A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG Compared to Gamunex-C in Subjects With Primary Humoral Immunodeficiency
Phase: PHASE3
Conditions: Primary Immunodeficiency
Sponsor: Grifols Therapeutics LLC

 
Official Title: 
A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, 
Bioequivalence Study to Evaluate the Pharmacokinetics, Safety, and 
Tolerability of IVIG-PEG compared to Gamunex-C in Subjects with Primary 
Humoral Immunodeficiency 
NCT Number: 
 
NCT04561115 
 
Document Date: 
 
Protocol Amendment 4, Version 4.0: 01 March 2021 
 
 
 
 
 
 

Summary of Changes for Amendment 3
Protocol Version
Date of 
Approval/Effective Date
4.0
Amendment 3 + Integrated Protocol 
See left margin
3.0
Amendment 2 + Integrated Protocol
29 Jul 2020
2.0
Amendment 1 + Integrated Protocol
04 Mar 2020
1.0
Original
25 Sep 2019
Amendment 3
The protocol for GC1902 (Version 3.0, dated 29 July 2020) has been amended as Protocol 
Amendment 3,Version 4.0. See Appendix 5 for a summary of changes for Protocol 
Amendment 3.
3 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence Study to Evaluate
the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to Gamunex-C in Subjects with Primary
Effective

PROTOCOL SYNOPSIS
Title of Study: A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, 
Bioequivalence Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of IVIG-
PEG compared to Gamunex-C in Subjects with Primary Humoral Immunodeficiency
Study Number: GC1902
Phase: 3
Study Objectives:
Primary Pharmacokinetic Objective 
The primary pharmacokinetic (PK) objective is to demonstrate bioequivalence of IVIG-PEG 
with Gamunex-C (IVIG-C) at steady-state as determined by comparing total IgG area under 
the concentration time curve during the defined dosing interval ([AUC0-τ] either every 
3 weeks [AUC0-21 days] or every 4 weeks [AUC0-28 days]) and maximum concentration in a 
dosing interval (Cmax) in subjects diagnosed with primary humoral immunodeficiency (PI)
currently receiving chronic IVIG replacement treatment.
Other Pharmacokinetic Objectives
•
To evaluate the mean steady-state trough IgG levels obtained with IVIG-PEG and 
Gamunex-C treatment in subjects with PI

To evaluate the PK profile for total IgG in the steady-state of IVIG-PEG and Gamunex-C 
for time of maximum observed concentration (Tmax)

To evaluate the PK profile for total IgG in the steady-state of IVIG-PEG and 
Gamunex-C 10% for clearance (Cl) and volume of distribution (Vd)
Secondary Efficacy Objectives
•
To evaluate the rate of serious bacterial infection (SBI)
•
To evaluate all infections of any kind (serious/nonserious including acute sinusitis, 
exacerbation of chronic sinusitis, acute otitis media, pneumonia, acute bronchitis, 
infectious diarrhea, etc.) as determined by the Investigator
•
Number of days on antibiotics (including oral, parenteral, oral plus parenteral, 
prophylactic and therapeutic). Use of prophylactic antibiotics will be distinguished from 
antibiotics for treatment of acute infection
•
Number of hospitalizations due to infection
•
Number of days of work/school/daily activities missed per subject year due to infections 
and their treatment
Exploratory Objectives
•
To evaluate trough levels of IgG subclasses (IgG1, IgG2, IgG3, IgG4)
•
To evaluate antibody levels for Streptococcus pneumoniae (S. pneumoniae), 
Haemophilus influenzae (H. influenzae), and tetanus (Clostridium tetani [C. tetani])
4 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence Study to Evaluate
the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to Gamunex-C in Subjects with Primary
Effective

•
To evaluate validated infections documented by positive radiograph, fever (>38°C oral or 
>39°C rectal), culture, or diagnostic testing for microorganisms, e.g., bacterial, viral, 
fungal, or protozoal pathogens (for instance, rapid streptococcal antigen detection test)
•
Trough measles antibody titers (functional assay) is an exploratory variable for 
informational purposes
Safety Objective
The safety objective is to evaluate the safety and tolerability of IVIG-PEG as replacement
therapy in subjects with PI.
Overall Study Design and Description:
This is a clinical Phase 3, multicenter, open-label, single-sequence, cross-over, 
bioequivalence study to assess the steady-state PK, safety, and tolerability of IVIG-PEG 
compared with Gamunex-C in adult subjects with PI. A total of approximately 35 adult 
subjects will be enrolled in order to have 20 evaluable subjects for PK analysis.
The study will include the following phases:
•
Screening Phase of approximately 28 days
•
Gamunex-C Run-in Phase (IV administration of Gamunex-C) of up to 4.5 months (if 
applicable)
•
Gamunex-C PK Phase of 3 or 4 weeks
•
IVIG-PEG Treatment Phase of up to 4.5 months
•
IVIG-PEG PK Phase of 3 or 4 weeks
•
Final Visit/Early Termination visit 
Prior to enrollment into the study, subjects with PI currently receiving IVIG replacement 
treatment will be screened during the Screening Phase. Subjects must meet all the inclusion 
criteria and meet none of the exclusion criteria to be enrolled in this study. 
Depending on their current IVIG treatment regimen, eligible subjects may enter directly into 
the Gamunex-C PK Phase (those who are on a stable Gamunex-C treatment) or may be 
required to enter the Gamunex-C Run-in Phase. Eligible subjects not on stable Gamunex-C 
treatment will be required to enter the Gamunex-C Run-in Phase to receive Gamunex-C 
treatment (Sponsor provided) to achieve an approximate steady-state condition prior to 
entering the Gamunex-C PK Phase. Subjects meeting the following conditions are required to 
enter the Run-in Phase:

Not currently receiving Gamunex-C 

Not on a stable dose of Gamunex-C 

Not receiving Gamunex-C every 3 weeks or 4 weeks 
After reaching a stable dose and approximate steady-state (i.e., administration of 5 
consecutive doses of Gamunex-C for subjects on every 4 weeks dosing regimen and 6 
consecutive doses of Gamunex-C for subjects on every 3 weeks dosing regimen), the subjects 
will then enter the Gamunex-C PK Phase to determine the total IgG AUC profile of IV 
5 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence Study to Evaluate
the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to Gamunex-C in Subjects with Primary
Effective

infusions of Gamunex-C. Subjects currently receiving Gamunex-C who have been stable for 
4.5 to 5 months (i.e., administration of at least 5 consecutive stable doses for subjects on 
every 4 weeks dosing regimen and administration of at least 6 consecutive stable doses for 
subjects on every 3 weeks dosing regimen) at doses between 200 and 800 mg/kg prior to the 
Screening Visit will directly enter the Gamunex-C PK Phase.
After the Screening Phase or Run-in Phase, subjects will enter the Gamunex-C PK Phase of 
3 or 4 weeks duration depending on the individual dosing interval. PK samples will be drawn 
30 minutes prior to the start of the PK Phase Gamunex-C infusion, immediately upon the 
completion of the PK Phase Gamunex-C infusion (within 10 minutes of infusion 
completion), and at 1, 3, 6, 24, and 48 hours; and 4, 7, 14, 21, and 28 days (the PK sample 
drawn at 28 days applies only for subjects on every 4 weeks dosing regimen) after the 
completion of the PK Phase Gamunex-C infusion.
After the completion of the Gamunex-C PK Phase, subjects will enter the IVIG-PEG 
Treatment Phase. Subjects will receive a total of 5 or 6 consecutive doses of IVIG-PEG 
according to the subject’s previous Gamunex-C dosing interval (i.e., administration of 
5 consecutive doses for subjects on the every 4 weeks regimen and administration of 
6 consecutive doses for subjects on the every 3 weeks regimen). The dose of IVIG-PEG 
administered during this phase will be the same as the subject’s dose during the Gamunex-C 
PK Phase.
Trough IgG levels will be obtained prior to all infusions in the Screening, Gamunex-C Run-
in, and IVIG-PEG Treatment phases. 
At the conclusion of the IVIG-PEG Treatment Phase (i.e., after 5 or 6 infusions of IVIG-PEG 
depending on the individual dosing interval), subjects will enter into the IVIG-PEG PK Phase 
lasting 3 or 4 weeks in duration depending on the individual dosing interval. Pharmacokinetic 
samples will be drawn 30 minutes prior to the start of the IVIG-PEG infusion in the PK 
Phase, immediately upon the completion of the PK Phase IVIG-PEG infusion (within 10 
minutes of infusion completion), and at 1, 3, 6, 24, and 48 hours; and 4, 7, 14, 21, and 28 
days (the PK sample drawn at 28 days applies only for subjects on every 4 weeks dosing 
regimen) after the end of the PK Phase IVIG-PEG infusion.
At the end of the IVIG-PEG PK Phase, subjects will have their Final Visit. 
Treatment visits for the Gamunex-C Run-In Phase, Gamunex-C PK Phase, IVIG-PEG PK 
Phase, and the Final Visit/Early Termination Visit may be performed at the study site or, if 
deemed appropriate, at an alternate site (e.g., subject's residence, local healthcare 
professional's site) under the care and supervision of trained healthcare personnel.  
Some treatment visits for the IVIG-PEG Treatment Phase may also be performed at the study 
site or, if deemed appropriate, at an alternate site (e.g., subject's residence, local healthcare 
professional's site) under the care and supervision of trained healthcare personnel. IVIG-PEG 
#1 and IVIG-PEG #2 treatment visits are to be performed at the study site. 
6 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence Study to Evaluate
the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to Gamunex-C in Subjects with Primary
Effective

Number of Subjects Planned:
Approximately 35 adult subjects are planned to be enrolled, in which a minimum number of 
6 subjects are planned to be enrolled in each dosing interval (i.e., 3-weeks dosing interval vs 
4-weeks dosing interval).
7 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence Study to Evaluate
the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to Gamunex-C in Subjects with Primary
Effective

Diagnosis and Main Criteria for Inclusion:
Inclusion Criteria:
A subject must meet all the following inclusion criteria to be eligible for participation in this 
study.
1. Male or female between 18 and 75 years of age (inclusive) at Screening
2. Documented and confirmed pre-existing diagnosis of PI with features of 
hypogammaglobulinemia requiring IV IgG replacement therapy including but not limited 
to the following humoral-based immunodeficiency syndromes (e.g., X-linked 
agammaglobulinemia, common variable immunodeficiency), and combined 
immunodeficiency syndromes without lymphocytopenia (e.g., hyper immunoglobulin M 
[IgM] immunodeficiency syndrome). Please also refer to Exclusion Criteria 
3. IgG trough level ≥500 mg/dL at Screening Visit 
Note: Patients entering Group 1 must additionally have trough levels ≥500 mg/dL 
documented within the previous year. For patients entering Group 2, if Screening trough 
levels are not ≥500 mg/dL, the subject will be a Screen Failure, but may be rescreened 
following dose adjustment of their original IV IgG replacement therapy regimen and 
recording an IgG trough level ≥500 mg/dL
4. Has not had an SBI within the last 6 months prior to Screening or during the Screening
Phase
5. Medical records are available to document diagnosis, previous infections, and treatment
6. Willing to comply with all aspects of the study protocol, including blood sampling, for 
the duration of the study
7. Signed and dated a written informed consent form confirming his or her willingness to 
participate in Study GC1902
Exclusion Criteria
A subject meeting any of the following exclusion criteria is NOT eligible for participation in 
the study.
1. Has an acquired medical condition that is known to cause secondary immune deficiency, 
such as chronic lymphocytic leukemia, lymphoma, multiple myeloma, chronic or 
recurrent neutropenia (absolute neutrophil count less than 1000/μL [1.0 x 109/L]), or 
human immunodeficiency virus (HIV) infection/acquired immune deficiency syndrome 
(AIDS)
2. Has known selective IgA deficiency (with or without antibodies to IgA).(Note: exclusion 
is for the specific diagnostic entity. It does not exclude other forms of primary humoral 
immunodeficiency which have decreased IgA in addition to decreased IgG requiring IgG 
replacement)
3. Has isolated IgG subclass deficiency or an isolated specific antibody deficiency disorder, 
or transient hypogammaglobulinemia of infancy
4. The subject has had a known serious adverse reaction to immunoglobulin or any severe 
anaphylactic reaction to blood or any blood-derived product
8 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence Study to Evaluate
the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to Gamunex-C in Subjects with Primary
Effective

5. Has a history of thrombotic complications following IVIG therapy 
6. Has a history of or current diagnosis of deep venous thrombosis (DVT) or 
thromboembolism (e.g., myocardial infarction, cerebrovascular accident or transient 
ischemic attack); history refers to an incident in the year prior to the Screening Visit or 2 
episodes over lifetime or has thrombosis risk factors (e.g., prolonged immobilization, use 
of estrogens, indwelling central vascular catheters)
7. Has a known hyperviscosity syndrome or hypercoagulable states
8. Has liver enzyme levels (alanine aminotransferase [ALT], aspartate aminotransferase 
[AST], gammaglutamyl transferase [GGT], or lactate dehydrogenase [LDH]) greater than 
2.5 times the upper limit of normal (ULN) at the Screening Visit as defined by the testing 
laboratory
9. Has pre-existing renal impairment (defined by serum creatinine greater than 1.5 times the 
ULN or blood urea nitrogen [BUN] greater than 2.5 times the ULN, or any subject who is 
on dialysis) at the Screening Visit or any history of acute renal injury
10. Has clinically significant history of drug or alcohol abuse or dependence in the opinion of 
the Investigator (must be within the past 12 months and noted in the subject’s medical 
records or documented at Screening)
11. Clinical evidence of any significant acute or chronic medical condition (e.g., renal 
disease or predisposing conditions for renal disease, coronary artery disease, or protein 
losing state) that, in the opinion of the Investigator, may interfere with the conduct of the 
study or may place the subject at undue medical risk
12. Females of childbearing potential who are pregnant, have a positive pregnancy test at 
Screening (human chorionic gonadotropin [HCG]-based assay), are breastfeeding, or 
unwilling to practice a highly effective method of contraception (e.g., oral, injectable or 
implanted hormonal methods of contraception, placement of an intrauterine device [IUD] 
or intrauterine system [IUS], condom or occlusive cap with spermicidal 
foam/gel/film/cream/suppository, male sterilization, or true abstinence) throughout the 
study
Note: True abstinence: When this is in line with the preferred and usual lifestyle of the 
subject. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, post-ovulation 
methods], declaration of abstinence for the duration of a trial, and withdrawal are not 
acceptable methods of contraception)
13. Receiving any of the following medications: (a) immunosuppressants including 
chemotherapeutic agents, (b) immunomodulators, (c) long-term systemic corticosteroids 
defined as daily dose >1 mg of prednisone equivalent/kg/day for >30 days 
Note: Intermittent courses not exceeding >1mg of prednisone equivalent/kg/day for 
>30 days would not exclude the subject. Inhaled or topical corticosteroids are 
allowed
14. Has uncontrolled arterial hypertension (systolic blood pressure [SBP] >160 mm Hg 
and/or diastolic blood pressure [DBP] >100 mm Hg)
15. Has hemoglobin <11 g/dL at the Screening Visit 
16. Unable or unwilling to provide a storage serum sample at the Screening Visit 
9 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence Study to Evaluate
the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to Gamunex-C in Subjects with Primary
Effective

Note: a pre-treatment serum sample to be stored at -94°F (-70ºC) for possible future 
testing is required
17. Received any live virus vaccine within 5 months prior to the Screening Visit and not 
willing to postpone receiving any live virus vaccines until 6 months after completing 
study treatment
18. Has a known previous infection with or clinical signs and symptoms consistent with 
current hepatitis B virus (HBV) or hepatitis C virus (HCV) infection
19. Has participated in another clinical trial within 30 days prior to Screening or has received 
any investigational product, with the exception of other IgG products, within the previous 
3 months prior to the Screening Visit
Test Product, Dose, and Mode of Administration
IVIG-PEG will be investigated in this study.
The IVIG-PEG dose and dosing interval will be individualized based on the previous 
Gamunex-C treatment the subject was receiving for PI either at the Screening Visit or at the 
end of the Run-in Phase (for subjects not directly entering the Gamunex-C Treatment Phase).
Subjects will receive IVIG-PEG by means of an infusion pump at a dose of 200 to 800 mg/kg 
per infusion at an infusion rate of 1 mg/kg/min or up to 8 mg/kg/min depending on subject 
tolerance. IVIG-PEG will be administered every 3 weeks (±4 days) or 4 weeks (±4 days), 
depending on the subject’s prior IVIG dosing schedule.
Duration of Treatment:
The duration of Gamunex-C treatment will include the Gamunex-C PK Phase (up to 4 
weeks) plus the additional Gamunex-C Run-in Phase (up to 4.5 months) for subjects not 
receiving Gamunex-C or not on a stable dose of Gamunex-C upon entering the trial. The 
approximate maximum duration is up to 6 months.
The duration of IVIG-PEG treatment will include the IVIG-PEG Treatment Phase (up to 4.5 
months) and the IVIG-PEG PK Phase (up to 4 weeks), for an approximate maximum of up to 
6 months.
Reference Therapy, Dose and Mode of Administration
Gamunex-C will be evaluated in this study as a comparator to IVIG-PEG.
The Gamunex-C dose and dosing interval will be individualized based on the previous IVIG 
treatment the subject was receiving for PI during the Screening Visit.
Subjects will receive Gamunex-C by means of an infusion pump at a dose of 200 to 
800 mg/kg per infusion at an infusion rate of 1 mg/kg/min or up to 8 mg/kg/min depending 
on subject tolerance. The subject’s usual mg/kg dose (given on either a 3 or 4 week repeating 
schedule) will be the same mg/kg dose and schedule that the subject was receiving prior to 
entering screening. This mg/kg dose and schedule will be used throughout the study duration. 
Note that the weight of the subject will be measured at each visit and if the subject’s weight 
changes, the actual weight at each visit will be used to calculate amount of drug (mg) to be 
10 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence Study to Evaluate
the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to Gamunex-C in Subjects with Primary
Effective

administered. Gamunex-C will be administered every 3 weeks (±4 days) or 4 weeks (±4 
days), depending on the subject’s prior IVIG dosing schedule.
Key Study Variables:
Primary Pharmacokinetic Variables:
The primary PK variables are steady-state AUC of total IgG over a regular dosing interval 
(τ), either every 3 weeks or every 4 weeks (i.e., AUC0-21 days or AUC0-28 days, respectively) and 
Cmax in subjects with PI
Other Pharmacokinetic Variables:
•
Mean steady-state trough concentration of total IgG following IV administration of 
Gamunex-C and following IV administration of IVIG-PEG 
•
Tmax
•
Cl
•
Vd
Key Secondary Efficacy Variables:
•
Rate of SBIs
•
All infections of any kind as determined by the Investigator
•
Number of days on antibiotics
Key Exploratory Variables:
•
Antibody levels for S. pneumonia, H. influenzae, and C. tetani
•
Validated infections 
Safety Variables:

Adverse events including serious adverse events (SAEs) and suspected adverse drug 
reactions (ADRs) (i.e., potentially drug-related AEs)

Clinical laboratory panels: hematology, clinical chemistry, and urinalysis 

Physical assessments

Vital signs (temperature [T], heart rate [HR], respiratory rate [RR], SBP, and DBP)

Thromboembolic and hemolytic risk assessments
Key Assessments and Procedures:
Complete schedules of study procedures and events are located in Appendix 1, Table A (for 
subjects on an every 3 weeks dosing regimen) and Table B (for subjects on an every 4 weeks 
dosing regimen).
Assessments for the Primary Pharmacokinetic Objective:
11 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence Study to Evaluate
the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to Gamunex-C in Subjects with Primary
Effective

Total IgG concentration will be assessed throughout the study, with total IgG trough PK 
samples taken within 1 hour prior to each IP infusion during the Gamunex-C Run-in and the 
IVIG-PEG Treatment phases. During the Gamunex-C and IVIG-PEG PK phases, total IgG 
PK samples will be taken within 30 minutes prior to the start of the IP infusion, immediately 
upon the completion of the infusion (within 10 minutes of infusion completion), and at 1, 3, 
6, 24, and 48 hours; and 4, 7, 14, 21, and 28 days (the PK sample drawn at 28 days applies 
only for subjects on every 4 weeks dosing regimen) after the end of the infusion. A PK 
sample will also be taken at the last visit (Final/Early Termination Visit) of any subjects
discontinuing from the study early.
Statistical Methods:
Unless otherwise specified, descriptive statistics will include the number of non-missing 
observations, mean, standard deviation (SD), median, minimum, and maximum values for 
the continuous/quantitative data or absolute and relative frequency counts and percentages 
for categorical/qualitative data.
Data handling and evaluation procedures will be described in the Statistical Analysis Plan 
(SAP).
Primary Pharmacokinetic Analyses
Total IgG concentrations will be summarized for IVIG-PEG and Gamunex-C by each time 
point. Individual and mean total IgG concentrations versus time curves will be plotted. PK 
parameters of total IgG will be determined by noncompartmental PK methods using 
WinNonlin. Steady-state PK parameters to be calculated, as appropriate, or as permitted by 
data, will include AUC, Cmax, tmax, Cl and Vd. All PK parameters will be calculated 
separately for IVIG-PEG and Gamunex-C administration and will be tabulated and 
summarized descriptively. The mean and the lower and upper bounds of the 90% confidence 
interval (CI) will be calculated on ln-transformed AUC parameters. These mean and lower 
and upper bounds will be back-transformed (exponentiated) to provide the geometric mean 
and 90% CI on the original scale.
Pharmacokinetic analyses will be performed on the PK population. The Primary PK 
endpoints are the steady-state AUC over a dosing interval defined as AUC0- τ (i.e., the AUC 
over a regular dosing interval (τ) at an approximate steady-state condition, either every 3 
weeks or every 4 weeks, i.e., AUC0-21 days or AUC0-28 days, respectively) and Cmax. The 
hypothesis to be tested is that the IV dose of IVIG-PEG will achieve an approximate steady-
state AUC0-τ and Cmax of total IgG that is bioequivalent to that achieved by the IV dose of 
Gamunex-C. Bioequivalence of steady-state IgG AUC and Cmax between IVIG-PEG and 
Gamunex-C will be tested based on established regulatory guidelines for bioequivalence 
testing. Analysis of covariance (ANCOVA) with a mixed-effect model will be used with 
study PK phase as a fixed effect, the exact administered dose and dose frequency during the 
PK phase as covariates, and subject as a random effect. The 90% CI of the geometric least-
squares mean (LSM) AUC and Cmax ratio of IVIG-PEG to Gamunex-C will be calculated. 
IVIG-PEG is considered to be bioequivalent to Gamunex-C if the 90% CI for the geometric 
12 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence Study to Evaluate
the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to Gamunex-C in Subjects with Primary
Effective

LSM AUC and Cmax ratio of IVIG-PEG to Gamunex-C is within (0.80, 1.25) based on log-
transformed data.
Depending on the number of subjects being dosed at 3- or 4-week dosing intervals, subgroup 
analyses may be performed to evaluate PK variables by IV dosing interval. Subgroup 
analyses will additionally include age, sex, race, and/or other factors as appropriate.
Other Pharmacokinetic Analyses
Other PK parameters will be listed and summarized for IVIG-PEG and Gamunex-C using 
arithmetic as well as geometric means and SD, percentage coefficient of variation (CV), 
median, and minimum/maximum, as appropriate.
Other PK parameters include steady-state mean trough concentration of total IgG, Tmax, Cl, 
and Vd. The steady-state mean trough concentrations of total IgG will be determined as the 
average value of trough concentration measurements obtained at the PK visit and at 21 or 28 
days after the PK infusion (depending on dosing interval). Descriptive statistics will be 
calculated for the steady-state mean trough concentration of total IgG and for the tmax, Cl, and 
Vd.
Secondary Efficacy and Exploratory variables
Secondary efficacy and exploratory parameters will be summarized descriptively. The 
generalized linear model procedure for Poisson regression with log link will be used to 
estimate the SBI rate and its one-sided 99% upper confidence bound. 
Safety Analysis
The safety analyses will be addressed by listing and tabulation of AEs (includes suspected 
ADRs [i.e., potentially related AEs]), vital signs, physical assessments and clinical laboratory 
tests. Data will be described using descriptive analyses. The safety analyses are based on the 
safety population.
Determination of Sample Size
A total sample size of 20 subjects achieves at least 90% power at a 0.05 significant level for 
each one-sided test with the CV of 20% on the primary PK parameter assuming the true ratio 
of the test to reference is 1.0 and equivalent limits of (0.8, 1.25). An approximate 35 subjects 
are planned to be enrolled to have 20 evaluable subjects in the PK population for PK 
analysis.
13 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence Study to Evaluate
the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to Gamunex-C in Subjects with Primary
Effective

TABLE OF CONTENTS
PROTOCOL SYNOPSIS ..........................................................................................................4
GLOSSARY AND ABBREVIATIONS..................................................................................19
1
GENERAL INFORMATION..........................................................................................22
2
BACKGROUND INFORMATION ................................................................................22
2.1
Name and Description of the Investigational Products..........................................22
2.2
Relevant Findings from Nonclinical and Clinical Trials.......................................22
2.3
Known and Potential Risks and Benefits to Human Subjects ...............................23
2.4
Description of and Justification for the Route of Administration, Dosage, 
Dosage Regimen, and Treatment Phase(s) ............................................................25
2.4.1
Administration of Investigational Products .................................................25
2.4.2
Justification for Selection of Doses/Timing of Investigational Products ....25
2.5
Compliance Statement ...........................................................................................25
2.6
Study Population....................................................................................................26
2.7
Relevant Data and Literature Review....................................................................26
2.7.1
Primary Humoral Immunodeficiency ..........................................................26
2.7.2
Primary Humoral Immunodeficiency Treatment.........................................26
2.7.3
Isoagglutinins and Hemolytic Adverse Events............................................27
3
STUDY OBJECTIVES AND PURPOSE .......................................................................28
3.1
Pharmacokinetic Objectives...................................................................................28
3.1.1
Primary Pharmacokinetic Objective ............................................................28
3.1.2
Other Pharmacokinetic Objectives ..............................................................28
3.1.3
Secondary Efficacy Objectives....................................................................28
3.1.4
Exploratory Objectives ................................................................................29
3.2
Safety Objectives ...................................................................................................29
4
STUDY DESIGN.............................................................................................................29
4.1
Endpoints ...............................................................................................................29
4.1.1
Primary Pharmacokinetic Endpoints............................................................29
4.1.2
Other Pharmacokinetic Endpoints ...............................................................29
4.1.3
Secondary Efficacy Endpoints.....................................................................29
4.1.4
Exploratory Endpoints .................................................................................30
4.1.5
Safety Endpoints..........................................................................................30
4.2
Study Design and Plan...........................................................................................30
4.2.1
Screening Phase ...........................................................................................32
4.2.2
Gamunex-C Phase........................................................................................33
4.2.2.1
Run-in Phase......................................................................................33
4.2.2.2
Gamunex-C PK Phase........................................................................34
4.2.3
IVIG-PEG Phase..........................................................................................35
14 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence Study to Evaluate
the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to Gamunex-C in Subjects with Primary
Effective

4.2.3.1
IVIG-PEG Treatment Phase ..............................................................35
4.2.3.2
IVIG-PEG PK Phase..........................................................................35
4.2.4
Final Visit/Early Termination Visit .............................................................35
4.3
Measures Taken to Minimize/Avoid Bias .............................................................38
4.3.1
Subject Numbering ......................................................................................38
4.3.2
Randomization.............................................................................................38
4.3.3
Blinding........................................................................................................38
4.4
Study Treatments ...................................................................................................38
4.4.1
Treatments to Be Administered ...................................................................38
4.4.1.1
IVIG-PEG ..........................................................................................38
4.4.1.2
Gamunex-C........................................................................................38
4.4.2
Labeling of Investigational Products ...........................................................39
4.4.3
Packaging of Investigational Products.........................................................39
4.4.4
Storage of Investigational Products .............................................................39
4.5
Expected Duration of Subject Participation in the Study ......................................39
4.6
Discontinuation Criteria for Individual Subjects and Study..................................39
4.6.1
Discontinuation Criteria for Individual Subjects.........................................39
4.6.2
Premature Termination of Study/Closure of Center....................................40
4.6.2.1
Study Stopping Rules.........................................................................40
4.7
Accountability Procedures for Investigational Products........................................41
4.8
Maintenance of Treatment Randomization Codes.................................................41
5
SELECTION AND WITHDRAWAL OF SUBJECTS...................................................41
5.1
Inclusion Criteria ...................................................................................................41
5.2
Exclusion Criteria ..................................................................................................42
5.3
Subject Withdrawal Criteria ..................................................................................44
5.3.1
Screen Failures.............................................................................................44
5.3.2
Removal of Subjects ....................................................................................44
5.3.3
Subject Replacement....................................................................................45
5.3.4
Follow-up of Subjects Withdrawn from Study............................................45
6
TREATMENT OF SUBJECTS.......................................................................................45
6.1
Administration and Timing of Investigational Products for Each Subject............45
6.2
Prior and Concomitant Therapy.............................................................................46
6.2.1
Prohibited Medications Prior to Study Participation ...................................46
6.2.2
Prohibited Concomitant Medications during the Study...............................46
6.2.3
Restricted Concomitant Medications during the Study ...............................47
6.2.4
Drug Interactions .........................................................................................47
6.3
Treatment Compliance...........................................................................................48
7
ASSESSMENT OF PHARMACOKINETIC AND OTHER STUDY 
PARAMETERS...............................................................................................................48
15 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence Study to Evaluate
the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to Gamunex-C in Subjects with Primary
Effective

7.1
Pharmacokinetic, Secondary Efficacy, and Exploratory Variables.......................48
7.1.1
Primary Pharmacokinetic Variables ............................................................48
7.1.1.1
Other Pharmacokinetic Variables ......................................................48
7.1.2
Secondary Efficacy Variables......................................................................48
7.1.3
Exploratory Variables ..................................................................................48
7.2
Methods and Timing for Assessing, Recording, and Analyzing Parameters ........49
7.2.1
Observations and Measurements .................................................................49
7.2.1.1
Screening Phase .................................................................................49
7.2.1.2
Gamunex-C Phase..............................................................................50
7.2.1.3
IVIG-PEG Phase................................................................................55
7.2.1.4
Final Visit/Early Termination Visit ...................................................60
7.2.2
Description of Laboratory Tests and Procedures.........................................61
7.2.3
Immunoglobulin G Assessments .................................................................62
7.2.4
Assessment and Recording of Infections.....................................................63
7.2.5
Virus Safety Testing ....................................................................................63
8
ASSESSMENT OF SAFETY..........................................................................................64
8.1
Safety Parameters...................................................................................................64
8.2
Methods and Timing for Assessing, Recording, and Analyzing Safety 
Parameters..............................................................................................................64
8.2.1
Adverse Events ............................................................................................64
8.2.2
Clinical Laboratory Evaluations ..................................................................64
8.2.3
Vital Signs....................................................................................................65
8.2.4
Physical Examinations.................................................................................65
8.2.5
Monitoring of Events of Special interest .....................................................65
8.2.5.1
Monitoring of Thrombotic Events .....................................................65
8.2.5.2
Monitoring of Hemolysis...................................................................66
8.3
Procedures for Eliciting Reports of and for Recording and Reporting Adverse 
Event and Intercurrent Illnesses.............................................................................67
8.3.1
Warnings/Precautions ..................................................................................67
8.3.2
Adverse Event Monitoring...........................................................................67
8.3.3
Adverse Event Definitions...........................................................................67
8.3.3.1
Adverse Events ..................................................................................67
8.3.3.2
Suspected Adverse Drug Reactions/Adverse Reactions....................67
8.3.4
Assessment of Causality of Adverse Event .................................................67
8.3.5
Severity of Adverse Event or Suspected Adverse Drug Reaction...............68
8.3.6
Expectedness of Adverse Event or Suspected Adverse Drug Reaction ......69
8.3.7
Seriousness of Adverse Event or Suspected Adverse Drug Reaction .........69
8.3.8
Adverse Event Documentation ....................................................................70
8.3.9
Reporting of Serious Adverse Events..........................................................71
8.3.9.1
Reporting of Serious Adverse Events................................................71
8.3.9.2
Reporting Pregnancy..........................................................................71
16 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence Study to Evaluate
the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to Gamunex-C in Subjects with Primary
Effective

8.4
Type and Duration of the Follow-Up of Subjects after Adverse Events...............72
9
STATISTICS ...................................................................................................................72
9.1
Statistical Methods.................................................................................................72
9.1.1
Demographic and Baseline Characteristics .................................................72
9.1.2
Pharmacokinetic Analysis............................................................................73
9.1.3
Secondary Efficacy and Exploratory Analyses............................................74
9.1.4
Safety Analysis ............................................................................................74
9.1.4.1
Adverse Events ..................................................................................74
9.1.4.2
Clinical Laboratory Values................................................................75
9.1.4.3
Vital Signs..........................................................................................75
9.1.4.4
Physical Assessment ..........................................................................75
9.2
Determination of Sample Size ...............................................................................76
9.3
Level of Significance to Be Used ..........................................................................76
9.4
Criteria for Termination of the Study ....................................................................76
9.5
Procedure for Accounting for Missing, Unused, and Spurious Data.....................76
9.6
Reporting Deviation(s) from the Statistical Analysis Plan....................................76
9.7
Subject Populations for Analysis...........................................................................77
9.7.1
Safety Population.........................................................................................77
9.7.2
Pharmacokinetic Population ........................................................................77
9.7.3
Immunoglobulin G Population ....................................................................77
10
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS..............................................77
11
QUALITY CONTROL AND QUALITY ASSURANCE...............................................77
12
ETHICS............................................................................................................................78
12.1
Institutional Review Board/Ethics Committee ......................................................78
12.2
Ethical Conduct of the Study.................................................................................78
12.3
Regulatory Authority Approvals/Authorizations...................................................79
12.4
Subject Information and Consent...........................................................................79
12.5
Confidentiality .......................................................................................................79
13
DATA HANDLING AND RECORD KEEPING ...........................................................79
13.1
Data Handling........................................................................................................79
13.2
Record Retention ...................................................................................................80
14
FINANCING AND INSURANCE..................................................................................80
15
PUBLICATION POLICY ...............................................................................................80
16
REFERENCES ................................................................................................................82
17
APPENDICES .................................................................................................................86
Appendix 1
Schedule of Procedures and Events...................................................87
Appendix 2
Diagnostic Criteria for Serious Infection Types ................................93
Appendix 3
Monitoring of Thromboembolic Events Risk....................................95
Appendix 4
Detection of Hemolysis....................................................................100
17 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence Study to Evaluate
the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to Gamunex-C in Subjects with Primary
Effective

Appendix 5
Summary of Changes.......................................................................104
LIST OF IN-TEXT TABLES
Table 4-1
Subject Entry Criteria ..................................................................................33
Table 7-1
Name, Description, and Location of Laboratory Tests and Procedures ......61
LIST OF IN-TEXT FIGURES
Figure 4-1
Overall Study Schema – Subjects on Every 3-Week Dosing Regimen.......36
Figure 4-2
Overall Study Schema – Subjects on Every 4-Week Dosing Regimen.......37
18 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence Study to Evaluate
the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to Gamunex-C in Subjects with Primary
Effective

GLOSSARY AND ABBREVIATIONS
ADR
adverse drug reaction
AE
adverse event
AIDS
acquired immune deficiency syndrome
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AP
anterior-posterior
AR
adverse reaction
ARC
absolute reticulocyte count
AST
aspartate aminotransferase
AUC0-τ
area under the plasma and/or serum concentration time curve during the 
defined interval 
B19V
Parvovirus B19
BMI
body mass index
BUN
blood urea nitrogen
CI
confidence interval
CIDP
chronic inflammatory demyelinating polyneuropathy
Cl
clearance
cGMP
current Good Manufacturing Practice
Cmax
maximum concentration in a dosing interval
CRO
Contract Research Organization
CV
coefficient of variation
CVID
common variable immunodeficiency
DAT
direct antiglobulin test
DBP
diastolic blood pressure
DNA
deoxyribonucleic acid
DVT
deep venous thrombosis 
eCRF
case report form/electronic case report form
EDC
electronic data capture
FDA
Food and Drug Administration
GCP
Good Clinical Practice
19 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence Study to Evaluate
the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to Gamunex-C in Subjects with Primary
Effective

GGT
gammaglutamyl transferase
HAV
Hepatitis A virus
HBV
Hepatitis B virus
HCG
human chorionic gonadotropin
HCV
Hepatitis C virus
HIV
Human Immunodeficiency Virus
HR
heart rate
IB
Investigator’s Brochure
ICD-9-CM
International Classification of Diseases, Ninth Revision, Clinical 
Modification
ICF
informed consent form
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
IgA
Immunoglobulin A
IG
immunoglobulin
IgG
Immunoglobulin G
IgM
Immunoglobulin M
IM
intramuscular
IP
investigational product
IRB/EC
Institutional Review Board/Ethics Committee
ITP
primary immune thrombocytopenia
IUD
intrauterine device
IUS
intrauterine system
IV
intravenous
IVIG
intravenous immunoglobulin   
IVIG-C
Immune Globulin (Human), 10% Caprylate/Chromatography Purified
OR Gamunex-C
IVIG-PEG
Immune Globulin (Human) 10% (Gamunex-C) PEG process
LDH
lactate dehydrogenase
MedDRA
Medical Dictionary for Regulatory Activities
NAT
nucleic acid amplification technology
NSAID
nonsteroidal anti-inflammatory drug
20 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence Study to Evaluate
the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to Gamunex-C in Subjects with Primary
Effective

OPK
opsonophagocytic killing
PA
posterior-anterior
PI
primary humoral immunodeficiency
PK
pharmacokinetic(s)
PRN
as needed
RBC
red blood cell
RR
respiratory rate
SAE
serious adverse event
SAP
Statistical Analysis Plan
SBI
serious bacterial infection
SBP
systolic blood pressure
SC
subcutaneous
SCIG
subcutaneous immunoglobulin
SD
standard deviation
SRC
Safety Review Committee
T
temperature
TBL
total bilirubin
TE
thromboembolic
TEAE
treatment-emergent adverse event
Tmax
time of maximum observed plasm/serum concentration
TRALI
transfusion related acute lung injury
ULN
upper limit of normal
US
United States
Vd
volume of distribution
WBC
white blood cell
XLA
X-linked agammaglobulinemia
21 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence Study to Evaluate
the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to Gamunex-C in Subjects with Primary
Effective

1
GENERAL INFORMATION
Protocol title and other key study information are provided on the title page. Information 
regarding additional key personnel and organizations involved in the conduct of the study, 
including names and contact details of participating Investigators, monitors, clinical 
laboratories, technical departments and/or institutions, as well as information on members of 
additional study committees, will be found in the study files of the sponsor and at the 
Investigator sites within the study reference manual/file.
Investigators and staff will receive training either via an Investigators meeting or other 
appropriate training session(s).
2
BACKGROUND INFORMATION
A modified Gamunex-C manufacturing process has been developed by Grifols to produce 
Immune Globulin (Human) 10% (Gamunex-C) PEG process (IVIG-PEG). Upon agreement 
with the United States (US) Food and Drug Administration (FDA), a clinical, bioequivalence 
study to compare the pharmacokinetics (PK), safety, and tolerability of IVIG-PEG with those 
of Gamunex-C in adult subjects with primary humoral immunodeficiency (PI) has been 
developed. The manufacturing process for Gamunex-C has been revised to produce the test 
product, IVIG-PEG, that contains the same product characteristics as Gamunex-C. 
In addition to the information provided below, please refer to the Investigator’s Brochure 
(IB) and any additional data supplied by the sponsor (1).
2.1
Name and Description of the Investigational Products
IVIG-PEG is a sterile, liquid, highly purified, unmodified, human immunoglobulin (primarily 
immunoglobulin G [IgG]) product intended for intravenous (IV) administration. IVIG-PEG 
is made from large pools of human plasma via modifications of the Immune Globulin 
(Human), 10% Caprylate/Chromatography Purified Gamunex-C (IVIG-C) manufacturing 
process. 
Gamunex-C, used as a comparator (reference therapy) to IVIG-PEG in this study, is a ready-
to-use sterile solution of human IgG indicated in the United States (US) for IV administration 
in subjects with PI, primary immune thrombocytopenia (ITP), and chronic inflammatory 
demyelinating polyneuropathy (CIDP). Gamunex-C consists of 9 to 11% IgG in 0.16 to 0.24 
M glycine. 
See Section 4.4 Study Treatments for detail.
2.2
Relevant Findings from Nonclinical and Clinical Trials
The nonclinical efficacy, PK, safety and toxicity profile of IVIG-PEG is similar to Gamunex-
C, as assessed in multiple nonclinical studies:
•
In vitro efficacy studies of opsonophagocytic killing (OPK) or serum bactericidal killing 
(SBA) of select bacteria IVIG-PEG demonstrate functional activity comparable to 
22 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence Study to Evaluate
the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to Gamunex-C in Subjects with Primary
Effective

Gamunex-C. Two virulent pathogens of clinical significance were included: 
Streptococcus pneumoniae (S. pneumoniae) and Haemophilus influenzae (H. influenzae) 
type b.
•
In a safety pharmacology study in cynomolgus monkeys with IVIG-PEG doses up to 
2000 mg/kg, no clinically relevant changes were observed in cardiovascular, respiratory, 
and neurological function.
•
In New Zealand White rabbits, PK parameters of human IgG were similar between IVIG-
PEG and Gamunex-C comparator following single administration by either IV or 
subcutaneous (SC) routes at both low and high dose levels. The IV to SC dose adjustment 
factor of 1.37×was confirmed using area under the curve concentration (AUC) analysis. 
•
Safety of IVIG-PEG was demonstrated in a repeated dose toxicology study in Sprague-
Dawley rats. IVIG-PEG was administered using either IV or SC routes of delivery at 
doses up to 1000 mg/kg/day for 5 consecutive days; these doses were well-tolerated. 
Based on the long half-life of human IgG, these doses were essentially cumulative. No 
differences between IVIG-PEG and Gamunex-C were noted in hematology, coagulation, 
clinical chemistry, or urinalysis parameters. Any findings were limited to repeated 
exposure to human xenogenic proteins.
•
A repeated dose toxicology study in New Zealand White rabbits was confounded by 
species-specific adverse effects observed with both IVIG-PEG and Gamunex-C. 
Nonetheless, no differences between IVIG-PEG and Gamunex-C in hematology, 
coagulation, clinical chemistry, or urinalysis parameters were noted in this study.
2.3
Known and Potential Risks and Benefits to Human Subjects
The PI diseases are a heterogeneous group of disorders in which there is an intrinsic defect in 
the tissues, cells, and/or proteins of the immune system resulting in immune deficiency. 
Many of these disorders are characterized by hypogammaglobulinemia and/or defective 
antibody production and, and as a consequence, increased susceptibility to infection (2).
Administration of polyclonal IG preparations of human origin, including intravenous 
immunoglobulin (IVIG), have long been used as replacement therapy in patients with PI (3). 
Administered intravenously, Gamunex-C is indicated as a replacement therapy for patients 
with PI to prevent infection. It is approved in 57 countries worldwide under different trade 
names and for several indications. Gamunex-C was initially approved in 2003 in the United 
States (US). This IG preparation has been extensively prescribed and confirmed to be safe, 
well-tolerated, and effective. Its safety profile is well established with a total number of 
8,159,628 estimated infusions (4).
IVIG-PEG results from an improved purification process for Gamunex-C, which allows a 
process simplification as well as an improvement of final product purity by reducing the 
levels of isoagglutinins (anti-A/anti-B). The manufacturing process developed by Grifols is 
based on the implementation of an initial PEG precipitation step in the Gamunex-C 
manufacturing process as a replacement for the caprylate precipitation step.
23 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence Study to Evaluate
the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to Gamunex-C in Subjects with Primary
Effective

The PEG precipitation step has been used in the manufacturing process of another Grifols 
product, Flebogamma® DIF (Instituto Grifols, S.A. Parets del Vallès, Barcelona, Spain) for 
many years. Flebogamma DIF is another IVIG product manufactured by Grifols that was first 
authorized for marketing in the US in 2007 (5). This change in the manufacturing process of 
Gamunex-C is not expected to change either the structure of the IG, its activity, or the safety 
of the product.
With the administration of any IG preparation, there is the potential for acute adverse 
reactions to occur. Symptoms observed with the infusion of immunoglobulins include 
transfusion related acute lung injury (TRALI), pyrexia, rigors, cyanosis, hypoxia, 
bronchospasm, hepatic dysfunction, leukopenia, pancytopenia, tremor, erythema multiforme, 
epidermolysis, pulmonary edema, seizures, hypotension, thrombosis, warmth, flushing, 
urticaria, eczema, back pain, headache, fever, chills, anxiety, malaise, faintness, dizziness, 
nausea, vomiting, muscle and joint pain, abdominal pain, chest pain, chest tightness, isolated 
cases of hemolysis/hemolytic anemia, dyspnea, wheezing, tachycardia, pruritus and rash.
Intravenous IG administration may result in mild hemolytic reactions, usually due to the 
presence of anti-A or anti-B isoagglutinins or, less commonly, anti-D or anti-K antibodies. 
These blood group antibodies often result in a slight degree of hemolysis, mild 
hyperbilirubinemia, and a positive direct Coombs’ test. These events are usually subclinical 
(6). The PEG precipitation step in IVIG-PEG manufacturing is aimed to reduce the levels of 
isoagglutinins. 
True anaphylactic reactions to IVIG may occur in recipients with documented prior histories 
of severe allergic reactions to immunoglobulins. Very rarely an anaphylactoid reaction may 
occur in subjects with no prior history of severe allergic reactions to IG administration. 
Gamunex-C is contraindicated in individuals with known anaphylactic or severe systemic 
response to Immune Globulin (Human) and in IgA deficient subjects with antibodies against 
IgA and history of hypersensitivity.
Intravenous IG products have been reported to be associated with renal dysfunction, acute 
renal failure, osmotic nephrosis and death (7). Subjects predisposed to acute renal failure 
include subjects with any degree of pre-existing renal insufficiency, diabetes mellitus, age 
greater than 65, volume depletion, sepsis, paraproteinemia, or subjects receiving known 
nephrotoxic drugs. In subjects with a predisposition to renal insufficiency, IVIG products 
should be administered at the minimum concentration available and at the minimum rate of 
infusion. While these reports of renal dysfunction and acute renal failure have been 
associated with the use of many of the licensed IVIG products, those products containing 
sucrose as a stabilizer accounted for a disproportionate share of the total number. Gamunex-
C does not contain sucrose but contains glycine, a natural amino acid, as a stabilizer. In 
addition, proper hydration will be ensured in this study and IVIG will be discontinued if 
signs/symptoms of renal insufficiency develop.
Both IVIG-PEG and Gamunex-C are prepared from human plasma obtained from healthy 
donors. For products of biological origin, the presence of infectious agents cannot be totally 
excluded. However, in the case of products prepared from human plasma, the risk is reduced 
by: (1) epidemiological controls on the donor population and selection of individual donors 
24 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence Study to Evaluate
the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to Gamunex-C in Subjects with Primary
Effective

by a medical interview, (2) screening of individual donations and plasma pools for viral 
infection markers, and (3) manufacturing procedures with demonstrated capacity to 
inactivate/remove pathogens.
Grifols has designed a clinical program to acquire clinical data in support of an application to 
the regulatory authorities on biologics for marketing authorization for IVIG-PEG.
2.4
Description of and Justification for the Route of Administration, 
Dosage, Dosage Regimen, and Treatment Phase(s)
2.4.1
Administration of Investigational Products 
IVIG-PEG and Gamunex-C will be administered intravenously (peripheral or central vein) 
through a separate infusion line. Mixing and administration of any other drug (including 
normal saline) with the supplied product is strictly prohibited. It is recommended that the 
investigational products (IPs) should initially be infused at a rate of 0.01 mL/kg/min
(1 mg/kg/min) for the first 30 minutes. If well-tolerated, the rate may be gradually increased 
to a maximum of 0.08 mL/kg per minute (8 mg/kg/min). If AEs occur, the rate may be 
reduced or the infusion interrupted until symptoms subside. Lack of tolerance at any given 
rate must be recorded as an adverse event (AE) at that rate. The infusion may then be 
resumed at the rate that is tolerable for the subject.
2.4.2
Justification for Selection of Doses/Timing of Investigational Products
Gamunex-C is approved in a number of countries for IV administration for a number of 
immune disorders. In general, the recommended IV dosing regimen for PI varies from 
country to country from as low as 100 mg/kg to up to 800 mg/kg per local labeling.
The dose of Gamunex-C and IVIG-PEG for subjects with PI is between 200 and 800 mg/kg 
body weight (2 mL/kg to 8 mL/kg) administered every 3 to 4 weeks and will be 
individualized based on each subject’s current IgG regimen, which is assumed to be an 
effective dose. Subjects are required to have been clinically stable at a dose of between 
200 and 800 mg/kg Gamunex-C administered every 3 or 4 weeks, for at least 6 or 5 
consecutive doses respectively, prior to the first dose of IVIG-PEG. Dosing is based on 
current Gamunex-C labeling (8,9).
The dosing schedule has been designed to maintain IgG trough levels ≥500 mg/dL, which are 
considered to be protective as a replacement therapy in PI subjects (8,9).
The recommended initial infusion rate is 0.01 mL/kg/min (1 mg/kg/min). If the infusion is 
well-tolerated, the rate may be gradually increased to a maximum of 0.08 mL/kg/min 
(8 mg/kg/min). For subjects judged to be at risk for renal dysfunction or thrombosis, IP 
infusion should be at the minimum infusion rate practicable. 
2.5
Compliance Statement
This study will be conducted under the conditions described in this protocol and in 
compliance with the International Council for Harmonisation of Technical Requirements for 
25 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence Study to Evaluate
the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to Gamunex-C in Subjects with Primary
Effective

Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) and all applicable 
regulatory requirements.
2.6
Study Population
Eligible participants for this study include male or female subjects who are between 18 and 
75 years of age (inclusive) and have a diagnosis of PI requiring IV IgG replacement therapy. 
Subjects who initially fail to meet the eligibility criteria may be rescreened once. Subjects 
who fail to meet eligibility criteria upon rescreening will be considered screen failures and 
will not be eligible to participate in the study.
2.7
Relevant Data and Literature Review
2.7.1
Primary Humoral Immunodeficiency
Primary humoral immunodeficiency diseases are a family of congenital disorders of the 
immune system that lead to an increase in frequency of infections, notably, but not limited to, 
bacterial infections of the respiratory tract (2). Results from a recent study suggest that in the 
US alone, 1 in 2,000 children and 1 in 1,200 persons (including adults and children) are 
diagnosed with PI, yielding a total US PI patient population estimate of approximately 
250,000 adults and children (10). Worldwide upper estimates suggest that 6 million people 
(638,000 in Europe alone) may be living with a PI, although only a fraction of these patients 
have been identified in registries (11). Patients with inherited deficiencies leading to 
impaired humoral immunity are highly susceptible to a wide range of infections, most 
commonly bacterial infections. The efficacy of IgG replacement therapy in the treatment of 
these disorders has been well established (12,13) since 1952 when the use of serum globulin 
fraction was reported to reduce the frequency of infections in a patient with 
agammaglobulinemia (14). 
Although PI was the first US FDA-approved indication for IG therapy, it is becoming 
increasingly recognized for the treatment of other immunodeficiency diseases for which B-
cell function and antibody production are implicated in the immunodeficiency, but for which 
the role is not clearly identified. Although the prevalence of subjects with 
immunodeficiencies is very low, IG therapy is vital for minimizing potentially fatal 
infections and improving quality of life and overall clinical outcomes (15). 
2.7.2
Primary Humoral Immunodeficiency Treatment
Immune globulin therapy is the mainstay of treatment for a variety of PI states, and it is 
indicated for most PI diseases in accordance with recommendations from expert guidelines
(3,20,21). A systematic literature review performed by the American Academy of Allergy, 
Asthma & Immunology designated IVIG and subcutaneous immunoglobulin (SCIG) as 
definitely beneficial therapies across several PI diseases with an evidence category IIb and 
strength of recommendation B (3).
The therapeutic management of PI has been carried out via intramuscular (IM), IV, and SC 
injections of various IG preparations (16,17). Patients with mild PI were historically treated 
26 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence Study to Evaluate
the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to Gamunex-C in Subjects with Primary
Effective

with IG administered via the IM route up to a maximum dose of 25 mg/kg/wk, limiting the 
dose administration in subjects with more severe forms of deficiency who required higher 
doses. Intravenous preparations allowed for the treatment of subjects with severe PI disease 
(i.e., X-linked agammaglobulinemia [XLA], and common variable immunodeficiency 
[CVID]) with higher doses of IG (18); however, the efficacy of IVIG for treatment of IgG 
subclass deficiency, with or without IgA deficiency, is uncertain. Subcutaneous infusion of 
IG is considered an effective alternative to IV therapy, with the convenience of at home 
dosing (19).
2.7.3
Isoagglutinins and Hemolytic Adverse Events
Antibody-mediated hemolysis is a rare AE of IVIG products. Clinically significant hemolytic
reactions reported after IVIG infusion have been attributed to isoagglutinins, antibodies 
present in IVIG products that react with red blood cell (RBC) antigens of the Rh and ABO 
blood group systems (e.g., anti-Rh(D), anti-A, anti-B).The hemolytic reactions range from 
mild cases in which there may be a positive direct antiglobulin test (DAT, Coombs’ test) to 
acute severe cases in which intravascular hemolysis can cause hemoglobinemia (excess of 
hemoglobin in the plasma), hemoglobinuria, and renal damage/dysfunction (22-31).
An investigation of 1000 patients receiving IVIG identified 16 cases of hemolysis (1.6 
percent) in which females, non-O blood type subjects, and subjects receiving high-dose IVIG 
infusions (e.g., >100 grams) were at the greatest risk for hemolysis (23,32,33). The onset of 
hemolysis ranged from 12 hours to 10 days with a mean decrease in hemoglobin of 3.2 g/dL
and over half of the patients presented with these risk factors.
In addition, it has been reported that dividing the total IVIG dose into 4 or 5 doses 
administered on consecutive days may minimize the occurrence of hemolysis (34).
The purpose of the IVIG-PEG manufacturing change is to reduce the levels of isoagglutinins 
in the final product in order to reduce the chance of antibody mediated hemolysis occurring 
post-administration. The process changes are focused on the replacement of the caprylate 
precipitation step by a PEG precipitation step. To date, consistency of the IVIG-PEG process 
has been evaluated with 3 different processes at clinical scale (approximately 3500 L plasma 
equivalent) that demonstrate that the proposed process changes consistently result in a 10% 
IVIG product with reduced levels of isoagglutinins while maintaining the current product 
characteristics and safety profile.
A detailed study of the isoagglutinin reduction capacity of the process has been conducted. 
For this purpose, a new method for Anti A/B isoagglutinins determination by flow cytometry 
has been developed, allowing an increased sensitivity. The process has also been followed 
with a DAT. The results confirmed the capacity of the process to reduce isoagglutinins, 
reaching lower levels than are currently present in Gamunex-C. In addition, a full 
characterization study has been conducted including purity, functionality, process, and 
product related carry over constituents, antibodies titers, and procoagulant activity. The 
results of these studies do not show significant variations due to the IVIG-PEG process.
27 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence Study to Evaluate
the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to Gamunex-C in Subjects with Primary
Effective

Decreasing the presence of isoagglutinins in IVIG products through manufacturing changes 
has been recommended to decrease in the incidence of hemolysis associated with IVIG 
administration (35). The PEG precipitation step in the IVIG-PEG manufacturing process can 
further reduce isoagglutinin levels in the final product compared to Gamunex-C, which in 
turn may have an effect on the incidence of hemolytic AEs. Events of hemolysis in this study
will therefore be treated as events of special interest.
3
STUDY OBJECTIVES AND PURPOSE
3.1
Pharmacokinetic Objectives
3.1.1
Primary Pharmacokinetic Objective
The primary PK objective is to demonstrate bioequivalence of IVIG-PEG with Gamunex-C
at steady-state as determined by comparing total IgG area under the concentration time curve 
during the defined dosing interval ([AUC0-τ] either every 3 weeks [AUC0-21 days] or every 4 
weeks [AUC0-28 days]) and maximum concentration in a dosing interval (Cmax) in subjects 
diagnosed with PI currently receiving chronic IVIG replacement treatment.
3.1.2
Other Pharmacokinetic Objectives
Other PK objectives include: 
•
To evaluate the mean steady-state trough IgG levels obtained with IVIG-PEG and 
Gamunex-C treatment in subjects with PI.

To evaluate the PK profile for total IgG in the steady-state of IVIG-PEG and Gamunex-C 
for time of maximum observed concentration (Tmax)

To evaluate the PK profile for total IgG in the steady-state of IVIG-PEG and 
Gamunex-C 10% for clearance (Cl) and volume of distribution (Vd)
3.1.3
Secondary Efficacy Objectives
•
To evaluate the rate of serious bacterial infections (SBIs)
•
All infections of any kind (serious/nonserious including acute sinusitis, exacerbation of 
chronic sinusitis, acute otitis media, pneumonia, acute bronchitis, infectious diarrhea, 
etc.) as determined by the Investigator
•
Number of days on antibiotics (including oral, parenteral, oral plus parenteral, 
prophylactic and therapeutic). Use of prophylactic antibiotics will be distinguished from 
antibiotics for treatment of acute infection
•
Number of hospitalizations due to infection
•
Number of days of work/school/daily activities missed per subject year due to infections 
and their treatment
28 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence Study to Evaluate
the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to Gamunex-C in Subjects with Primary
Effective

3.1.4
Exploratory Objectives
•
To evaluate trough levels of IgG subclasses (IgG1, IgG2, IgG3, IgG4)
•
To evaluate antibody levels for S. pneumoniae, H. influenzae, and tetanus (Clostridium 
tetani [C. tetani])
•
To evaluate validated infections documented by positive radiograph, fever (>38°C oral or 
>39°C rectal), culture, or diagnostic testing for microorganisms, e.g., bacterial, viral, 
fungal, or protozoal pathogens (for instance, rapid streptococcal antigen detection test)
•
Trough measles antibody titers (functional assay) is an exploratory variable for 
informational purposes
3.2
Safety Objectives
The safety objective is to evaluate the safety and tolerability of IVIG-PEG as replacement 
therapy in subjects with PI.
4
STUDY DESIGN
4.1
Endpoints
4.1.1
Primary Pharmacokinetic Endpoints
The primary PK endpoints are total IgG AUC0-τ (where τ represents the dosing interval of 
either every 3 weeks [AUC0-21 days] or every 4 weeks [AUC0-28 days]) and Cmax.
•
AUC0-21: the AUC over a regular dosing interval of every 3 weeks at an approximate 
steady-state condition following the regular IV infusion
•
AUC0-28: the AUC over a regular dosing interval of every 4 weeks at an approximate 
steady-state condition following the regular IV infusion
4.1.2
Other Pharmacokinetic Endpoints
The other PK endpoints include:
•
Mean steady-state trough concentration of total IgG following Gamunex-C
administration and following IVIG-PEG administration
•
Tmax 
•
Cl
•
Vd
4.1.3
Secondary Efficacy Endpoints
•
Rate of SBIs
29 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence Study to Evaluate
the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to Gamunex-C in Subjects with Primary
Effective

•
All infections of any kind (serious/nonserious including acute sinusitis, exacerbation of 
chronic sinusitis, acute otitis media, pneumonia, acute bronchitis, infectious diarrhea, 
etc.) as determined by the Investigator
•
Number of days on antibiotics (including oral, parenteral, oral plus parenteral, 
prophylactic and therapeutic). Use of prophylactic antibiotics will be distinguished from 
antibiotics for treatment of acute infection
•
Number of hospitalizations due to infection
•
Number of days of work/school/daily activities missed per subject year due to infections 
and their treatment
4.1.4
Exploratory Endpoints
The exploratory endpoints include:
•
Trough levels of IgG subclasses (IgG1, IgG2, IgG3, IgG4)
•
Antibody levels for S. pneumoniae, H. influenzae, and tetanus (C. tetani)
•
Validated infections documented by positive radiograph, fever (>38°C oral or >39°C 
rectal), culture, or diagnostic testing for microorganisms, e.g., bacterial, viral, fungal, or 
protozoal pathogens (for instance, rapid streptococcal antigen detection test)
•
Trough measles antibody titers (functional assay) is an exploratory variable for 
informational purposes
4.1.5
Safety Endpoints
Safety endpoints include AEs, SAEs, suspected adverse drug reactions ([ADRs], i.e., 
potentially related AEs), ARs, clinical safety laboratory tests, vital signs, and physical 
assessments.
4.2
Study Design and Plan
This is a Phase 3, multicenter, open-label, single-sequence, cross-over, bioequivalence 
clinical study to assess the steady-state PK, safety, and tolerability of IVIG-PEG compared 
with Gamunex-C in adult subjects with PI. A total of approximately 35 adult subjects in 
which a minimum of 6 subjects are planned to be enrolled in each dosing interval (i.e., 3-
week dosing interval vs 4-week dosing interval) will be enrolled in order to have 20 
evaluable subjects for PK analysis.
The study will include a Screening Phase of approximately 28 days, a Gamunex-C Run-in
Phase (IV administration of Gamunex-C) of up to 4.5 months, a Gamunex-C PK Phase of 3 
or 4 weeks, an IVIG-PEG Treatment Phase of up to 4.5 months, an IVIG-PEG PK Phase of 3 
or 4 weeks, and a Final Visit/Early Termination visit. 
Prior to enrollment into the study, subjects with PI currently receiving IVIG replacement 
treatment will be screened during the Screening Phase. Subjects must meet all the specific 
30 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence Study to Evaluate
the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to Gamunex-C in Subjects with Primary
Effective

inclusion criteria and meet none of the exclusion criteria described in Section 5.1 and 
Section 5.2, respectively to be enrolled in this study. 
Depending on their current IVIG treatment regimen, eligible subjects may be required to 
enter the Gamunex-C Run-in Phase to receive Gamunex-C treatment (sponsor provided) to 
achieve an approximate steady-state condition prior to entering the Gamunex-C PK Phase. 
Subjects meeting the following conditions are required to enter the Run-in Phase
(Section 4.2.2.1):

Not currently receiving Gamunex-C 

Not on a stable dose of Gamunex-C 

Not receiving Gamunex-C every 3 weeks or 4 weeks 
After reaching a stable dose and approximate steady-state (i.e., administration of 5 
consecutive doses of Gamunex-C for subjects on every 4 weeks dosing regimen and 6 
consecutive doses of Gamunex-C for subjects on every 3 weeks dosing regimen), the subjects 
will then enter the Gamunex-C PK Phase to determine the AUC profile of IV infusions of 
Gamunex-C.
Subjects receiving Gamunex- C at Screening who have been stable for 4.5 to 5 months (i.e., 
administration of at least 5 consecutive stable doses for subjects on every 4 weeks dosing 
regimen and administration of at least 6 consecutive stable doses for subjects on every 3 
weeks dosing regimen) at doses between 200 and 800 mg/kg prior to the Screening Visit will 
directly enter the Gamunex-C PK Phase.
After the Screening Phase or Gamunex-C Run-in Phase, subjects will enter the Gamunex-C
PK Phase of 3- or 4-weeks duration depending on the individual dosing interval. PK samples 
will be drawn 30 minutes prior to the start of the PK Phase Gamunex-C infusion, 
immediately upon the completion of the PK Phase Gamunex-C infusion (within 10 minutes 
of infusion completion), and at 1, 3, 6, 24, and 48 hours; and 4, 7, 14, 21, and 28 days (the 
PK sample drawn at 28 days applies only for subjects on every 4 weeks dosing regimen) after 
the end of the PK Phase Gamunex-C infusion.
After the completion of the Gamunex-C PK Phase, subjects will enter the IVIG-PEG
Treatment Phase. Subjects will receive a total of 5 or 6 consecutive doses of IVIG-PEG
according to the subject’s previous Gamunex-C dosing interval (i.e., administration of 5 
consecutive doses for subjects on the every 4 weeks regimen and administration of 6 
consecutive doses for subjects on the every 3 weeks regimen).
Trough IgG levels will be obtained prior to all infusions in the Screening, Gamunex-C Run-
in, and IVIG-PEG Treatment Phases. 
At the conclusion of the IVIG-PEG Treatment Phase (i.e., after 5 or 6 infusions of IVIG-PEG
depending on the individual dosing interval), subjects will enter into the IVIG-PEG PK Phase 
lasting 3 or 4 weeks in duration depending on the individual dosing interval. Pharmacokinetic 
samples will be drawn 30 minutes prior to the start of the IVIG-PEG infusion in the PK 
Phase, immediately upon the completion of the PK Phase  IVIG-PEG infusion (within 10 
31 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence Study to Evaluate
the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to Gamunex-C in Subjects with Primary
Effective

minutes of infusion completion), and at 1, 3, 6, 24, and 48 hours; and 4, 7, 14, 21, and 28 
days (the PK sample drawn at 28 days applies only for subjects on every 4 weeks dosing 
regimen) after the end of the PK Phase IVIG-PEG infusion.
At the end of the IVIG-PEG PK Phase, subjects will have their Final Visit.
Safety variables will be assessed at all study visits. 
Detailed study schedules are included in Appendix 1, Table A for every 3 weeks dosing 
regimen, and Table B for every 4 weeks dosing regimen. The specific time points for PK 
sampling for Gamunex-C and IVIG-PEG administration are outlined in Sections 7.2.1.2.3
and 7.2.1.3.3, respectively.
Treatment visits for the Gamunex-C Run-In Phase, Gamunex-C PK Phase, IVIG-PEG PK 
Phase and the Final Visit/Early Termination Visit may be performed at the study site or, if 
deemed appropriate, at an alternate site (e.g., subject's residence, local healthcare 
professional's site) under the care and supervision of trained healthcare personnel.  
Some treatment visits for the IVIG-PEG Treatment Phase may also be performed at the study 
site or, if deemed appropriate, at an alternate site (e.g., subject's residence, local healthcare 
professional's site) under the care and supervision of trained healthcare personnel. IVIG-PEG 
#1 and IVIG-PEG #2 treatment visits are to be performed at the study site. 
4.2.1
Screening Phase
At Screening, subjects will be categorized into 2 groups: 1) those subjects who can directly 
enter the Gamunex-C PK Phase of the study, and 2) those subjects who will require a 
4-month or 4.5-month Run-in Phase (corresponding to administration of 5 or 6 consecutive 
doses of Gamunex-C depending on previous dosing regimen) (Table 4-1 and Figure 4-1). 
The Screening Phase lasts up to 28 days.
32 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence Study to Evaluate
the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to Gamunex-C in Subjects with Primary
Effective

Table 4-1 Subject Entry Criteria
Group
Subject Populations at Screening Based upon Most Recent IgG 
Treatment History (All must have confirmed diagnosis of PI)
Required Study Entry Point
1
Receiving stable dose of Gamunex-C between 200 and 800 mg/kg, 
every 3 or 4 weeks (6 consecutive doses when receiving every 3 
weeks administration regimen or 5 consecutive doses when 
receiving every 4 weeks administration regimen) and have 
documented trough levels equal to or greater than 500 mg/dL 
within the previous year documented at the Screening Visit
Gamunex-C PK Phase
2
Receiving IVIG other than Gamunex-C
OR
Receiving Gamunex-C, but either not on stable dose (≥5 months) 
OR dose is not between 200 and 800 mg/kg OR interval is not 
every 3 or 4 weeks
Run-in Phase (5 or 6
consecutive doses of 
Gamunex-C depending on 
previous dosing regimen)
4.2.2
Gamunex-C Phase
4.2.2.1
Run-in Phase
Subjects will be evaluated during the Screening Visit and placed into 1 of 2 groups based on 
their previous IVIG regimen as follows:
Group 1 - Subjects are eligible for direct entry into the Gamunex-C PK Phase:
Subjects who are currently receiving a stable dose of Gamunex-C between 200 and 
800 mg/kg per infusion every 3 or 4 weeks and have trough levels equal to or greater than 
500 mg/dL within the previous year and documented at the Screening Visit are not required
to enter the Run-in Phase and may proceed directly to the Gamunex-C PK Phase.
Group 2 – Subjects required to enter the Gamunex-C Run-in Phase:
Those subjects who are receiving an IVIG therapy other than Gamunex-C prior to Screening 
(i.e., a different commercially available IVIG), and those subjects who are currently 
receiving Gamunex-C, but either have not been on a stable dose for the 5 months prior to 
Screening, the dose is not between 200 and 800 mg/kg, or the dosing frequency is not every 3 
or 4 weeks, will be required to enter the Run-in Phase and receive 5 or 6 consecutive doses of 
IV Gamunex-C (at a dose between 200 and 800 mg/kg and a dosing interval as in their 
previous IVIG therapy [i.e., 5 consecutive doses for subjects on the every 4 weeks dosing 
regimen and 6 consecutive doses for subjects on every 3 weeks dosing regimen]). Subjects 
that are receiving an IVIG therapy other than Gamunex-C prior to Screening will be required 
to switch their normal immunoglobulin product dose to a proportional dose of intravenous 
Gamunex-C (between 200 to 800 mg/kg every 3 or 4 weeks) to ensure that they receive the 
same IVIG dose during the Run-in Phase as with their previous immunoglobulin product.
33 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence Study to Evaluate
the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to Gamunex-C in Subjects with Primary
Effective

Furthermore, any subject whose prior dosing frequency was not every 3 to 4 weeks will be 
adjusted to one of these two frequency options by their physician during the Run-in Phase
also to ensure that they receive the same dose as with their previous immunoglobulin 
product.  
During the Run-in Phase, subjects will receive an individualized dose of Gamunex-C 
between 200 to 800 mg/kg that treating physicians consider appropriate compared to their 
previous IVIG treatment regimen. The subject’s usual mg/kg dose (given on either a 3 or 4 
week repeating schedule) will be the same mg/kg dose and schedule that the subject was 
receiving prior to entering screening. This mg/kg dose and schedule will be used throughout 
the study duration. Note that the weight of the subject will be measured at each visit and if 
the subject’s weight changes, the actual weight at each visit will be used to calculate amount 
of drug (mg) to be administered. The first 3 consecutive doses of Gamunex-C during the 
Run-in Phase (visits #1, #2, and #3) can be adjusted as needed by treating physicians to 
achieve a stable dose for subjects, and then such stable dose should be maintained throughout 
the remainder of the Run-in Phase (visits #4, #5, and #6). Doses during visits #4, #5, and #6 
cannot vary from each other or from the dose given during visit #3 by more than 20%. 
Subjects who cannot achieve a stable dose of Gamunex-C during the Run-in Phase may not 
continue to the Gamunex-C PK Phase and will be withdrawn from the study (see 
Section 5.3.2).
Trough levels will be measured within 1 hour prior to the start of each infusion of 
Gamunex-C.
Treatment visits for the Gamunex-C Run-In Phase may be performed at the study site or, if 
deemed appropriate, at an alternate site (e.g., subject's residence, local healthcare 
professional's site) under the care and supervision of trained healthcare personnel.  
4.2.2.2
Gamunex-C PK Phase
After Screening (for subjects in Group 1) or after the Run-in Phase (for subjects in Group 2),
subjects will enter the Gamunex-C PK Phase and receive 1 additional dose of Gamunex-C. 
Pharmacokinetic samples will be collected within 30 minutes prior to the start of the last of 
Gamunex-C infusion, immediately upon the completion of the last Gamunex-C infusion 
(within 10 minutes of infusion completion), and at 1, 3, 6, 24, and 48 hours and 4, 7, 14, 21, 
and 28 days (the PK sample drawn at 28 days applies only for subjects on every 4 weeks 
dosing regimen) after the end of the last the Gamunex-C infusion for determination of a PK 
curve. 
Visits for the Gamunex-C PK Phase may be performed at the study site or, if deemed 
appropriate, at an alternate site (e.g., subject's residence, local healthcare professional's site) 
under the care and supervision of trained healthcare personnel.  
34 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence Study to Evaluate
the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to Gamunex-C in Subjects with Primary
Effective

4.2.3
IVIG-PEG Phase
4.2.3.1
IVIG-PEG Treatment Phase
At the end of the Gamunex-C PK Phase, all subjects will enter the IVIG-PEG Treatment 
Phase. During the IVIG-PEG Treatment Phase, all subjects will receive 6 or 5 doses of 
IVIG-PEG at either 3-week or 4-week intervals. The dose and frequency of IVIG-PEG 
administered during this phase will be the same as the subject’s dose and frequency during 
the Gamunex-C PK Phase.
Trough IgG levels will be measured within 1 hour prior to each infusion.
Some treatment visits for the IVIG-PEG Treatment Phase may be performed at the study site 
or, if deemed appropriate, at an alternate site (e.g., subject's residence, local healthcare
professional's site) under the care and supervision of trained healthcare personnel. IVIG-PEG 
#1 and IVIG-PEG #2 treatment visits are to be performed at the study site. If there are 
extenuating circumstances that prevent the subject from returning to the study site for these 
visits, the PI or designee is to discuss the situation with the sponsor. Sponsor approval may
be granted to conduct the visit(s) at an alternate location under the care and supervision of 
trained healthcare personnel.
4.2.3.2
IVIG-PEG PK Phase
Subjects will enter the IVIG-PEG PK Phase at the conclusion of the IVIG-PEG Treatment 
Phase and will receive 1 additional dose of IVIG-PEG. Pharmacokinetic samples will be 
collected within 30 minutes prior to the start of the last IVIG-PEG infusion, immediately 
upon the completion of the last IVIG-PEG infusion (within 10 minutes of infusion 
completion), and at 1, 3, 6, 24, and 48 hours and 4, 7, 14, 21 and 28 days (the PK sample 
drawn at 28 days applies only for subjects on every 4 weeks dosing regimen) after the end of 
the last the IVIG-PEG infusion for determination of a PK curve.
Visits for the IVIG-PEG PK Phase may be performed at the study site or, if deemed 
appropriate, at an alternate site (e.g., subject's residence, local healthcare professional's site) 
under the care and supervision of trained healthcare personnel.  
4.2.4
Final Visit/Early Termination Visit
After the completion of the IVIG-PEG PK Phase, subjects will complete the Final Visit/Early 
Termination Visit. 
The Final Visit/Early Termination Visit may be performed at the study site or, if deemed 
appropriate, at an alternate site (e.g., subject's residence, local healthcare professional's site) 
under the care and supervision of trained healthcare personnel.  
The overall study diagram is depicted in Figure 4-1 and Figure 4-2 below.
35 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence Study to Evaluate
the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to Gamunex-C in Subjects with Primary
Effective

4.3
Measures Taken to Minimize/Avoid Bias
4.3.1
Subject Numbering
Within each study site, subjects in the study will receive a consecutive subject number. 
Subject numbers are generated beginning with the study center number (3 digits, assigned by 
the sponsor) followed consecutively with a unique number for each subject (4 digits, 
including leading zeros). For example, if the Investigators’ center number is 301, subject 
number will be 3010001, 3010002, 3010003, etc., in consecutive order. Subject numbers, 
once assigned, will not be reused at any center.
4.3.2
Randomization
This is an open-label, single-sequence, cross-over study design, therefore randomization is 
not applicable.
4.3.3
Blinding
Blinding is not applicable for this study.
4.4
Study Treatments
4.4.1
Treatments to Be Administered
IVIG-PEG and Gamunex-C (reference therapy) will be administered during this study.
4.4.1.1
IVIG-PEG
IVIG-PEG is a 10% solution of purified human IgG made from large pools of human plasma 
via modifications of the Gamunex-C manufacturing process. IVIG-PEG is a sterile, liquid, 
highly purified, unmodified human IgG product intended for IV administration. In this study, 
administration of IVIG-PEG will be via the IV route only.
IVIG-PEG consists of 9 to 11% IgG in 0.16 to 0.24 M glycine. IVIG-PEG 10% may be 
supplied in vial sizes of 10, 25, 50, 100, 200 and 400 mL. For this study, IVIG-PEG will be 
supplied in 100 mL vials.
4.4.1.2
Gamunex-C
Gamunex-C is a ready-to-use sterile solution of human IgG protein for IV or SC 
administration. Gamunex-C is a licensed product. Gamunex-C vials may be supplied in the 
vial sizes of 10, 25, 50, 100, and 200 mL. In this study, administration of Gamunex-C will be 
via the IV route only.
Gamunex-C consists of 9 to 11% IgG in 0.16 to 0.24 M glycine. The buffering capacity of 
Gamunex-C is 35.0 mEq/L (0.35 mEq/g protein). A dose of 1 g/kg body weight therefore 
represents an acid load of 0.35 mEq/kg body weight. The total buffering capacity of whole 
blood in a normal individual is 45 to 50 mEq/L of blood, or 3.6 mEq/kg body weight. Thus, 
38 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence Study to Evaluate
the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to Gamunex-C in Subjects with Primary
Effective

the acid load delivered with a dose of 1 g/kg of Gamunex-C would be neutralized by the 
buffering capacity of whole blood alone, even if the dose was infused instantaneously (4).
4.4.2
Labeling of Investigational Products
Investigational products will be labeled according to the requirements of local law and 
legislation. Label text will be approved according to agreed Grifols’ procedures and a copy 
of the labels will be made available to each individual study site.
4.4.3
Packaging of Investigational Products
The sponsor will be responsible for ensuring that the IP is manufactured in accordance with 
applicable current Good Manufacturing Practice regulations and requirements.
4.4.4
Storage of Investigational Products
IVIG-PEG and Gamunex-C must be stored in a secure area accessible to study personnel 
authorized by the Investigator, such as the study staff responsible for the preparation and 
dispensing of IPs.
IVIG-PEG and Gamunex-C may be stored for up to 36 months from the date of manufacture 
at 2 to 8°C (36 to 46°F). The products may be stored at temperatures not exceeding 25°C 
(77°F) for up to 6 months any time during the shelf life from date of manufacture, after 
which the product must be used immediately or discarded. Do not freeze. All partially used 
vials should be discarded as no preservative is present. Do not use after expiration date. 
Investigators, or designees, are responsible for maintaining storage temperature logs and for 
immediately reporting deviations in temperature to the monitor.
Details for the storage are located in the pharmacy manual provided to each study site.
4.5
Expected Duration of Subject Participation in the Study
The study consists of a Screening Phase (up to 28 days), a Gamunex-C Run-in Phase (up to 
4.5 months) for subjects not currently receiving Gamunex-C or not on a stable dose of 
Gamunex-C, a Gamunex-C PK Phase (up to 4 weeks), an IVIG-PEG Treatment Phase (up to 
4.5 months), an IVIG-PEG PK Phase (up to 4 weeks), and a Final Visit/Early Termination 
Visit. The expected duration of a subject’s participation in this study will be up to 54 weeks 
depending on dosing frequency and Run-in Phase requirement.
4.6
Discontinuation Criteria for Individual Subjects and Study
4.6.1
Discontinuation Criteria for Individual Subjects
See Section 5.3 Subject Withdrawal Criteria
39 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence Study to Evaluate
the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to Gamunex-C in Subjects with Primary
Effective

4.6.2
Premature Termination of Study/Closure of Center
The sponsor, Institutional Review Board/Ethics Committee (IRB/EC), and/or regulatory 
authorities have the right to close this study or a study center, and the Investigator/sponsor 
has the right to close a center, at any time, although this should occur only after consultation 
between involved parties. The IRB/EC must be informed. Should the study/center be closed 
prematurely, all study materials (except documentation that has to remain stored at site) must 
be returned to the sponsor. The Investigator will retain all other documents until notification 
given by the sponsor for destruction.
The reasons a study center can be closed include, but are not limited to, the following 
reasons:
•
Lack of enrollment 
•
Non-compliance with the requirements of the study protocol
•
Non-compliance with ICH GCP
4.6.2.1
Study Stopping Rules
As a conservative measure, if 5 subjects on IVIG-PEG develop a serious adverse event 
(SAE) of exactly the same type (i.e., the same MedDRA [Medical Dictionary for Regulatory 
Activities] preferred term) which is not an infection or manifestation of an underlying 
disorder documented in medical history, then this would constitute an unanticipated 
clustering which could signal a potential safety concern. If this situation were to arise, the 
Sponsor will constitute a Safety Review Committee (SRC) whose members (from Grifols) 
will be impartial and independent of the clinical trial team. In cases where there is a clear 
medical plausibility supporting an uncommon clustering of SAEs of the same type (not 
including infections), and these sentinel SAEs are designated as ‘definitely related’, 
‘probably related’, or ‘possibly related’ by both the Investigator and the SRC, consideration 
would be given to possibly discontinuing the study.
Furthermore, if any of the two following situations occur for subjects on IVIG-PEG: 
•
Three or more subjects develop at least a 50% decrease in trough IgG level from 
Screening or initiation of the first infusion, whichever is lower, and IVIG-PEG is 
correctly dosed in terms of mg/kg dosage and treatment interval in all cases.
•
Study subjects develop a total of 6 independent and temporally distinct SBIs while on 
IVIG-PEG given at the correct dose and treatment time interval.
All subsequent infusions of IVIG-PEG will be temporarily suspended in all study subjects 
and the SRC convene to consider whether to discontinue the study or not in agreement with 
the PI. 
If the SRC and Investigator decision is to discontinue the study due to any of the 
circumstances described above, all subjects will complete a Final Visit/Early Termination 
Visit before initiation of treatment with a licensed IVIG.
40 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence Study to Evaluate
the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to Gamunex-C in Subjects with Primary
Effective

4.7
Accountability Procedures for Investigational Products
IVIG-PEG and Gamunex-C are to be used only for the study in accordance with the 
directions given in this protocol and pharmacy/study manual. The Investigator, or designee 
such as the study pharmacist, is responsible for the distribution of the IPs in accordance with 
directions given in the protocol and pharmacy manual.
The Investigator, or designee such as the study pharmacist, is responsible for maintaining 
accurate records of the IVIG-PEG and Gamunex-C for his/her site. Investigational product 
inventory/dispensing documentation verifying the receipt, dispensing, destruction, or return 
must be maintained and kept current by the Investigator, or designee. The inventory must be 
made available for inspection by the monitor. IVIG-PEG and Gamunex-C supplies must be 
accounted for by the monitor and inventory/dispensing logs must be verified by the monitor 
prior to the return or destruction of IVIG-PEG and Gamunex-C. Written documentation of 
any used and unused inventory is required. At the end of the study, a copy of the 
inventory/dispensing log(s) will be retrieved by the monitor and returned to Grifols.
An IP accountability record for both the IPs must be kept current by the clinical site and must 
contain:

Subject number

Initials of the staff person dispensing the product

Dates and quantities of IP received

Dates and quantities of IP dispensed

Dates and quantities of IP returned
4.8
Maintenance of Treatment Randomization Codes 
This is an open-label, single-sequence, cross-over study design; therefore, randomization is 
not applicable.
5
SELECTION AND WITHDRAWAL OF SUBJECTS 
This study will be carried out in adult subjects previously diagnosed with PI currently 
receiving stable replacement therapy with IVIG (either on a 3-week or 4-week treatment 
schedule) whose disease process is expected to be stable for the duration of the study.
Subjects who initially fail to meet certain eligibility criteria may be rescreened once upon 
consultation with the sponsor. Subjects who fail to meet eligibility criteria upon rescreening 
will be considered screen failures and will not be eligible to participate in the study.
5.1
Inclusion Criteria
A subject must meet all the following inclusion criteria to be eligible for enrollment in this 
study:
41 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence Study to Evaluate
the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to Gamunex-C in Subjects with Primary
Effective

1. Male or female between 18 and 75 years of age (inclusive) at Screening
2. Documented and confirmed pre-existing diagnosis of PI with features of 
hypogammaglobulinemia requiring IV IgG replacement therapy including but not limited 
to the following humoral-based immunodeficiency syndromes (e.g., X-linked 
agammaglobulinemia, common variable immunodeficiency), and combined 
immunodeficiency syndromes without lymphocytopenia (e.g., hyper immunoglobulin M 
[IgM] immunodeficiency syndrome). Please also refer to Section 5.2 Exclusion Criteria 
3. IgG trough level ≥500 mg/dL at Screening Visit 
Note: Patients entering Group 1 must additionally have trough levels ≥500 mg/dL 
documented within the previous year. For patients entering Group 2, if Screening trough 
levels are not ≥500 mg/dL, the subject will be a Screen Failure, but may be rescreened 
following dose adjustment of their original IV IgG replacement therapy regimen and 
recording an IgG trough level ≥500 mg/dL
4. Has not had an SBI within the last 6 months prior to Screening or during the Screening
5. Medical records are available to document diagnosis, previous infections, and treatment.
6. Willing to comply with all aspects of the study protocol, including blood sampling, for 
the duration of the study
7. Signed and dated a written informed consent form (ICF) confirming his or her 
willingness to participate in study GC1902 (See Section 12.4)
5.2
Exclusion Criteria
A subject meeting any of the following exclusion criteria is NOT eligible for participation in 
the study.
1. Has an acquired medical condition that is known to cause secondary immune deficiency, 
such as chronic lymphocytic leukemia, lymphoma, multiple myeloma, chronic or 
recurrent neutropenia (absolute neutrophil count less than 1000/μL [1.0 x 109/L]), or 
human immunodeficiency virus (HIV) infection/acquired immune deficiency syndrome 
(AIDS)
2. Has known selective IgA deficiency (with or without antibodies to IgA).(Note: exclusion 
is for the specific diagnostic entity. It does not exclude other forms of primary humoral 
immunodeficiency which have decreased IgA in addition to decreased IgG requiring IgG 
replacement)
3. Has isolated IgG subclass deficiency or an isolated specific antibody deficiency disorder, 
or transient hypogammaglobulinemia of infancy
4. The subject has had a known serious adverse reaction to immunoglobulin or any severe 
anaphylactic reaction to blood or any blood-derived product
5. Has a history of thrombotic complications following IVIG therapy 
6. Has a history of or current diagnosis of deep venous thrombosis (DVT) or 
thromboembolism (e.g., myocardial infarction, cerebrovascular accident or transient 
ischemic attack); history refers to an incident in the year prior to the Screening Visit or 2 
episodes over lifetime or has thrombosis risk factors (e.g., prolonged immobilization, use 
of estrogens, indwelling central vascular catheters)
42 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence Study to Evaluate
the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to Gamunex-C in Subjects with Primary
Effective

7. Has a known hyperviscosity syndrome or hypercoagulable states
8. Has liver enzyme levels (alanine aminotransferase [ALT], aspartate aminotransferase 
[AST], gammaglutamyl transferase [GGT], or lactate dehydrogenase [LDH]) greater than 
2.5 times the upper limit of normal (ULN) at the Screening Visit as defined by the testing 
laboratory
9. Has pre-existing renal impairment (defined by serum creatinine greater than 1.5 times the 
ULN or blood urea nitrogen [BUN] greater than 2.5 times the ULN, or any subject who is 
on dialysis) at the Screening Visit or any history of acute renal injury
10. Has clinically significant history of drug or alcohol abuse or dependence in the opinion of 
the Investigator (must be within the past 12 months and noted in the subject’s medical 
records or documented at Screening)
11. Clinical evidence of any significant acute or chronic medical condition (e.g., renal 
disease or predisposing conditions for renal disease, coronary artery disease, or protein 
losing state) that, in the opinion of the Investigator, may interfere with the conduct of the 
study or may place the subject at undue medical risk
12. Females of childbearing potential who are pregnant, have a positive pregnancy test at 
Screening (human chorionic gonadotropin [HCG]-based assay), are breastfeeding, or 
unwilling to practice a highly effective method of contraception (e.g., oral, injectable or 
implanted hormonal methods of contraception, placement of an intrauterine device [IUD] 
or intrauterine system [IUS], condom or occlusive cap with spermicidal 
foam/gel/film/cream/suppository, male sterilization, or true abstinence) throughout the 
study
Note: True abstinence: When this is in line with the preferred and usual lifestyle of the 
subject. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, post-
ovulation methods], declaration of abstinence for the duration of a trial, and 
withdrawal are not acceptable methods of contraception)
13. Receiving any of the following medications: (a) immunosuppressants including 
chemotherapeutic agents, (b) immunomodulators, (c) long-term systemic corticosteroids 
defined as daily dose >1 mg of prednisone equivalent/kg/day for >30 days 
Note: Intermittent courses not exceeding >1mg of prednisone equivalent/kg/day for >30 
days would not exclude the subject. Inhaled or topical corticosteroids are allowed
14. Has uncontrolled arterial hypertension (systolic blood pressure [SBP] >160 mm Hg 
and/or diastolic blood pressure [DBP] >100 mm Hg)
15. Has hemoglobin <11 g/dL at the Screening Visit 
16. Unable or unwilling to provide a storage serum sample at the Screening Visit 
Note: A pre-treatment serum sample to be stored at -94°F (-70ºC) for possible future 
testing is required
17. Received any live virus vaccine within 5 months prior to the Screening Visit and not 
willing to postpone receiving any live virus vaccines until 6 months after completing 
study treatment
18. Has a known previous infection with or clinical signs and symptoms consistent with 
current hepatitis B virus (HBV) or hepatitis C virus (HCV) infection
43 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence Study to Evaluate
the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to Gamunex-C in Subjects with Primary
Effective

19. Has participated in another clinical trial within 30 days prior to Screening or has received 
any investigational product, with the exception of other IgG products, within the previous 
3 months prior to the Screening Visit
5.3
Subject Withdrawal Criteria
5.3.1
Screen Failures
Screening evaluations will be used to determine the eligibility of each subject for enrollment.  
Subjects who fail to meet eligibility criteria during screening evaluations will be allowed to 
be rescreened once upon consultation with the sponsor. Subjects who fail to meet the 
eligibility criteria upon rescreening will be considered screen failures and will not be allowed 
to participate in the study. 
5.3.2
Removal of Subjects
Subjects may withdraw or be withdrawn from the study for the following reasons:
•
At their own request or at the request of their legally acceptable representative
•
If, in the Investigator's opinion, continuation in the study would be detrimental to the 
subject's well-being
•
At the specific request of the sponsor 
Also, subjects must be withdrawn from IP or the study for the following reasons: 
•
The subject is uncooperative and noncompliant (defined as 2 consecutive or 3 overall 
missed study visits) with respect to provisions of the protocol
•
The subject develops infection with HBV, HCV, or HIV as determined by the appropriate 
combination of nucleic acid testing (NAT) and serological tests for each virus
•
The subject has a serious AE while participating in the study that, at the discretion of the 
site Investigator, should lead to discontinuation
•
Subjects who develop two SBIs while participating in the study
•
The subject becomes pregnant while participating in the study
•
The subject requires treatment with any of the medications listed under exclusion criteria
•
A subject entering through the Run-in Phase cannot achieve a stable dose of Gamunex-C 
during the Run-in Phase, i.e., doses during Run-in visits #4, #5, and #6 vary from each 
other or from the dose given during visit #3 by more than 20%.
In all cases, the reason for withdrawal must be recorded in the eCRF and in the subject's 
records. 
Subjects who have completed the study and subjects who have withdrawn from the study 
cannot participate in the study for a second time.
44 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence Study to Evaluate
the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to Gamunex-C in Subjects with Primary
Effective

5.3.3
Subject Replacement 
Subjects who are withdrawn from the study will not be replaced.
5.3.4
Follow-up of Subjects Withdrawn from Study
Subjects who receive any amount of IP and discontinue early from the study will be 
requested to return for the Final Visit/Early Termination Visit procedures as close as 
practical to 30 days after their last administration of IP, provided that the subjects do not 
withdraw their consent to participate in this study.
6
TREATMENT OF SUBJECTS
See Section 4.4 for the treatments to be administered, including the names of all the products, 
the doses, the dosing schedules, the route/modes of administration.
6.1
Administration and Timing of Investigational Products for Each 
Subject
The Gamunex-C dose and dosing interval during the Run-in Phase or Gamunex-C PK Phase 
will be individualized based on the previous IVIG treatment the subject was receiving for PI 
during the Screening Phase. During the IVIG-PEG phases, the IVIG-PEG dose and dosing 
interval will be individualized based on the previous Gamunex-C treatment the subject was 
receiving for PI either during the Screening Phase or at the end of the Gamunex-C Run-in
Phase (for subjects not directly entering the Gamunex-C PK Phase).
Subjects will receive IVIG-PEG and Gamunex-C by means of an infusion pump at a dose of 
200 to 800 mg/kg per infusion at an infusion rate of 1 mg/kg/min or up to 8 mg/kg/min 
depending on subject tolerance. The subject’s usual mg/kg dose (given on either a 3 or 4 
week repeating schedule) will be the same mg/kg dose and schedule that the subject was 
receiving prior to entering screening. This mg/kg dose and schedule will be used throughout 
the study duration. Note that the weight of the subject will be measured at each visit and if 
the subject’s weight changes, the actual weight at each visit will be used to calculate amount 
of drug (mg) to be administered. IVIG-PEG and Gamunex-C will be administered every 3 
weeks (±4 days) or 4 weeks (±4 days), depending on the subject’s prior IVIG dosing 
schedule. 
Subjects currently on stable Gamunex-C (for administration of at least 5 consecutive doses) 
will directly enter the Gamunex-C PK Phase, followed by the IVIG-PEG Treatment Phase in 
which they will receive 5 or 6 consecutive doses of IVIG-PEG according to their previous 
dosing regimen (every 4 weeks or every 3 weeks, respectively) and IVIG-PEG PK Phase. 
Subjects currently on IVIG therapy other than Gamunex-C or on Gamunex-C treatment but 
not at a stable dose of 200 to 800 mg/kg per infusion or not at every 3- or 4-week intervals 
will receive Gamunex-C for approximately 4.5 months during the Run-in Phase, prior to the 
Gamunex-C PK Phase, IVIG-PEG Treatment Phase, and IVIG-PEG PK Phase. 
45 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence Study to Evaluate
the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to Gamunex-C in Subjects with Primary
Effective

All infusions for both study drugs will be administered using a standard (e.g., polyvinyl 
chloride) administration kit prepared by qualified personnel, working to local standard 
operating procedures and under aseptic conditions.
IVIG-PEG and Gamunex-C will be brought to room temperature before each infusion. The 
nurse performing the infusion should verify by touch that the temperature of product is 
approximately room temperature. Heating devices should not be used to bring product to 
room temperature.
6.2
Prior and Concomitant Therapy
Concomitant medications must be recorded in the subject’s source documents and eCRF, 
including the trade and generic names of the medication, the dose, the route of 
administration, and the duration of the medication (frequency).
Use of prophylactic antibiotics must be recorded as appropriate in the subject’s medical 
records and eCRF to distinguish between prophylactic use and use for treatment of an 
episode of infection.
6.2.1
Prohibited Medications Prior to Study Participation
Use of the following medications excludes a subject from participating in this study:
•
Received any investigational product, with the exception of other IgG products, within 
the previous 3 months prior to the Screening Visit
•
At the time of Screening, receiving systemic corticosteroids (i.e., long-term daily doses 
>1 mg of prednisone equivalent/kg/day for >30 days; intermittent courses not exceeding 
1mg of prednisone equivalent/kg/day for >30 days would not exclude the subject)
Note: Inhaled or topical corticosteroids are allowed
•
At the time of Screening, receiving immunosuppressants including chemotherapeutic 
agents or immunomodulators
•
Clinically significant drug or alcohol abuse or dependence in the opinion of the 
Investigator (must be within the past 12 months and noted in the subject’s medical 
records or documented at Screening) excludes a subject from participating in this study
6.2.2
Prohibited Concomitant Medications during the Study
All concomitant medications used and therapies received by subjects will be recorded on the 
appropriate subject’s medical records and eCRF page. Use of the following medications is 
prohibited during study participation:
•
Any IgG replacement therapy other than IVIG-PEG or Gamunex-C provided in this study
with the exception of the screening visit, when subjects will receive their usual IVIG 
treatment
•
Investigational products not included in this study
46 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence Study to Evaluate
the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to Gamunex-C in Subjects with Primary
Effective

•
Corticosteroids in excess of stipulations delineated in Section 6.2.1
•
Immunosuppressants including chemotherapeutic agents or immunomodulators
6.2.3
Restricted Concomitant Medications during the Study
This section describes medications that are restricted, but not prohibited during study 
participation. Subjects cannot receive routine premedication during this study. Adequate 
hydration will be administered to all subjects prior to initiation of infusion with IVIG-PEG. If 
a subject who previously required premedication is to be enrolled, they must start this study 
without routine premedication. The previous use of premedication as well as the AE for 
which the premedication was used must be recorded on the subject’s medical records and 
Screening eCRF page. If an AE which may be prevented by the use of a premedication 
occurs 2 or 3 times, the AE must be documented on the subject’s medical records and 
appropriate eCRF page, and use of the premedication may be resumed for the remaining 
study infusions of the same product (i.e., subjects who required premedication in the 
Gamunex-C Run-in period should start the IVIG-PEG period without using premedication).
The medications listed below are not allowed during the study as premedication (unless after 
2 or 3 times occurrence as explained above) to an infusion; however, these medications are 
allowed during the study for general use (e.g., to treat an AE):

Acetaminophen

Antihistamines

NSAIDs

Steroids (provided dosing is as outlined in Section 6.2.1)
When premedication is needed, it is recommended that premedication is started using 
acetaminophen or/and antihistamines, and that NSAIDS as well as steroids are used only if 
the symptoms are not controlled appropriately with acetaminophen or/and antihistamines.
Note: When premedication is administered, the medication will need to be entered into the 
eCRF each time that it is administered. The premedication should not be entered into 
the eCRF only once with the frequency of as needed (PRN).
6.2.4
Drug Interactions
In the setting of a PI disease state, live viral vaccines have various contraindications and 
specific risks/degrees of effectiveness dependent on the type/category of the immune 
deficiency (35). Subjects may not have received any live virus vaccine within the 5 months 
prior to the Screening Visit (as per exclusion criterion 17). Passive transfer of antibodies 
from IVIG-PEG or Gamunex-C may transiently interfere with the immune response to live 
viral vaccines such as measles, mumps, rubella, and varicella in the normal host with an 
intact immune system. Best medical practices should be followed regarding immunization 
requirements.
47 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence Study to Evaluate
the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to Gamunex-C in Subjects with Primary
Effective

6.3
Treatment Compliance
Reasons for any deviation from the administration of less than 100% of the IP dose as 
prepared by the pharmacist, or designee, must be recorded in the eCRF and in the subject’s 
medical records.
7
ASSESSMENT OF PHARMACOKINETIC AND OTHER STUDY 
PARAMETERS
7.1
Pharmacokinetic, Secondary Efficacy, and Exploratory Variables
7.1.1
Primary Pharmacokinetic Variables
The primary PK variables are steady-state AUC of total IgG over a regular dosing interval 
(τ), defined as AUC0-τ, either every 3 weeks or every 4 weeks (i.e., AUC0-21 days or AUC0-28 
days, respectively) and Cmax in subjects with PI.
7.1.1.1
Other Pharmacokinetic Variables
The other PK variables include:
•
Mean steady-state trough concentration of total IgG following IV administration of 
Gamunex-C and following IV administration of IVIG-PEG 
•
Tmax
•
Cl
•
Vd
7.1.2
Secondary Efficacy Variables
•
Rate of SBIs
•
All infections of any kind (serious/nonserious including acute sinusitis, exacerbation of 
chronic sinusitis, acute otitis media, pneumonia, acute bronchitis, infectious diarrhea, 
etc.) as determined by the Investigator
•
Number of days on antibiotics (including oral, parenteral, oral plus parenteral, 
prophylactic and therapeutic). Use of prophylactic antibiotics will be distinguished from 
antibiotics for treatment of acute infection
•
Number of hospitalizations due to infection
•
Number of days of work/school/daily activities missed per subject year due to infections 
and their treatment
7.1.3
Exploratory Variables
Exploratory variables include:
48 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence Study to Evaluate
the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to Gamunex-C in Subjects with Primary
Effective

•
Trough levels of IgG subclasses (IgG1, IgG2, IgG3, IgG4)
•
Antibody levels for S. pneumoniae, H. influenzae, and tetanus (C. tetani)
•
Validated infections documented by positive radiograph, fever (>38°C oral or >39°C 
rectal), culture, or diagnostic testing for microorganisms, e.g., bacterial, viral, fungal, or 
protozoal pathogens (for instance, rapid streptococcal antigen detection test)
•
Trough measles antibody titers (functional assay) are an exploratory variable for 
informational purposes
7.2
Methods and Timing for Assessing, Recording, and Analyzing 
Parameters
The study phases are described in Section 4.2. The study consists of 4 phases, a Screening 
Phase (up to 28 days), a Gamunex-C Phase consisting of a Run-in Phase (up to 4.5 months) 
for subjects not eligible for direct entry into the Gamunex-C PK Phase and a Gamunex-C PK 
Phase (up to 4 weeks), an IVIG-PEG Phase consisting of an IVIG-PEG Treatment Phase (up 
to 4.5 months) and an IVIG-PEG PK Phase (up to 4 weeks), and a Final Visit/Early 
Termination Visit. The total duration of study participation may be up to 54 weeks.
7.2.1
Observations and Measurements
The following sections describe the procedures/assessments to take place at each study visit. 
See the Schedules of Study Procedures and Events in Appendix 1 for a summary of study 
visits and the procedures to be conducted at each visit.
7.2.1.1
Screening Phase
Subjects who initially fail to meet eligibility criteria may be rescreened once upon 
consultation with the sponsor. Subjects who fail to meet eligibility criteria upon rescreening 
will be considered screen failures and will not be eligible to participate in the study. The 
duration of the Screening Phase is approximately 28 days.
The Screening Phase will include the following:
•
Obtain written informed consent prior to initiation of any Screening procedures
•
Assess inclusion and exclusion criteria to determine subject eligibility
•
Assign and record subject number
•
Record medical history 
•
Record demographics: year of birth, age at screening (years), gender (if female, fertility 
status), race, and ethnic origin
•
Record specific diagnosis of type of PI, date of diagnosis, and name, start/stop date and 
dose of current IgG replacement regimen
•
Record available IgG trough levels within previous year period
49 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence Study to Evaluate
the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to Gamunex-C in Subjects with Primary
Effective

•
Record prior medication history
•
Perform full physical exam (excluding breast and genitourinary exam) 
•
Perform chest X-ray (if chest X-ray or CT have not been performed within past 6 months 
prior to Screening) Note: at least one radiographic view (anterior-posterior [AP] or 
posterior-anterior [PA]) is required)
•
Vital signs: SBP and DBP, heart rate (HR), temperature (T), respiratory rate (RR) after 5 
minutes at rest 
•
Measure body weight and height
•
Administration of the subject’s usual IVIG treatment
•
Blood and/or urine sample for: (see Table 7-1). 
-
Hematology: Hb, hct, platelets, RBC count including morphology, white blood cell 
(WBC) count with differential; absolute reticulocyte count (ARC) 
-
Clinical chemistry: sodium, potassium, creatinine, chloride, calcium, BUN, 
bicarbonate, albumin, LDH, AST, ALT, GGT, alkaline phosphatase (ALP), glucose, 
total bilirubin (TBL), indirect and direct bilirubin
-
Urinalysis: pH, protein, glucose, ketones, bilirubin, nitrites, urobilinogen, blood, 
leukocyte esterase (with microscopic examination of urine sediment if abnormal), 
specific gravity
-
Serum pregnancy test (females of child-bearing potential only see Section 5.2) 
-
Total IgG trough level determination: participants are required to have a documented 
total IgG level of ≥500 mg/dL to enroll
-
D-dimer (collected only once during this visit, before their standard of care infusion)
-
Virus safety retains
•
Wells Scoring
•
Evaluation of clinical signs and symptoms of thromboembolic (TE) events (e.g., pain, 
dyspnea, discoloration [paleness or redness] in lower extremities) after the completion of 
the infusion (Appendix 3)
•
Record AEs (including infusion reactions and prophylactic treatment, if applicable) and 
history of SBIs up to 1 year
Subjects who are eligible for the clinical trial will enter into the Gamunex-C Run-in Phase or 
directly into the Gamunex-C PK Phase with the next visit scheduled to coincide with the date 
for their next IV infusion.
7.2.1.2
Gamunex-C Phase
The duration of the Gamunex-C Phase is approximately 6 months including a Run-in Phase 
of up to 4.5 months depending on the subject’s dosing frequency (every 3 or every 4 weeks) 
and a Gamunex-C PK Phase of up to 4 weeks (those subjects already receiving stable doses 
of Gamunex-C can enter directly the Gamunex-C PK Phase and skip the Run-in Phase). 
50 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence Study to Evaluate
the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to Gamunex-C in Subjects with Primary
Effective

7.2.1.2.1
RUN-IN PHASE –RUN-IN #1, RUN-IN #3, AND RUN-IN #5/#6 VISITS
The following procedures and tests will be completed at the Run-in #1, Run-in #3, and Run-
in #5/#6 visits (for the every 4 weeks and every 3 weeks dosing regimens, respectively) 
during the Run-in Phase for those subjects who are required to enter the Run-in Phase (see 
Section 4.2.2.1). 
•
Pre-dose abbreviated physical examination
•
Pre-dose vital signs (pre-infusion: SBP and DBP, HR, T, RR) measured within 30 ± 10 
minutes before the beginning of each infusion
•
Pre-dose body weight
•
Pre-dose blood and urine samples for: (see Table 7-1). 
-
Hematology: Hb, Hct, platelets, RBC count including morphology, WBC count with 
differential; ARC 
-
Clinical chemistry: sodium, potassium, creatinine, chloride, calcium, BUN, 
bicarbonate, albumin, LDH, AST, ALT, GGT, ALP, glucose, TBL, indirect and direct 
bilirubin
-
Urinalysis: pH, protein, glucose, ketones, bilirubin, nitrites, urobilinogen, blood, 
leukocyte esterase (with microscopic examination of urine sediment if abnormal), 
specific gravity
-
Urine pregnancy test (Run-in #1 Visit only and for females of child-bearing potential 
only see Section 5.2) 
-
Hemolysis detection: plasma free Hb, haptoglobin, DAT, blood smear, urine 
sediment, measuring of hemoglobinuria, and hematuria
-
Pre-dose blood draw for trough total IgG prior to IV infusion (within 1 hour prior to 
the start of infusion)
-
Pre-dose blood draw for IgG subclass levels and antibody titer
-
Pre-dose virus safety retains
•
D-dimer (within 8 hours prior to the infusion and 30 ±10 minutes after the completion of 
the infusion)
•
IV Gamunex-C infusion 
•
Post-dose vital signs (SBP, DBP, HR, T, and RR) measured within 30 ± 10 minutes post-
completion of each infusion
•
Wells scoring (post-infusion)
•
Evaluation of clinical signs and symptoms of TE events (e.g., pain, dyspnea, 
discoloration [paleness or redness] in lower extremities) after the completion of the 
infusion 
(Appendix 3)
•
Evaluation of the signs and symptoms of hemolysis including red/dark urine, jaundice, as 
well as other signs and symptoms of anemia (such as pallor or tachycardia) during the 
51 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence Study to Evaluate
the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to Gamunex-C in Subjects with Primary
Effective

infusion visit (pre-infusion and post-infusion) and by a phone call at 10 days (±2 days) 
after each infusion (Appendix 4).
•
Record AEs including SBIs (subjects who develop two SBIs during the study will be 
discontinued and requested to complete a Final Visit either 21 or 28 days after the last 
infusion of IP [depending on the subject’s dosing schedule]). Note: Record any SBIs 
(defined in Appendix 2), hospitalizations due to infections, and non-serious infections (by 
category*) as detailed in Section 7.2.4. (*The site is to record non-serious infections [by 
category], which include infections of any kind including, for example, acute sinusitis, 
exacerbation of chronic sinusitis, acute otitis media, pneumonia, acute bronchitis, 
infectious diarrhea, etc., which will be recorded as an AE with the Investigator answering 
the following question affirmatively in the subject’s medical records and eCRF: “Is this 
an infection?” [verbatim term delineating nature of infection]. Also record validated 
infections documented by positive radiograph, fever [>38°C oral or >39°C rectal], 
culture, or diagnostic testing for microorganisms, e.g., bacterial, viral, fungal, or 
protozoal pathogens [for instance, rapid streptococcal antigen test]. The specific 
evaluations performed to validate infections must be recorded in the medical records and 
the eCRF.)
-
Note: If a subject develops an SBI, a serum IgG level should be obtained.
•
Record concomitant medications
•
Record days lost from work/school/daily activities due to infections and treatment
Gamunex-C Run-in #1, Run-in #3, and Run-in #5/#6 visits may be performed at the study 
site or, if deemed appropriate, at an alternate site (e.g., subject's residence, local healthcare 
professional's site) under the care and supervision of trained healthcare personnel. 
7.2.1.2.2
RUN-IN PHASE –RUN-IN #2, RUN-IN #4, AND RUN-IN #5 VISITS
The following procedures and tests will be completed at the Run-in #2 and #4 visits for all 
subjects in the Run-in Phase, and at the Run-in #5 visit for subjects on the 3 weeks dosing 
regimen only (see Section 4.2.2.1). 
•
Pre-dose abbreviated physical examination
•
Pre-dose vital signs (pre-infusion: SBP and DBP, HR, T, RR) measured within 30 ± 10 
minutes before the beginning of each infusion
•
Pre-dose body weight
•
Hemolysis detection (pre-infusion)
-
Blood: whole blood Hb, RBC, hematocrit, plasma free Hb, haptoglobin, LDH, DAT, 
ARC, TBL, indirect and direct bilirubin, and blood smear
-
Urine: urine sediment, measuring of hemoglobinuria, and hematuria
•
Pre-dose blood draw for trough total IgG prior to IV infusion (within 1 hour prior to the 
start of infusion)
52 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence Study to Evaluate
the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to Gamunex-C in Subjects with Primary
Effective

•
D-dimer (within 8 hours prior to the infusion and 30 ±10 minutes after the completion of 
the infusion)
•
IV Gamunex-C infusion
•
Post-dose vital signs (SBP, DBP, HR, T, and RR) measured within 30 ± 10 minutes post-
completion of each infusion
•
Wells scoring (post-infusion)
•
Evaluation of clinical signs and symptoms of TE events (e.g., pain, dyspnea, 
discoloration [paleness or redness] in lower extremities) after the completion of the 
infusion
(Appendix 3)
•
Evaluation of the signs and symptoms of hemolysis including red/dark urine, jaundice, as 
well as other signs and symptoms of anemia (such as pallor or tachycardia) during the 
infusion visit (pre-infusion and post-infusion) and by a phone call at 10 days (±2 days) 
after each infusion (Appendix 4)
•
Record AEs including SBIs (subjects who develop two SBIs during the study will be 
discontinued and requested to complete a Final Visit either 21 or 28 days after the last 
infusion of IP [depending on the subject’s dosing schedule]). Note: Record any SBIs 
(defined in Appendix 2), hospitalizations due to infections, and non-serious infections (by 
category*) as detailed in Section 7.2.4. (*The site is to record non-serious infections [by 
category], which include infections of any kind including, for example, acute sinusitis, 
exacerbation of chronic sinusitis, acute otitis media, pneumonia, acute bronchitis, 
infectious diarrhea, etc., which will be recorded as an AE with the Investigator answering 
the following question affirmatively in the subject’s medical records and eCRF: “Is this 
an infection?” [verbatim term delineating nature of infection]. Also record validated 
infections documented by positive radiograph, fever [>38°C oral or >39°C rectal], 
culture, or diagnostic testing for microorganisms, e.g., bacterial, viral, fungal, or 
protozoal pathogens [for instance, rapid streptococcal antigen test]. The specific 
evaluations performed to validate infections must be recorded in the subject’s medical 
records and eCRF.)
-
Note:  If a subject develops an SBI, a serum IgG level should be obtained.
•
Record concomitant medications
•
Record days lost from work/school/daily activities due to infections and treatment
Gamunex-C Run-in #2, Run-in #4, and Run-in #5 visits may be performed at the study site 
or, if deemed appropriate, at an alternate site (e.g., subject's residence, local healthcare 
professional's site) under the care and supervision of trained healthcare personnel.  
7.2.1.2.3
GAMUNEX-C PK PHASE
The duration of the Gamunex-C PK Phase is up to 4 weeks (depending on the subject’s 
dosing frequency). For subjects receiving infusions every 3 weeks, the Gamunex-C PK #1 
infusion will correspond to the seventh infusion; for subjects receiving infusions every 4 
53 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence Study to Evaluate
the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to Gamunex-C in Subjects with Primary
Effective

weeks, the Gamunex-C PK #1 infusion will correspond to the sixth infusion. The following 
procedures and tests will be completed during the Gamunex-C PK Phase. 
•
Pre-dose abbreviated physical examination
•
Pre-dose vital signs (pre-infusion: SBP and DBP, HR, T, RR) measured within 30 ± 10 
minutes before the beginning of each infusion 
•
Pre-dose body weight
•
Hemolysis detection (pre-infusion)
-
Blood: whole blood Hb, RBC, hematocrit, plasma free Hb, haptoglobin, LDH, DAT, 
ARC, TBL, indirect and direct bilirubin, and blood smear
-
Urine: urine sediment, measuring of hemoglobinuria, and hematuria
•
Pre-dose blood draw for trough total IgG prior to IV infusion (within 30 min prior to the 
start of infusion)
•
Pre-dose blood draw for IgG subclass levels and antibody titer
•
Urine pregnancy test (only for females of child-bearing potential skipping the Run-in 
Phase who enter directly into the Gamunex-C PK Phase [see Section 4.2.1]) 
•
Pre-dose virus safety retain samples (only for subjects skipping the Run-in Phase who 
enter directly into the Gamunex-C PK Phase [see Section 4.2.1]).
•
D-dimer (within 8 hours prior to the infusion and 30 ±10 minutes after the completion of 
the infusion)
•
IV Gamunex-C infusion
•
Post-dose vital signs (SBP, DBP, HR, T, and RR) measured within 30 ± 10 minutes post-
completion of each infusion
•
Wells scoring (post-infusion)

Evaluation of clinical signs and symptoms of TE events (e.g., pain, dyspnea, 
discoloration [paleness or redness] in lower extremities) after the completion of the 
infusion
(Appendix 3)

Evaluation of the signs and symptoms of hemolysis including red/dark urine, jaundice, as 
well as other signs and symptoms of anemia (such as pallor or tachycardia) during the 
infusion visit (pre-infusion and post-infusion) and by a phone call at 10 days (±2 days) 
after each infusion (Appendix 4)

Serial PK blood sample collection immediately upon the completion of the last 
Gamunex-C infusion (within 10 minutes of infusion completion), and at 1, 3, and 6 hours 
(±10 minutes), 24 and 48 hours (±2 hours), and 4 (±2 hours), 7 (±1 d), 14 (±1 d), 21 
(±2 d), and 28 (±2 d) days (the 28 day sample applies only for subjects on every 4 weeks 
dose regimen) after the end of the Gamunex-C infusion.

Record concomitant medications
54 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence Study to Evaluate
the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to Gamunex-C in Subjects with Primary
Effective


Record AEs including SBIs (subjects who develop two SBIs during the study will be 
discontinued and requested to complete a Final Visit either 21 or 28 days after the last 
infusion of IP [depending on the subject’s dosing schedule]). Note: Record any SBIs 
(defined in Appendix 2), hospitalizations due to infections, and non-serious infections (by 
category*) as detailed in Section 7.2.4. (*The site is to record non-serious infections [by 
category], which include infections of any kind including, for example, acute sinusitis, 
exacerbation of chronic sinusitis, acute otitis media, pneumonia, acute bronchitis, 
infectious diarrhea, etc., which will be recorded as an AE with the Investigator answering 
the following question affirmatively in the subject’s medical records and eCRF: “Is this 
an infection?” [verbatim term delineating nature of infection]. Also record validated 
infections documented by positive radiograph, fever [>38°C oral or >39°C rectal], 
culture, or diagnostic testing for microorganisms, e.g., bacterial, viral, fungal, or 
protozoal pathogens [for instance, rapid streptococcal antigen test]. The specific 
evaluations performed to validate infections must be recorded in the subject’s medical 
records and eCRF.)
-
Note:  If a subject develops an SBI, a serum IgG level should be obtained.
Gamunex-C PK Visits may be performed at the study site or, if deemed appropriate, at 
alternate site (e.g., subject's residence, local healthcare professional's site) under the care and
supervision of trained healthcare personnel.
7.2.1.3
IVIG-PEG Phase 
The duration of the IVIG-PEG Phase is up to 6 months, including an IVIG-PEG Treatment 
Phase of up to 4.5 months depending on the subject’s dosing frequency (every 3 or every 4 
weeks) and an IVIG-PEG PK Phase of up to 4 weeks.
7.2.1.3.1
IVIG-PEG TREATMENT PHASE – IVIG-PEG #1, IVIG-PEG #3, AND IVIG-PEG
#5/#6 VISITS
The following procedures and tests will be completed at IVIG-PEG #1, IVIG-PEG #3, and 
IVIG-PEG #5/#6 (for every 4 weeks and every 3 weeks dosing regimens, respectively) Visits 
during the IVIG-PEG Treatment Phase.
•
Pre-dose abbreviated physical examination
•
Pre-dose vital signs (pre-infusion: SBP and DBP, HR, T, RR) measured within 30 ± 10 
minutes before the beginning of each infusion 
•
Pre-dose body weight
•
Pre-dose blood and urine samples for: (see Table 7-1). 
-
Hematology: Hb, Hct, platelets, RBC count including morphology, WBC count with 
differential; ARC 
-
Clinical chemistry: sodium, potassium, creatinine, chloride, calcium, BUN, 
bicarbonate, albumin, LDH, AST, ALT, GGT, ALP, glucose, TBL, indirect and direct 
bilirubin
55 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence Study to Evaluate
the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to Gamunex-C in Subjects with Primary
Effective

-
Hemolysis detection: plasma free Hb, haptoglobin, DAT, blood smear, urine 
sediment, measuring of hemoglobinuria, and hematuria
-
Urinalysis: pH, protein, glucose, ketones, bilirubin, nitrites, urobilinogen, blood, 
leukocyte esterase (with microscopic examination of urine sediment if abnormal), 
specific gravity
-
Urine pregnancy test (for females of child-bearing potential only see Section 5.2) 
-
Pre-dose blood draw for trough total IgG prior to IV infusion (within 1 hour prior to 
the start of infusion).
-
Pre-dose blood draw for IgG subclass levels and antibody titer
-
Pre-dose virus safety retains
•
D-dimer (within 8 hours prior to the infusion and 30 ±10 minutes after the completion of 
the infusion)
•
IVIG-PEG infusion
•
Post-dose vital signs (SBP, DBP, HR, T, and RR) measured within 30 ± 10 minutes post-
completion of each infusion
•
Wells scoring (post-infusion)
•
Evaluation of clinical signs and symptoms of TE events (e.g., pain, dyspnea, 
discoloration [paleness or redness] in lower extremities) after the completion of the 
infusion
(Appendix 3)
•
Evaluation of the signs and symptoms of hemolysis including red/dark urine, jaundice, as 
well as other signs and symptoms of anemia (such as pallor or tachycardia) during the 
infusion visit (pre-infusion and post-infusion) and by a phone call at 10 days (±2 days) 
after each infusion (Appendix 4)
•
Record AEs including SBIs (subjects who develop two SBIs during the study will be 
discontinued and requested to complete a Final Visit either 21 or 28 days after the last 
infusion of IP [depending on the subject’s dosing schedule]). Note: Record any SBIs 
(defined in Appendix 2), hospitalizations due to infections, and non-serious infections (by 
category*) as detailed in Section 7.2.4. (*The site is to record non-serious infections [by 
category], which include infections of any kind including, for example, acute sinusitis, 
exacerbation of chronic sinusitis, acute otitis media, pneumonia, acute bronchitis, 
infectious diarrhea, etc., which will be recorded as an AE with the Investigator answering 
the following question affirmatively in the subject’s medical records and eCRF: “Is this 
an infection?” [verbatim term delineating nature of infection]. Also record validated 
infections documented by positive radiograph, fever [>38°C oral or >39°C rectal], 
culture, or diagnostic testing for microorganisms, e.g., bacterial, viral, fungal, or 
protozoal pathogens [for instance, rapid streptococcal antigen test]. The specific 
evaluations performed to validate infections must be recorded in the subject’s medical 
records and eCRF.)
-
Note:  If a subject develops an SBI, a serum IgG level should be obtained.
•
Record concomitant medications
56 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence Study to Evaluate
the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to Gamunex-C in Subjects with Primary
Effective

•
Record days lost from work/school/daily activities due to infections and treatment
IVIG-PEG #3 and IVIG-PEG #5/#6 visits may be performed at the study site or, if deemed 
appropriate, at an alternate site (e.g., subject's residence, local healthcare professional's site) 
under the care and supervision of trained healthcare personnel. The IVIG-PEG #1 treatment 
visit is to be performed at the study site. If there are extenuating circumstances that prevent 
the subject from returning to the study site for these visits, the PI or designee is to discuss the 
situation with the sponsor. Sponsor approval may be granted to conduct the visit(s) at an 
alternate location under the care and supervision of trained healthcare personnel.
7.2.1.3.2
IVIG-PEG TREATMENT PHASE – IVIG-PEG #2, IVIG-PEG #4, AND IVIG-PEG
#5 VISITS 
The following procedures and tests will be completed at the IVIG-PEG #2 and #4 visits for 
all subjects, and at the IVIG-PEG #5 visit for subjects on the 3 weeks dosing regimen only, 
during the IVIG-PEG Treatment Phase:
•
Pre-dose abbreviated physical examination
•
Pre-dose vital signs (pre-infusion: SBP and DBP, HR, T, RR) measured within 30 ± 10 
minutes before the beginning of each infusion
•
Pre-dose body weight
•
Hemolysis detection (pre-infusion)
-
Blood: whole blood Hb, RBC, hematocrit, plasma free Hb, haptoglobin, LDH, DAT, 
ARC, TBL, indirect and direct bilirubin, and blood smear
-
Urine: urine sediment, measuring of hemoglobinuria, and hematuria
•
Pre-dose blood draw for trough total IgG prior to IV infusion (within 1 hour prior to the 
start of infusion).
•
D-dimer (within 8 hours prior to the infusion and 30 ±10 minutes after the completion of 
the infusion)
•
Pre-dose urine pregnancy test (for females of child-bearing potential only see 
Section 5.2) 
•
IVIG-PEG infusion
•
Post-dose vital signs (SBP, DBP, HR, T, and RR) measured within 30 ± 10 minutes post-
completion of each infusion
•
Wells scoring (post-infusion)
•
Evaluation of clinical signs and symptoms of TE events (e.g., pain, dyspnea, 
discoloration [paleness or redness] in lower extremities) after the completion of the 
infusion
(Appendix 3)
57 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence Study to Evaluate
the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to Gamunex-C in Subjects with Primary
Effective

•
Evaluation of the signs and symptoms of hemolysis including red/dark urine, jaundice, as 
well as other signs and symptoms of anemia (such as pallor or tachycardia) during the 
infusion visit (pre-infusion and post-infusion) and by a phone call at 10 days (±2 days) 
after each infusion (Appendix 4)
•
Record AEs including SBIs (subjects who develop two SBIs during the study will be 
discontinued and requested to complete a Final Visit either 21 or 28 days after the last 
infusion of IP [depending on the subject’s dosing schedule]). Note: Record any SBIs 
(defined in Appendix 2), hospitalizations due to infections, and non-serious infections (by 
category*) as detailed in Section 7.2.4. (*The site is to record non-serious infections [by 
category], which include infections of any kind including, for example, acute sinusitis, 
exacerbation of chronic sinusitis, acute otitis media, pneumonia, acute bronchitis, 
infectious diarrhea, etc., which will be recorded as an AE with the Investigator answering 
the following question affirmatively in the subject’s medical records and eCRF: “Is this 
an infection?” [verbatim term delineating nature of infection]. Also record validated 
infections documented by positive radiograph, fever [>38°C oral or >39°C rectal], 
culture, or diagnostic testing for microorganisms, e.g., bacterial, viral, fungal, or 
protozoal pathogens [for instance, rapid streptococcal antigen test]. The specific 
evaluations performed to validate infections must be recorded in the subject’s medical 
records and eCRF.)
-
Note:  If a subject develops an SBI, a serum IgG level should be obtained.
•
Record concomitant medications
•
Record days lost from work/school/daily activities due to infections and treatment
IVIG-PEG #4 and IVIG-PEG #5 visits (as applicable) may be performed at the study site or, 
if deemed appropriate, at an alternate site (e.g., subject's residence, local healthcare 
professional's site) under the care and supervision of trained healthcare personnel. The IVIG-
PEG #2 treatment visit is to be performed at the study site. If there are extenuating 
circumstances that prevent the subject from returning to the study site for these visits, the PI 
or designee is to discuss the situation with the sponsor. Sponsor approval may be granted to 
conduct the visit(s) at an alternate location under the care and supervision of trained 
healthcare personnel.
7.2.1.3.3
IVIG-PEG PK PHASE
The duration of the IVIG-PEG PK Phase is up to 4 weeks (depending on the subject’s dosing 
frequency). For subjects receiving infusions every 3 weeks, the IVIG-PEG PK #1 infusion 
will correspond to the seventh infusion; for subjects receiving infusions every 4 weeks, the 
IVIG-PEG PK #1 infusion will correspond to the sixth infusion. The following procedures 
and tests will be completed during the IVIG-PEG PK Phase. 

Pre-dose abbreviated physical examination

Pre-dose vital signs (pre-infusion: SBP and DBP, HR, T, RR) measured within 30 ± 10 
minutes before the beginning of each infusion
58 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence Study to Evaluate
the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to Gamunex-C in Subjects with Primary
Effective


Pre-dose body weight
•
Hemolysis detection (pre-infusion)
-
Blood: whole blood Hb, RBC, hematocrit, plasma free Hb, haptoglobin, LDH, DAT, 
ARC, TBL, indirect and direct bilirubin, and blood smear
-
Urine: urine sediment, measuring of hemoglobinuria, and hematuria

Pre-dose blood draw for trough total IgG prior to IV infusion (within 30 min prior to the 
start of infusion)

Pre-dose blood draw for IgG subclass levels and antibody titer

D-dimer (within 8 hours prior to the infusion and 30 ±10 minutes after the completion of 
the infusion)

Pre-dose urine pregnancy test (for females of child-bearing potential only see 
Section 5.2) 

IVIG-PEG infusion

Post-dose vital signs (SBP, DBP, HR, T, and RR) measured within 30 ± 10 minutes post-
completion of each infusion

Wells scoring (post-infusion)

Evaluation of clinical signs and symptoms of TE events (e.g., pain, dyspnea, 
discoloration [paleness or redness] in lower extremities) after the completion of the 
infusion
(Appendix 3)

Evaluation of the signs and symptoms of hemolysis including red/dark urine, jaundice, as 
well as other signs and symptoms of anemia (such as pallor or tachycardia) during the 
infusion visit (pre-infusion and post-infusion) and by a phone call at 10 days (±2 days) 
after each infusion (Appendix 4)

Serial PK blood sample immediately upon the completion of the last IVIG-PEG infusion 
(within 10 minutes of infusion completion), and at 1, 3, and 6 hours (±10 minutes), 24 
and 48 hours (±2 hours), and 4 (±2 hours), 7 (±1 d), 14 (±1 d), 21 (±2 d), and 28 (±2 d) 
days (the 28 day sample applies only for subjects on every 4 weeks dose regimen) after 
the end of the infusion.

Record concomitant medications

Record AEs including SBIs (subjects who develop two SBIs during the study will be 
discontinued and requested to complete a Final Visit either 21 or 28 days after the last 
infusion of IP [depending on the subject’s dosing schedule]). Note: Record any SBIs 
(defined in Appendix 2), hospitalizations due to infections, and non-serious infections (by 
category*) as detailed in Section 7.2.4. (*The site is to record non-serious infections [by 
category], which include infections of any kind including, for example, acute sinusitis, 
exacerbation of chronic sinusitis, acute otitis media, pneumonia, acute bronchitis, 
infectious diarrhea, etc., which will be recorded as an AE with the Investigator answering 
the following question affirmatively in the subject’s medical records and eCRF: “Is this 
an infection?” [verbatim term delineating nature of infection]. Also record validated 
infections documented by positive radiograph, fever [>38°C oral or >39°C rectal], 
culture, or diagnostic testing for microorganisms, e.g., bacterial, viral, fungal, or 
59 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence Study to Evaluate
the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to Gamunex-C in Subjects with Primary
Effective

protozoal pathogens [for instance, rapid streptococcal antigen test]. The specific 
evaluations performed to validate infections must be recorded in the subject’s medical 
records and eCRF.)
-
Note:  If a subject develops an SBI, a serum IgG level should be obtained.
IVIG-PEG PK Visits may be performed at the study site or, if deemed appropriate, at 
alternate site (e.g., subject's residence, local healthcare professional's site) under the care and
supervision of trained healthcare personnel.
7.2.1.4
Final Visit/Early Termination Visit
The Final Visit will be scheduled either 21 or 28 days after the last infusion of IP (depending 
on the subject’s dosing schedule). If a subject discontinues at any point during the study after 
the first visit, the subject will be requested to return to the study site for an Early Termination 
Visit. The assessments at this visit will be the same as the Final Visit, with the exception of 
an added PK sample for subjects who prematurely discontinue the study during the PK 
curves sampling periods (i.e., Gamunex-C PK Phase and IVIG-PEG PK Phase) and a sample 
for total IgG concentration for safety purposes for subjects prematurely discontinuing the 
study at any point.
The following procedures and tests (see Appendix 1) will be completed at the Final 
Visit/Early Termination Visit (note that no study-related infusion will be scheduled):
•
Full physical exam (excluding breast and genitourinary exam)
•
Vital signs (SBP, DBP, HR, T, RR)
•
Blood and urine samples for clinical laboratory assessments (e.g., hematology, clinical 
chemistry, special tests, urinalysis, and pregnancy testing) (see Table 7-1). 
˗
Hematology: Hb, Hct, platelets, RBC count including morphology, WBC count with 
differential; ARC 
˗
Clinical chemistry: sodium, potassium, creatinine, chloride, calcium, BUN, 
bicarbonate, albumin, LDH, AST, ALT, GGT, ALP, glucose, TBL, indirect and direct 
bilirubin
˗
Urinalysis: pH, protein, glucose, ketones, bilirubin, nitrites, urobilinogen, blood, 
leukocyte esterase (with microscopic examination of urine sediment if abnormal), 
specific gravity
˗
Urine pregnancy test (for females of child-bearing potential only see Section 5.2) 
˗
Blood draw for total IgG concentration for safety purposes (only for subjects 
prematurely discontinuing the study)
˗
Pre-dose virus safety retain samples
•
Record concomitant medications
•
Record AEs including SBIs
60 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence Study to Evaluate
the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to Gamunex-C in Subjects with Primary
Effective

-
Record any SBIs (defined in Appendix 2), hospitalizations due to infections, and non-
serious infections (by category) as detailed in Section 7.2.4.
-
Note:  If a subject develops an SBI, a serum IgG level should be obtained.
•
Record days lost from work/school/daily activities due to infections and treatment
The Final Visit/Early Termination Visit may be performed at the study site or, if deemed 
appropriate, at an alternate site (e.g., subject's residence, local healthcare professional's site) 
under the care and supervision of trained healthcare personnel.  
7.2.2
Description of Laboratory Tests and Procedures
Detailed descriptions of laboratory test procedures are located in the study Laboratory 
Manual. Table 7-1 provides an example summary of the laboratory tests conducted for this 
study. Under extraordinary circumstances, some of the laboratory tests can be performed at 
the site’s local laboratory if testing is unable to be performed by the central laboratory.  
When feasible and time permits, the site should discuss the extraordinary circumstances in 
advance with the sponsor and/or Contract Research Organization (CRO).
Table 7-1 Name, Description, and Location of Laboratory Tests and 
Procedures
Test Panel
Description
Location
Hematologya
Hemoglobin, hematocrit, platelets, RBC count including RBC 
morphology, WBC count with differential; ARC
Central
Hemolysis detectiona,b
Blood: whole blood Hb, RBC, hematocrit, plasma free Hb, 
haptoglobin, LDH, DAT, ARC, TBL, indirect and direct 
bilirubin, and blood smear
Urine: urine sediment, measuring of hemoglobinuria, and 
hematuria
Central 
(central DAT 
if feasible)
Thromboembolic events 
riska,b
D-Dimer
Central
Chemistrya
Sodium, potassium, creatinine, chloride, calcium, BUN, 
bicarbonate, albumin, LDH, AST, ALT, ALP, GGT, glucose, 
TBL, indirect and direct bilirubin
Central
IgG levelsa 
Total IgG levels will consist of trough (pre-dose) measurements 
in all subjects, and for PK profiling of IVIG-PEG and a total IgG 
concentration for safety purposes for subjects prematurely 
discontinuing the study
Central
IgG subclass levels and 
antibody titersa
Measurement of IgG subclasses (IgG1, IgG2, IgG3, IgG4). 
Measurement of levels of selected specific antibodies against 
H. influenzae, anti-pneumococcal polysaccharide (S. 
pneumoniae), tetanus (C. tetani), and measles 
Specialty
Serum pregnancy testa
Quantitative serum β-HCG for females of child-bearing potential 
will be performed at Screening
Central
61 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence Study to Evaluate
the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to Gamunex-C in Subjects with Primary
Effective

Table 7-1 Name, Description, and Location of Laboratory Tests and 
Procedures
Test Panel
Description
Location
Urine pregnancy test
Qualitative urine pregnancy test for females of child-bearing 
potential will be performed prior to the first dose received for 
each IP as well as prior to each IVIG-PEG infusion, and at the 
Final Visit/Early Termination Visit
Local
Viral NAT testinga,c
Collect retain samples for hepatitis A virus (HAV) RNA, HBV 
DNA, HCV RNA, HIV RNA, and parvovirus B19 (B19V) DNA 
testing
Central
Viral serology testinga,c
Collect retain samples for hepatitis A antibody differential 
(IgM/IgG), hepatitis B core antibody differential (IgM/IgG), 
hepatitis C antibody, HIV-1/-2 + Group O antibody, and B19V 
antibody differential (IgM/IgG) testing
Central
Urinalysisa
Microscopic evaluation is done only with cause.
pH, protein, glucose, ketones, bilirubin, nitrites, urobilinogen, 
blood, leukocyte esterase (with microscopic examination of the 
urine if abnormal), specific gravity, and urine sediment
Central
a
Samples collected for laboratory analyses that are non-analyzable due to any factor (i.e., lost, quantity not 
sufficient, laboratory error) need to be recollected by contacting the subject and arranging for re-sampling.
b
Laboratory samples must be taken prior to administrating Gamunex-C or IVIG-PEG (within 8 hours prior 
to the infusion) and analyzed as described for monitoring TE and hemolytic AEs in Appendix 3 and 
Appendix 4 only.
c
Virus safety (NAT and serology) retain samples collected during the study will only be tested if subject 
exhibits clinical signs and symptoms consistent with HAV, HBV, HCV, HIV or B19V infection while 
participating in the study. Virus safety retain samples will be retained until all analyses in support of the 
study are complete.
7.2.3
Immunoglobulin G Assessments
All subjects will have trough (pre-dose) total IgG measurements performed at Screening and 
prior to every infusion to ensure that adequate IgG concentration levels are maintained (not 
less than 500 mg/dL) to avoid serious infections. Furthermore, if a subject develops an SBI, a 
serum IgG level should be obtained. Additionally, IgG subclass antibody levels (IgG1, IgG2, 
IgG3, and IgG4) will be measured prior to the Gamunex-C PK infusion, prior to Infusions 1, 
3, and 5 or 6 (for subjects on every 4- or 3-weeks dosing regimen, respectively) during the 
Gamunex-C Run-in Phase and IVIG-PEG Treatment Phase, and prior to the IVIG-PEG PK 
infusion.
Specific antibody levels to the following pathogens will also be measured prior to the 
Gamunex-C PK infusion, prior to Infusions 1, 3, and 5 or 6 (for subjects on every 4- or 3-
weeks dosing regimen, respectively) during the Gamunex-C Run-in Phase and IVIG-PEG 
Treatment Phase, and prior to the IVIG-PEG PK infusion: H. influenzae, anti-pneumococcal 
polysaccharide (S. pneumoniae), tetanus (C. tetani), and measles.
Samples will be retained until all analyses in support of the study specified in Section 7.2.1
are complete.
62 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence Study to Evaluate
the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to Gamunex-C in Subjects with Primary
Effective

Total IgG PK profiling will be performed as described in Section 7.2. Samples will be 
obtained within 30 minutes prior to the start of the last Gamunex-C and IVIG-PEG infusion 
and at the following post-infusion time points:
•
Immediately upon the completion of the infusion (within 10 minutes of infusion 
completion)
•
1 hour ±10 min after completion of infusion
•
3 hours ±10 min after completion of the infusion
•
6 hours ±10 min after the completion of the infusion
•
24 hours ±2 hours after the completion of the infusion
•
48 hours ±2 hours after the completion of the infusion
•
4 days ±2 hours after the completion of the infusion
•
7 days ±1 day after the completion of the infusion
•
14 days ±1 day after the completion of the infusion
•
21 days ±2 days after the completion of the infusion (last sample for subjects on a 3-week 
dosing schedule)
•
28 days ±2 days after the completion of the infusion (only for subjects on a 4-week 
dosing schedule)
7.2.4
Assessment and Recording of Infections
The site is to record non-serious infections (by category), which include infections of any 
kind including, for example, acute sinusitis, exacerbation of chronic sinusitis, acute otitis 
media, pneumonia, acute bronchitis, infectious diarrhea, etc., which will be recorded as an 
AE with the Investigator answering the following question affirmatively in the subject’s 
medical records and eCRF: “Is this an infection?” (verbatim term delineating nature of 
infection). Validated infections documented by positive radiograph, fever (>38°C oral or 
>39°C rectal), culture, or diagnostic testing for microorganisms, e.g., bacterial, viral, fungal, 
or protozoal pathogens (for instance, rapid streptococcal antigen test) will be recorded in the 
subject’s source documents and eCRF. The specific evaluations performed to validate 
infections must be recorded in the subject’s medical records and eCRF.
7.2.5
Virus Safety Testing
Virus safety (viral NAT and viral serology) retain samples will be collected prior to the first 
infusions of Gamunex-C, and IVIG-PEG and at the Final/Early Termination Visit and will 
only be tested if the subject exhibits clinical signs and symptoms consistent with hepatitis A 
virus (HAV), HBV, HCV, HIV, or parvovirus B19 (B19V) infection while participating in 
the study. Virus safety samples will be retained until all analyses in support of the study are 
complete. Additional blood samples for viral NAT and viral serology testing may be 
63 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence Study to Evaluate
the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to Gamunex-C in Subjects with Primary
Effective

collected and tested during the study only if the subject exhibits clinical signs and symptoms 
consistent with HAV, HBV, HCV, HIV, or B19V infection while participating in the study.
If samples collected for laboratory analyses are non-analyzable due to various factors (i.e., 
lost, quantity not sufficient/useful, laboratory error), they will be recollected by contacting 
the subject and arranging for resampling.
8
ASSESSMENT OF SAFETY
8.1
Safety Parameters
Safety of IVIG-PEG and Gamunex-C will be evaluated in this study.
The following safety variables will be assessed:
•
Adverse events, suspected ADRs (i.e., potentially related AEs), adverse reactions (ARs), 
SAEs, and discontinuations due to AEs and SAEs
•
Criteria for events of special interest (See Section 8.2.5)
•
Vital signs during clinic visits (SBP, DBP, HR, T, RR)
•
Physical assessments
•
Laboratory assessments including chemistry, hematology, special tests, and urinalysis. 
8.2
Methods and Timing for Assessing, Recording, and Analyzing 
Safety Parameters
See Section 7.2.1 and Appendix 1 for a full accounting of PK and safety assessments by 
study phase and visit.
8.2.1
Adverse Events 
Adverse events (including ARs) occurring at any time between signing of the subject’s ICF 
and the last day of the subject’s participation in the study will be reported and recorded in the 
subject’s source documentation and on the appropriate eCRF page. 
It is the Investigator’s responsibility to ensure that all AEs are appropriately recorded. 
Adverse events will be elicited by spontaneous reporting by the study individual or by a non-
leading inquiry or direct observation by the study staff.
8.2.2
Clinical Laboratory Evaluations
Clinical laboratory data for hematology, chemistry, and urinalysis will be collected as 
detailed in Appendix 1. All clinical laboratory data for hematology, chemistry, and urinalysis 
will be listed for each study subject. 
64 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence Study to Evaluate
the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to Gamunex-C in Subjects with Primary
Effective

The Investigator will be required to classify laboratory results out of the normal range 
reported by the laboratory as clinically significant or not according to his/her criteria. 
Laboratory results out of the normal range judged by the Investigator as clinically significant 
will be considered AEs.
8.2.3
Vital Signs
Vital signs will be measured by a medically certified individual or a nurse according to 
his/her standard clinical practice. The following vital signs will be assessed:

Temperature

Blood pressure (SBP and DBP)

Heart rate

Respiratory rate 
Vital signs will be routinely monitored by the study staff as detailed in Appendix 1. The 
Investigator will be required to classify vital signs abnormalities as clinically significant or 
not according to his/her criteria. Results will be recorded in source documents and on the
subject eCRF. Vital signs abnormalities judged by the Investigator as clinically significant 
will be considered AEs.
8.2.4
Physical Examinations
A medically certified individual will conduct either a full or abbreviated physical 
examination (excluding breast and genitourinary examination) as indicated in Appendix 1.
8.2.5
Monitoring of Events of Special interest
8.2.5.1
Monitoring of Thrombotic Events
Subjects will be monitored by the Investigator and/or study staff for signs and symptoms of 
arterial and venous TE events at Screening and occurring between the first infusion (either 
the first infusion of Gamunex-C during the Run-in Phase or the first infusion of IVIG-PEG 
during the IVIG-PEG Treatment Phase) and the Final Visit/Early Termination Visit. 
In addition, the Grifols Medical Monitor will routinely review reported AEs for possible TE 
events. Arterial and venous TE events will be identified according to definitions in the 
International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM). 
Such TE events include, but are not limited to, DVT, PE, acute myocardial infarction, 
cerebrovascular accident, acute coronary syndrome, limb thrombosis, sagittal sinus 
thrombosis, and portal vein or mesenteric artery thrombosis. All TE events will be recorded 
as AEs and reported accordingly.
At Screening and during all infusion visits, TE events risk will be assessed using: 
1. D-dimer blood levels (within 8 hours prior to the study IP infusion and 30 ±10 minutes 
after the completion of the infusion)
65 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence Study to Evaluate
the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to Gamunex-C in Subjects with Primary
Effective

Note: The sample for the D-dimer blood level is only collected before the subject’s 
standard-of-care infusion at the Screening Visit. 
2. The Wells prediction score for DVT and for PE (after the completion of the infusion)
3. Evaluation of clinical signs and symptoms of TE events (such as, dyspnea, pain, swelling, 
tenderness and discoloration [paleness or redness] in lower extremities) after the 
completion of the infusion
After getting results from (1) to (3) and prior to the next study infusion visit, a medical doctor 
will assess the risk of TE events considering algorithms provided in Appendix 3 from the 
first Gamunex-C to the last IVIG-PEG study infusions.
Active medical monitoring of thromboembolic AEs of special interest is described in a 
detailed manner in Appendix 3.
8.2.5.2
Monitoring of Hemolysis
Subjects will be monitored for signs and symptoms of hemolysis occurring between the first 
infusion (either the first infusion of Gamunex-C during the Run-in Phase or the first infusion 
of IVIG-PEG during the IVIG PEG Treatment Phase) and the Final Visit/Early Termination 
Visit. 
In addition, the Grifols Medical Monitor will routinely review reported AEs for possible 
hemolysis. Hemolysis will be recorded as an AE and reported accordingly.
During all infusion visits, hemolysis detection will be evaluated using: 
1. Blood assessments including whole blood hemoglobin, plasma free hemoglobin, 
haptoglobin, LDH, DAT, ARC, RBC, hematocrit, total and indirect and direct bilirubin, 
and blood smear within 8 hours prior to the infusion
2. Urinalysis including urinary sediment, hematuria, and hemoglobinuria within 8 hours 
prior to the infusion
3. Clinical parameters including red/dark urine, jaundice, as well as other signs and 
symptoms of anemia (such as pallor or tachycardia) will be evaluated at each infusion 
visit (pre-infusion and post infusion) and by a phone call at 10 days (±2 days) after each 
infusion
After getting results from (1) to (3) and prior to the next study infusion visit, a medical doctor 
will assess the hemolysis considering algorithm provided in Appendix 4from the first 
Gamunex-C to the last IVIG-PEG study infusions.
Active medical monitoring of hemolysis AEs of special interest is described in detail in 
Appendix 4.
66 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence Study to Evaluate
the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to Gamunex-C in Subjects with Primary
Effective

8.3
Procedures for Eliciting Reports of and for Recording and 
Reporting Adverse Event and Intercurrent Illnesses
8.3.1
Warnings/Precautions
For complete information on IVIG-PEG refer to the IB.
8.3.2
Adverse Event Monitoring
Subjects must be carefully monitored for AEs. This monitoring includes clinical and 
laboratory tests and physical signs and symptoms. Adverse events should be assessed in 
terms of their seriousness, severity, and causal relationship to the IP. 
Adverse events will be elicited by spontaneous reporting by the study individual or by a non-
leading inquiry or direct observation by the study staff. 
8.3.3
Adverse Event Definitions
8.3.3.1
Adverse Events 
An AE is defined as any untoward medical occurrence in a subject or clinical investigation 
subject administered a medicinal product or study treatment and which does not necessarily 
have a causal relationship with this administration. An AE can therefore be any unfavorable 
and unintended sign (including any abnormal laboratory finding, for example), symptom, or 
disease temporally associated with the use of a medicinal product, whether or not considered 
related to the medicinal product.
Infusional AEs (i.e., AEs temporally associated with an infusion of IP) will be defined and 
reported. Any AE occurred during infusion or within 72 hours after completion of infusion 
will be considered temporally associated with the infusion and labelled as infusional AEs.
8.3.3.2
Suspected Adverse Drug Reactions/Adverse Reactions
All noxious and unintended responses to a medicinal product or study treatment related to 
any dose should be considered suspected ADRs (i.e., potentially related AE). The phrase 
“responses to a medicinal product” means that a causal relationship between a medicinal 
product or study treatment and an AE is at least a reasonable possibility. 
8.3.4
Assessment of Causality of Adverse Event
The Investigator is required to provide a causality assessment for each AE reported to the 
Sponsor. The Sponsor will consider the Investigator’s causality assessment and also provide 
its own assessment. 
Causal relationship to the IPs will be established according to medical judgment on whether 
there is a reasonable possibility of a causal relationship between the AE and IP 
administration.
67 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence Study to Evaluate
the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to Gamunex-C in Subjects with Primary
Effective

The Investigator must determine and classify the AE causality according to the following 
categories:
Unrelated/Not related: there is not a reasonable possibility of causal relationship between 
the AE and the IP.
Possibly related: there is evidence to suggest a causal relationship between the IP and the 
AE.
Definitely related: there is a reason to conclude that the IP caused the AE.
Criteria to assess the causal relationship should take into account of the following conditions: 
1) a plausible temporal sequence from the IP administration to the AE onset; 2) whether the 
event follows a known response pattern to the suspected treatment; 3) whether the AE could 
be reasonably explained by the subject’s clinical state, comorbidities, or concomitant 
medications, as well as 4) the occurrence of improvement on stopping/reducing the treatment 
(positive dechallenge) and/or reappearance of the event on repeated exposure (positive 
rechallenge).
For expedited safety reporting purposes, AEs assessed as either “definitively related” or 
“possibly related” will be considered POTENTIALLY RELATED or just RELATED.
For any subject, all AEs that occur at any time from the beginning of IP administration until 
the final visit of the study will be considered treatment-emergent AEs (TEAEs).
8.3.5
Severity of Adverse Event or Suspected Adverse Drug Reaction
Adverse events and suspected ADRs (i.e., potentially related AEs) will be classified 
depending on their severity according to the following definitions:
Mild: an AE which is well tolerated by the subject, causing minimum degree of malaise and 
without affecting normal activities.
Moderate: an AE that interferes with the subject’s normal activities.
Severe: an AE that prevents the subject from performing their normal activities.
Adverse event and suspected ADR (i.e., potentially related AE) severity gradation must be 
distinguished from AE and suspected ADR seriousness gradation, which is defined according 
to event consequence. For example, headache can be mild, moderate or severe but not 
necessarily serious in all these cases.
The Investigator will be responsible for assessing the AE and suspected ADR intensity 
during the study, taking into account current criteria included in this section.
68 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence Study to Evaluate
the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to Gamunex-C in Subjects with Primary
Effective

8.3.6
Expectedness of Adverse Event or Suspected Adverse Drug Reaction
An AE or suspected ADR (i.e., potentially related AE) is considered “unexpected” if the 
nature, seriousness, severity or outcome of the reaction(s) is not consistent with the reference 
information. The expectedness shall be determined by the Sponsor according to the reference 
document for any serious ADRs (potentially related SAEs) for expedited safety reporting 
purposes. 
8.3.7
Seriousness of Adverse Event or Suspected Adverse Drug Reaction  
An AE or suspected ADR (i.e., potentially related AE) is considered “serious” if, in the view 
of either the Investigator or Sponsor, it results in any of the following outcomes: 
•
Death
•
Life-threatening AE (life-threatening in the definition of “serious” 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 
which hypothetically might have caused death if it were more severe)
•
In-patient hospitalization or prolongation of existing hospitalization
•
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
•
A congenital anomaly/birth defect
•
An important medical event (important medical event in the definition of “serious” refers 
to those events which may not be immediately life-threatening, or result in death, or 
hospitalization, but from medical and scientific judgment may jeopardize the subject 
or/and may require medical or surgical intervention to prevent one of the other outcomes 
listed above).
* Hospitalization is to be considered only hospital admission (including emergency room 
stay) for equal or more than 24 hours. The following hospitalizations should not be 
reported as SAEs:
-
Hospitalization or prolongation of hospitalization needed for procedures required by 
the study protocol, or as part of a routine procedure followed by the center.
-
Admissions not associated with an AE (e.g., social hospitalization for the purpose of 
respite care survey visits or annual physicals).
-
Elective or pre-planned hospitalizations for a pre-existing condition that had not 
worsened from Baseline (e.g., elective or scheduled surgery arranged prior to start of 
the study).
This definition permits either the Sponsor or the Investigator to decide whether an event is 
“serious”. If either the Sponsor or the Investigator believes that the event is serious, the event 
must be considered “serious” and evaluated by the Sponsor for expedited reporting. 
69 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence Study to Evaluate
the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to Gamunex-C in Subjects with Primary
Effective

8.3.8
Adverse Event Documentation
All AEs and SAEs occurring after the subject has signed the ICF through the Final Visit 
(i.e., end of study) must be fully recorded in the subject’s source documentation and eCRF, 
and in the SAE form (if serious) as well as in the medical record. If no AE has occurred 
during the study phase, this should also be indicated in the eCRF.
It is the responsibility of the Investigator to ensure that AEs are appropriately recorded.
At each visit, AEs will be elicited by asking the individual a non-leading question such as 
“Do you feel different in any way since the last visit?” Moreover, AEs will also be collected 
through directly observed events or spontaneously volunteered by the subject. Clearly related 
signs, symptoms and abnormal diagnostic procedures should preferably be grouped together 
and recorded as a single diagnosis or syndrome wherever possible.
The following variables must be recorded in the AE CRF/eCRF and the subject’s source 
documents:
•
The verbatim term (a diagnosis is preferred)
•
Date/time of onset
•
Date/time of resolution
•
Severity (mild, moderate, severe)
•
Causality (unrelated, possibly related, definitely related)*
•
Seriousness (yes, no)
•
Action taken (with regard to IP)
•
Other action (to treat the event)
•
Outcome and sequelae (follow-up on AE)
*Causality assessment will be made only when the AE occurs after the subject has initiated at 
least one infusion of the IP. An AE occurring before subject's exposure to IP will be always 
labeled as "unrelated".
For AEs that occur during infusions, the infusion rate in effect at the time of onset of the AE 
(if applicable), the time of onset of the AE and the time of AE change materially in intensity 
and/or resolve will be captured in the eCRF and the subject’s source document. 
In addition to the Investigator’s own description of the AEs, each AE will be encoded 
according to the Medical Dictionary for Regulatory Activities (MedDRA).
For example, a laboratory test abnormality considered clinically significant, e.g., causing the 
subject to withdraw from the study, requiring treatment or causing apparent clinical 
manifestations, or judged clinically significant in the context of the subject’s medical history 
by the Investigator, should be reported as an AE. Each event must be described in detail 
70 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence Study to Evaluate
the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to Gamunex-C in Subjects with Primary
Effective

along with start and stop dates, severity, relationship to IP, action taken and outcome. Each 
event must be adequately supported by documentation as it appears in the subject’s medical 
or case file.
8.3.9
Reporting of Serious Adverse Events 
8.3.9.1
Reporting of Serious Adverse Events
Any SAE (see Section 8.3.7) that occurs after signing the study ICF through the Final 
Visit (i.e., end of study) must be expeditiously reported whether or not considered 
attributable to the IP. Each SAE must be fully recorded in the subject’s medical records and 
the CRF/eCRF and SAE Report Form. 
In addition, any SAE that occurs in a subject after their last study visit should be reported 
only to Grifols Global Pharmacovigilance if the Investigator becomes aware of the event and 
feels that it is related to the use of IP.
SAEs will be reported using the designated paper SAE Report Form. When the Investigator 
becomes aware of an SAE, she/he must submit a completed, signed and dated SAE Report 
Form (in English) within 24 hours to the Sponsor by email/fax. The date of this SAE 
discovery by the site staff should be documented in the source documents (i.e., medical 
records).
Each SAE reported must be followed up until resolution or stabilization. After the initial 
report, all relevant information for SAE follow-up, and for the outcome, must also be 
supplied to the Sponsor in a timely manner (within 3 days from its identification or within 24
hours for relevant new information) by means of the SAE Report Form. In addition, the 
Sponsor or CRO may request additional information and/or reports.
All SAE Report Forms must be reported to Grifols by email to:
Grifols Global Pharmacovigilance
Email: 
FAX (back-up only): 
(US/Canada)
(International)
When required, and according to local law and regulations, SAEs must be reported to the 
IRB/EC and regulatory authorities.
8.3.9.2
Reporting Pregnancy
While pregnancy itself is not a true “AE,” pregnancy occurring in a clinical study must be 
followed, to collect information regarding the experiences of gestation and pregnancy with IP 
71 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence Study to Evaluate
the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to Gamunex-C in Subjects with Primary
Effective

exposure. The Investigator must report any pregnancy that occurs in a study subject 
subsequent to informed consent until 28 days after the last dose of IP. 
A pregnancy will not be considered an AE, unless a relation to the IP is suspected. In any 
case, a Pregnancy Report Form must be completed and sent as soon as possible to the 
Sponsor. A copy of the form should be filed at the study site for follow-up until the end of 
the pregnancy. Any pregnancy must be followed by the Investigator until delivery or to the 
end of pregnancy. Any anomalies, complications, abnormal outcomes, or birth defect 
observed in the child must be reported as an SAE within 24 hours of the Investigator or study 
personnel’s first knowledge. 
Please use the email address or fax numbers (back up only) in Section 8.3.9.1 for reporting 
pregnancy.
Pregnancy exposures that result in AEs/SAEs should be followed by the Investigator until 
delivery or to the end of pregnancy.
8.4
Type and Duration of the Follow-Up of Subjects after Adverse 
Events 
Insofar as is possible, all individuals will be followed up until the AE or suspected ADR (i.e., 
potentially related AE) has been resolved. If an AE/suspected ADR/SAE is present when the 
subject has completed the study, the course of the event must be followed until the final 
outcome is known, or the event has been stabilized and no further change is expected, and the 
Investigator decides that no further follow-up is necessary.
Any SAE that occurs after the end of the study or after study completion due to early 
termination will not be actively collected. However, if such cases are reported by the 
Investigator as related to the study treatment, they will be considered for expedited reporting 
purposes.
9
STATISTICS
9.1
Statistical Methods 
Unless otherwise specified, descriptive statistics will include the number of non-missing 
observations, mean, standard deviation (SD), median, minimum, and maximum values for 
the continuous/quantitative data or absolute and relative frequency counts and percentages
for categorical/qualitative data.
Data handling and evaluation procedures will be described in the Statistical Analysis Plan 
(SAP).
9.1.1
Demographic and Baseline Characteristics
Demographic and baseline characteristics will be summarized. For quantitative variables, 
mean, SD, median, and minimum/maximum will be provided. For qualitative variables, the 
frequency and percentage will be provided.
72 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence Study to Evaluate
the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to Gamunex-C in Subjects with Primary
Effective

9.1.2
Pharmacokinetic Analysis 
Total IgG concentrations will be summarized for IVIG-PEG and Gamunex-C by each time 
point. Individual and mean total IgG concentrations versus time curves will be plotted. 
Pharmacokinetic parameters of total IgG will be determined by noncompartmental PK 
methods using WinNonlin. Steady-state PK parameters to be calculated, as appropriate, or as 
permitted by data, will include AUC, Cmax, tmax, Cl, and Vd. All PK parameters will be 
calculated separately for IVIG-PEG and Gamunex-C administration and will be tabulated 
and summarized descriptively. The mean and the lower and upper bounds of the 90% CI will 
be calculated on natural log-transformed AUC parameters. These mean and lower and upper 
bounds will be back-transformed (exponentiated) to provide the geometric mean and 90% CI 
on the original scale.
Pharmacokinetic analyses will be performed on the PK population. The Primary PK 
endpoints are the steady-state AUC over a dosing interval defined as AUC0-τ (i.e., the AUC 
over a regular dosing interval (τ) at an approximate steady-state condition, either every 3 
weeks or every 4 weeks, i.e., AUC0-21 days or AUC0-28 days, respectively) and Cmax. The 
hypothesis to be tested is that the IV dose of IVIG-PEG will achieve an approximate steady-
state AUC0-τ and Cmax of total IgG that is bioequivalent to that achieved by the IV dose of 
Gamunex-C. Bioequivalence of steady-state IgG AUC and Cmax between IVIG-PEG and 
Gamunex-C will be tested based on established regulatory guidelines for bioequivalence 
testing. Analysis of covariance (ANCOVA) with a mixed-effect model will be used with 
study PK phase as a fixed effect, the exact administered dose and dose frequency during the 
PK phase as covariates, and subject as a random effect. The 90% CI of the geometric least-
squares mean (LSM) AUC and Cmax ratio of IVIG-PEG to Gamunex-C will be calculated. 
IVIG-PEG is considered to be bioequivalent to Gamunex-C if the 90% CI for the geometric 
LSM AUC and Cmax ratio of IVIG-PEG to Gamunex-C is within (0.80, 1.25) based on log-
transformed data.
Other PK parameters will be listed and summarized for IVIG-PEG and Gamunex-C using 
arithmetic as well as geometric means and SD, percentage coefficient of variation (CV), 
median, and minimum/maximum, as appropriate.
Other PK parameters include steady-state mean trough concentration of total IgG, Tmax, Cl, 
and Vd. The steady-state mean trough concentrations of total IgG will be determined as the 
average value of trough concentration measurements obtained at the PK visit and at 21 or 28 
days after the PK infusion (depending on dosing interval). Descriptive statistics will be 
calculated for the steady-state mean trough concentration of total IgG and for the Tmax, Cl, 
and Vd.
Depending on the number of subjects being dosed at 3- or 4-week dosing intervals, subgroup 
analyses may be performed to evaluate PK variables by IV dosing interval. Subgroup 
analyses will additionally include age, sex, race, and/or other factors as appropriate.
Furthermore, baseline corrected PK parameters (i.e., AUC and Cmax) will be calculated and 
analyzed as a sensitivity analysis similar to the primary PK endpoints.
73 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence Study to Evaluate
the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to Gamunex-C in Subjects with Primary
Effective

9.1.3
Secondary Efficacy and Exploratory Analyses
Summaries will be provided for trough concentration of total IgG and each of its subclasses 
for IVIG-PEG and Gamunex-C. Summaries of trough level concentration of antibody titers 
against H. influenzae, anti-pneumococcal polysaccharide (S. pneumoniae), and tetanus 
(C. tetani) will also be provided. Trough measles antibody titers (functional assay) will be 
summarized as an exploratory variable for informational purposes.
The number of SBIs and percentage of subjects with SBIs will be summarized for IVIG-PEG 
and Gamunex-C. The generalized linear model procedure for Poisson regression with log 
link will be used to estimate the SBI rate and its one-sided 99% upper confidence bound. 
Person-year will be calculated for each subject and will be used in the generalized linear 
model as offset variable. No covariates but the intercept term are included in the model. The 
estimated intercept term and the upper limit of its confidence interval (CI) will be 
transformed by using the natural exponential function.
The other variables of all infections, validated infusions, days missed of work/school/daily 
activities, days on antibiotics, and hospitalizations will be summarized descriptively for the 
number and percentage of subjects with the events, the total number of events or days, the 
annualized rate of events or days for individual subjects, and the rate of events or days per 
person per year for IVIG-PEG and Gamunex-C. Annualized rate of all infections, validated 
infusions, days missed of work/school/daily activities, days on antibiotics, and 
hospitalizations will be calculated.
9.1.4
Safety Analysis
The safety analyses will be addressed by listing and tabulation of AEs (including suspected 
ADRs [i.e., potentially related AEs]), vital signs, physical assessments and clinical laboratory 
tests. Data will be described using descriptive analyses. The safety analyses are based on the 
safety population.
9.1.4.1
Adverse Events
Adverse events will be coded and classified using MedDRA® terms (system organ class and 
preferred terms). 
Adverse events will be classified as treatment-emergent AEs (TEAEs) or non-treatment-
emergent AEs (non-TEAEs) depending on the comparison of AE onset date/time with the 
start date/time of study treatment with the IP. A TEAE will be defined as an AE which 
occurs between the beginning of the first infusion of IP and the final visit of the study. A 
non-TEAE will be defined as an AE which occurs prior to the start of study treatment. Non-
TEAEs and TEAEs will be summarized separately.
All AEs, suspected ADRs (i.e., potentially related AEs), ARs, SAEs, and discontinuations 
due to AEs and SAEs will be summarized by presenting subject incidences and percentages 
and will also be listed by system organ class and preferred terms.
74 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence Study to Evaluate
the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to Gamunex-C in Subjects with Primary
Effective

In addition, TEAEs, including suspected ADRs, will be summarized by each treatment, 
system organ class, preferred term, causal-relationship, intensity (severity) and seriousness 
(serious versus non-serious) using descriptive statistics. At each level of summarization, a 
subject will only be counted once per system organ class or preferred term using the most 
severe AE or the AE with the strongest causal relationship to the IP. 
Infusional AEs will be defined as any AE that occurred during infusion or within 24 and 72 
hours after completion of infusion. Infusional AEs within 24 and 72 hours after completion 
of the infusion will be separately summarized. Also, the infusional AE rate per infusion and 
the proportion of infusions with one or more infusional AEs will be summarized.
Subjects with deaths, SAEs, and AEs leading to premature discontinuation from the study 
will be listed and presented in a narrative form.
9.1.4.2
Clinical Laboratory Values
All clinical laboratory data collected will be listed for each subject. 
The Investigator will be required to classify out of the normal range laboratory results 
reported by the laboratory as clinically significant or not according to his/her criteria. 
Out of the normal range laboratory results judged by the Investigator as clinically significant 
in the context of the subject’s medical history will be considered AEs. 
For all laboratory tests, the original value and the change from Baseline will be summarized 
for numeric results and frequency/percentage will be summarized for qualitative results. For 
laboratory tests with normal ranges, out of normal range values will be flagged and shift 
tables will be provided.
9.1.4.3
Vital Signs
Vital signs (T, RR, HR, SBP and DBP) will be listed for each study subject. In case a subject 
presents a clinically significant abnormality of vital signs during an infusion, the event will 
be flagged and reported as an AE temporally associated to the infusion.
Clinical relevance will be based on the Investigator’s criteria. For each subject and for each 
infusion, every vital sign will be considered.
For all vital signs, the original value and the change from Baseline will be summarized for 
numeric results. 
9.1.4.4
Physical Assessment
Physical findings (normal and abnormal) will be listed for each study subject. Any clinically 
significant abnormality developed by an individual subject during the study and not already 
present at baseline will be reported as AE. 
75 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence Study to Evaluate
the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to Gamunex-C in Subjects with Primary
Effective

9.2
Determination of Sample Size
A total sample size of 20 subjects achieves at least 90% power at a 0.05 significance level for 
each one-sided test with the CV of 20% on the primary PK parameter assuming the true ratio 
of the test to reference is 1.0 and equivalent limits of (0.8, 1.25). An approximate 35 subjects 
are planned to be enrolled to have 20 evaluable subjects in the PK population for PK 
analysis.
9.3
Level of Significance to Be Used
The relative alpha level for statistical significance to be used is 0.1 (alpha=0.05 for one-sided 
test), or a 90% CI is to be used for the bioequivalence test.
9.4
Criteria for Termination of the Study 
The Sponsor, IRB/EC, and/or regulatory authorities have the right to close this study or a 
study center, and the Investigator/Sponsor has the right to close a study center, at any time, 
although this should occur only after consultation between involved parties. The IRB/EC 
must be informed. Should the study/study center be closed prematurely, all study materials 
(except documentation that has to remain stored at the site) must be returned to the Sponsor. 
The Investigator will retain all other documents until notification given by the Sponsor for 
destruction.
A study center can be closed for the following reasons:
•
Lack of enrollment
•
Non-compliance with the requirements of the study protocol
•
Non-compliance with ICH GCP
Additional details on study stopping rules can be found in Section 4.6.2.1.
9.5
Procedure for Accounting for Missing, Unused, and Spurious Data
Handling of missing, unused, and spurious data will be described in the SAP. All available 
PK and safety data will be included in data listings.
9.6
Reporting Deviation(s) from the Statistical Analysis Plan
The detailed statistical analysis methodologies will be documented in the SAP. If there are 
any deviations from the originally planned analyses in the SAP, they will be fully described 
and justified in the protocol amendment(s) and/or final Clinical Study Report.
76 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence Study to Evaluate
the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to Gamunex-C in Subjects with Primary
Effective

9.7
Subject Populations for Analysis
9.7.1
Safety Population
The safety population will include all subjects who received any amount of study drug 
(IVIG-PEG and/or Gamunex-C) and will be used for safety, secondary efficacy, and 
exploratory analyses.
9.7.2
Pharmacokinetic Population
The PK population will consist of all subjects who received study drug and have sufficient 
and valid total IgG concentration versus time data for either the IVIG-PEG PK Phase or 
Gamunex-C PK Phase to allow calculation of AUC0-τ (the primary PK endpoint).  
The validity of total IgG concentrations will be reviewed and determined before database 
lock based on consideration of treatment compliance and blood sampling/testing issues (such 
as collection problem). Any invalid total IgG concentrations will be flagged with the reason 
for invalidity in the subject listing.  
9.7.3
Immunoglobulin G Population
The IgG population will consist of all subjects who receive study drugs and have any total 
IgG concentration data. The summary of total IgG concentration data, mean trough, IgG 
subclasses, and antibody titers will be based on the IgG Population.
10 DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
The data will be recorded and kept current in the subject’s medical records and the eCRFs by 
the study site personnel directly responsible for the information and reviewed for 
completeness by the monitor. Grifols personnel or designee can review the records.
In accordance with ICH GCP guidelines, the monitor must have direct access to the 
Investigator’s source documentation in order to verify the data recorded in the CRF/eCRFs 
for consistency and to verify adherence to the protocol, and the completeness, consistency, 
and accuracy of data entered. “Source documentation” includes individual subject files, 
separate from the eCRFs, which should be maintained and include visit dates, laboratory 
results, concomitant treatment, vital signs, medical history, examinations, AEs, IP dispensing 
logs, and other notes as appropriate. The Investigator agrees to cooperate with the monitor to 
ensure that any problems noted during the course of these monitoring visits are resolved.
11 QUALITY CONTROL AND QUALITY ASSURANCE
Monitoring and auditing procedures defined/agreed by the Sponsor will be followed, in order 
to comply with ICH GCP guidelines. Each center will be visited at regular intervals by a 
monitor to ensure compliance with the study protocol, ICH GCP and legal aspects. The on-
site verification of the eCRF for completeness and clarity will include cross checking with 
source documents, and clarification of administrative matters. Query verification of data will 
be described in the Data Management Plan.
77 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence Study to Evaluate
the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to Gamunex-C in Subjects with Primary
Effective

Representatives of regulatory authorities or of Grifols may conduct audits or inspections or 
audits of the Investigator study site. If the Investigator is notified of an audit or inspection by 
a regulatory authority, the Investigator agrees to notify the Grifols representative (e.g., 
Clinical Assessment Monitor [CAM], Project Manager [PM], Project Lead [PL]) 
immediately. The Investigator agrees to provide to representatives of a regulatory authority 
or Grifols access to records, facilities, and personnel for the effective conduct of an audit or 
inspection.
12 ETHICS
12.1
Institutional Review Board/Ethics Committee  
Documented approval from appropriate IRBs/ECs will be obtained for all participating 
centers/countries prior to study start, according to ICH GCP guidelines, local laws, 
regulations and organizations. When necessary, an extension, amendment or renewal of the 
IRBs/ECs approval must be obtained and also forwarded to the Sponsor. The IRBs/ECs must 
supply to the Sponsor, upon request, a list of the IRBs/ECs members involved in the vote and 
a statement to confirm that the IRBs/ECs are organized and operate according to ICH GCP 
guidelines and applicable laws and regulations.
12.2
Ethical Conduct of the Study
The procedures set out in this protocol, pertaining to the conduct, evaluation, and 
documentation of this study, are designed to ensure that the Sponsor and Investigator abide 
by ICH GCP guidelines. The study will also be carried out in keeping with applicable local 
law(s) and regulation(s). This may include an audit by the Sponsor representatives and/or an 
inspection by Regulatory Authority representatives at any time. The Investigator must agree 
to the audit or inspection of study-related records by the Sponsor representatives and/or 
Regulatory Authority representatives and must allow direct access to source documents to the 
Sponsor and/or Regulatory Authority representatives.  
Modifications to the study protocol will not be implemented by either the Sponsor or the 
Investigator without agreement by both parties. However, the Investigator may implement a 
deviation from, or a change to, the protocol to eliminate an immediate hazard(s) to the study 
subjects without prior IRB/EC/Sponsor approval/favorable opinion. As soon as possible, the 
implemented deviation or change, the reasons for it and if appropriate the proposed protocol 
amendment should be submitted to the IRB/EC/Sponsor. Any deviations from the protocol 
must be fully explained and documented by the Investigator.
No medical waivers for protocol inclusion/exclusion criteria will be allowed by the Sponsor. 
If a need for changes to the protocol inclusion/exclusion criteria is identified, the protocol 
will be amended to include such changes. The protocol amendment will be submitted to the 
competent regulatory authority and/or IRB/EC as applicable per regulations, which allows 
implementation of the revised inclusion/exclusion criteria in the study.
78 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence Study to Evaluate
the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to Gamunex-C in Subjects with Primary
Effective

12.3
Regulatory Authority Approvals/Authorizations
Regulatory Authority approvals/authorizations/notifications, where required, must be in place 
and fully documented prior to study start. Study information including contact information 
for Investigator sites responsible for conducting the study will be posted on a publicly 
accessible clinical registry(ies) as required by local law.
12.4
Subject Information and Consent
Subject information and ICF will be provided to Investigator sites. Prior to the beginning of 
the study, the Investigator must have the written approval/favorable opinion of the written 
ICF by the IRB/EC and any other written information to be provided to subjects. The written 
approval of the IRB/EC together with the approved subject information/ICF must be filed in 
the study files and a copy of the documents must also be provided to the Sponsor by the 
Investigator site. 
Written ICF must be obtained before any study specific procedure takes place. Participation 
in the study and date of ICF signed by the subject should be documented appropriately in the 
subject’s files. A signed copy of the subject ICF will be provided to the subject or subject’s 
authorized representative.
12.5
Confidentiality
All records identifying the subject will be kept confidential and, to the extent permitted by 
the applicable laws and/or regulations, will not be made publicly available.
Subject names will not be supplied to the Sponsor. Only the subject code number will be 
recorded in the eCRF, and if the subject’s name appears on any other document (e.g., 
pathologist report), it must be redacted before a copy of the document is supplied to the 
Sponsor. Study findings stored on a computer will be stored in accordance with local data 
protection laws. Subjects will be informed in writing that representatives of the Sponsor, 
IRB/EC, or Regulatory Authorities may inspect their medical records and personal health 
information to verify the information collected, and that all personal information made 
available for an audit or inspection will be handled in strictest confidence and in accordance 
with local data protection laws.
If the results of the study are published, the subject’s identity will remain confidential. 
The Investigator will maintain a list to enable subjects’ records to be identified.
13 DATA HANDLING AND RECORD KEEPING
13.1
Data Handling
The study data will be recorded and kept current in the subject’s medical records and eCRF 
by the site study personnel directly responsible for the information. Entries made in the eCRF 
must be verifiable against source documents, or have been directly entered into the eCRF, in 
which case the entry in the eCRF will be considered the source data. The data in the eCRF 
79 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence Study to Evaluate
the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to Gamunex-C in Subjects with Primary
Effective

will be monitored at the site by Grifols representatives at regular intervals and reviewed for 
completeness and compared with the source documents. Examples of acceptable source 
documents include individual subject medical records, prospective information gathered on 
source documentation worksheets, lab reports and other diagnostics pertinent to this study 
which are separate from the eCRFs. The listing of types of source documents which will be 
defined in the source data agreement will be filed in TMF.
All AEs and SAEs must be recorded. All SAEs must be recorded on the SAE form. The SAE 
form must be kept in site records with a copy provided to the designated person as detailed in 
the study file.  
13.2
Record Retention
At study completion, all study data will be transferred to Grifols according to ICH GCP 
guidelines, local laws, regulations, and Grifols requirements. The study file and all source 
data should be retained until notification is given by the Sponsor for destruction.
An Investigator is required by ICH GCP guidelines to retain the study files. If an Investigator 
moves, withdraws from an investigation or retires, the responsibility for maintaining the 
records may be transferred to another person (e.g., other Investigator). Grifols must be 
notified in writing of the person responsible for record retention and the notification will be 
retained in the Sponsor study file and the Investigator site file.
14 FINANCING AND INSURANCE
In the event of subject injury as a direct result of either administration of IP or any non-
standard of care study procedure, the Sponsor will pay for the costs of treatment, provided 
the subject has followed the instructions given by the study doctor and the illness or injury is 
not due to the natural progression of any conditions existing before the subject participated in 
the study. Financial compensation for such things as lost wages, disability, or discomfort due 
to any research-related injury is not available.
The Sponsor shall maintain comprehensive general liability insurance or self-insurance in 
amounts adequate to cover any damage, demand, claim, loss or liability caused or incurred 
by the Sponsor, or as otherwise required by applicable laws and/or regulations.
15 PUBLICATION POLICY
Institution and the Investigator agree that the first publication shall be made in conjunction 
with the presentation of a joint, multi-center publication of the study results from all 
appropriates sites. If such a multi-center publication is not submitted within twelve (12) 
months after conclusion of the study at all sites or after Grifols confirms there will be no 
joint, multi-center publication, then Institution and/or Investigator shall have the right, at 
their discretion, to publish, either in writing or orally, the results of the study performed 
under the protocol, subject to the conditions outlined below:
•
The results of the study will be reported in the publicly accessible registry(ies).
80 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence Study to Evaluate
the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to Gamunex-C in Subjects with Primary
Effective

•
Institution and/or Investigator shall furnish Grifols with a copy of any proposed 
publication at least thirty (30) days in advance of the date of submission for publication.
•
Within said thirty (30) day period, Grifols shall:
-
Review such proposed publication for Confidential Information (other than Study 
results) and for subject information subject to the Health Insurance Portability and 
Accountability Act of 1996 (“HIPAA”) and other applicable privacy laws;
-
Review such proposed publication for the unauthorized use of the name, symbols 
and/or trademarks of Grifols;
-
By written notice to the Investigator, identify with specificity the text or graphics in 
such proposed publication that Grifols contends contains Confidential Information, 
protected subject information, or the unauthorized use of Grifols’ name, symbols 
and/or trademarks so that the proposed publication may be edited appropriately to 
remove such text or graphics before publication; and 
-
By written request, Grifols may delay proposed publications up to sixty (60) days to 
allow Grifols to protect its interests in Grifols Inventions described in such 
publications.
•
Institution and/or Investigator shall give Grifols the option of receiving an 
acknowledgment for its sponsorship of the study in all such publications or presentation.
81 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence Study to Evaluate
the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to Gamunex-C in Subjects with Primary
Effective

16 REFERENCES
1. Immune Globulin (Human) 10% (Gamunex-C) PEG process (IVIG-PEG) Investigator’s 
Brochure. Grifols. 2019.
2. Bousfiha A, Jeddane L, Picard C, et al. The 2017 IUIS Phenotypic Classification for 
Primary Immunodeficiencies. J Clin Immunol 2017;38(1):129-43.
3. Perez EE, Orange JS, Bonilla F, et al. Work group report of the American Academy of 
Allergy, Asthma, and Immunology: Update on the use of immunoglobulin in human 
disease: A review of evidence. J Allergy Clin Immunol 2017;139(3S):S1-S46.
4. Immune Globulin (Human), 10% Caprylate/Chromatography Purified (IVIG-C) 
Investigator’s Brochure. Grifols. 2019.
5. FLEBOGAMMA 5% DIF (Immune Globulin Intravenous [Human]), solution for 
intravenous administration. Package Insert. Instituto Grifols S.A. 2016.
6. Stiehm ER. Adverse effects of human immunoglobulin therapy. Transfus Med Rev 
2013;27:171-8.
7. Cayco AV, Perazella MA, Hayslett JP. Renal insufficiency after intravenous immune 
globulin therapy: a report of two cases and an analysis of the literature. J Am Soc 
Nephrol 1997 Nov;8(11):1788-94.
8. Electronic Medicines Compendium. Gamunex 10% Summary of Product Characteristics. 
Grifols UK Ltd. 2018. (https://www.medicines.org.uk/emc/product/4854/smpc)
9. GAMUNEX®-C, [Immune Globulin Injection (Human), 10% Caprylate/Chromatography 
Purified] Package insert. Grifols Therapeutics Inc. 2003
10. Boyle J, Buckley R. Population prevalence of diagnosed primary immunodeficiency 
diseases in the United States. J Clin Immunol 2007;27(5):497-502.
11. Bousfiha AA, Jeddane L, Ailal F, Benhsaien I, Mahlaoui N, Casanova J-L et al. Primary 
immunodeficiency diseases worldwide: more common than generally thought. J Clin 
Immunol. 2013;33:1-7.
12. Buckley R, Schiff Run-in. The use of intravenous immune globulin in immunodeficiency 
diseases. N Engl J Med 1991;11(2):110-7.
13. Sacher RA. Intravenous immunoglobulin consensus statement. J Allergy Clin Immunol 
2001;(4 Suppl):S139-S146.
14. Bruton OC. Agammaglobulinemia. Pediatrics. 1952 Jun 1;9(6):722-8.
15. Wierda WG. Immunologic monitoring in chronic lymphocytic leukaemia. Curr Oncol 
Rep 2003;5:419-25.
82 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence Study to Evaluate
the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to Gamunex-C in Subjects with Primary
Effective

16. Helbert M, Farragher A. Subcutaneous immunoglobulin for patients with antibody 
deficiency. British Journal of Hospital Medicine. 2007;68(4):206-10.
17. Gardulf A. Immunoglobulin treatment for primary antibody deficiencies advantages of 
the subcutaneous route. Biodrugs 2007;21(2):105-16.
18. Carrock Sewell WA, et al. Therapeutic strategies in common variable immunodeficiency. 
Drugs 2003;63:1359-71.
19. Normal Immunoglobulins product lookup. In: Brayfield, Alison. Martindale: The 
Complete Drug Reference. 39th edition. The Royal Pharmaceutical Society of Great 
Britain, 2017. 
20. Bonilla FA, Khan DA, Ballas ZK, Chinen J, Frank MM, Hsu JT, et al. Practice parameter 
for the diagnosis and management of primary immunodeficiency. J Allergy Clin 
Immunol 2015;136(5):1186-205. 
21. Australasian Society of Clinical Immunology and Allergy (ASCIA): Primary 
immunodeficiencies (PID) – Clinical update. 2017.
(https://allergy.org.au/images/stories/pospapers/ASCIA_HP_Clinical_Update_PID_2017.
pdf)
22. Pierce LR, Jain N. Risks associated with the use of intravenous immunoglobulin. 
Transfus Med Rev 2003;17(4):241.
23. Welles CC, Tambra S, Lafayette RA. Hemoglobinuria and acute kidney injury requiring 
hemodialysis following intravenous immunoglobulin infusion. Am J Kidney Dis 
2010;55(1):148.
24. Salama A, Mueller-Eckhardt C, Kiefel V. Effect of intravenous immunoglobulin in 
immune thrombocytopenia. Lancet 1983;2(8343):193.
25. Nakamura S, Yoshida T, Ohtake S, Matsuda T. Hemolysis due to high-dose intravenous 
gammaglobulin treatment for patients with idiopathic thrombocytopenic purpura. Acta 
Haematol 1986;76(2-3):115.
26. Copelan EA, Strohm PL, Kennedy MS, Tutschka PJ. Hemolysis following intravenous 
immune globulin therapy. Transfusion 1986;26(5):410.
27. Brox AG, Cournoyer D, Sternbach M, Spurll G. Hemolytic anemia following intravenous 
gamma globulin administration. Am J Med 1987;82(3 Spec No):633.
28. Comenzo RL, Malachowski ME, Meissner HC, et al. Immune hemolysis, disseminated 
intravascular coagulation, and serum sickness after large doses of immune globulin given 
intravenously for Kawasaki disease. J Pediatr 1992;120(6):926.
29. Mohamed M, Bates G, Eastley B. Massive intravascular haemolysis after high dose 
intravenous immunoglobulin therapy. Br J Haematol 2013 Mar;160(5):570. 
83 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence Study to Evaluate
the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to Gamunex-C in Subjects with Primary
Effective

30. Quinti I, Pulvirenti F, Milito C et al. Hemolysis in patients with antibody deficiencies on 
immunoglobulin replacement treatment. Transfusion 2015;55(5):1067.
31. Health Canada. Canadian Adverse Reaction Newsletter. Intravenous immune globulin 
(IVIG): hemolytic reactions. 2009;19(4).
32. Daw Z, Padmore R, Neurath D, et al. Hemolytic transfusion reactions after administration 
of intravenous immune (gamma) globulin: A case series analysis. Transfusion 
2008;48:1598.
33. Kahwaji J, Barker E, Pepkowitz S, et al. Acute hemolysis after high-dose intravenous 
immunoglobulin therapy in highly HLA sensitized patients. Clin J Am Soc Nephrol 
2009;4:1993.
34. Pintova S, Bhardwaj AS, Aledort LM. IVIG--a hemolytic culprit. N Engl J Med 2012; 
367:974.
35. Special Issue: Hemolysis Supplement Strategies to Address Hemolytic Complications of 
Immune Globulin Infusions. Transfusion. 2015;55:i–ii, S1–S127.
36. Medical Advisory Committee of the Immune Deficiency Foundation [Shearer WT, 
Fleisher TA, Buckley RH, Ballas Z, Ballow M, Blaese RM et al. Recommendations for 
live viral and bacterial vaccines in immunodeficient patients and their close contacts. J 
Allergy Clin Immunol 2014;133(4):961-6.
37. Levy MM, Fink MP, Marshall JC et al. 2001 SCCM/ESICM/ACCP/ATS/SIS 
International Sepsis Definitions Conference. Crit Care Med 2003;31:1250-6.
38. International Consensus Conference on Pediatric Sepsis. Pediatric Crit Care Med 
2005;6:2-8. 
39. FDA Guidance for Industry "Acute Bacterial Meningitis - Developing Antimicrobial 
Drugs for Treatment," Draft Guidance, July 1998.
http://www.fda.gov/cder/guidance/2573dft.pdf. Last checked: 13 Feb 2015. 
40. FDA Guidance for Industry "Community Acquired Pneumonia - Developing 
Antimicrobial Drugs for Treatment," Draft Guidance, July 1998.   
http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidanc
es/ucm123686.pdf. Last checked: 13 Feb 2015.
41. The International Classification of Disease, Eleventh Revision (ICD-11). The World 
Health Organization. 2018. http://www.who.int/classifications/icd/en/
42. Adam SS, Key NS, Greenberg CS. D-dimer antigen: current concepts and future 
prospects. Blood 2009;113(13):2878-87.
43. Wells PS. Integrated strategies for the diagnosis of venous thromboembolism. J Thromb 
Haemost 2007;5 Suppl 1:41-50.
84 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence Study to Evaluate
the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to Gamunex-C in Subjects with Primary
Effective

44. Thavendiranathan P, Bagai A, Ebidia A, et al. Do Blood Tests Cause Anemia in 
Hospitalized Patients? The Effect of Diagnostic Phlebotomy on Hemoglobin and 
Hematocrit Levels. J Gen Intern Med 2005;20:520–4.
45. Tuncer Elmaci N, Ratip S, Ince-Günal D, et al. Myasthenia gravis with thymoma and 
autoimmune haemolytic anaemia. A case report. Neurol Sci 2003;24(1):34-36.
85 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence Study to Evaluate
the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to Gamunex-C in Subjects with Primary
Effective

17 APPENDICES
86 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence Study to Evaluate
the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to Gamunex-C in Subjects with Primary
Effective

Appendix 1
Schedule of Procedures and Events
Table A. Every 3 Weeks Dosing Regimen
Study Phase
Screening 
Visit (up 
to 28 days)
Run-in Phase
(Gamunex-C every 3 weeks)
Gamunex-C 
PK Phase
Treatment Phase
(IVIG-PEG every 3 weeks)
IVIG-PEG 
PK Phase
Final Visit/Early 
Termination
Visit
Run-
in #1
Run-
in #2
Run-
in #3
Run-
in #4
Run-
in #5
Run-
in #6
Gamunex-C 
PK#1
IVIG-
PEG #1
IVIG-
PEG #2
IVIG-
PEG #3
IVIG-
PEG #4
IVIG-
PEG #5
IVIG-
PEG #6
IVIG-PEG 
PK#1
Procedure
Informed consent 
X
Inclusion/exclusion criteria 
X
Medical history & demographics
X
Prior medication history
X
Full physical exama
X
X
X
Abbreviated physical examb
X
X
X
X
X
X
X
X
X
X
X
X
X
Chest X-rayc
X
Vital signs
X
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
X
Height
X
Body weighte
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum pregnancy testf
X
Urine pregnancy testf
X
Xu
X
X
X
X
X
X
X
X
Laboratory assessments 
(hematology, chemistry, 
urinalysis)g,h,i,s
X
Xs
Xs
Xs
Xs
Xs
Xs
X
Thromboembolism evaluationj
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hemolysis detectionk
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Total IgG trough level 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xt
Sample for IgG subclass levels 
and Ab titerl,m
X
X
X
X
X
X
X
X
Virus safety retainn,
X
X
X
X
Xu
X
X
X
X
Gamunex-C infusiono
X
X
X
X
X
X
X
IVIG-PEG infusiono
X
X
X
X
X
X
X
Serial PK samplesp
X
X
Concomitant medications 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
AE assessments including 
infectionsq
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Record days lost from 
work/school/daily activities
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Monitor signs and symptoms of 
hemolysisr
X
X
X
X
X
X
X
X
X
X
X
X
X
X
87 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence
Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to
G
C i S bj
t
ith P i
H
l I
d fi i
Effective

a
A full physical exam will be performed (excluding breast and genitourinary exam). 
b
Pre-dose abbreviated physical exam (targeted to symptoms and to include examination of heart, lungs, ears/nose/throat, and inspection of previous injection 
sites.)
c
Only if chest X-ray or CT have not been performed in the 6 months prior to the Screening Visit. 
d
Vital signs (SBP, DBP, HR, T, and RR) will be measured within 30 ± 10 minutes before the beginning of each infusion and within 30 ± 10 minutes post-
completion of each infusion. 
e
Body weight will be measured prior to the infusion to determine the IP dose.
f
Females of child-bearing potential only; results must be negative to participate in the study or continue on IP. Quantitative serum β-HCG will be performed 
at the Screening Visit. A qualitative urine pregnancy test will be performed prior to the first dose received for each IP as well as prior to each IVIG-PEG 
infusion, and at the Final Visit/Early Termination Visit. Pregnancy testing will be repeated at any time if pregnancy is suspected.
g
Hematology will include: hemoglobin, hematocrit, platelets, RBC count including RBC morphology, WBC count with differential, and ARC. 
h
Chemistry will include: sodium, potassium, creatinine, chloride, calcium, BUN, bicarbonate, albumin, LDH, AST, ALT, ALP, GGT, glucose, TBL, indirect
and direct bilirubin. 
i
Urinalysis will include: pH, protein, glucose, ketones, bilirubin, nitrites, urobilinogen, blood, leukocyte esterase (with microscopic examination of urine 
sediment if abnormal), and specific gravity.
j
During study IP infusion visits, D-dimer testing is to be performed within 8 hours prior to the infusion and 30 ±10 minutes after the completion of the 
infusion. At the Screening Visit, blood for the D-dimer level will only be collected prior to the subject’s standard of care infusion. Wells scoring is to be 
performed post-infusion. Section 7.2 describes at each visit evaluation of clinical signs and symptoms of thromboembolic events (e.g., pain, dyspnea, 
discoloration [paleness or redness] in lower extremities) after the completion of infusion (Appendix 3)
k
Laboratory samples must be taken prior to IP infusion (within 8 hours prior to the infusion) and analyzed as described for monitoring hemolytic AEs in 
Appendix 4; specific laboratory parameters include the following: blood specimens (DAT, blood smear, hematocrit, RBC count, ARC, Hb, plasma free-Hb, 
haptoglobin, LDH, total indirect and direct bilirubin); and urine specimens (urinary sediment, hemoglobinuria, and hematuria).
l
IgG subclasses IgG1, IgG2, IgG3, IgG4 measured prior to the start of the infusion.
m
Antibody levels for S. pneumoniae, H. influenzae, C. tetani (tetanus), and measles are measured prior to the start of the infusion.
n
Collect virus safety retain samples prior to the infusion but test only if the subject exhibits clinical signs and symptoms consistent with HAV, HBV, HCV,
HIV, or B19V infection while participating in the study. See Section 7.2.5 and Table 7-1 for details.
o
IP infusion intervals will be either every 3 weeks (21 days) or 4 weeks (28 days) depending on the subject’s previous IVIG dosing interval. Any subject 
who’s prior dosing frequency was not every 3 to 4 weeks will be adjusted to one of these two frequency options by their physician during the Run-in Phase.
p
PK samples will be obtained as follows: within 30 minutes prior to the start of the intravenous infusion, immediately upon the completion of the infusion 
(within 10 minutes of infusion completion), and at 1, 3, and 6 hours (±10 minutes), 24 and 48 hours (±2 hours), and 4 (±2 hours), 7 (±1 d), 14 (±1 d), 21 (±2 
d), and 28 (±2 d) days (the 28 day PK sample applies only for subjects on every 4 weeks dosing regimen) after the end of the infusion. An added PK sample 
will be requested for subjects who prematurely discontinue the study during the PK curves sampling periods (i.e., Gamunex-C PK Phase and IVIG-PEG PK 
Phase).
q
Record any SBIs (defined in Appendix 2), hospitalizations due to infections, and non-serious infections (by category). If a subject develops an SBI, a serum 
IgG level should be obtained. 
88 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence
Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to
G
C i S bj
t
ith P i
H
l I
d fi i
Effective

r
Clinical evaluation of the signs and symptoms of hemolysis including red/dark urine, jaundice, as well as other signs and symptoms of anemia (such as 
pallor or tachycardia) during the infusion visit (pre-infusion and post infusion) and by a phone call by the Investigator or appropriate study staff (medical 
doctor) at 10 days (±2 days) after each infusion.(Appendix 4).
s
Pre-dose sample.
t
PK samples will only be taken at a subject’s final visit if they discontinue the study prematurely. A sample for total IgG concentration for safety purposes 
will be taken from subjects prematurely discontinuing the study.
u
Only for subjects skipping the Run-in Phase who entered directly into the Gamunex-C PK Phase (see Section 4.2.1).
89 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence
Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to
G
C i S bj
t
ith P i
H
l I
d fi i
Effective

Table B. Every 4 Weeks Dosing Regimen
Study Phase
Screening 
Visit (up to 
28 days)
Run-in Phase
(Gamunex-C every 4 weeks)
Gamunex-C 
PK Phase
Treatment Phase
(IVIG-PEG every 4 weeks)
IVIG-PEG 
PK Phase
Final 
Visit/Early 
Termination
Visit
Run-
in-#1
Run-
in-#2
Run-
in-#3
Run-
in-#4
Run-
in #5
Gamunex-C 
PK#1
IVIG-
PEG-#1
IVIG-
PEG -#2
IVIG-
PEG -#3
IVIG-
PEG -#4
IVIG-
PEG -#5
IVIG-PEG 
PK#1
Procedure
Informed consent 
X
Inclusion/exclusion criteria 
X
Medical history & 
demographics
X
Prior medication history
X
Full physical exama
X
X
X
Abbreviated physical examb
X
X
X
X
X
X
X
X
X
X
X
Chest X-rayc
X
Vital signs
X
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
X
Height
X
Body weighte
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum pregnancy testf
X
Urine pregnancy testf
X
Xu
X
X
X
X
X
X
X
Laboratory assessments 
(hematology, chemistry, 
urinalysis)g,h,i,s
X
Xs
Xs
Xs
Xs
Xs
Xs
X
Thromboembolism evaluationj
X
X
X
X
X
X
X
X
X
X
X
X
X
Hemolysis detectionk
X
X
X
X
X
X
X
X
X
X
X
X
Total IgG trough level 
X
X
X
X
X
X
X
X
X
X
X
X
X
Xt
Sample for IgG subclass levels 
and Ab titerl,m
X
X
X
X
X
X
X
X
Virus safety retainn
X
X
X
X
Xu
X
X
X
X
Gamunex-C infusiono
X
X
X
X
X
X
IVIG-PEG infusiono
X
X
X
X
X
X
Serial PK samplesp
X
X
Concomitant medications 
X
X
X
X
X
X
X
X
X
X
X
X
X
AE assessments including 
infectionsq
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Record days lost from 
work/school/daily activities
X
X
X
X
X
X
X
X
X
X
X
X
X
Monitor signs and symptoms of 
hemolysisr
X
X
X
X
X
X
X
X
X
X
X
X
90 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence
Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to
G
C i S bj
t
ith P i
H
l I
d fi i
Effective

a
A full physical exam will be performed (excluding breast and genitourinary exam). 
b
Pre-dose abbreviated physical exam (targeted to symptoms and to include examination of heart, lungs, ears/nose/throat, and inspection of previous injection 
sites).
c
Only if chest X-ray or CT have not been performed in the 6 months prior to the Screening Visit. 
d
Vital signs (SBP, DBP, HR, T, and RR) will be measured within 30 ± 10 minutes before the beginning of each infusion and within 30 ± 10 minutes post-
completion of each infusion. 
e
Body weight will be measured prior to the infusion to determine the IP dose.
f
Females of child-bearing potential only; results must be negative to participate in the study or continue on IP. Quantitative serum β-HCG will be performed 
at the Screening Visit. A qualitative urine pregnancy test will be performed prior to the first dose received for each IP as well as prior to each IVIG-PEG 
infusion, and at the Final Visit/Early Termination Visit. Pregnancy testing will be repeated at any time if pregnancy is suspected.
g
Hematology will include: hemoglobin, hematocrit, platelets, RBC count including RBC morphology, WBC count with differential, and ARC. 
h
Chemistry will include: sodium, potassium, creatinine, chloride, calcium, BUN, bicarbonate, albumin, LDH, AST, ALT, ALP, GGT, glucose, TBL, indirect 
and direct bilirubin. 
i
Urinalysis will include: pH, protein, glucose, ketones, bilirubin, nitrites, urobilinogen, blood, leukocyte esterase (with microscopic examination of urine 
sediment if abnormal), and specific gravity.
j
During study IP infusion visits, D-dimer testing is to be performed within 8 hours prior to the infusion and 30 ±10 minutes after the completion of the 
infusion.  At the Screening Visit, blood for the D-dimer level will only be collected prior to the subject’s standard of care infusion. Wells scoring is to be 
performed post-infusion. Section 7.2 describes at each visit evaluation of clinical signs and symptoms of thromboembolic events (e.g., pain, dyspnea, 
discoloration [paleness or redness] in lower extremities) after the completion of infusion (Appendix 3). 
k
Laboratory samples must be taken prior to IP infusion (within 8 hours prior to the infusion) and analyzed as described for monitoring hemolytic AEs in 
Appendix 4; specific laboratory parameters include the following: blood specimens (DAT, blood smear, hematocrit, RBC, ARC, Hb, plasma free-Hb, 
haptoglobin, LDH, total, indirect and direct bilirubin); and urine specimens (urinary sediment, hemoglobinuria, and hematuria).
l
IgG subclasses IgG1, IgG2, IgG3, IgG4 measured prior to the start of the infusion.
m
Antibody levels for S. pneumoniae, H. influenzae, C. tetani (tetanus), and measles are measured prior to the start of the infusion.
n
Collect virus safety retain samples prior to the infusion but test only if the subject exhibits clinical signs and symptoms consistent with HAV, HBV, HCV, 
HIV, or B19V infection while participating in the study. See Section 7.2.5 and Table 7-1 for details.
o
IP infusion intervals will be either every 3 weeks (21 days) or 4 weeks (28 days) depending on the subject’s previous IVIG dosing interval. Any subject 
who’s prior dosing frequency was not every 3 to 4 weeks will be adjusted to one of these two frequency options by their physician during the Run-in Phase.
p
PK samples will be obtained as follows: within 30 minutes prior to the start of the intravenous infusion, immediately upon the completion of the infusion 
(within 10 minutes of infusion completion), and at 1, 3, and 6 hours (±10 minutes), 24 and 48 hours (±2 hours), and 4 (±2 hours), 7 (±1 d), 14 (±1 d), 21 (±2 
d), and 28 (±2 d) days (the 28 day PK sample applies only for subjects on every 4 weeks dosing regimen) after the end of the infusion. An added PK sample 
will be requested for subjects who prematurely discontinue the study during the PK curves sampling periods (i.e., Gamunex-C PK Phase and IVIG-PEG PK 
Phase).
q
Record any SBIs (defined in Appendix 2), hospitalizations due to infections, and non-serious infections (by category). If a subject develops an SBI, a serum 
IgG level should be obtained.
r
Clinical evaluation of the signs and symptoms of hemolysis including red/dark urine, jaundice, as well as other signs and symptoms of anemia (such as 
pallor or tachycardia) during the infusion visit (pre-infusion and post infusion) and by a phone call by the Investigator or study staff (medical doctor) at 10 
days (±2 days) after each infusion (Appendix 4).
s
Pre-dose sample.
91 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence
Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to
G
C i S bj
t
ith P i
H
l I
d fi i
Effective

t
PK samples will only be taken at a subject’s final visit if they discontinue the study prematurely. A sample for total IgG concentration for safety purposes 
will be taken from subjects prematurely discontinuing the study.
u
Only for subjects skipping the Run-in Phase who entered directly into the Gamunex-C PK Phase (see Section 4.2.1).
92 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence
Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to
G
C i S bj
t
ith P i
H
l I
d fi i
Effective

Appendix 2
Diagnostic Criteria for Serious Infection Types
Infection: Bacteremia/Sepsisa
•
Symptoms: chills, rigors  
•
Physical findings: fever, hypothermia, tachycardia, tachypnea, hypocarbia, hypotension (systolic 
blood pressure <90 mmHg or a reduction of >40 mmHg from Baseline in the absence of other 
causes of hypotension), altered mental status, petechiae, purpura, oliguria, cutaneous 
vasodilation/vasoconstriction 
•
Laboratory tests: positive blood cultureb, leukocytosis (white blood cell [WBC] count 
> 12,000/mm3), differential WBC count demonstrating >10% immature (band) neutrophils, 
leukopenia, thrombocytopenia, coagulopathy, lactic acidosis
Infection: Bacterial Meningitis 
•
Symptoms: headache, stiff neck, mental status changes, irritability, decreased feeding (infants), 
photophobia, nausea/vomiting, rigors, seizures 
•
Physical findings: Kernig’s sign, Brudzinski’s sign, meningococcal rash, fever of >38°C oral or 
>39°C rectal 
•
Laboratory tests: positive cerebrospinal fluid (CSF) Gram stain and/or culture and/or positive CSF 
bacterial antigen assay, positive blood culture, CSF leukocytosis with neutrophil predominance, 
decrease in CSF glucose
Infection: Osteomyelitis/Septic Arthritis 
•
Symptoms: pain, decreased range of motion, tenderness, edema, redness, warmth over the involved 
site (local inflammatory symptoms/signs may be lacking in adults) 
•
Physical findings: evidence of soft tissue infection adjacent to the involved bone/joint, drainage 
from sinus tract from involved bone, fever of >38°C oral or >39°C rectal 
•
Laboratory tests: positive blood culture, positive probe to bone, positive bone aspirate culture, 
positive bone biopsy culture, positive bone histopathology, positive joint fluid Gram stain and 
culture 
Imaging studies: positive X-ray, nuclear medicine bone scan, magnetic resonance imaging 
(MRI) scan, or computed tomography (CT) scan showing bony destruction with radiolucent 
areas; for chronic osteomyelitis: sequestra, involucra
Note: Items in bold are considered essential diagnostic features. 
a Two of the following should be present to make the diagnosis of sepsis in adults: temperature >38°C oral/ 
>39°C rectal or <36°C oral or <37°C rectal; heart rate >90 beats/min; respiratory rate >20 breaths/min, or 
PaCO2 <32 mmHg; WBC count >12,000/mm3, <4,000/mm3, or >10% immature (band) forms (36). For 
pediatric subjects, we recommend you employ the definition of sepsis using age-specific criteria as 
recommended by the International Consensus Conference on Pediatric Sepsis (38). 
b Indwelling catheter- or vascular access device-related blood-borne infections are not included because 
evidence is lacking that these are preventable with IVIG replacement therapy. For subjects without indwelling 
catheters or vascular access devices, a single blood culture positive for a pathogenic organism will meet the 
diagnostic criteria for bacteremia. (Multiple blood cultures are typically obtained in cases of suspected 
bacteremia/sepsis, as per standard medical practice, and the finding of a single positive culture should prompt 
additional confirmatory cultures). Subjects meeting criteria for positive blood culture but without 2 or more of 
the sepsis criteria listed above will be classified as having bacteremia. 
93 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence Study to Evaluate
the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to Gamunex-C in Subjects with Primary
Effective

c A blood culture positive for growth of S. pneumoniae, Neisseria meningitides, or H. influenzae, in 
combination with CSF leukocytosis and/or decrease in CSF glucose, can serve to confirm the diagnosis of 
acute bacterial meningitis (39). 
Infection: Bacterial Pneumoniad
•
Symptoms: productive cough/change in character of sputum, dyspnea or tachypnea, chills, chest pain, 
rigors, headache, fatigue, sweats, anorexia, myalgias 
•
Physical findings: rales; pulmonary consolidation as reflected by: dullness on percussion, bronchial 
breath sounds, egophony; fever >38°C oral or >39°C rectal, or <36°C, hypothermia (temperature 
<36°C oral or <37°C rectal) 
•
Laboratory tests: leukocytosis, differential WBC count of >10% band neutrophils, leukopenia, 
hypoxemia (PaO2 <60 mm Hg on room air), positive blood culture, Gram stain and culture of deep 
expectorated sputume, positive culture with or without positive Gram stain of transtracheal aspirate, 
pleural fluid culture, lung biopsy, bronchoscopy with bronchoalveolar lavage or protected brush 
sampling.
•
Imaging studies: pulmonary infiltrate with consolidation on chest X-Ray (CXR) (new in comparison 
with Baseline CXR)
Infection: Visceral Abscess 
•
Symptoms: abdominal pain, anorexia, weight loss, cough/pleuritic chest pain (hepatic abscess), rigors 
(seldom present) 
•
Physical findings: intermittent fevers (temperature >38°C oral or >39°C rectal), abdominal 
tenderness, palpable mass, hepatomegaly, jaundice 
•
Laboratory tests: positive Gram stain and/or culture from the infected site, with isolation of an 
appropriate pathogen, positive blood culture, leukocytosis with accompanying left shift, differential 
WBC count of >10% immature (band) neutrophils, elevated serum amylase concentration (pancreatic 
abscess), elevated alkaline phosphatase concentration (hepatic abscess) pyuria in renal abscess 
•
Imaging studies: typical findings on ultrasound, CT scan, MRun-in scan, or radionuclide scan
Note: Items in bold are considered essential diagnostic features.
d For the diagnosis of pneumonia in adults, commonly at least 2 of the listed symptoms and/or signs should be 
present in conjunction with at least one laboratory and one imaging studies diagnostic element. However, for 
the purposes of counting serious infection episodes in a clinical trial of IVIG, the finding of a new pulmonary 
infiltrate with consolidation on CXR is considered sufficient. To establish the diagnosis of bacterial 
pneumonia for pediatric patients, most of the same diagnostic criteria listed may be used, with the following 
exceptions: Because pediatric patients may not produce a sputum specimen for culture, blood cultures or 
serology may be substituted to identify the etiologic bacterial pathogen. In infants age 3 to 24 months, who 
tend to have a higher baseline temperature, fever is defined as a rectal temperature >38.3°C (101°F). In 
children >2 years, fever is more commonly defined as a rectal temperature >38°C (100.4°F). In pediatric 
patients, elevations of WBC counts >15,000/mm3 are frequent but could be variable in patients with bacterial 
pneumonia, or leukopenia with WBC count <5000/mm3 may be observed, usually associated with severe 
infection (40).
e We recommend a deep expectorated sputum gram stain to demonstrate the presence of microorganisms on 
examination of 10 to 20 oil immersion microscopic fields and <10 squamous epithelial cells and 
>25 polymorphonuclear leukocytes at 10× low power magnification to determine suitability of sputum culture 
(40).
94 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence Study to Evaluate
the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to Gamunex-C in Subjects with Primary
Effective

Appendix 3
Monitoring of Thromboembolic Events Risk
At Screening and during all the infusion visits, subjects will be actively monitored for signs 
and symptoms of arterial and venous thromboembolic (TE) events. Arterial and venous TE 
events will be identified according to definitions in the International Classification of 
Diseases (ICD) [41]. Such events include, but are not limited to, deep vein thrombosis 
(DVT), pulmonary embolism (PE), acute myocardial infarction, cerebral infarction, acute 
ischaemic heart disease, embolism or thrombosis of arteries of lower extremities, sagittal 
sinus thrombosis, portal vein thrombosis and injury of mesenteric artery.
All TE events will be recorded as adverse events (AEs) and reported accordingly. Any TE 
event fulfilling any of the criteria for “serious” will be reported as a serious adverse event 
(SAE).
The Sponsor’s Medical Monitor (or designee) will routinely review reported AEs for possible 
TE events.
In addition, TE events risk will be evaluated using the following assessments, schedule 
(Table 1) and algorithms (Figure 1 and 2):
1. Measurement of D-dimer blood levels (42);
2. The Wells Score (43) will be utilized to assess the clinical characteristics indicative of 
possible DVT or PE (Table 2);
3. Evaluation of clinical signs and symptoms of arterial and venous TE (such as, dyspnea, 
pain, swelling, tenderness and discoloration [paleness or redness] in lower extremities).
After getting results from (1) to (3) and prior to the next study infusion visit, a medical doctor 
will assess the risk of TE events considering algorithms (provided in Figure 1 and Figure 2 
below) from the first Gamunex-C to the last IVIG-PEG study infusions.
Table 1. Schedule of Monitoring of Thromboembolic Events Risk
Study Visit
D-dimera
Wells Scoreb
Clinical Assessment 
TEc
Screening Visit
Once during Screening Visit, 
prior to IVIG infusion
During Screening 
Visit
During Screening 
Visit
Run-in #1
Pre-infusion and 
Post-Infusion
Post-infusion
Post-infusion
Run-in #2
Pre-infusion and 
Post-Infusion
Post-infusion
Post-infusion
Run-in #3
Pre-infusion and 
Post-Infusion
Post-infusion
Post-infusion
Run-in #4
Pre-infusion and 
Post-Infusion
Post-infusion
Post-infusion
Run-in #5
Pre-infusion and 
Post-Infusion
Post-infusion
Post-infusion
95 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence Study to Evaluate
the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to Gamunex-C in Subjects with Primary
Effective

Study Visit
D-dimera
Wells Scoreb
Clinical Assessment 
TEc
Run-in #6d
Pre-infusion and 
Post-Infusion
Post-infusion
Post-infusion
Gamunex-C PK#1
Pre-infusion and 
Post-Infusion
Post-infusion
Post-infusion
IVIG-PEG #1
Pre-infusion and 
Post-Infusion
Post-infusion
Post-infusion
IVIG-PEG #2
Pre-infusion and 
Post-Infusion
Post-infusion
Post-infusion
IVIG-PEG #3
Pre-infusion and 
Post-Infusion
Post-infusion
Post-infusion
IVIG-PEG #4
Pre-infusion and 
Post-Infusion
Post-infusion
Post-infusion
IVIG-PEG #5
Pre-infusion and 
Post-Infusion
Post-infusion
Post-infusion
IVIG-PEG #6d
Pre-infusion and 
Post-Infusion
Post-infusion
Post-infusion
IVIG-PEG PK#1
Pre-infusion and 
Post-Infusion
Post-infusion
Post-infusion
Final Visit/Early 
Termination
Not performed
Not performed
Not performed
a.
A blood sample for D-dimer testing will be collected within 8 hours pre-infusion and 30 ±10 minutes 
post-completion of infusion. At the Screening Visit, blood for the D-dimer level will only be collected 
prior to the subject’s standard of care infusion. 
b.
Wells score completed after the infusion by the Investigator or appropriate study staff (medical doctor, 
study nurse, or study coordinator).
c.
Evaluation of clinical signs and symptoms of arterial and venous TE is performed after the infusion by 
the Investigator or designee medical doctor or study nurse.
d.
These visits only apply to subjects on the every 3 weeks dosing regimen.
96 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence Study to Evaluate
the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to Gamunex-C in Subjects with Primary
Effective

Table 2: Wells Prediction Score
DEEP VEIN THROMBOSIS
Clinical Characteristic
Score
Active cancer (treatment ongoing, within previous 6 months or palliative)
1
Paralysis, paresis, or recent plaster immobilization of the lower extremities
1
Recently bedridden >3 days or major surgery within previous 12 weeks 
requiring general or regional anesthesia
1
Previously documented DVT
1
Localized tenderness along distribution of deep venous system
1
Entire leg swollen
1
Calf swelling 3 cm larger than asymptomatic side (measured 10 cm below 
tibial tuberosity)
1
Pitting edema confined to the symptomatic leg
1
Collateral superficial veins (non-varicose)
1
Alternative diagnosis at least as likely as DVT
-2
Total Score:
PULMONARY EMBOLISM
Clinical Characteristic
Score
Previous DVT or PE 
1.5
Surgery or bedridden for 3 days during past 4 weeks
1.5
Active cancer (treatment within 6 months or palliative)
1
Hemoptysis
1
Heart rate >100 beats/min
1.5
Clinical signs of DVT
3
Alternative diagnosis less likely than PE
3
Total Score:
97 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence Study to Evaluate
the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to Gamunex-C in Subjects with Primary
Effective

After getting results from D-dimer levels, Wells Score, and evaluation of signs and 
symptoms of TE, and prior to the next study visit, the Investigator or designee medical doctor 
will assess the risk of DVT and PE considering the following algorithms adapted from Wells 
[43] (Figure 1 and Figure 2):
Figure 1. Algorithm to assess thromboembolic events risk for DVT
Any subject with a total Wells prediction score >1 for DVT assessment should have further 
diagnostic testing per study site standard of care to confirm the occurrence of a TE event 
(Figure 1).
Any subject with a total Wells prediction score ≤1 for DVT assessment and a positive D-
dimer value (i.e., above baseline and out of normal range of the reporting laboratory) in 
combination with clinical signs or symptoms of a TE event (as per AEs assessment and such 
as pain, dyspnea, discoloration—paleness or redness—in lower extremities) should have 
further diagnostic testing per study site standard of care to confirm the occurrence of a TE 
event (Figure 1). For this purpose, “baseline” refers to the first study infusion (Run-In #1 or 
Gamunex-C PK visit).
If the subject experiences a confirmed TE event, the study treatment must be discontinued 
and if necessary standard therapy started.
•
The Wells Score
•
D-dimer
•
Signs & symptoms of TE
No TE risk
The Wells Score 
(>1 in DVT)
TE risk
The Wells Score 
(≤1 in DVT)
D-dimer (-)
D-dimer (-)
D-dimer (+)
D-dimer (+)
Signs & 
symptoms of 
TE (present)
Signs & 
symptoms of TE 
(not present)
No TE risk
TE risk
TE risk 
98 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence Study to Evaluate
the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to Gamunex-C in Subjects with Primary
Effective

Figure 2. Algorithm to assess thromboembolic events risk for PE
Any subject with a total Wells prediction score >4 for PE assessment should have further 
diagnostic testing per study site standard of care to confirm the occurrence of a TE event 
(Figure 2).
Any subject with a total Wells prediction score ≤4 for PE assessment and a positive D-dimer 
value (i.e., above baseline and out of normal range of the reporting laboratory) should have 
further diagnostic testing per study site standard of care to confirm the occurrence of a TE 
event (Figure 2). For this purpose, “baseline” refers to the first study infusion (Run-In #1 or 
Gamunex-C PK visit).
If the subject experiences a confirmed TE event, the study treatment must be discontinued 
and if necessary standard therapy started.
•
The Wells Score
•
D-dimer
•
Signs & symptoms of TE
No TE risk
The Wells Score 
(>4 in PE)
TE risk
The Wells Score 
(≤4 in PE)
D-dimer (negative)
D-dimer (positive)
TE risk
D-dimer (negative)
D-dimer (positive)
TE risk
99 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence Study to Evaluate
the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to Gamunex-C in Subjects with Primary
Effective

Appendix 4
Detection of Hemolysis
During all the infusion visits, subjects will be monitored for signs of hemolysis associated 
with the administration of the IP.
All hemolytic events will be recorded as adverse events (AEs) and reported accordingly. Any 
hemolytic event fulfilling any of the criteria for “serious” will be reported as a serious 
adverse event (SAE).
The Sponsor’s Medical Monitor (or designee) will routinely review reported AEs for possible 
hemolytic events.
Hemolysis will be monitored using the following assessments and schedule (Table 1):
1. Blood testing: whole blood hemoglobin, plasma free hemoglobin, haptoglobin, lactate 
dehydrogenase (LDH), direct antiglobulin test (DAT), absolute reticulocyte count (ARC), 
red blood count (RBC), hematocrit, total and indirect and direct bilirubin, and blood 
smear.
2. Urine testing: urinary sediment, and hemoglobinuria.
3. Evaluation of clinical parameters including red/dark urine, jaundice, as well as other 
signs and symptoms of anemia (such as pallor or tachycardia) evaluated by the 
Investigator or appropriate study staff (medical doctor) at any time on the day of infusion 
before the infusion and after the completion of the infusion, and via a phone call 10 days 
(±2 days) after the initiation of the infusion by the Investigator or appropriate study staff 
(medical doctor).
100 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence Study to Evaluate
the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to Gamunex-C in Subjects with Primary
Effective

Table 1. Schedule of Detection of Hemolysis
Study Visit
Blood Testinga
Urine Testinga
Clinical Parametersb
Screening Visit
Not performed
Not performed
Not performed
Run-in #1
Pre-infusion
Pre-infusion
Pre-infusion, Post-Infusion, 
and 10±2 days after
Run-in #2
Pre-infusion
Pre-infusion
Pre-infusion, Post-Infusion, 
and 10±2 days after
Run-in #3
Pre-infusion
Pre-infusion
Pre-infusion, Post-Infusion, 
and 10±2 days after
Run-in #4
Pre-infusion
Pre-infusion
Pre-infusion, Post-Infusion, 
and 10±2 days after
Run-in #5
Pre-infusion
Pre-infusion
Pre-infusion, Post-Infusion, 
and 10±2 days after
Run-in #6d
Pre-infusion
Pre-infusion
Pre-infusion, Post-Infusion, 
and 10±2 days after
Gamunex-C PK#1
Pre-infusion
Pre-infusion
Pre-infusion, Post-Infusion, 
and 10±2 days after
IVIG-PEG #1
Pre-infusion
Pre-infusion
Pre-infusion, Post-Infusion, 
and 10±2 days after
IVIG-PEG #2
Pre-infusion
Pre-infusion
Pre-infusion, Post-Infusion, 
and 10±2 days after
IVIG-PEG #3
Pre-infusion
Pre-infusion
Pre-infusion, Post-Infusion, 
and 10±2 days after
IVIG-PEG #4
Pre-infusion
Pre-infusion
Pre-infusion, Post-Infusion, 
and 10±2 days after
IVIG-PEG #5
Pre-infusion
Pre-infusion
Pre-infusion, Post-Infusion, 
and 10±2 days after
IVIG-PEG #6d
Pre-infusion
Pre-infusion
Pre-infusion, Post-Infusion, 
and 10±2 days after
IVIG-PEG PK#1
Pre-infusion
Pre-infusion
Pre-infusion, Post-Infusion, 
and 10±2 days after
Final Visit/Early 
Termination
Not performed
Not performed
Not performed
a.
Blood and urine testing must be performed within 8 hours prior to the infusion at each study visit. If the 
Investigator or designee medical doctor performing the Day 10 (±2 days) phone call considers that the 
subject is at risk of suffering from a hemolytic event, additional testing may be also requested.
b.
The clinical assessment at Day 10 (±2 days) after each infusion to be performed via phone call by the 
Investigator or appropriate study staff (medical doctor).
101 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence Study to Evaluate
the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to Gamunex-C in Subjects with Primary
Effective

During the phone call, the following questions may be asked to the subject in addition to 
questions that the Investigator or designee medical doctor will consider necessary to monitor 
the potential risk of hemolysis associated with the use of IP:
•
Are you more tired since the last infusion of the study drug?
•
Do you feel an increase in your heart rate since the last infusion of the study drug?
•
Do you have yellow eyes since the last infusion of the study drug?
•
Is your urine dark since the last infusion of the study drug?
•
Do you have pale face or hands?
Important note:
If the Investigator or designee medical doctor detect any evidence of risk of hemolysis during 
the assessment of clinical parameters of hemolysis after each infusion or by the phone call (at 
Day 10, ±2 days following each infusion), additional blood and urine testing will also be 
performed. In case the risk of hemolysis is identified during the phone call, the subject will 
be asked to go to the investigational site to have a blood draw and to provide urine sample.
Definition of hemolysis associated with the administration of IP:
In this study, a hemolytic reaction is one in which there is evidence of a new hemolytic 
process within 10 days (±2 days) of each IP administration (31).
The following laboratory signs must be present: 
1. Drop in whole blood hemoglobin of ≥1 g/dL1; and
2. Positive result of DAT2; and
3. At least 2 of the following:
•
Increased ARC1
•
Hemoglobinemia (excess of hemoglobin 
in the plasma)2
•
Increased LDH level1
•
Hemoglobinuria2
•
Low haptoglobin level1
•
Presence of significant spherocytosis2
•
Unconjugated hyperbilirubinemia2
1
Changes from baseline values (For this purpose, “baseline” refers to the first study infusion [Run-In #1 or 
Gamunex-C PK visit].)
2
Results from blood and urine testing performed after infusion and/or at Day 10 after infusion of the IP.
Subjects from this study may be severely ill and may have anemia for a number of reasons. 
Therefore, it is important to exclude the underlying condition and concomitant medications 
as a cause of anemia. The exclusions are:
•
History or examination consistent with an alternative cause of anemia including blood 
loss (e.g., frequent phlebotomy is highly associated with changes in hemoglobin and 
102 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence Study to Evaluate
the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to Gamunex-C in Subjects with Primary
Effective

hematocrit levels for patients admitted to an internal medicine service [44,45]), iron-
deficiency anemia and other drug-induced hemolytic anemia).
•
Negative DAT.
•
Absence of evidence of hemolysis.
If the subject has confirmed hemolysis due to the administration of IP, the study treatment 
must be discontinued and, if necessary, standard therapy started.
103 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence Study to Evaluate
the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to Gamunex-C in Subjects with Primary
Effective

Appendix 5
Summary of Changes
(Note: Administrative changes including minor administrative corrections are not included in Protocol Summary of Changes.)
Sections
Change From:
(Version 3.0, dated 29 Jul 2020)
(Strikethrough is added to highlight deleted text.)
Change To:
(Version 4.0)
(Underline is added to highlight new text.)
Rationale:
Synopsis,
Study 
Objectives
Gamunex-C
Gamunex-C (IVIG-C)
Clarification about 
which agent is referred 
to by providing the 
generic abbreviation as 
well as the trade name
Synopsis, 
(Overall Study 
Design and 
Description)
4.2
A total of approximately 25 adult subjects will be 
enrolled in order to have 20 evaluable subjects for PK 
analysis.
A total of approximately 35 adult subjects will be 
enrolled in order to have 20 evaluable subjects for PK 
analysis.
Increased sample size to 
ensure a minimum of 20 
evaluable subjects for 
PK analysis
Synopsis, 
Overall Study 
Design and 
Description
Treatment visits for the Gamunex-C Run-In Phase, 
Gamunex-C PK Phase, IVIG-PEG PK Phase, and the 
Final Visit/Early Termination Visit may be performed 
at the study site or, if deemed appropriate, at an 
alternate site (e.g., subject's residence, local healthcare 
professional's site) under the care and supervision of 
trained healthcare personnel.  
Some treatment visits for the IVIG-PEG Treatment 
Phase may also be performed at the study site or, if 
deemed appropriate, at an alternate site (e.g., subject's 
residence, local healthcare professional's site) under the 
care and supervision of trained healthcare personnel. 
IVIG-PEG #1 and IVIG-PEG #2 treatment visits are to 
be performed at the study site.
Addition of clarifying 
new paragraphs to 
further explain where 
treatment visits may be 
conducted
104 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence
Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to
G
C i S bj
t
ith P i
H
l I
d fi i
Effective

Sections
Change From:
(Version 3.0, dated 29 Jul 2020)
(Strikethrough is added to highlight deleted text.)
Change To:
(Version 4.0)
(Underline is added to highlight new text.)
Rationale:
Synopsis, 
(Number of 
Subjects 
Planned)
Approximately 25 adult subjects are planned to be 
enrolled, in which a minimum number of 6 subjects 
are planned to be enrolled in each dosing interval 
(i.e., 3-weeks dosing interval vs 4-weeks dosing 
interval).
Approximately 35 adult subjects are planned to be 
enrolled, in which a minimum number of 6 subjects are 
planned to be enrolled in each dosing interval (i.e., 3-
weeks dosing interval vs 4-weeks dosing interval).
Increased sample size to 
ensure a minimum of 20 
evaluable subjects for 
PK analysis
Synopsis, 
Inclusion 
Criteria
2. Documented and confirmed pre-existing diagnosis 
of PI with features of hypogammaglobulinemia 
requiring IgG replacement therapy including but not 
limited to the following humoral-based 
immunodeficiency syndromes (e.g., X-linked 
agammaglobulinemia, common variable 
immunodeficiency), and combined 
immunodeficiency syndromes without 
lymphocytopenia (e.g., hyper immunoglobulin M 
[IgM] immunodeficiency syndrome). Please also 
refer to Exclusion Criteria
2. Documented and confirmed pre-existing diagnosis of 
PI with features of hypogammaglobulinemia requiring 
IV IgG replacement therapy including but not limited to 
the following humoral-based immunodeficiency 
syndromes (e.g., X-linked agammaglobulinemia, 
common variable immunodeficiency), and combined 
immunodeficiency syndromes without 
lymphocytopenia (e.g., hyper immunoglobulin M [IgM] 
immunodeficiency syndrome). Please also refer to 
Exclusion Criteria
Clarification that eligible 
previous IgG 
replacement therapy 
must be intravenous
3. IgG trough level ≥500 mg/dL at Screening Visit 
Note: Patients entering Group 1 must additionally 
have trough levels ≥500 mg/dL documented within 
the previous year. For patients entering Group 2, if 
Screening trough levels are not ≥500 mg/dL, the 
subject will be a Screen Failure, but may be 
rescreened following dose adjustment of their original 
IgG replacement therapy regimen and recording an 
IgG trough level ≥500 mg/dL
3. IgG trough level ≥500 mg/dL at Screening Visit 
Note: Patients entering Group 1 must additionally have 
trough levels ≥500 mg/dL documented within the 
previous year. For patients entering Group 2, if 
Screening trough levels are not ≥500 mg/dL, the subject 
will be a Screen Failure, but may be rescreened 
following dose adjustment of their original IV IgG 
replacement therapy regimen and recording an IgG 
trough level ≥500 mg/dL
Clarification that eligible 
previous IgG 
replacement therapy 
must be intravenous
Synopsis, 
Duration of 
Treatment
IGIV-C
Gamunex-C
Consistent replacement 
of IGIV-C with 
Gamunex-C
105 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence
Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to
G
C i S bj
t
ith P i
H
l I
d fi i
Effective

Sections
Change From:
(Version 3.0, dated 29 Jul 2020)
(Strikethrough is added to highlight deleted text.)
Change To:
(Version 4.0)
(Underline is added to highlight new text.)
Rationale:
Synopsis, 
Reference 
Therapy, Dose 
and Mode of 
Administration
Subjects will receive Gamunex-C by means of an 
infusion pump at a dose of 200 to 800 mg/kg per 
infusion at an infusion rate of 1 mg/kg/min or up to 
8 mg/kg/min depending on subject tolerance. 
Gamunex-C will be administered every 3 weeks (±4 
days) or 4 weeks (±4 days), depending on the 
subject’s prior IVIG dosing schedule.
Subjects will receive Gamunex-C by means of an 
infusion pump at a dose of 200 to 800 mg/kg per 
infusion at an infusion rate of 1 mg/kg/min or up to 
8 mg/kg/min depending on subject tolerance. The 
subject’s usual mg/kg dose (given on either a 3 or 4 
week repeating schedule) will be the same mg/kg dose 
and schedule that the subject was receiving prior to 
entering screening. This mg/kg dose and schedule will 
be used throughout the study duration. Note that the 
weight of the subject will be measured at each visit and 
if the subject’s weight changes, the actual weight at 
each visit will be used to calculate amount of drug (mg) 
to be administered. Gamunex-C will be administered 
every 3 weeks (±4 days) or 4 weeks (±4 days), 
depending on the subject’s prior IVIG dosing schedule.
Clarification of dosing 
by weight procedure
Glossary and 
Abbreviations
CRO
Contract Research Organization
Addition of new 
abbreviation that appears 
more than once in the 
text
IGIV-C
IVIG-C
Correction of acronym
Immune Globulin (Human), 10% 
Caprylate/Chromatography Purified 
Immune Globulin (Human), 10% 
Caprylate/Chromatography Purified OR Gamunex-C
Clarification that the 
product described is 
Gamunex-C
Section 2.1
(IGIV-C or Gamunex-C)
Gamunex-C (IVIG-C)
Clarification of wording 
to specify that Gamunex-
C is IVIG-C
Section 2.2
IGIV-C
Gamunex-C
Correction of IVIG-
C/IGIV-C acronym and 
consistent replacement 
of IGIV-C with 
Gamunex-C
106 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence
Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to
G
C i S bj
t
ith P i
H
l I
d fi i
Effective

Sections
Change From:
(Version 3.0, dated 29 Jul 2020)
(Strikethrough is added to highlight deleted text.)
Change To:
(Version 4.0)
(Underline is added to highlight new text.)
Rationale:
Section 2.6
Eligible participants for this study include male or 
female subjects who are between 18 and 75 years of 
age (inclusive) and have a diagnosis of PI requiring 
IgG replacement therapy. 
Eligible participants for this study include male or 
female subjects who are between 18 and 75 years of age 
(inclusive) and have a diagnosis of PI requiring IV IgG 
replacement therapy. 
Clarification that eligible 
previous IgG 
replacement therapy 
must be intravenous
Section 4.2
Treatment visits for the Gamunex-C Run-In Phase, 
Gamunex-C PK Phase, IVIG-PEG PK Phase and the 
Final Visit/Early Termination Visit may be performed 
at the study site or, if deemed appropriate, at an 
alternate site (e.g., subject's residence, local healthcare 
professional's site) under the care and supervision of 
trained healthcare personnel.  
Some treatment visits for the IVIG-PEG Treatment 
Phase may also be performed at the study site or, if 
deemed appropriate, at an alternate site (e.g., subject's 
residence, local healthcare professional's site) under the 
care and supervision of trained healthcare personnel. 
IVIG-PEG #1 and IVIG-PEG #2 treatment visits are to 
be performed at the study site.
Addition of clarifying 
new paragraphs to 
further explain where 
treatment visits may be 
conducted
107 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence
Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to
G
C i S bj
t
ith P i
H
l I
d fi i
Effective

Sections
Change From:
(Version 3.0, dated 29 Jul 2020)
(Strikethrough is added to highlight deleted text.)
Change To:
(Version 4.0)
(Underline is added to highlight new text.)
Rationale:
Section 4.2.2.1
During the Run-in Phase, subjects will receive an 
individualized dose of Gamunex-C between 200 to 
800 mg/kg that treating physicians consider 
appropriate compared to their previous IVIG 
treatment regimen. The first 3 consecutive doses of 
Gamunex-C during the Run-in Phase (visits #1, #2, 
and #3) can be adjusted as needed by treating 
physicians to achieve a stable dose for subjects, and 
then such stable dose should be maintained 
throughout the remainder of the Run-in Phase (visits 
#4, #5, and #6). Doses during visits #4, #5, and #6 
cannot vary from each other or from the dose given 
during visit #3 by more than 20%. Subjects who 
cannot achieve a stable dose of Gamunex-C during 
the Run-in Phase may not continue to the Gamunex-C 
PK Phase and will be withdrawn from the study (see 
Section 5.3.2).
During the Run-in Phase, subjects will receive an 
individualized dose of Gamunex-C between 200 to 800 
mg/kg that treating physicians consider appropriate 
compared to their previous IVIG treatment regimen. 
The subject’s usual mg/kg dose (given on either a 3 or 4 
week repeating schedule) will be the same mg/kg dose 
and schedule that the subject was receiving prior to 
entering screening. This mg/kg dose and schedule will 
be used throughout the study duration. Note that the 
weight of the subject will be measured at each visit and 
if the subject’s weight changes, the actual weight at 
each visit will be used to calculate amount of drug (mg) 
to be administered. The first 3 consecutive doses of 
Gamunex-C during the Run-in Phase (visits #1, #2, and 
#3) can be adjusted as needed by treating physicians to 
achieve a stable dose for subjects, and then such stable 
dose should be maintained throughout the remainder of 
the Run-in Phase (visits #4, #5, and #6). Doses during 
visits #4, #5, and #6 cannot vary from each other or 
from the dose given during visit #3 by more than 20%. 
Subjects who cannot achieve a stable dose of Gamunex-
C during the Run-in Phase may not continue to the 
Gamunex-C PK Phase and will be withdrawn from the 
study (see Section 5.3.2).
Clarification of dosing 
by weight procedure
Section 4.2.2.1
Treatment visits for the Gamunex-C Run-In Phase may 
be performed at the study site or, if deemed appropriate, 
at an alternate site (e.g., subject's residence, local 
healthcare professional's site) under the care and 
supervision of trained healthcare personnel.  
Addition of new 
paragraph to clarify 
where Gamunex-C Run-
In Phase visits may be 
conducted
108 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence
Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to
G
C i S bj
t
ith P i
H
l I
d fi i
Effective

Sections
Change From:
(Version 3.0, dated 29 Jul 2020)
(Strikethrough is added to highlight deleted text.)
Change To:
(Version 4.0)
(Underline is added to highlight new text.)
Rationale:
Section 4.2.2.2
Visits for the Gamunex-C PK Phase may be performed 
at the study site or, if deemed appropriate, at an 
alternate site (e.g., subject's residence, local healthcare 
professional's site) under the care and supervision of 
trained healthcare personnel.  
Addition of new 
paragraph to clarify 
where Gamunex-C PK 
Phase visits may be 
conducted
Section 4.2.3.1
Some treatment visits for the IVIG-PEG Treatment 
Phase may be performed at the study site or, if deemed 
appropriate, at an alternate site (e.g., subject's residence, 
local healthcare professional's site) under the care and 
supervision of trained healthcare personnel. IVIG-PEG 
#1 and IVIG-PEG #2 treatment visits are to be 
performed at the study site. If there are extenuating 
circumstances that prevent the subject from returning to 
the study site for these visits, the PI or designee is to 
discuss the situation with the sponsor. Sponsor approval 
may be granted to conduct the visit(s) at an alternate 
location under the care and supervision of trained 
healthcare personnel. 
Addition of new 
paragraph to clarify 
where treatment visits 
may be performed, and 
the procedure to obtain 
approval for an alternate 
location
Section 4.2.3.2
Visits for the IVIG-PEG PK Phase may be performed at 
the study site or, if deemed appropriate, at an alternate 
site (e.g., subject's residence, local healthcare 
professional's site) under the care and supervision of 
trained healthcare personnel.  
Addition of new 
paragraph to clarify 
where IVIG-PEG PK 
Phase visits may be 
conducted
Section 4.2.4
The Final Visit/Early Termination Visit may be 
performed at the study site or, if deemed appropriate, at 
an alternate site (e.g., subject's residence, local 
healthcare professional's site) under the care and 
supervision of trained healthcare personnel. 
Addition of new 
paragraph to clarify 
where the Final 
Visit/Early Termination 
Visit may be conducted
109 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence
Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to
G
C i S bj
t
ith P i
H
l I
d fi i
Effective

Sections
Change From:
(Version 3.0, dated 29 Jul 2020)
(Strikethrough is added to highlight deleted text.)
Change To:
(Version 4.0)
(Underline is added to highlight new text.)
Rationale:
Section 4.3.1
For example, if the Investigators’ center number is 
301, subject number will be 3011001, 3011002, 
3011003, etc., in consecutive order. Subject numbers, 
once assigned, will not be reused at any center.
For example, if the Investigators’ center number is 301, 
subject number will be 3010001, 3010002, 3010003, 
etc., in consecutive order. Subject numbers, once 
assigned, will not be reused at any center.
Corrections to the 
subject numbering 
schema example
Section 4.4.1.1
IVIG-PEG consists of 9 to 11% IgG in 0.16 to 0.24 
M glycine. IGIV-PEG 10% may be supplied in vial 
sizes of 10, 25, 50, 100, 200 and 400 mL. For this 
study, IGIV-PEG will be supplied in 100 mL vials.
IVIG-PEG consists of 9 to 11% IgG in 0.16 to 0.24 M 
glycine. IVIG-PEG 10% may be supplied in vial sizes 
of 10, 25, 50, 100, 200 and 400 mL. For this study, 
IVIG-PEG will be supplied in 100 mL vials.
Corrections to the 
acronym for one of the 
study drugs, IVIG-PEG
Section 5.1
2. Documented and confirmed pre-existing diagnosis 
of PI with features of hypogammaglobulinemia 
requiring IgG replacement therapy including but not 
limited to the following humoral-based 
immunodeficiency syndromes (e.g., X-linked 
agammaglobulinemia, common variable 
immunodeficiency), and combined 
immunodeficiency syndromes without 
lymphocytopenia (e.g., hyper immunoglobulin M 
[IgM] immunodeficiency syndrome). Please also 
refer to Exclusion Criteria
2. Documented and confirmed pre-existing diagnosis of 
PI with features of hypogammaglobulinemia requiring 
IV IgG replacement therapy including but not limited to 
the following humoral-based immunodeficiency 
syndromes (e.g., X-linked agammaglobulinemia, 
common variable immunodeficiency), and combined 
immunodeficiency syndromes without 
lymphocytopenia (e.g., hyper immunoglobulin M [IgM] 
immunodeficiency syndrome). Please also refer to 
Exclusion Criteria
Clarification that eligible 
previous IgG 
replacement therapy 
must be intravenous
3. IgG trough level ≥500 mg/dL at Screening Visit 
Note: Patients entering Group 1 must 
additionally have trough levels ≥500 mg/dL 
documented within the previous year. For 
patients entering Group 2, if Screening trough 
levels are not ≥500 mg/dL, the subject will be a 
Screen Failure, but may be rescreened following 
dose adjustment of their original IgG 
replacement therapy regimen and recording an 
IgG trough level ≥500 mg/dL
3. IgG trough level ≥500 mg/dL at Screening Visit 
Note: Patients entering Group 1 must additionally 
have trough levels ≥500 mg/dL documented within 
the previous year. For patients entering Group 2, if 
Screening trough levels are not ≥500 mg/dL, the 
subject will be a Screen Failure, but may be 
rescreened following dose adjustment of their 
original IV IgG replacement therapy regimen and 
recording an IgG trough level ≥500 mg/dL
Clarification that eligible 
previous IgG 
replacement therapy 
must be intravenous
110 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence
Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to
G
C i S bj
t
ith P i
H
l I
d fi i
Effective

Sections
Change From:
(Version 3.0, dated 29 Jul 2020)
(Strikethrough is added to highlight deleted text.)
Change To:
(Version 4.0)
(Underline is added to highlight new text.)
Rationale:
Section 6.1 
Subjects will receive IVIG-PEG and Gamunex-C by 
means of an infusion pump at a dose of 200 to 800 
mg/kg per infusion at an infusion rate of 1 mg/kg/min 
or up to 8 mg/kg/min depending on subject tolerance. 
IVIG-PEG and Gamunex-C will be administered 
every 3 weeks (±4 days) or 4 weeks (±4 days), 
depending on the subject’s prior IVIG dosing 
schedule. 
Subjects will receive IVIG-PEG and Gamunex-C by 
means of an infusion pump at a dose of 200 to 800 
mg/kg per infusion at an infusion rate of 1 mg/kg/min 
or up to 8 mg/kg/min depending on subject tolerance. 
The subject’s usual mg/kg dose (given on either a 3 or 4 
week repeating schedule) will be the same mg/kg dose 
and schedule that the subject was receiving prior to 
entering screening. This mg/kg dose and schedule will 
be used throughout the study duration. Note that the 
weight of the subject will be measured at each visit and 
if the subject’s weight changes, the actual weight at 
each visit will be used to calculate amount of drug (mg) 
to be administered. IVIG-PEG and Gamunex-C will be 
administered every 3 weeks (±4 days) or 4 weeks (±4 
days), depending on the subject’s prior IVIG dosing 
schedule. 
Clarification of dosing 
by weight procedure
All infusions will be administered at the study site
using a standard (eg, polyvinyl chloride) 
administration kit prepared by the clinical site staff. 
Qualified personnel, working to local standard 
operating procedures and under aseptic conditions, 
will prepare all infusions for both study drugs.
All infusions for both study drugs will be administered 
using a standard (e.g., polyvinyl chloride) 
administration kit prepared by qualified personnel, 
working to local standard operating procedures and 
under aseptic conditions.
Clarification of who can 
administer study drug, 
and removing the 
specification that it be 
conducted at the study 
site
Section 7.2.1.1 •
Record demographics: year of birth, gender, race, 
and ethnic origin
•
Record demographics: year of birth, age at 
screening (years), gender (if female, fertility 
status), race, and ethnic origin
Addition of age at 
screening and 
clarification of gender 
demographic for females 
to accurately reflect the 
Case Report Form data 
collection 
111 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence
Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to
G
C i S bj
t
ith P i
H
l I
d fi i
Effective

Sections
Change From:
(Version 3.0, dated 29 Jul 2020)
(Strikethrough is added to highlight deleted text.)
Change To:
(Version 4.0)
(Underline is added to highlight new text.)
Rationale:
- Urinalysis: pH, protein, glucose, ketones, bilirubin, 
nitrites, urobilinogen, blood, leukocyte esterase (with 
microscopic examination of urine sediment if 
abnormal)
- Urinalysis: pH, protein, glucose, ketones, bilirubin, 
nitrites, urobilinogen, blood, leukocyte esterase (with 
microscopic examination of urine sediment if 
abnormal), specific gravity
Clarification of specific 
gravity as part of 
urinalysis
- D-dimer 
- D-dimer (collected only once during this visit, before 
their standard of care infusion)
Additional clarification 
of when blood for D-
dimer level is to be 
collected
Section 
7.2.1.2.1
- Urinalysis: pH, protein, glucose, ketones, bilirubin, 
nitrites, urobilinogen, blood, leukocyte esterase (with 
microscopic examination of urine sediment if 
abnormal)
- Urinalysis: pH, protein, glucose, ketones, bilirubin, 
nitrites, urobilinogen, blood, leukocyte esterase (with 
microscopic examination of urine sediment if 
abnormal), specific gravity
Clarification of specific 
gravity as part of 
urinalysis
Gamunex-C Run-in #1, Run-in #3, and Run-in #5/#6 
visits may be performed at the study site or, if deemed 
appropriate, at an alternate site (e.g., subject's residence, 
local healthcare professional's site) under the care and 
supervision of trained healthcare personnel. 
Addition of new 
paragraph to clarify 
where Gamunex-C Run-
in visits may be 
performed
Section 
7.2.1.2.2
Gamunex-C Run-in #2, Run-in #4, and Run-in #5 visits 
may be performed at the study site or, if deemed 
appropriate, at an alternate site (e.g., subject's residence, 
local healthcare professional's site) under the care and 
supervision of trained healthcare personnel.  
Addition of new 
paragraph to clarify 
where Gamunex-C Run-
in visits may be 
performed
Section 
7.2.1.2.3
Gamunex-C PK Visits may be performed at the study 
site or, if deemed appropriate, at alternate site (e.g., 
subject's residence, local healthcare professional's site) 
under the care and supervision of trained healthcare 
personnel.
Addition of new 
paragraph to clarify 
where Gamunex-C PK 
visits may be performed
112 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence
Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to
G
C i S bj
t
ith P i
H
l I
d fi i
Effective

Sections
Change From:
(Version 3.0, dated 29 Jul 2020)
(Strikethrough is added to highlight deleted text.)
Change To:
(Version 4.0)
(Underline is added to highlight new text.)
Rationale:
Section 
7.2.1.3.1
- Urinalysis: pH, protein, glucose, ketones, bilirubin, 
nitrites, urobilinogen, blood, leukocyte esterase (with 
microscopic examination of urine sediment if 
abnormal)
- Urinalysis: pH, protein, glucose, ketones, bilirubin, 
nitrites, urobilinogen, blood, leukocyte esterase (with 
microscopic examination of urine sediment if 
abnormal), specific gravity
Clarification of specific 
gravity as part of 
urinalysis
IVIG-PEG #3 and IVIG-PEG #5/#6 visits may be 
performed at the study site or, if deemed appropriate, at 
an alternate site (e.g., subject's residence, local 
healthcare professional's site) under the care and 
supervision of trained healthcare personnel. The IVIG-
PEG #1 treatment visit is to be performed at the study 
site. If there are extenuating circumstances that prevent 
the subject from returning to the study site for these 
visits, the PI or designee is to discuss the situation with 
the sponsor. Sponsor approval may be granted to 
conduct the visit(s) at an alternate location under the 
care and supervision of trained healthcare personnel.
Addition of new 
paragraph to clarify 
where IVIG-PEG 
treatment visits may be 
performed, and how 
approval is to be sought 
for a change in location
Section 
7.2.1.3.2
IVIG-PEG #4 and IVIG-PEG #5 visits (as applicable) 
may be performed at the study site or, if deemed 
appropriate, at an alternate site (e.g., subject's residence, 
local healthcare professional's site) under the care and 
supervision of trained healthcare personnel. The IVIG-
PEG #2 treatment visit is to be performed at the study 
site. If there are extenuating circumstances that prevent 
the subject from returning to the study site for these 
visits, the PI or designee is to discuss the situation with 
the sponsor. Sponsor approval may be granted to 
conduct the visit(s) at an alternate location under the 
care and supervision of trained healthcare personnel.
Addition of new 
paragraph to clarify 
where IVIG-PEG 
treatment visits may be 
performed, and how 
approval is to be sought 
for a change in location
113 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence
Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to
G
C i S bj
t
ith P i
H
l I
d fi i
Effective

Sections
Change From:
(Version 3.0, dated 29 Jul 2020)
(Strikethrough is added to highlight deleted text.)
Change To:
(Version 4.0)
(Underline is added to highlight new text.)
Rationale:
Section 
7.2.1.3.3
IVIG-PEG PK Visits may be performed at the study 
site or, if deemed appropriate, at alternate site (e.g., 
subject's residence, local healthcare professional's site) 
under the care and supervision of trained healthcare 
personnel.
Addition of new 
paragraph to clarify 
where IVIG-PEG PK 
visits may be performed
Section 7.2.1.4
The assessments at this visit will be the same as the 
Final Visit, with the exception of an added PK sample 
for subjects who prematurely discontinue the study.
The assessments at this visit will be the same as the 
Final Visit, with the exception of an added PK sample 
for subjects who prematurely discontinue the study 
during the PK curves sampling periods (i.e., Gamunex-
C PK Phase and IVIG-PEG PK Phase) and a sample for 
total IgG concentration for safety purposes for subjects
prematurely discontinuing the study at any point.
Specifics about the PK 
sample and a separate 
safety sample for 
subjects who 
prematurely discontinue 
the study
- Urinalysis: pH, protein, glucose, ketones, bilirubin, 
nitrites, urobilinogen, blood, leukocyte esterase (with 
microscopic examination of urine sediment if 
abnormal)
- Urinalysis: pH, protein, glucose, ketones, bilirubin, 
nitrites, urobilinogen, blood, leukocyte esterase (with 
microscopic examination of urine sediment if 
abnormal), specific gravity
Clarification of specific 
gravity as part of 
urinalysis
˗
Blood draw for total IgG concentration (only 
for subjects prematurely discontinuing the 
study)
˗
Blood draw for total IgG concentration for 
safety purposes (only for subjects prematurely 
discontinuing the study)
Reason for blood draw 
for total IgG 
concentration from 
subjects who 
prematurely discontinue 
participation in the study
The Final Visit/Early Termination Visit may be 
performed at the study site or, if deemed appropriate, at 
an alternate site (e.g., subject's residence, local 
healthcare professional's site) under the care and 
supervision of trained healthcare personnel.  
Addition of new 
paragraph to clarify 
where the Final 
Visit/Early Termination
Visit may be performed
114 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence
Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to
G
C i S bj
t
ith P i
H
l I
d fi i
Effective

Sections
Change From:
(Version 3.0, dated 29 Jul 2020)
(Strikethrough is added to highlight deleted text.)
Change To:
(Version 4.0)
(Underline is added to highlight new text.)
Rationale:
Section 7.2.2
Detailed descriptions of laboratory test procedures are 
located in the study Laboratory Manual. Table 7-1
provides an example summary of the laboratory tests 
conducted for this study.
Detailed descriptions of laboratory test procedures are 
located in the study Laboratory Manual. Table 7-1
provides an example summary of the laboratory tests 
conducted for this study. Under extraordinary 
circumstances, some of the laboratory tests can be 
performed at the site’s local laboratory if testing is 
unable to be performed by the central laboratory.  When 
feasible and time permits, the site should discuss the 
extraordinary circumstances in advance with the 
sponsor and/or Contract Research Organization (CRO). 
Circumstances under 
which some laboratory 
tests may be performed 
at the site’s local 
laboratory, and that the 
site should discuss the 
circumstances with the 
sponsor and/or CRO
Table 7-1
Total IgG levels will consist of trough (pre-dose) 
measurements in all subjects, and for PK profiling of 
IVIG-PEG 
Total IgG levels will consist of trough (pre-dose) 
measurements in all subjects, and for PK profiling of 
IVIG-PEG and a total IgG concentration for safety 
purposes for subjects prematurely discontinuing the 
study
Clarification of blood 
draw for total IgG 
concentration from 
subjects who 
prematurely discontinue 
participation in the study
Qualitative serum β-HCG for females of child-
bearing potential will be performed at Screening
Quantitative serum β-HCG for females of child-bearing 
potential will be performed at Screening
Correction for serum β-
HCG, which is a 
quantitative test
Microscopic evaluation is done only with cause.
pH, protein, glucose, ketones, bilirubin, nitrites, 
urobilinogen, blood, leukocyte esterase (with 
microscopic examination of the urine if abnormal) 
Microscopic evaluation is done only with cause.
pH, protein, glucose, ketones, bilirubin, nitrites, 
urobilinogen, blood, leukocyte esterase (with 
microscopic examination of the urine if abnormal), 
specific gravity, and urine sediment
Addition to accurately 
reflect urinalysis
Section 8.2.5.1
Subjects will be monitored by the Investigator and/or 
study staff for signs and symptoms of arterial and 
venous TE events occurring between the first infusion 
(either the first infusion of Gamunex-C during the 
Run-in Phase or the first infusion of IVIG-PEG 
during the IVIG-PEG Treatment Phase) and the Final 
Visit/Early Termination Visit.
Subjects will be monitored by the Investigator and/or 
study staff for signs and symptoms of arterial and 
venous TE events at Screening and occurring between 
the first infusion (either the first infusion of Gamunex-
C during the Run-in Phase or the first infusion of IVIG-
PEG during the IVIG-PEG Treatment Phase) and the 
Final Visit/Early Termination Visit.
Clarification that 
subjects would also be 
monitored for TE events 
at Screening
115 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence
Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to
G
C i S bj
t
ith P i
H
l I
d fi i
Effective

Sections
Change From:
(Version 3.0, dated 29 Jul 2020)
(Strikethrough is added to highlight deleted text.)
Change To:
(Version 4.0)
(Underline is added to highlight new text.)
Rationale:
During all infusion visits, TE events risk will be 
assessed using: 
At Screening and during all infusion visits, TE events 
risk will be assessed using: 
Clarification that 
subjects would also be 
monitored for TE events 
at Screening
1. D-dimer blood levels (within 8 hours prior to the 
infusion and 30 ±10 minutes after the completion of 
the infusion)
1. D-dimer blood levels (within 8 hours prior to the 
study IP infusion and 30 ±10 minutes after the 
completion of the infusion)
Note:  The sample for the D-dimer blood level is 
only collected before the subject’s standard-of-care 
infusion at the Screening Visit. 
Clarification that the 
infusion is of the study 
IP, and the timing of the 
D-dimer blood test 
sample
Section 8.3.9.1
contract research organization 
CRO
Use of abbreviation, as 
this is the second time 
the term appears in the 
protocol
Section 9.2
An approximate 25 subjects are planned to be 
enrolled to have 20 evaluable subjects in the PK 
population for PK analysis
An approximate 35 subjects are planned to be enrolled 
to have 20 evaluable subjects in the PK population for 
PK analysis.
Increased sample size to 
ensure a minimum of 20 
evaluable subjects for 
PK analysis
Section 16
4. Immune Globulin (Human), 10% 
Caprylate/Chromatography Purified (IGIV-C) 
Investigator’s Brochure. Grifols. 2019.
4. Immune Globulin (Human), 10% 
Caprylate/Chromatography Purified (IVIG-C) 
Investigator’s Brochure. Grifols. 2019.
Correction of acronym
Appendix 1,
Table A,
footer i
Urinalysis will include: pH, protein, glucose, ketones, 
bilirubin, nitrites, urobilinogen, blood, leukocyte 
esterase (with microscopic examination of urine 
sediment if abnormal).
Urinalysis will include: pH, protein, glucose, ketones, 
bilirubin, nitrites, urobilinogen, blood, leukocyte 
esterase (with microscopic examination of urine 
sediment if abnormal), and specific gravity.
Clarification of specific 
gravity as part of 
urinalysis
Appendix 1, 
Table A, 
footer j
During infusion visits, D-dimer testing is to be 
performed within 8 hours prior to the infusion and 30 
±10 minutes after the completion of the infusion. 
Wells scoring is to be performed post-infusion. 7.2
During study IP infusion visits, D-dimer testing is to be 
performed within 8 hours prior to the infusion and 30 
±10 minutes after the completion of the infusion. At the 
Screening Visit, blood for the D-dimer level will only 
Clarifying wording to 
specify which infusion, 
the timing of the blood 
116 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence
Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to
G
C i S bj
t
ith P i
H
l I
d fi i
Effective

Sections
Change From:
(Version 3.0, dated 29 Jul 2020)
(Strikethrough is added to highlight deleted text.)
Change To:
(Version 4.0)
(Underline is added to highlight new text.)
Rationale:
describes at each visit evaluation of clinical signs and 
symptoms of thromboembolic events (e.g., pain, 
dyspnea, discoloration [paleness or redness] in lower 
extremities) after the completion of infusion 
(Appendix 3)
be collected prior to the subject’s standard of care 
infusion. Wells scoring is to be performed post-
infusion. Section 7.2 describes at each visit evaluation 
of clinical signs and symptoms of thromboembolic 
events (e.g., pain, dyspnea, discoloration [paleness or 
redness] in lower extremities) after the completion of 
infusion (Appendix 3)
sample for D-dimer 
level, and to specify 
Section in reference to 
the number provided
Appendix 1, 
Table A, 
footer p
PK samples will be obtained as follows: 30 minutes 
prior to the start of the intravenous infusion, 
immediately upon the completion of the infusion 
(within 10 minutes of infusion completion), and at 1, 
3, and 6 hours (±10 minutes), 24 and 48 hours (±2 
hours), and 4 (±2 hours), 7 (±1 d), 14 (±1 d), 21 (±2 
d), and 28 (±2 d) days (the 28 day PK sample applies 
only for subjects on every 4 weeks dosing regimen) 
after the end of the infusion. 
PK samples will be obtained as follows: within 30 
minutes prior to the start of the intravenous infusion, 
immediately upon the completion of the infusion 
(within 10 minutes of infusion completion), and at 1, 3, 
and 6 hours (±10 minutes), 24 and 48 hours (±2 hours), 
and 4 (±2 hours), 7 (±1 d), 14 (±1 d), 21 (±2 d), and 28 
(±2 d) days (the 28 day PK sample applies only for 
subjects on every 4 weeks dosing regimen) after the end 
of the infusion. An added PK sample will be requested 
for subjects who prematurely discontinue the study 
during the PK curves sampling periods (i.e., Gamunex-
C PK Phase and IVIG-PEG PK Phase).
Clarifying wording 
regarding timing of the 
first PK sample, and the 
added PK sample for 
subjects who 
prematurely discontinue 
participation
Appendix 1, 
Table A, 
footer r
Clinical evaluation of the signs and symptoms of 
hemolysis including red/dark urine, jaundice, as well 
as other signs and symptoms of anemia (such as 
pallor or tachycardia) during the infusion visit (pre-
infusion and post infusion) and by a phone call at 10 
days (±2 days) after each infusion.(Appendix 4).
Clinical evaluation of the signs and symptoms of 
hemolysis including red/dark urine, jaundice, as well as 
other signs and symptoms of anemia (such as pallor or 
tachycardia) during the infusion visit (pre-infusion and 
post infusion) and by a phone call by the Investigator or 
appropriate study staff (medical doctor) at 10 days (±2 
days) after each infusion.(Appendix 4).
Additional clarity about 
who would evaluate 
hemolysis signs and 
symptoms
Appendix 1, 
Table A, 
PK samples will only be taken at a subject’s final 
visit if they discontinue the study prematurely. 
PK samples will only be taken at a subject’s final visit 
if they discontinue the study prematurely. A sample for 
total IgG concentration for safety purposes will be 
Clarification of the total 
IgG concentration 
sample from subjects 
117 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence
Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to
G
C i S bj
t
ith P i
H
l I
d fi i
Effective

Sections
Change From:
(Version 3.0, dated 29 Jul 2020)
(Strikethrough is added to highlight deleted text.)
Change To:
(Version 4.0)
(Underline is added to highlight new text.)
Rationale:
footer t
taken from subjects prematurely discontinuing the 
study.
prematurely 
discontinuing the study
Appendix 1,
Table B,
footer i
Urinalysis will include: pH, protein, glucose, ketones, 
bilirubin, nitrites, urobilinogen, blood, leukocyte 
esterase (with microscopic examination of urine 
sediment if abnormal).
Urinalysis will include: pH, protein, glucose, ketones, 
bilirubin, nitrites, urobilinogen, blood, leukocyte 
esterase (with microscopic examination of urine 
sediment if abnormal), and specific gravity.
Clarification of specific 
gravity as part of 
urinalysis
Appendix 1, 
Table B,  
footer j
During infusion visits, D-dimer testing is to be 
performed within 8 hours prior to the infusion and 30 
±10 minutes after the completion of the infusion. 
Wells scoring is to be performed post-infusion. 7.2
describes at each visit evaluation of clinical signs and 
symptoms of thromboembolic events (e.g., pain, 
dyspnea, discoloration [paleness or redness] in lower 
extremities) after the completion of infusion 
(Appendix 3)
During study IP infusion visits, D-dimer testing is to be 
performed within 8 hours prior to the infusion and 30 
±10 minutes after the completion of the infusion. At the 
Screening Visit, blood for the D-dimer level will only 
be collected prior to the subject’s standard of care 
infusion. Wells scoring is to be performed post-
infusion. Section 7.2 describes at each visit evaluation 
of clinical signs and symptoms of thromboembolic 
events (e.g., pain, dyspnea, discoloration [paleness or 
redness] in lower extremities) after the completion of 
infusion (Appendix 3)
Clarifying wording to 
specify which infusion, 
the timing of the blood 
sample for D-dimer 
level, and to specify 
Section in reference to 
the number provided
Appendix 1, 
Table B,  
footer p
PK samples will be obtained as follows: 30 minutes 
prior to the start of the intravenous infusion, 
immediately upon the completion of the infusion 
(within 10 minutes of infusion completion), and at 1, 
3, and 6 hours (±10 minutes), 24 and 48 hours (±2 
hours), and 4 (±2 hours), 7 (±1 d), 14 (±1 d), 21 (±2 
d), and 28 (±2 d) days (the 28 day PK sample applies 
only for subjects on every 4 weeks dosing regimen) 
after the end of the infusion. 
PK samples will be obtained as follows: within 30 
minutes prior to the start of the intravenous infusion, 
immediately upon the completion of the infusion 
(within 10 minutes of infusion completion), and at 1, 3, 
and 6 hours (±10 minutes), 24 and 48 hours (±2 hours), 
and 4 (±2 hours), 7 (±1 d), 14 (±1 d), 21 (±2 d), and 28 
(±2 d) days (the 28 day PK sample applies only for 
subjects on every 4 weeks dosing regimen) after the end 
of the infusion. An added PK sample will be requested 
for subjects who prematurely discontinue the study 
during the PK curves sampling periods (i.e., Gamunex-
C PK Phase and IVIG-PEG PK Phase).
Clarifying wording 
regarding timing of the 
first PK sample, and the 
added PK sample for 
subjects who 
prematurely discontinue 
participation
118 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence
Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to
G
C i S bj
t
ith P i
H
l I
d fi i
Effective

Sections
Change From:
(Version 3.0, dated 29 Jul 2020)
(Strikethrough is added to highlight deleted text.)
Change To:
(Version 4.0)
(Underline is added to highlight new text.)
Rationale:
Appendix 1, 
Table B,  
footer r
Clinical evaluation of the signs and symptoms of 
hemolysis including red/dark urine, jaundice, as well 
as other signs and symptoms of anemia (such as 
pallor or tachycardia) during the infusion visit (pre-
infusion and post infusion) and by a phone call at 10 
days (±2 days) after each infusion.(Appendix 4).
Clinical evaluation of the signs and symptoms of 
hemolysis including red/dark urine, jaundice, as well as 
other signs and symptoms of anemia (such as pallor or 
tachycardia) during the infusion visit (pre-infusion and 
post infusion) and by a phone call by the Investigator or 
appropriate study staff (medical doctor) at 10 days (±2 
days) after each infusion.(Appendix 4).
Additional clarity about 
who would evaluate 
hemolysis signs and 
symptoms
Appendix 1, 
Table B, 
footer t
PK samples will only be taken at a subject’s final 
visit if they discontinue the study prematurely. 
PK samples will only be taken at a subject’s final visit 
if they discontinue the study prematurely. A sample for 
total IgG concentration for safety purposes will be 
taken from subjects prematurely discontinuing the 
study.
Clarification of the total 
IgG concentration 
sample from subjects 
prematurely 
discontinuing the study
Appendix 3, 
Table 1
During Screening Visit
Once during Screening Visit, prior to IVIG infusion
Clarification of timing of 
blood sample for D-
dimer level
Appendix 3,
Table 1,
footer a
A blood sample for D-dimer testing will be collected 
within 8 hours pre-infusion and 30 ±10 minutes 
post-completion of infusion. 
A blood sample for D-dimer testing will be collected 
within 8 hours pre-infusion and 30 ±10 minutes 
post-completion of infusion. At the Screening Visit, 
blood for the D-dimer level will only be collected prior 
to the subject’s standard of care infusion.
Clarification of timing of 
blood sample for D-
dimer level
119 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence
Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to
G
C i S bj
t
ith P i
H
l I
d fi i
Effective

Sections
Change From:
(Version 3.0, dated 29 Jul 2020)
(Strikethrough is added to highlight deleted text.)
Change To:
(Version 4.0)
(Underline is added to highlight new text.)
Rationale:
Appendix 3
Any subject with a total Wells prediction score ≤1 for 
DVT assessment and a positive D-dimer value (i.e., 
above baseline and out of normal range of the 
reporting laboratory) in combination with clinical 
signs or symptoms of a TE event (as per AEs 
assessment and such as pain, dyspnea, 
discoloration—paleness or redness—in lower 
extremities) should have further diagnostic testing per 
study site standard of care to confirm the occurrence 
of a TE event (Figure 1). 
Any subject with a total Wells prediction score ≤1 for 
DVT assessment and a positive D-dimer value (i.e., 
above baseline and out of normal range of the reporting 
laboratory) in combination with clinical signs or 
symptoms of a TE event (as per AEs assessment and 
such as pain, dyspnea, discoloration—paleness or 
redness—in lower extremities) should have further 
diagnostic testing per study site standard of care to 
confirm the occurrence of a TE event (Figure 1). For 
this purpose, “baseline” refers to the first study infusion 
(Run-In #1 or Gamunex-C PK visit).
Clarification of what is 
meant by ‘baseline’
Any subject with a total Wells prediction score ≤4 for 
PE assessment and a positive D-dimer value (i.e., 
above baseline and out of normal range of the 
reporting laboratory) should have further diagnostic 
testing per study site standard of care to confirm the 
occurrence of a TE event (Figure 2). 
Any subject with a total Wells prediction score ≤4 for 
PE assessment and a positive D-dimer value (i.e., above 
baseline and out of normal range of the reporting 
laboratory) should have further diagnostic testing per 
study site standard of care to confirm the occurrence of 
a TE event (Figure 2). For this purpose, “baseline” 
refers to the first study infusion (Run-In #1 or 
Gamunex-C PK visit).
Clarification of what is 
meant by ‘baseline’
Appendix 4
3. Evaluation of clinical parameters including 
red/dark urine, jaundice, as well as other signs and 
symptoms of anemia (such as pallor or tachycardia) 
evaluated by the Investigator or appropriate study 
staff (medical doctor) at any time on the day of 
infusion before the infusion and after the completion 
of the infusion, and via a phone call 10 days (±2 
days) after the initiation of the infusion.
3. Evaluation of clinical parameters including red/dark 
urine, jaundice, as well as other signs and symptoms of 
anemia (such as pallor or tachycardia) evaluated by the 
Investigator or appropriate study staff (medical doctor) 
at any time on the day of infusion before the infusion 
and after the completion of the infusion, and via a 
phone call 10 days (±2 days) after the initiation of the 
infusion by the Investigator or appropriate study staff 
(medical doctor).
Clarification of who is to 
evaluate clinical 
parameters
120 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence
Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to
G
C i S bj
t
ith P i
H
l I
d fi i
Effective

Sections
Change From:
(Version 3.0, dated 29 Jul 2020)
(Strikethrough is added to highlight deleted text.)
Change To:
(Version 4.0)
(Underline is added to highlight new text.)
Rationale:
3. At least 2 of the following:
•
Increased ARC1
•
Increased LDH level1
•
Low haptoglobin level1
•
Unconjugated hyperbilirubinemia2
1
Changes from baseline values 
2
Results from blood and urine testing performed 
after infusion and/or at Day 10 after infusion of 
the IP.
3. At least 2 of the following:
•
Increased ARC1
•
Increased LDH level1
•
Low haptoglobin level1
•
Unconjugated hyperbilirubinemia2
1
Changes from baseline values (For this purpose, 
“baseline” refers to the first study infusion [Run-In 
#1 or Gamunex-C PK visit].)
2
Results from blood and urine testing performed 
after infusion and/or at Day 10 after infusion of the 
IP.
Clarification of what is 
meant by ‘baseline’
121 of 121
 
 
 
Effective Date 
Page 
 
Status 
 
Version 
 
Number 
 
 
 
Bioscience Industrial Group 
BIG-CL-PRT-000010
4.0
01-Mar-2021
GC1902 - A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence
Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG  compared to
G
C i S bj
t
ith P i
H
l I
d fi i
Effective