Conditions: Primary Immunodeficiency
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 49
Healthy volunteers: no

Brief summary:
This multicenter, open-label, parallel-arm, non-randomized study is designed to evaluate safety and tolerability of higher infusion parameters of IgPro20 in subjects with primary immunodeficiency (PID). A total of 45 subjects (including at least 14 \[30%\] pediatric subjects ≤ 17 years of age and at least 9 \[20%\] obese subjects with body mass index \[BMI\] of ≥30 kg/m2) with confirmed PID will be evaluated in the study. The study will include three cohorts of 15 subjects each as follows: i) Pump-Assisted Volume Cohort (weekly infusions), volume per injection site of 25 mL up to 50 mL, ii) Pump Assisted Flow Rate Cohort (weekly infusions), flow rate per injection site of 25 mL/hour up to 100 mL/hour, iii) Manual Push Flow Rate Cohort (2 to 7 infusions per week), flow rate per injection site of 25 to 30 mL/hour up to 120 mL/hour (equivalent of approximately 0.5 mL/minute up to 2 mL/minute). Each cohort will test 3 infusion parameter levels (4 for the pump-assisted flow rate cohort), repeated at least 4 times over a duration of 12 weeks (16 weeks for the flow rate cohort). After 4 infusion weeks at each level, qualifying subjects (responders) will switch to the next infusion parameter level (eg, from 25 to 50 mL/h). During the study, the weekly dose will remain unchanged (as prescribed by treating physician, usually within 100-200 mg/kg per week range); only the respective infusion parameter under evaluation will change.

Detailed description:

Arms:
arm 1: Weekly volumes per injection site of 25 mL up to 50 mL administered subcutaneously. arm 2: Weekly flow rates per injection site of 25 mL/hour up to 100 mL/hour administered subcutaneously. arm 3: Frequent (ie, 2 to 7 times per week) flow rates per injection site of 25 to 30 mL/hour up to 120 mL/hour (equivalent of approximately 0.5 mL/minute up to 2 mL/minute) administered subcutaneously.

Interventions: intervention 1: IgPro20
Intervention descriptions: intervention 1: A liquid formulation of normal human IgG at a concentration of 20% administered as a subcutaneous infusion at a dose prescribed by subject's physician prior to study entry.

Protocol document:
Prot_000.pdf: 
 
 
 
 
 
 
CRD-TPL-077 Version 1.0 
 
Page 1 of 76 
 
Confidential 
 
CLINICAL STUDY PROTOCOL 
 
An Open-Label Multicenter Study to Evaluate the Safety and Tolerability of Higher 
Infusion Parameters of Immune Globulin Subcutaneous (Human), 20% Liquid 
(Hizentra®) in Subjects with Primary Immunodeficiency 
Study Number: 
IgPro20_4004 
Study Product: 
IgPro20 (Hizentra®) 
Development Phase: 
IV 
Sponsor: 
CSL Behring LLC 
1020 1st Avenue 
King of Prussia 
PA 19406-1310 
USA 
Protocol Version: 
Amendment 3 
EudraCT Number: 
Not applicable 
IND Number: 
 
Protocol Date: 
2 December 2017 
Compliance: 
This study will be conducted in accordance with standards of 
Good Clinical Practice (as defined by the International Conference 
on Harmonisation), ethical principles that have their origin in the 
Declaration of Helsinki and all applicable national and local 
regulations.  
 
This protocol includes information and data that contain trade secrets and privileged or confidential information 
that is the property of the sponsor (“CSL”).  This information must not be made public without written 
permission from CSL.  These restrictions on disclosure will apply equally to all future information supplied to 
you.  This material may be disclosed to and used by your staff and associates as may be necessary to conduct the 
clinical study. 
 
 
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List of Personnel and Organizations Responsible for Conduct of the Study 
 
A list of personnel and organizations responsible for the conduct of the study will be supplied 
to study sites as part of the Investigator’s Study File. This list will be updated by CSL (or 
delegate) and provided to the study sites as needed. 
 
 


PPD
33'
PPD


 
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Signature of Investigator 
 
Study Title: An Open-Label Multicenter Study to Evaluate the Safety and Tolerability of 
Higher Infusion Parameters of Immune Globulin Subcutaneous (Human), 20% Liquid 
(Hizentra®) in Subjects with Primary Immunodeficiency 
Protocol Number: 
IgPro20_4004 
I have read the protocol titled “An Open-Label Multicenter Study to Evaluate the Safety and 
Tolerability of Higher Infusion Parameters of Immune Globulin Subcutaneous (Human), 20% 
Liquid (Hizentra®) in Subjects with Primary Immunodeficiency”. 
By signing this 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 protocol, the principles of the Declaration of Helsinki (2008), the standards of Good 
Clinical Practice (as defined by the International Conference on Harmonisation) and 
applicable regulatory requirements. 
Changes to the protocol will only be implemented after written approval is received from 
CSL Behring LLC (CSL) and the Institutional Review Board or Independent Ethics 
Committee (as appropriate), with the exception of medical emergencies. 
I will ensure that study staff fully understand and follow the protocol. 
 
 
 
 
Name of investigator 
Affiliation of investigator 
 
 
Date  
(DD MMM YYYY) 
 
 


 
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Protocol Synopsis 
Title 
An Open-Label Multicenter Study to Evaluate the Safety and Tolerability 
of Higher Infusion Parameters of Immune Globulin Subcutaneous 
(Human), 20% Liquid (Hizentra®) in Subjects with Primary 
Immunodeficiency 
Study Number 
IgPro20_4004 
Sponsor 
CSL Behring LLC (CSL) 
Development Phase 
IV 
Study Product 
IgPro20 (Hizentra®) 
Indication 
Primary immunodeficiency 
Study Summary 
This multicenter, open-label, parallel-arm, non-randomized study is 
designed to evaluate safety and tolerability of higher infusion parameters 
of IgPro20 in subjects with primary immunodeficiency (PID). The study 
will include 3 cohorts with a minimum of15 subjects each as follows: 
• 
Pump-Assisted Volume Cohort (weekly infusions): Volume per 
injection site of 25 mL up to 50 mL. 
• 
Pump-Assisted Flow Rate Cohort (weekly infusions): Flow rate 
per injection site of 25 mL/hour up to 100 mL/hour. 
• 
Manual Push Flow Rate Cohort (2 to 7 infusions per week): Flow 
rate per injection site of 25 to 30 mL/hour up to 120 mL/hour 
(equivalent of approximately 0.5 mL/minute up to 2 mL/minute). 
Each cohort will test 3 (for pump-assisted flow rate cohort – 4) infusion 
parameter levels, repeated at least 4 times over a duration of 12 (for flow 
rate cohort – 16) weeks. After 4 infusion weeks at each level, qualifying 
subjects (responders) will switch to the next infusion parameter level (eg, 
from 25 to 50 mL/h). During the study, the weekly dose will remain 
unchanged (as prescribed by treating healthcare provider, usually within 
100 to 200 mg/kg per week range); only the respective infusion 
parameter under evaluation will change. 
Primary Objective(s) 
The primary objective of this study is to determine the responder rate at 
higher infusion parameters of IgPro20 under the following conditions: 
• 
Pump-Assisted: Volume per injection site of 25 mL, 40 mL, and 
50 mL. 
• 
Pump-Assisted: Flow rate per injection site of 25 mL/h, 50 mL/h, 
75 mL/h and 100 mL/h. 
• 
Manual Push (manual infusion using syringe without a pump): 
Flow rate per injection site of 30 mL/h, 60 mL/h, and 120 mL/h 
(0.5 mL/min, 1 mL/min, and 2 mL/min, correspondingly). 


 
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Primary Endpoint(s) 
The primary endpoints are as follows: 
• 
Pump-Assisted Volume Cohort: Percentage of responders for 
each planned volume (ie, 25 mL, 40 mL and 50 mL per injection 
site). 
• 
Pump-Assisted Flow Rate Cohort: Percentage of responders for 
each planned flow rate (ie, 25 mL/h, 50 mL/h, 75 mL/h and 
100 mL/h per injection site). 
• 
Manual Push Flow Rate Cohort: Percentage of responders for 
each planned flow rate (ie, 30 mL/h [0.5 mL/min], 60 mL/h 
[1 mL/min], and 120 mL/h [2 mL/min] per injection site). 
Secondary Objective(s) 
The secondary objectives of the study are: 
• 
To evaluate the safety of pump-assisted IgPro20 infusions at 
higher infusion parameters (volume and flow rate). 
• 
To evaluate the safety of manual push IgPro20 infusions. 
• 
To evaluate the tolerability of higher infusion parameters of 
IgPro20. 
Secondary Endpoint(s) 
The secondary endpoints are as follows: 
• 
The rate of total adverse events (AEs) per subject and per 
infusion by cohort and by each of the infusion parameter levels 
within the cohort. 
• 
The rate of local reactions per subject and per infusion by cohort 
and by each of the infusion parameter levels within the cohort. 
• 
The time to onset of local reactions per subject and per infusion 
by cohort and by each of the infusion parameter levels within the 
cohort. 
• 
Severity of local reactions per subject and per infusion by cohort 
and by each of the infusion parameter levels within the cohort. 
• 
Duration of local reactions per subject and per infusion by cohort 
and by each of the infusion parameter levels within the cohort. 
• 
For all cohorts: Tolerability of a certain infusion parameter, ie, 
percentage of infusions per cohort by volume/flow rate subgroup 
experiencing no severe local reactions for each of the infusion 
parameter levels. 
Exploratory 
Objective(s) 
 
 
Exploratory 
Endpoint(s) 
 
 
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Study Design 
This multicenter, open-label, parallel-arm, non-randomized study is 
designed to evaluate safety and tolerability of higher infusion parameters 
of IgPro20 in subjects with PID. 
Number of Subjects 
Approximately 50 subjects will be enrolled into the study. A target of 
45 evaluable subjects (ie, 15 subjects per cohort) is needed. Enrolled 
subjects will include a target of 14 (30%) pediatric subjects ≤ 17 years of 
age and a target of 9 (20%) obese subjects with BMI of  ≥ 30 kg/m2. 
Pediatric and obese subjects may be distributed across any or all of the 
treatment cohorts without respect to balanced enrollment within the 
cohorts for these subpopulations. 
Study Duration 
The duration of the study for an individual subject is expected to be 
3 months per subject in the Manual Push Flow Rate and Pump-Assisted 
Volume Cohorts, and 4 months in the Pump-Assisted Flow Rate Cohort. 
The overall study duration (ie, first subject’s Screening visit to last 
subject’s End of Study visit) will be approximately 18 months. 
Study Population and 
Main Criteria for 
Eligibility 
 
Subjects meeting all of the following inclusion criteria may be enrolled 
into the study: 
1. Capable of providing informed consent/assent and willing and 
able to adhere to all protocol requirements. The subject’s 
parent(s) or legally acceptable representative(s) capable of 
providing written informed consent. 
2. Male or female on stable dose of IgPro20 (Hizentra) therapy. 
3. Women of childbearing potential must be using and agree to 
continue using medically approved contraception (which must be 
discussed with the study doctor) and must have a negative 
pregnancy test at Screening. 
4. Subjects with PID, eg, with a diagnosis of common variable 
immunodeficiency or X-linked agammaglobulinemia, as defined 
by the Pan American Group for Immune Deficiency and the 
European Society of Immune Deficiencies or by the International 
Union of Immunological Societies Expert Committee. 
5. With infusion parameters as specified below: 
Pump-Assisted Flow Rate Cohort subjects only* 
5a. Experience with pump-assisted infusions of IgPro20 at the 
tolerated flow rate of 25 mL/h** per injection site for at least 
1 month prior to Day 1.   
Pump-Assisted Volume Cohort subjects only* 
5b. Total weekly IgPro20 dose of ≥ 50 mL (≥ 10 g). 
5c. Experience with pump-assisted infusions of IgPro20 at 
tolerated volumes of 25 mL/injection site for at least 1 month 


 
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prior to Day 1. 
Manual Push Flow Rate Cohort subjects only 
5d. Experience with frequent (2-7 times per week) infusions of 
IgPro20 at the tolerated flow rate of approximately 0.5 mL/min 
(equivalent of 25-30 mL/h) per injection site for at least 1 month 
prior to Day 1. The dose (volume) per injection site should not 
exceed 25 mL. 
*Subjects who tolerated higher infusion parameters relevant for 
their study cohort prior to the study based on their chart records 
will not be allowed to participate in the study. If records are not 
available, information may be obtained by asking the subject. 
**Subjects who use an infusion pump that operates by 
maintaining a constant pressure as opposed to a constant flow 
rate, may not have experienced flow rates that are exactly 
25 mL/h. Flow rates for constant pressure pumps (adjusted for 
needle gauge and infusion tubing size) that are within ± 20% of 
25 mL/h per injection site are acceptable for study entry. 
Study Product Dose, 
Dosing Regimen and 
Administration  
IgPro20 will be administered subcutaneously at a dose prescribed by 
subject’s healthcare provider prior to study entry (usually 100 to 
200 mg/kg per week). Subjects in the Pump-Assisted Cohorts will 
administer weekly treatment and subjects in the Manual Push Cohort will 
administer more frequent than weekly treatment (ie, 2 to 7 times per 
week). 
Comparator Product,  
Dose, Dosing Regimen 
and Administration 
Not applicable. 
Efficacy Assessments 
 
• 
 
 
Safety Assessments 
Safety will be assessed by: 
• 
The frequency and severity of AEs. 
• 
Local reactions (injection site reactions). 
• 
Tolerability of a certain infusion parameter (ie, percentage of 
subjects and infusions per cohort by volume/flow rate subgroup 
experiencing no severe local reactions for each of the infusion 
parameter levels). 
• 
Physical examination. 
• 
Vital signs. 
• 
Clinical laboratory tests. 
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o Biochemistry  
o Hematology  
Pharmacokinetics 
Not applicable. 
Pharmacodynamics 
Not applicable. 
Other Assessments 
Not applicable. 
Statistical Analyses 
Subject Disposition 
The number of subjects who were screened, enrolled into the study, and 
completed the study, will be presented in summary tables by treatment 
group and total subjects. The reason for discontinuing the study product 
or withdrawing a subject from the study will be listed by subject. 
Subject Characteristics 
At a minimum, subject characteristics will be presented in summary 
tables. Continuous data will be summarized by descriptive statistics 
(number of observations, mean, standard deviation, minimum, maximum, 
median, Q1, Q3) and categorical data will be summarized by frequency 
distributions. Age will be described as both a continuous and a discrete 
variable. 
Efficacy Analyses 
 
Safety Analyses 
All safety endpoints will be summarized descriptively only within each 
of the 3 cohort separately. Adverse events will be further summarized by 
the values of infusion parameters within each cohort; rates per injection 
will be presented as well. Adverse events will be presented including a 
virtual System Organ Class comprising local reaction (identified by 
Medical Dictionary for Regulatory Activities high level terms: 
“administration site reactions NEC”, “infusion site reactions”, and 
“injection site reactions”) and by severity. Further, time to onset and 
duration will be presented descriptively. Tolerability of a certain infusion 
parameter within a cohort will be calculated as ‘number of infusions 
without severe local reaction / number of all infusions’ and be presented 
by infusion parameter and cohort. 
Interim Analyses 
Not applicable. 
 
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Schedule of Assessments – Pump-Assisted Flow Rate Cohort 
Study Period 
Screening 
Forced Upward Titration  
End of 
Study
Study Day 
-35 to -7 
1 
8 
15 
22 
29 
36 
43 
50 
57 
64 
71 
78 
85 
92 
99 
106
113±1 day 
Week Number 
1f 
2 
3 
4 
5 f 
6 
7  
8 
9 f 
10 
11 
12 
13 f 
14 
15 
16  
17 f 
Informed consent/assent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion / exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history and 
demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Physical examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Systolic and diastolic blood 
pressure, respiratory rate, pulse 
rate, and body temperature 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Body weight and height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Hematology a & biochemistry b 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Infusion training / supervised 
infusion / supervised entry of 
infusion data in the subject eDiary 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
IgPro20 dispensation and IRT 
update 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
Subject eDiary c training and 
review  
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X g 
IgPro20 administration (weekly 
for pump-assisted infusions) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Serum IgG trough level d 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Adverse events (including 
injection site assessments) e 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant therapies 
X 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
eDiary = electronic diary; IgG = immunoglobulin G; IgPro20 = Hizentra; IRT = Interactive Response Technology. 
a. 
Hematology: hemoglobin, hematocrit, mean corpuscular volume, erythrocytes, leukocytes, differential count, platelets. 
b. 
Biochemistry: sodium, potassium, chloride, bicarbonate, urea, creatinine, gamma glutamyl transferase, alkaline phosphatase, alanine aminotransferase, aspartate 
transaminase. 
c. 
eDiary will be used for collecting infusion parameters and adverse events. A paper diary is available as a back-up if the eDiary is unavailable. As soon as the eDiary becomes 
available, the data from the paper diary must be transcribed into the eDiary and the paper diary retained as source. 


 
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d. 
Within approximately 1 hour before next infusion. 
e. 
Subjects who drop out of the study due to reasons other than ‘consent withdrawn’ or ‘lost to follow-up’ will be followed up by weekly telephone calls by site personnel for 
the full duration of their planned study participation, in order to collect information on AEs. 
f. 
Office visit at Weeks 1, 5, 9, 13, and End of Study. 
g. 
eDiary / back-up paper diary collection and review.  The eDiary device will also be collected, if provisioned.  


 
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Schedule of Assessments – Manual Push Flow Rate & Pump-Assisted Volume Cohorts 
Study Period 
Screening 
Forced Upward Titration  
End of Study 
Study Day 
-35 to -7 
1 
8 
15 
22 
29 
36 
43 
50 
57 
64 
71 
78 
85±1 day 
Week number 
1 f 
2 
3 
4 
5 f 
6 
7  
8 
9 f 
10 
11 
12  
13 f 
Informed consent/assent 
X 
 
 
 
 
 
 
 
 
Inclusion / exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
Medical history and demographics 
X 
 
 
 
 
 
 
 
 
Pregnancy test 
X 
 
 
 
 
 
 
 
 
X 
Physical examination 
X 
 
 
 
 
 
 
 
 
X 
Systolic and diastolic blood pressure, 
respiratory rate, pulse rate, and body 
temperature 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Body weight and height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Hematology a & biochemistry b 
X 
 
 
 
 
 
 
 
 
X 
Infusion training / supervised infusion /
supervised entry of infusion data in the 
subject eDiary  
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
IgPro20 dispensation and IRT update  
X 
 
 
 
X 
 
 
 
X 
 
 
 
Subject eDiaryc training and review  
X 
 
 
 
X 
 
 
 
X 
 
 
 
X g 
IgPro20 administration (weekly for 
pump-assisted infusion; 2 to 7 times per 
week for manual push) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Serum IgG trough level d 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Adverse events (including injection site 
assessments) e 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant therapies 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
eDiary = electronic diary; IgG = immunoglobulin G; IgPro20 = Hizentra; IRT = Interactive Response Technology. 
a. 
Hematology: hemoglobin, hematocrit, mean corpuscular volume, erythrocytes, leukocytes, differential count, platelets. 
b. 
Biochemistry: sodium, potassium, chloride, bicarbonate, urea, creatinine, gamma glutamyl transferase, alkaline phosphatase, alanine aminotransferase, aspartate 
transaminase. 
c. 
eDiary will be used for collecting infusion parameters and adverse events. A paper diary is available as a back-up for use if the eDiary is unavailable. As soon as the eDiary 
becomes available, the data from the paper diary must be transcribed into the eDiary and the paper diary retained as source. 
d. 
Within approximately 1 hour before next infusion. 


 
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e. 
Subjects who drop out of the study due to reasons other than ‘consent withdrawn’ or ‘lost to follow-up’ will be followed up by weekly telephone calls by site personnel for 
the full duration of their planned study participation, in order to collect information on AEs. 
f. 
Office visit at Weeks 1, 5, 9, and End of Study. 
g. 
eDiary / back-up paper diary collection and review.  The eDiary device will be collected, if provisioned. 


 
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Table of Contents 
List of Personnel and Organizations Responsible for Conduct of the Study ........................... 2 
Signature on Behalf of Sponsor ............................................................................................. 3 
Signature of Investigator ....................................................................................................... 4 
Protocol Synopsis .................................................................................................................. 5 
Schedule of Assessments – Pump-Assisted Flow Rate Cohort ............................................. 10 
Schedule of Assessments – Manual Push Flow Rate & Pump-Assisted Volume Cohorts ..... 12 
Table of Contents ................................................................................................................ 14 
List of Tables ...................................................................................................................... 18 
List of Figures ..................................................................................................................... 18 
List of Abbreviations ........................................................................................................... 19 
Definition of Terms ............................................................................................................. 20 
1. 
Introduction ........................................................................................................... 21 
1.1 
Background ........................................................................................................... 21 
1.1.1 
Primary Immunodeficiency ................................................................................... 21 
1.1.2 
Subcutaneous Immunoglobulin Replacement Therapy ........................................... 21 
1.1.3 
Manual Push Technique ........................................................................................ 22 
1.1.4 
SCIG Infusion Parameters ..................................................................................... 23 
1.2 
Background Information on IgPro20 ..................................................................... 25 
1.2.1 
Overview .............................................................................................................. 25 
1.2.2 
Nonclinical Evaluation .......................................................................................... 26 
1.2.3 
Previous Clinical Experience ................................................................................. 27 
1.3 
Study Overview .................................................................................................... 29 
1.4 
Potential Risks and Benefits .................................................................................. 29 
2. 
Study Objectives and Endpoints ............................................................................ 31 
2.1 
Primary Objective and Endpoints .......................................................................... 31 
2.1.1 
Primary Objective ................................................................................................. 31 
2.1.2 
Primary Endpoints ................................................................................................. 31 
2.2 
Secondary Objectives and Endpoints ..................................................................... 32 
2.2.1 
Secondary Objectives ............................................................................................ 32 
2.2.2 
Secondary Endpoints ............................................................................................. 32 
2.3 
Exploratory Objective and Endpoints .................................................................... 33 
2.3.1 
Exploratory Objective ........................................................................................... 33 
2.3.2 
Exploratory Endpoints ........................................................................................... 33 
3. 
Study Design ......................................................................................................... 33 
3.1 
Study Design and Rationale................................................................................... 33 
3.2 
Dose and Dosing Regimen .................................................................................... 35 
3.3 
Planned Study Duration ......................................................................................... 35 
3.4 
Planned Number of Sites ....................................................................................... 35 


 
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3.5 
Planned Number of Subjects ................................................................................. 35 
3.6 
Study Monitoring Procedures ................................................................................ 36 
3.6.1 
Data and Safety Monitoring Board ........................................................................ 36 
3.6.2 
Other Monitoring Committees ............................................................................... 36 
4. 
Selection and Withdrawal of Subjects ................................................................... 36 
4.1 
Eligibility Criteria ................................................................................................. 36 
4.1.1 
Inclusion Criteria ................................................................................................... 36 
4.1.2 
Exclusion Criteria.................................................................................................. 37 
4.2 
Subject Withdrawal ............................................................................................... 38 
4.2.1 
Subject Withdrawal ............................................................................................... 38 
4.2.2 
Procedures for Handling Withdrawals ................................................................... 39 
4.2.3 
Replacement Policy ............................................................................................... 39 
5. 
Study Interventions ............................................................................................... 39 
5.1 
Description of Investigational MEDICINAL Product ............................................ 39 
5.1.1 
IgPro20 ................................................................................................................. 39 
5.1.2 
Comparator Product .............................................................................................. 40 
5.2 
Packaging, Labeling, Supply and Storage .............................................................. 40 
5.2.1 
Packaging and Labeling ........................................................................................ 40 
5.2.2 
Supply and Storage ............................................................................................... 40 
5.3 
Accountability and Destruction ............................................................................. 40 
5.4 
Other Intervention(s) ............................................................................................. 40 
5.5 
Rescue Therapy ..................................................................................................... 41 
6. 
Allocation, Dosing and Administration .................................................................. 41 
6.1 
Allocation to Treatment ......................................................................................... 41 
6.1.1 
Subject Assignment ............................................................................................... 41 
6.1.2 
Randomization Procedures .................................................................................... 41 
6.1.3 
Blinding Procedures .............................................................................................. 41 
6.2 
Dosing and Administration .................................................................................... 41 
6.2.1 
Dosing and Administration .................................................................................... 41 
6.2.2 
Infusion Rates ....................................................................................................... 42 
6.3 
Treatment Compliance .......................................................................................... 43 
7. 
Contraindications, Permitted Therapies and PROHIBITED Therapies ................... 43 
7.1 
Contraindications and Precautions to Further Dosing............................................. 43 
7.2 
Permitted Therapies............................................................................................... 44 
7.3 
Prohibited Therapies ............................................................................................. 44 
7.4 
Dietary and Lifestyle Restrictions .......................................................................... 44 
7.5 
Overdose ............................................................................................................... 44 
8. 
Study Procedures and Visit Schedule ..................................................................... 45 
8.1 
Clinical Procedures ............................................................................................... 45 
8.2 
Retention of Samples ............................................................................................ 46 


 
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8.3 
Concomitant Therapies .......................................................................................... 46 
8.4 
Visit Schedule ....................................................................................................... 46 
8.4.1 
Screening .............................................................................................................. 46 
8.4.2 
Pump-Assisted Flow Rate Cohort .......................................................................... 47 
8.4.3 
Manual Push Flow Rate & Pump-Assisted Volume Cohorts .................................. 50 
8.4.4 
End of Study ......................................................................................................... 53 
9. 
Adverse Events ..................................................................................................... 54 
9.1 
Definitions ............................................................................................................ 54 
9.1.1 
Adverse Event ....................................................................................................... 54 
9.1.2 
Adverse Event of Special Interest .......................................................................... 55 
9.1.3 
Serious Adverse Event .......................................................................................... 55 
9.2 
Severity of Adverse Events ................................................................................... 56 
9.3 
Causality of Adverse Events .................................................................................. 56 
9.4 
Observation Period for Adverse Events ................................................................. 57 
9.5 
Adverse Event Reporting....................................................................................... 57 
9.5.1 
Adverse Events ..................................................................................................... 57 
9.5.2 
Adverse Events of Special Interest ........................................................................ 58 
9.6 
Serious Adverse Event Reporting .......................................................................... 58 
9.6.1 
Requirements for Reporting of Serious Adverse Events ......................................... 58 
9.6.2 
Unusual Failure of Efficacy (Canadian sites only) ................................................. 59 
9.7 
Other Significant Event Reporting ......................................................................... 59 
9.7.1 
Medication Compliance......................................................................................... 59 
9.7.2 
Pregnancy and Lactation ....................................................................................... 60 
9.8 
IRB / IEC Reporting Requirements ....................................................................... 60 
9.9 
Follow-up of Adverse Events ................................................................................ 60 
10. 
Assessments .......................................................................................................... 61 
10.1 
Subject Characteristics .......................................................................................... 61 
10.2 
Efficacy Assessments ............................................................................................ 61 
10.3 
Safety Assessments ............................................................................................... 61 
10.4 
Pharmacokinetic and Pharmacodynamics .............................................................. 62 
10.5 
Other Assessments ................................................................................................ 62 
11. 
Statistics ................................................................................................................ 62 
11.1 
Sample Size Estimation ......................................................................................... 62 
11.2 
Description of Analysis Datasets ........................................................................... 62 
11.2.1 
Full Analysis Set ................................................................................................... 62 
11.2.2 
Safety Population .................................................................................................. 63 
11.3 
Statistical Analyses and Methods .......................................................................... 63 
11.3.1 
Subject Disposition and Characteristics ................................................................. 63 
11.3.2 
Efficacy Analyses.................................................................................................. 63 
11.3.3 
Safety Analyses ..................................................................................................... 63 


 
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11.3.4 
Pharmacokinetics and Pharmacodynamic Data ...................................................... 64 
11.3.5 
Other Analyses – Infusion Parameters ................................................................... 64 
11.3.6 
Interim Analysis .................................................................................................... 66 
12. 
Quality Assurance ................................................................................................. 66 
13. 
Regulatory and Ethics Considerations ................................................................... 67 
13.1 
Regulatory Considerations .................................................................................... 67 
13.2 
Institutional Review Board / Independent Ethics Committee ................................. 67 
13.3 
Subject Information and Informed Consent ........................................................... 67 
13.4 
Subject Identification and Confidentiality .............................................................. 68 
13.5 
Indemnity and Compensation ................................................................................ 68 
14. 
Administrative Considerations .............................................................................. 69 
14.1 
Clinical Trial Agreement ....................................................................................... 69 
14.2 
Clinical Study Registration and Results Disclosure................................................ 69 
14.3 
Implementation of the Protocol / Protocol Amendment(s) ..................................... 69 
14.4 
Protocol Deviations ............................................................................................... 70 
14.5 
Documentation and Record Keeping ..................................................................... 70 
14.5.1 
Data Collection ..................................................................................................... 70 
14.5.2 
Data Quality Assurance ......................................................................................... 71 
14.5.3 
Record Retention ................................................................................................... 72 
14.6 
Study and Site Closure .......................................................................................... 72 
14.7 
Clinical Study Report ............................................................................................ 72 
14.8 
Use of Data and Publications ................................................................................. 73 
15. 
References............................................................................................................. 74 
 
 


 
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List of Tables 
Table 1. 
Average Flow Rates in Manual Push Infusions .................................................. 24 
Table 2. 
Infusion Time .................................................................................................... 42 
Table 3.  
Clinical Procedures: Demographics and Safety Evaluation ................................ 45 
Table 4. 
Clinical Procedures ............................................................................................ 45 
Table 5. 
Time Windows for Assessments ........................................................................ 46 
Table 6. 
Criteria for Valid Infusions ................................................................................ 65 
Table 7. 
Responder Requirements in Manual Push Cohort .............................................. 65 
 
List of Figures 
Figure 1. Study Overview ................................................................................................. 35 
 
 


 
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List of Abbreviations 
Abbreviation 
Definition 
AE 
Adverse event 
AUC 
Area under the concentration-time curve 
BMI 
Body mass index 
eCRF 
Electronic case report form 
eDiary 
Electronic diary 
EAE 
Experimental allergic encephalomyelitis 
EU 
European Union 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
ICF 
Informed Consent Form 
IEC 
Independent Ethics Committee 
ICH 
International Conference on Harmonisation 
IgA 
Immunoglobulin A 
IgG 
Immunoglobulin G 
IMP 
Investigational Medicinal Product 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
IV 
Intravenous 
IVIG 
IV immunoglobulin 
PID 
Primary immunodeficiency 
PK 
Pharmacokinetic 
SAE 
Serious adverse event 
SBIs 
Serious bacterial infections 
SC 
Subcutaneous 
SCIG 
SC immunoglobulin 
US 
United States 
 
 


 
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Definition of Terms 
Term 
Definition 
Eligible subject 
Eligible subjects are subjects meeting the 
inclusion/exclusion criteria. 
 
 
Enrolled subject 
Enrolled subjects are eligible subjects who freely 
signed informed consent form and enrolled in the 
study. 
 
 
Full Analysis Set 
The Full Analysis Set (FAS) will comprise all 
subjects who provide informed consent and who are 
included in the study; ie,  who undergo study 
procedures 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. 
 
 
Safety Population 
The Safety Population will comprise all subjects in 
the Full Analysis Set who received at least 1 dose or 
a partial dose of IgPro20 in the study. 
 
 
Treatment-emergent adverse event 
Treatment-emergent adverse events are adverse 
events occurring after the start of the first IgPro20 
infusion in the study and up to the End of Study 
visit. 
 
 
Pump-Assisted Volume Cohort 
Subjects testing volumes per injection site of 25 mL 
up to 50 mL. 
 
 
Pump-Assisted Flow Rate Cohort 
Subjects testing flow rates per injection site of 
25 mL/hour up to 100 mL/hour. 
 
 
Manual Push Flow Rate Cohort 
Subjects testing flow rates per injection site of 25 to 
30 mL/hour up to 120 mL/hour (equivalent of 
approximately 0.5 mL/minute up to 2 mL/minute) 
 
 


 
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1. 
Introduction 
1.1 
Background 
1.1.1 Primary Immunodeficiency 
Primary immunodeficiency (PID) represents a variety of disorders characterized by an 
intrinsic defect in the immune system that renders patients more susceptible to infections, 
which may be fatal if left untreated. Major clinical manifestations include multiple infections 
despite aggressive treatment, opportunistic infections and failure to thrive (Cooper et al, 
2003). PID constitutes a spectrum of more than 300 innate defects in the body’s immune 
system. They can be divided into 9 groups: disorders of humoral and cellular immunity, 
combined immunodeficiency with associated or syndromic features, predominantly antibody 
deficiency syndromes, diseases of immune dysregulation, congenital phagocyte defects, 
defects in intrinsic and innate immunity, auto-inflammatory disorders, complement disorders, 
and phenocopies of PID. Predominantly antibody deficiency syndromes are the most 
common PID subtype (Yong et al, 2008; Bousfiha et al, 2015; Picard et al, 2015). PID is 
considered to be a rare disease, with the prevalence depending on the type of 
immunodeficiency (Raje and Dinakar, 2015). Registry data from various countries estimated 
the overall prevalence of PID at 1.94/100,000 (United Kingdom) or 2.3/100,000 (Japan) to 
5.38/100,000 (France) and up to 30.5/100,000 (Turkey) (Ishimura et al, 2011; Bousfiha et al, 
2013; Kilic et al, 2013). However, current epidemiological data indicate a higher overall 
prevalence than previously thought, being estimated at up to 83.3/100,000 (Bousfiha et al, 
2013). 
Patients with PID are not only at a higher risk for infections, but also to develop other 
conditions such as chronic lung disease, gastrointestinal diseases, malignancies and 
autoimmune diseases (Morimoto and Routes, 2008). For the past 3 decades, immunoglobulin 
replacement therapy has been used for patients with all PID conditions, to prevent infections 
and infection-related complications (Sriaroon and Ballow, 2015). 
1.1.2 Subcutaneous Immunoglobulin Replacement Therapy 
Immunoglobulin replacement therapy is the lifelong treatment for patients with PID and can 
be administered through intravenous (IV) or subcutaneous (SC) routes (Sriaroon and Ballow, 


 
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2015), usually with special pumps. Providing passive immunity and maintaining consistent 
serum immunoglobulin G (IgG) concentrations controls most of the recurrent infections and 
results in an improved quality of life for these patients (Borte et al, 2011). 
Although both IV and SC treatment regimens in equal doses provide a similar efficacy in the 
prevention of serious bacterial infections, there are some advantages of the SC route (Chapel 
et al, 2000; Sriaroon and Ballow, 2015). With SC treatment regimens, smaller doses of IgG 
are given more frequently, resulting in altered pharmacokinetics (PK) with lower peak and 
higher trough levels of IgG as compared to the large boluses given less frequently, usually 
once every 3-4 weeks, with IV infusions (Berger, 2004). This increased stability of IgG 
concentration improves the patients’ well-being, since it reduces symptoms such as fatigue 
and myalgia at the end of the dosing cycle (Berger, 2008). Unlike IV immunoglobulin 
(IVIG), SC immunoglobulin (SCIG) does not require a good venous access and therefore 
does not lead to potential problems with venous access in the future due to frequent IV 
infusion (Jolles et al, 2015). Since an IV port is also not required for SC therapy, this is 
associated with lower risk of various infusion complications, from thrombo-embolic events to 
septicemia (Sriaroon and Ballow, 2015). Other important aspects of SCIG treatment, since it 
can be administered at home, are the improved quality of life, treatment satisfaction, and 
therapy convenience, in both children and adults (Gardulf et al, 2004; Nicolay et al, 2006). 
1.1.3 Manual Push Technique 
The conventional mode of SCIG administration has been an infusion pump, delivering IgG 
volumes of up to 25 mL per injection site, which can take up to 2 hours (Berger, 2008; 
Shapiro, 2010). Infusion pumps may be difficult to use for some patients and the potential 
costs might be unfavorable (Misbah et al, 2009). As an alternative, the manual push 
technique, also called rapid push, has been established in recent years for the administration 
of SCIG. It is a simple method where SCIG is given manually by injection using syringe and 
a short tubing with a butterfly needle. The total weekly dose is divided into several smaller 
doses, depending on each patient’s dose and preference. Compared to weekly pump-assisted 
infusions, infusion times are much shorter, ranging from 5 to 20 minutes, and fewer injection 
sites are used. Furthermore, it provides effective and cost-efficient drug delivery, improved 
patient autonomy and convenience (Shapiro 2010; Shapiro 2013a; Martin et al, 2013). Based 
on a retrospective analysis comparing standard pump administration vs. rapid push 


 
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administration, it has been shown that serum IgG levels as well as the overall safety and 
tolerability profiles are comparable between the 2 SCIG infusion methods. In addition, 
manual push is well tolerated in both pediatric and obese adult patients and can be a practical 
treatment option in most PID patient subpopulations requiring SCIG replacement therapy, 
improving treatment satisfaction and supporting patient adherence (Shapiro 2013a; Misbah et 
al, 2009; Shapiro 2013b; Shapiro 2013c). 
1.1.4 SCIG Infusion Parameters 
The currently approved Hizentra® infusion parameters in the United States (US) and abroad 
include a volume per injection site of up to 25 mL, and a flow rate of up to 25 mL/h per site 
(US package insert, European Union [EU] package insert), as outlined below: 
‘Volume – For the first infusion of Hizentra, do not exceed a volume of 15 mL per injection 
site. The volume may be increased to 20 mL per site for the fifth infusion and then to 25 mL 
per site as tolerated. 
Rate – For the first infusion of Hizentra, the recommended flow rate is 15 mL per hour per 
site. For subsequent infusions, the flow rate may be increased to 25 mL per hour per site as 
tolerated’. 
Higher infusion parameters, such as an increased flow rate and volume per injection site, 
reduce the time needed for infusion and decrease the number of injection sites, independent 
of the method used. An infusion of up to 60 mL per site and a flow rate of more than 60 mL/h 
using the manual push method have been previously described. In retrospective analyses of 
adult and pediatric patients using the rapid push method, the majority of subjects reported an 
infusion time of 9 minutes or less. With a mean volume per site of 15.8 mL in adults, an 
average flow rate of 1.75 mL/min or 105 mL/h can be assumed. In the age group of 10 to 18 
years, an even higher flow rate of 1.9 mL/min (114 mL/h) can be assumed with a mean 
volume per site of 17.1 mL. Furthermore, in obese adults (body mass index [BMI] ≥ 30 
kg/m2) a mean volume per site of 17.8 mL was documented, providing an average flow rate 
of 1.97 mL/min (118.67 mL/h) without tolerability issues (Shapiro 2013a; Shapiro 2013b; 
Shapiro 2013c).  


 
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While the flow rate in manual push is not usually presented in mL/h due to small volumes 
and short infusion times, a more detailed analysis of average flow rates, based on data from 
available publications, is presented in Table 1. 
Table 1. 
Average Flow Rates in Manual Push Infusions 
Manual push flow rate as originally 
reported 
Flow rate, mL/min 
Flow rate, 
mL/h 
References 
15 min per 3 mL 
0.2 
12 
Berger, 2008. 
1-2 cc/min 
1-2 
60-120 
Misbah et al. 2009. 
9 min per 15 mL 
1.7 
100 
Shapiro, 2013b. 
5 min per 10 mL 
2  
120 
Richter et al., 2013. 
9 min per 20 mL 
2.2 
133 
Shapiro, 2013b. 
For pump-assisted infusions, higher infusion parameters have also been tested previously in 
clinical studies with IgPro20 (Hizentra). In the US PID extension study, IgPro20_3001, the 
protocol allowed for up to 40 mL per site and an infusion rate of up to 35 mL/h. In the EU 
PID pivotal study, ZLB06_001CR, the maximum infusion parameters allowed were 25 mL 
per site and 35 mL/h (Jolles et al, 2015). The same infusion parameters have been 
successfully tested in IgPro20 studies conducted in Japan (Kanegane et al, 2014). In all of 
these studies, there were no safety issues related to the higher injection site volumes or rates, 
although they were not evaluated in a systematic manner and there were not enough data 
collected to be able to draw robust conclusions. Additionally, in the recently completed 
IgPro20 study in subjects with chronic inflammatory demyelinating polyneuropathy, 
IgPro20_3003, injection site volumes and rates of 50 mL/site and 35 mL/h/site, respectively, 
were allowed. A substantial number of study subjects have already used these higher infusion 
parameters without safety issues. 
In a recently published study of 20% SCIG administered to PID subjects in the US, the 
reported median infusion rate was 60 mL/h/site (range 4.4-180) and the median infusion 
volume per injection site was 39.50 mL (range 6.4-76.0), with 71.6% of subjects reaching a 
flow rate of at least 60 mL/h and 10.8% of subjects receiving a volume of at least 60 mL/site 
(Suez Det al, 2016). In the corresponding EU study, 41.6% of subjects reached a maximum 
infusion rate of ≥ 40 mL/h/site, with a number of study participants injecting 20% SCIG at 
60 mL/h/site and with a volume of up to 48 mL/site (Borte Met al, 2016).  


 
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The above-mentioned publications, as well as numerous personal communications from 
immunologists treating PID patients demonstrate that, in current clinical practice, Hizentra 
infusions are sometimes conducted at significantly higher than currently approved flow rate 
and volume per injection site, with or without infusion pump (by manual push). The safety 
and tolerability of these new infusion parameters and techniques has not been evaluated in a 
systematic manner. 
Therefore, the aim of this study is to obtain safety and tolerability data of higher infusion 
parameters of IgPro20 (Hizentra) in PID patients, for both pump-assisted and manual push 
techniques, allowing for greater flexibility and convenience of Hizentra infusions. 
1.2 
Background Information on IgPro20 
1.2.1 Overview 
IgPro20 is a ready-to-use formulation of polyvalent SCIG. The IgG portion represents all IgG 
subclasses present in human plasma and retains all IgG function (ie, Fc receptor interaction 
site [Fc] and antigen binding fragment [Fab] mediated activity). The sterile 20% IgG solution 
is stabilized with 250 mmol/L L-proline at pH 4.8. IgPro20 also contains 8 to 30 mg/L 
polysorbate 80 (P80). IgPro20 has a low sodium content (< 10 mmol/L) and an osmolality of 
approximately 390 mOsmol/kg. 
The protein moiety of IgPro20 is highly purified IgG (≥ 98% purity). More than 90% of the 
IgG consists of monomers and dimers. IgPro20 is prepared from large donor pools and 
represents the antibody spectrum present in the donor population. Careful selection of donors, 
as well as testing of each individual donation and the plasma pool for viral markers, helps to 
ensure viral safety of the finished product. 
The manufacturing process (IgG isolation) for IgPro20 is based on the manufacturing process 
for Privigen® (IgPro10). After production of the active substance solution, the final IgPro20 
product is formulated and concentrated to the higher protein content of 20%. 
IgPro20 was approved for PID in the US, the EU, Canada, Switzerland, Japan, Australia, and 
several other countries under the trade name Hizentra. 


 
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1.2.2 Nonclinical Evaluation 
Human immunoglobulins 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. Nonclinical studies with IgPro20 focused on its SC use (local tolerance, 
PK), functionality (in vitro Fab and Fc function, in vivo efficacy in experimental allergic 
encephalomyelitis [EAE] rat model), safety regarding hypotensive effects, and repeated SC 
administrations. 
Fab and Fc functions of IgPro20 are comparable to those of Privigen and other marketed 
IVIG products. In the EAE rat model (a nonclinical model of human multiple sclerosis) 
IgPro20 administered SC attenuated the symptoms of EAE and led to a lower mortality. 
The bioavailability of IgPro20 was assessed after SC administration to rats on 5 consecutive 
days; a dose-dependent increase in area under the concentration-time curve (AUC) and 
maximum serum concentration of human IgG was found. In 2 repeated-dose toxicity studies 
in rats with SC administration of IgPro20 every other day for 28 days and 6 months, 
respectively, all animals developed antibodies against human IgG in a dose dependent 
manner. In spite of this antibody formation, human IgG was detected in the serum of the 
animals; serum concentrations increased to a steady-state (28-day study) with a slight decline 
in the second half of the in-life phase of the 6 months study. Thus antibody development 
against human IgG did not result in total removal of human IgG from the blood of the 
animals. The highest dose administered in this study resulted in IgG serum levels in the 
animals that are comparable to IgG levels obtained in patients treated with IgPro20, and was 
considered a no observed adverse effect level. 
IgPro20 was also tolerated locally after SC, IV, paravenous, and intra-arterial application in 
rabbits. 
IgPro20 contains 250 mmol/L of the non-essential amino acid L-proline as a stabilizer. 
Studies on L-proline in safety pharmacology, multiple dose toxicity, reproduction toxicity 
and in juvenile animals were conducted during development of Privigen. Studies with IV and 
SC administration of L-proline were included. L-proline is a suitable excipient of IVIGs at 


 
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the specified concentrations which was confirmed in clinical studies conducted with Privigen. 
These results were confirmed in a 28-day repeated-dose toxicity study in rats with daily SC 
administration of L-proline performed during IgPro20 development. Considering the lower 
amount of L-proline infused with IgPro20 compared with Privigen, due to smaller doses in 
average weekly SCIG vs. average 3- or 4-weekly IVIG dosing regimens and the good 
tolerability of IgPro20 administered SC to rabbits, it can be concluded that L-proline can be 
safely used as an excipient in IgPro20.  
1.2.3 Previous Clinical Experience 
The approval of IgPro20 for the treatment of patients with PID was based on data from 
3 pivotal studies in the US, Europe, and Japan (ie, studies ZLB04_009CR, ZLB06_001CR, 
and ZLB06_002CR, respectively). In addition, extension studies to the 3 aforementioned 
phase 3 pivotal studies have been conducted and completed: 1 study each in the US (US 
extension study IgPro20_3001), in Europe (European extension study ZLB07_002CR), and 
in Japan (follow-up study ZLB07_001CR). A further long-term extension study in Japan 
(IgPro20_3006) has also been completed. 
1.2.3.1 Phase 3 PID Study ZLB04_009CR (US Pivotal Study) 
This prospective, open-label, phase 3 study was conducted in the US and investigated the 
efficacy, safety, local tolerability, and PK of SC IgPro20 in 49 subjects with PID. Subjects 
previously receiving monthly treatment with IVIG were switched to weekly SC 
administration of IgPro20 for 15 months. Subjects were initially treated with 1.30 times their 
previous IVIG dose during a 12-week wash-in/wash-out period and had their IgPro20 dose 
further adjusted based on the results of the PK substudy for the subsequent 12 month efficacy 
period. Doses were adjusted to ensure equivalent systemic IgG exposure to IVIG as measured 
by the serum IgG AUC. 
The primary efficacy variable was the annualized rate of serious bacterial infections (SBIs, as 
defined in the Food and Drug Administration [FDA] Guidance for Industry [FDA, 2013]). 
None of the subjects had an SBI and the annualized rate of total infections per subject was 
2.76. Overall, SC infusions with IgPro20 provided a high level of efficacy in subjects with 
PID in terms of passive immunity and maintaining adequate and consistent serum IgG levels. 
There were no safety concerns with the use of IgPro20. 


 
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1.2.3.2 Phase 3 PID Study ZLB06_001CR (European Pivotal Study) 
This prospective, open-label phase 3 study was conducted in Europe that investigated the 
efficacy, safety, tolerability, and PK of SC IgPro20 in 51 subjects with PID. The study 
consisted of a 12-week wash-in/wash-out followed by a 28-week efficacy period. The 
IgPro20 weekly doses administered during this study were generally equal to the subjects’ 
previous weekly equivalent IVIG or SCIG doses. The primary efficacy variable was a 
descriptive comparison of IgG trough levels at 6 consecutive weeks at steady-state within the 
study. During the study, the mean of individual median IgG trough levels increased by 8.1% 
with IgPro20 treatment (from 7.49 g/L with the previous IgG therapy to 8.10 g/L during 
Infusions 12 to 17). None of the subjects had an SBI during the efficacy period of this study 
(after washout of the previous IgG product), and only one subject had an SBI during the 
wash-in/wash-out period, resulting in an annualized rate of 0.03 SBIs/subject. The annualized 
rate of total infections was 5.18 infections/subject. Overall, it was demonstrated that SCIG 
therapy with IgPro20 is a highly effective treatment for adult and pediatric subjects with PID 
when administered at approximately 100% of the weekly equivalent doses during the 
subjects’ preceding therapy. There were no safety concerns with the use of IgPro20. 
1.2.3.3 Phase 3 PID study ZLB06_002CR (Japan Pivotal Study) 
This phase 3 study was conducted in Japan including 25 subjects, with a PK sub-study 
including 8 subjects, to investigate the efficacy, safety, tolerability, and PK of IgPro20 in 
subjects with PID. The weekly dose of IgPro20 was the weekly equivalent dose of the 
previous IVIG treatment, and IgPro20 treatment included a 12-week wash-in/wash-out period 
followed by a 12-week efficacy period. The primary efficacy variable was maintenance of the 
mean of individual median IgG concentration at trough level (Ctrough) values expressed via the 
ratio of geometric mean concentrations. IgG Ctrough values increased by 9% with IgPro20 
treatment, from 6.53 g/L in the IVIG period to 7.15 g/L during the SCIG efficacy period, 
meeting the primary objective. IgG Ctrough values <5 g/L on IgPro20 therapy during the Japan 
pivotal study were seen in only 1 of 24 subjects. In this study, none of the subjects had an 
SBI. A total of 52.4% of subjects had an infection in the efficacy period, resulting in an 
annualized rate of 2.98 infections/subject. Overall, it was demonstrated that SCIG therapy 
with IgPro20 is an effective treatment for adult and pediatric subjects with PID in Japan when 


 
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administered at approximately 100% of the weekly equivalent doses of the subjects’ 
preceding IVIG therapy. There were no safety concerns with the use of IgPro20. 
Long-term extension and follow-up studies, as outlined in Section 1.2.3, have further 
confirmed the high efficacy and safety of IgPro20 at steady-state dosing. In addition to safety 
data from the clinical development program, postmarketing experience with IgPro20 has 
shown the product to be well tolerated, with a similar safety profile in pediatric and geriatric 
patients as documented for adult patients. 
1.3 
Study Overview 
This is a multicenter, open-label, parallel-arm, non-randomized study designed to evaluate 
safety and tolerability of higher infusion parameters of IgPro20 in subjects with PID. 
The primary objective of this study is to characterize the responder rate at higher infusion 
parameters of IgPro20. Subjects will be assigned to 1 of 3 treatment cohorts: Pump-Assisted 
administration with 3 upward volume titrations (25 mL, 40 mL, and 50 mL); Pump-Assisted 
administration with 4 upward flow rates per injection site (25 mL/h, 50 mL/h, 75 mL/h and 
100 mL/h) and Manual Push administration (manual infusion using syringe without a pump) 
with upward titration of flow rate per injection site of 30 mL/h, 60 mL/h, and 120 mL/h 
(0.5 mL/min, 1 mL/min, and 2 mL/min, correspondingly). 
Further details of the study design can be found in Section 3. 
1.4 
Potential Risks and Benefits 
Safety data from the 3 pivotal studies performed by CSL for the authorization of IgPro20 in 
PID showed that almost all adverse events (AEs) (99%) were mild or moderate in intensity. 
There was no dose-dependent increase in the overall rate of AEs, within the range of doses 
and flow rates tested in these studies, and there was no evidence in either study of severe 
systemic AEs. 
Adverse reactions such as local reactions, headache, fatigue, nausea, pain, pruritus, rash, 
vomiting, and pyrexia were observed during the clinical development program. In addition, in 
the postmarketing setting, reactions such as hypersensitivity, tremor, and burning sensation 
were reported, as well as rare events such as anaphylaxis, aseptic meningitis syndrome and 


 
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thrombotic events. SC infusions generally result in lower rates of headache and other 
systemic adverse reactions than IV infusions, which is attributed to the more stable serum 
IgG concentrations attained with SCIG treatment. 
The risk that products manufactured from plasma could transmit an infectious agent has been 
reduced by screening plasma donors for prior exposure to pathogens and by testing the 
donations for the presence of certain markers of infections. In addition, different 
complementary virus elimination processes used during the manufacture of IgPro20 
(incubation at pH 4, virus filtration, fractionation, and depth filtration) effectively reduce the 
potential for viral transmission. The manufacturing process was also investigated for its 
capacity to eliminate hamster-adapted scrapie agent 263K, which is considered to be a model 
for Creutzfeldt-Jakob disease and variant Creutzfeldt-Jakob disease. The results demonstrated 
substantial removal of the infectious agent by the manufacturing process in all model 
systems. To date, no viral infection related to the infusion of IgPro20 was reported. However, 
the possibility of transmitting infective agents cannot be totally excluded. 
As previously noted, Hizentra infusions at higher than currently approved volume and flow 
rate parameters per injection site have been used in both clinical research and clinical practice 
without apparent safety signals (see Section 1.1.4 [SCIG Infusion Parameters]). However, 
there are insufficient data to allow for objective quantification of any potential increase in 
safety risks associated with these higher infusion parameters. 
The benefits of manual push include the use of smaller volumes per infusion compared to less 
frequent infusion schedules. Other advantages associated with manual push include the 
ability to maintain more even serum IgG concentrations with higher trough levels compared 
to weekly or twice weekly schedules, which could potentially confer better protection against 
infections, as well as lower time per infusion and total time per weekly/monthly dose 
compared to pump-assisted infusions. The use of manual push is also associated with a 
simpler infusion technique (ie, there is no requirement to load and handle a pump) and 
reduced healthcare costs as there is no expenditure on a pump. The benefits of the higher 
flow rates and volumes, as proposed for the current study, include reduced infusion time, and 
fewer injection sites per infusion. 


 
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A number of disadvantages are associated with use of the manual push technique, including 
the difficulty to control the syringe to deliver a stable flow rate and the manual strength 
required to operate the syringe for several minutes. 
Overall, the associated benefit-risk assessment of the study is considered acceptable for 
subjects enrolled in the study. 
2. 
Study Objectives and Endpoints 
2.1 
Primary Objective and Endpoints 
2.1.1 Primary Objective 
The primary objective of this study is to determine the responder rate at higher infusion 
parameters of IgPro20 under the following conditions: 
• Pump-Assisted: Volume per injection site of 25 mL, 40 mL, and 50 mL. 
• Pump-Assisted: Flow rate per injection site of 25 mL/h, 50 mL/h, 75 mL/h and 
100 mL/h. 
• Manual Push (manual infusion using syringe without a pump): Flow rate per injection 
site of 30 mL/h, 60 mL/h, and 120 mL/h (0.5 mL/min, 1 mL/min, and 2 mL/min, 
correspondingly). 
2.1.2 Primary Endpoints 
The primary endpoints are as follows: 
• Pump-Assisted Volume Cohort: Percentage of responders for each planned volume 
(ie, 25 mL, 40 mL and 50 mL per injection site). 
• Pump-Assisted Flow Rate Cohort: Percentage of responders for each planned flow 
rate (ie, 25 mL/h, 50 mL/h, 75 mL/h and 100 mL/h per injection site). 
• Manual Push Flow Rate Cohort: Percentage of responders for each planned flow rate 
(ie, 30 mL/h [0.5 mL/min], 60 mL/h [1 mL/min], and 120 mL/h [2 mL/min] per 
injection site). 


 
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2.2 
Secondary Objectives and Endpoints 
2.2.1 Secondary Objectives 
The secondary objectives of the study are: 
• To evaluate the safety of pump-assisted IgPro20 infusions at higher infusion 
parameters (volume and flow rate). 
• To evaluate the safety of manual push IgPro20 infusions. 
• To evaluate the tolerability of higher infusion parameters of IgPro20. 
2.2.2 Secondary Endpoints 
The secondary endpoints are as follows: 
• The rate of total AEs per subject and per infusion by cohort and by each of the 
infusion parameter levels within the cohort. 
• The rate of local reactions per subject and per infusion by cohort and by each of the 
infusion parameter levels within the cohort. 
• The time to onset of local reactions per subject and per infusion by cohort and by each 
of the infusion parameter levels within the cohort. 
• Severity of local reactions per subject and per infusion by cohort and by each of the 
infusion parameter levels within the cohort. 
• Duration of local reactions per subject and per infusion by cohort and by each of the 
infusion parameter levels within the cohort. 
• For all cohorts: Tolerability of a certain infusion parameter; ie, percentage of 
infusions per cohort by volume/flow rate subgroup experiencing no severe local 
reactions for each of the infusion parameter levels. 


 
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2.3 
Exploratory Objective and Endpoints 
2.3.1 Exploratory Objective 
 
 
2.3.2 Exploratory Endpoints 
 
 
3. 
Study Design 
3.1 
Study Design and Rationale 
This multicenter, open-label, parallel-arm, non-randomized study is designed to evaluate 
safety and tolerability of higher infusion parameters of IgPro20 in subjects with PID. The 
study will include 3 cohorts with a minimum of 15 subjects each as follows: 
• Pump-Assisted Volume Cohort (weekly infusions): Volume per injection site of 
25 mL up to 50 mL. 
• Pump-Assisted Flow Rate Cohort (weekly infusions): Flow rate per injection site of 
25 mL/hour up to 100 mL/hour. 
• Manual Push Flow Rate Cohort (2 to 7 infusions per week): Flow rate per injection 
site of 25 to 30 mL/hour up to 120 mL/hour (equivalent of approximately 
0.5 mL/minute up to 2 mL/minute; see Table 1). 
Each cohort will test 3 infusion parameter levels (for Pump-Assisted Flow Rate Cohort – 4) 
for at least 4 weeks each over a duration of 12 weeks (for Pump-Assisted Flow Rate Cohort – 
16 weeks). After the fourth week on each level, qualifying subjects (responders) will switch 
to the next infusion parameter level (eg, from 25 to 50 mL/h). During the study the weekly 
dose will remain unchanged (as prescribed by treating healthcare provider, usually within 
100-200 mg/kg per week range); only the respective infusion parameter under evaluation will 
change. If a subject is unable to tolerate the respective infusion parameter level (ie, is a non-
responder at that level, for definition see Section 11.3.5), the subject will continue study 
CCI
CCI


 
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participation at the individually previously tolerated infusion parameter level for the 
remaining full study duration, to collect safety information. 
If a subject within the Pump-Assisted Cohort is able to perform ≥ 3 out of 4 (75%) valid 
infusions at a certain infusion parameter level, he/she will be considered to be a responder for 
this infusion parameter level (eg, completed 3 infusions with 50 mL/h means responder for 
50 mL/h). Valid infusions do not need to be consecutive. Determination of a responder in the 
Manual Push Cohort is more complex due to the expected variable frequency of infusions per 
week for different subjects (see Section 11.3.5 for further details). Valid infusions in this 
cohort also do not need to be consecutive. However, each subject needs to adhere to the same 
schedule (number of infusions per week) throughout the study. 
An infusion parameter will be considered successfully achieved if at least one third of the 
subjects in the corresponding cohort (5 of 15) are responders at that infusion parameter level, 
as defined above. The highest achieved infusion parameter level will be used for the label 
change. The rationale for this is based on medical experience (personal communications with 
several key opinion leaders and limited clinical research experience). A response rate for 
reaching the top infusion parameter for each endpoint of 50% is assumed. Using a binomial 
distribution with 15 evaluable subjects, there will be a 94% probability that the observed 
response rate for a single endpoint in the study is ≥ 33%. 
Excluding the differences in infusion parameters/administration, all 3 cohorts have a similar 
overall study design (including AE collection). A schematic overview of the study is 
presented in Figure 1. 
 


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kg/m2. Pediatric and obese subjects may be distributed across any or all of the treatment 
cohorts without respect to balanced enrollment within the cohorts for these subpopulations.. 
3.6 
Study Monitoring Procedures 
3.6.1 Data and Safety Monitoring Board  
An independent Data and Safety Monitoring Board will be established to monitor safety 
events in this study. Further details will be described in the Data and Safety Monitoring 
Board Charter. 
3.6.2 Other Monitoring Committees 
Not applicable. 
4. 
Selection and Withdrawal of Subjects 
4.1 
Eligibility Criteria 
The study population will be selected on the basis of the inclusion and exclusion criteria 
described in the sections below. Subject eligibility should be reviewed and documented by an 
appropriately medically qualified member of the investigator’s study team before subjects are 
included in the study. 
4.1.1 Inclusion Criteria 
Subjects meeting all of the following inclusion criteria may be enrolled into the study: 
1. Capable of providing informed consent/assent and willing and able to adhere to all 
protocol requirements. The subject’s parent(s) or legally acceptable representative(s) 
capable of providing written informed consent. 
2. Male or female on stable dose of IgPro20 (Hizentra) therapy. 
3. Women of childbearing potential must be using and agree to continue using medically 
approved contraception (which must be discussed with the study doctor) and must have a 
negative pregnancy test at Screening. 
4. Subjects with PID, eg, with a diagnosis of common variable immunodeficiency or 
X-linked agammaglobulinemia, as defined by the Pan American Group for Immune 


 
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Deficiency and the European Society of Immune Deficiencies or by the International Union 
of Immunological Societies Expert Committee. 
5. With infusion parameters as specified below: 
Pump-Assisted Flow Rate Cohort subjects only* 
5a. Experience with pump-assisted infusions of IgPro20 at the tolerated flow rate of 
25 mL/h** per injection site for at least 1 month prior to Day 1. 
Pump-Assisted Volume Cohort subjects only* 
5b. Total weekly IgPro20 dose of ≥ 50 mL (≥ 10 g). 
5c. Experience with pump-assisted infusions of IgPro20 at tolerated volumes of 
25 mL/injection site for at least 1 month prior to Day 1. 
Manual Push Flow Rate Cohort subjects only 
5d. Experience with frequent (2-7 times per week) infusions of IgPro20 at the 
tolerated flow rate of approximately 0.5 mL/min (equivalent of 25-30 mL/h) per 
injection site for at least 1 month prior to Day 1. The dose (volume) per injection site 
should not exceed 25 mL. 
 
*Subjects who tolerated higher infusion parameters relevant for their study cohort 
prior to the study based on their chart records will not be allowed to participate in the 
study. If records are not available, information may be obtained by asking the subject. 
**Subjects who use an infusion pump that operates by maintaining a constant pressure as 
opposed to a constant flow rate, may not have experienced flow rates that are exactly 
25 mL/h. Flow rates for constant pressure pumps (adjusted for needle gauge and infusion 
tubing size) that are within ± 20% of 25 mL/h per injection site are acceptable for study entry. 
4.1.2 Exclusion Criteria 
Subjects meeting any of the following exclusion criteria must not be enrolled into the study: 
1. Ongoing SBI at the time of Screening. Serious bacterial infections as defined by FDA 
Guidance (2008).    
2. Other significant medical conditions that could increase the risk to the subject. 
3. Females who are pregnant, breast feeding, or planning a pregnancy during the course of 
the study. 
4. Participation in a study with an Investigational Medicinal Product (IMP) other than 
IgPro20 within three months prior to enrollment. 


 
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5. Evidence of uncooperative attitude or unable to complete scheduled visits for any reason. 
6. Any condition that is likely to interfere with evaluation of the IMP or satisfactory conduct 
of the study. 
7. Subjects who are employees at the investigational study site, or relatives or spouse of the 
investigator. 
8. Female subject of childbearing potential either not using or not willing to use a medically 
reliable method of contraception or not sexually abstinent during the study, or not 
surgically sterile. 
9. Alcohol, drug or medication abuse within 1 year before the study. 
10. Currently receiving a therapy not permitted during the study, as defined in Section 7.3. 
11. Mental condition rendering the subject (or the subject’s legally acceptable 
representative[s]) unable to understand the nature, scope and possible consequences of the 
study. 
12. Known or suspected hypersensitivity to IgPro20, or to any excipients of IgPro20. 
13. Any issue that, in the opinion of the investigator, would render the subject unsuitable for 
participation in the study. 
4.2 
Subject Withdrawal 
4.2.1 Subject Withdrawal 
Subjects may withdraw from the study at any time at their own request, or they may be 
withdrawn at any time at the discretion of the investigator or CSL for safety, behavioral or 
administrative reasons (eg, due to an AE, protocol deviation, loss to follow-up, subject 
noncompliance, and study termination). 
In accordance with International Conference on Harmonisation (ICH) principles of Good 
Clinical Practice (GCP) the investigator always has the option to advise a subject to withdraw 
from the study if the subject's safety or well-being is compromised by his or her further 
participation in the study. Concern for the interests of the subject must always prevail over 
the interests of the study. 
If a subject is withdrawn from the study or further participation is declined, they will continue 
to have access to medical care and will be treated as per routine medical practice. 


 
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4.2.2 Procedures for Handling Withdrawals 
If a subject declines further participation or is withdrawn from the study, attempts will be 
made to complete and document the final assessment. If the subject is withdrawn from the 
study after receiving IgPro20, every effort will be made to ensure that the relevant safety 
assessments are completed. The subject may also be asked by the investigator to complete 
other study assessments. 
If the subject withdraws from the study, and also withdraws consent for disclosure of future 
information, CSL may retain and continue to use any data collected before such withdrawal 
of consent. 
In the event that a subject withdraws from the study, the investigator should record the reason 
and date of withdrawal in the electronic case report form (eCRF) and in the subject's medical 
records. 
4.2.3 Replacement Policy 
Subjects withdrawn from the study will not be replaced. 
5. 
Study Interventions 
5.1 
Description of Investigational MEDICINAL Product 
5.1.1 IgPro20 
Substance number 
IgPro20 
Active substance 
Human normal immunoglobulin 
Trade name 
Hizentra 
Dosage form 
Solution for SC injection (ready-to-use formulation of polyvalent 
SCIG) 
Dose 
As prescribed by subject’s healthcare provider prior to study 
entry, usually within 100-200 mg/kg per week range. 
Mode of administration 
SC 
SC=subcutaneous. 
The study IMP, IgPro20, will be manufactured by CSL in accordance with Good 
Manufacturing Practice guidelines and local regulatory requirements, and will be labelled as 
the IMP for this study. 


 
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5.1.2 Comparator Product 
Not applicable. 
5.2 
Packaging, Labeling, Supply and Storage 
5.2.1 Packaging and Labeling 
IgPro20 will be packaged and labeled according to current ICH Good Manufacturing Practice 
and GCP guidelines, and national legal requirements. 
5.2.2 Supply and Storage 
IgPro20 will be supplied to the study sites by external service providers on behalf of CSL. 
IgPro20 must be stored between 2°C and 25°C (36°F and 77°F) and protected from light, in a 
secure storage area as specified in the IMP Handling Instructions. 
5.3 
Accountability and Destruction 
All supplies of IgPro20 must be accounted for throughout the study. At the end of the study, 
the original IMP Inventory Log, dated and signed by the investigator or delegate (eg, 
pharmacist), must be retained at the study site as verification of final accountability of 
IgPro20. 
Records for the delivery of IgPro20 to the study site, the inventory at the study site, the use 
by each subject, and the destruction or return of IgPro20 to CSL’s external service providers 
must be maintained by the investigator (or delegate). The records will include dates, 
quantities, lot numbers, kit numbers and unique code numbers assigned to IgPro20 and 
assigned to the subjects. The investigator must provide reasons for any discrepancies in IMP 
accountability. 
Information on the destruction of IgPro20 is provided in the IMP Handling Instructions / 
Pharmacy Manual. 
5.4 
Other Intervention(s) 
Not applicable. 


 
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5.5 
Rescue Therapy 
Not applicable. 
6. 
Allocation, Dosing and Administration 
6.1 
Allocation to Treatment 
6.1.1 Subject Assignment 
After providing written informed consent, the subject will be issued with a study-level unique 
subject identification number. The subject identification number will be used to identify the 
subject for the duration of the study. Subject identification numbers will not be reassigned or 
reused. 
6.1.2 Randomization Procedures 
Each study cohort requires specific entry criteria (Section 4.1.1). However, these criteria are 
not mutually exclusive, and if a subject qualifies to be enrolled into more than 1 of the study 
cohorts, he/she may be assigned to either cohort at the investigator’s discretion. 
6.1.3 Blinding Procedures 
Not applicable. 
6.2 
Dosing and Administration 
6.2.1 Dosing and Administration 
IgPro20 will only be administered by subjects included in this study following the procedures 
set out in this study protocol. An Interactive Response Technology (IRT) system will be 
utilized during the study for IMP accountability. 
Enrolled subjects will administer SC IgPro20 at a dose prescribed by their healthcare 
provider prior to study entry (usually 100-200 mg/kg per week). Subjects in the 
Pump-Assisted Cohorts will administer weekly treatment and subjects in the Manual Push 
Cohort will administer frequent infusions (ie, 2-7 times per week). Subjects in the Manual 
Push Cohort should maintain the same frequency of infusions per week throughout the whole 


 
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study, including 1 month prior to Day 1. The infusion parameters not under test (eg, volume 
per injection site in the flow rate cohort) should not exceed the levels used before the study. 
IgPro20 can be stored at room temperature between 2°C and 25°C (36°F and 77°F), protected 
from light. The IMP should be at room temperature before use. The IMP should not be 
shaken. Excessive shaking will cause foaming. For a more detailed description of the 
preparation of the IMP, refer to the handling instructions in the Subject IMP Handling Guide. 
6.2.2 Infusion Rates 
For pump-assisted infusions, the volume and flow rate will be determined according to the 
pump display readings. As it is physically not possible to perform manual push at a constant 
rate, and it is performed in clinical practice by series of short manual pushes on the syringe 
plunger with small breaks between them, average flow rate per infusion in this cohort will be 
estimated by dividing volume infused in milliliters by the time of infusion in minutes. 
The subject electronic diary (eDiary) for study participants in the Manual Push Cohort will 
provide recommendations of infusion duration depending on the actual dose (volume) to be 
infused and the target flow rate in mL/min for every subject using the following calculations 
(Table 2). If the eDiary is not available, a back-up paper diary will be provided for patient use 
until the eDiary becomes available. As soon as the eDiary is available, the data in the back-up 
paper diary will be entered into the eDiary. The back-up paper diary, if used, will be retained 
as a source document. During the time period when a back-up paper diary is in use, 
designated site staff will contact the subject on a weekly basis to ensure recording of infusion 
data and any AEs. 
Table 2. 
Infusion Time 
Flow rate, 
mL/min 
Volume, mL  
0.5 
1 
2 
 
Infusion Time, minutes 
2 
4 
2 
1 
3 
6 
3 
1.5 
4 
8 
4 
2 
5 
10 
5 
2.5 
6 
12 
6 
3 
7 
14 
7 
3.5 
8 
16 
8 
4 
9 
18 
9 
4.5 


 
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Flow rate, 
mL/min 
Volume, mL  
0.5 
1 
2 
10 
20 
10 
5 
11 
22 
11 
5.5 
12 
24 
12 
6 
13 
26 
13 
6.5 
14 
28 
14 
7 
15 
30 
15 
7.5 
16 
32 
16 
8 
17 
34 
17 
8.5 
18 
36 
18 
9 
19 
38 
19 
9.5 
20 
40 
20 
10 
6.3 
Treatment Compliance 
All doses of IgPro20 will be administered by SC infusion, with an office visit every 4 weeks, 
where the dose will be administered by the subject under the observation of the study staff; 
the remainder of the infusions will be done at home after confirmed and observed training at 
the first infusion (office visit). Treatment compliance will be monitored by reviewing the 
subject eDiaries and counting the used vials, the results of which should be documented. 
7. 
Contraindications, Permitted Therapies and PROHIBITED Therapies 
7.1 
Contraindications and Precautions to Further Dosing 
IgPro20 is contraindicated in subjects: 
• Who have had an anaphylactic or severe systemic reaction to the administration of 
human immune globulin or to components of the immunoglobulin formulation, such 
as polysorbate 80 in IgPro20. 
• With hypersensitivity to homologous immunoglobulins, especially in the rare cases of 
immunoglobulin A (IgA) deficiency when the subject has antibodies against IgA. 
• With hyperprolinemia type I or II. 
Full details of guidance on precautions for IgPro20 can be found in the Investigator’s 
Brochure and Prescribing Information.  


 
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7.2 
Permitted Therapies 
The following therapies are PERMITTED during the study: 
• Any medications that do not have the primary purpose of masking local or systemic 
AEs, and that are taken by the subject on a regular basis. 
• Prescribed medications required for the management of chronic medical conditions  
• Over the counter medications and dietary supplements. 
7.3 
Prohibited Therapies 
The following therapies are NOT PERMITTED during the study: 
• Any immunoglobulins other than IgPro20 provided for the study. 
• Any other investigational product at any time during the study. 
• Any medications with the primary purpose of masking local or systemic AEs 
(including but not limited to analgesics and anesthetics +/-12h around the infusion). 
• Any systemic immunosuppressants that can affect serum IgG concentration (except 
for stable steroid doses required for pre-existing conditions). 
Subjects are not to be enrolled into the study if they receive any prohibited therapy or any 
therapy in a prohibited dosage that cannot be discontinued or reduced to a permitted dose 
before enrollment. 
If administration of any prohibited therapy becomes necessary during the study for medical 
reasons, the subject may be withdrawn from further study participation. 
7.4 
Dietary and Lifestyle Restrictions  
Not applicable. 
7.5 
Overdose 
Overdose is defined as the accidental or intentional infusion or ingestion of any dose of a 
product that is considered excessive. The effects of any potential overdose with IgPro20 have 
not been studied. 


 
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8. 
Study Procedures and Visit Schedule 
8.1 
Clinical Procedures 
The clinical procedures related to demographics and safety are provided in Table 3. All other 
clinical procedures are provided in Table 4. Refer to the Laboratory Manual for detailed 
instructions on how the assessments should be performed. 
Table 3.  Clinical Procedures: Demographics and Safety Evaluation 
Assessment 
Description 
Demographics 
Date of birth, age, sex, and race. 
Medical history 
Relevant medical history. 
PID history, including specific PID diagnosis, date of diagnosis, and historic pre-treatment 
serum IgG level at the time of PID diagnosis. 
Contraception method. 
Current/concomitant therapies. 
Pregnancy test 
Blood test for beta-human chorionic gonadotropin. 
Physical 
examination 
As per the site’s standard procedure 
Vital signs 
• Blood pressure (systolic and diastolic) and respiratory rate after the subject has rested in 
a sitting or supine position ≥ 5 minutes 
• Pulse rate (per minute) will be measured from the radial pulse counted manually or with 
an automatic blood pressure monitor over ≥15 seconds 
• Body temperature using sublingual or tympanic measurement (consistent method to be 
throughout the study for a given subject) 
• Body weight 
• Height. 
Hematology 
• Erythrocytes 
• Hematocrit 
• Hemoglobin  
• Leukocytes 
• Differential counta 
• Mean corpuscular volume  
• Platelets 
Biochemistry 
• Alanine aminotransferase 
• Alkaline phosphatase 
• Aspartate transaminase 
• Bicarbonate 
• Chloride 
• Creatinine 
• Gamma glutamyl transferase 
• Potassium 
• Sodium 
 
• Urea or BUN 
 
 
BUN = blood urea nitrogen; IgG = immunoglobulin G; PID = primary immunodeficiency. 
aDifferential count: neutrophils, eosinophils, lymphocytes, monocytes, basophils. 
Table 4. 
Clinical Procedures 
Procedure 
Description 
Serum IgG assessment 
• 
Blood samples will be collected for assessment of serum IgG trough 
levels. 
IgG = immunoglobulin G.  
 


 
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The timing and frequency of all clinical procedures are described in the Schedule of 
Assessments. Refer to the Laboratory Manual for details about the collection, storage, 
handling and transportation of biological specimens. 
8.2 
Retention of Samples 
Samples will not be retained after the completion of the study. 
8.3 
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 during the study, are 
regarded as concomitant therapies and must be documented as such in the eCRF. 
8.4 
Visit Schedule 
The timing and frequency of the study visits are described in the Schedule of Assessments. 
Time windows for all assessments are detailed in Table 5. 
Table 5. 
Time Windows for Assessments 
Visit / Procedure 
Time window (relative to scheduled visit / procedure) 
Screening 
Between Day -35 and -7. 
Vital signs 
± 5 min 
Blood collection for clinical laboratory 
tests 
Between Day -35 and -7 and at the End of Study visit on 
Day 85 (±1) day (Day 113 [±1] day for the Pump-Assisted Flow 
Rate Cohort). 
Blood collection for IgG 
On Day 1 and End of Study visit (within approximately 1 hour 
before next infusion). 
 
8.4.1 Screening 
All subjects, or the subjects’ parent(s) or legally acceptable representative(s), must provide 
written informed consent before any study-specific assessments or procedures are performed. 
Written informed consent is not required for assessments or procedures performed according 
to standard of care (eg, for diagnosis or treatment); results from such assessments may be 
used in the determination of study eligibility. 
A Screening examination should be performed between Day -35 and -7. The following 
procedures will be conducted and documented at the Screening visit: 


 
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• Obtain written informed consent. 
• Review inclusion/exclusion criteria. 
• Record information regarding medical history and demographics. 
• Collect blood sample for beta-human chorionic gonadotropin for females of child-
bearing potential. 
• Perform a physical examination. 
• Measure vital signs: 
o Systolic blood pressure, diastolic blood pressure, respiratory rate, pulse rate, 
and body temperature 
o Body weight  
o Height 
• Collect blood samples for laboratory safety evaluation (biochemistry and 
hematology). 
• Start recording AEs and use of concomitant therapies. 
Subjects who complete all of these assessments and who fulfil the eligibility criteria (ie, 
eligible subjects) will be enrolled into the study. If the subject is not eligible for the study, the 
primary reason for screen failure must be entered in the eCRF. 
8.4.2 Pump-Assisted Flow Rate Cohort  
8.4.2.1 Week 1 (Day 1) 
The following procedures will be conducted and documented at this office visit: 
• Review inclusion/exclusion criteria. 
• Measure systolic blood pressure, diastolic blood pressure, respiratory rate, pulse rate, 
and body temperature. 
• Collect blood sample for IgG trough level assessment (within approximately 1 hour 
before infusion). 
• Train subjects on how to use pump for infusion of IgPro20. 
• Train subjects on how to use the subject eDiary / back-up paper diary. 
• Supervised infusion of IgPro20. Supervised entry of infusion data in the subject 
eDiary / back-up paper diary. 
• IgPro20 dispensation and IRT update. 


 
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• Evaluate for AEs (including injection site reaction[s]), record any findings in the 
eCRF. Train subjects to record AEs in the subject eDiary / back-up paper diary. 
Confirm that AEs have been recorded in the subject eDiary / back-up paper diary. 
• Record use of any concomitant therapy(ies). 
8.4.2.2 Weeks 2 (Day 8±1), 3 (Day 15±1) & 4 (Day 22±1) 
The following procedures will be conducted and documented at home: 
• Administer IgPro20. Infusion data should be recorded in the subject eDiary / back-up 
paper diary. 
• Evaluate for AEs (including injection site reaction[s]) and record any findings in the 
subject eDiary / back-up paper diary.  
8.4.2.3 Week 5 (Day 29±1) 
The following procedures will be conducted and documented at this office visit: 
• Measure systolic blood pressure, diastolic blood pressure, respiratory rate, pulse rate, 
and body temperature. 
• Review the subject eDiary / back-up paper diary and provide re-training, if necessary. 
• Supervised infusion of IgPro20. Supervised entry of infusion data in the subject 
eDiary / back-up paper diary. 
• IgPro20 dispensation and IRT update. 
• Review instructions for how to use pump for infusion of IgPro20, if necessary. 
• Evaluate for AEs (including injection site reaction[s]), record any findings in the 
eCRF, and confirm that AEs have also been recorded in the subject eDiary / back-up 
paper diary. Re-train subjects to record AEs in the subject eDiary / back-up paper 
diary, if necessary. 
• Review if subject has met definition of non-responder for this infusion parameter 
level. 
• Record use of any concomitant therapy(ies). 
8.4.2.4 Weeks 6 (Day 36±1), 7(Day 43±1) & 8 (Day 50±1) 
The following procedures will be conducted and documented at home: 


 
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• Administer IgPro20. Infusion data should be recorded in the subject eDiary / back-up 
paper diary. 
• Evaluate for AEs (including injection site reaction[s]) and record any findings in the 
subject eDiary / back-up paper diary.  
8.4.2.5 Week 9 (Day 57±1) 
The following procedures will be conducted and documented at this office visit: 
• Measure systolic blood pressure, diastolic blood pressure, respiratory rate, pulse rate, 
and body temperature. 
• Supervised infusion of IgPro20. Supervised entry of infusion data in the subject 
eDiary / back-up paper diary. 
• IgPro20 dispensation and IRT update. 
• Review instructions for how to use pump for infusion of IgPro20, if necessary. 
• Review the subject eDiary / back-up paper diary and provide re-training, if necessary. 
• Evaluate for AEs (including injection site reaction[s]), record any findings in the 
eCRF, and confirm that AEs have also been recorded in the subject eDiary / back-up 
paper diary. Re-train subjects to record AEs in the subject eDiary / back-up paper 
diary, if necessary.  
• Review if subject has met definition of non-responder for this infusion parameter 
level. 
• Record use of any concomitant therapy(ies). 
8.4.2.6 Weeks 10 (Day 64±1), 11 (Day 71±1), 12 (Day 78±1) 
The following procedures will be conducted and documented at home: 
• Administer IgPro20. Infusion data should be recorded in the subject eDiary / back-up 
paper diary. 
• Evaluate for AEs (including injection site reaction[s]) and record any findings in the 
subject eDiary / back-up paper diary.  
8.4.2.7 Week 13 (Day 85±1) 
The following procedures will be conducted and documented at this office visit: 


 
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• Measure systolic blood pressure, diastolic blood pressure, respiratory rate, pulse rate, 
and body temperature. 
• Review the subject eDiary / back-up paper diary and provide re-training, if necessary. 
• Supervised infusion of IgPro20. Supervised entry of infusion data in the subject 
eDiary / back-up paper diary. 
• IgPro20 dispensation and IRT update. 
• Review instructions for how to use pump for infusion of IgPro20, if necessary. 
• Evaluate for AEs (including injection reaction[s]), record any findings in the eCRF, 
confirm that AEs have also been recorded in the subject eDiary / back-up paper diary. 
Re-train subjects to record AEs in the subject eDiary / back-up paper diary, if 
necessary.  
• Review if subject has met definition of non-responder for this infusion parameter 
level. 
• Record use of any concomitant therapy(ies). 
8.4.2.8 Weeks 14 (Day 92±1), 15 (Day 99±1) & 16 (Day 106±1) 
The following procedures will be conducted and documented at home: 
• Administer IgPro20. Infusion data should be recorded in the subject eDiary / back-up 
paper diary. 
• Evaluate for AEs (including injection site reaction[s]) and record any findings in the 
subject eDiary / back-up paper diary.  
8.4.3 Manual Push Flow Rate & Pump-Assisted Volume Cohorts  
8.4.3.1 Week 1 (Day 1) 
The following procedures will be conducted and documented at this office visit: 
• Review inclusion/exclusion criteria. 
• Measure systolic blood pressure, diastolic blood pressure, respiratory rate, pulse rate, 
and body temperature. 
• Collect blood sample for IgG trough level assessment (within approximately 1 hour 
before infusion). 
• Train subjects on how to administer an infusion of IgPro20. 


 
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• Train subjects on how to use the subject eDiary / back-up paper diary. 
• Supervised infusion of IgPro20 via whichever method the subject will use (either 
pump or manual push). Supervised entry of infusion data in the subject eDiary / back-
up paper diary. 
• IgPro20 dispensation and IRT update. 
• Evaluate for AEs (including injection site reaction[s]) and record any findings in the 
eCRF. Train subjects to record AEs in the subject eDiary / back-up paper diary. 
Confirm that AEs have been recorded in the subject eDiary / back-up paper diary.  
• Record use of any concomitant therapy(ies). 
8.4.3.2 Weeks 2 (Day 8±1), 3 (Day 15±1) & 4 (Day 22±1) 
The following procedures will be conducted and documented at home: 
• Administer IgPro20 (weekly for pump-assisted infusions, more frequent than weekly 
[2-7 days per week] for manual push). Infusion data should be recorded in the subject 
eDiary / back-up paper diary. 
• Evaluate for AEs (including injection site reaction[s]) and record any findings in the 
subject eDiary / back-up paper diary.  
8.4.3.3 Week 5 (Day 29±1) 
The following procedures will be conducted and documented at this office visit: 
• Measure systolic blood pressure, diastolic blood pressure, respiratory rate, pulse rate, 
and body temperature. 
• Review the subject eDiary / back-up paper diary and provide re-training, if necessary. 
• Supervised infusion of IgPro20 (weekly for pump-assisted infusions, more frequent 
than weekly [2-7 days per week] for manual push). Supervised entry of infusion data 
in the subject eDiary / back-up paper diary. 
• IgPro20 dispensation and IRT update. 
• Review how to use pump for infusion of IgPro20, if necessary. 
• Evaluate for AEs (including injection site reaction[s]), record any findings in the 
eCRF, and confirm that AEs have also been recorded in the subject eDiary / back-up 
paper diary. Re-train subjects to record AEs in the subject eDiary / back-up paper 
diary, if necessary.  


 
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• Review if subject has met definition of non-responder for this infusion parameter 
level. 
• Record use of any concomitant therapy(ies). 
8.4.3.4 Weeks 6 (Day 36±1), 7 (Day 43±1) & 8 (Day 50±1) 
The following procedures will be conducted and documented at home: 
• Administer IgPro20 (weekly for pump-assisted infusions, more frequent than weekly 
[2-7 days per week] for manual push). Infusion data should be recorded in the subject 
eDiary / back-up paper diary. 
• Evaluate for AEs (including injection site reaction[s]) and record any findings in the 
subject eDiary / back-up paper diary.  
8.4.3.5 Week 9 (Day 57±1) 
The following procedures will be conducted and documented at this office visit: 
• Measure systolic blood pressure, diastolic blood pressure, respiratory rate, pulse rate, 
and body temperature. 
• Review the subject eDiary / back-up paper diary and provide re-training, if necessary. 
• Supervised infusion of IgPro20 (weekly for pump-assisted infusions, more frequent 
than weekly [2-7 days per week] for manual push). Supervised entry of infusion data 
in the subject eDiary / back-up paper diary. 
• IgPro20 dispensation and IRT update. 
• Review instructions for how to use pump for infusion of IgPro20, if necessary. 
• Evaluate for AEs (including injection site reaction[s]), record any findings in the 
eCRF, and confirm that AEs have also been recorded in the subject eDiary / back-up 
paper diary. Re-train subjects to record AEs in the subject eDiary / back-up paper 
diary, if necessary.  
• Review if subject has met definition of non-responder for this infusion parameter 
level. 
• Record use of any concomitant therapy(ies). 
8.4.3.6 Weeks 10 (Day 64±1), 11 (Day 71±1) & 12 (Day 78±1) 
The following procedures will be conducted and documented at home: 


 
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• Administer IgPro20 (weekly for pump-assisted infusions, more frequent than weekly 
[2-7 days per week] for manual push). Infusion data should be recorded in the subject 
eDiary / back-up paper diary. 
• Evaluate for AEs (including injection site reaction[s]) and record any findings in the 
subject eDiary / back-up paper diary.  
8.4.4 End of Study 
The scheduled end of study participation for an individual subject occurs during Week 13 on 
Day 85 ± 1 day for the Manual Push Flow Rate & Pump Assisted Volume cohorts (Week 17 
on Day 113 ± 1 day for the Pump-Assisted Flow Rate Cohort). After that no further study-
related procedures will be performed. The following procedures will be performed and 
documented at this office visit: 
• Collect blood sample for beta-human chorionic gonadotropin for females of child-
bearing potential. 
• Perform a physical examination. 
• Measure vital signs: 
o Systolic blood pressure, diastolic blood pressure, respiratory rate, pulse rate, 
and body temperature 
o Body weight  
o Height 
• Collect blood sample for IgG trough level assessment (within approximately 1 hour 
before infusion). 
• Collect blood samples for laboratory safety evaluation (biochemistry and 
hematology). 
• Review and collection of subject eDiary / back-up paper diary and collection of 
eDiary device, if provisioned. 
• Evaluate for AEs (including injection site reaction[s]) and record any findings.  
• Record use of any concomitant therapy(ies). 
Subjects who discontinue the study early will be asked to complete the End of Study 
procedures. 


 
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9. 
Adverse Events 
9.1 
Definitions 
9.1.1 Adverse Event 
As per the ICH guidelines, an AE is any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have a causal relationship with this treatment. An AE can, therefore, be any unfavorable and 
unintended sign (including an abnormal, clinically significant laboratory finding), symptom, 
or disease temporally associated with the use of a medicinal (investigational) product, 
whether or not considered related to the medicinal (investigational) product. 
The period of observation for AEs extends from the time the subject gives informed consent 
until the End of Study (see Section 9.4 for further details). 
Adverse events may include: 
• Exacerbation (ie, an increase in the frequency or severity) of a pre-existing condition. 
Illness present before study entry should be recorded in the medical history section of 
the eCRF and only be reported as an AE if there is an increase in the frequency or 
severity of the condition during the study. 
• A clinical event occurring after consent but before IgPro20 administration. 
• Intercurrent illnesses with an onset after administration of IgPro20. 
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 due to pre-existing conditions, which have not worsened. 
o Hospitalizations that occur for procedures not due to an AE (eg, cosmetic surgery). 
o Hospitalizations for a diagnostic procedure where the hospital stay is less than 24 h 
in duration or for normal management procedures (eg, chemotherapy). 
• Overdose of IgPro20 or any concomitant therapy that does not result in any adverse 
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For laboratory safety parameters, any instances of absolute values being outside the reference 
range or changes at any visit after study start that are considered by the investigator as 
clinically significant must be recorded in the eCRF as AEs. In addition, at the investigator’s 
discretion, any changes or trends over time in laboratory parameters can be recorded in the 
eCRF as AEs if such changes or trends are considered to be clinically relevant, even if the 
absolute values are within the reference range. 
Laboratory findings do not need to be reported as AEs in the following cases: 
• Laboratory parameters already beyond the reference range at Screening, unless a 
further increase/decrease can be considered an exacerbation of a pre-existing 
condition. 
• Abnormal laboratory parameters caused by mechanical or physical influences on the 
blood sample (eg, in vitro hemolysis) and flagged as such by the laboratory in the 
laboratory report. 
• Abnormal parameters that are obviously biologically implausible (eg, values that are 
incompatible with life or outside the measuring range). 
• An abnormal laboratory value that cannot be confirmed after repeat analysis, 
preferably in the same laboratory (ie, the previous result could be marked as not valid 
and should not necessarily be reported as an AE). 
9.1.2 Adverse Event of Special Interest 
Not applicable. 
9.1.3 Serious Adverse Event 
A serious adverse event (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. 


 
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• Requires in-patient hospitalization or prolongation of existing hospitalization – CSL 
considers “hospitalization or prolongation of existing hospitalization” for at least 24 h as 
the defining criterion for an SAE. Hospital admissions for planned surgery or for normal 
disease management procedures (eg, chemotherapy) are not considered as defining 
criteria for SAEs. 
• Results in persistent or significant disability or incapacity. 
• Is a congenital anomaly or birth defect. 
• Is medically significant – A medically significant event is defined as an event that does 
not necessarily meet any of the SAE criteria, but which is judged by a  qualified 
healthcare provider 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. 
9.2 
Severity of Adverse Events 
The severity of each AE (ie, nonserious and serious AEs) is to be assessed by the investigator 
as follows: 
Severity 
Definition 
Mild 
A type of AE that is usually transient and may require only minimal treatment or therapeutic 
intervention. The event does not generally interfere with usual activities of daily living. 
Moderate 
A type of AE that is usually alleviated with additional specific therapeutic intervention. The 
event interferes with usual activities of daily living, causing discomfort but poses no 
significant or permanent risk of harm to the subject. 
Severe 
A type of AE that interrupts usual activities of daily living, or significantly affects clinical 
status, or may require intensive therapeutic intervention. 
CDISC SDTM Severity Intensity Scale for Adverse Event Terminology. 
AE = adverse event. 
If AE severity is not reported (missing), it will be conservatively assessed as a severe AE. 
9.3 
Causality of Adverse Events 
The causal relationship of an AE to IgPro20 must always be assessed by the investigator. All 
AEs will be classified as either related or not related to IgPro20. If a causality assessment is 
not provided for an AE (including an SAE), the AE will be considered related to IgPro20. 


 
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The degree of certainty with which an AE is attributed to IgPro20 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. 
• 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, IMP withdrawal or 
reproduced on rechallenge). 
9.4 
Observation Period for Adverse Events 
The observation period for AE (and SAE) reporting in an individual subject will start at the 
time of giving written informed consent for participation in the current study and finish with 
the End of Study visit. 
If the investigator becomes aware of an SAE that has started after the observation period has 
finished, and the event is considered to be associated with IgPro20, then this must be reported 
to CSL. 
9.5 
Adverse Event Reporting 
9.5.1 Adverse Events 
At each clinical evaluation, the investigator (or delegate) will determine whether any AEs 
have occurred. AEs will be recorded in the AE page of the eCRF. If known, the medical 
diagnosis of an AE should be recorded in preference to the listing of individual signs and 
symptoms. The investigator must follow up on the course of an AE until resolution or 
stabilization. If an AE is ongoing after the End of Study visit, the AE will continue to be 
followed up until resolution, stabilization, or the subject is lost to follow-up. Subjects who 
drop out of the study due to reasons other than ‘consent withdrawn’ or ‘lost to follow-up’ will 
be followed up by weekly telephone calls by site personnel for the full duration of their 
planned study participation, in order to collect information on AEs. 


 
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If, during the study period, a subject presents with a preexisting condition that was not noted 
at the time of study entry, the condition should be retrospectively recorded in the Medical 
History section of the eCRF. 
9.5.2 Adverse Events of Special Interest 
Not applicable. 
9.6 
Serious Adverse Event Reporting 
This study will comply with all applicable regulatory requirements and adhere to the full 
requirements of ICH Topic E2A (Clinical Safety Data Management: Definitions and 
Standards for Expedited Reporting). 
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, must be entered into the eCRF immediately (within 24 h of the investigator 
becoming aware of the event).  
Adverse events occurring in the period between the time the subject gave written informed 
consent and the first exposure to IgPro20 that meet 1 or more of the seriousness criteria for 
AEs must be entered into the eCRF in the same manner as other SAEs and will be included in 
the clinical study database. 
Any SAE that occurs after the End of Study visit that is considered to be causally related to 
IgPro20 must be reported immediately (ie, within 24 h of the investigator becoming 
aware of the event) to CSL. 
9.6.1 Requirements for Reporting of Serious Adverse Events 
The minimum reporting requirements for reporting of SAEs include: 
• Identifiable subject. 
• Suspected medicinal product and / or procedure. 
• Event term. 
• Identifiable reporting source. 


 
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In addition, the investigator must: 
• Report all SAEs to the relevant Institutional Review Board / Independent Ethics 
Committee (IRB / IEC) within the timeframe specified by the IRB / IEC. 
• Enter follow-up information in the eCRF until the SAE has resolved, or, in the case of 
permanent impairment, until stabilized. 
• Ensure that the causality assessment for all SAEs is entered in the eCRF. 
If the minimum requirements for reporting are fulfilled, the investigator should not wait to 
receive additional information to fully document the event. 
In cases of death, the investigator should supply CSL and the IEC / IRB (as applicable) with 
any additional information as it becomes available (eg, autopsy reports and detailed medical 
reports). 
9.6.2 Unusual Failure of Efficacy (Canadian sites only) 
For study sites located in Canada only, unusual failure of efficacy is also to be reported to 
CSL using the same process and requirements as for serious adverse events in order to 
comply with Health Canada’s Food and Drug Regulations. The rationale for this is if a health 
product fails to produce the expected intended effect, there may be an adverse outcome for 
the patient, including an exacerbation of the condition for which the health product is being 
used.  In cases where the investigator is uncertain whether an adverse event should be 
considered as a report of unusual failure in efficacy, the adverse event should be treated as 
such and reported accordingly. 
 
9.7 
Other Significant Event Reporting 
9.7.1 Medication Compliance 
Details of actual doses of IgPro20 administered (ie, volume, location of infusions, infusion 
rate) will be recorded in the subject eDiary or a back-up paper diary if the eDiary is not 
available. Once the eDiary becomes available, the data recorded in the back-up paper diary 
will be transcribed to the eDiary. The back-up paper diary will be retained as a source 


 
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document. Any overdose that is considered by the investigator to be medically significant 
must be reported as an SAE (see Section 9.6). 
9.7.2 Pregnancy and Lactation 
A female subject who becomes pregnant while participating in the study, or up to and 
including 20 weeks after the last study dose of IgPro20, must notify the investigator 
immediately. 
If a female subject becomes pregnant, she must discontinue forced upward titration treatment 
regimen with IgPro20. Her study participation will be discontinued and the procedure for 
discontinuation of a subject will be followed, as described in Section 4.2. 
This requirement is not because IgPro20 is potentially harmful to pregnant women or the 
fetus, but because pregnancy is likely to alter IgG metabolism and may result in medical need 
to adjust the IgPro20 dose, which will affect her ability to follow the forced upward titration 
schedule. 
CSL must be notified within 5 days of the investigator becoming aware of the pregnancy. 
Whenever possible, a pregnancy in a subject exposed to IgPro20 should be followed to term 
so as to assess any potential occurrence of congenital anomalies or birth defects. Any 
follow-up information, including premature termination and the status of the mother and 
child after delivery, should be reported by the investigator to CSL using a Pregnancy 
Reporting / Outcome Form. 
9.8 
IRB / IEC Reporting Requirements 
The time frame within which an IRB / IEC must be notified of deaths and investigational 
product-related unexpected SAEs is stipulated by each IRB / IEC. It is the investigator’s 
responsibility to comply with the requirements for IRB / IEC notification. CSL will provide 
investigators with all details of all SAEs reported to regulatory authorities. 
9.9 
Follow-up of Adverse Events 
Every effort should be made to follow-up subjects who continue to experience an AE or an 
SAE on completion of the study until the AE resolves, is stabilized, or until the subject is lost 


 
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to follow-up. Further details on follow-up of subjects who drop out from the study are 
described in Section 9.5.1. All follow-up information should be entered into the eCRF within 
24 hours of awareness and documented in the subject’s medical records. Information on 
attempted follow-up contacts should be documented in the subject’s medical records. 
If an ongoing AE becomes serious after completion of the study, this information should be 
sent as follow-up and must be reported immediately (within 24 hours of the investigator 
becoming aware of the event) to CSL as described in Section 9.6.  
All follow-up information (and attempted follow-up contacts) should be documented in the 
subject’s medical records. Details of the subject’s progress should also be submitted to CSL 
Global Clinical Safety and Pharmacovigilance. 
10. Assessments 
10.1 
Subject Characteristics 
Subject characteristics to be evaluated will include: 
• Demographic data (eg, sex, race). 
• Medical and surgical history. 
• Details of diagnosis and disease status at enrollment into the study. 
• Previous and concomitant therapy. 
10.2 
Efficacy Assessments 
 
• 
. 
10.3 
Safety Assessments 
Safety will be assessed by: 
• The frequency and severity of AEs. 
• Local reactions (injection site reactions). 
• Tolerability of a certain infusion parameter (ie, percentage of subjects and infusions per 
cohort by volume/flow rate subgroup experiencing no severe local reactions for each of 
the infusion parameter levels). 
• Physical examination. 
CCI
CCI


 
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• Vital signs. 
• Clinical laboratory tests: 
o Biochemistry 
o Hematology 
Clinical laboratory tests will be performed at time points as detailed in the Schedule of 
Assessments. More frequent evaluations may be performed, if clinically indicated, at the 
discretion of the investigator. 
10.4 
Pharmacokinetic and Pharmacodynamics 
Not applicable. 
10.5 
Other Assessments 
Not applicable. 
11. Statistics 
11.1 
Sample Size Estimation 
A minimum of 45 evaluable (15 per cohort) subjects will be needed. This is based on an 
assumed response rate for reaching the top infusion parameter for each endpoint of 50% (ie, 
100 mL/h for the Pump-Assisted Flow Rate Cohort, 50 mL per injection site for the 
Pump-Assisted Volume Cohort, and 2 mL/min for Manual Push Flow Rate Cohort). Using a 
binomial distribution with 15 evaluable subjects, there will be a 94% probability that the 
observed response rate for a single endpoint in the study is ≥ 33%. 
11.2 
Description of Analysis Datasets 
11.2.1 Full Analysis Set 
The Full Analysis Set (FAS) will comprise all subjects who provide informed consent and 
who are included in the study; ie,  who undergo study procedures 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. 


 
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11.2.2 Safety Population 
The Safety Population will comprise all subjects in the Full Analysis Set who received at 
least 1 dose or a partial dose of IgPro20 in the study. 
11.3 
Statistical Analyses and Methods 
A complete description of the statistical analyses and methods will be available in a 
Statistical Analysis Plan, which will be finalized before the database is locked. 
11.3.1 Subject Disposition and Characteristics 
11.3.1.1 Subject Disposition 
The number of subjects who were screened, enrolled into the study, and completed the study 
will be presented in summary tables by treatment group and total subjects. The reason for 
discontinuing the study product or withdrawing a subject from the study will be listed by 
subject. 
11.3.1.2 Subject Characteristics 
At a minimum, subject characteristics will be presented in summary tables. Continuous data 
will be summarized by descriptive statistics (number of observations, mean, standard 
deviation, minimum, maximum, median, Q1, Q3) and categorical data will be summarized by 
frequency distributions. Age will be described as both a continuous and a discrete variable. 
Supportive data will be listed by subject. 
11.3.2 Efficacy Analyses 
 
. 
11.3.3 Safety Analyses 
AEs, laboratory, and vital signs will be summarized descriptively only within each of the 
3 cohorts separately. No analysis combining data from 3 separate cohorts or comparing safety 
outcomes between cohorts will be performed. 
CCI


 
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If a subject is a non-responder at a certain infusion parameter level, AEs reported at the 
individually tolerable infusion parameter level after the non-response in the subject, ie, AEs 
starting at or after the next infusion following the infusion leading to non-response, will be 
listed and flagged, and analysed separately from the AEs reported prior to that time. 
AEs will be summarized by the values of infusion parameters within each cohort. Rates per 
infusion will be presented as well. Adverse events will be presented including a virtual 
System Organ Class comprising local reaction (identified by the Medical Dictionary for 
Regulatory Activities high level terms: “administration site reactions NEC”, “infusion site 
reactions”, and “injection site reactions”) and by severity. Further, time to onset and duration 
will be presented descriptively. Tolerability of a certain infusion parameter within a cohort 
will be calculated as ‘number of infusions without severe local reaction / number of all 
infusions’ and be presented by infusion parameter and cohort. All infusions, regardless of the 
validity of the procedure (see Section 11.3.5) will be considered. 
11.3.4 Pharmacokinetics and Pharmacodynamic Data 
Not applicable. 
11.3.5 Other Analyses – Infusion Parameters 
For the primary endpoints, number and percentage of subjects with response will be 
provided.  
If a subject is a non-responder at a certain infusion parameter level, data collected up to the 
time of non-response are taken into account for the analysis of response. Data collected at the 
individually tolerable infusion parameter level after the non-response in the subject will not 
be included in the analysis of response but will only be listed and flagged. 
Percentages will be calculated as follows: 
a) An infusion will be considered ‘valid’ if the subject completes the full dose per 
scheduled infusion parameter (volume or flow rate) under test without interruptions or 
decrease during that infusion as detailed in Table 6. Other protocol deviations may 
also lead to invalidation of an infusion. Protocol deviations will be treated on an 
infusion basis, not on a subject basis. 


 
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Table 6. 
Criteria for Valid Infusions 
Cohort 
Criteria for a valid infusion 
Pump assisted volume 
cohort 
• 
Maximum volume administered per injection site is at least 95% of the 
planned maximum volume (ie, 25 mL, 40 mL or 50 mL) for at least one 
injection site 
and 
• 
Infusion was not interrupted or stopped prematurely for any reason as 
documented in the eDiary  
and 
• 
Total dose administered is at least 95% of the planned dose 
Pump assisted flow rate 
cohort 
• 
Injection site flow rate is at least 95% of the planned flow rate (ie, 25 mL/h, 
50 mL/h, 75 mL/h or 100 mL/h) for at least one injection site. 
and 
• 
Infusion was not interrupted or stopped prematurely for any reason as 
documented in the eDiary  
and 
• 
Total dose administered is at least 95% of the planned dose 
Manual push cohort 
• 
The actual infusion duration is not more than 1 minute or 10% (whichever is 
larger) longer than the calculated infusion duration based on the desired flow 
rate (ie, 0.5 mL/min, 1 mL/min, or 2 mL/min) and the actual volume infused.  
and   
• 
The actual infusion volume is at least 95% of the planned infusion volume for 
that infusion day. 
b) For the Pump-Assisted Cohorts, a subject is considered as a ‘responder’ for a certain 
infusion parameter if he/she has performed ≥3 valid infusions (see a) for that infusion 
parameter in any order, ie, not necessarily consecutive). 
c) For the Manual Push Flow Rate Cohort, a subject is considered as a ‘responder’ for a 
certain infusion parameter if he/she has performed ≥k valid infusions (see a) for that 
infusion parameter in any order, ie, not necessarily consecutive) during the 4 weeks 
planned for that infusion parameter level, where k is specified in Table 7. 
Table 7. 
Responder Requirements in Manual Push Cohort 
Manual push infusions /wk 
Infusions scheduled for parameter set (n) 
Minimum No. of valid infusions (k) 
2 
8 
5 
3 
12 
7 
4 
16 
10  
5 
20 
12  
6 
24 
15  
7 
28 
17  
 
d) For each cohort (c) the percentage of subjects with response to a certain infusion 
parameter (p), Rc,p, will be calculated as [%]: 
100*(Number of responders for p in cohort c) / (number of subjects from the Safety 
Population in cohort c) 
where response is defined as outlined in b) and c), respectively. 
 


 
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The success criterion for any Rc,p will be considered fulfilled if Rc,p ≥ 33%. Within each 
cohort, the highest infusion parameter with fulfilled success criterion will be considered the 
new top infusion parameter to be recommended for the Hizentra label. No formal statistical 
testing will be performed. All subjects included in the Safety Population of a cohort will be 
included in the denominator for calculation of Rc,p.  
Rationale for number of valid infusions to qualify a responder in the manual push cohort: The 
probability for a subject to be a responder for a certain infusion parameter is assumed to be 
50% irrespective of the value of the infusion parameter itself, ie, identical to the assumed 
response rate in Section 11.1. This assumption is based on the expectation that there will be 
no infusion-related reasons for a subject to interrupt the infusion or change the infusion 
parameters. To achieve ≥ 3 out of 4 valid infusions the probability for a single infusion to be 
valid has to be ≥ 61% for pump assisted cohorts. Using this 61% success probability for a 
single infusion in the manual push cohort the minimum of successes (k) in above table 
corresponds to a probability for a subject to be a responder of at least 50%.  
The primary endpoints will be considered and evaluated independently from each other. 
No imputation of missing data will be performed. 
Descriptive subgroup analyses will be performed for Infusion Parameters by:  
• Age class (≤ 17 years, > 17 years). 
• BMI class (< 30 kg/m2, ≥ 30 kg/m2). 
11.3.6 Interim Analysis 
Not applicable. 
12. Quality Assurance 
The study may be subject to an audit by CSL, an authorized representative(s) of CSL and / or 
inspections by an authorized regulatory authority (eg, US FDA). Regulatory authorities may 
request access to all study documentation, including source documents for inspection and 
copying, in keeping with local regulations. CSL will immediately notify the investigator of an 
upcoming audit/inspection. 


 
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In the event of an audit, all pertinent study-related documentation must be made available to 
the auditor(s). If an audit or inspection occurs, the investigator at each study site will permit 
the auditor/inspector direct access to all relevant documents and allocate their time as well as 
the time of relevant staff to discuss the findings and any relevant issues. 
13. Regulatory and Ethics Considerations 
13.1 
Regulatory Considerations 
CSL or its agents will submit the appropriate documents to the local regulatory agencies and 
will await approval before study start. 
This study will be conducted under a Clinical Trial Agreement between the sponsor (or 
delegate) and the respective institutions representing the study sites and documented in 
accordance with the applicable regulatory guidelines and requirements. 
The procedures set out in this study protocol are designed to ensure that CSL and the 
investigator abide by the principles of the current ICH GCP guideline on the conduct, 
evaluation and documentation of this study, as described in ICH Topic E6 (Guideline for 
GCP). The study will also be carried out according to all applicable international and national 
regulatory requirements. 
13.2 
Institutional Review Board / Independent Ethics Committee 
The investigator must submit the protocol and informed consent forms (ICFs) for review by 
an authorized and properly constituted (according to local guidelines) IRB/IEC. Written 
approval must be received from the IRB/IEC before commencement of the study. 
13.3 
Subject Information and Informed Consent 
The principles of informed consent 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 whenever possible and deemed appropriate by the 
IRB/IEC. Subjects, their relatives (or if necessary, legally acceptable representatives) must be 
given ample opportunity to inquire about details of the study. 


 
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Should there be any amendments to the protocol that would directly affect the subject’s 
participation in the study (eg, a change in any procedure), the ICF must be amended to 
incorporate this modification. Subject must be informed of the change and they must sign the 
amended ICF indicating that they re-consent to participate in the study. 
13.4 
Subject Identification and Confidentiality 
All subject names and contact details will be kept confidential. Subjects will be identified 
throughout documentation and evaluation by the number allotted to them during the study. 
Each subject will be told that all study findings will be handled in the strictest confidence. 
The investigator at the study site will be responsible for retaining sufficient information about 
each subject (eg, name, address, phone number and identity in the study) so that regulatory 
agencies or CSL may access this information should the need arise. These records should be 
retained in a confidential manner as long as legally mandated according to local 
requirements. 
Subject medical records pertaining to the study may be inspected/audited at any time by CSL 
employees or their duly authorized representatives, a regulatory authority or the IRB/IEC. All 
records accessed will be strictly confidential. Consent to participate in the study includes 
consent to these inspections/audits. 
13.5 
Indemnity and Compensation 
It is CSL policy that persons who participate in CSL’s clinical studies should be no worse off 
for their having been involved in the study. These persons include the subjects/volunteers, the 
investigator, the hospital and the IRB/IEC. 
CSL has taken out insurance to cover its obligations under both the Indemnity and the 
Compensation guidelines for injury to subjects involved in the study. 
Other details regarding compensation and the obligations of the investigator/CSL are 
provided in the Clinical Trial Agreement for the study (see Section 14.1). 


 
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14. Administrative Considerations 
14.1 
Clinical Trial Agreement 
This study will be conducted under a Clinical Trial Agreement between CSL (“Sponsor”) and 
the institution(s) representing the investigational study site(s) (“Authority”). Financial 
support to the investigational site(s) will be detailed in the Clinical Trial Agreement. The 
Clinical Trial Agreement must be signed before the commencement of the study and will 
clearly delineate the responsibilities and obligations of investigator and CSL, and will form 
the contractual basis under which the clinical study will be conducted.  
14.2 
Clinical Study Registration and Results Disclosure  
CSL will provide the relevant study protocol information in public database(s) before or at 
commencement of the study. CSL may also provide study information for inclusion in 
national registries according to local regulatory requirements. 
Results of this study will be disclosed according to the relevant regulatory requirements. All 
publications in peer-reviewed medical journals resulting from this study will be listed in the 
original study protocol registration record. 
14.3 
Implementation of the Protocol / Protocol Amendment(s) 
With the exception of medical emergencies, no changes or deviations in the conduct of the 
signed protocol will be permitted without documented approval of the CSL Medical Monitor 
and the IRB/IEC. In the event of a medical emergency, the investigator at the study site will 
institute any medical procedures deemed appropriate. However, all such procedures must be 
promptly reported to the CSL Medical Monitor and the IRB/IEC. 
Modifications to the protocol that may affect subject safety or the way the study is to be 
conducted will be documented in a protocol amendment, which must be approved by the 
IRB/IEC. 
Administrative changes to the protocol, defined as minor corrections and/or clarifications that 
have no effect on the way the study is to be conducted, will not require IRB/IEC approval, 
but will be submitted to the IRB/IEC for their information. 


 
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14.4 
Protocol Deviations 
All instances where the requirements of the study protocol were not complied with will be 
tracked. Corresponding subjects may be withdrawn from the study at the discretion of the 
investigator and/or CSL. Study protocol deviations arise when subjects who have been 
entered in the study deviate from the IRB/IEC -approved study protocol.  
If a major protocol deviation (ie, a deviation that could have a significant effect on the 
subject’s safety, rights, or welfare and/or on the integrity of the study data) occurs, the 
investigator must notify CSL and the appropriate IRB/IEC as soon as possible or as per local 
requirements.  
An infusion will be considered ‘valid’ if performed according to the predefined time, total 
volume, and infusion rate. Any deviation from these for each infusion parameter step will 
disqualify the infusion and be considered a ‘failure’ in the analysis of this set of infusion 
parameters. However, if it is conducted as stated in Section 11.3.5, it can be evaluated for the 
actual parameter as conducted. For example, if a subject was scheduled to a test volume of 
50 mL/site, but for some reasons tested 45 mL/site, it will not count for the 50 mL level, but 
if that infusion was otherwise uneventful and performed in full without interruption, it will be 
considered valid for the 45 mL/site level, even though it was not planned.  
Protocol deviations may result in an invalid infusion even if there is adherence to the infusion 
parameters, as stated above. These include, but are not limited to, prohibited concomitant 
medication use. Full details regarding validation failure will be included in the statistical 
analysis plan. 
14.5 
Documentation and Record Keeping  
14.5.1 Data Collection 
The investigator (or delegate) will maintain individual records for each subject. These records 
should include dates when a subject visited the study site, records of vital signs, medical 
history, or physical examinations, administration of IgPro20 or concomitant therapy, any AEs 
experienced, and other notes as appropriate. These records constitute source data. 


 
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An eCRF and eDiary will be provided by CSL (or delegate) for each subject enrolled into the 
study. The investigator is responsible for ensuring accurate and proper completion of the 
eCRF and eDiary in a timely manner so that it always reflects the latest observations on the 
subjects enrolled in the study. All entries on the eCRF must be backed up by source data (ie, 
the eDiary). A paper diary is provided for use as a back-up if the eDiary becomes unavailable 
for use. Once the eDiary becomes available again, the data recorded in the back-up paper 
diary will be transcribed into the eDiary. 
All source data will be kept according to all applicable regulatory requirements. Source data 
must be completed legibly for each subject enrolled into the study and signed by the 
investigator (or delegate). The back-up paper diary, if used, will be retained as source. 
The subject will enter infusion data into the eDiary under supervision by the study staff on 
Day 1. The subject will enter the infusion data into the eDiary for all home infusions and 
record if any AE occurred. It must be completed in a timely manner so that it always reflects 
the latest observations on the subjects enrolled in the study. At office visits on Days 29, 57 or 
85 (Flow Rate Cohort) and Days 29 and 57 (Manual Push and Pump-Assisted Volume 
Cohorts) as well as the End of Study visit, subjects will review the eDiary and back-up paper 
diary with study staff. 
14.5.2 Data Quality Assurance 
Subjects will receive mandatory, formal training for correct completion of the eDiary / back-
up paper diary (including drug usage and AE reporting) before issuing the diary. 
Data generated throughout the study will be monitored and the eCRFs checked against the 
subject records (including the eDiary / back-up paper diary) for completeness and accuracy. 
CSL’s (or delegate) study monitor will perform this function. 
Following completion of eCRF pages and entry of the data into a database, the data will be 
checked electronically for consistency and plausibility. Queries will be generated for 
questionable data and clarification sought from the investigator. These data queries must be 
resolved in a timely manner by the investigator (or delegate). 


 
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14.5.3 Record Retention 
An investigator study file prepared by CSL (or delegate), containing all applicable documents 
for use at the study site, will be made available to the investigator before the start of the 
study. All study documentation and materials maintained in the investigator study file must 
be kept in conformance with applicable national laws and regulations. 
All study documentation and materials maintained in the investigator study file at the study 
site must be available for inspection by the CSL’s study monitor (or delegate) to determine 
that all required documentation is present and correct.  
The study may be audited or inspected by qualified delegates from CSL or a competent 
regulatory authority. 
Following completion of the study, the investigator is responsible for archiving the 
investigator’s study file, the subject’s records and the source data according to applicable 
regulatory requirements.  
14.6 
Study and Site Closure 
CSL reserves the right to prematurely discontinue or suspend the study either at a particular 
site or at all study sites at any time and for any reason. If such action is taken, the CSL study 
monitor (or delegate) will discuss this with the investigator at each study site at that time and 
notify the investigators in writing. If the study is suspended or terminated for safety reasons 
all investigators and the relevant regulatory agencies will be immediately notified of the 
action as well as the reason for it. The investigator at each study site will advise the IRB/IEC 
overseeing the study at their site. 
14.7 
Clinical Study Report 
A clinical study report will be written after the completion of the study. CSL or its agent will 
write the report in consultation with the investigator or, if applicable, a nominated 
coordinating investigator (or delegate). It is required by CSL that the coordinating 
investigator will sign the clinical study report.  


 
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Progress reports may be provided to the relevant regulatory bodies in accordance with their 
requirements. 
14.8 
Use of Data and Publications 
The rights and obligations of investigators and CSL concerning any formal presentation or 
publication of data collected as a direct or indirect result of this study will be addressed 
specifically in the Clinical Trial Agreement for the study. 
 


 
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15. References 
Berger M. Subcutaneous immunoglobulin replacement in primary immunodeficiencies. Clin 
Immunol 2004;112:1-7. 
Berger M. Principles of and advances in immunoglobulin replacement therapy for primary 
immunodeficiency. Immunol Allergy Clin North Am 2008;28:413-37. 
Borte M, Bernatowska E, Ochs HD and Roifman CM. Efficacy and safety of home-based 
subcutaneous immunoglobulin replacement therapy in paediatric patients with primary 
immunodeficiencies. Clin Exp Immunol. 2011 Jun;164(3):357-64.  
Borte M, Krivan G, Derfalvi B, Marodi L, Harrer T, Jolles S, et al. Efficacy, safety, 
tolerability and pharmacokinetics of a novel human immune globulin subcutaneous, 20%: a 
Phase 2/3 study in Europe in patients with primary immunodeficiencies. Clin Exp Immunol. 
2016. 
Bousfiha A, Jeddane L, Al-Herz W, et al. The 2015 IUIS Phenotypic Classification for 
Primary Immunodeficiencies. J Clin Immunol 2015. 
Bousfiha A, Jeddane L, Ailal F, et al. Primary immunodeficiency diseases worldwide: more 
common than generally thought. J Clin Immunol 2013;33:1-7. 
Chapel HM, Spickett GP, Ericson D, Engl W, Eibl MM, Bjorkander J. The comparison of the 
efficacy and safety of intravenous versus subcutaneous immunoglobulin replacement therapy. 
J Clin Immunol 2000;20:94-100. 
Cooper MA, Pommering TL, Koranyi K. Primary immunodeficiencies. Am Fam Physician 
2003;68:2001-8. 
FDA. Guidance for Industry. Antibacterial Therapies for Patients With Unmet Medical Need 
for the Treatment of Serious Bacterial Diseases. July 2013. 
FDA Guidance for Industry. Safety, Efficacy, and Pharmacokinetic Studies to Support 
Marketing of Immune Globulin Intravenous (Human) as Replacement Therapy for Primary 
Humoral Immunodeficiency. June 2008 


 
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Gardulf A, Nicolay U, Math D et al. Children and adults with primary antibody deficiencies 
gain quality of life by subcutaneous IgG self-infusions at home. J Allergy Clin Immunol. 
2004 Oct;114(4):936-42. 
Ishimura M, Takada H, Doi T, Imai K, Sasahara Y, Kanegane H et al. Nationwide survey of 
patients with primary immunodeficiency diseases in Japan. J Clin Immunol. 31(6), 968-76, 
2011. 
Jolles S, Orange JS, Gardulf A, et al. Current treatment options with immunoglobulin G for 
the individualization of care in patients with primary immunodeficiency disease. Clin Exp 
Immunol 2015;179:146-60. 
Kanegane H, Imai K, Yamada M, et al. Efficacy and safety of IgPro20, a subcutaneous 
immunoglobulin, in Japanese patients with primary immunodeficiency diseases. J Clin 
Immunol 2014;34:204-11. 
Kilic SS, Ozel M, Hafizoglu D, Karaca NE, Aksu G, Kutukculer N. The prevalences and 
patient characteristics of primary immunodeficiency diseases in Turkey--two centers study. 
Clin Immunol. 33(1), 74-83, 2013. 
Martin A, Lavoie L, Goetghebeur M, Schellenberg R. Economic benefits of subcutaneous 
rapid push versus intravenous immunoglobulin infusion therapy in adult patients with 
primary immune deficiency. Transfus Med 2013;23:55-60. 
Misbah S, Sturzenegger MH, Borte M, et al. Subcutaneous immunoglobulin: opportunities 
and outlook. Clin Exp Immunol 2009;158 Suppl 1:51-9. 
Morimoto Y, Routes JM. Immunodeficiency overview. Prim Care 2008;35:159–173, viii. 
Nicolay U, Kiessling P, Berger M, et al. Health-related quality of life and treatment 
satisfaction in North American patients with primary immunedeficiency diseases receiving 
subcutaneous IgG self-infusions at home. J Clin Immunol 2006;26:65-72. 
 


 
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Picard C, Al-Herz W, Bousfiha A, et al. Primary Immunodeficiency diseases: an Update on 
the Classification from the International Union of Immunological Societies Expert 
Committee for Primary Immunodeficiency 2015.  J Clin Immunol 2015. 
Raje N, Dinakar C. Overview of Immunodeficiency Disorders. Immunol Allergy Clin North 
Am. 35(4):599-623, 2015. 
Richter A. Experience with rapid push subcutaneous immunoglobulin therapy from a UK 
clinic. UKPIN 2013 Abstracts, p. 74. 
Shapiro R. Subcutaneous immunoglobulin therapy by rapid push is preferred to infusion by 
pump: a retrospective analysis. J Clin Immunol 2010;30:301-7. 
Shapiroa RS. Subcutaneous immunoglobulin therapy given by subcutaneous rapid push vs 
infusion pump: a retrospective analysis. Ann Allergy Asthma Immunol 2013;111:51-5. 
Shapirob RS. Subcutaneous immunoglobulin: rapid push vs. infusion pump in pediatrics. 
Pediatr Allergy Immunol 2013;24:49-53. 
Shapiroc R. Subcutaneous immunoglobulin (16 or 20%) therapy in obese patients with 
primary immunodeficiency: a retrospective analysis of administration by infusion pump or 
subcutaneous rapid push. Clin Exp Immunol 2013;173:365-71. 
Sriaroon P, Ballow M. Immunoglobulin Replacement Therapy for Primary 
Immunodeficiency. Immunol Allergy Clin North Am 2015;35:713-30. 
Suez D, Stein M, Gupta S, Hussain I, Melamed I, Paris K, et al. Efficacy, Safety, and 
Pharmacokinetics of a Novel Human Immune Globulin Subcutaneous, 20 % in Patients with 
Primary Immunodeficiency Diseases in North America. Journal of Clinical Immunology. 
2016;36(7):700-12. 
Yong PF, Chee R, Grimbacher B. Hypogammaglobulinaemia. Immunol Allergy Clin North 
Am 2008;28:691-713, vii. 
 


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SAP_001.pdf: 
CONFIDENTIAL 
 
 Page 1 of 48 
 
STATISTICAL ANALYSIS PLAN 
 
Study Title:  An Open-Label Multicenter Study to Evaluate the Safety and Tolerability 
of Higher Infusion Parameters of Immune Globulin Subcutaneous (Human), 20% 
Liquid (Hizentra®) in Subjects with Primary Immunodeficiency 
Investigational Medicinal Product:  IgPro20 (Hizentra®) 
Protocol Number:  IgPro20_4004 
Version:  1.0 
Version Date:  26 JUL 2018 
 
 
 
Sponsor: 
CSL Behring LLC 
 
 
 
 
This document includes information and data that contain trade secrets and privileged or confidential 
information which is the property of CSL Behring LLC and/or its affiliates (“CSL”). This information 
must not be made public without written permission from CSL. These restrictions on disclosure will 
apply equally to all future information supplied to you. 
 


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CSL Behring 
Statistical Analysis Plan 
Protocol Number: IgPro20_4004 
Product Name: Hizentra® 
 
 
CONFIDENTIAL 
 
 
 Page 7 of 48 
List of Tables 
Table 1: Infusion parameter levels per cohort ......................................................................... 33 
Table 2: Minimum criteria for a valid infusion ........................................................................ 34 
Table 3: Responder requirements in Manual Push Flow Rate Cohort ..................................... 37 
 
List of Figures 
Figure 1 Study Flowchart ........................................................................................................ 17 
 


CSL Behring 
Statistical Analysis Plan 
Protocol Number: IgPro20_4004 
Product Name: Hizentra® 
 
 
CONFIDENTIAL 
 
 Page 8 of 48 
1 Modification History 
 
Version 
Effective Date  
Author of 
Modification 
Reason for Change 
1.0 
26 Jul 2018 
 
N/A – New document. 
 
 
 
 
 
 


CSL Behring 
Statistical Analysis Plan 
Protocol Number: IgPro20_4004 
Product Name: Hizentra® 
 
 
CONFIDENTIAL 
 
 
 Page 9 of 48 
2 Abbreviations and Definitions 
2.1 Abbreviations 
Abbreviation 
Definition 
AE 
Adverse Event 
ATC 
Anatomical Therapeutic Chemical 
BMI 
Body Mass Index 
CI 
Confidence Interval 
CSR 
Clinical Study Report 
eCRF 
Electronic Case Report Form 
ESP 
External Service Provider 
EOS 
End of Study 
FAS 
Full Analysis Set 
h 
Hour 
ICH 
International Conference on Harmonization 
IgG 
Immunoglobulin G 
kg 
Kilogram 
m 
Meter 
mg 
Milligram 
mL 
Milliliter 
MedDRA 
Medical Dictionary for Regulatory Activities 
N 
Number of Subjects 
PAFR 
Pump-Assisted Flow Rate 
PID 
Primary Immunodeficiency 
PT  
Preferred Term 
SAE 
Serious Adverse Event 
SAF 
Safety Analysis Set 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis System 
ScAS 
Screened Analysis Set 
SD 
Standard Deviation 
SDTM 
Study Data Tabulation Model 
SOC 
System Organ Class 


CSL Behring 
Statistical Analysis Plan 
Protocol Number: IgPro20_4004 
Product Name: Hizentra® 
 
 
CONFIDENTIAL 
 
 
 Page 10 of 48 
 
Abbreviation 
Definition 
TEAEs 
Treatment-Emergent Adverse Events 
TFLs 
Tables, Figures, and Listings 
WHO-DDE 
World Health Organization Drug Dictionary Enhanced 
2.2 Definitions 
Item 
Definition 
Analysis Sets 
Screened Analysis 
Set 
(ScAS) 
Subjects who provided written informed consent and who undergo 
study screening procedures 
Full Analysis Set 
(FAS) 
Subjects of the ScAS who are included in the study, i.e. who 
undergo study procedures after Screening. 
Safety Analysis Set 
(SAF) 
Subjects in the FAS who received at least 1 dose or a partial dose 
of IgPro20 in the study. 
Cohorts 
Pump-Assisted 
Volume Cohort  
Weekly infusions: volume per injection site of infusion parameter 
levels: 25 mL, 40 mL, and 50 mL; each infusion parameter level 
for 4 weeks 
Pump-Assisted Flow 
Rate Cohort 
Weekly infusions: flow rate per injection site of infusion parameter 
levels: 25 mL/h, 50 mL/h, 75 mL/h, and 100 mL/h; each infusion 
parameter level for 4 weeks 
Manual Push Flow 
Rate Cohort 
2 to 7 infusions per week: flow rate per injection site of infusion 
parameter levels: 30 mL/h, 60 mL/h, and 120 mL/h (equivalent of 
approximately 0.5 mL/minute, 1 mL/minute, and 2 mL/minute) ; 
each infusion parameter level for 4 weeks 
Responder Analysis 
Criteria for Valid Infusion Definition Per Protocol 
Pump-Assisted 
Volume Cohort  
• 
Maximum volume administered per injection site is at least 
95% of the planned maximum volume (i.e., 25 mL, 40 mL or 
50 mL) for at least one injection site 
and 
• 
Infusion was not interrupted or stopped prematurely for any 
reason as documented in the diary 
and 


CSL Behring 
Statistical Analysis Plan 
Protocol Number: IgPro20_4004 
Product Name: Hizentra® 
 
 
CONFIDENTIAL 
 
 
 Page 11 of 48 
Item 
Definition 
• 
No prohibited concomitant medication 
and 
Total dose administered over all injection sites is at least 95% of 
the planned dose 
Pump-Assisted Flow 
Rate Cohort 
• 
Injection site flow rate is at least 95% of the planned flow rate 
(i.e., 25 mL/h, 50 mL/h, 75 mL/h or 100 mL/h) for at least one 
injection site. 
and 
• 
Infusion was not interrupted or stopped prematurely for any 
reason as documented in the diary  
and 
• 
No prohibited concomitant medication 
and 
Total dose administered over all injection sites is at least 95% of 
the planned dose 
Manual Push Flow 
Rate Cohort 
• 
The actual infusion duration is no more than 1 minute or 10% 
(whichever is longer) longer than the calculated infusion 
duration based on the desired flow rate (i.e., 30 mL/h 
[0.5 mL/min], 60 mL/h [1 mL/min], or 120 mL/h [2 mL/min]) 
and the actual volume infused 
and  
• 
No prohibited concomitant medication 
and 
The actual infusion volume is at least 95% of the planned infusion 
volume for that infusion day over all infusion sites. 
Criteria for Valid Infusion Modified Definition 
Pump-Assisted 
Volume Cohort  
• 
Maximum volume administered per injection site is at least 
95% of the planned maximum volume (i.e., 25 mL, 40 mL or 
50 mL) for at least one injection site 
and 
• 
Infusion may be stopped for technical reasons* only; no 
related AEs started during interrupted or stopped infusion. 
and 
• 
No prohibited concomitant medication 
and 
Total dose administered over all injection sites is at least 95% of 
the planned dose. 
(*Technical reason: technical problem with any part of equipment 
[pump, syringe, tubing, needle, including needle placement] used 
for infusion.) 


CSL Behring 
Statistical Analysis Plan 
Protocol Number: IgPro20_4004 
Product Name: Hizentra® 
 
 
CONFIDENTIAL 
 
 
 Page 12 of 48 
Item 
Definition 
Pump-Assisted Flow 
Rate Cohort 
• 
Injection site flow rate is at least 95% of the planned flow rate 
(i.e., 25 mL/h, 50 mL/h, 75 mL/h or 100 mL/h) for at least one 
injection site. 
and 
• 
Infusion may be stopped for technical reasons* only; no 
related AEs started during interrupted or stopped infusion. 
and 
• 
No prohibited concomitant medication 
and 
Total dose administered over all injection sites is at least 95% of 
the planned dose. 
(*Technical reason: technical problem with any part of equipment 
[pump, syringe, tubing, needle, including needle placement] used 
for infusion.) 
Manual Push Flow 
Rate Cohort 
• 
The actual infusion duration is no more than 1 minute or 10% 
(whichever is longer) longer than the calculated infusion 
duration based on the desired flow rate (i.e., 30 mL/h 
[0.5 mL/min], 60 mL/h [1 mL/min], or 120 mL/h [2 mL/min]) 
and the actual volume infused 
and  
• 
No prohibited concomitant medication 
and 
The actual infusion volume is at least 95% of the planned infusion 
volume for that infusion day over all infusion sites. 
Definition of Responder per Infusion Parameter Level 
Pump-Assisted 
Volume Cohort  
≥ 3 valid infusions in any order (out of 4 infusions) 
Pump-Assisted Flow 
Rate Cohort 
≥ 3 valid infusions in any order (out of 4 infusions) 
Manual Push Flow 
Rate Cohort 
≥ k valid infusions in any order during the 4 weeks planned for that 
infusion parameter level, with k being 
Manual push 
infusions per week 
Total number of infusions 
scheduled for parameter set 
Minimum number of 
valid infusions (k) 
2 
8 
5 
3 
12 
7 
4 
16 
10  
5 
20 
12  
6 
24 
15  
7 
28 
17  


CSL Behring 
Statistical Analysis Plan 
Protocol Number: IgPro20_4004 
Product Name: Hizentra® 
 
 
CONFIDENTIAL 
 
 
 Page 13 of 48 
Item 
Definition 
Success Criterion 
Percentage responder for infusion parameter p in cohort c 
Rc,p(%) = 100 ∗(Number of responder for 𝑝 in cohort 𝑐) 
Number of subjects in the SAF for cohort 𝑐
 
with the success criterion for any Rc,p being fulfilled if Rc,p ≥ 33%. 
Start Date of 
Non-Response 
Date of the next infusion after a subject was classified as 
non-responder. 
Terms 
AE Rate per Infusion 
Number of Adverse Events for a Particular PT / Number of 
Infusions Within Cohort 
Baseline 
Most recent non-missing value prior to or on the first study 
treatment dose date 
Body Mass Index 
(kg/m2) 
Body weight (kg) / Height (m)2 
Compliance per 
Infusion (%) 
(Actual amount per infusion/prescribed or planned amount per 
infusion)*100, where amount is dose (mg/kg) or volume (mL) 
Duration of Event 
End date of the event – start date of the event + 1 
Elapsed Time Until 
Event 
Event date – reference date 
Local TEAEs 
TEAEs identified by MedDRA high level terms “administration 
site reactions NEC”, “infusion site reactions”, and “injection site 
reactions” 
Tolerability of an 
Infusion Parameter 
Within Cohort 
Number of infusions without severe local reactions within cohort / 
number of infusions within cohort (irrespective of their validity); 
an infusion without severe local reactions is defined as no 
occurrence of a severe local reaction from the start date and time of 
an infusion until the start date and time of the next infusion or 
study end if this was the last infusion. 
Treatment-Emergent 
Event which started on or after the date (and time) of first 
administration of study treatment 
 
 


CSL Behring 
Statistical Analysis Plan 
Protocol Number: IgPro20_4004 
Product Name: Hizentra® 
 
 
CONFIDENTIAL 
 
 
 Page 14 of 48 
3 Purpose 
This SAP provides a detailed and complete description of the planned statistical analyses for 
the final analysis of the study IgPro20_4004 to support the Clinical Study Report (CSR). 
Mock tables, figures, and listings (TFLs) shells are provided in separate supporting 
documents. 
This SAP complies with the International Conference on Harmonization (ICH) Harmonized 
Tripartite Guideline Topic E9, Statistical Principles for Clinical Trials. It is based upon the 
following study documents: 
• Study Protocol (dated 15 Aug 2016); 
• Study Protocol Amendment 1 (dated 1 Feb 2017); 
• Study Protocol Amendment 2 (dated 31 May 2017); 
• Study protocol Amendment 3 (dated 2 Dec 2017); 
• Annotated electronic Case Report Form (eCRF) (dated 02 Feb 2017); 
• Annotated eCRF (dated 29 Jan 2018); 
• Annotated eCRF (dated 26 Jun 2018); 
• Screen Report for eDiary (dated 14 Mar 2017). 
All decisions regarding the final analysis of the study results, as defined in this SAP 
document, have been made prior to Database Freeze of the study data. 
4 Study Design 
4.1 Study Design 
This multicenter, open-label, parallel-arm, non-randomized study is designed to evaluate 
safety and tolerability of higher infusion parameters of IgPro20 in subjects with primary 
immunodeficiency (PID). A target of 45 evaluable subjects (i.e., 15 subjects per cohort) is 
needed. Enrolled subjects will include a target of 14 (30%) pediatric subjects ≤ 17 years of 
age and a target of 9 (20%) obese subjects with body mass index (BMI) of ≥ 30 kg/m2. 
Pediatric and obese subjects may be distributed across any or all of the treatment cohorts 
without respect to balanced enrollment within the cohorts for these subpopulations.. 
Assignment to one of the cohorts will take place at the Screening visit and subjects cannot be 


CSL Behring 
Statistical Analysis Plan 
Protocol Number: IgPro20_4004 
Product Name: Hizentra® 
 
 
CONFIDENTIAL 
 
 
 Page 15 of 48 
changed later to another cohort. The study will include 3 cohorts with a minimum of 15 
subjects each as follows: 
• Pump-Assisted Volume Cohort (weekly infusions): Volume per injection site of 25 mL 
up to 50 mL; 
• Pump-Assisted Flow Rate Cohort (weekly infusions): Flow rate per injection site of 
25 mL/hour (h) up to 100 mL/h 
• Manual Push Flow Rate Cohort (2 to 7 infusions per week): Flow rate per injection 
site of 25 to 30 mL/h up to 120 mL/h (equivalent of approximately 0.5 mL/minute up 
to 2 mL/minute) 
Each cohort will test 3 infusion parameter levels (for Pump-Assisted Flow Rate Cohort – 
4 levels) for at least 4 weeks each over a duration of 12 weeks (for Pump-Assisted Flow Rate 
Cohort – 16 weeks). After the fourth week on each level, subjects may switch to the next 
infusion parameter level, if the current level has been tolerated (e.g., from 25 to 50 mL/h). 
During the study the weekly dose will remain unchanged (as prescribed by treating healthcare 
provider, usually within 100-200 mg/kg per week range); only the respective infusion 
parameter under evaluation will change. If a subject is unable to tolerate the respective 
infusion parameter level (i.e., is a non-responder at that level, for definition see Section 11.2), 
the subject will continue study participation at the individually previously tolerated infusion 
parameter level for the remaining full study duration, to collect safety information. 
The final analysis to support the CSR will take place after all subjects have completed or 
terminated the study. 
The schedule of assessments planned for the study can be found in the protocol.  
4.2 Objectives and Endpoints 
 
Objectives 
Endpoints 
Primary 
 
The primary objective of this study is to 
determine the responder rate at higher 
infusion parameters of IgPro20 under the 
following conditions: 
The primary endpoints are as follows: 
• Pump-Assisted Volume Cohort: 
Percentage of responders for each 


CSL Behring 
Statistical Analysis Plan 
Protocol Number: IgPro20_4004 
Product Name: Hizentra® 
 
 
CONFIDENTIAL 
 
 
 Page 16 of 48 
Objectives 
Endpoints 
• Pump-Assisted: Volume per 
injection site of 25 mL, 40 mL, and 
50 mL; 
• Pump-Assisted: Flow rate per 
injection site of 25 mL/h, 50 mL/h, 
75 mL/h and 100 mL/h; 
• Manual Push (manual infusion using 
syringe without a pump): Flow rate 
per injection site of 30 mL/h, 
60 mL/h, and 120 mL/h 
(0.5 mL/minute, 1 mL/minute, and 
2 mL/minute, correspondingly). 
planned volume (i.e., 25 mL, 40 mL 
and 50 mL per injection site). 
• Pump-Assisted Flow Rate Cohort: 
Percentage of responders for each 
planned flow rate (i.e., 25 mL/h, 
50 mL/h, 75 mL/h and 100 mL/h per 
injection site). 
• Manual Push Flow Rate Cohort: 
Percentage of responders for each 
planned flow rate (i.e., 30 mL/h 
[0.5 mL/minute], 60 mL/h 
[1 mL/minute], and 120 mL/h 
[2 mL/minute] per injection site). 
Secondary 
 
• To evaluate the safety of 
pump-assisted IgPro20 infusions at 
higher infusion parameters (volume 
and flow rate). 
• To evaluate the safety of manual 
push IgPro20 infusions. 
• To evaluate the tolerability of higher 
infusion parameters of IgPro20. 
 
• The rate of total adverse events 
(AEs) per subject and per infusion 
by cohort and by each of the 
infusion parameter levels within the 
cohort. 
• The rate of local reactions per 
subject and per infusion by cohort 
and by each of the infusion 
parameter levels within the cohort. 
• The time to onset of local reactions 
per subject and per infusion by 
cohort and by each of the infusion 
parameter levels within the cohort. 
• Severity of local reactions per 
subject and per infusion by cohort 
and by each of the infusion 
parameter levels within the cohort. 
• Duration of local reactions per 
subject and per infusion by cohort 
and by each of the infusion 
parameter levels within the cohort. 
• For all cohorts: Tolerability of a 
certain infusion parameter, i.e. 
percentage of infusions per cohort 
by volume/flow rate subgroup 
experiencing no severe local 
reactions for each of the infusion 
parameter levels. 


CSL Behring 
Statistical Analysis Plan 
Protocol Number: IgPro20_4004 
Product Name: Hizentra® 
 
 
CONFIDENTIAL 
 
 
 Page 17 of 48 
Objectives 
Endpoints 
Exploratory 
 
• 
 
 
 
 
 
• 
 
 
 
 
4.3 Study Treatments  
The study treatment, IgPro20 (trade name Hizentra®), will be manufactured by CSL and will 
be labelled as investigational medicinal product for this study. 
The active substance is human normal immunoglobin in a ready-to-use formulation for 
subcutaneous injection. The same dose as prescribed by the subject’s healthcare provider 
prior to study entry will be used throughout the study, usually within 100-200 mg/kg per 
week range. 
Subjects will administer infusions following the schedule below: 
Figure 1 Study Flowchart 
 
Subjects in the Pump-Assisted Cohorts will administer weekly treatment and subjects in the 
Manual Push Cohort will administer frequent infusions (i.e., 2-7 times per week). Subjects in 
the Manual Push Cohort should maintain the same frequency of infusions per week 
throughout the whole study; including one month prior to Day 1 (date of Week 1 visit at the 
CCI
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CSL Behring 
Statistical Analysis Plan 
Protocol Number: IgPro20_4004 
Product Name: Hizentra® 
 
 
CONFIDENTIAL 
 
 
 Page 19 of 48 
6 Study Analysis Sets 
6.1 Screened Analysis Set 
The Screened Analysis Set (ScAS) will comprise all subjects who provided written informed 
consent and who undergo study screening procedures.   
6.2 Full Analysis Set 
The Full Analysis Set (FAS) will comprise all subjects who provided written informed 
consent and who are included in the study, i.e. who undergo study procedures after Screening. 
Screening failures will not be included in the FAS. 
6.3 Safety Analysis Set 
The Safety Analysis Set (SAF) will comprise all subjects in the FAS who received at least 1 
dose or a partial dose of IgPro20 in the study. 
7 General Considerations 
Database Format 
Datasets will be provided in Study Data Tabulation Model (SDTM) format. Analysis datasets 
will be created according to Clinical Data Interchange Standards Consortium standards.  
For each subject, data up to the time of study completion, loss to follow-up, or withdrawal 
from study, whichever is latest, will be included in the appropriate analysis sets defined in 
Section 6. If a subject withdraws consent, the subject’s data will only be used until the time 
when consent is withdrawn. 
Statistical Analysis System (SAS) Version 
SAS version 9.3 or higher will be used to perform all data analyses and to generate TFLs.  
Reporting Standards for Continuous and Categorical Variables 
Continuous variables will be summarized in terms of the number of observations, mean, 
standard deviation (SD), median, first quartile, third quartile, minimum, and maximum. Other 
descriptive statistics (e.g., 95% confidence intervals [CIs]) may be reported when 
appropriate. Categorical variables will be summarized using frequency counts and 
percentages. Missing values will be presented as separate category. Percentages will be based 


CSL Behring 
Statistical Analysis Plan 
Protocol Number: IgPro20_4004 
Product Name: Hizentra® 
 
 
CONFIDENTIAL 
 
 
 Page 20 of 48 
on the non-missing values. Analyses that use other descriptive statistics will have the specific 
descriptive statistics required identified with the analysis in the applicable SAP section. 
TFLs Format 
All ICH required data in the database will be presented in data listings. 
Data will be displayed as described in this SAP and in the supporting, separate TFL shells 
document(s). 
Tables will be presented by cohort and infusion parameter within cohort (Pump-Assisted 
Volume: Volume per Site 25 mL, 40 mL, 50 mL, and Total; Pump-Assisted Flow Rate: 
25 mL, 50 mL, 75 mL, 100 mL, and Total; and Manual Push Flow Rate: 30 mL/h [0.5 
mL/minute], 60 mL/h [1 mL/minute], 120 mL/h [2 mL/minute], and Total) as specified in the 
respective sections. As subjects may participate in more than one infusion parameter group, 
the total column may not be the sum of the infusion parameter columns. Subjects and events 
will be counted once in the total column. Events and assessments will be assigned to the 
infusion parameter level under which they occur. There will be total columns within cohorts, 
but no total column over cohorts. Details will be specified in the TFL shells document and in 
the corresponding SAP section. 
Listings will include cohort and infusion parameter, site number, subject number, and basic 
demographics (age, sex, BMI at Screening). Events and assessments will be assigned to the 
infusion parameter under which they occurred or were assessed. In subject-level listings, the 
subjects will be assigned to the highest infusion parameter which they successfully reached. 
Listings will be presented for a specific analysis set or for all available data depending on the 
nature of the information listed. In the listings for all available data, a column will be inserted 
showing the smallest analysis set the subject is assigned to (hierarchy of analysis sets in terms 
of size/subset: SAF ≤ FAS ≤ ScAS, analysis sets may comprise the same subjects). 
Unless otherwise stated, listings will be sorted by treatment status (not treated subjects 
followed by treated subjects), and within treatment status by cohort and infusion parameter, 
site-subject number, and by visit date and time or by event date and time. In case of partial 
dates, date sorting will be by year, month, and day. If any of these variables does not apply to 
a listing, then that listing will use only those variables which are applicable in the order given 
here. 


CSL Behring 
Statistical Analysis Plan 
Protocol Number: IgPro20_4004 
Product Name: Hizentra® 
 
 
CONFIDENTIAL 
 
 
 Page 21 of 48 
Unless otherwise stated, summary tables including figures will be reported by cohort and 
infusion parameter. The cohort/infusion parameter will be labelled as specified in Section 0. 
Tables presented by cohort and infusion parameter may contain a total column or block. 
If there is no data available for a table or listing (e.g., no deaths occurred in the study), the 
planned output will be displayed as “No data to report”. 
Decimal Places 
Summary statistics of mean, median, and quartiles (location parameters) will be reported to 
one more decimal place than the collected data. For derived data, the maximum number of 
decimal places of the variables used in the derivation will determine the number of decimal 
places of the derived variable. For example, BMI uses 2 collected variables, height in meters 
(m) and weight in kilograms (kg). If the height is collected in centimeters, height in m will 
have 2 decimal places. Weight may be collected with 1 decimal place. Thus BMI will be 
considered to have 2 decimal places on observation level. The SD (parameter for variability) 
will be reported to one more decimal place than the mean. For example, the mean and median 
for age will be reported to one decimal place because it is collected in full years. The SD of 
age will then be reported to 2 decimal places. Descriptive percentages and proportions will be 
displayed to one decimal place. Duration of AEs will be displayed to 1 decimal place. 
Formatting for Dates and Times 
• Dates only – ddmmmyyyy; 
• Times only – hh:mm or hh:mm.ss (as appropriate); 
• Dates and times – ddmmmyyyy hh:mm or ddmmmyyyy hh:mm:ss (as appropriate). 
Planned and Actual Times in Summaries 
Planned times for study treatment dosing will be used in all tables and summary figures. 
Generally, only pre-specified planned times will be used in the summaries, statistical 
analyses, and calculations of any derived parameters; unscheduled assessments will be 
included in the listings. However, both unscheduled and scheduled assessments will be 
included in worst-case post-baseline shift displays for laboratory data and in any summary or 
listing of potential clinical importance values for vital signs. 
The infusion start date and time will be mapped to study weeks in the following way: The 
infusions will be sorted by start date and time and will be consecutively numbered. The 
infusions will be mapped to study weeks using the consecutive numbers. 


CSL Behring 
Statistical Analysis Plan 
Protocol Number: IgPro20_4004 
Product Name: Hizentra® 
 
 
CONFIDENTIAL 
 
 
 Page 22 of 48 
Study 
Week 
Pump-
Assisted 
Cohorts 
Manual Push Flow Rate Cohort 
Infusions Per Week 
2 
3 
4 
5 
1 
Infusion 1 
Infusion 1-2 
Infusion 1-3 
Infusion 1-4 
Infusion 1-5 
2 
Infusion 2 
Infusion 3-4 
Infusion 4-6 
Infusion 5-8 
Infusion 6-10 
3 
Infusion 3 
Infusion 5-6 
Infusion 7-9 
Infusion 9-12 
Infusion 11-15 
4 
Infusion 4 
Infusion 7-8 
Infusion 10-12 
Infusion 13-16 
Infusion 16-20 
5 
Infusion 5 
Infusion 9-10 
Infusion 13-15 
Infusion 17-20 
Infusion 21-25 
. . . 
. . . 
 
 
 
 
9 
Infusion 9 
Infusion 17-18 
Infusion 25-27 
Infusion 33-36 
Infusion 41-45 
. . . 
. . . 
 
 
 
 
12 
Infusion 12 
Infusion 23-24 
Infusion 34-36 
Infusion 45-48 
Infusion 56-60 
. . . 
. . . 
 
 
 
 
16 
Infusion 16 
(PAFR) 
 
 
 
 
PAFR: Pump-Assisted Flow Rate Cohort 
7.1 Multicenter Studies 
Data from all participating sites will be pooled prior to analysis. Listings will include site 
information. The site will not be considered in any analysis. 
7.2 Treatment Descriptors 
For output displayed by cohort the following labels and order will be used:  
• Pump-Assisted Volume Cohort; 
• Pump-Assisted Flow Rate Cohort; 
• Manual Push Flow Rate Cohort; 
• Total (optional). 
For output displayed by infusion parameters within cohort the following labels and order will 
be used: 
• Pump-Assisted Volume Cohort: 25 mL, 40 mL, 50 mL, Total (optional); 
• Pump-Assisted Flow Rate Cohort: 25 mL/h, 50 mL/h, 75 mL/h, 100 mL/h, Total 
(optional); 


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CSL Behring 
Statistical Analysis Plan 
Protocol Number: IgPro20_4004 
Product Name: Hizentra® 
 
 
CONFIDENTIAL 
 
 
 Page 28 of 48 
The analysis of infusion parameters will be presented stratified by  
• Age class (≤ 17 years, > 17 years); 
• BMI class (< 30 kg/m2, ≥ 30 kg/m2). 
It will be specified in the respective sections which tables will be affected. 
8.3 Study Periods Relative to Treatment 
Not applicable. 
8.4 Values of Potential Clinical Importance 
Not applicable. 
9 Study Population 
Unless otherwise stated, tables will be based on the SAF. Listings will usually show all data 
available (i.e. based on the ScAS); listing for derived variables may be based on a particular 
analysis set which will be specified in the corresponding section. Summaries and data listings 
will use labels as specified in Section 7.2. 
9.1 Disposition of Subjects 
A summary table based on the ScAS will be provided by cohort and Total showing the 
number of subjects with the following information: 
• Number of subjects screened; 
• Number of screening failures and reason for screening failure; 
• Number of subjects enrolled into the study; 
• Number of subjects who entered each infusion parameter level; 
• Number of subjects who completed the study; 
• Number of subjects who discontinued from the study prematurely with reason for 
discontinuation; 
• Infusion parameter level at which subjects discontinued from the study. 
Reasons for study discontinuation will be presented in descending order of their frequency. 


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A by-subject listing for all available data with the information as described in Section 7 as 
well as screening status, reason for screening failure (in- or exclusion criterion numbers), date 
of enrollment, date of informed consent, date of eligibility, date of first and last treatment, 
maximum tolerated infusion parameter level, date of study completion or discontinuation, 
and reason for study discontinuation will be presented. Another listing for all available data 
will present the individual visit dates for all visits (scheduled and unscheduled) which the 
subject attended.  
9.2 Protocol Deviations 
In this study, the ScAS, the FAS, and the SAF are defined. Thus, protocol deviations will not 
have any impact on the statistical analysis of the study as no subjects will be excluded from 
the defined analysis sets because of protocol deviations. From a clinical perspective, there is 
still an interest to report protocol deviations.  
A summary table by cohort and Total with the number and percentages of subjects in the 
analysis sets Screened, FAS, and Safety will be provided. 
The following by-subject listings for all available data with the information as described in 
Section 7 as well as the information listed below will be provided: 
• Inclusion and exclusion protocol deviations; 
• Other protocol deviations. 
9.3 Demographic and Baseline Characteristics 
The following summaries will be provided for the SAF; tables will be presented by cohort 
and Total: 
• Demographic characteristics: sex, age (years), age category, race, ethnicity, height (cm), 
weight (kg), and BMI (kg/m2) at Screening. Age, height, weight, and BMI will be 
summarized as continuous variables. Age and BMI will also be categorized and 
summarized (Age: < 18 years, ≥ 18 - ≤ 65 years, > 65 years; 0 - ≤ 27 days, > 27 days - 
< 2years, ≥ 2 - < 12 years, ≥ 12 - < 18 years, ≥ 18 - ≤ 65 years, > 65 - ≤ 84 years, > 84 
years; ≤ 17 years and > 17 years. BMI: < 30 kg/m2 and ≥ 30 kg/m2); 
• Disease characteristics: PID category, time since first PID diagnosis (years), historic IgG 
levels at diagnosis (g/L), and pre-study trough levels (g/L); 


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• Medical history: coded using Medical Dictionary for Regulatory Activities (MedDRA) 
version 20.0 or higher will be presented by System Organ Class (SOC) and Preferred 
Term (PT) – include medical history terms with Medical History Start Date Type 
“Historical Condition” as entered in the eCRF or medication end date / evidence for end 
date prior to or on the informed consent date; 
• Concomitant diseases (by SOC and PT) will be presented along with concomitant 
therapies and method of contraception (by Anatomical Therapeutic Chemical [ATC] Class 
level 4 and unique term) – include medical history terms with Medical History Start Date 
Type “Concomitant Disease” as entered in the eCRF or end date / evidence for end date 
after the informed consent date or flagged “Ongoing” and concomitant medication terms 
which are flagged ongoing, have end date missing, or end date / evidence for end date 
after the informed consent date. 
By-subject listings for all available data with the information as described in Section 7 will be 
provided for: 
• Demographic data: sex, age (years), age group, race, ethnicity, height (cm), body weight 
(kg), and BMI (kg/m2) at Screening; 
• Disease characteristics: PID category, time since first PID diagnosis (years), historic IgG 
level at the time of diagnosis (g/L), pre-study IgG level (g/L); 
• Medical history and concomitant diseases (medical history term, SOC, PT, start and end 
date, medical history term type); 
• Reproductive system findings (childbearing potential, method of birth control, pregnancy 
during the study, date of pregnancy test, and pregnancy test result). 
9.4 Concomitant Medications 
Concomitant medications will be coded using World Health Organization Drug Dictionary 
Enhanced (WHO-DDE) B2 version March 2016 or more recent version. The summary of 
concomitant medications will show the number and percentage of subjects taking 
concomitant medications by ATC class and unique term. ATC Level 4 will be used for the 
summary tables and listing unless coding is not available at level 4. In these cases level 3 
ATC name will be used. Similarly, if the level 3 ATC name is not available then the level 2 
ATC name will be used and if the level 2 ATC name is not available then the level 1 ATC 


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name will be used. ATC Level 1 information will be included in the dataset created but will 
not appear in the listing or summary except when all other levels are not available. 
The following classification of concomitant medication related to start date of study 
treatment will be applied: 
• Assign to ‘Prior Only’ if the concomitant medication start date and end date is prior to 
study treatment start date; if the subject has not taken any study treatment; or the 
concomitant medication start date is missing and the concomitant medication end date is 
before the study treatment start date. If the concomitant medication start or end date is 
partially missing, the concomitant medication will only be assigned to ‘Prior Only’ if the 
partial dates give clear evidence that the concomitant medication stopped prior to study 
treatment start date; 
• Assign to ‘Prior and Concomitant’ if the concomitant medication start date is prior to 
study treatment start date and the concomitant medication end date is on or after study 
treatment start date or missing (ongoing treatment). If the concomitant medication start or 
end date is partially missing, the concomitant medication will only be assigned to ‘Prior 
and Concomitant’ if the partial start date gives clear evidence that the concomitant 
medication started prior to study treatment start date; 
• Assign to ‘Concomitant Only’ if the concomitant medication start date is on or after the 
study treatment start date or the concomitant medication start date is partially or 
completely missing and there is no clear evidence from the partial date that the 
concomitant medication falls into one of the other categories above.  
In the summary of concomitant medications, each subject will be counted once within each 
unique term (Any Medication, ATC Class, and unique term). For example, if a subject takes 
Amoxicillin on two separate occasions, the subject will be counted only once under the 
medication “Amoxicillin”, once in the corresponding ATC class, and once for “Any 
Medication”. The number and percentages of subjects based on the SAF along with the 
number of reports will be presented for ‘Prior and Concomitant’ and for ‘Concomitant Only’ 
medications by cohort and Total. 
A by-subject listing for all available data with the information as described in Section 7 as 
well as medication/therapy, start and end date and time or ongoing, dose, route, frequency, 
primary indication for the concomitant medication, AE term if applicable, medical history 


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where amount is either the dose (mg/kg) or the volume (mL). 
In the Pump-Assisted Cohorts, the compliance per infusion equals the weekly compliance as 
one infusion per week is scheduled. In the Manual Push Flow Rate Cohort, subject’s weekly 
compliance will be calculated as the mean over all infusions in the particular week. 
The following summaries will be provided by cohort and infusion parameter level based on 
the SAF: 
• Descriptive statistics for overall compliance and subject’s weekly compliance; 
• Percentage overall compliance categorized by < 90%, 90% - 110%, and > 110%.  
A by-subject listing for the SAF with the information as described in Section 7 as well as 
prescribed and actual dose per infusion, planned and actual volume per infusion, compliance 
for dose and volume per infusion, subject’s weekly dose compliance, and overall dose 
compliance will be provided. 
11 Safety Analyses 
All safety analyses will be based on the SAF as defined in Section 6.  
11.1 Responder (Primary Endpoint) 
For each cohort the percentage of responders will be calculated for each infusion parameter 
level. The infusion parameter levels per cohort are displayed in Table 1.  
Table 1: Infusion parameter levels per cohort 
Cohort (c) 
Infusion Parameter Levels (p) 
Pump-Assisted Volume Cohort  
Planned maximum volume per injection site 
• 25 mL 
• 40 mL 
• 50 mL 


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Cohort (c) 
Infusion Parameter Levels (p) 
Pump-Assisted Flow Rate Cohort 
Planned maximum flow rate per injection 
site 
• 25 mL/h 
• 50 mL/h 
• 75 mL/h 
• 100 mL/h 
Manual Push Flow Rate Cohort 
Planned flow rate per injection site 
• 30 mL/h [0.5 mL/min] 
• 60 mL/h [1 mL/min] 
• 120 mL/h [2 mL/min] 
The definition of responder is based on the definition of valid infusions. Both definitions are 
provided in the following. 
Definition of valid infusions 
An infusion will be considered ‘valid’ if the subject completes the full dose per scheduled 
infusion parameter (volume or flow rate) under test without interruptions or decrease during 
that infusion. Table 2 specifies for each cohort when an infusion is considered valid.  
Table 2: Minimum criteria for a valid infusion 
Pump-Assisted Volume Cohort 
Infusion 
Parameter 
Definition Per Protocol 
Modified Definition 
Volume 
Maximum volume 
administered per injection site 
is at least 95% of the planned 
max volume (i.e., 25 mL, 40 
mL or 50 mL) for at least 1 
injection site. 
No modification 
Flow rate 
Not applicable 
Not applicable 
Dose 
Total dose administered is at 
least 95% of the planned dose. 
No modification 


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Pump-Assisted Volume Cohort 
Interruptions or 
stops 
Not interrupted or stopped 
prematurely for any reason as 
documented in the eDiary. 
May be stopped for technical 
reasons* only. 
AEs 
Not addressed. 
No related AEs started during 
interrupted or stopped infusion. 
*Technical reason: technical problem with any part of equipment (pump, syringe, tubing, 
needle, including needle placement) used for infusion. 
 
Pump-Assisted Flow Rate Cohort 
Infusion 
Parameter 
Definition Per Protocol 
Modified Definition 
Volume 
Not applicable 
Not applicable 
Flow rate 
Injection site flow rate is at 
least 95% of the planned flow 
rate (i.e., 25 mL/h, 50 mL/h, 75 
mL/h, or 100 mL/h) for at least 
one injection site. 
No modification 
Dose 
Total dose administered is at 
least 95% of the planned dose. 
No modification 
Interruptions or 
stops 
Not interrupted or stopped 
prematurely for any reason as 
documented in the eDiary. 
May be stopped for technical 
reasons* only. 
AEs 
Not addressed. 
No related AEs started during 
interrupted or stopped infusion. 
*Technical reason: technical problem with any part of equipment (pump, syringe, tubing, 
needle, including needle placement) used for infusion. 
 


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Manual Push Flow Rate Cohort 
Infusion 
Parameter 
Definition Per Protocol 
Modified Definition 
Volume 
The actual infusion volume is 
at least 95% of the planned 
infusion volume for that 
infusion day. 
No modification 
Flow rate 
The actual infusion duration is 
not more than 1 minute or 10% 
(whichever is larger) longer 
than the calculated infusion 
duration based on the desired 
flow rate (i.e., 0.5 mL/minute, 
1 mL/minute, or 2 mL/minute) 
and the actual volume infused. 
No modification 
Any deviation from the above defined criteria for each infusion parameter step will be 
considered a ‘failure’ (i.e. invalid infusion) in the analysis of this set of infusion parameters. 
However, if it is conducted as stated in the protocol but at a lower parameter level, it can be 
evaluated for the actual parameter as conducted. For example, if a subject was scheduled to a 
test volume of 50 mL/injection site, but for some reasons tested 45 mL/injection site, it will 
not count for the 50 mL level, but if that infusion was otherwise uneventful and performed in 
full without interruption, it will be considered valid for the 45 mL/injection site level, even 
though it was not planned. These unplanned parameter levels will be summarized in a 
separate column “Other” in the tables depending on the scenario. The data may not be 
summarized if the unplanned level only occurs in one subject. If all subjects have the same 
unplanned infusion parameter level, a column labelled with this unplanned level will be 
added. This unplanned column will not be included in the table shell but will only be inserted 
into the table output as necessary. 
Protocol deviations may result in an invalid infusion even if there is adherence to the criteria 
as stated in Table 2. The following protocol deviations will lead to invalidation of an infusion 
(this will have no impact on the assignment of a subject to the analysis sets): 


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• Prohibited concomitant medication 
o Any medications with the primary purpose of masking local or systemic AEs 
(including but not limited to analgesics and anesthetics ± 12h around the 
infusion). 
o Any Ig product other than the study medication 
These protocol deviations will be assessed on an infusion basis, not on a subject basis. Prior 
to DB lock, the infusion data will be merged with the concomitant medication data so that the 
start date of an infusion can be compared with the start date of concomitant medication. This 
list will be provided to CSL as an Excel file. CSL will manually review this file and flag the 
infusions which will have to be considered invalid due to prohibited concomitant medication. 
Only concomitant medication with complete start dates can be considered in the merge to 
infusion data. 
Definition of responder 
For the Pump-Assisted Cohorts, a subject is considered as a ‘responder’ for a certain infusion 
parameter if he/she has performed ≥ 3 valid infusions for that infusion parameter in any order 
(i.e., not necessarily consecutive). 
For the Manual Push Flow Rate Cohort, a subject is considered as a ‘responder’ for a certain 
infusion parameter if he/she has performed ≥ k valid infusions for that infusion parameter in 
any order (i.e., not necessarily consecutive) during the 4 weeks planned for that infusion 
parameter level, where k is specified in Table 3: 
Table 3: Responder requirements in Manual Push Flow Rate Cohort 
Manual push infusions 
per week 
Total number of infusions 
scheduled for parameter set 
Minimum number of valid 
infusions (k) 
2 
8 
5 
3 
12 
7 
4 
16 
10  
5 
20 
12  
6 
24 
15  
7 
28 
17  
 


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Rationale for number of valid infusions to qualify a responder in the Manual Push Flow Rate 
Cohort: The probability for a subject to be a responder for a certain infusion parameter is 
assumed to be 50% irrespective of the value of the infusion parameter itself, i.e. identical to 
the assumed response rate in Clinical Study Protocol Section 11.1. This assumption is based 
on the expectation that there will be no infusion-related reasons for a subject to interrupt the 
infusion or change the infusion parameters. To achieve ≥ 3 out of 4 valid infusions the 
probability for a single infusion to be valid has to be ≥ 61% for Pump-Assisted Cohorts. 
Using this 61% success probability for a single infusion in the Manual Push Flow Rate 
Cohort the minimum number of successes (k) in Table 3 corresponds to a probability for a 
subject to be a responder of at least 50%. 
Calculation of percentage of responder 
The percentage of subjects with response Rc,p in cohort c to a certain infusion parameter p, 
Rc,p, will be calculated as: 
Rc,p(%) = 100 ∗(Number of responder for 𝑝 in cohort 𝑐) 
Number of subjects in the SAF for cohort 𝑐
 
where response is defined as outlined above. 
The success criterion for any Rc,p will be considered fulfilled if Rc,p ≥ 33%.  
Within each cohort, the highest infusion parameter with fulfilled success criterion will be 
considered the new top infusion parameter to be recommended for the Hizentra® label. No 
formal statistical testing will be performed. 
All subjects included in the SAF of a cohort will be included in the denominator for 
calculation of Rc,p. 
Number of infusions and number and percentage of valid infusions and number and 
percentage of responder will be presented by cohort and infusion parameter level. The base 
for the percentages will be the number of infusions and the number of subjects within the 
cohort.  


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Subgroup analyses for  
• Age class (≤ 17 years, > 17 years) and 
• BMI class (< 30 kg/m2, ≥ 30 kg/m2) 
will be produced (Table 14.3.2). 
A by-subject listing with the information as described in Section 7 as well as start and end 
date and time of infusion, depending on the cohort and planned infusion parameter level: 
actual parameter level and percentage of planned and for manual push actual infusion 
duration and calculated infusion duration, for all cohorts: infusion interrupted or stopped, 
prohibited concomitant medication administered, validity of the infusion, and responder 
(no/yes) will be provided. In this listing, the data which is collected after a subject has been 
classified as non-responder will be flagged. 
11.2 Non-Responder 
If a subject is unable to tolerate a certain infusion parameter level (i.e., is a non-responder at 
that level), the subject will continue study participation at the highest individually tolerable 
infusion parameter level for the remaining full study duration to collect safety information. 
If a subject is a non-responder at a certain infusion parameter level, data collected until the 
time of non-response will be taken into account for the analysis of response. Data collected at 
the individually tolerable infusion parameter level after the non-response in the subjects will 
not be included in the analysis of response but will by listed and flagged in the listing. 
The start date of non-response is the start date of the next infusion after the subject has been 
classified as non-responder. If a subject is a non-responder at the last infusion parameter 
level, the start date of non-response will be missing as no further data will be collected after 
the last infusion parameter level. 


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11.3 Extent of Exposure 
Actual dose in mg/kg will be taken as entered in the database. For the Manual Push Flow 
Rate Cohort, the planned weekly volume will be derived from the planned weekly dose as 
entered in the eCRF assuming the nominal IgG content of IgPro20 being 200 mg/mL: 
planned volume (mL) = planned dose (mg/kg) * body weight (kg) / 200 mg/mL. 
Subject’s duration of exposure (days) in each infusion parameter level will be calculated as 
(minimum of (treatment end date in parameter level [i] + 7 days, treatment start date in 
parameter level [i+1] – 1 day, study completion date) – treatment start date in parameter level 
[i]) + 1. 
Subject’s overall duration of exposure (days) will be calculated as 
 
study completion date – date of first treatment + 1. 
Duration in weeks will be derived by dividing the above item by 7. 
Descriptive statistics for duration of exposure in weeks for each infusion parameter level and 
overall will be presented. In addition, the subject-years of exposure for each infusion 
parameter level and cohort will be given. 
Subject’s prescribed and actual dose (mg/kg) and total planned and actual volume (mL) per 
week will be summarized descriptively by cohort and infusion parameter level. 
Number and percentage of incomplete infusions or infusions stopped will be presented. The 
base for the percentage will be the total number of infusions within the cohort. 
11.4 AEs 
AEs starting on or after the date (and time if available) of the first administration of study 
treatment will be considered treatment-emergent AEs (TEAEs). This is the formal definition 
of a TEAE. It should be kept in mind that all subjects have been on a stable Hizentra® dose 
prior to study start. 
When the AE start date is missing or partially missing, AEs will be assumed to be 
treatment-emergent, unless there is clear evidence (through comparison of partial dates) to 
suggest that the AE started prior to the first dose of study treatment. For the assignment of 
AEs within 72 hours after administration of treatment (temporally associated AEs), only AEs 


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with complete start dates will be considered. The start time will also be considered if 
available. AEs which start during infusion or within 72 hours after the end of an infusion will 
be considered temporally associated AEs. 
Only TEAEs occurring until EOS visit will be included in the summary tables. All AEs will 
be listed. 
For non-responder subjects at a certain infusion parameter level, AEs reported at the 
individually tolerable infusion parameter level after the non-response in the subject, i.e., AEs 
starting at or after the next infusion following the infusion leading to non-response, will be 
listed and flagged. These AEs will be analyzed separately from the AEs reported prior to that 
time. 
AEs will be coded using the MedDRA version 20.0 or higher. AEs will be primarily classified 
by MedDRA PT. Analyses will be performed by SOC and PT. Aggregated incidences at SOC 
level and Any TEAE will also be provided. 
Summaries of TEAEs will count the number of subjects, that is, subjects with multiple 
occurrences of the same PT will be counted once. Summaries of TEAEs will also include the 
number of events for each PT. Summaries will be presented for each infusion parameter and 
total within cohort. TEAEs will be assigned to the infusion parameter level under which they 
occurred. In the Total column within cohort, each subject will only be counted once with all 
events experienced. 
AE rates per infusion will be calculated within cohort in the following way for each infusion 
parameter level: 
• AE Rate per Infusion = 
Number of Events for a Particular PT
Number of Infusions 
 
where number of infusions will be the sum of all infusions that subjects received within 
infusion parameter level irrespective of their validity as defined in Section 11.1. 
Each AE summary table will present the number of subjects, percentage of subjects based on 
the SAF, number of events, and AE rate per infusion. 
One overview summary of TEAEs table with entries for:  
• any TEAE;  


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• causally related TEAEs; 
• temporally associated TEAEs within 72 h; 
• causally related or temporally associated TEAEs within 72 h 
• deaths;  
• causally related deaths; 
• serious TEAEs; 
• causally related serious TEAEs; 
• study discontinuation due to TEAE; 
• causally related study discontinuation due to TEAE; 
• study drug withdrawal due to TEAE; 
• causally related study drug withdrawal due to TEAE; 
• local TEAEs; 
• causally related local TEAEs; 
• maximum severity of TEAEs. 
will be produced. 
The following summary tables of TEAEs will be produced: 
• by SOC and PT; 
• SAEs by SOC and PT; 
• by SOC, PT, and maximum severity (missing severity will be presented as separate 
category); 
• by SOC, PT, and causality (missing causality will be considered “Related” as outlined 
in Section 8.1.1); 
• by SOC and PT temporally associated within 72 hours after treatment; 
• by SOC and PT causally related or temporally associated within 72 hours after 
treatment; 


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• time to onset of TEAEs (descriptive statistics and categories 0 days, 1 day, 2 days, 3 
days, > 3 days); 
• duration of TEAEs (descriptive statistics and categories 1 day, 2 days, 3 days, > 3 
days); 
• tolerability of the infusion parameter (number of infusions without severe local 
reactions / number of all infusions). 
Time to onset of TEAE will be calculated as 
 
TEAE start date and time – infusion start date and time.  
For the categories, the time will be rounded to days. 
Duration of TEAEs will be calculated as defined in Section 8.2.3. 
Tolerability of a certain infusion parameter within a cohort will be calculated as 
 
number of infusions without severe local reactions / number of infusions 
and will be presented by infusion parameter and cohort.The number of infusions irrespective 
of their validity as defined in Section 11.1 will be used as denominator for the assessment of 
tolerability. The total number of infusions within infusion parameter level and within cohort 
will be considered as denominator for the tolerability within infusion parameter level and 
within cohort, respectively. An infusion without severe local reactions is defined as no 
occurrence of a severe local reaction from the start date and time of an infusion until the start 
date and time of the next infusion or study end if this was the last infusion. 
Local TEAEs will be identified by the MedDRA high level terms “administration site 
reactions NEC”, “infusion site reactions”, and “injection site reactions”. The MedDRA high 
level terms will be reviewed prior to database lock and the list of terms to be included into 
Local TEAEs will be updated. Local TEAEs will be included in all tables by using a virtual 
SOC called “Local Adverse Events”. In addition, the local TEAEs will also be presented by 
their MedDRA SOC “General disorders and administration site conditions”. 
TEAEs will be sorted in descending order of total incidence by SOC and PT. 
The summary will report for the Any TEAE row, each SOC, and each PT, the number of 
subjects with at least one TEAE, counted for the maximum reported severity in the table by 
severity. Local TEAEs will be reported only once in the Any row. 
A listing of MedDRA SOC, PT, and verbatim text will be provided. 


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CSL Behring 
Statistical Analysis Plan 
Protocol Number: IgPro20_4004 
Product Name: Hizentra® 
 
 
CONFIDENTIAL 
 
 
 Page 48 of 48 
Appendices 
16.1 Display Conventions 
Visit names: 
Pump-Assisted Flow Rate 
Cohort 
Pump-Assisted Volume Cohort & 
Manual Push Flow Rate Cohort 
Screening 
Screening 
Day 1 
Day 1 
Day 8 
Day 8 
Day 15 
Day 15 
Day 22 
Day 22 
Day 29 
Day 29 
Day 36 
Day 36 
Day 43 
Day 43 
Day 50 
Day 50 
Day 57 
Day 57 
Day 64 
Day 64 
Day 71 
Day 71 
Day 78 
Day 78 
Day 85 
 
Day 92 
 
Day 99 
 
Day 106 
 
Day 113 (EOS) 
Day 85 (EOS)