A Multicenter, Randomized, Open-label, Crossover, Phase 2 Study to Evaluate the Safety and Pharmacokinetics of IgPro20 (Subcutaneous Immunoglobulin, Hizentra®) and IgPro10 (Intravenous Immunoglobulin, Privigen®) in Adults With Systemic Sclerosis (SSc)
Phase: PHASE2
Conditions: Diffuse Cutaneous Systemic Sclerosis
Sponsor: CSL Behring

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 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.  
 
CLINICAL STUDY PROTOCOL 
 
A Multicenter, Randomized, Open-label, Crossover, Phase 2 Study to Evaluate the 
Safety and Pharmacokinetics of IgPro20 (subcutaneous immunoglobulin, Hizentra®) 
and IgPro10 (intravenous immunoglobulin, Privigen®) in Adults with Systemic 
Sclerosis (SSc) 
Study Number: 
IgPro20_2001 
Study Product: 
IgPro20 (subcutaneous immunoglobulin, Hizentra®) 
IgPro10 (intravenous immunoglobulin, Privigen®) 
Development Phase: 
Phase 2 
Sponsor: 
CSL Behring GmbH  
Emil-von-Behring-Strasse 76 
35041 Marburg 
Germany 
Protocol Version: 
Amendment 4 
EudraCT Number: 
2018-003149-41 
IND Number: 
Not applicable 
Protocol Date: 
22 February 2021 
Compliance: 
This study will be conducted in accordance with standards of 
Good Clinical Practice (as defined by the International Council 
for Harmonisation), ethical principles that have their origin in 
the Declaration of Helsinki, and all applicable national and 
local regulations.  

CSL Behring 
Study Number: 
IgPro20_2001 
 
Study Product: 
IgPro20  
 
Protocol version: Amendment 4 
 
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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: 
IgPro20_2001 
 
Study Product: 
IgPro20  
 
Protocol version: Amendment 4 
 
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Date 
Version  
Summary of Changes 
21 October 2020 
Amendment 3 
• Revision of exclusion criterion 17 
• Define adjustments that are effective 
during the COVID-19 pandemic and 
provided detailed guidance and procedures 
that allow investigators the flexibility to 
complete critical protocol safety and 
efficacy assessments while limiting 
subject exposure to COVID-19 at study 
sites 
• 
Minor corrections and clarifications 
 
22 February 2021 
Amendment 4 
• Added guidance in Section 5.2.3 regarding 
dispensing investigational product to 
subjects during a state of emergency or 
public health crisis 
• Added an option for remote visits during a 
state of emergency or public health crisis 
in Section 8.6.10 
• Revised contingencies in Appendix #4  
that are effective during a state of 
emergency or a public health crisis  

CSL Behring 
Study Number: 
IgPro20_2001 
 
Study Product: 
IgPro20  
 
Protocol version: Amendment 4 
 
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Clinical Study Protocol Synopsis 
Title 
A Multicenter, Randomized, Open-label, Crossover, Phase 2 
Study to Evaluate the Safety and Pharmacokinetics of IgPro20 
(subcutaneous immunoglobulin, Hizentra®) and IgPro10 
(intravenous immunoglobulin, Privigen®) in Adults with Systemic 
Sclerosis (SSc) 
Study Number 
IgPro20_2001  
Sponsor 
CSL Behring (CSLB) 
Phase 
Phase 2  
Study Product 
IgPro20 (Hizentra) 
IgPro10 (Privigen) 
Indication 
Systemic Sclerosis (SSc) 
Study Summary and 
Overview 
This is a prospective, multicenter, randomized, open-label, 
crossover study to investigate the safety, tolerability, relative 
bioavailability and pharmacokinetics (PK) of weekly 
subcutaneous (SC) administration of IgPro20 and intravenous 
(IV) administration of Ig Pro10 every 4 weeks (over 2 to 5 
consecutive days) in subjects with diffuse cutaneous SSc (dcSSc) 
over 16 week treatment periods.  
Primary Objectives 
The primary objective of the study is to evaluate the safety of 
IgPro20 in adults with dcSSc. 
Primary Endpoints 
The primary endpoint is the safety of IgPro20 based on adverse 
events (AEs) and the change in other clinical tests measured by 
treatment, treatment sequence, combination of treatment, at the 
end of each treatment period (Period 1, Week 16; Period 2, Week 
32; combination of treatment, Week 32): 
• Number and percentage of subjects with AEs, treatment-
emergent AEs, serious AEs, and AEs of special interest (total, 
severity, causality, and outcome) 
• Number and percentage of subjects with AEs categorized as 
infusion site reactions (ISRs) (total, severity, causality and 
outcome) 
• Rate of ISRs per subject and per infusion 
• Onset and duration of ISRs 
• Changes from baseline in vital signs and body weight, clinical 
laboratory tests, electrocardiogram (ECG), and pulmonary 
function tests (PFTs) 

CSL Behring 
Study Number: 
IgPro20_2001 
 
Study Product: 
IgPro20  
 
Protocol version: Amendment 4 
 
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Secondary Objectives 
The secondary objectives of the study are to evaluate: 
• Relative bioavailability of IgPro20 
• PK of IgPro20  
• PK of IgPro10  
• Safety of IgPro10 
Secondary Endpoints 
The secondary endpoints to be determined at the end of each 
treatment period (Period 1, Week 16; Period 2, Week 32; 
combination of treatment, Week 32) are: 
• IgPro20 relative bioavailability (%F) 
• IgPro20 PK parameters (area under the curve [AUC]0-tau, 
AUC0-last, maximum [peak] plasma drug concentration [Cmax], 
minimum plasma drug concentration [Ctrough]) 
• IgPro10 PK parameters (AUC0-tau, AUC0-last, Cmax, Ctrough) 
• The safety of IgPro10 based on: 
o AEs 
o Change in other clinical tests 
Study Design 
Multicenter, randomized, open-label, crossover, phase 2 study 
Number of Subjects 
Approximately 26 eligible subjects will be enrolled and 
randomized to expect 20 evaluable subjects (10 subjects per 
treatment sequence) to complete the study. 
Study Duration 
Up to 40 weeks for each subject, including a Screening Period of 
up to 4 weeks, a Treatment Period of 32 weeks (16 weeks each for 
Treatment Period 1 and Treatment Period 2) and a follow-up 
telephone call at 4 weeks after end of treatment  
The overall duration of this study (eg, first subject’s Screening Visit 
to last subject’s End of Study [EOS] telephone call) will be 
approximately 24 months. 
Study Population and 
Main Criteria for 
Eligibility 
Key inclusion criteria 
To be enrolled into the study, subjects must meet all of the 
following inclusion criteria: 
• Age ≥ 18 years (male or female) at time of providing written 
informed consent 
• Documented diagnosis of systemic sclerosis (scleroderma) 
according to American College of Rheumatology and European 
League Against Rheumatism criteria 2013 (diffuse cutaneous 
form of SSc)  
• 
 
• Disease duration ≤ 5 years defined as the time from the first non-
Raynaud’s phenomenon manifestation 
CCI

CSL Behring 
Study Number: 
IgPro20_2001 
 
Study Product: 
IgPro20  
 
Protocol version: Amendment 4 
 
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Statistical Analyses 
The sample size is mainly based on feasibility, not driven by power 
calculations for statistical hypothesis testing. With the target 
sample size of 20 subjects (10 patients per sequence) and each 
subject receiving 28 IgPro20 SC infusions, there are a total of 560 
planned IgPro20 infusions overall for the entire study. If the rate of 
ISRs per infusion is 0.1, the study will have 80% chance to have a 
95% confidence interval with half width ≤ 0.0261 using Wilson 
score method; if the rate is 0.5, the half width of the 95% 
confidence interval will be ≤ 0.0414. 

CSL Behring 
Study Number: 
IgPro20_2001 
 
Study Product: 
IgPro20  
 
Protocol version: Amendment 4 
 
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Notes to the schedule of assessments: 
A: Sequence A, Treatment Period 1 (IgPro20): Weeks 2, 4, 6, 8, 10, 12, 14, and 15 are home visits. Infusions and additional procedures, as applicable, are to be 
completed at home by a nurse at these visits. 
B: A visit window of ± 2 days relative to Randomization is applicable to all treatment visits. 
C: At unscheduled visits, any procedure may be performed at the discretion of the investigator.  
D: All assessments should be done before randomization with the exception of the infusion and completion of the infusion form. Vital signs should be assessed 
before and after infusion. 
E: A full physical exam will be conducted at Screening and Week 1. An abbreviated physical exam will be performed at all other applicable visits. 
F: At the Week 1 Visit, only 
 is to be assessed.  
G: See Table 1 for specific laboratory tests.  
H: Hemolysis safety assessments; refer to Section 8.1.1.2 for detailed description. 
I: 
TEE safety assessments; refer to Section 8.1.1.3 for detailed description. 
J: Renal function assessments (blood chemistry parameters and urine sample). Refer to Section 8.1.1.4. 
K: Serum for retention and analysis of biomarkers and whole blood for RNA and DNA to be collected. Blood for DNA collected only at Screening. Blood for 
autoantibodies not collected Week 5. 
L: Refer to Pharmacokinetic Schedule of Assessments: Sequence A for full PK sample collection schedules. 
M: At the Week 1 Visit, the patient diary will only be dispensed, not reviewed. 
N: The first IgPro20 infusion of the week at Weeks 1, 3, 5, 7, 9, 11 and 13 will be administered at the study site. The second infusion may be administered at 
home by a nurse. Additional procedures to be completed at these visits: Vital sign assessment as per Table 2, Infusion form completion, Patient diary 
completion, and AE and concomitant medication documentation. 
O: IgPro20 infusion at UNS visit only if applicable per dosing schedule. IgPro20 assignment at UNS visit only if weight change requires dose volume 
adjustment; changes of > 10% of body weight from baseline / reference visit will require a dose adjustment. 
P: Patient diary is to be completed (at the study site or home at any time between infusion and next study visit. IgPro20 infusion form to be completed by study 
personnel or nurse only, immediately after infusion. 
Q: Adverse events and concomitant therapy will not be recorded at site or home visits if PK sample collection is the only scheduled activity.  
 
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CSL Behring 
Study Number: 
IgPro20_2001 
 
Study Product: 
IgPro20  
 
Protocol version: Amendment 4 
 
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L: Serum for retention and analysis of biomarkers and whole blood for RNA and DNA to be collected. Blood for DNA collected only at Screening. Blood for 
autoantibodies not collected Week 5. 
M: Refer to Pharmacokinetic Schedule of Assessments: Sequence B for full PK sample collection schedules. 
N: IgPro10 will be administered at the study site over 2 to 5 consecutive days. IgPro10 assignment at UNS visit only if weight change requires dose volume 
adjustment; changes of > 10% of body weight from baseline / reference visit will require a dose adjustment. IgPro10 infusion at UNS visit only if applicable 
per dosing schedule. 
O: Adverse events and concomitant therapy will not be recorded at site or home visits if PK sample collection is the only scheduled activity. 
 
 

CSL Behring 
Study Number: 
IgPro20_2001 
 
Study Product: 
IgPro20  
 
Protocol version: Amendment 4 
 
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M: At the Week 1 Visit, the patient diary will only be dispensed, not reviewed. 
N: The first IgPro20 infusion of the week at Weeks 17, 19, 21, 23, 25, 29, and 31 will be administered at the study site. The second infusion may be 
administered at home by a nurse. Additional procedures to be completed at these visits: Vital sign assessment as per Table 2, Infusion form completion, 
Patient diary completion, and AE and concomitant medication documentation. 
O: IgPro20 infusion at UNS visit only if applicable per dosing schedule. IgPro20 assignment at UNS visits only if weight change requires dose volume 
adjustment; changes of > 10% of body weight from baseline / reference visit will require a dose adjustment. 
P: Patient diary is to be completed (at the study site or home) at any time between infusion and next study visit. IgPro20 infusion form to be completed by study 
personnel or nurse only, immediately after infusion. 
Q: Adverse events and concomitant therapy will not be recorded at site or home visits if PK sample collection is the only scheduled activity. 
 
 
 
 

CSL Behring 
Study Number: 
IgPro20_2001 
 
Study Product: 
IgPro20 (Hizentra®) 
 
Protocol version: Amendment 4 
 
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Table of Contents 
Clinical Study Protocol Synopsis .............................................................................................. 5 
Schedule of Assessments: Sequence A, Treatment Period 1 (IgPro20) ................................... 10 
Schedule of Assessments: Sequence A, Treatment Period 2 (IgPro10) ................................... 13 
Schedule of Assessments: Sequence B, Treatment Period 1 (IgPro10) ................................... 15 
Schedule of Assessments: Sequence B, Treatment Period 2 (IgPro20) ................................... 18 
Pharmacokinetic Schedule of Assessments: Sequence A ........................................................ 21 
Pharmacokinetic Schedule of Assessments: Sequence B ........................................................ 22 
Table of Contents ..................................................................................................................... 23 
List of Tables............................................................................................................................ 30 
List of Figures .......................................................................................................................... 30 
List of Abbreviations ............................................................................................................... 31 
1 
Introduction .......................................................................................................... 36 
1.1 
Background ...................................................................................................... 36 
1.2 
Information on Study Products ........................................................................ 38 
1.2.1 
Overview ...................................................................................................... 38 
1.2.2 
Nonclinical Evaluation ................................................................................. 39 
1.2.3 
Clinical Experience ...................................................................................... 39 
1.3 
Study Overview ................................................................................................ 40 
1.4 
Potential Risks and Benefits ............................................................................. 40 
1.4.1 
Potential Risks .............................................................................................. 40 
1.4.1.1 
IgPro20 Risks ........................................................................................... 40 
1.4.1.2 
IgPro10 Risks ........................................................................................... 41 
1.4.1.3 
Crono S-PID-100 Infusion Pump Risks ................................................... 42 
1.4.2 
Potential Benefits ......................................................................................... 42 
1.4.2.1 
IgPro20 Benefits ....................................................................................... 42 
1.4.2.2 
IgPro10 Benefits ....................................................................................... 42 
1.4.3 
Benefit-risk Conclusion ................................................................................ 43 
2 
Study Objectives and Endpoints ........................................................................... 43 
2.1 
Primary Objective and Endpoints .................................................................... 43 
2.1.1 
Primary Objective ......................................................................................... 43 
2.1.2 
Primary Endpoints ........................................................................................ 43 

CSL Behring 
Study Number: 
IgPro20_2001 
 
Study Product: 
IgPro20 (Hizentra®) 
 
Protocol version: Amendment 4 
 
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2.2 
Secondary Objectives and Endpoints ............................................................... 44 
2.2.1 
Secondary Objectives ................................................................................... 44 
2.2.2 
Secondary Endpoints .................................................................................... 44 
2.3 
 
2.3.1 
 
2.3.2 
 
2.4 
 
3 
Study Overview .................................................................................................... 47 
3.1 
Study Design and Rationale ............................................................................. 47 
3.2 
Dose and Dosing Regimen ............................................................................... 48 
3.2.1 
IgPro20 ......................................................................................................... 49 
3.2.2 
IgPro10 ......................................................................................................... 49 
3.3 
Scientific Rationale .......................................................................................... 49 
3.3.1 
Study Design Rationale ................................................................................ 49 
3.3.2 
Dose Rationale ............................................................................................. 50 
3.4 
Planned Study Duration ................................................................................... 50 
3.5 
Planned Number of Subjects ............................................................................ 50 
3.6 
Definition of End of the Clinical Study ........................................................... 51 
3.7 
Stopping Criteria .............................................................................................. 51 
4 
Selection and Withdrawal of Subjects .................................................................. 51 
4.1 
Eligibility Criteria ............................................................................................ 51 
4.1.1 
Inclusion Criteria .......................................................................................... 51 
4.1.2 
Exclusion Criteria ......................................................................................... 52 
4.2 
Screen Failures ................................................................................................. 54 
4.3 
Discontinuation of Treatment and / or Subject Withdrawal ............................. 54 
4.3.1 
Discontinuation of Study Treatment ............................................................. 54 
4.3.2 
Subject Withdrawal ...................................................................................... 55 
4.3.3 
Procedures for Handling Withdrawals.......................................................... 56 
4.3.4 
Subjects Lost to Follow-up ........................................................................... 56 
5 
Study Interventions ............................................................................................... 56 
5.1 
Investigational Products ................................................................................... 56 
5.1.1 
Description of IgPro20 ................................................................................. 56 
5.1.2 
Description of IgPro10 ................................................................................. 57 
5.1.3 
Dosing and Administration of Investigational Products ............................... 57 
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CSL Behring 
Study Number: 
IgPro20_2001 
 
Study Product: 
IgPro20 (Hizentra®) 
 
Protocol version: Amendment 4 
 
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5.1.3.1 
Treatment Compliance .............................................................................. 60 
5.1.3.2 
Overdose ................................................................................................... 61 
5.1.4 
Medical Devices ........................................................................................... 61 
5.2 
Packaging, Labeling, Supply and Storage ........................................................ 61 
5.2.1 
Packaging and Labeling ............................................................................... 61 
5.2.2 
Supply and Storage ....................................................................................... 61 
5.2.3 
Dispensing Investigational Product to Subjects During Emergencies ......... 62 
5.3 
Accountability and Destruction ........................................................................ 62 
5.4 
Access to Investigational Product After the End of Study ............................... 62 
6 
Allocation to Treatment ........................................................................................ 62 
6.1 
Subject Assignment .......................................................................................... 62 
6.2 
Randomization Procedures ............................................................................... 63 
6.3 
Blinding Procedures ......................................................................................... 63 
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 
Reproductive Restrictions ................................................................................ 65 
8 
Study Procedures and Visit Schedule ................................................................... 66 
8.1 
Clinical Procedures .......................................................................................... 66 
8.1.1 
Demographics, Baseline, and Safety Assessments ....................................... 66 
8.1.1.1 
Physical Examination ............................................................................... 68 
8.1.1.2 
Hemolysis Safety Assessment .................................................................. 69 
8.1.1.3 
Thromboembolic Events Safety Assessment ............................................ 70 
8.1.1.4 
Renal Function Assessments .................................................................... 71 
8.1.1.5 
12-lead Electrocardiogram ....................................................................... 72 
8.1.1.6 
Vital Signs ................................................................................................. 72 
8.1.1.7 
Pregnancy Tests ........................................................................................ 72 
8.1.1.8 
Pulmonary Function Tests ........................................................................ 72 
8.1.1.9 
Clinical Laboratory Tests .......................................................................... 73 
8.1.1.10 
Patient Diary ............................................................................................. 73 
8.1.2 
Pharmacokinetic Assessments ...................................................................... 73 
8.1.3 
Efficacy Assessments ................................................................................... 73 
8.1.4 
Pharmacodynamic Assessments ................................................................... 77 
8.1.5 
Other Assessments ........................................................................................ 77 

CSL Behring 
Study Number: 
IgPro20_2001 
 
Study Product: 
IgPro20 (Hizentra®) 
 
Protocol version: Amendment 4 
 
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8.1.5.1 
 
8.1.5.2 
 
8.1.5.3 
 
8.2 
 
8.3 
Blood Samples .................................................................................................. 79 
8.4 
Retention of Samples ....................................................................................... 79 
8.5 
Concomitant Therapies..................................................................................... 80 
8.6 
Visit Schedule ................................................................................................... 80 
8.6.1 
Screening ...................................................................................................... 81 
8.6.2 
Week 1 (Site Visit; Sequence A and Sequence B) ........................................ 82 
8.6.3 
Sequence A / Treatment Period 1 (IgPro20) ................................................. 83 
8.6.3.1 
Week 1 (Site Visit) .................................................................................... 83 
8.6.3.2 
Weeks 3, 7, and 11 (Site Visits) ................................................................ 84 
8.6.3.3 
Weeks 5, 9, and 13 (Site Visits) ................................................................ 84 
8.6.3.4 
Weeks 1, 3, 5, 7, 9, 11, and 13 (Home Visits)........................................... 85 
8.6.3.5 
Weeks 2, 4, 6, 8, 10, and 12 (Home Visits) .............................................. 85 
8.6.3.6 
Week 14 (Home Visit) .............................................................................. 86 
8.6.3.7 
Week 15 (Home Visit) .............................................................................. 86 
8.6.4 
Sequence A / Treatment Period 2 (IgPro10) ................................................. 86 
8.6.4.1 
Week 17 (Site Visit) .................................................................................. 86 
8.6.4.2 
Weeks 19, 23, and 27 (Site Visits) ............................................................ 88 
8.6.4.3 
Weeks 21, 25, and 29 (Site Visits) ............................................................ 88 
8.6.4.4 
Week 30 (Home Visit) .............................................................................. 89 
8.6.4.5 
Week 31 (Site Visit) .................................................................................. 89 
8.6.5 
Sequence B / Treatment Period 1 (IgPro10) ................................................. 89 
8.6.5.1 
Week 1 (Site Visit) .................................................................................... 90 
8.6.5.2 
Weeks 3, 7, and 11 (Site Visits) ................................................................ 90 
8.6.5.3 
Week 5, Week 9, and Week 13 (Site Visits) .............................................. 90 
8.6.5.4 
Week 15 (Site Visit) .................................................................................. 91 
8.6.5.5 
Weeks 14 and 16 (Home Visit) ................................................................. 92 
8.6.6 
Sequence B / Treatment Period 2 (IgPro20) ................................................. 92 
8.6.6.1 
Week 17 (Site Visit) .................................................................................. 92 
8.6.6.2 
Weeks 19, 23, 27 (Site Visits) ................................................................... 93 
8.6.6.3 
Weeks 21, 25, and 29 (Site Visits) ............................................................ 94 
8.6.6.4 
Weeks 17, 19, 21, 23, 25, 27, and 29 (Home Visits) ................................ 95 
8.6.6.5 
Weeks 18, 20, 22, 24, 26, and 28 (Home Visits) ...................................... 95 
8.6.6.6 
Week 30 (Home Visit) .............................................................................. 95 
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CSL Behring 
Study Number: 
IgPro20_2001 
 
Study Product: 
IgPro20 (Hizentra®) 
 
Protocol version: Amendment 4 
 
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8.6.6.7 
Week 31 (Home Visit) .............................................................................. 95 
8.6.7 
End of Treatment (Week 32; Sequence A and Sequence B) / Early 
Termination (Site Visit) ................................................................................ 96 
8.6.8 
End of Study (Week 36; Sequence A and  Sequence B; Telephone Call) .... 97 
8.6.9 
Unscheduled Visits (Sequence A and Sequence B) ...................................... 97 
8.6.10 
Remote Visits During Emergencies .............................................................. 97 
9 
Adverse Events ..................................................................................................... 98 
9.1 
Definitions ........................................................................................................ 98 
9.1.1 
Adverse Event .............................................................................................. 98 
9.1.2 
Serious Adverse Event .................................................................................. 99 
9.1.3 
Adverse Event of Special Interest .............................................................. 100 
9.1.4 
Medical Device Incident ............................................................................ 101 
9.2 
Intensity of Adverse Events ............................................................................ 101 
9.3 
Causality of Adverse Events .......................................................................... 101 
9.4 
Observation Period for Adverse Events ......................................................... 102 
9.5 
Follow-up of Adverse Events ......................................................................... 102 
9.6 
Adverse Event Reporting ............................................................................... 103 
9.6.1 
Adverse Events ........................................................................................... 103 
9.6.2 
Serious Adverse Events .............................................................................. 103 
9.6.3 
Medical Device Incidents ........................................................................... 104 
9.6.4 
Adverse Events of Special Interest Incidents ............................................. 104 
9.6.5 
Overdose ..................................................................................................... 105 
9.6.6 
Pregnancy and Breastfeeding ..................................................................... 105 
9.7 
IRB / IEC Reporting Requirements ............................................................... 105 
10 
Statistics .............................................................................................................. 106 
10.1 
Sample Size Estimation .................................................................................. 106 
10.2 
Description of Study Analysis Sets ................................................................ 106 
10.2.1 
Full Analysis Set ......................................................................................... 106 
10.2.1.1 
Safety Analysis Set ................................................................................. 106 
10.2.1.2 
Pharmacokinetic Analysis Set ................................................................ 106 
10.3 
Statistical Analyses and Methods ................................................................... 107 
10.3.1 
Subject Disposition and Characteristics ..................................................... 107 
10.3.1.1 
Subject Disposition ................................................................................. 107 
10.3.1.2 
Subject Characteristics ........................................................................... 107 
10.3.2 
Analyses of Primary Endpoints .................................................................. 107 
10.3.2.1 
Safety of IgPro20 .................................................................................... 107 

CSL Behring 
Study Number: 
IgPro20_2001 
 
Study Product: 
IgPro20 (Hizentra®) 
 
Protocol version: Amendment 4 
 
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10.3.2.2 
Other Clinical Tests ................................................................................ 108 
10.3.3 
Analyses of Secondary Endpoints .............................................................. 108 
10.3.3.1 
Relative Bioavailability of IgPro20 ........................................................ 108 
10.3.3.2 
Pharmacokinetic Parameters ................................................................... 108 
10.3.3.3 
Safety of IgPro10 .................................................................................... 109 
10.4 
 
10.4.1 
Extent of Exposure ..................................................................................... 110 
10.4.2 
Interim Analyses ......................................................................................... 110 
11 
Quality Assurance ............................................................................................... 110 
12 
Regulatory and Ethics Considerations ................................................................ 110 
12.1 
Regulatory Considerations ............................................................................. 110 
12.2 
Institutional Review Board / Independent Ethics Committee ........................ 111 
12.3 
Subject Information and Informed Consent ................................................... 111 
12.4 
Subject Confidentiality ................................................................................... 111 
12.5 
Indemnity and Compensation ......................................................................... 112 
13 
Administrative Considerations ........................................................................... 112 
13.1 
Clinical Trial Research Agreement ................................................................ 112 
13.2 
Clinical Study Registration and Results Disclosure ....................................... 112 
13.3 
Implementation of the Protocol / Protocol Amendment(s) ............................ 112 
13.4 
Protocol Deviations ........................................................................................ 113 
13.5 
Documentation and Record Keeping ............................................................. 113 
13.5.1 
Data Collection ........................................................................................... 113 
13.5.2 
Data Quality Assurance .............................................................................. 114 
13.5.3 
Record Retention ........................................................................................ 115 
13.6 
Study and Site Closure ................................................................................... 115 
13.7 
Clinical Study Report ..................................................................................... 115 
13.8 
Use of Data and Publications ......................................................................... 116 
14 
References .......................................................................................................... 117 
15 
Appendices ......................................................................................................... 123 
Appendix 1 Signatures ........................................................................................................... 123 
Signature on Behalf of Sponsor ............................................................................................. 123 
Signature of Principal Investigator ........................................................................................ 124 
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Study Product: 
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Protocol version: Amendment 4 
 
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Appendix 2 The American College of Rheumatology / European League Against Rheumatism 
Criteria for the Classification of Systemic Sclerosis (SSc) ................................ 125 
Appendix 3 Diffuse Cutaneous Systemic Sclerosis (dcSSc) Versus Limited Cutaneous 
Systemic Sclerosis (lcSSc) ................................................................................. 126 
Appendix 4 Contingency Procedures ..................................................................................... 127 
 

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List of Tables 
Table 1 
Baseline and Safety Assessments .................................................................... 67 
Table 2 
Visit / Procedure Time Window (relative to scheduled visit / procedure) ....... 80 
 
List of Figures 
Figure 1 
IgPro20_2001 Study Design ............................................................................ 48 
Figure 2 
Management of Elevation in Renal Function Parameters ............................... 71 
 
 
 

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List of Abbreviations 
Abbreviation 
Term 
ACR 
American College of Rheumatology 
AE 
Adverse event 
AESI 
Adverse event of special interest 
AMS 
Aseptic meningitis syndrome 
AUC 
Area under the curve 
β-hCG 
Beta-human chorionic gonadotropin 
CI  
Confidence interval  
CIDP  
Chronic inflammatory demyelinating polyneuropathy  
Cmax 
Maximum plasma drug concentration 
COVID-19 
Coronavirus disease 2019 
 
  
CSLB 
CSL Behring 
Ctrough 
Minimum plasma drug concentration 
dcSSc  
Diffuse cutaneous systemic sclerosis  
 
 
DVT 
Deep vein thrombosis 
ECG 
Electrocardiogram 
eCOA 
Electronic clinical outcomes assessment 
eCRF 
Electronic case report form 
eGFR 
Estimated glomerular filtration rate 
EOS 
End of Study 
EOT 
End of Treatment 
EU 
European Union 
EULAR 
European League Against Rheumatism  
FAS 
Full analysis set 
 
 
GCP  
Good Clinical Practice  
GMP 
Good Manufacturing Practice 
 
 
  
  
HIV 
Human immunodeficiency virus 
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Abbreviation 
Term 
HRCT 
High-resolution computed tomography 
ICF 
Informed consent form 
ICH 
International Council on Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use  
ID 
Identification 
IEC 
Independent Ethics Committee 
IgA 
Immunoglobulin A 
IgG 
Immunoglobulin G 
IP 
Investigational product 
IRB 
Institutional Review Board 
IRT 
Interactive response technology 
ISR  
Infusion site reaction  
ITP 
Immune thrombocytopenic purpura 
IV  
Intravenous  
IVIG 
Intravenous immunoglobulin 
lcSSc  
Limited cutaneous systemic sclerosis  
 
 
 
  
PE 
Pulmonary embolism 
PFT  
Pulmonary function test(s)  
  
  
PID 
Primary immunodeficiency 
PK 
Pharmacokinetic(s) 
SAE 
Serious adverse event 
SC 
Subcutaneous 
SCIG 
Subcutaneous immunoglobulin 
 
  
SMQ 
Standardized MedDRA queries 
SSc  
Systemic sclerosis  
 
 
TEAE 
Treatment-emergent adverse event 
TEE 
Thromboembolic events 
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Study Product: 
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Protocol version: Amendment 4 
 
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Glossary 
Baseline 
The most recent assessment before the first infusion in 
Treatment Period 1. 
End of Study (EOS) 
The follow-up telephone call occurs 4 weeks after completing 
study treatment or early termination follow-up visit, 
whichever occurs later. 
Reference visit 
Reference visit for Treatment Period 1 is defined as the 
baseline of the study. Reference visit for Treatment Period 2 is 
defined as the most recent assessment before the first infusion 
in Treatment Period 2, after completion of planned treatment 
in Treatment Period 1.  
Session 
Each weekly dose of IgPro20 will be divided into two 
separate infusions and administered in two sessions: Session 1 
and Session 2. Each treatment of IgPro10 will be administered 
over 2 to 5 consecutive days every 4 weeks. 
Sequence 
The study will consist of 2 sequences, Sequence A or 
Sequence B. Each subject will be randomized to 1 of the 2 
treatment sequences. 
Sequence A 
IgPro20 0.5g/kg/week subcutaneous (SC) infusion in 
Treatment Period 1 + IgPro10 2g/kg/4 weeks intravenous (IV) 
infusion in Treatment Period 2  
Sequence B 
IgPro10 2g/kg/4 weeks IV infusion in Treatment Period 1 + 
IgPro20 0.5g/kg/week subcutaneous (SC) infusion in 
Treatment Period 2 
Treatment 
Treatment will be either IgPro20 0.5g/kg/week or IgPro10 
2g/kg/4 weeks. 

CSL Behring 
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Study Product: 
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Protocol version: Amendment 4 
 
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Treatment period 
Each sequence will consist of two 16-week periods of 
treatment, a period of IgPro20 treatment and a period of 
IgPro10 treatment.  
 

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Study Product: 
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1 
Introduction 
1.1 
Background 
Systemic sclerosis (SSc) is a rare and progressive autoimmune connective tissue disorder 
with a prevalence rate of approximately 50-300 cases per million worldwide [Chifflot et al, 
2008]. SSc is one of the most life-threatening rheumatic autoimmune diseases [Ioannidis et 
al, 2005; Elhai et al, 2012]; cumulative survival for patients with this disease has been 
estimated at 74.9% at 5 years and 62.5% at 10 years from diagnosis [Rubio-Rivas et al, 
2014]. Pulmonary involvement represents the main cause of death in these patients [Rubio-
Rivas et al, 2014; Tyndall et al, 2010; Lefevre et al, 2013]. The clinical manifestations of SSc 
are extremely heterogeneous and the prognosis is generally poor, with the majority of patients 
having skin thickening and variable involvement of internal organs [van den Hoogen et al, 
2013; Denton, 2016; Denton and Khanna, 2017]. The disease is characterized by progressive 
vascular damage (Raynaud’s phenomenon, digital ulcers, hypertensive renal failure, 
cardiomyopathy, and pulmonary hypertension) and organ fibrosis (skin thickening, 
pulmonary fibrosis, gastrointestinal dysmotility, and myocardial fibrosis). The most widely 
accepted clinical criterion is to separate patients with SSc based on the distribution of skin 
thickening into limited cutaneous systemic sclerosis (lcSSc) and diffuse cutaneous systemic 
sclerosis (dcSSc) [LeRoy et al, 1988; Leroy and Medsger, 2001]. Patients with lcSSc in 
general have skin thickening limited to areas distal to the elbows and knees, face, and neck 
while dcSSc is characterized by skin thickening over the entire extremity. Patients with 
dcSSc, accounting for 20% to 40% of all of cases of SSc, generally experience early rapid 
progression of skin thickening and are at high risk for early, widespread, and severe internal 
organ involvement [Ferreli et al, 2017]. Therefore, dcSSc is associated with numerous 
detrimental effects on health-related quality of life and often results in disability and 
substantial morbidity and mortality [Ferreli et al, 2017; Khanna et al, 2011a].  
While treatment recommendations were recently published for SSc, the mainstays of current 
treatment of SSc are organ-based and primarily aimed at improving symptoms and managing 
complications [Young and Khanna, 2015; Kowal-Bielecka et al, 2017]. There are no 
approved disease-modifying treatment modalities for the disease. Available systemic 
therapeutic options, primarily immunosuppressants, are used off label (except in Japan where 
cyclophosphamide and azathioprine are approved for refractory SSc based on evidence in the 
public domain) and are generally only partially effective and associated with unwanted 
immunosuppressive side effects including severe infection [Kowal-Bielecka et al, 2017; 
Khanna et al, 2016b]. Therefore, there is a high unmet medical need for new therapeutic 
options for the SSc patient population. 

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Study Product: 
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Protocol version: Amendment 4 
 
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Immunoglobulin G (IgG) therapy has been part of the treatment armamentarium for 
autoimmune disorders for many years [Enk et al, 2016; Kerr et al, 2014; Sewell et al, 2014; 
Baleva and Nikolov et al, 2011]. IgPro20 (Hizentra®, 20% SC human immunoglobulin) and 
IgPro10 (Privigen®, 10% IV human immunoglobulin) have been approved for the treatment 
of autoimmune diseases (IgPro20 – chronic inflammatory demyelinating polyneuropathy 
[CIDP]; IgPro10 – CIDP and chronic immune thrombocytopenic purpura [ITP]). Although a 
relatively small number of publications are available on intravenous immunoglobulin (IVIG) 
use in patients with SSc, including lcSSc and dcSSc, IVIG may have a beneficial effect on 
multiple clinical manifestations in SSc patients [Baleva and Nikolov, 2011; Cantarini et al, 
2015; Poelman et al, 2015; Raja et al, 2016; Sanges et al, 2017], 
 
 
 
 
  
Based on experience in other indications, it is known that the adverse event (AE) profiles of 
IVIG and SCIG are different and mostly specific to the route of administration. SCIGs are 
characterized by a lower rate than IVIGs of systemic AEs such as flushing, fever, nausea, and 
vomiting during or shortly after infusion, lower rates of hemolysis, fewer thromboembolic 
events (TEEs), lower rates of aseptic meningitis, and a minimal “wearing off” effect at the 
end of the dosing interval in the treatment [Perez et al, 2017]. The most common AEs 
associated with SCIG products are local infusion site reactions (ISRs); eg, erythema, edema, 
local itch, heat, or pain. However, ISRs are predominantly mild and quickly resolve without 
special treatment and usually decrease in frequency over time [Cherin et al, 2016; Ballow et 
al, 2017; Perez et al, 2017]. Overall lower rates of systemic AEs, flexible dosing regimens, 
improved quality of life, and cost savings are all important advantages of SCIG 
administration for treatment of any condition currently treated with IVIG [Berger et al, 2010; 
Jolles et al, 2011; Shapiro, 2013; Perez et al, 2017]. 
Nevertheless, the safety of SCIG products in SSc requires special attention as this disease 
pathology is characterized by small vessel vasculopathy and excessive collagen deposition in 
the skin and internal organs. The change in skin and SC tissues leads to fibrosis and 
sometimes ulceration [Denton, 2016], and this vasculopathy and other alterations in 
connective tissues may impact the safety profile and pharmacokinetics (PK) (eg, absorption) 
of immunoglobulin through SC administration to patients with SSc. Therefore, before 
efficacy and safety of any other SCIG product is assessed in a large-scale clinical study, a 
separate investigation of safety, as well as a PK assessment of IgPro20 in dcSSc patients is 
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CSL Behring 
Study Number: 
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Study Product: 
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Protocol version: Amendment 4 
 
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warranted. In order to assess the relative bioavailability of IgPro20, the PK of IgPro10 will 
also be evaluated in the same patient in the proposed study population. 
1.2 
Information on Study Products 
1.2.1 
Overview 
IgPro20 is a ready-to-use 20% liquid formulation of human IgG with > 98% IgG purity for 
SC administration, and is manufactured by CSL Behring (CSLB). IgPro20 is approved in the 
United States of America (US), the European Union (EU), and other countries under the 
brand name Hizentra® for SC application in primary immunodeficiency (PID) syndromes and 
other indications. 
IgPro10 is a ready-to-use 10% liquid formulation of IgG with > 98% IgG purity for 
intravenous (IV) administration, and is manufactured by CSLB. The protein moiety of 
IgPro10 is approved in the US under the brand name Privigen® for the treatment of PID in 
patients ≥ 3 years of age, for CIDP in adults, and for chronic ITP for patients ≥ 15 years of 
age. In addition, Privigen is approved for the treatment of CIDP in the adult and pediatric 
populations in the EU, Switzerland, Canada, and other countries.  
The mechanism of action of IgG therapy in autoimmune conditions and, specifically, in SSc, 
is complex and not fully understood [Baleva and Nikolov, 2011; Cantarini et al, 2015; Berger 
and Steen, 2017]. Published reports suggest that the potential mechanisms of action of 
therapeutic IgG includes neutralizing toxins and super-antigens, neutralizing and / or 
increasing the catabolism of autoantibodies, blocking Fc receptors, inhibiting inflammatory 
mediators (eg, cytokines and chemokines), and reducing immune complexes [Baleva and 
Nikolov, 2011; Galeotti et al, 2017; Schwab and Nimmerjahn, 2013]. However, detailed 
studies in autoimmune neuropathies suggest that the most important mechanisms in vivo are 
anti-idiotypic neutralization of pathogenic autoantibodies, increased catabolism of 
autoantibodies, and inhibition of complement deposition and activation [Berger, 2013]. To the 
extent that autoantibodies contribute to the pathophysiology of SSc, it may thus be expected 
that IgG therapy may ameliorate their effects by these mechanisms. The anti-fibrotic effects 
of IgG may also be mediated through the suppression of profibrotic cytokines, down-
regulation of fibroblast transforming growth factor-beta, inhibition of complement activation, 
and through the presence of anti-fibrotic antibodies within IgG preparations [Cantarini et al, 
2015]. 
A detailed description of the chemistry, pharmacology, efficacy, and safety of IgPro20 and 
IgPro10 is provided in the respective Investigator’s Brochures. 

CSL Behring 
Study Number: 
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Study Product: 
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Protocol version: Amendment 4 
 
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1.2.2 
Nonclinical Evaluation 
Human IgGs are naturally occurring proteins with a well-established safety and tolerability 
record. The testing of human immunoglobulin preparations in animal models is of limited 
value because immunoglobulins are immunologically active and can cross-react between 
species. IgPro20 contains the same purified IgG drug substance as IgPro10, the marketing 
approval of which was based on a broad nonclinical assessment. Therefore, the nonclinical 
studies with IgPro20 focused on its SC use (local tolerance after single and multiple doses, 
PK) and safety regarding hypotensive effects. None of these studies identified any relevant 
safety findings that might translate into a safety concern in clinical studies of IgPro20. The 
safety of the excipient L-proline was assessed in a nonclinical study with IgPro20 as well as 
in a number of studies during the development of IgPro10, from which it was concluded that 
the use of L-proline as an excipient at the specified concentrations raises no safety concerns. 
1.2.3 
Clinical Experience 
IgPro20 has been developed for clinical use in immunoglobulin replacement therapy. Three 
pivotal phase 3 studies and 4 extension and follow-up studies in a total of 231 subjects with 
PID were completed, and 2 studies are ongoing (70 total subjects planned). A phase 4 
postmarketing study in PID and secondary immunodeficiency was also completed (this study 
enrolled 25 subjects; all subjects with PID). 
IgPro20 has also been developed for the treatment of CIDP as maintenance therapy to prevent 
relapse of neuromuscular disability and impairment. Two CIDP studies were completed:  
1 pivotal phase 3 study with a total of 172 subjects (115 IgPro20 and 57 placebo subjects); 
and 1 extension study with a total of 82 subjects; all extension study subjects also participated 
in the pivotal study). 
In addition, 1 phase 1 study in 28 healthy subjects was conducted, which investigated the 
local tolerability and safety of IgPro20, IgPro16, and Vivaglobin. 
Marketing approval of IgPro10 was based on 2 pivotal, prospective, open-label, single-arm, 
multicenter, phase 3 studies; 1 study performed in the EU in subjects with chronic ITP 
(Study ZLB03_003CR) and another study performed in the US and the EU in subjects with 
PID (Study ZLB03_002CR).  
Moreover, Study ZLB05_006CR was an extension study to Study ZLB03_002CR in subjects 
with PID, and Study IgPro10_4001 was performed in the EU in subjects with ITP. 

CSL Behring 
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Study Product: 
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Protocol version: Amendment 4 
 
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CSLB has also completed 2 phase 3 studies with IgPro10 in the neurological indication CIDP 
(Study IgPro10_3001 in the EU, and Study IgPro20_3003 in the EU, the US and other 
regions), and has 1 ongoing phase 3/4 study with IgPro10 in pediatric CIDP (Study 
IgPro10_4002 in the US). 
1.3 
Study Overview 
This prospective, multicenter, randomized, open-label, crossover study will investigate the 
safety, tolerability, and PK of IgPro20 at the weekly SC dose of 0.5g/kg body weight in 
subjects with dcSSc. The study also aims to evaluate the relative bioavailability of IgPro20, 
and characterize PK of IgPro20 and IgPro10, respectively, in subjects with dcSSc. 
Additionally, the safety of IgPro10 will be assessed. See Section 3.1 for specific details about 
this study. 
1.4 
Potential Risks and Benefits  
1.4.1 
Potential Risks 
1.4.1.1 
IgPro20 Risks 
Although the safety profile of IgPro20 has not been evaluated in patients with SSc, IgPro20 
has, in general, been demonstrated to be a safe product based on safety data obtained from 
previous clinical studies sponsored by CSLB in various indications. IgPro20 safety data have 
been accumulated with weekly doses up to 0.4 mg/kg. In a recently completed global CIDP 
program (IgPro20_3003; a 24-week pivotal study [172 subjects] and a 48-week extension 
study [82 subjects]), 0.4 and 0.2 g/kg weekly doses were evaluated. In both CIDP studies, the 
systemic AE rate was low and local reactions were mild to moderate and decreased in 
frequency over time. Neither infusion rate nor volume had an effect on systemic AEs or local 
reaction rates.  
The most commonly reported adverse reactions have included local ISRs (see below), 
headache, diarrhea, fatigue, back pain, nausea, pain in extremities, cough, rash, pruritis, 
vomiting, abdominal pain, migraine, pain, and nasopharyngitis. The majority of adverse 
reactions in all completed clinical studies were mild to moderate.  
IgPro20 is also associated with important identified risks, including local reactions, 
ulceration-like ISRs, anaphylactic reactions, aseptic meningitis syndrome (AMS), and TEE. 
Other unknown IgPro20-associated risks maybe linked with home based SC (self-) 
administration, such as exacerbation of existing hyperprolinemia, hemolysis, or transmission 
of infectious agents.  

CSL Behring 
Study Number: 
IgPro20_2001 
 
Study Product: 
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Protocol version: Amendment 4 
 
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The most common AEs associated with SCIG products are local ISRs; eg, erythema, edema, 
local itch, heat, or pain. Depending on the method and timing of evaluation, these AEs occur 
very commonly in patients administered SCIG. However, ISRs are predominantly mild, 
quickly resolve without special treatment, and usually decrease in frequency over time 
[Cherin et al, 2016; Ballow et al, 2017; Perez et al, 2017]. For this population of SSc patients 
with skin conditions, ISRs will be monitored and evaluated during this study.  
Further details on identified potential risks of IgPro20 are available in the Investigator’s 
Brochure. 
1.4.1.2 
IgPro10 Risks 
IgPro10 has been demonstrated to have a favorable safety profile based on safety data 
obtained from previous clinical studies sponsored by CSLB in various indications, including 
PID, secondary immunodeficiency, chronic ITP and CIDP, and postmarketing experience 
collected over the past 11 years.  
The important identified risks with the use of IVIG products are AMS, hemolysis, 
hypersensitivity and anaphylactic reactions, TEEs, and acute renal failure. Important potential 
risks include transfusion-related acute lung injury and potential for transmission of infectious 
agents.  
Thrombosis may occur following treatment with immunoglobulin products. Thromboembolic 
events such as myocardial infarction, cerebral vascular accident (including stroke), 
pulmonary embolism, and deep vein thromboses are assumed to be related to a relative 
increase in blood viscosity through the high influx of immunoglobulin in patients at high risk. 
Enrollment of subjects with high risk factors for thrombosis or histories of TEEs will be 
limited in this study. To prevent potentially severe hypersensitivity and anaphylactic 
reactions, the study will also exclude subjects with a history of anaphylactic or severe 
systemic reaction to the administration of human immune globulin or immunoglobulin A 
(IgA)-deficiency with known anti-IgA antibodies. Acute renal dysfunction / failure may occur 
with the use of IVIG products, particularly in those products containing sucrose (IgPro10 
does not contain sucrose). The study will ensure that patients are not volume depleted and 
their renal function is adequately monitored. Additionally, enrollment will exclude subjects 
with severe and moderate-to-severe chronic renal disease (see Section 4.1.2 [exclusion 
criterion 8] and Section 8.1.1.4). 
Further details on identified potential risks of IgPro10 are available in the Investigator’s 
Brochure. 

CSL Behring 
Study Number: 
IgPro20_2001 
 
Study Product: 
IgPro20 (Hizentra®) 
 
Protocol version: Amendment 4 
 
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1.4.1.3 
Crono S-PID-100 Infusion Pump Risks 
IgPro20 will be administered using the Crono S-PID-100 Infusion Pump. There are no 
specific risks associated with Crono S-PID-100 Infusion Pump use. Technical malfunctioning 
or leakage from connections between syringe, tubing and / or needle, or the infusion site itself 
(eg, due to inadequate placement of the butterfly needle) may occur.  
1.4.2 
Potential Benefits 
1.4.2.1 
IgPro20 Benefits 
To date, there are no published data on the use of SCIG products in any form of SSc. 
Although a relatively small number of publications are available on IVIG use in patients with 
SSc, including lcSSc and dcSSc, IVIG may have a beneficial effect on multiple clinical 
manifestations in SSc patients [Baleva and Nikolov, 2011; Cantarini et al, 2015]. 
 
 
 
 
 
  
In addition, the kinetics and dosing regimen of SCIG are different from that of IVIG; 
therefore, it is possible that SCIG will have fewer systemic reactions and wear-off effect 
[Perez et al, 2017]. Furthermore, SCIG administration and home therapy regimens in clinical 
practice have been found to be generally well tolerated and associated with improvement in 
quality of life and treatment satisfaction due to increased independence and scheduling 
flexibility as compared with IVIG administration. The dose of SCIG can be divided into 
smaller portions and self-administered after adequate training 1 to 2 times a week or more 
frequently depending on individual dose and tolerability in other indications [Jones et al, 
2012; Sidhu et al, 2014; Sriaroon and Ballow, 2015]. 
1.4.2.2 
IgPro10 Benefits 
A potential benefit of IgPro10 is the improvement in skin score and stabilization of organ 
function as measured by the outcome assessments. As indicated earlier, based on current 
literature, an improvement from pretreatment baseline in skin score / thickening and other 
clinical outcome measures by 2g/kg/month IVIG in patients with SSc has been observed 
[Baleva and Nikolov, 2011; Cantarini et al, 2015]. IVIG preparations in general have a well-
known safety and efficacy profile in autoimmune diseases in dermatology, neurology, and 
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Study Product: 
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Protocol version: Amendment 4 
 
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chronic ITP [Enk et al, 2016; Baleva and Nikolov, 2011; Cantarini et al, 2015; Eibl, 2003; 
Wittstock and Zettl, 2006].  
1.4.3 
Benefit-risk Conclusion 
Overall, based on the associated benefit-risk for this study, it is acceptable for subjects who 
continue on their current background therapy (see Section 7.2) to be enrolled into this phase 2 
study to evaluate the safety and PK of IgPro20 and IgPro10 in patients with dcSSc. 
2 
Study Objectives and Endpoints 
2.1 
Primary Objective and Endpoints 
2.1.1 
Primary Objective 
The primary objective of the study is to evaluate the safety of IgPro20 in adults with dcSSc. 
2.1.2 
Primary Endpoints 
The primary endpoint of the study is the safety of IgPro20 based on: 
Safety Endpoints 
Summary Measure 
AEs, including any AEs, treatment-
emergent adverse events (TEAEs), 
serious adverse events (SAEs), and 
adverse events of special interest 
(AESIs)  
AEs measured by treatment, treatment sequence, 
combination of treatment, and treatment period 
(Period 1, Week 16; Period 2, Week 32; 
combination of treatment, Week 32): 
• Number and percentage of subjects with AEs, 
TEAEs, SAEs, and AESIs (total, severity, 
causality, and outcome) 
• Number and percentage of subjects with AEs 
categorized as ISRs (total, severity, causality 
and outcome) 
• Rate of ISRs per subject and per infusion 
• Onset and duration of ISRs 
Change in other clinical tests 
Changes from baseline as measured by 
treatment, treatment sequence, combination of 
treatment and treatment period:  
• Vital signs 
• Body weight  
• Clinical laboratory tests  
• Electrocardiogram (ECG)  
• Pulmonary function tests (PFTs)  

CSL Behring 
Study Number: 
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Study Product: 
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2.2 
Secondary Objectives and Endpoints 
2.2.1 
Secondary Objectives 
The secondary objectives of the study are to evaluate: 
 Relative bioavailability of IgPro20 
 PK of IgPro20  
 PK of IgPro10  
 Safety of IgPro10 
2.2.2 
Secondary Endpoints 
Secondary 
Objective 
Endpoint 
Summary Measure(s) 
(To be determined at the end of each treatment 
period [Period 1, Week 16; Period 2, Week 32; 
combination of treatment, Week 32]) 
1 
IgPro20 relative bioavailability 
(%F) 
Geometric mean ratio of area under the serum 
IgG concentration time curves within a dosing 
duration (dose-normalized area under the 
curve to the end of the dosing period 
[AUC0-tau]) following administration of the 
first dose of IgPro20 or IgPro10 in the last 
week of dosing for Sequence A and / or 
Sequence B 
2 
IgPro20 PK parameters (AUC0-tau, 
area under the curve to the last 
dosing period [AUC0-last], maximum 
[peak] plasma drug concentration 
[Cmax], minimum plasma drug 
concentration [Ctrough]) 
Geometric mean of PK parameters and 
corresponding 95% confidence interval (CI) 
by treatment in each sequence 
3 
IgPro10 PK parameters (AUC0-tau, 
AUC0-last, Cmax, Ctrough)  
Geometric mean of PK parameters and 
corresponding 95% CI by treatment in each 
sequence 
4 
The safety of IgPro10 based on AEs, 
including any AEs, TEAEs, SAEs, 
and AESIs 
AEs measured by treatment, treatment 
sequence, combination of treatment and 
treatment period: 
 Number and percentage of subjects with 
AEs, TEAEs, SAEs, and AESIs (total, 
severity, causality and outcome) 
 Number and percentage of subjects with 
categorized as ISRs (total, severity, 
causality and outcome) 

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Study Product: 
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Protocol version: Amendment 4 
 
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Secondary 
Objective 
Endpoint 
Summary Measure(s) 
(To be determined at the end of each treatment 
period [Period 1, Week 16; Period 2, Week 32; 
combination of treatment, Week 32]) 
 
The safety of IgPro10 based on the 
change in other clinical tests 
Changes from baseline as measured by 
treatment, treatment sequence, combination of 
treatment and treatment period 
 Vital signs  
 Body weight  
 Clinical laboratory tests  
 ECG 
 PFTs 
2.3 
 
2.3.1 
 
 
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2.3.2 
 
 
2.4 
 
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3 
Study Overview 
3.1 
Study Design and Rationale  
This is a prospective, multicenter, randomized, open-label, crossover study to investigate the 
safety and PK of IgPro20 and IgPro10 in subjects with dcSSc. The PK portion of the study 
aims to evaluate the relative bioavailability of IgPro20, and characterize the PK of IgPro20 
and IgPro10, respectively, in subjects with dcSSc. 
The study design is illustrated in Figure 1. Subjects with a diagnosis of dcSSc with disease 
duration ≤ 5 years and skin thickness scores of ≥ 15 to ≤ 45 as measured by 
 will be 
eligible to enroll in the study. During a screening period, investigators will evaluate the 
eligibility of potential subjects utilizing the 2013 European League Against Rheumatism / 
American College of Rheumatology (EULAR / ACR) criteria [van den Hoogen et al, 2013] 
for SSc and diffuse features [LeRoy and Medsger, 2001; LeRoy et al, 1988] to accurately 
confirm their classification as dcSSc. All eligible subjects will be randomized (1:1) to 
Sequence A (IgPro20-IgPro10 treatment sequence) or Sequence B (IgPro10-IgPro20 
treatment sequence). Each subject will complete Treatment Period 1 and Treatment Period 2 
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Study Product: 
IgPro20 (Hizentra®) 
 
Protocol version: Amendment 4 
 
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(16 weeks each), with up to 40 weeks (including Screening) of study duration for an 
individual subject. 
In this crossover study, subjects in Sequence A will receive a total dose of 0.5 g/kg IgPro20 
over 2 sessions per week every week in Treatment Period 1, and a total dose of 2 g/kg 
IgPro10 over 2 to 5 sessions on consecutive days every 4 weeks in Treatment Period 2. 
Subjects in Sequence B will receive a total dose of 2 g/kg IgPro10 over 2 to 5 sessions on 
consecutive days every 4 weeks in Treatment Period 1 and a total dose of 0.5 g/kg IgPro20 
over 2 sessions per week every week in Treatment Period 2.  
The weekly 0.5 g/kg body weight dose of IgPro20 is equivalent to an every 4 week dose of 
IgPro10 (2 g/kg body weight) if using a 1:1 conversion. This is the highest possible IgPro20 
SC dose due to volume limitation and safety (ISR) concerns in subjects with SSc. Stable 
background therapy will be allowed in the study (see Section 7.2).  
All subjects who complete the study or discontinue early will have a follow-up visit 
approximately 4 weeks after the last dose of IP is administered.  
Figure 1 
IgPro20_2001 Study Design 
 
dcSSc = Diffuse cutaneous systemic sclerosis; EOT = End of Treatment; i.v. = intravenous; PK = 
pharmacokinetics; s.c. = subcutaneous; WK = Week  
3.2 
Dose and Dosing Regimen 
The total dose / volume of all IPs will be calculated based on body weight. Body weight will 
be measured at every site visit prior to IP infusion and changes of > 10% of body weight from 
baseline / reference visit will require a dose adjustment. Once a dose adjustment as a result of 
body weight change occurs at a certain visit, body weight at that visit would become the 

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Study Product: 
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Protocol version: Amendment 4 
 
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reference assessment for future body weight change calculations in that treatment period. See 
Section 5.1.3 for additional dosing information. 
3.2.1 
IgPro20 
Subjects will receive IgPro20 infusions at a total weekly dose of 0.5g/kg split between 2 
infusion sessions (eg, Day 1 and Day 3 or Day 4 for each week) every week. The total dose / 
volume of IP will be calculated based on body weight (see Section 3.2). 
3.2.2 
IgPro10 
Subjects will receive IgPro10 at a total dose of 2 g/kg split over 2, 3, 4, or 5 consecutive days, 
depending on total dose and individual tolerability, every 4 weeks. The total dose / volume of 
all IP will be calculated based on body weight. Changes of > 10% of body weight and the 
corresponding adjustment will follow the same way as IgPro20 in Section 3.2. 
3.3 
Scientific Rationale 
3.3.1 
Study Design Rationale 
The proposed crossover design with 2 sequences will provide a reliable estimate of IgPro20 
relative bioavailability because IgPro20 and IgPro10 treatment differences are measured 
within a subject rather than between subjects with SSc; both inter- and intra-individual 
variability will be characterized. This study design will also help to investigate the potential 
difference in the relative bioavailability of IgPro20 (SCIG) when given before or after 
IgPro10 (IVIG) in SSc subjects. During both Treatment Period 1 and Treatment Period 2 in 
each sequence, several PK samples to measure IgG trough concentrations will be collected to 
assess the steady state of IgPro20 or IgPro10 and carry-over effects on Treatment Period 2 
from Treatment Period 1. In addition, PK samples will be frequently collected over the last 
dose period to fully characterize the PK of IgPro20 and IgPro10, respectively, for each 
treatment period in this patient population. Specific PK assessments are described in Section 
8.1.2.  
 
The 16 weeks of treatment for both IgPro20 and IgPro10 will allow for the assessment of 
safety and preliminary efficacy signals as well as assessment of IgPro20 and IgPro10 PK 
profiles at the steady state. The duration of PK assessments is based on IgG trough 
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Study Product: 
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Protocol version: Amendment 4 
 
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concentrations measured in the pivotal phase 3 study in patients with CIDP (IgPro20_3003 
study), indicating that IgPro20 and IgPro10 would reach steady state within approximately 
8 weeks. Importantly, several trough concentrations will be determined for IgPro20 and 
IgPro10 in this study to confirm that steady state is reached before the full PK profile of 
IgPro20 or IgPro10 is assessed in subjects with SSc. 
Not having a washout period between treatments will not impact the full PK characterization, 
since the full PK profile of IgPro10 in the respective treatment period of each sequence will 
be obtained at the end of the treatment period, when it is assumed that steady state will be 
reached. The relative bioavailability of IgPro20 will be evaluated based on the dose-
normalized AUC0-tau of IgPro20 and IgPro10 without the need of a washout interval. 
Moreover, no washout period between the 2 treatments will shorten the study duration and 
potentially be less burdensome for SSc subjects. 
3.3.2 
Dose Rationale 
There are no published data on any SCIG products in the treatment of SSc. The majority of 
IVIG studies used 2 g/kg/4 weeks and provided promising clinical benefits in SSc. The 
conversion of IVIG to SCIG (1:1 ratio) is based on the methodology used in other 
autoimmune indications (eg, CIDP). IgPro20 0.5 g/kg/week is proposed for this first study in 
SSc subjects. In addition, an IgPro20 dose higher than 0.5g/kg/week is limited due to SC 
volume and safety concerns where subjects with pathological changes in skin and SC tissues 
may impact ISRs in SSc.  
3.4 
Planned Study Duration 
After up to 4 weeks of screening, the duration of the study for an individual subject who 
completes the study is expected to be approximately 36 weeks.  
The overall study duration (ie, first subject’s Screening Visit to last subject’s End of Study 
[EOS] telephone call) will be approximately 24 months. 
3.5 
Planned Number of Subjects 
Approximately 26 eligible subjects will be enrolled and randomized to achieve 20 evaluable 
subjects (10 subjects per treatment sequence) completing the study. 

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Study Product: 
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Protocol version: Amendment 4 
 
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3.6 
Definition of End of the Clinical Study 
The end of the clinical study (ie, completion of the study at all participating study sites) is 
defined as the date of the last visit of the last subject and consists of a telephone call to assess 
safety. 
3.7 
Stopping Criteria 
No specific study stopping rules will be implemented.  
A subject may withdraw from the study at any time point for any reason at their own request 
or at the discretion of the investigator or CSLB. Specific stopping criteria for a subject to 
discontinue study treatment are described in detail in Section 4.3.1. If IP is discontinued, 
regardless of the reason, the End of Treatment (EOT) / Early Termination evaluations will be 
performed as completely as possible.  
4 Selection and Withdrawal of Subjects 
4.1 
Eligibility Criteria 
The study population will be selected based on 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 
enrolled in the study and reconfirmed at Week 1 before administration of IP. 
4.1.1 
Inclusion Criteria 
To be enrolled into the study, subjects must meet all of the following inclusion criteria: 
1. Age ≥ 18 years (male or female) at time of providing written informed consent 
2. Documented diagnosis of SSc (scleroderma) according to ACR and EULAR criteria 2013 
(dcSSc) 
3. 
 ≥ 15 and ≤ 45 at screening 
4. Disease duration ≤ 5 years defined as the time from the first non-Raynaud’s phenomenon 
manifestation 
5. Capable of providing written informed consent and willing and able to adhere to all 
protocol requirements 
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Study Product: 
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Protocol version: Amendment 4 
 
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4.1.2 
Exclusion Criteria 
Subjects must not be enrolled into the study if they meet any of the following exclusion 
criteria: 
1. Primary rheumatic autoimmune disease other than dcSSc, including but not limited to 
rheumatoid arthritis, systemic lupus erythematosus, mixed connective tissue disorder, 
polymyositis, dermatomyositis, as determined by the investigator. Note: subjects with 
fibromyalgia, secondary Sjogren’s syndrome, and scleroderma-associated myopathy at 
screening are not excluded 
2. 
  
3. History of skin condition or clinical signs and symptoms of a chronic skin disease other 
than SSc or skin manifestation of an allergic disease or other dermatological conditions 
precluding SC infusion at potential SC infusion sites (eg, dermatitis, eczema, psoriasis)  
4. Subject has clinical signs and symptoms of skin irritation (eg, pruritus, burning, 
erythema) or hypo / hyperpigmentation (eg, scars, tattoos) at the potential SC infusion 
sites 
5. Significant pulmonary arterial hypertension as documented by mean pulmonary arterial 
pressure > 30 mmHg on right heart catheterization requiring SC or IV prostacyclin or use 
of dual oral therapies 
6. 
  
  
7. SSc renal crisis within 2 years before screening 
8. Evidence of chronic kidney disease with an estimated glomerular filtration rate (eGFR) of 
< 45 mL/min/1.73 m2 (as calculated by the Chronic Kidney Disease Epidemiology 
Collaboration equation) [Levey et al, 2009; Stevens et al, 2010] or if subject is receiving 
dialysis. Subjects with current confirmed diagnosis of diabetes mellitus requiring 
medication with an eGFR < 90 mL/min/1.73m2 
9. History of documented thrombotic episode eg, pulmonary embolism, deep vein 
thrombosis, myocardial infarction, thromboembolic stroke at any time (note: history of 
superficial thrombophlebitis is not exclusionary) 
10. Known documented thrombophilic abnormalities including current blood hyperviscosity 
(within 4 weeks before screening), protein S or protein C deficiency, anti-thrombin-3 
deficiency, plasminogen deficiency, antiphospholipid syndrome, Factor V Leiden 
mutation, dysfibrinogenemia, or prothrombin G20210A mutation 
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Study Product: 
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Protocol version: Amendment 4 
 
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11. Recent surgery requiring general anesthesia within the last 4 weeks before Screening 
12. Greater than 3 specified current risk factors for TEEs (documented and currently ongoing 
conditions): atrial fibrillation, coronary disease, diabetes mellitus, dyslipidemia, 
hypertension, obesity (body mass index ≥ 30 kg/m2), recent significant trauma and 
immobility (wheelchair-bound or bedridden) 
13. Cardiac insufficiency (New York Heart Association Class III or IV), cardiomyopathy, 
significant persistent arrhythmia, unstable or advanced ischemic heart disease or 
uncontrolled hypertension 
14. Ongoing active serious infection (including, but not limited to, pneumonia, 
bacteremia / septicemia, osteomyelitis / septic arthritis, bacterial meningitis, visceral 
abscess) at screening or hospitalization and / or treatment with IV antibiotics for a serious 
infection within 2 months before screening 
15. A positive result at screening of any of the following viral markers: human 
immunodeficiency virus -1 / -2 (HIV-1 / 2), hepatitis C virus, and hepatitis B virus  
16. Malignancy in the past 2 years, except for non-melanoma skin cancer, cervical carcinoma 
in situ, or other in situ cancer if it has been excised and treated within the past year 
17. Known medical conditions whose symptoms and effects could alter protein catabolism 
and or IgG utilization (eg, protein-losing enteropathies, nephrotic syndrome) and 
proteinuria (defined as albumin-to-creatinine ratio, ACR > 30mg/g)  
Note: Transient and clinically insignificant proteinuria as based on investigator’s judgment should be discussed 
with the Medical Monitor and is not exclusionary. 
18. Known hyperprolinemia type I or II 
19. Known IgA deficiency or serum IgA level < 5% lower limit of normal  
20. History of clinically significant or uncontrolled illness that, in the opinion of the 
investigator, would prevent participation in the study 
21. Psychiatric, addictive, or other disorders that compromise the ability to give informed 
consent for participating in this study. This includes subjects with a recent history of 
abusing alcohol or illicit drugs 
22. Clinically significant abnormal 12-lead ECG that, in the opinion of the investigator, 
would prevent participation in the study 
23. Clinically significant abnormal laboratory testing at screening that, in the opinion of the 
investigator, would prevent participation in the study 

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Study Product: 
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Protocol version: Amendment 4 
 
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24. Currently receiving or having received therapy not permitted during the study or during 
predefined windows before screening: for a list of prohibited medications, see Section 7.3 
25. Known allergic or other severe reactions to immunoglobulins or other blood products, 
including a history of hemolysis after IVIG infusion 
26. Known or suspected antibodies to the IP, or to excipients of the IP 
27. A female who is pregnant, breastfeeding, or is a woman of childbearing potential who 
does not agree to use acceptable methods of contraception; a male who does not agree to 
use acceptable methods of contraception 
28. Participated in another study with an investigational agent within 3 months 
29. Involved in the planning and / or conduct of the study (applies to CSLB staff and 
dependents, staff at the study site, site examiner, or third-party vendors) 
30. Individuals who have institutionalized as a result of an official or court order 
31. Any issues or conditions that would render the subject unsuitable for participation in the 
study 
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, and screen failure 
details should be recorded for all individuals considered screen failures.  
Individuals who do not meet the criteria for participation in this study (ie, screen failure) may 
be rescreened once after Medical Monitor review and approval. 
4.3 
Discontinuation of Treatment and / or Subject Withdrawal 
4.3.1 
Discontinuation of Study Treatment  
Subjects may discontinue treatment with the IP at any time at their own request, or at the 
discretion of the investigator or CSLB for safety, behavioral, or administrative reasons 
(eg, due to an AE, protocol deviation, loss to follow-up, subject noncompliance, study 
termination). 
Infusions will be stopped and treatment with IP will be discontinued if the subject: 
 Develops anaphylaxis.  

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• Develops any severe or Grade 3 infusion-related reactions such as, but not limited to, 
TEEs (see Section 8.1.1.3), acute lung injury / pulmonary edema, acute renal injury (see 
Section 8.1.1.4), or Grade 3 or higher hemolysis (see Section 8.1.1.2). 
Subjects will discontinue treatment with IP at the discretion of the Investigator when the 
reaction(s) is / are not rapidly responsive to symptomatic medication and / or brief 
interruption of infusion, or if symptoms recur following initial improvement or upon 
re-initiating infusion. 
Subjects who discontinue treatment with IgPro20 or IgPro10 will be withdrawn from the 
study. Refer to Section 4.3.2 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 CSLB for safety, behavioral, or administrative reasons. The reasons for 
withdrawal must be determined by the investigator and recorded in the subject’s medical 
records and on the electronic case report form (eCRF). If the subject is withdrawn for more 
than 1 reason, each should be documented in the source document and the most clinically 
relevant reason should be entered on the eCRF. Reasons for discontinuation include but are 
not limited to: 
• Disease exacerbation that requires prohibited medication 
• An AE 
• Protocol deviation 
• Loss to follow-up 
• Subject noncompliance 
• Study withdrawal 
• Death 
• Withdrawal by subject 
• Other (must be specified) 
In accordance with International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) principles of Good Clinical Practice (GCP), the 
investigator always has the option to advise a subject to withdraw from the study if the 
subject's safety or well-being is compromised by his or her further participation in the study. 
Concern for the interests of the subject must always prevail over the interests of the study.  

CSL Behring 
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Study Product: 
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Protocol version: Amendment 4 
 
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4.3.3 
Procedures for Handling Withdrawals 
If a subject is withdrawn from the study, attempts will be made to complete and document the 
EOT / Early Termination assessments listed in the Schedule of Assessments (Sequence A or 
Sequence B). If the subject is withdrawn from the study after receiving IgPro20 or IgPro10, 
every effort will be made to ensure that the relevant safety assessments are completed.  
If the subject withdraws from the study, and also withdraws consent for disclosure of future 
information, CSLB may retain and continue to use any data collected before such withdrawal 
of consent. 
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 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 source documents 
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. All efforts should 
be made to contact the subject, including the sending of a certified letter. Subjects lost to 
follow-up will be considered to have withdrawn from the study. 
5 
Study Interventions 
5.1 
Investigational Products 
5.1.1 
Description of IgPro20  
Substance name 
IgPro20  
Active substance 
Normal human immunoglobulin  
Trade name 
Hizentra®  
Storage 
IgPro20 will be supplied to the study sites by CSLB. 
IgPro20 must be stored under temperature-monitored 
conditions in a secure storage area as specified in the Site 
IP Manual. 
Dosage form 
Sterile solution for SC infusion containing  
 0.2 g per mL (20%) of IgPro20.  

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Study Product: 
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Protocol version: Amendment 4 
 
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5.1.2 
Description of IgPro10 
Substance name 
IgPro10  
Active substance 
Normal human immunoglobulin  
Trade name 
Privigen®  
Storage 
IgPro10 will be supplied to the study sites by CSLB. 
IgPro10 must be stored under temperature-monitored 
conditions in a secure storage area as specified in the Site 
IP Manual. 
Dosage form 
Sterile solution for IV infusion containing 0.1 g per mL 
(10%) of IgPro10.  
 
 
IgPro20 and IgPro10 will be manufactured by CSLB in accordance with ICH Good 
Manufacturing Practice (GMP) guidelines and local regulatory requirements. 
Information on the preparation and administration of IgPro20 and IgPro10 is provided in the 
Site IP Manual. 
5.1.3 
Dosing and Administration of Investigational Products 
The investigator (or delegate) will administer or dispense IgPro20 or IgPro10 only to subjects 
included in this study following the procedures set out in this study protocol. 
IgPro20 Administration 
Subjects will receive SC IgPro20 infusions at 2 sessions at a total dose of 0.5 g/kg every 
week. The total dose / volume of IgPro20 will be calculated based on body weight. Body 
weight will be measured at every site visit before infusion and possible adjustment to  
dose / volume may occur as described in Section 3.2. Subjects weighing ≥ 100 kg will 
receive a fixed dose of 50 g, every week. A dosing regimen of 2 times a week (eg, Day 1 and 
Day 3 or Day 4 each week) will be followed. 
The SC infusions should be performed at appropriate infusion sites with sufficient normal 
skin areas or 
 ≤ 2 and any other skin conditions precluding SC infusion (eg, on the 
abdomen, thighs, and / or lateral hip). Infusion sites in the normal skin or 
 ≤ 2 in 
abdominal area are recommended in this study, with at least 2 inches (~5 cm) between 
infusion sites. Other anatomic locations approved for SC infusions should be used with 
extreme caution and only if recommended by the study investigator. The number of infusion 
sites depends on the total volume to be administered and tolerability, not to exceed 4 infusion 
sites simultaneously. Any changes in volume or rate of infusion should be discussed with the 
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Principal Investigator. The maximum rate and the maximum volume per infusion site should 
not be exceeded, and any increase rate or volume should be done gradually, as tolerated. The 
maximum rate and the maximum volume per infusion site is recommended: 
Volume  
1st 2 infusion sessions : ≤ 20 mL/site; all subsequent infusions: ≤ 50 mL/site as 
tolerated 
Rate  
1st 2 infusion sessions : ≤ 20 mL/h/site; all subsequent infusions: ≤ 50 mL/h/site as 
tolerated 
Note: Attempts to reach the maximum values for both the volume and flow rate per infusion site during the 
same infusion should be performed gradually with caution and strictly as tolerated.  
 
Detailed information in reference to IgPro20 administration (eg, infusion start time / day, 
infusion stop time / day, number of infusion sites, infusion rate, total administered IgPro20 
dose, site of administration, and whether infusion was omitted, interrupted or stopped and 
reason) will be documented on the IgPro20 infusion form completed by site personnel or 
home health nurse qualified to administer IgPro20. Refer to the Site IP Manual for further 
information. 
IgPro10 Administration  
Subjects will receive IV IgPro10 infusions split over 2, 3, 4 or 5 consecutive days, depending 
on total dose and individual tolerability, at a total dose of 2 g/kg every 4 weeks. The total 
dose / volume of all IPs will be calculated based on body weight. Body weight will be 
collected before each infusion and possible adjustment to dose / volume may occur as 
described in Section 3.2. Subjects weighing ≥ 100 kg will receive a fixed dose of 200 g, 
every 4 weeks. 

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Recommended Rate of Infusion:  
First infusion session 
Rate of 0.3 mL/kg/h (30 mg/kg/h; 0.005 mL/kg/min; 
0.5 mg/kg/min); 
If well tolerated within 30 min: increase to 0.6 mL/kg/h 
(60 mg/kg/h; 0.01 mL/kg/min; 1.0 mg/kg/min) for 
another 30 min; 
If well tolerated within an additional 30 min: increase to 
1.2 mL/kg/h (120 mg/kg/h; 0.02 mL/kg/min; 
2.0 mg/kg/min). 
Second infusion session 
Rate of 0.3 mL/kg/h (30 mg/kg/h; 0.5 mg/kg/min; 
0.005 mL/kg/min); 
If well tolerated within 30 min: increase to 0.6 mL/kg/h 
(60 mg/kg/h; 0.01 mL/kg/min; 1.0 mg/kg/min) for 
another 30 min;  
If well tolerated within an additional 30 min can increase 
to 1.2 mL/kg/h; 
If well tolerated within an additional 30 min can increase 
to 2.4 mL/kg/h. 
Subsequent infusions  
Initial rate of 0.3 mL/kg/h (30 mg/kg/h; 
0.005 mL/kg/min; 0.5 mg/kg/min), incremental increases 
of infusion rate can exceed 1.2 mL/kg/h as tolerated (up 
to the maximum recommended infusion rate of 
4.8 mL/kg/h [480 mg/kg/h; 0.08 mL/kg/min; 
8 mg/kg/min]). 
 

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Recommended Rate of Infusion in Subjects with Renal Dysfunction: 
First infusion 
Rate of 0.3 mL/kg/h (30 mg/kg/h; 0.005 mL/kg/min; 
0.5 mg/kg/min); 
If well tolerated within 30 min: increase to 0.6 mL/kg/h 
(60 mg/kg/h; 0.01 mL/kg/min; 1.0 mg/kg/min); 
If well tolerated within an additional 30 min: increase to 
1.2 mL/kg/h (120 mg/kg/h; 0.02 mL/kg/min; 
2.0 mg/kg/min). 
Subsequent infusions 
Rate of 0.3 mL/kg/h (30 mg/kg/h; 0.005 mL/kg/min; 
0.5 mg/kg/min); 
If well tolerated within 30 min: increase to 0.6 mL/kg/h 
(60 mg/kg/h; 0.01 mL/kg/min; 1.0 mg/kg/min) for 
another 30 min; 
If well tolerated within an additional 30 min increase to 
1.2 mL/kg/h (120 mg/kg/h; 0.02 mL/kg/min; 
2 mg/kg/min);  
If well tolerated within an additional 30 min increase to 
2 mL/kg/h (200 mg/kg/h; .033 mL/kg/min; 
3.3 mg/kg/min)  
(An infusion rate 2 mL/kg/h is the maximum for subjects 
with eGFR < 90 mL/min/1.73m2 at Screening and for 
subjects with elevated serum creatinine level as detailed 
in the renal safety management algorithm in 
Section 8.1.1.4; lower infusion rates may be administered 
at the discretion of the investigator). 
  
Increases in infusion rate should be performed cautiously, as the risk of AEs in IVIG 
infusions generally tends to correlate with the infusion rate. Subjects with renal insufficiency 
should always be infused at the lowest practicable rate. 
Detailed information in reference to IgPro10 administration (eg, amount of IgPro10 received, 
any dose adjustments, infusion rate, whether infusion was omitted, interrupted or stopped and 
reason, and infusion start / stop time / date) will be documented on the IgPro10 infusion 
form.  
5.1.3.1 
Treatment Compliance 
All doses of IgPro20 will be administered by qualified personnel at the study site or at home 
by a home health nurse. All doses of IgPro10 will be administered by qualified personnel at 
the study site. Details of all infusions will be recorded. The number of unused, partially used, 
and empty vials will be recorded and kept until the drug accountability documentation has 

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been checked by the monitor. Treatment compliance will be monitored by counting the used 
vials, the results of which will be recorded. Treatment compliance for IgPro20 and IgPro10 
will be measured as a percentage (= 100 * [used vials divided by planned vials]) overall and 
summarized using descriptive statistics. A percentage between 80% and 120% is regarded as 
compliant to treatment. 
5.1.3.2 
Overdose 
Overdose is defined as the accidental or intentional infusion of any dose of a product that is 
considered excessive of the dose specified in the protocol. The effects of any potential 
overdose with IgPro20 or IgPro10 have not been studied. IgPro20 and IgPro10 are normal 
human proteins with broad range of normal concentrations in serum. The risk of overdosing 
with IgPro20 or IgPro10 is considered to be negligible. See Section 9.6.5 for overdose 
reporting requirements. 
5.1.4 
Medical Devices 
The Crono Infusion Pump Model S-PID 100 is an ambulatory syringe infusion pump (Cane 
S.R.L., Turin, Italy) that is being provided for use in this study for the purposes of 
administration of IgPro20. See the Crono S-PID 100 User Guide for further details of the 
device including proper use and training. 
Medical device incidents, including those resulting from malfunctions of the device, must be 
detected, documented, and reported by the investigator throughout the study.  
5.2 
Packaging, Labeling, Supply and Storage 
5.2.1 
Packaging and Labeling 
IgPro20 and IgPro10 will be packaged and labeled according to current ICH GMP and GCP 
guidelines, and national legal requirements. 
Specific details regarding packaging of IgPro20 and IgPro10 are provided in the Site IP 
Manual. IgPro20 and IgPro10 will be labeled as required per country requirements. 
5.2.2 
Supply and Storage 
IgPro20 and IgPro10 will be supplied to the study sites by CSLB or delegate.  
IgPro20 and IgPro10 must be stored under temperature-controlled and monitored conditions 
at the predefined temperature range, and protected from light, in a secure storage area as 
specified in the Site IP Manual. 

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5.2.3 
Dispensing Investigational Product to Subjects During 
Emergencies 
If required to as a response to a state of emergency or public health crisis, IP may be 
dispensed from the study site to the subject and will be delivered in accordance with all 
applicable local regulations. 
5.3 
Accountability and Destruction 
IgPro20 and IgPro10 must be used only as directed in this clinical study protocol. 
The investigator or study site personnel delegated by the investigator will confirm receipt of 
all shipments of IP in the interactive response technology (IRT) system. 
All supplies of IgPro20 and IgPro10 must be accounted for throughout the study. 
Records for the delivery of IgPro20 and IgPro10 to the study site, the inventory at the study 
site, the use by each subject, and the destruction or return of IgPro20 and IgPro10 to CSLB / 
designee must be maintained by the investigator (or delegate) using the appropriate form or 
IRT system. 
The investigator (or delegate) must provide reasons for any discrepancies in drug 
accountability.  
Further details regarding accountability and destruction of IgPro20 and IgPro10 are provided 
in the Site IP Manual. 
5.4 
Access to Investigational Product After the End of Study 
Subjects will not be provided with IP by CSLB after completion or discontinuation from 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 (ID) number via the 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. 

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6.2 
Randomization Procedures 
Eligible subjects will be randomized in a 1:1 ratio by means of IRT to either one of the 
following sequences: IgPro20 followed by IgPro10 (Sequence A) or IgPro10 followed by 
IgPro20 (Sequence B).  
The randomization list will be generated by the IRT external service provider according to the 
approved randomization specifications. The IRT external service provider will keep the 
randomization code on file.  
6.3 
Blinding Procedures 
Not applicable. 
7 
Contraindications, Permitted Therapies and Prohibited  
Therapies 
7.1 
Contraindications and Precautions to Further Dosing 
Hypersensitivity and anaphylactic reactions: True hypersensitivity reactions are rare. They 
can occur in the very rare cases of IgA deficiency with anti-IgA antibodies.  
Rarely, human normal immunoglobulin can induce a fall in blood pressure with an 
anaphylactic reaction, even in subjects who have tolerated previous treatment with human 
immunoglobulin.  
In case of an adverse reaction, either the rate of administration must be reduced or the 
infusion stopped. The treatment required depends on the nature and severity of the reaction. 
In case of shock, standard medical treatment for shock should be implemented.  
Thrombotic events: Thrombotic events can occur in treatment with IgPro20 and IgPro10. 
Subjects should be informed about the first symptoms of thrombotic events, including 
shortness of breath, pain and swelling of a limb, focal neurological deficits, and chest pain 
and should be advised to contact their physician immediately upon onset of symptoms. 
Subjects should be sufficiently hydrated before the use of IgPro20 and IgPro10 and TEE 
safety assessments will be performed at every site study visit as described in Section 8.1.1.3. 
Aseptic meningitis syndrome: AMS can occur with IgPro20 and IgPro10. The syndrome 
usually begins within several hours to 2 days following treatment. AMS is characterized by 
the following signs and symptoms: severe headache, neck stiffness, drowsiness, fever, 
photophobia, nausea, and vomiting. Subjects exhibiting signs and symptoms of AMS should 

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receive a thorough neurological examination, including cerebral spinal fluid studies, to rule 
out other causes of meningitis. Discontinuation of immunoglobulin treatment may result in 
remission of AMS within several days without sequelae.  
Hemolysis: Cases of clinically significant hemolysis are rare but can appear during treatment 
with IgPro10. If a subject has a confirmed hemolysis of Grade 3, no further IgG should be 
infused and the subject should be removed from the study.  
Transfusion-related acute lung injury: Noncardiogenic pulmonary edema may very rarely 
occur following treatment with IVIG products. Transfusion-related acute lung injury is 
characterized by severe respiratory distress, pulmonary edema, hypoxemia, normal left 
ventricular function, and fever. Symptoms typically appear within 1 to 6 hours following 
treatment.  
Monitor patients for pulmonary adverse reactions. Transfusion-related acute lung injury may 
be managed using oxygen therapy with adequate ventilatory support.  
Premedication: Premedication according to local standards may precede the IVIG 
application.  
Hydration: In all subjects, hydration status should be assessed before initiation of the IVIG 
infusion. 
Vaccination: Immunoglobulin administration may impair the efficacy of live attenuated virus 
vaccines such as measles, mumps, rubella, and varicella for a period of at least 6 weeks and 
up to 3 months. After administration of this product, an interval of 3 months should elapse 
before vaccination with live attenuated virus vaccines. In the case of measles, this impairment 
may persist for up to 1 year. Therefore, subjects receiving measles vaccines should have their 
antibody status checked before treatment. 
7.2 
Permitted Therapies 
Prednisone or equivalent to ≤ 7.5 mg/day, mycophenolate (≤ 3g/day), methotrexate 
(≤ 25 mg/week), azathioprine (≤ 3 mg/kg/day), hydroxychloroquine (≤ 400 mg/day; stable 
dose 1 month before screening) are permitted during the study. There can be no change in 
these permitted concomitant therapies during the study; however, temporary adjustment to 
permitted stable treatment during the study (eg. immunosuppressant dose interruption during 
infection or acute treatment with prednisone for systemic reaction / allergy) will be allowed. 

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7.3 
Prohibited Therapies 
Excluded Previous and Concomitant Therapy 
The following medications / therapy are prohibited: 
• Within 1 month or 5 times the half-life, whichever is longer: 
o Tocilizumab 
o Tumor necrosis factor-α inhibitors 
o Abatacept 
o Any other non-topical immunosuppressive or immunomodulatory medications 
• Within 3 months or 5 times the half-life, whichever is longer: 
o Plasma exchange, blood, or IgG 
o Cyclophosphamide 
• Within 6 months before screening: 
o Rituximab 
7.4 
Reproductive Restrictions  
To be eligible for study participation, female subjects should be either: 
• Post-menopausal (24 consecutive months of spontaneous amenorrhea and age ≥ 51) 
• Surgically sterile (having undergone one of the following surgical procedures: 
hysterectomy, bilateral tubal ligation, bilateral oophorectomy or bilateral salpingectomy) 
and at least 3 months post-sterilization 
• Females with a negative serum pregnancy test at screening and negative urine pregnancy 
test on Week 1 before dosing 
Female subjects of childbearing potential or male subjects must use a medically reliable form 
of contraception for the study duration and for 30 days after the last infusion of IP. 
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 IP 

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• 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 
• At least 2 barrier methods. For example, female or male condoms with spermicidal foam 
or spermicidal jelly, or diaphragm with spermicidal foam or spermicidal jelly. The female 
condom and male condom should not be used together 
• Use of intrauterine device (placed more than 3 months before providing informed 
consent) 
• Bilateral tubal occlusion of female subjects (3 months before providing informed consent) 
• Vasectomy of male subjects (3 months before providing informed consent) 
Periodic abstinence (calendar, symptothermal, postovulation methods), withdrawal (coitus 
interruptus), spermicides only, and lactational amenorrhoea method are NOT acceptable 
definitions of contraception. 
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 evaluations may be performed, if 
clinically indicated, at the discretion of the investigator. Refer to the provided study manuals 
for detailed instructions on how the assessments should be performed. 
All assessments and procedures are to be performed by an investigator or a qualified designee 
who has been trained on the study protocol. 
8.1.1 
Demographics, Baseline, and Safety Assessments 
Demographic information such as age, sex, ethnicity / race will be collected as allowed by 
local law. 
Medical history will include specific questions on SSc (date of diagnosis, date of first 
Raynaud's phenomena, date of the first non-Raynaud and its description). The history of co-
morbid autoimmune disorders will be collected. Medical history will also include tobacco 
use. Additionally, specific cardiopulmonary, renal, and TEE risk history will be obtained. 

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The clinical procedures to be conducted during this study-related to the evaluation of safety 
are provided in Table 1. Clinical laboratory assessments are to be performed at time points as 
detailed in the Schedule of Assessments. The time windows for each type of assessment are 
detailed in Table 2.  
Table 1 
Baseline and Safety Assessments 
Assessment 
Description 
Physical 
examination 
Full: an evaluation of the following 
body systems: general appearance, 
hydration status, skin, eyes / ears / 
nose / throat, spine / neck / thyroid, 
musculoskeletal, cardiovascular, 
pulmonary, abdomen, and 
neurological 
Abbreviated: a review of the 
following body systems: hydration 
status, skin, cardiovascular, 
respiratory, and abdomen 
ECG  
Heart Rate 
QT Interval 
QRS Duration 
Interpretation (investigator’s overall 
interpretation) 
PR Interval 
QTcB Interval 
QTcF Interval 
Vital signs 
BP (Systolic and Diastolic) in mmHg 
Respiratory rate (breaths / minute) 
Pulse rate (beats per minute) 
Body temperature (Celsius) 
Pregnancy test 
 
Urine or serum test for β-hCG, as indicated for women of childbearing 
potential 
Document contraception method 
Hematology 
laboratory tests 
 
Hb 
DAT 
ESR 
Leukocytes with 
differential counts 
(neutrophil, basophils, 
eosinophils, 
lymphocytes, 
monocytes) 
Hct 
Platelets 
Erythrocytes (RBC 
Count) with all indices 
IgA 
Spherocytes 
d-dimersa 
Reticulocytes 
RBC: MCV; MCH; 
MCHC; RDW 
ABO blood group 
including Rh factor 

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Assessment 
Description 
Serum chemistry 
laboratory tests 
 
Bicarbonate 
Urate (Uric Acid) 
Glucose 
LDH 
ALT 
AST 
eGFR 
Haptoglobin 
Potassium 
Phosphate 
Albumin 
ALP 
Bilirubin (total, direct 
and indirect) 
GGT 
Creatinine 
Sodium 
Chloride 
Calcium 
BUN 
CRP 
CK 
Aldolase 
Protein (total) 
Urine clinical 
laboratory tests 
Total urinalysis including microscopic examination of the urine sediment. 
Virology clinical 
laboratory tests 
Blood samples are to be tested for the presence of antibodies to human 
immunodeficiency virus, hepatitis B, and hepatitis C.  
Hemolysis safety 
assessment  
Hematology, serum chemistry, urine for hemolysis testing, physical 
examination; see Section 8.1.1.2 for details 
TEE safety 
assessments 
TEE risk assessment; see Section 8.1.1.3 for details 
Renal function 
assessments 
Serum chemistry (creatinine, BUN, eGFR) and urine testing (albumin / 
creatinine ratio); see Section 8.1.1.4 for details 
PFTs 
Spirometry including 
, 
 
Patient diary 
Review or dispense new diary 
AEs 
Evaluation of all AEs (eg, causality / relatedness, severity, outcome, 
seriousness) 
Evaluation of AEs categorized as ISRs 
ABO = Histo-blood group ABO system transferase; AE = adverse event; ALP = alkaline phosphatase; 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; β-hCG = beta-human chorionic 
gonadotropin; BP = blood pressure; BUN = blood urea nitrogen; CK = creatine kinase; CRP = C-reactive 
protein; DAT = direct antiglobin test; 
 = 
; 
ECG = electrocardiogram; eGFR = estimated glomerular filtration rate; ESR = erythrocyte sedimentation rate; 
 = 
; GGT = gamma-glutamyl transferase; Hb = hemoglobin; Hct = hematocrit; 
IgA = immunoglobulin A; ISR = infusion site reaction; LDH = lactate dehydrogenase; MCH = mean 
corpuscular hemoglobin; MCHC = mean corpuscular hemoglobin concentration; MCV = mean corpuscular 
volume; PFT = pulmonary function test; RBC = red blood cell; RDW = red blood cell distribution width; Rh = 
rhesus; TEE = thromboembolic event 
a 
Will be performed only if TEE risk is high or TEE suspected 
8.1.1.1 
Physical Examination 
A full physical exam will be conducted at Screening, Weeks 1 and 17, and EOT / Early 
Termination by a qualified individual, licensed in their respective state or region (eg, 
physician, physician’s assistant, or nurse practitioner). 
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Full physical examination will include an evaluation of the following body systems: general 
appearance, hydration status, skin, eyes / ears / nose /throat, spine / neck / thyroid, 
musculoskeletal, cardiovascular, pulmonary, abdomen, and neurological. Abbreviated 
physical examination, performed at time points as detailed in the Schedule of Assessments, 
will be composed of a review of the following body systems: hydration status, skin, 
cardiovascular, respiratory, and abdomen. 
Any unfavorable findings considered by the investigator to be clinically significant at 
screening will be documented in the medical history of the subject. Unfavorable changes 
occurring thereafter will be documented as an AE.   
8.1.1.2 
Hemolysis Safety Assessment  
Clinical hemolysis will be assessed at time points as detailed in the Schedule of Assessments. 
The time windows for each assessment are detailed in Table 2. 
Criterion A  
• Drop in hemoglobin of > 1 g/dL within a 28-day interval since the time of last 
administration of IgPro10 without clinical evidence of blood loss from gastrointestinal 
bleeding, menorrhagia, hemoptysis, major hematoma, or injury and not explained by 
repeated phlebotomy.  
Criterion B 
Presence of minor criteria documented within 28 days of last exposure to IgPro10, consisting 
of: 
• Direct antiglobulin test (DAT) positive 
• Haptoglobin < lower limit of normal 
• Lactate dehydrogenase > upper limit of normal  
• Total or indirect (unconjugated) bilirubin > upper limit of normal or jaundiced 
• Hemoglobinuria or red / dark urine 
• Hemoglobinemia 
• Spherocytosis 
• Hepatosplenomegaly 

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Subjects fulfilling criterion A and at least 2 of the minor criteria of criterion B, where 1 of the 
minor criteria must be DAT positive, will be considered to have hemolysis.  
If an AE of hemolysis is reported it should be graded by the investigator using this scale: 
• Grade 1 – Laboratory evidence of hemolysis only (eg, direct antiglobulin test, 
schistocytes, decreased haptoglobin 
• Grade 2 – Clinical evidence of hemolysis and ≥ 2 g/dL decrease in hemoglobin 
• Grade 3 – Transfusion or medical intervention indicated (eg, steroids) 
• Grade 4 – Life-threatening consequences; urgent intervention indicated 
• Grade 5 – Death 
Subjects with hemolysis Grade 3 and above will be assessed by an investigator or medically 
qualified designee whether it is in the best interest of the subject to continue the study and 
safe to continue the investigational treatment. 
8.1.1.3 
Thromboembolic Events Safety Assessment 
To reduce the risk of potential TEEs, this study excludes specific patient groups 
(Section 4.1.2 includes 4 exclusion criteria pertaining to TEE risk). Nevertheless, TEE risk 
will be monitored continuously during the study.  
The Treating Physician will assess the subject for the suspicion of a TEE at every study visit 
using Wells' Deep Vein Thrombosis (DVT) Criteria or Wells' Pulmonary Embolism (PE) 
Criteria. If there is no suspicion of DVT or PE, the Wells’ Criteria will not be assessed and a 
score of “0” will be entered in the eCRF.  
If there is suspicion of DVT or PE (score of ≥ 1), the Wells’ DVT Criteria [Modi et al, 
2016] or Wells’ PE Criteria [Doherty, 2017] numerical score will be assessed and entered in 
the eCRF.  
Positive D-dimer testing in any subject regardless of Wells’ Criteria score requires ultrasound 
imaging to rule out DVT.  
In order to diagnose PE, additional imaging, eg, computerized tomographic pulmonary 
angiography or ventilation / perfusion scan, or other modalities will be done per the site’s 
standard of care.  

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When a diagnosis of DVT or PE is confirmed, IP treatment should be discontinued; however, 
the subject may continue in the study for other study assessments. 
All TEEs, including but not limited to DVT and PE, will be classified as AESIs (see Sections 
9.1.3 and 9.6.4). Follow-up monitoring and treatment (eg, anticoagulation) will be performed 
according to the site’s standard of care using established guidelines (eg, American Society of 
Hematology, 2018).  
8.1.1.4 
Renal Function Assessments 
All subjects will have their renal function assessed as measured by physical examination 
(including weight) and clinical laboratory tests (including serum creatinine, BUN in blood 
and ACR in urine) as detailed in the Schedule of Assessments. 
The recommendations for management of elevation in renal function parameters, including 
subject stopping rules are presented in Figure 2. Acute renal injury events will be reported to 
CSLB as AESIs (see Section 9.1.3). 
Figure 2 
Management of Elevation in Renal Function Parameters 
 
Scr = serum creatinine 
a  
Stages align with creatinine level changes for acute renal injury [Kidney Disease: Improving Global 
Outcomes, 2012]. 
b  
As soon as possible from when abnormal Scr results are reported (within 2 weeks). 
c  
Two consecutive visits / assessments. 
d  
Permanent treatment discontinuation reasons include scleroderma renal crisis and persistent and clinically 
significant increases in systolic or diastolic blood pressure as judged by the investigator. 

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8.1.1.5 
12-lead Electrocardiogram 
A 12-lead ECG will be performed at times specified in the Schedule of Assessments. When 
ECG and PK results are collected on the same day, the ECG must be monitored before the 
PK results are collected. All ECGs will be performed using central ECG provider’s 
equipment. An instruction manual will be provided. The investigator’s assessment of ECG 
tracing as normal or abnormal must be recorded and if abnormal his / her determination of 
whether abnormality is clinically significant or not will be documented.  
Any abnormal findings considered by the investigator to be clinically significant at screening 
will be documented in the medical history of the subject. Unfavorable changes occurring 
thereafter will be documented as an AE. 
8.1.1.6 
Vital Signs 
Vital signs will be measured at times specified in the Schedule of Assessments and will 
include sitting blood pressure (systolic and diastolic), pulse rate, sitting respiratory rate, oral 
or tympanic temperature. Measurements will be taken by a trained individual. The time 
windows for each assessment are detailed in Table 2. 
Any abnormal findings considered by the investigator to be clinically significant at screening 
will be documented in the medical history of the subject. Unfavorable changes occurring 
thereafter will be documented as an AE. 
8.1.1.7 
Pregnancy Tests 
Serum or urine beta-human chorionic gonadotropin (β-hCG) pregnancy tests will be 
conducted at the study sites as indicated in the Schedule of Assessments.  
Entry into the study and continued participation is contingent on negative pregnancy test 
results. Additional pregnancy tests may be performed at the investigator’s discretion. 
8.1.1.8 
Pulmonary Function Tests 
Pulmonary function tests will be performed at times specified in the Schedule of 
Assessments. Subjects will undergo a complete spirometry test, lung volume, and 
 
measurements. PFT measurements will be performed according to American Thoracic 
Society / European Respiratory Society consensus and standardization. The measurements 
will be reported as absolute values and as percentages of predicted. The predicted normal 
values will be calculated according to sex, age, height, and race using the appropriate 
reference ratio. 
 values will be adjusted to anemia (hemoglobin levels). Experienced, 
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trained and certified healthcare professionals will be performing PFTs. Manuals from the 
central laboratory will be provided to sites. 
8.1.1.9 
Clinical Laboratory Tests 
Clinical laboratory tests will be obtained from the subject as outlined in the Schedule of 
Assessments. Clinical laboratory test results from the central and / or local laboratory that are 
outside the normal reference range and are deemed clinically significant by the investigator 
are to be recorded as AEs (Section 9.6.1) or SAEs (Section 9.6.2). Refer to Table 1 for 
specific serum biochemistry, hematology, urinalysis, and virology parameters for testing. 
Safety parameters should be repeated if the specimen is hemolyzed. 
Refer to the Laboratory Manual for details about the collection, storage, handling, and 
transportation of biological specimens. 
For laboratory safety parameters, any instances of absolute values being outside the reference 
range or changes at any visit after study start that are considered by the investigator as 
clinically significant must recorded as AEs. In addition, at the investigator’s discretion, any 
changes or trends over time in laboratory parameters can be recorded as AEs if such changes 
or trends are considered to be clinically relevant, even if the absolute values are within the 
reference range. Verification of sample collection and a notation for out of range laboratory 
results (yes / no) to be assessed for clinical significance will be documented.  
8.1.1.10 
Patient Diary 
Subjects will receive a patient diary at each site visit during the IgPro20 sequence and will be 
instructed to record any side effects that occur between site visits, including start and stop 
dates. Subjects will return the diary at the next site visit and receive a new diary. Investigators 
will review the diaries and determine if any of the side effects qualify as AEs. 
8.1.2 
Pharmacokinetic Assessments 
The PK assessments are to be performed at time points as detailed in the Pharmacokinetic 
Schedule of Assessments. The PK parameters AUC0-tau, AUC0-last, Cmax, and Ctrough will be 
assessed in order to determine the relative bioavailability of IgPro20. 
8.1.3 
Efficacy Assessments 
Efficacy assessments are to be performed at time points as detailed in the Schedule of 
Assessments. The time windows for each type of assessment are detailed in Table 2. 

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Study Product: 
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Protocol version: Amendment 4 
 
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8.1.4 
Pharmacodynamic Assessments 
Not applicable. 
8.1.5 
Other Assessments 
8.1.5.1 
 
 
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8.1.5.2 
 
 
8.1.5.3 
 
 
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8.2 
 
 
8.3 
Blood Samples 
During the study, a maximum total of approximately 218 mL of blood will be taken from 
each subject for mandatory and scheduled laboratory safety assessments, PK evaluations, and 
viral testing. Detailed information on the volume of blood to be sampled for each assessment 
will be available in the ICF and Laboratory Manual. 
Repeat or unscheduled blood samples may be taken for safety reasons or for technical issues 
with the samples. 
Refer to the study Laboratory Manual for details about the collection, storage, handling, and 
processing of blood samples. 
8.4 
Retention of Samples 
Retention samples of serum and plasma for virology will be obtained during the study, as 
specified in the Schedule of Assessments. Virology retention samples will be stored at the 
central laboratory. In case of any evidence of a possible treatment-emergent virus infection 
within 1 year after study completion, the retention sample will be analyzed in the central 
laboratory.  
 
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Study Product: 
IgPro20 (Hizentra®) 
 
Protocol version: Amendment 4 
 
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8.5 
Concomitant Therapies 
All drugs and / or procedures currently being administered to a subject at the time of signing 
informed consent, and which continue to be taken in addition to IgPro20 or IgPro10 during 
the study, are regarded as concomitant therapies and must be documented as such in the 
eCRF. Refer to Section 7.3 for details about prohibited therapies during the study. 
8.6 
Visit Schedule 
Table 2 
Visit / Procedure Time Window (relative to scheduled visit / 
procedure) 
Visit / Procedure 
Time Window (Relative to Visit / Procedure) 
Screening 
Up to 28 days before randomization 
Week 1 through Week 32 
± 2 days 
EOS Phone call (Week 36) 
~28 days after EOT 
Sequence A, Treatment Period 1 
Blood collection for PK  
Weeks 1, 5, 9, 13, 14, and 15 
Refer to the Pharmacokinetic Schedule of Assessments: 
Sequence A for individual sampling time windows. 
Sequence A, Treatment Period 2 
Blood collection for PK  
Weeks 17, 21, 25, 29, 30, 31 and EOT 
/ Early Termination 
Refer to the Pharmacokinetic Schedule of Assessments: 
Sequence A for individual sampling time windows. 
Sequence B, Treatment Period 1 
Blood collection for PK  
Weeks 1, 5, 9, 13, 14, 15, and 16 
Refer to the Pharmacokinetic Schedule of Assessments: 
Sequence B for individual sampling time windows. 
Sequence B, Treatment Period 2 
Blood collection for PK 
Weeks 17, 21, 25, 29, 30, 31, and EOT 
/ Early Termination 
Refer to the Pharmacokinetic Schedule of Assessments: 
Sequence B for individual sampling time windows. 
Hemolysis testing  
Refer to the Schedule of Assessments. 
Renal function assessments 
Refer to the Schedule of Assessments. 
Pregnancy testing 
Before infusion 
Physical examination 
Before infusion 
Vital signs  
Before PK blood sample 
Before PFTs  
Relative to IgPro20 infusion: 
• Within 30 min before infusion 
• Within 30 min after infusion 
Relative to IgPro10 Infusion: 

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• Conduct ECG 
• Perform PFTs (
) 
• Measure vital signs 
• Measure body weight  
• Collection of urine sample to assess the following: 
o Urinalysis 
o Renal function 
o Hemolysis 
• Collection of blood samples to assess the following: 
o Hematology 
o Serum chemistry  
o Serum pregnancy test, if applicable 
o Renal function 
o Virology markers of HIV-1 / -2, Hepatitis B, and Hepatitis C  
o Hemolysis 
o Biomarkers 
o Autoantibodies 
o Serum IgA 
o ABO rhesus 
• TEE safety assessment 
• Conduct 
 
• Assess and record AEs 
• Record prior and concomitant therapies 
8.6.2 
Week 1 (Site Visit; Sequence A and Sequence B) 
Before Randomization 
• Confirmation of inclusion and exclusion criteria 
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• Perform full physical examination 
• TEE safety assessment 
• Perform 
  
• Perform 
 
• Perform 
 
• Conduct ECG 
• Perform PFT (
) 
• Measure vital signs 
• Measure body weight 
• Collection of blood sample for PK assessment (see Pharmacokinetic Schedule of 
Assessments: Sequence A or Pharmacokinetic Schedule of Assessments: Sequence B) 
• Collection of urine sample for Pregnancy test, if applicable 
• Conduct 
 
• Conduct 
 
• Conduct 
 
• Conduct 
 
• 
 score to be derived programmatically 
• Conduct 
 
• Conduct 
 
• Assess and record AEs 
• Record concomitant therapies 
8.6.3 
Sequence A / Treatment Period 1 (IgPro20) 
The following procedures are to be performed at each visit: 
8.6.3.1 
Week 1 (Site Visit) 
After Randomization 
• Dispense IgPro20 patient diary 
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Study Product: 
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Protocol version: Amendment 4 
 
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• IP assignment 
• Infusion of IgPro20 
 
After Infusion 
• Measure vital signs 
• Completion of infusion form 
8.6.3.2 
Weeks 3, 7, and 11 (Site Visits) 
Before Infusion 
• Abbreviated physical exam 
• TEE safety assessment 
• Measure vital signs 
• Measure body weight 
• Review of IgPro20 patient diary / dispense new IgPro20 patient diary 
• Assess and record AEs 
• Record concomitant therapies 
• IP assignment 
• Infusion of IgPro20 (Session 1) 
After Infusion 
• Measure vital signs 
• Completion of infusion form 
8.6.3.3 
Weeks 5, 9, and 13 (Site Visits) 
Before Infusion 
• Abbreviated physical exam 
• TEE safety assessment 
• Measure vital signs 

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Study Product: 
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Protocol version: Amendment 4 
 
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• Measure body weight 
• Collection of blood sample for PK (see Pharmacokinetic Schedule of Assessments: 
Sequence A) and biomarkers (biomarkers are only assessed at Week 5) 
• Collection of urine sample for pregnancy test, if applicable 
• Review of IgPro20 patient diary / dispense new IgPro20 patient diary 
• Assess and record AEs 
• Record concomitant therapies 
• IP assignment 
• Infusion of IgPro20 (Session 1) 
After Infusion 
• Measure vital signs 
• Completion of infusion form 
8.6.3.4 
Weeks 1, 3, 5, 7, 9, 11, and 13 (Home Visits) 
• Assess and record AEs 
• Record concomitant therapies 
• Measure vital signs before and after each session  
• Infusion of IgPro20 (Session 2)  
• Completion of infusion form  
8.6.3.5 
Weeks 2, 4, 6, 8, 10, and 12 (Home Visits) 
• Assess and record AEs 
• Record concomitant therapies 
• Measure vital signs before and after each session  
• Infusion of IgPro20 (Sessions 1 and 2)  
• Completion of infusion form  

CSL Behring 
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Study Product: 
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Protocol version: Amendment 4 
 
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8.6.3.6 
Week 14 (Home Visit) 
• Measure vital signs before and after each session  
• Collection of blood sample for PK (see Pharmacokinetic Schedule of Assessments: 
Sequence A) 
• Assess and record AEs 
• Record concomitant therapies 
• Infusion of IgPro20 (Sessions 1 and 2)  
• Completion of infusion form  
8.6.3.7 
Week 15 (Home Visit) 
• Collection of blood sample for PK (see Pharmacokinetic Schedule of Assessments: 
Sequence A) 
8.6.4 
Sequence A / Treatment Period 2 (IgPro10)  
The following procedures are to be performed at each visit: 
8.6.4.1 
Week 17 (Site Visit) 
Before Infusion 
• Perform full physical examination  
• TEE safety assessment 
• Perform 
  
• Perform 
 
• Perform 
 
• Conduct ECG 
• Perform PFTs (
) 
• Measure vital signs 
• Measure body weight 
• Collection of blood samples to assess the following: 
o Hematology 
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Study Product: 
IgPro20 (Hizentra®) 
 
Protocol version: Amendment 4 
 
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o Serum chemistry  
o Renal function 
o Biomarkers 
o Autoantibody 
o Hemolysis 
o PK (see Pharmacokinetic Schedule of Assessments: Sequence A) 
• Collection of urine sample to assess the following: 
o Urinalysis  
o Renal function 
o Urine Pregnancy test, if applicable 
o Hemolysis 
• Conduct 
 
• Conduct 
 
• Conduct 
 
• Conduct 
 
• Conduct 
 
• Conduct 
 
• 
 score to be derived programmatically 
• Review of IgPro20 patient diary  
• Assess and record AEs 
• Record concomitant therapies 
• IP assignment 
• Infusion of IgPro10 over 2 to 5 consecutive days 
During Infusion 
• Measure vital signs 
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IgPro20_2001 
 
Study Product: 
IgPro20 (Hizentra®) 
 
Protocol version: Amendment 4 
 
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After Infusion 
• Measure vital signs 
• Completion of infusion form 
8.6.4.2 
Weeks 19, 23, and 27 (Site Visits) 
• Abbreviated physical exam 
• TEE safety assessments 
• Collection of blood sample to assess the following: 
o Renal function 
o Hemolysis 
• Collection of urine sample to assess the following:  
o Renal function 
o Hemolysis 
• Assess and record AEs 
• Record concomitant therapies 
8.6.4.3 
Weeks 21, 25, and 29 (Site Visits) 
Before Infusion 
• Abbreviated physical exam 
• TEE safety assessment 
• Measure vital signs 
• Measure body weight 
• Collection of urine sample for pregnancy test, if applicable 
• Collection of blood sample for PK (see Pharmacokinetic Schedule of Assessments: 
Sequence A) 
• Assess and record AEs 
• Record concomitant therapies 
• IP assignment 

CSL Behring 
Study Number: 
IgPro20_2001 
 
Study Product: 
IgPro20 (Hizentra®) 
 
Protocol version: Amendment 4 
 
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• Infusion of IgPro10 over 2 to 5 consecutive days 
During Infusion 
• Measure vital signs 
After Infusion 
• Collection of blood sample for PK (Week 29 only; see Pharmacokinetic Schedule of 
Assessments: Sequence A) 
• Measure vital signs 
• Completion of infusion form 
8.6.4.4 
Week 30 (Home Visit) 
• Collection of blood sample for PK (see Pharmacokinetic Schedule of Assessments: 
Sequence A) 
8.6.4.5 
Week 31 (Site Visit) 
• Abbreviated physical exam 
• Measure body weight 
• Collection of urine samples to assess the following:  
o Renal function 
o Hemolysis 
• Collection of blood samples to assess the following: 
o Renal function 
o Hemolysis 
o PK (see Pharmacokinetic Schedule of Assessments: Sequence A)  
• Assess and record AEs 
• Record concomitant therapies 
8.6.5 
Sequence B / Treatment Period 1 (IgPro10) 
The following procedures are to be performed at each visit: 

CSL Behring 
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IgPro20_2001 
 
Study Product: 
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Protocol version: Amendment 4 
 
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8.6.5.1 
Week 1 (Site Visit) 
After Randomization 
• IP assignment 
• Infusion of IgPro10 over 2 to 5 consecutive days  
During Infusion 
• Measure vital signs 
After Infusion 
• Measure vital signs 
• Completion of infusion form 
8.6.5.2 
Weeks 3, 7, and 11 (Site Visits) 
• Abbreviated physical exam 
• TEE safety assessment 
• Collection of urine sample to assess the following: 
o Renal function 
o Hemolysis 
• Collection of blood sample to assess the following:  
o Renal function 
o Hemolysis  
• Assess and record AEs 
• Record concomitant therapies 
8.6.5.3 
Week 5, Week 9, and Week 13 (Site Visits) 
Before Infusion 
• Abbreviated physical exam 
• TEE safety assessment 
• Measure vital signs  

CSL Behring 
Study Number: 
IgPro20_2001 
 
Study Product: 
IgPro20 (Hizentra®) 
 
Protocol version: Amendment 4 
 
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• Measure body weight 
• Urine pregnancy test, if applicable 
• Collection of blood sample for PK (see Pharmacokinetic Schedule of Assessments: 
Sequence B) and biomarkers (biomarkers are only assessed at Week 5) 
• IP assignment 
• Infusion of IgPro10 over 2 to 5 consecutive days 
• Assess and record AEs 
• Record concomitant therapies 
During Infusion 
• Measure vital signs 
After Infusion 
• Collection of blood samples for PK (Week 13 only; see Pharmacokinetic Schedule of 
Assessments: Sequence B) 
• Measure vital signs  
• Completion of infusion form 
8.6.5.4 
Week 15 (Site Visit) 
• Abbreviated physical exam 
• Measure body weight 
• TEE safety assessment 
• Collection of urine sample to assess the following:  
o Renal function 
o Hemolysis 
• Collection of blood sample to assess the following:  
o Renal function 
o Hemolysis 
o PK (see Pharmacokinetic Schedule of Assessments: Sequence B) 

CSL Behring 
Study Number: 
IgPro20_2001 
 
Study Product: 
IgPro20 (Hizentra®) 
 
Protocol version: Amendment 4 
 
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• Assess and record AEs 
• Record concomitant therapies 
8.6.5.5 
Weeks 14 and 16 (Home Visit) 
• Collection of blood sample for PK (see Pharmacokinetic Schedule of Assessments: 
Sequence B) 
8.6.6 
Sequence B / Treatment Period 2 (IgPro20) 
The following procedures are to be performed at each visit: 
8.6.6.1 
Week 17 (Site Visit) 
Before Infusion 
• Perform full physical examination 
• TEE safety assessment 
• Perform 
  
• Perform 
  
• Perform and 
 
• Conduct ECG 
• Perform PFTs (
) 
• Measure vital signs 
• Measure body weight  
• Collection of blood samples for safety to assess the following: 
o 
Hematology 
o 
Serum chemistry  
o 
Renal function 
o 
Hemolysis 
o 
Biomarkers  
o 
Autoantibody 
o 
PK (see Pharmacokinetic Schedule of Assessments: Sequence B) 
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Study Number: 
IgPro20_2001 
 
Study Product: 
IgPro20 (Hizentra®) 
 
Protocol version: Amendment 4 
 
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Date: 22 February 2021 
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Effective Date: Week commencing 25-June-2018 
• Collection of urine sample to assess the following: 
o 
Urinalysis  
o 
Renal function  
o 
Urine Pregnancy test, if applicable 
o 
Hemolysis 
• Conduct 
 
• Conduct 
 
• Conduct 
 
• Conduct 
 
• Conduct 
 
• Conduct 
 
• 
 score to be derived programmatically 
• Dispense new IgPro20 patient diary 
• Assess and record AEs 
• Record concomitant therapies 
• IP assignment  
• Infusion of IgPro20  
After Infusion 
• Completion of infusion form 
• Measure vital signs 
8.6.6.2 
Weeks 19, 23, 27 (Site Visits) 
Before Infusion 
• Abbreviated physical exam 
• TEE safety assessment 
• Measure vital signs 
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Study Number: 
IgPro20_2001 
 
Study Product: 
IgPro20 (Hizentra®) 
 
Protocol version: Amendment 4 
 
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Date: 22 February 2021 
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• Measure body weight 
• Review of IgPro20 patient diary / dispense new IgPro20 patient diary 
• Assess and record AEs 
• Record concomitant therapies 
• IP assignment  
• Infusion of IgPro20 (Session 1) 
After Infusion 
• Measure vital signs 
• Completion of infusion form 
8.6.6.3 
Weeks 21, 25, and 29 (Site Visits) 
Before Infusion 
• Abbreviated physical exam 
• TEE safety assessment 
• Measure vital signs 
• Measure body weight 
• Collection of blood sample for PK (see Pharmacokinetic Schedule of Assessments: 
Sequence B) 
• Collection of urine sample for pregnancy test, if applicable 
• Review of IgPro20 patient diary / dispense new IgPro20 patient diary 
• Assess and record AEs 
• Record concomitant therapies 
• IP assignment 
• Infusion of IgPro20 (Session 1) 
After Infusion 
• Measure vital signs 

CSL Behring 
Study Number: 
IgPro20_2001 
 
Study Product: 
IgPro20 (Hizentra®) 
 
Protocol version: Amendment 4 
 
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• Completion of infusion form 
8.6.6.4 
Weeks 17, 19, 21, 23, 25, 27, and 29 (Home Visits) 
• Assess and record AEs 
• Record concomitant therapies 
• Measure vital signs before and after each session  
• Infusion of IgPro20 (Session 2)  
• Completion of infusion form  
8.6.6.5 
Weeks 18, 20, 22, 24, 26, and 28 (Home Visits) 
• Assess and record AEs 
• Record concomitant therapies 
• Measure vital signs before and after each session  
• Infusion of IgPro20 (Sessions 1 and 2)  
• Completion of infusion form 
8.6.6.6 
Week 30 (Home Visit) 
• Assess and record AEs 
• Record concomitant therapies 
• Measure vital signs before and after each session 
• Infusion of IgPro20 (Sessions 1 and 2)  
• Completion of infusion form  
• Collection of blood sample for PK (see Pharmacokinetic Schedule of Assessments: 
Sequence B) 
8.6.6.7 
Week 31 (Home Visit) 
• Collection of blood sample for PK (see Pharmacokinetic Schedule of Assessments: 
Sequence B) 
 

CSL Behring 
Study Number: 
IgPro20_2001 
 
Study Product: 
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Protocol version: Amendment 4 
 
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8.6.7 
End of Treatment (Week 32; Sequence A and Sequence B) / 
Early Termination (Site Visit) 
The following procedures are to be performed at the EOT / Early Termination Visit: 
• Perform full physical examination  
• Perform 
  
• Perform 
 
• Perform 
 
• Conduct ECG 
• Perform PFTs (
) 
• Measure vital signs 
• TEE safety assessment 
• Collection of blood samples to assess the following: 
o Hematology 
o Serum chemistry 
o Virology markers of HIV-1 / -2, Hepatitis B, and Hepatitis C  
o Serum pregnancy test, if applicable  
o Renal function, if applicable 
o Hemolysis, if applicable 
o Biomarkers (optional, only for subjects that provided baseline sample) 
o Autoantibody 
o PK, if applicable 
• Collection of urine sample to assess the following: 
o Urinalysis  
o Renal function, if applicable 
o Hemolysis  
• Conduct 
 
• Conduct 
 
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• Conduct 
 
• Conduct 
 
• Conduct 
 
• Conduct 
 
• 
 score to be derived programmatically 
• Conduct 
 (only subjects that completed both 
treatments) 
• Assess and record AEs 
• Record concomitant therapies 
• Review of IgPro20 patient diary, if applicable  
8.6.8 
End of Study (Week 36; Sequence A and  
Sequence B; Telephone Call) 
The safety follow-up EOS Visit (Week 36) is to be conducted via telephone: 
• Assess and record AEs 
• Record concomitant therapies 
 
8.6.9 
Unscheduled Visits (Sequence A and Sequence B) 
The following procedures are to be performed at any unscheduled visit: 
• Assess and record AEs 
• Record concomitant therapies 
• Any other assessments or procedures may be performed at the discretion of the 
investigator 
8.6.10 
Remote Visits During Emergencies 
In the event of a state of emergency or public health threat resulting in restrictions that 
prevent a subject from returning to the study site for required study assessments or 
procedures, these may be conducted remotely with CSLB approval. Options that may be 
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implemented in the event of local restrictions at the discretion of CSLB are provided in 
Appendix 4. 
9 
Adverse Events 
9.1 
Definitions 
9.1.1 
Adverse Event 
As per the ICH guidelines, an AE is any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have a causal relationship with this treatment. An AE can, therefore, be any unfavorable and 
unintended sign (including an abnormal, clinically significant laboratory finding), symptom, 
or disease temporally associated with the use of a medicinal (investigational) product, 
whether or not considered related to the medicinal (investigational) product.  
The period of observation for AEs extends from the time the subject gives informed consent 
until the EOS (see Section 9.4 for further details). 
 Adverse events may include: 
• Exacerbation (ie, an increase in the frequency or severity) of a pre-existing condition 
other than SSc.  
• 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 IgPro20 or IgPro10 administration. 
• Intercurrent illnesses with an onset after administration of IgPro20 or IgPro10. 
 
Adverse events do not include: 
• Events identified at screening that meet exclusion criteria 
• Medical or surgical procedures (the condition that leads to the procedure is the AE) 
• Situations where an untoward medical occurrence has not taken place. For example: 
o Planned hospitalizations (except for receiving IP infusions) due to pre-existing 
conditions, which have not worsened. 
o Hospitalizations that occur for procedures not due to an AE (eg, cosmetic surgery). 

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Protocol version: Amendment 4 
 
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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 IgPro20 or IgPro10. 
o Any concomitant therapy that does not result in any adverse signs or symptoms.  
Laboratory findings do not need to be reported as AEs in the following cases: 
• Laboratory parameters already beyond the reference range at screening, unless a further 
increase / decrease can be considered an exacerbation of a pre-existing condition.  
• Abnormal laboratory parameters caused by mechanical or physical influences on the 
blood sample (eg, in vitro hemolysis) and flagged as such by the laboratory in the 
laboratory report. 
• Abnormal parameters that are obviously biologically implausible (eg, values that are 
incompatible with life or outside the measuring range). 
• An abnormal laboratory value that cannot be confirmed after repeat analysis, preferably 
in the same laboratory (ie, the previous result could be marked as not valid and should not 
necessarily be reported as an AE).  
Any clinically significant findings in vital signs, ECG, spirometry, or any other assessment, 
including information in the patient diary that is considered by the investigator to be 
clinically significant should be reported as an AE. 
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 – 
CSLB considers “hospitalization or prolongation of existing hospitalization” for at least 
24 hours as the defining criterion for an SAE. Hospital admissions for planned surgery or 

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for normal disease management procedures (eg, chemotherapy) are not considered as 
defining criteria for SAEs.  
• Results in persistent or significant disability or incapacity. 
• Is a congenital anomaly or birth defect. 
• Is medically significant – A medically significant event is defined as an event that does 
not necessarily meet any of the SAE criteria, but which is judged by a physician to 
potentially jeopardize the subject or require medical or surgical intervention to prevent 
one of the above outcomes listed as an SAE criterion. 
Adverse events that do not fall into the above categories are defined as nonserious AEs. 
9.1.3 
Adverse Event of Special Interest 
An AESI is an AE of scientific and medical concern specific to the sponsor’s product or 
program, for which ongoing monitoring and rapid communication by the investigator to the 
sponsor is appropriate. Such an event might require further investigation in order to 
characterize and understand it. Depending on the nature of the event, rapid communication by 
the sponsor to other parties (eg, IDMC, regulators) might also be warranted.  
The safety risk management plan of IgPro20 specifies the ‘Important Identified Risks’ and 
‘Important Potential Risks’ for IgPro20. This involves systemic reactions reported to occur 
with IgPro20. 
In this study, hemolysis, TEEs, and acute renal injury will be treated as AESIs.  
All hemolysis events under the standardized MedDRA queries (SMQ) “hemolytic disorders, 
broad” will be considered AESI. 
The following 3 narrow SMQs will be utilized for TEE evaluation: 
• Embolic and thrombotic events, arterial 
• Embolic and thrombotic events, venous 
• Embolic and thrombotic events, vessel type unspecified and mixed arterial and 
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All acute renal injury events under SMQ “acute renal failure, narrow” will be considered 
AESIs. 
9.1.4 
Medical Device Incident 
A medical device incident is any malfunction or deterioration in the characteristics and / or 
performance of a device as well as any inadequacy in the labeling or the instructions for use 
which, directly or indirectly, might lead to or might have led to the death of a 
subject / user / other person or to a serious deterioration in his / her state of health.  
Note, not all medical device incidents lead to death or serious deterioration in health. The 
nonoccurrence of such a result might have been because of fortunate circumstances or to the 
intervention of health care personnel. 
Examples of medical device incidents include: 
• A subject, user, caregiver, or healthcare professional is injured as a result of a medical 
device failure or its misuse. 
• A subject’s study intervention is interrupted or compromised by a medical device failure. 
The reporting requirements for medical device incidents are detailed in Section 9.6.3. 
9.2 
Intensity of Adverse Events 
The intensity of each AE is to be assessed by the investigator as follows: 
Severity 
Definition 
Mild 
A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual activities 
of daily living. 
Moderate 
A type of AE that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, causing 
discomfort but poses no significant or permanent risk of harm to the subject. 
Severe 
A type of AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention. 
9.3 
Causality of Adverse Events 
The causal relationship of an AE to IgPro20 or IgPro10 must always be assessed by the 
investigator. All AEs will be classified as either related or not related to IgPro20 or IgPro10. 

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If a causality assessment is not provided for an AE (including an SAE), that AE will be 
considered related to IgPro20 or IgPro10. 
The degree of certainty with which an AE is attributed to IgPro20 or IgPro10 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 IgPro20 or IgPro10. 
• Clinically and / or pathophysiologically plausible context. 
• Reaction of a similar nature previously observed with similar products, or reported in the 
literature for similar products as being product related (eg, headache, facial flushing, 
pallor). 
• Plausibility supported by the temporal relationship (eg, the event being related by time to 
administration or termination of treatment with IgPro20 or IgPro10, drug withdrawal or 
reproduced 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 of giving written informed consent for participation in the current study and 
finish 4 weeks after the last visit.  
If the investigator becomes aware of an SAE or that has started after the observation period 
has finished, and there is at least a possible causal relationship to IgPro20 or IgPro10, the 
event must be reported to CSLB (see Section 9.6.2). 
Medical device incidents or malfunctions that result in an AE are to be reported during all 
periods of the study in which the medical device is used. If the investigator becomes aware of 
any incident that has started after a subject has been discharged from the study, and such 
incident is considered at least possibly related to a medical device provided for the study, the 
event must be reported to CSLB (see Section 9.6.3). 
9.5 
Follow-up of Adverse Events 
Every effort should be made to follow AEs until resolution or stabilization. Ongoing, 
non-serious AEs that have not resolved or stabilized will be followed until the subject 
completes the study. Serious adverse events will be followed until the AE resolves, stabilizes, 
or the subject is lost to follow-up or death.  

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All medical device incidents involving an AE will be followed and reported in the same 
manner as other AEs. 
9.6 
Adverse Event Reporting 
9.6.1 
Adverse Events 
At each clinical evaluation, the investigator (or delegate) will determine whether any AEs 
have occurred. AEs will be recorded in the AE page of the eCRF. If known, the medical 
diagnosis of an AE should be recorded in preference to the listing of individual signs and 
symptoms. The investigator must follow-up on the course of an AE until resolution or 
stabilization. If an AE is ongoing after the EOS Visit, the AE will continue to be followed up 
until resolution, stabilization, or the subject is lost to follow-up. 
If, during the study period, a subject presents with a pre-existing condition that was not noted 
at the time of study entry, the condition should be retrospectively recorded in the Medical 
History eCRF. 
9.6.2 
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 
IgPro20 or IgPro10, must be reported and entered into the eCRF immediately (within 
24 hours of the event) to CSLB.  
Adverse events occurring in the period between the times the subject gave written informed 
consent and the first exposure to IgPro20 or IgPro10 that meet 1 or more of the seriousness 
criteria will 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 EOS Visit that is considered to be causally related to IgPro20 
or IgPro10 must be reported immediately (ie, within 24 hours of the investigator 
becoming aware of the event) to CSLB.  

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The minimum reporting requirements for reporting of SAEs include: 
• Subject identification number. 
• Suspected medicinal product and / or procedure. 
• Event term. 
• Reporting source identification. 
If the minimum requirements for reporting are fulfilled, the investigator should not wait to 
receive additional information to fully document the event.  
In addition, the investigator must: 
• Report all SAEs to the relevant Institutional Review Board (IRB) / Independent Ethics 
Committee (IEC) within the timeframe specified by the IRB / IEC. 
• Enter follow-up information in the eCRF until the SAE has resolved, or, in the case of 
permanent impairment, until stabilized. 
• Ensure that the causality assessment for any SAE is entered in the eCRF. 
In cases of death, the investigator should supply CSLB and the IEC / IRB (as applicable) with 
any additional information as it becomes available (eg, autopsy reports and detailed medical 
reports). 
9.6.3 
Medical Device Incidents 
The investigator must promptly report all incidents occurring with any medical device 
provided for use in the study in order for CSLB to fulfill the legal responsibility to notify 
appropriate regulatory authorities and other entities about certain safety information relating 
to medical devices being used in clinical studies 
Any event that meets the definition of a medical device incident must be documented in the 
appropriate page of the eCRF immediately (within 24 hours of the investigator becoming 
aware of the event). Medical device incidents that meet the definition of an AE or SAE must 
also be reported as described in Section 9.6.1 (AEs) and Section 9.6.2 (SAEs). 
9.6.4 
Adverse Events of Special Interest Incidents 
Adverse events of special interest, whether or not causally related to IgPro20 or IgPro10, 
must be reported and entered into the eCRF immediately (within 24 hours of the event) to 

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CSLB. 
Any AESIs that occurs after the EOS Visit that is considered to be causally related to IgPro20 
or IgPro10 must be reported immediately (ie, within 24 hours of the investigator becoming 
aware of the event) to CSLB. 
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 9.6.2).  
Details (ie, volume, location of infusions, infusion rate) of administration of IgPro20 or 
IgPro10 (defined in Section 5.1.3.2) 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 who becomes pregnant while participating in the study, or up to and 
including 30 days after the last dose of IgPro20 or IgPro10, must notify the investigator 
immediately.  
If a female subject becomes pregnant, she must discontinue treatment with IgPro20 or 
IgPro10, 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). 
CSLB must be notified within 5 days of the investigator becoming aware of the pregnancy.  
Whenever possible, a pregnancy in a subject exposed to IgPro20 or IgPro10 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 CSLB using a 
Pregnancy Reporting / Outcome Form.  
9.7 
IRB / IEC Reporting Requirements 
The time frame within which an IRB / IEC must be notified of deaths and IP-related 
unexpected SAEs is stipulated by each IRB / IEC. It is the investigator’s responsibility to 

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comply with the requirements for IRB / IEC notification. CSLB will provide investigators 
with all details of all SAEs reported to regulatory authorities. 
10 
Statistics 
10.1 
Sample Size Estimation 
The sample size is mainly based on feasibility, not driven by power calculations for statistical 
hypothesis testing. However, based on the 9 IgPro20 studies completed by CSLB (8 studies 
on PID and 1 study in CIDP), the rate of ISRs per IgPro20 infusion is expected to be 
approximately 0.1, with 0.5 likely to be the maximum. With the target sample size of 20 
subjects (10 patients per sequence) and each subject receiving 28 IgPro20 SC infusions, there 
are a total of 560 planned IgPro20 infusions overall for the entire study. If the rate of ISRs per 
infusion is 0.1, the study will have 80% chance to have a 95% CI with half width ≤ 0.0261 
using Wilson score method; if the rate is 0.5, the half width of the 95% CI will be ≤ 0.0414. 
10.2 
Description of Study Analysis Sets 
10.2.1 
Full Analysis Set 
The Full Analysis Set (FAS) will comprise all subjects who provide informed consent / assent 
and who are enrolled in the study after Screening. Screening failures will not be included in 
the FAS. However, the number of screening failures will be summarized in the disposition 
tables and all screening failures will be listed.  
10.2.1.1 
Safety Analysis Set 
The Safety Analysis Set (SAF) will comprise all subjects who receive at least 1 infusion of 
IgPro20 or IgPro10. 
10.2.1.2 
Pharmacokinetic Analysis Set 
The PK Analysis Set will be primarily used for the PK parameter (AUC0-tau, AUC0-last, Cmax, 
and Ctrough) estimation and analysis. The PK Analysis Set will comprise all subjects in the 
safety population who receive at least 1 infusion of IgPro20 or IgPro10 and for whom at least 
1 concentration value is reported.  
Reasons for exclusion from the PK Analysis Set (eg, potentially confounding concomitant 
medication or major protocol deviations) will be assessed case-by-base before database lock. 

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10.3 
Statistical Analyses and Methods 
A complete description of the statistical analyses and methods will be available in the 
Statistical Analysis Plan, which will be finalized before database lock. 
For continuous endpoints, descriptive statistics including number of subjects (n), mean, SD, 
median, first quantile, third quantile, minimum, and maximum, will be provided. For 
categorical variables, frequency distributions with counts and corresponding percentages of 
subjects in each category, will be calculated. 
10.3.1 
Subject Disposition and Characteristics 
10.3.1.1 
Subject Disposition 
Summary tables by treatment sequence, treatment period, and total population will present: 
• The number of subjects enrolled into the study (ie, signed the ICF) (FAS set). 
• The number of subjects treated (SAF set). 
• The number of subjects who completed study treatment. 
• The number of subjects who prematurely discontinued IP. 
• The number of subjects who were withdrawn from the study. 
Reasons for discontinuing the IP and withdrawing a subject from the study will be listed by 
subject. 
10.3.1.2 
Subject Characteristics 
Subject characteristics will be presented in summary tables. Continuous data will be 
summarized in descriptive statistics by treatment sequence. Categorical data will be 
summarized in frequency distributions by treatment sequence. Age will be described as both 
a continuous and a discrete variable. Supportive data will be listed by subject. 
10.3.2 
Analyses of Primary Endpoints 
10.3.2.1 
Safety of IgPro20 
Safety data collected while subjects are treated with IgPro20 will be summarized by 
treatment sequence. All AEs will be coded by the Medical Dictionary for Regulatory 
Activities in System Organ Class and Preferred Term. Treatment-emergent adverse events, 
defined as AEs reported at or after the start of the first infusion in the study, will be 
summarized in number and percentages by treatment sequence. Summaries of TEAEs by 

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severity, causal relationship, seriousness, and leading to interruption and / or withdrawal will 
be provided. 
Infusion site reactions will also be summarized separately following the analyses for all 
TEAEs. Additional summary statistics including 95% CIs will be presented for rate of ISRs 
per subject and per infusion. Descriptive statistics of time to onset and duration of ISRs will 
be presented. Detailed information about ISRs related to infusion sites will be provided. 
10.3.2.2 
Other Clinical Tests 
Observed values and changes from baseline / reference visit to assessment time point in 
clinical laboratory parameters, vital signs will be presented in descriptive statistics by 
treatment, treatment sequence, and combination of treatment and treatment period. ECG, 
PFTs, use of concomitant medications, and clinical significant changes in physical 
examinations will be listed.  
10.3.3 
Analyses of Secondary Endpoints  
10.3.3.1 
Relative Bioavailability of IgPro20 
Relative bioavailability of IgPro20 will be assessed using Mixed Model Repeated Measures 
on Log-transformed Dose-normalized AUC0-tau. The model will include treatment, treatment 
period, and treatment-by-period interaction as fixed effects, and subject as a random effect 
with an unstructured covariance matrix. Geometric mean ratio and corresponding 90% CI 
derived from the statistical model will be used to assess the relative bioavailability of IgPro20 
based on dose-normalized AUC0-tau. In addition, the relative bioavailability of IgPro20 will be 
summarized in descriptive statistics by sequence. 
Subjects with either IgPro20 or IgPro10 dose-normalized AUC0-tau unavailable will be 
excluded from the assessment of relative bioavailability. 
10.3.3.2 
Pharmacokinetic Parameters 
The PK parameters (AUC0-tau, AUC0-last, Cmax, and Ctrough) will be derived from serum IgG 
levels using a non-compartmental analysis approach. PK parameters will be summarized 
descriptively by sequence and treatment period with geometric means and corresponding 
95% CI. 
Additional information on the analyses of PK parameters will be provided in the Statistical 
Analysis Plan. 

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10.3.3.3 
Safety of IgPro10 
Safety data of IgPro10 will be summarized in the same manner as IgPro20 as described in 
Section 10.3.2.1. In addition, hemolysis will be analyzed descriptively. 
10.4 
 
 
 
CCI
CCI

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10.4.1 
Extent of Exposure 
Summary statistics will be provided to describe treatment administration data on infusion 
level and on subject level by treatment. The characteristics of treatment administration to be 
summarized include but are not limited to, treatment duration, planned and actual volumes, 
infusion rates, and infusion duration. The data will be listed by subject with additional 
information on the lot number, start and end date, time of infusion, and dose adjustment if 
applicable. 
10.4.2 
Interim Analyses 
An interim analysis is planned after all subjects randomized to Sequence A have finished 
IgPro20 treatment (Treatment Period 1). This interim analysis is planned for safety review 
and reporting. 
11 
Quality Assurance 
The study may be subject to an audit by CSLB, an authorized representative(s) of CSLB 
and / or inspections by an authorized regulatory authority (eg, US Food and Drug 
Administration). Regulatory authorities may request access to all study documentation, 
including source documents for inspection and copying, in keeping with local regulations. 
CSLB will notify the investigator of any upcoming audit / inspection. 
In the event of an audit, all pertinent study-related documentation must be made available to 
the auditor(s). If an audit or inspection occurs, the investigator at each study site will permit 
the auditor / inspector direct access to all relevant documents and allocate their time as well 
as the time of relevant staff to discuss the findings and any relevant issues. 
12 
Regulatory and Ethics Considerations 
12.1 
Regulatory Considerations 
CSLB or its agents will submit the appropriate documents to the local regulatory agencies 
and will await approval before study start. 
This study will be conducted under a registered clinical trial application in the EU, and under 
Therapeutic Goods Administration Clinical Trial Notification and documented in accordance 
with the applicable regulatory guidelines and requirements. 
The procedures set out in this study protocol are designed to ensure that CSLB and the 
investigator abide by the principles of the current ICH GCP guideline on the conduct, 

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evaluation and documentation of this study, as described in ICH Topic E6 (Guideline for 
GCP). The study will also be carried out according to all applicable international and national 
regulatory requirements. 
12.2 
Institutional Review Board / Independent Ethics Committee 
The investigator must submit the protocol and 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 and the principles in 
the Declaration of Helsinki must be implemented in this clinical study before protocol-
specified procedures are carried out. Information should be given in both oral and written 
form and should be deemed appropriate by the IRB / IEC. Subjects, their relatives (or if 
necessary, legally acceptable representatives) must be given ample opportunity to inquire 
about details of the study. 
The subject (or if necessary, legally acceptable representatives) must be provided with a copy 
of the signed informed consent form. 
Should there be any amendments to the protocol that would directly affect the subject’s 
participation in the study (eg, a change in any procedure), the ICF must be amended to 
incorporate this modification. Subjects must be informed of the change and they must sign 
the amended ICF indicating that they re-consent to participate in the study. 
12.4 
Subject Confidentiality 
All subject names and contact details will be kept confidential. Subjects will be identified 
throughout documentation and evaluation by the number allotted to them during the study. 
Each subject will be told that all study findings will be handled in the strictest confidence. 
The investigator at the study site will be responsible for retaining sufficient information about 
each subject (eg, name, address, phone number and identity in the study) so that regulatory 
agencies or CSLB 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 
CSLB employees or their duly authorized representatives, a regulatory authority or the 

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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 
CSLB 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 / CSLB are 
provided in the Clinical Trial Agreement for the study (see Section 13.1). 
13 
Administrative Considerations 
13.1 
Clinical Trial Research Agreement 
This study will be conducted under a Clinical Trial Agreement between CSLB (“Sponsor”) 
and the institution(s) representing the investigational study site(s) (“Authority”). Financial 
support to the investigational site(s) will be detailed in the Clinical Trial Agreement. The 
Clinical Trial Agreement must be signed before the commencement of the study and will 
clearly delineate the responsibilities and obligations of investigator and CSLB, and will form 
the contractual basis under which the clinical study will be conducted. Clinical Trial 
Agreements may be executed by electronic signature (current provider DocuSign) in 
compliance with 21 CFR Part 11 and simple or advanced electronic signature according to 
EU Regulation No 910/2014 – eIDAS. 
13.2 
Clinical Study Registration and Results Disclosure  
CSLB will provide the relevant study protocol information in public database(s) before or at 
commencement of the study. CSLB may also provide study information for inclusion in 
national registries according to local regulatory requirements. 
Results of this study will be disclosed according to the relevant regulatory requirements. All 
publications in peer-reviewed medical journals resulting from this study will be listed in the 
original study protocol registration record. 
13.3 
Implementation of the Protocol / Protocol Amendment(s) 
With the exception of medical emergencies, no changes or deviations in the conduct of the 
signed protocol will be permitted without documented approval of the CSLB Medical 
Monitor or designee and the IRB / IEC. In the event of a medical emergency, the investigator 

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at the study site will institute any medical procedures deemed appropriate. However, all such 
procedures must be promptly reported to the CSLB Medical Monitor and the IRB / IEC.  
Modifications to the protocol that may affect subject safety or the way the study is to be 
conducted will be documented in a protocol amendment, which must be approved by the 
IRB / IEC.  
Administrative changes to the protocol, defined as minor corrections and / or clarifications 
that have no effect on the way the study is to be conducted, will not require IRB / IEC 
approval, but will be submitted to the IRB / IEC for their information. 
13.4 
Protocol Deviations 
All instances where the requirements of the study protocol were not complied with will be 
tracked. Corresponding subjects may be withdrawn from the study at the discretion of the 
investigator and / or CSLB. Study protocol deviations arise when either subjects who have 
been entered in the study and / or the study sites deviate from the IEC / IRB-approved study 
protocol.  
If a major protocol deviation (ie, a deviation that could have a significant effect on the 
subject’s safety, rights, or welfare and / or on the integrity of the study data) occurs, the 
investigator must notify CSLB and the appropriate IRB / IEC as soon as possible or as per 
local requirements.  
13.5 
Documentation and Record Keeping  
13.5.1 
Data Collection 
The investigator (or delegate) will maintain individual records for each subject. These records 
should include dates when a subject visited the study site, records of vital signs, medical 
history, or physical examinations, administration of IgPro20, IgPro10, 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). In this study, the 
eCRF will not be used as the source document. 
An eCRF will be provided by CSLB (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 

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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). 
An eCOA solution will be used by the subjects and / or sites.  
The eCOA solution is provided as a means to capture electronic source data in a controlled 
and consistent way, and to provide access for investigators to these source data. The system 
also allows the subject's health status to be remotely monitored during the study. The data 
residing in the eCOA system provider’s database are considered the source, and are under the 
control of the investigator at all times. 
The investigator (or delegate) will have access to all eCOA data entered at site via a secure, 
role-based web portal provided by an external eCOA system provider. The eCOA system 
provider will transfer a copy of the source data across to CSLB's clinical data warehouse at a 
predefined frequency via a secure data channel for systematic review by the CSLB clinical 
team. 
The eCOA vendor engaged for this study is responsible for providing a solution that 
conforms to all pertinent regulations. The solution is not in any way intended as a substitute 
for normal medical care of the subject. The vendor provides the service of hosting of the 
eCOA data on behalf of the study investigators, until such a time as the investigator is in 
receipt of a certified archive copy of all data relating to subjects at that site and has confirmed 
it is readable. 
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. CSLB’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). 

CSL Behring 
Study Number: 
IgPro20_2001 
 
Study Product: 
IgPro20 (Hizentra®) 
 
Protocol version: Amendment 4 
 
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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 CSLB (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 CSLB’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 CSLB or a competent 
regulatory authority. 
Following completion of the study, the investigator is responsible for archiving the 
investigator’s study file, the subject’s records and the source data according to applicable 
regulatory requirements.  
13.6 
Study and Site Closure 
CSLB 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 CSLB 
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 clinical study report will be written after the completion of the study. CSLB or its agent 
will write the report in consultation with the investigator or, if applicable, a nominated 
coordinating investigator (or delegate). It is required by CSLB that the coordinating 
investigator will sign the clinical study report.  
Progress reports may be provided to the relevant regulatory bodies in accordance with their 
requirements. 

CSL Behring 
Study Number: 
IgPro20_2001 
 
Study Product: 
IgPro20 (Hizentra®) 
 
Protocol version: Amendment 4 
 
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13.8 
Use of Data and Publications 
The rights and obligations of investigators and CSLB concerning any formal presentation or 
publication of data collected as a direct or indirect result of this study will be addressed 
specifically in the Clinical Trial Agreement for the study. 

CSL Behring 
Study Number: 
IgPro20_2001 
 
Study Product: 
IgPro20 (Hizentra®) 
 
Protocol version: Amendment 4 
 
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14 
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Study Product: 
IgPro20 (Hizentra®) 
 
Protocol version: Amendment 4 
 
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IgPro20_2001 
 
Study Product: 
IgPro20 (Hizentra®) 
 
Protocol version: Amendment 4 
 
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Study Product: 
IgPro20 (Hizentra®) 
 
Protocol version: Amendment 4 
 
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Study Product: 
IgPro20 (Hizentra®) 
 
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Signature of Principal Investigator 
 
Study Title: 
A Multicenter, Randomized, Open-label, Crossover, Phase 2 
Study to Evaluate the Safety and Pharmacokinetics of IgPro20 
(subcutaneous immunoglobulin, Hizentra®) and IgPro10 
(intravenous immunoglobulin, Privigen®) in Adults with 
Systemic Sclerosis (SSc) 
Protocol Number: 
IgPro20_2001 
Site Number:  
I have read the Clinical Study Protocol entitled “A Multicenter, Randomized, Open-label, 
Crossover, Phase 2 Study to Evaluate the Safety and Pharmacokinetics of IgPro20 
(subcutaneous immunoglobulin, Hizentra®) and IgPro10 (intravenous immunoglobulin, 
Privigen®) in Adults with Systemic Sclerosis (SSc).” 
By signing this Clinical Study Protocol, I agree to conduct the clinical study, after approval 
by an Institutional Review Board or Independent Ethics Committee (as appropriate), in 
accordance with the Clinical Study Protocol, the standards of Good Clinical Practice (as 
defined by the International Conference on Harmonisation) and applicable regulatory 
requirements. 
Changes to the Clinical Study Protocol will only be implemented after written approval is 
received from CSLB and the Institutional Review Board or Independent Ethics Committee 
(as appropriate) with the exception of medical emergencies. 
I will ensure that study staff fully understand and follow the Clinical Study Protocol. 
 
 
 
(Signature) 
 
 
Date (DD MMM YYYY) 
Printed name 
(Title) 
 
 

CSL Behring 
Study Number: 
IgPro20_2001 
 
Study Product: 
IgPro20 (Hizentra®) 
 
Protocol version: Amendment 4 
 
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Appendix 2 
The American College of Rheumatology / European League 
Against Rheumatism Criteria for the Classification of Systemic 
Sclerosis (SSc) 
 
Item 
Sub-item(s) 
Weight / 
Score† 
Skin thickening of the fingers of both 
hands extending proximal to the 
metacarpophalangeal joints (sufficient 
criteria) 
- 
9 
Skin thickening of the fingers (only count 
the highest score) 
Puffy fingers 
Sclerodactyly of fingers 
(distal to the 
metacarpophalangeal joints 
but proximal to the proximal 
interphalangeal joints) 
2 
4 
Fingertip lesion (only count the highest 
score)  
Digital up ulcers 
Fingertip pitting scars 
2 
3 
Telangiectasia 
- 
2 
Abnormal nail fold capillaries 
- 
2 
Pulmonary arterial hypertension and / or 
interstitial lung disease  
(Maximum score is 2) 
Pulmonary arterial 
hypertension 
Interstitial lung disease 
2 
 
2 
Raynaud’s phenomenon 
- 
3 
SSc-related autoantibodies 
(anticentromere, anti-topoisomerase I 
[anti-Scl-70], anti-RNA polymerase III) 
(maximum score is 3) 
 
3 
Reference:  
van den Hoogen, 2013 
 

CSL Behring 
Study Number: 
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Study Product: 
IgPro20 (Hizentra®) 
 
Protocol version: Amendment 4 
 
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Appendix 3 
Diffuse Cutaneous Systemic Sclerosis (dcSSc) Versus Limited 
Cutaneous Systemic Sclerosis (lcSSc) 
 
 
References  
 
LeRoy and Medsger, 2001 
LeRoy et al, 1988 
 
 
 

CSL Behring 
Study Number: 
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Study Product: 
IgPro20 (Hizentra®) 
 
Protocol version: Amendment 4 
 
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Appendix 4 
Contingency Procedures  
 
In the event of a state of emergency or public health threat resulting in restrictions that 
prevent a subject from returning to the study site for protocol-specified study assessments or 
procedures, some assessments / procedures may be omitted or completed remotely (as 
indicated) with CSL Behring approval. The following options may be implemented “on-
demand” in the event of local restrictions and at the discretion of CSL Behring.   
If the investigator implements changes to the protocol for subject safety and to limit subjects’ 
exposure to COVID-19 other than those specified in these contingencies, those changes 
should be documented as deviations resulting from the COVID-19 pandemic. Documented 
deviations must be reported to the Institutional Review Board (IRB) / Independent Ethic 
Committee (IEC) and appropriate regulatory authorities. 
The purpose of these contingencies is to make coronavirus disease 2019 (COVID-19) 
pandemic related adjustments to the most current protocol. These contingencies are effective 
during the COVID-19 pandemic and provide detailed guidance and procedures to 
investigators, allowing them the flexibility to complete critical safety and efficacy protocol 
assessments while limiting subjects’ exposure to COVID-19 at a study center / site. 
The following apply to subjects who are treated with IgPro20 and IgPro10 during the 
COVID-19 pandemic: 
1. 
Eligibility Confirmation on 
 
 
 
Documented 
 (
) results 
obtained up to 1 year before Screening can be used by investigators for eligibility 
confirmation with prior approval by the Medical Monitor. 
 
Reason: 
• 
 testing at pulmonary centers other than the study center / site may be 
restricted due to management of COVID-19 patients 
• To limit a subject’s potential exposure to COVID-19 at the study center / site 
CCI
CCI
CCI
CCI

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Study Product: 
IgPro20 (Hizentra®) 
 
Protocol version: Amendment 4 
 
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2. 
Body Temperature Measurement / Methodology (Safety Assessment - Vital Signs) 
 
In addition to the listed oral and tympanic measurements of body temperature in 
Section 8.1.1.6, other standard methodologies in use at the study center / site are 
allowed.   
Reason: Allows study centers / sites to follow their standard procedures of body 
temperature collection during the COVID-19 pandemic. 
3. 
For Subjects in the Treatment Period Receiving IgPro20 
 
Scheduled visits can be conducted as a telephone or video conference (remote visit) or 
as a home visit, if approved in advance by the investigator and the Medical Monitor, 
except for Screening, Baseline Week 17 and End of Study Visit. Telephone or video 
conferencing and home visits are intended only to be conducted if a study subject is 
unable to visit the study center / site due to the COVID-19 pandemic. Safety 
assessments, including laboratory tests, should not be missed. If safety assessments are 
unable to be performed at the study center / site, blood and urine samples for safety 
assessments should be collected, if possible, by a home health nurse as a part of a 
home visit.  
 
The following should be performed by designated study site personnel when 
conducting a study visit or portion of a study visit by telephone or video conferencing: 
• Investigational product (IP) assignment (IP may be shipped to the subject’s home 
following a CSL defined procedure) 
• Confirm compliance with and record the results of home pregnancy testing in 
women of childbearing potential at protocol-defined time points (study center / site 
staff to liaise with home health nurse to verify that a pregnancy test was performed 
and record the result)        
• Record concomitant therapies 
• Assess and record adverse events 
• Review the subject diary 
• Thromboembolic Events (TEE) safety assessment 
Note: If the risk for TEE has increased or there is any suspicion that a TEE has 

CSL Behring 
Study Number: 
IgPro20_2001 
 
Study Product: 
IgPro20 (Hizentra®) 
 
Protocol version: Amendment 4 
 
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occurred, the subject should have a full TEE evaluation as per study site's standard of care as 
soon as possible. 
 
The following assessments should be performed by the home health nurse while 
conducting a study visit or portion of a study visit as a home visit: 
• Vital signs, including body weight at protocol-defined time points  
• IgPro20 SC infusion 
• Complete the infusion form including assessment and recording of potential 
adverse events 
• Pharmacokinetic sample collection at protocol-defined time points as needed 
• Safety laboratory sample collection (including pregnancy testing) as needed 
• Assess changes in health and / or concomitant therapies 
• Collect and dispense a new subject diary 
The following assessments are not required when conducting remote visits:  
• Physical examination 
In case the IP has been dispensed from the study center / site to the subject’s home, 
subject personal and medical data will be protected; a special courier service and a 
process that ensures confidentiality will be utilized. 
 
 
Reason: The purpose of this change is to indicate the type of visits required for 
collecting critical safety and efficacy data. 
 
If the investigator implements changes to the protocol for subject safety and to limit 
subjects’ exposure to COVID-19 other than those specified in these contingencies, 
those changes should be documented as deviations resulting from the COVID-19 
pandemic. Documented deviations must be reported to the IRB / IEC and appropriate 
regulatory authorities. 
 
4. 
For Subjects in the Treatment Period Receiving IgPro10 
 
For subjects in the IgPro10 treatment period, procedures should be followed per 
protocol. Actual visits may occur prior to or after a defined visit window if necessary, 
if approved by the Medical Monitor in advance. Intravenous infusions must be 

CSL Behring 
Study Number: 
IgPro20_2001 
 
Study Product: 
IgPro20 (Hizentra®) 
 
Protocol version: Amendment 4 
 
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conducted at the study center / site. Safety assessments, including hemolysis safety, 
renal function, and TEE risk assessments, should not be missed. If safety assessments 
are unable to be performed at the study site, blood and urine samples for hemolysis, 
renal function, and other safety assessments should be collected by a home health 
nurse as a part of a home visit. 
 
Remote Visits (Sequence A: Weeks 19, 23, 27, 31; Sequence B: Weeks 3, 7, 11, 15) 
Site visits at which no infusions are to be given can be conducted remotely via 
telephone or video conferencing if approved in advance by the Medical Monitor. 
Remote telephone or video conferencing study visits are preferred. These remote visits 
are intended only to be conducted when a study subject is unable to attend the study 
site due to the COVID-19 associated restrictions. 
The following critical assessments should be performed by study site personnel when 
conducting a remote study visit or portion of a remote study visit via telephone or 
video conferencing:  
• Record concomitant therapies 
• Assess and record adverse events 
• TEE safety assessment 
Note: If the risk for TEE has increased or there is any suspicion that a TEE has occurred, the 
subject should have a full TEE evaluation as per study site's standard of care as soon as possible. 
• Assess for clinical signs of hemolysis (eg, ask the subject about any changes in 
urine color or skin color, problems associated with physical exercise, chills, 
abdominal pain, or dizziness) 
• Blood and urine samples for hemolysis and renal function safety assessments 
should be collected by a home health nurse as a part of a remote visit 
Note: Study site personnel should liaise with home nursing service to ensure appropriate tests are 
performed according to the protocol.  
 
As stated above, for subjects receiving IgPro10, home infusions are not allowed. If a 
subject who is scheduled for an IgPro10 infusion is unable or unwilling to attend a 
scheduled on-site study infusion visit, that subject should be discontinued from the 
study after discussion with and approval of the Medical Monitor. 

CSL Behring 
Study Number: 
IgPro20_2001 
 
Study Product: 
IgPro20 (Hizentra®) 
 
Protocol version: Amendment 4 
 
Page 131 of 131 
Date: 22 February 2021 
Confidential 
CS-SOP-04-T02 Version 2.0 
 
 
Effective Date: Week commencing 25-June-2018 
Reason: The purpose of these changes is to limit subject exposure to COVID-19 at the 
study center / site yet maintain a safe level of treatment and monitoring of subjects 
receiving IgPro10. 
5. 
Critical Visits 
 
For subjects in either the IgPro20 or IgPro10 treatment periods, Screening, Baseline, 
Week 17, and the End of Treatment (EOT) Visits should be conducted on-site and all 
procedures performed as outlined in protocol. These critical visits may occur at the 
study center / site within the protocol defined visit window and if further adjustment to 
accommodate a subject is needed, an approval by Medical Monitor should be 
requested in advance. If the EOT Visit cannot be performed within the protocol-
defined day the EOT Visit in its entirety should be performed as soon as possible after 
that date. 
 
 
Reason: This change ensures the critical visits and EOT Visit are conducted, at the 
study center / site, even if delayed. 
 
If the investigator deviates from the protocol for subject safety and to limit subjects’ 
exposure to COVID-19 other than those specified in these contingencies, such deviations 
should be documented as resulting from the COVID-19 pandemic and must be reported to 
the IRB / IEC and appropriate regulatory authorities. 
 
If an investigator or the Medical Monitor determines that the safety of a subject cannot be 
assured using the monitoring approaches described within these contingencies, the subject 
should be discontinued from the study. 
 
 

Version: 1.0
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glbdctmp
Print Date: 13-Dec-2022 09:19:06 GMT-05:00
Signature Page
IgPro20_2001 - Protocol Amendment - 4 - 22Feb2021
Signed By
Date (GMT)
Approved-Clinical Safety Physician Approval
24-Feb-2021 20:17:57
Approved-
 Approval
24-Feb-2021 20:33:55
Approved-
 Approval
25-Feb-2021 08:44:49
Approved-Clinical Safety Physician Approval
25-Feb-2021 09:36:55
PPD
PPD
PPD
PPD
PPD
PPD