capacity 
FXIIa 
Activated coagulation factor XII 
GGT 
Gamma-Glutamyl-Transferase 
hs-CRP 
High sensitivity-C reactive protein 
HDL 
High density lipoprotein 
IDMC 
Independent data monitoring committee 
ICH 
International council for harmonisation 
ICF 
Informed consent form 
INR 
International normalized ratio 
IP 
Investigational product 
IPF 
Idiopathic pulmonary fibrosis 
IRT 
Interactive response technology 
IV 
Intravenous 
LDH 
Lactate dehydrogenase 
LDL 
Low density lipoprotein 
LLN 
Lower limit of normal 
LLOQ 
Lower level of quantification 
LSMean 
Least square mean 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 
MedDRA 
Medical dictionary for regulatory activities 
MMRM 
Mixed-model repeated measure 
MSAP 
Modeling and simulation analysis plan 
PAI-1 
plasminogen activator inhibitor 1 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
PROC3 
released N terminal pro-peptide of type III collagen 
PROC6 
C terminal of released C5 domain of type VI collagen 


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Abbreviation 
Term 
PT 
Prothrombin time 
RDW 
Red cell (erythrocyte) distribution width 
REML 
Restricted maximum likelihood 
Q1 
First quartile 
Q3 
Third quartile 
RBC 
Red blood cell 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SC 
Subcutaneous 
SD 
Standard deviation 
SDG 
Standardized drug grouping 
SDTM 
Study data tabulation model 
SI units 
International system of units 
SMQ 
Standard MedDRA query 
SP-A 
surfactant protein A 
SP-D 
surfactant protein D 
SOC 
System organ class 
TEAE 
Treatment-emergent adverse event 
TEE 
Thromboembolic event 
Tmax 
Time to reach maximum plasma concentration 
ULN 
Upper limit of normal 
WBC 
White blood cell count 
WHO 
World health organization 
WHO-DDE 
World health organization drug dictionary enhanced 
 


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3 
Purpose 
This statistical analysis plan (SAP) provides a detailed and complete description of the 
planned statistical analyses of the data for the study CSL312_2002 “A Randomized, Double-
blind, Placebo-controlled, Study to Investigate the Safety, Pharmacokinetics, and 
Pharmacodynamics of CSL312 in Subjects with Idiopathic Pulmonary Fibrosis (IPF)”. 
This SAP complies with the International Council for Harmonisation (ICH) E9 ‘Statistical 
Principles for Clinical Trials’ and is based upon the following study documents: 
•
CSL312_2002 Clinical Study Protocol (CSP), Original (dated 07 June 2021);
o
CSP Amendment 1 (dated 15 November 2021);
o
CSP Amendment 2 (dated 18 January 2022);
•
CSL312_2002 electronic Case Report Form (eCRF), Version 1.0
(dated 08 February 2022). 
All decisions regarding the final analysis of the study results, as defined in this SAP, will be 
made before database lock (DBL) of the study data. 
Deviations from the analyses in this SAP will be detailed in the clinical study report (CSR). 
4 
Study Design 
This is a prospective, randomized, double-blind, placebo-controlled study to investigate the 
safety, PK, and pharmacodynamic (PD) of CSL312 in patients with IPF (Figure 1). 
Approximately 80 patients with a confirmed diagnosis of IPF will be enrolled and 
randomized in a 1:1 ratio; to achieve a total of 70 evaluable subjects by Week 14 (Day 92); 
35 subjects in the CSL312 600 mg group and 35 subjects in the placebo group. It is expected 
that the dropout rate is approximately 12%. 
Eligible subjects will be randomized to enter the Treatment and Observation Period for 
14 weeks, during which subjects will receive an intravenous (IV) loading dose of CSL312 or 
placebo followed by 3 subcutaneous (SC) doses of CSL312 or placebo. A total of 12 study 
visits are planned (1 Screening Visit and 11 visits during the Treatment and Observation 
Period). A final safety check will be conducted by telephone approximately 90 days after the 
last administration of investigational product (IP) (see the Schedule of Assessments). The 
study will end when the last subject has completed the 14-week Treatment and Observation 
Period and the Follow-up visit (Telephone Call). 


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Figure 1 
Study Design Schematic 
 
EOT = End of Treatment; IPF = idiopathic pulmonary fibrosis; IV = intravenous; n = number of subjects in the 
treatment group; SC = subcutaneous. 
 
The duration of the study for an individual subject is expected to be up to 6 months. This 
estimate is based on: 
• Screening / Washout Period of up to 28 days; 
• 14-week Treatment and Observation Period; 
• Follow-up Telephone Call at 90 days after the last investigational product 
administration. 
The overall study duration (ie, first subject’s Screening Visit to last subject’s Follow-up 
Telephone call) will be approximately 17 to 19 months. 
4.1 
Objectives and Endpoints 
The primary objective of this study is to investigate the safety of CSL312 in subjects with 
IPF. 
 
 


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The secondary objectives of the study are: 
1. To characterize the systemic PK of CSL312 in patients with IPF. 
2. To investigate the PD activity of CSL312 in patients with IPF. 
The exploratory objectives of the study are: 
1. To investigate the potential effect of CSL312 on FXII-related pathways in patients 
with IPF. 
2. To investigate the effect of CSL312 on lung function in patients with IPF. 
Table 1 
Study Objectives and Endpoints 
Objectives 
Endpoints and /or Estimand 
Summary Measure(s) 
Primary  
Subjects experiencing treatment-
emergent adverse events (TEAEs) 
including: 
• Serious adverse events (SAEs) 
• Adverse events of special interest 
(AESIs [bleeding events, 
thromboembolic events (TEE), 
severe hypersensitivity]) 
• CSL312-induced antidrug 
antibodies (ADAs) 
• Clinically significant 
abnormalities in laboratory 
assessments that are reported as 
adverse events (AEs) 
Number and proportion of subjects 
experiencing the specified safety 
events after treatment with IP 
(CSL312 or placebo) 
Secondary 
 
 
1 
Plasma PK parameters after SC 
administration of CSL312 at each 
SC dosing interval: 
• Trough plasma concentration 
(Ctrough) 
• Maximum plasma concentration 
(Cmax) (last SC dosing interval 
only) 
• Time to reach maximum plasma 
concentration (Tmax) (last SC 
dosing interval only) 
• Area under the plasma 
concentration-time curve after 
the first dose interval (AUC0-tau) 
(last SC dosing interval only) 
• Mean (SD) and geometric mean 
(geometric percent coefficient of 
variation [geometric %CV]) for 
all PK parameters except for Tmax 
• Median (minimum, maximum) 
for Tmax 


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Objectives 
Endpoints and /or Estimand 
Summary Measure(s) 
1 
Plasma PK parameters after the IV 
dose of CSL312: 
• Cmax 
• Tmax 
• Ctrough 
• Mean (SD) and geometric mean 
(geometric %CV) for all PK 
parameters except for Tmax 
• Median (minimum, maximum) 
for Tmax 
2 
Effect of treatment with CSL312 on 
activated coagulation factor XII 
(FXIIa) mediated kallikrein activity 
• Mean (SD) change from Baseline 
in FXIIa-mediated kallikrein 
activity by treatment 
• Mean percentage of Baseline in 
FXIIa-mediated kallikrein activity 
by treatment 
Exploratory 
 
 
1 
Concentration of PD and 
biomarkers in blood 
• Mean (SD) change from Baseline 
in PD and biomarkers by 
treatment 
• Mean percent change from 
Baseline in PD and biomarkers by 
treatment 
2 
Change in forced vital capacity 
(FVC) 
• Absolute change from Baseline in 
FVC at 14 weeks (expressed in 
mL) 
• Absolute change from Baseline in 
FVC percent predicted at 14 
weeks 
• Number and proportion of 
subjects with ≥ 5% or ≥ 10% 
absolute or relative decline in 
FVC percent predicted at 14 
weeks 
 
4.1.1 
Primary Study Hypotheses 
There is no primary study hypothesis for this study. 
Methods to control for multiplicity are not required. 
 


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4.2 
Study Treatments 
IP will be administered as an IV loading dose followed by 3 subsequent SC injections at the 
following doses based on treatment group: 
• CSL312 Group: IV loading dose of CSL312 at 300 mg followed by a second dose of 
600 mg administered SC 7 days later (Week 2). Doses 3 and 4 of 600 mg will be 
administered SC at Weeks 6 and 10, respectively. The drug will be provided as a 
sterile solution for injection containing 100 mg/mL of CSL312 in 2-mL vials. 
• Placebo Group: IV loading dose of placebo (formulation buffer) followed by a second 
dose of placebo administered SC 7 days later (Week 2). Doses 3 and 4 of placebo will 
be administered SC at Weeks 6 and 10, respectively. The drug will be provided as a 
sterile solution for injection containing a formulation buffer in 2-mL vials. 
4.3 
Randomization Procedures and Blinding 
Subjects will be randomized in a ratio of 1:1 to either CSL312 600 mg or placebo group by 
means of the interactive response technology (IRT). A centralized randomization schedule 
will be used. 
The IRT external service provider will prepare the study randomization code according to 
approved specifications. The IRT external service provider will keep the randomization code 
on file. 
At Screening, subjects will be assigned a unique subject number via the IRT system. 
4.4 
Determination of the Sample Size 
The sample size for this study was determined based on feasibility, not based on a power 
calculation. It was estimated that enrolling approximately 80 subjects (40 in each treatment 
group), and taking into account a 12% dropout rate, a total of 70 evaluable subjects (35 in 
each treatment group), would be considered sufficient for assessment of safety, PK, and 
biomarker profiles. 
4.5 
Planned Interim Analyses and Sample Size Re-estimation 
No formal interim analyses and no sample size re-estimation is planned for this study. 


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4.5.1 
Independent Data Monitoring Committee 
The roles and responsibilities of the independent data monitoring committee (IDMC) and the 
safety data review schedules are described in the IDMC charter. Operationally, since the 
IDMC is ad-hoc and can be triggered before SAS programming can be done to generate 
summary output, in this case, only data dump listings will be generated. Otherwise, those 
summary tables will be provided for the following (along with their supporting listings): 
• Demographics; 
• Treatment and exposure; 
• AE overall summary, SAEs, AEs, AESIs. 
Other safety analysis output as listed below, will be provided as data listings: 
• Vital signs, physical exams and respiratory tests; 
• Safety laboratory parameters / urinalysis; 
• ECG; 
• Medical history; 
• Concomitant medication; 
• Spirometry. 
Please refer to Sections 9, 10, and 11 of this SAP for descriptions of the analysis listed above. 
5 
Changes from the Protocol Planned Analyses 
There are no changes to the planned analyses as previously documented in the CSP. 
The definition of screened analysis set was slightly modified, please refer to Section 6.1. 
6 
Study Analysis Sets 
6.1 
Screened Analysis Set 
The Screened Analysis Set comprises all subjects who provide written informed consent. 
Section 10.2.1 of the CSP had previously included a more narrow definition for the Screened 
Analysis Set, which read as follows: “The Screened Analysis Set comprises all subjects who 
provide written informed consent and who complete all of the Screening procedures. 


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6.2 
Safety Analysis Set 
The Safety Analysis Set comprises all subjects who receive any portion of an IV infusion or 
SC injection of CSL312 or placebo, and analyses will be based on the actual treatment 
received. 
6.3 
Pharmacokinetic Analysis Set 
The PK Analysis Set is defined as subjects in the Safety Analysis Set who receive ≥ 1 dose of 
CSL312 with ≥ 1 measurable concentration of CSL312 after administration. 
6.4 
Pharmacodynamic Analysis Set 
The PD Analysis Set is defined as subjects in the Safety Analysis Set for whom analysis 
results are obtained for ≥ 1 of the exploratory biomarkers of interest. 
7 
General Considerations 
Datasets will be created according to clinical data interchange standards consortium (CDISC) 
standards. Study data will be provided in study data tabulation model (SDTM) format. 
Analysis data will be provided in analysis data model (ADaM) format. 
SAS version 9.4 or higher will be used to perform all data analyses.  
Summaries of continuous variables will be in terms of the number of observations, mean, SD, 
median, first quartile (Q1), third quartile (Q3), minimum and maximum. Other descriptive 
statistics (eg, standard error, CV) may be reported when appropriate. Categorical variables 
will be summarized using frequency counts and percentages. Analyses that use other 
descriptive statistics will have the specific descriptive statistics identified with the analysis in 
the applicable SAP section. 
7.1 
COVID-19 Impact 
During the course of this study, the global coronavirus disease 2019 (COVID-19) pandemic 
is expected to continue. This might impact the study in a variety of ways. This section 
describes how the potential impact of COVID-19 will be reported. 
Subject Disposition: Study Treatment Discontinuation or Study Discontinuation 
Subjects who experience either study treatment discontinuation or study discontinuation due 
to COVID-19 will have the reason captured in the eCRF. On the appropriate eCRF form to 
record either study medication discontinuation (“End of Treatment” form) or study 


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discontinuation (“Conclusion of Subject Participation” form), a reason will be selected which 
includes a field for descriptive text. The reason can be either “Withdrawal by Subject,” 
“Physician Decision,” or “Other”. The associated free text field entry will include 
“COVID-19”. When either treatment or the study is discontinued due to an AE or death, the 
specific corresponding AE is collected. Discontinuations due to COVID-19 related AEs will 
then be identified based on whether the medical dictionary for regulatory activities 
(MedDRA) code for the AE is included in standardised MedDRA Query (SMQ): COVID-19 
(SMQ (broad)). 
Cases of study treatment discontinuation or study discontinuation due to COVID-19 will be 
included in the summary of subject disposition. 
Concomitant Medications 
For concomitant medications which are linked to specific AEs, the eCRF collects information 
to identify the specific AE. As described in the Adverse Events section, relevant AEs will be 
identified by standardised MedDRA Query (SMQ): COVID-19 (SMQ (broad)). Concomitant 
medications used to treat COVID-19 associated AEs will be summarized. 
Concomitant medications used to treat COVID-19 associated AEs will be flagged in the 
by-subject listing of prior and concomitant medications. 
Adverse Events 
AEs associated with COVID-19, which can include a clinically significant laboratory finding, 
will be reported by investigators following reporting requirements outlined in the CSP. 
COVID-19 associated AE are identified via MedDRA coding. Relevant AEs will be identified 
for reporting by standardised MedDRA Query (SMQ): COVID-19 (SMQ (broad)). All 
COVID-19 associated AEs will be included in standard AE tables. 
An overview summary table of COVID-19 associated TEAEs, including number and 
percentages of subjects as well as the number of events, will be provided for the following: 
• Any TEAE (related/not related); 
• Serious TEAE (related/not related); 
• TEAE resulting in death (related/not related); 
• TEAE leading to discontinuation of study treatment (related/not related); 
• TEAE leading to dose interruptions (related/not related); 


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• TEAE leading to study withdrawal (related/not related); 
• TEAE by maximum severity (mild, moderate, severe, missing). 
A by-subject listing showing all COVID-19 associated AEs will be provided. 
Visit Modality, Missed Visits and Missing Assessments 
Changes to subjects’ visits caused by the COVID-19 pandemic will be captured for each 
subject in the eCRF, on the “Visit Status” form. The eCRF page includes different options for 
the primary visit modality, as well as whether the missed visit/alternate visit modality is due 
to COVID-19. Changes to visit modality may be a protocol deviation, or could be permitted 
via a contingency amendment; in either case, this data is captured. Since assessments (eg, 
vital signs, laboratory data) collected at each visit are known, the data missing due to 
COVID-19 can be determined. 
Assessments that were missed or required alternate visit modality (eg, televisits or home 
health visits) due to COVID-19 will be summarized. In addition, the number of subjects with 
missed visits or alternate visit modality, by visit, will be summarized. Data will be listed. 
Protocol Deviations 
Protocol deviations due to the COVID-19 pandemic will be collected in the Clinical Trial 
Management System (CTMS) per the study specific Protocol Deviation plan. 
When a protocol deviation within the CSL CTMS, such as when a subject is outside of the 
visit window due to COVID-19 restriction, is detected, the protocol deviation captured would 
be with reason of ‘due to COVID-19 restrictions. 
COVID-19-related protocol deviations will be summarized as sub-categories under existing 
categories of protocol deviations (refer to Section 9.2). All COVID-19 related protocol 
deviations will appear in the by-subject listing of protocol deviations and will be flagged. 
COVID-19 Vaccinations 
COVID-19 vaccinations are not allowed in this study as 1 of the exclusion criteria. In case it 
does occur, it is a protocol deviation. Sites will be prompted to inquire whether a subject has 
received a COVID-19 vaccination and to record each dose of the vaccine on the concomitant 
medications form along with the exact date of administration and manufacturer of the 
vaccine. Customized drug grouping (CDG) from World Health Organization (WHO) Drug 


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Dictionary will be utilized to identify COVID-19 vaccines. Any vaccination related AEs 
experienced by study participants will be recorded on the AE/SAE eCRF page. As a 
mechanism to assess potential TEAEs associated with the COVID-19 vaccines, those TEAEs 
occurring within 7 days after COVID-19 vaccine administration will be listed. 
The following by-subject listings will be provided: 
• Listing of all subjects receiving COVID-19 vaccine during the study (included in 
protocol deviation listing and respectively flagged). 
Overview of COVID-19 Impact 
Number and percentages of subjects with ≥ 1of the following due to COVID-19 will be 
summarized in an overview table: 
• Subjects with Any COVID-19 Impact 
• Protocol Deviations; 
• Missing assessment; 
• Missing Visit; 
• Alternate Visit Modality; 
• Study Treatment Discontinuation; 
• Study Discontinuation; 
• Any AEs/TEAEs; 
• Any Serious AEs/TEAEs. 
8 
Data Handling Conventions 
8.1 
Missing Data 
Missing data occurs when any requested data are not provided, leading to blank fields on the 
collection instrument. These data will be indicated by the use of a “blank” in by-subject 
listing displays. Answers such as “Not applicable” and “Not evaluable” are not considered to 
be missing data and should be displayed as such. 
Because of the design and duration of the study, missing data are inevitable. The details of 
handling missing data are presented in the corresponding sections of this SAP for respective 
analyses (eg, primary and secondary endpoints, safety analyses). 


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8.2 
General Derived Variables 
8.2.1 
Reference Dates and Study Days 
Reference dates are used to assign study periods relative to treatment (Section 8.4). 
• The safety reference date is the treatment start date, and will be used to calculate 
study day for safety measures. 
The respective study day will be calculated as (date of interest - reference date) + 1 if the date 
of interest occurs on or after the reference date. If the date of interest occurs before the 
reference date, then the study day will be calculated as (date of interest – reference date). 
There will be no study day zero. 
8.2.2 
Durations 
Durations (eg, the duration of an AE) are calculated in days as: 
• Event end date – event start date + 1, if end time or start time not available; 
• Event end date / time – event start date / time, if both end time and start time 
available. 
Thus, there will be no duration of 0 if end time or start time are not available. If an AE has 
missing or partially missing start or end date, no duration will be calculated. 
To transform durations or elapsed times, which are calculated in days into weeks, divide the 
number of days by 7; to report in months, divide the number of days by 30.4375; to report in 
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 (the calendar days) between start 
date and stop date. The "year" used in these algorithms is 365.25 days long, and the "month" 
is one-twelfth of that year. 
8.2.3 
Baseline Definition 
Baseline is defined as the most recent, non missing value before the first IP administration 
(including unscheduled visits) for all assessments unless otherwise stated. 
 
 


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8.2.4 
Change from Baseline 
Change from baseline is calculated as: 
• Visit value – baseline value. 
Percentage change from baseline is calculated as: 
• (Change from baseline / baseline value) * 100. 
The percent of baseline is calculated as: 
• (Visit value / baseline value) * 100. 
If either the baseline or visit value is missing, the change and percent change from baseline is 
missing. 
8.2.5 
Multiple Assessments 
All data will be reported according to the nominal visit date for which they were reported 
(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 protocol). Unscheduled data will not be included in by-visit summaries, but 
will appear chronologically in by-subject listing. Data from all assessments (scheduled and 
unscheduled), including multiple assessments, will be included in by-subject listing. 
8.2.6 
Actual Treatment 
The subjects’ actual treatment will be derived from exposure data. If a subject receives a 
study treatment that is different from the planned treatment for the entire time of treatment, 
then actual treatment is the treatment actually received. In the event that a subject receives 
both CSL312 and placebo, the subject will be included in the CSL312 group for this analysis 
set. Subjects receiving only placebo will be included in the placebo group. 
8.3 
Stratification 
The study design does not include any stratification factors. There are no formal plans for 
investigating any covariates. 
 
 


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8.4 
Study Periods Relative to Treatment 
All data will be assigned to 1 of the 3 study time periods defined below. 
• Pre treatment is defined as the time before the subject’s first date / time of IP 
(Day 1). 
• On-treatment (Treatment and Observation Period) is defined as the time from first 
date / time of IP up to Week 14 (Day 1 to Day 92). 
• Post treatment begins after the end of the Treatment and Observation Period 
(Day 92) and continues through the Follow-up visit (follow-up telephone call) 
(Day 154). 
9 
Study Population 
Unless otherwise stated, all tables and listings in this section will be based on the Safety 
Analysis Set. 
9.1 
Subject Disposition 
The following summaries will be provided for the Screened Analysis Set by CSL312 group, 
placebo group, and total population for: 
• Subjects who underwent Screening – only total; 
• Subjects who are re screened – only total; 
• Screening failures with reason for failure – only total; 
• Subjects eligible for randomization – only total; 
• Subjects randomized – by treatment and total; 
• Subjects randomized but not treated – by treatment and total; 
• Subjects treated – by treatment and total; 
• Subjects treated who completed treatment through Day 64 – by treatment and total; 
• Subjects treated who completed the Treatment and Observation Period (Day 92) – by 
treatment and total; 
• Subjects treated who discontinued from the study before end of treatment (Day 64) 
with reason (including discontinuation due to COVID-19) – by treatment and total; 


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• Subjects treated who discontinued from the study before end of Treatment and 
Observation Period (Day 92) with reason (including discontinuation due to COVID-
19) – by treatment and total; 
• Subjects treated who completed the study through the Follow-up Visit – by treatment 
and total; 
• Subjects treated who discontinued from the study before the Follow-up Visit with 
reason (including discontinuation due to COVID-19) – by treatment and total; 
• Subjects in each of the analysis sets described in Section 6. 
Reasons for study withdrawal and study treatment discontinuation will be presented in the 
order they are displayed in the eCRF. 
By-subject listing will be provided for disposition status for each subject. This will include: 
• Randomization scheme based on the randomized treatment; 
• Subjects treatment used in safety analysis; 
• Subject disposition with date of screening (in case of re-screening, all screening 
records will be listed), date (and time) of randomization, date (and time) of first IP 
administration, date of completion of / or withdrawal from the Treatment and 
Observation Period, and date of study completion or withdrawal from the study; 
• Screening failures with the reason; 
• Subjects who discontinued from study treatment with the reason for discontinuation 
and subjects who discontinued from the study with the reason for discontinuation; 
• Subject assignment to analysis sets and reasons for exclusion. 
9.2 
Protocol Deviations 
A protocol deviation occurs when an investigator site, or study subject, does not adhere to 
protocol-specified requirements. Deviations will be assessed by CSL Behring as they are 
reported and then evaluated periodically during study conduct, based on the protocol 
deviation plan for this study developed by CSL Behring. 
Deviations will be categorized as either major or minor. Major protocol deviations for 
subjects in the Safety Analysis Set will be summarized for number and percentage of subjects 
with each protocol deviation, though all major and minor deviations will be listed. The 
summary will be given by treatment group and overall. 


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The final decision regarding protocol deviations and assignment of subjects to analysis 
population will be made during the blinded data review meeting. 
A by-subject listings will be provided based on the Safety Analysis Set covering the 
following information: 
• All protocol deviations (including inclusion and exclusion criteria violations). 
9.3 
Demographic and Baseline Characteristics 
Descriptive statistics as specified in Section 7 will be provided for continuous variables, 
number and percentage of subjects for categorical variables. 
The following summaries will be provided for the Safety Analysis Set by treatment group and 
overall: 
• Demographic characteristics (eg, age, race, ethnicity, sex, smoking history, baseline 
height, and baseline body weight, and body mass index (BMI)). In addition to 
summarization as a continuous variable, age will also be categorized and summarized 
by ≥ 40 to ≤ 64 years, ≥ 65 to ≤ 74 years, ≥ 75 to ≤ 84 years and ≥ 85 years; 
• Disease characteristics including the duration since IPF diagnosis and previous 
treatment with nintedanib or pirfenidone, baseline FXIIa-mediated kallikrein activity, 
baseline absolute and percent predicted in FVC; 
• Medical history (coded using MedDRA – the MedDRA version will be populated in 
the outputs) will be presented by SOC and preferred term. 
Corresponding by-subject listings will be provided. The by-subject listing for disease 
characteristics will include but is not limited to the year of diagnosis as well as the duration 
of IPF. The medical history by-subject listing will also provide an indicator of whether the 
condition was active at the time of entry into the screening period. 
Nonpharmacological procedures will only be presented in a by-subject listing. 
9.4 
Prior/Concomitant Medications 
Prior/concomitant medications will be coded using World Health Organization Drug 
Dictionary Enhanced (WHO-DDE) B3. The version will be populated in the outputs. 
The reported medication will be classified as ‘Prior only’, ‘Prior and concomitant’ or 
‘Concomitant only’. These 3 categories are mutually exclusive: 


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• ‘Prior only’: if the subject has not taken any IP; or if the medication end date (/time) 
is before IP start date (/time). If the medication end date is partially missing, the 
medication will only be assigned to ‘Prior only’ if the partial date gives clear evidence 
that the medication stopped before IP start date (eg, a partial medication stop date of 
– – Mar 2022 is clearly before an IP start date of 03 Apr 2022). 
• ‘Concomitant only’: if the medication start date (/time) is on or after IP start date 
(/time). If the medication start date is partially missing, the medication will only be 
assigned to ‘Concomitant only’ if the partial date gives clear evidence that the 
medication started on or after IP start date. 
• ‘Prior and concomitant’: all medications which are not assigned as ‘Prior only’ nor 
‘Concomitant only’. 
Concomitant medications (ie, medication classified as ‘Prior only’, ‘Concomitant only’ or 
‘Prior and concomitant’) will be summarized showing the number and percentage of subjects 
taking concomitant medications by ATC classification level 4 and preferred term. If the ATC 
level 4 coding is not available for a preferred term, the next available lower level ATC code 
will be used. Tables will be provided for the Safety Analysis Set by treatment group and 
overall. 
The following by-subject listing will be provided: 
• Prior and concomitant medication. 
9.5 
Study Population - Derived Variables 
Derivation of Body Mass Index (BMI) 
BMI data will be used from eCRF as collected. In case of missing BMI, BMI will be 
calculated using the following formula: 
BMI (kg/m2) = Weight (kg) / [Height (m)]2, 
using the height measured at Screening and the weight measured at Day 1 (if available). If 
weight at Day 1 is not available, the assessment at Screening will be used (if available). If 
neither is available, then BMI is missing. 
10 
 Efficacy Analyses 
There are no primary or secondary efficacy endpoints in this study. The analysis of FVC as 
exploratory efficacy endpoint is described in Section 13.2.1. 


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10.1 
Treatment Compliance 
The calculation of overall compliance is based on receiving the IV loading dose and all 3 SC 
injections of IP. An infusion or injection of at least 80% of the planned volume will satisfy 
the criteria of receiving a compliant infusion or injection at each of the 4 visits. The following 
summaries will be provided by treatment group for the Safety Analysis Set: 
• The number of subjects receiving all 4 doses of IP; 
• The number of subjects receiving at least 80% of the planned infusion/injection 
volume at each visit. 
A by-subject listing will be provided including: 
• By infusion/injection: the randomized and actual treatment administered, planned and 
actual volume of IP, individual and categorized compliance; 
• Overall (across all IP doses): cumulative planned and cumulative actual volume of IP, 
individual and categorized compliance, number of doses of IP. 
Calculation of compliance and extent of exposure (as described in Section 11.1) will be based 
on drug accountability data collected by eCRF. 
11 
Safety Analyses 
The safety analyses will be based on the Safety Analysis Set as defined in Section 6 and on 
the treatment which the subject received. 
11.1 
Extent of Exposure 
Exposure to the IP will be descriptively summarized by treatment group: 
• Number of subjects receiving loading dose; 
• Summary statistics for loading dose received; 
• Summary statistics for Total dose received (mg) per visit and overall; 
• Summary statistics for Total volume received (ml) per visit and overall. 
The listing of individual subject data will include all variables presented in the summary 
tables. 


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11.2 
Adverse Events 
AEs will be coded using the MedDRA dictionary (the MedDRA version will be populated in 
the tables output). AEs will start to be collected upon the subject’s signing of the informed 
consent form (ICF). TEAEs, defined as AEs starting on or after the date (and time if 
available) of the first administration of IP (IV loading dose) through the end of the Treatment 
and Observation Period, will be summarized. The summary will be given by treatment group 
and overall. All AEs regardless of whether they were treatment-emergent or not will be listed. 
Where AE start dates and/or times are missing or partially missing, AEs will be assumed to 
be treatment-emergent, except if the partial start dates and/or times or the AE end date and/or 
time indicate that the AE started before the first administration of IP (Table 2). 
Table 2 
TEAE Assignment in Case of Missing AE Start Date Elements 
Missing elements 
of AE start 
Rule 
 
Regardless of any missing information for AE start: 
AE end date / time < IP start date / time 
non TEAE 
Otherwise (ie, if AE end date / time ≥ IP start date / time) 
 
- 
all 
 
TEAE 
- 
day and month AE start year ≥ IP start year 
TEAE 
AE start year < IP start year 
non TEAE 
- 
day 
AE start month / year ≥ IP start month / year 
TEAE 
AE start month / year < IP start month / year 
non TEAE 
- 
time 
AE start date ≥ IP start date 
TEAE 
AE start date < IP start date 
non TEAE 
 
If AE start dates or end dates are missing or partially missing for an AE, no duration will be 
calculated. A missing category will be shown in summary tables by severity in case the 
severity is missing (the same is applicable for relationship to study treatment). No 
imputations for missing AE information will be done. 
The AESIs defined for this study are: 
• Bleeding events - Standardised MedDRA Query “Haemorrhages (SMQ)” (narrow) 
• Thromboembolic events (TEE) - Standardized MedDRA Query ”Embolic and 
thrombotic events (SMQ)” (narrow) consisting of: 


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o Embolic and thrombotic events, arterial (SMQ); 
o Embolic and thrombotic events, venous (SMQ); 
o Embolic and thrombotic events, vessel type unspecified and mixed arterial and 
venous (SMQ). 
• Severe Hypersensitivity including anaphylaxis - Standardised MedDRA Query 
“Hypersensitivity (SMQ)” (broad), “Anaphylactic reaction (SMQ)” (broad), and 
“Anaphylactic/anaphylactoid shock conditions (SMQ)” (broad). Here, broad scope 
includes narrow and broad search. 
An overview summary of TEAEs, including number and percentages of subjects as well as 
the number of events will be provided including the following: 
• Any TEAE; 
• TEAEs related to study treatment; 
• TEAEs in each severity category; 
• TEAEs leading to discontinuation of study treatment (obtained from AE eCRF); 
• TEAEs leading to study withdrawal (obtained from “End of Treatment” or 
“Conclusion of Subject Participation” eCRF); 
• TEAEs leading to dose adjustments or dose interruptions; 
• Treatment-emergent AESIs; 
• Treatment-emergent AESIs related to study treatment; 
• Serious TEAEs; 
• Serious TEAEs related to study treatment; 
• Fatal TEAEs. 
COVID-19 associated TEAEs will be included in AE overview table as (as described in 
Section 7.1): 
• Any TEAE (related/not related); 
• Serious TEAE (related/not related); 
• Fatal TEAE (related/not related); 


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• TEAE leading to discontinuation of study treatment (obtained from AE eCRF) 
(related/not related); 
• TEAE leading to dose adjustments or dose interruptions (related/not related); 
• TEAE leading to study withdrawal (related/not related); 
• TEAE by maximum severity (mild, moderate, severe, missing). 
The following frequency tables will be generated for TEAEs, including number and 
percentages of subjects and the number of events: 
• TEAEs by SOC and preferred term; 
• TEAEs by preferred term; 
• TEAEs by SOC, preferred term, and maximum severity (without number of events); 
• Related TEAEs by SOC and preferred term; 
• Related TEAEs by preferred term; 
• Treatment-emergent AESIs by preferred term; 
• Serious TEAEs by SOC and preferred term; 
• Related serious TEAEs by SOC and preferred term; 
• TEAEs with result in drug discontinuation; 
• TEAEs related to COVID-19 infection. 
AEs will be presented in summaries by decreasing overall frequency (overall frequency as 
the number of subjects with that AE beginning with the SOC, followed by preferred term). If 
2 AEs have the same overall frequency, the AEs will be ordered alphabetically. 
The following by-subject listings will be provided: 
• All AEs; 
• SAEs; 
• AEs leading to study withdrawal or permanent discontinuation of study treatment; 
• AESIs by type of AESI; 
• Subjects receiving COVID-19 vaccine; 
• AEs occurring within 7 days after COVID-19 vaccine administration. 


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11.3 
Clinical Laboratory Evaluations 
The following hematology and serum biochemistry central laboratory tests will be 
summarized by visit and by treatment group. The summaries will be provided for the analysis 
population (Safety Analysis Set) as described in Section 11. Data for urinalysis will only be 
listed. 
Hematology: Hematocrit, hemoglobin, platelet count, reticulocytes, erythrocytes (red blood 
cell count [RBC]) count, RBC indices of mean corpuscular hemoglobin concentration 
(MCHC); mean corpuscular hemoglobin (MCH); mean corpuscular volume (MCV); red cell 
(erythrocyte) distribution width (RDW), leukocyte (white blood cell count [WBC]) counts, 
differential (absolute and percentage) of neutrophils; neutrophil band forms, lymphocytes, 
monocytes, eosinophils, and basophils. 
Serum Biochemistry: Sodium, potassium, chloride, bicarbonate, calcium, blood urea 
nitrogen (BUN), urea, creatinine, glucose, protein, albumin, alkaline phosphatase, alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), 
gamma-glutamyl-transferase (GGT), bilirubin (total), bilirubin (direct), magnesium, 
phosphate, high sensitivity-C reactive protein (hs-CRP), cholesterol, high-density Lipoprotein 
(HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides, urate (uric acid), 
creatine kinase / creatine phosphokinase (CK / CPK), activated partial thromboplastin time 
(aPTT), prothrombin time (PT) / international normalized ratio (PT / INR), pF1+2, fibrinogen 
(Clauss assay), D-dimer. 
Urinalysis: Specific gravity, pH, occult blood, leukocyte esterase, nitrite, erythrocytes, 
ketones, bilirubin, protein, urobilinogen, glucose. 
Standard safety laboratory data from central lab will be presented in international system of 
units (SI units) and in the order presented as above given. Measured laboratory values will be 
summarized descriptively by scheduled visit. Changes from baseline for laboratory parameter 
will be derived and presented in the same way as measured laboratory values. 
A laboratory value that is outside the reference range is either high abnormal (value above the 
upper limit of the normal [ULN] reference range) or low abnormal (value below the lower 
limit of the normal [LLN] reference range). An abnormal laboratory value is not necessarily 
of potential clinical interest. For each of the hematology and serum biochemistry lab tests, 
shift tables will be constructed to compare the individual subject baseline value with respect 
to the normal range to their Day 92 (or last observed value prior to Day 92 in case of 
dropouts or missing assessment at Day 92) value with respect to the normal range. 


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The denominator in percentage calculation at a scheduled visit will be based on the number 
of subjects with a non missing value at that particular visit. The definition of the baseline 
assessment is given in Section 8.2.3. 
A by-subject listing of all laboratory values including flag for values out of normal range will 
be provided. By-subject listing will include in general all visits (scheduled and unscheduled). 
Immunogenicity: 
The number and percentage of subjects with a positive immunogenicity test (presence of 
binding antibodies to CSL312) at any time and separate for Day 36 and Day 92 during 
treatment will be summarized by treatment group for the analysis population (Safety Analysis 
Set) as described in Section 11. 
A by-subject listing for immunogenicity will be provided. 
11.4 
Other Safety Measures 
11.4.1 
Vital Signs 
The vital signs will be summarized by visit and by treatment group. The summaries will be 
provided for the analysis population (Safety Analysis Set) as described in Section 11. 
The following summaries will be provided for systolic and diastolic blood pressure, heart 
rate, respiratory rate, body temperature, weight, and BMI: 
• Values of vital signs by scheduled visit, 
• Change from baseline by scheduled visit. 
The position of vital sign measurement and the location of body temperature measurement 
will be not included in the summaries, ie the summaries will be not provided by position or 
location. 
A by-subject listing of all vital sign data (scheduled and unscheduled visits) will also be 
presented. The by-subject listing will include a flag for values of potential clinical 
importance. 
11.4.2 
Electrocardiogram (ECG) 
The ECG parameter (PR interval, QRS duration, QT interval, QTcB, QTcF, and heart rate) 
and their changes from baseline will be summarized by visit and by treatment group. The 


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summaries will be provided for the analysis population (Safety Analysis Set) as described in 
Section 11. 
A by-subject listing of all ECG data (scheduled and unscheduled visits) will also be 
presented. The by-subject listing will include a flag for values of potential clinical 
importance. 
11.4.3 
Diffusing Capacity of the Lungs for Carbon Monoxide (DLCO) 
DLCO and its changes from baseline will be summarized by visit and by treatment group. 
The summary will be provided for the analysis population (Safety Analysis Set) as described 
in Section 11. 
A by-subject listing for DLCO data (scheduled and unscheduled visits) will also be presented. 
11.4.4 
Physical Examination 
Abnormalities of physical examination reported at screening will be recorded as medical 
history. Abnormalities of physical examination reported at other visit will be recorded as an 
AE. 
12 
Pharmacokinetic Analyses 
All noncompartmental analyses are to be performed using CSL312 plasma concentrations 
according to CSL SOP PK-GDL-01 and will be performed by ICON, under the direction of 
CSL Behring Clinical Pharmacology and Pharmacometrics, by using WinNonLin® version 
8.0 or later. 
The merge of PK concentration data and CRF data to generate SDTM domain PC with 
nominal blood sampling times, actual blood sampling time relative to dosing, actual dosing, 
and CSL312 plasma concentrations will be performed after DBL by Parexel. Parexel will 
produce the SDTM PC domain needed by ICON for PK parameter derivation. 
ICON, under the direction of CSL Behring Clinical Pharmacology and Pharmacometrics, will 
derive the individual PK parameters and will provide them to Parexel. From this, Parexel will 
produce the SDTM domain PP and will generate the analysis dataset. Any CSL312 plasma 
concentrations which have been excluded from the derivation of the PK parameters will be 
flagged by ICON in SDTM PC domain and provided to Parexel. 
All analyses in this section will be based on the PK Analysis Set. 


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12.1 
Drug Concentration Measures 
Handling of PK concentration data and imputation of below limit of quantification (BLQ) 
values for non compartmental analyses will be performed according to PK-GDL-01. The 
imputation rules below will be used for summary statistics of CSL312 plasma concentrations. 
The summaries will be given by nominal (planned) time point. 
• The sampling time of pre dose samples relative to start of the dose will be treated as 
zero; 
• Concentration values that are BLQ in pre dose samples and in samples taken before 
the time of the first quantifiable concentration will be treated as zero; 
• Post dose BLQ concentrations flanked by quantifiable concentrations will be set to 
missing; 
• If 2 or more BLQ concentrations occur in succession, the profile will be considered to 
have terminated at the quantifiable concentration prior to the 2 consecutive BLQs. All 
subsequent values will be treated as missing; 
• Post dose BLQ concentrations after the last quantifiable point will be set to missing 
for summary statistics of plasma concentrations; 
• The mean/median value at a time point where 1 or more samples have BLQ values 
will be reported (in tabular or graphical fashion) even if the mean/median value is 
BLQ of the assay; 
• Zero mean or median values will be included in summary tables. 
The lower limit of quantification for CSL312 in plasma is 100.0 ng/mL. Concentrations that 
are below BLQ should be reported as “< LLOQ” in by-subject listings. 
Summary statistics for CSL312 plasma concentration-time data will be presented as follows: 
number of observations (n), mean, SD, %CV (CV% = 100* standard deviation / mean), 
median, geometric mean, geometric %CV, minimum, and maximum. 
Geometric CV% = 100 * ඥexp(𝑆𝑆𝑆𝑆2) −1. 
In addition, summary statistics will also 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 at each 
time point). 


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It should be noted that a high proportion of BLQ values may affect the summary statistics; if 
more than 50% of the values are imputed (i.e. BLQ), then the summary statistics (mean, SD, 
median, quartiles) will not be displayed. 
Individual CSL312 plasma concentration-time profiles (on linear and log-linear scale) will be 
plotted using actual sampling time. 
Plots for mean (± SD) CSL312 plasma concentration-time profiles (on linear and log-linear 
scale) will be plotted using nominal (planned) time. 
A by-subject listing of CSL312 plasma concentrations with the concentrations flagged that 
have been excluded from the derivation of the PK parameters based on the PK Analysis Set 
will support the summaries. 
12.2 
Deriving and Summarizing Pharmacokinetic Parameters 
For subjects belonging to the PK Analysis Set, the PK parameters provided in Appendix 15.1 
will be determined, if applicable, from plasma concentration-time data for CSL312. 
The PK parameter derivation including imputation of the values 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. The PK parameters will be calculated by standard 
non-compartmental analysis using actual sampling times and actual doses. 
The following PK parameters will be summarized after SC administration of CSL312 at each 
SC dosing interval: 
Variable 
Statistical Parameters: 
Ctrough after first, second and 
third SC dose; 
Cmax after last SC dose; 
AUC0-tau after last SC 
dosing interval 
n, arithmetic mean, SD, CV%, minimum, median, 
maximum, geometric mean and geometric CV% 
Tmax after last SC dose 
n, minimum, median, and maximum 
 
The following PK parameters will be derived and summarized after the IV administration of 
CSL312: 


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Variable 
Statistical Parameters: 
Cmax 
Ctrough 
n, arithmetic mean, SD, CV%, minimum, median, 
maximum, geometric mean and geometric CV% 
Tmax 
n, minimum, median, and maximum 
 
All PK parameters will be reported to at least 3 significant digits, but to no more significant 
digits than the precision of the original data. 
A by-subject listing of CSL312 PK parameters based on the PK Analysis Set will be 
provided. 
13 
Pharmacodynamic and Biomarkers Analyses 
Unless otherwise specified, analyses in this section will be based on the PD Analysis Set. 
13.1 
Pharmacodynamic Analyses 
The absolute change from baseline in FXIIa-mediated kallikrein activity over time will be 
calculated for each subject. The comparison of primary interest is the change from baseline at 
Day 92 (Week 14). The change from baseline will be compared between CSL312 and placebo 
using a mixed-model repeated measure (MMRM) analysis, with treatment group and visit as 
fixed effects, and baseline as a covariate. Interactions with visit will be included for treatment 
group and baseline. The analysis will be implemented by using SAS PROC MIXED. A 
restricted maximum likelihood (REML) approach will be used. An unstructured variance-
covariance structure will be used to model the within-subject errors. This variance-covariance 
matrix will be estimated across treatment groups. If the model fails to converge, a 
heterogeneous Toeplitz structure (the TOEPH option in SAS PROC MIXED) will be used. 
The Kenward-Roger approximation will be used to estimate denominator degrees of freedom 
and adjust standard errors. Mean difference in least square means (LSMeans) between 
treatment groups and its 95% confidence interval will be provided at each time point, 
assuming that the data is normally distributed. If the data are not normally distributed by 
visual inspection of residual plots (QQ plots), an appropriate data transformation, log 
transformation, may be done. 
FXIIa-mediated kallikrein activity will be summarized by nominal time point with the 
following descriptive statistics: n, mean, SD, %CV, minimum, Q1, median, Q3, maximum, 
geometric mean, geometric %CV, and percent below the limit of quantification (% BLQ). 


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Individual observed FXIIa-mediated kallikrein activity-time profiles will be plotted using 
actual sampling times. Mean (± SD) observed FXIIa-mediated kallikrein activity-time 
profiles will be plotted by using nominal (planned) time points. 
The absolute change from baseline, percent change from baseline, and percent of baseline of 
FXIIa-mediated kallikrein activity over time will be summarized using descriptive statistics 
as done for the observed values of FXIIa-mediated kallikrein activity. The absolute change 
from baseline and percent of baseline of FXIIa-mediated kallikrein activity will also be 
presented graphically by treatment group as done for the observed FXIIa-mediated kallikrein 
activity. 
Other observed PD parameter of FXII concentration will be summarized by nominal time 
point by descriptive statistics (n, mean, SD, %CV, minimum, Q1, median, Q3, maximum, 
geometric mean, geometric %CV). The absolute and percent change from baseline for those 
PD parameters will also be summarized by nominal time point by descriptive statistics. For 
all PD parameters, including aPTT,  the absolute changes from baseline will be analyzed by 
the MMRM as described for FXIIa-mediated kallikrein activity. 
Individual observed PD parameter time profiles will be plotted using actual sampling times. 
Mean (± SD) observed PD parameter time profiles will be plotted by using nominal (planned) 
time points. 
A by-subject listing of PD parameters including observed values, absolute and percent change 
from baseline will be provided. 
13.2 
Biomarker Analyses 
For biomarkers the observed values, the absolute and percent change from baseline will be 
summarized by nominal time point by descriptive statistics (n, mean, SD, %CV, minimum, 
Q1, median, Q3, maximum, geometric mean, geometric %CV). The MMRM as described for 
FXIIa-mediated kallikrein activity is also applicable for all biomarkers and aPTT (absolute 
change from baseline for each). 
Individual observed biomarker time profiles will be plotted using actual sampling times. 
Mean (± SD) observed biomarker time profiles will be plotted by using nominal (planned) 
time points. 
Biomarker: C-C motif chemokine ligand 18 (CCL-18), plasminogen activator inhibitor 1 
(PAI-1), surfactant protein A (SP-A), surfactant protein D (SP-D), YKL-40, released N 


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terminal pro-peptide of type III collagen (PROC3), C terminal of released C5 domain of type 
VI collagen (PROC6), neo-epitope of MMP-9 mediated degradation of type III collagen 
(C3M), neo-epitope of MMP-2 mediated degradation of type VI collagen (C6M). 
A by-subject listing of biomarkers including observed values, absolute and percent change 
from baseline will be provided. 
Additional exploratory biomarker analyses, if deemed necessary, will be reported in a 
separate report. 
13.2.1 
Pulmonary Function Data Analyses 
The Safety Analysis Set will be used for this analysis. 
The absolute change from baseline in FVC and percent predicted FVC over time will be 
analyzed using the same MMRM as for FXIIa-mediated kallikrein activity, with treatment 
group, and visit as fixed effects, and baseline as a covariate. Interactions with visit will be 
included for treatment group and baseline. Mean difference in LSMeans between treatment 
groups and its 95% confidence interval will be provided at each time point, assuming that the 
data is normally distributed. If the data are not normally distributed by visual inspection of 
residual plots or statistical testing, an appropriate data transformation may be done. There is 
no imputation of missing FVC data planned. 
For FVC and percent predicted FVC the observed values and absolute change from baseline 
will be summarized by nominal time point by descriptive statistics (n, mean, SD, minimum, 
Q1, median, Q3, maximum). The descriptive summary for both parameter will be provided 
for Safety Analysis Set and PD Analysis Set. 
Mean (± SD) time profiles for observed values and absolute change from baseline for FVC 
and percent predicted FVC will be plotted by using nominal (planned) time points. 
The number and proportion of subjects with ≥ 5% or ≥ 10% absolute (absolute change from 
baseline) or relative (percent change from baseline) decline in FVC percent predicted at Day 
92 will be presented. 
The absolute change from baseline in FVC at Day 92 versus the absolute change from 
baseline in FXIIa-mediated kallikrein activity at Day 92 will be graphically displayed by a 
scatter plot. The Pearson correlation coefficient and Spearman correlation coefficient by 
treatment group will displayed. Those scatter plots of absolute change in FVC at Day 92 
versus the absolute change at Day 92 will be repeated for all PD parameter (FXII 


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concentration and aPTT) and biomarkers (CCL-18, PAI-1, SP-A, SP-D, YKL-40, PROC3, 
PROC6, C3M, C6M). 
A second series of those scatter plots will be provided by using the percent change from 
baseline in FVC at Day 92 versus the percent change from baseline in PD parameter (FXIIa-
mediated kallikrein activity, FXII concentration, aPTT) and biomarkers (CCL-18, PAI-1, SP-
A, SP-D, YKL-40, PROC3, PROC6, C3M, C6M) at Day 92. 
A third series of those scatter plots will be provided by using the absolute change in FVC 
percent predicted at Day 92 versus the absolute change from baseline in PD parameter 
(FXIIa-mediated kallikrein activity, FXII concentration, aPTT) and biomarkers (CCL-18, 
PAI-1, SP-A, SP-D, YKL-40, PROC3, PROC6, C3M, C6M) at Day 92. 
A by-subject listing of FVC and percent predicted FVC including observed values, absolute 
and percent change from baseline will be provided. 
14 
References 
(1) PK-GDL-01, Guideline on the Conduct of Noncompartmental Pharmacokinetic Analyses, 
CSL Behring. 
 
 


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15 
Appendices 
15.1 
Pharmacokinetic Parameters 
Term 
Definition [unit] 
Calculation method 
AUC0-tau 
AUC during a dosing interval (tau) 
[mass * time * volume-1] 
Partial AUC from dosing time to 
dosing time plus Tau, using the 
linear up/log down rule 
Cmax 
Maximum observed in plasma [mass * 
volume-1] 
 
Ctrough 
Observed concentration at the end of a 
dosing interval, immediately before the 
next dose administration [mass * 
volume-1] 
 
Tmax 
Time to reach maximum (peak) drug 
concentration in plasma [time] 
 
 


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