A Multi-Center, Open-Label, Single-Arm Trial to Evaluate Efficacy, Pharmacokinetics, and Safety and Tolerability of IGSC 20% in Subjects With Primary Immunodeficiency
Phase: PHASE3
Conditions: Primary Immunodeficiency
Sponsor: Grifols Therapeutics LLC

 
Official Title: 
A Multi-Center, Open-Label, Single-Arm Trial to Evaluate Efficacy, 
Pharmacokinetics, and Safety and Tolerability of IGSC 20% in Subjects With 
Primary Immunodeficiency 
NCT Number: 
NCT02806986 
 
Document Dates: 
 
Protocol Version 2: 22 July 2016 
 
 
 
 
 
 
 
 

Protocol GTI 1503 - Amendment 2 
22Jul2016 
Clinical Study Protocol 
Protocol Title: 
Investigational Products: 
Sponsor's Name and Address: 
Sponsor's Telephone Number: 
Study Number/Protocol Version 
Number/Date: 
EUDRACT/CTA Number: 
Development Phase: 
A Multi-Center, Open-Label, Single-Arm Trial to 
Evaluate Efficacy, Phannacokinetics, and Safety 
and Tolerability of IGSC 20% in Subjects with 
Primary Immunodeficiency 
IGSC 20% 
Immune Globulin Subcutaneous (Human), 20% 
Caprylate/Chromatography Purified 
Grifols Therapeutics Inc. 
79 TW Alexander Drive 
Research Triangle Park, NC 27709 
, MD 
 
GTI1503/Version 2.0/22 Jul 2016 
Including GTI1503/Version 1.2/04 Dec 2015, 
GT11503/Draft Version 1.1/25 Nov 2015, and 
GTI 1503/V ersion I . 0/06 J ul 20 15 
2015-003290-15/TBD 
3 
The undersigned confirm that they agree to conduct the study under the conditions 
described in this protocol: 
Medical Monitor: 
, MD 
Signature: 
Date: 
Confidentiality 
Statement: 
CONFIDENTIAL 
The following confidential information is the property ofGrifols Therapeutics Inc. 
As long as the information contained in this protocol has not been published, it may 
only be used after permission has been obtained from Grifols Therapeutics Inc. It is 
not possible to make reproductions of all or sections of this protocol. Commercial 
use of the information is only possible with the permission of the proprietor and is 
subject to a license fee. 
Page I of 97 

Protocol GTI1503 - Amendment 2
22 Jul 2016
CONFIDENTIAL
Page 2 of 97
Summary of Changes for Amendment 2 Version 2.0
Protocol Version
Date of Approval
Version 2.0
Amendment 2 + Integrated Protocol
22 Jul 2016
Version 1.2
Amendment 1 + Integrated Protocol
04 Dec 2015
Draft Version 1.1
Amendment 1 + Integrated Protocol
25 Nov 2015
1.0
Original
06 Jul 2015
Protocol Amendment 2
The protocol for GTI1503 (Version 1.2, dated 04 Dec 2015) has been amended and reissued 
as Protocol Amendment 2, Version 2.0, dated 22 Jul 2016.  

Protocol GTI1503 - Amendment 2
22 Jul 2016
CONFIDENTIAL
Page 3 of 97
SUMMARY OF CHANGES FOR AMENDMENT 2 VERSION 2.0
(Note: Administrative changes including minor administrative corrections are not included in this Summary of Changes.)
Sections
Change From:
(Version 1.2 dated 04 Dec 2015)
(Strikethrough is added to highlight deleted text)
Change To:
(Version 2.0, dated 22 Jul 2016)
(Underline is added to highlight new text)
Rationale:
Synopsis: 
Study 
Objectives
Section 2.1.1
The primary efficacy objective of this Phase 3 study is to 
evaluate whether weekly administered Immune Globulin 
Subcutaneous (Human), 20% Caprylate/Chromatography 
Purified (IGSC 20%) over a one year period will achieve 
not more than 1 serious bacterial infection (SBI) per 
subject per year in primary immunodeficiency (PI) 
subjects.
The primary efficacy objective of this Phase 3 study is 
to evaluate whether weekly administered Immune 
Globulin Subcutaneous (Human), 20% 
Caprylate/Chromatography Purified (IGSC 20%) over a 
one year period will achieve less than 1 serious 
bacterial infection (SBI) per subject per year in primary 
immunodeficiency (PI) subjects.
Edited for consistency with 
EMA guideline wording
Synopsis: 
Target 
Population 
A documented trough IgG level of ≥ 500 mg/dL (within 
the previous 3 months) on this regimen is required.
A documented trough IgG level of ≥ 500 mg/dL (within 
the previous 6 months) on this regimen is required.
Increased 
the 
criterion 
window to allow for varying 
institutional standards
Synopsis: Key 
Assessments 
and Procedures
An SC infusion diary will be provided to each subject at 
Screening which may be used to record items including 
but not limited to: local infusion site reactions, 
concomitant 
medications 
(including 
antibiotics 
[prophylactic and therapeutic]), and details of SC drug 
administration (location and number of sites, date/clock 
time of start and end of infusion, dose/volume, duration 
and rates of infusion).
An SC infusion diary will be provided to each subject at 
the Baseline visit which may be used to record items 
including but not limited to: local infusion site 
reactions, 
concomitant 
medications 
(including 
antibiotics [prophylactic and therapeutic]), and details 
of SC drug administration (location and number of 
sites, date/clock time of start and end of infusion, 
dose/volume, duration and rates of infusion).
Revised the visit day when 
recording 
of 
diary 
data 
begins
Synopsis 
Inclusion 
Criteria
Section 3.2.1
5.
Documentation (within previous 3 months) of an IgG 
trough level of ≥ 500 mg/dL on current IgG 
replacement therapy regimen.
6.
Screening/pre-Baseline trough IgG levels must be ≥ 
500 mg/dL.
Note: If Screening and/or pre-Baseline trough levels 
are not above this threshold, the subject will be a 
Screen Failure, but may be re-screened following 
dose adjustment of their original IgG replacement 
therapy regimen and maintaining stable dosing for a 
period of at least 3 consecutive months prior to 
5. Documentation (within previous 6 months) of an 
IgG trough level of ≥ 500 mg/dL on current IgG 
replacement therapy regimen.
6. Screening/pre-Baseline trough IgG levels must be ≥ 
500 mg/dL.
Note: If Screening and/or pre-Baseline trough levels 
(not including pSC#2 trough) are not above this 
threshold, the subject will be a Screen Failure, but 
may be re-screened following dose adjustment of 
their original IgG replacement therapy regimen and 
maintaining stable dosing for a period of at least 3 
Increased criterion window 
to allow for varying 
institutional standards
Clarified that the blood draw 
occurring at the Baseline 
visit does not apply to this 
criterion since results are 
reported after the first 
investigational medicinal 
product (IMP) dose

Protocol GTI1503 - Amendment 2
22 Jul 2016
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Sections
Change From:
(Version 1.2 dated 04 Dec 2015)
(Strikethrough is added to highlight deleted text)
Change To:
(Version 2.0, dated 22 Jul 2016)
(Underline is added to highlight new text)
Rationale:
Screening a second time.
consecutive months prior to Screening a second 
time.
Synopsis 
Exclusion 
Criteria
Section 3.2.2
5. The subject has known selective immunoglobulin A 
(IgA) deficiency (with or without antibodies to IgA)
19.The subject has participated in another clinical trial 
within 30 days prior to Screening (observational 
studies without investigative treatments [non-
interventional] are permitted) or has received any 
investigational blood product within the previous 3 
months.
5.
The subject has known Selective Immunoglobulin 
A (IgA) Deficiency (with or without antibodies to 
IgA). (Note: exclusion is for the specific diagnostic 
entity. It does not exclude other forms of humoral 
primary immunodeficiency which have decreased 
IgA in addition to decreased IgG requiring immune 
globulin [IgG] replacement).
19. The subject has participated in another clinical trial 
within 30 days prior to Screening (observational 
studies without investigative
treatments [non-
interventional] are permitted) or has received any 
investigational blood product, with the exception of 
other IgG products, within the previous 3 months.
Note added to explain the 
intent of this criterion
Revised to exclude other IgG 
products as it is unnecessary 
to wait 3 months prior to 
screening a subject if they 
have 
received 
another 
investigational IgG product 
Section 3.1

Nonconsecutive Ctrough samples are acceptable for 
subjects on SCIG. The 4-week time allotment for the 
Screening/Previous Regimen Phase is necessary in 
order to ensure Screening human immunodeficiency 
virus (HIV) nucleic acid amplification technology 
(NAT) test results will be available before the 
Baseline Visit/Week 1 visit.

Nonconsecutive Ctrough samples are acceptable for 
subjects on SCIG. A minimum of 10 days is 
anticipated for the Screening/Previous Regimen 
Phase 
to 
ensure 
Screening 
human 
immunodeficiency 
virus 
(HIV) 
nucleic 
acid 
amplification technology (NAT) test results will be 
available before the Baseline Visit/Week 1 visit.
Revised 
to 
define 
a 
minimum time frame based 
on updated information from 
the 
Central 
Lab 
results 
timing
Section 3.2
Subjects who initially fail to meet eligibility criteria may 
be re-screened once upon consultation with the Sponsor.
Subjects who initially fail to meet eligibility criteria 
may be re-screened once upon consultation with the 
Medical Monitor.
Clarification 
that 
the 
delegated medical monitor 
role may be consulted for 
such cases
Section 3.4.3 
The medications listed below are not allowed during the 
study as premedication to an infusion; however, these 
medications are allowed during the study for general use 
(e.g., to treat an AE):
The medications listed below are not allowed during the 
study as premedication to an SC infusion; however, 
these medications are allowed during the study for 
general use (e.g., to treat an AE):
“SC” added as it is intended 
only to be applicable to the 
IP Treatment Phase
Section 3.6.2
No previous text
If there are logistical issues requiring schedule 
adjustment for weekly IGSC 20% administration, SC#1 
may be scheduled 6 to 9 days after pIV#2. Schedule 
adjustment may also be made after SC#3 or later (± 2 
Expansion of the visit 
window was added to 
accommodate subject 

Protocol GTI1503 - Amendment 2
22 Jul 2016
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Sections
Change From:
(Version 1.2 dated 04 Dec 2015)
(Strikethrough is added to highlight deleted text)
Change To:
(Version 2.0, dated 22 Jul 2016)
(Underline is added to highlight new text)
Rationale:
days from last infusion) when home infusion is 
initiated.
scheduling
Section 3.6.2.1
Screening Visit 
Assessments 
for all subjects
The duration of this phase is also dependent on the need 
for the HIV screening results that are required prior to 
Baseline/Week 1 of Treatment Stage 1, which may take 
more than 3 weeks to report.

AEs (including local infusion site reactions [see 
Section 4.3.1 for definitions]), prior and concomitant 
medications assessments (for antibiotics distinguish 
between prophylactic use and use for treatment of an 
episode of infection)

Record results of most recent chest X-ray within 12 
months (A chest X-ray will be necessary if not 
performed within 12 months of the Screening visit.)

SC infusion diary: An SC/IgG infusion diary will be 
provided to each subject at Screening which may be 
used to record items including but not limited to: local 
infusion site reactions, concomitant medications 
(including antibiotics [prophylactic and therapeutic]), 
and details of IgG drug administration (location and 
number of sites, date/clock time of start and end of 
infusion, dose/volume, duration and rates of infusion). 
The SC infusion diary may also be used to record 
days of missed work/school/daily activities due to 
infections 
and 
related 
treatment. 
During 
the 
Screening/Previous Regimen Phase for subjects 
entering study on IVIG the infusion diary may be 
used to record concomitant medications and days of 
missed work/school/daily activities due to infections 
and related treatment.
- Blood sample for previous regimen “random” IgG level 
The duration of this phase is also dependent on the need 
for the HIV screening results that are required prior to 
Baseline/Week 1 of Treatment Stage 1, which may take 
up to 2 weeks to report.

AEs (including infusion reactions [see Section 
4.3.1 for definitions]), prior and concomitant 
medications 
assessments 
(for 
antibiotics 
distinguish between prophylactic use and use for 
treatment of an episode of infection)

Record results of most recent chest X-ray within 12 
months (A chest X-ray will be necessary if not 
performed within 12 months of the Screening visit 
for adult subjects only as permitted per local 
requirements.) Note: at least one radiographic 
view (anterior-posterior [AP] or posterior-anterior 
[PA] is required)
Revised from 3 weeks to up 
to 2 weeks based on updated 
information from the Central 
Lab results timing
Expanded 
AE 
reporting 
criterion to include potential 
systemic infusion reactions
Removed requirement for a 
Screening x-ray to limit 
radiation 
exposure 
for 
pediatric subjects and to 
comply 
with 
local 
requirements 
for 
adult 
subjects
Moved initial use of the SC 
infusion 
diary 
from 
Screening to Baseline visit

Protocol GTI1503 - Amendment 2
22 Jul 2016
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Page 6 of 97
Sections
Change From:
(Version 1.2 dated 04 Dec 2015)
(Strikethrough is added to highlight deleted text)
Change To:
(Version 2.0, dated 22 Jul 2016)
(Underline is added to highlight new text)
Rationale:
Previous 
Regimen Phase 
pIV or pSC 
Visit #1 or #2
if pre-dose trough not coincident with the Screening Visit
-  Note the IgG trough values drawn during the Previous 
Regimen Phase constitute the Pre-baseline trough 
values which will confirm the final eligibility for 
subjects entering the study (must be ≥ 500 mg/dL).
Note: For subjects entering the study on an IVIG regimen 
where the Screening Visit does not coincide with pIV#1, 
safety laboratory testing (below italicized items only) 
should be repeated pre-IVIG dose at the visit for pIV#1 
because of the longer time duration before Baseline (see 
Figure 3 1 and Appendix 1):
-
Hemoglobin, hematocrit, platelets, red blood 
cell count including red blood cell morphology, 
white blood cell count with differential; ARC 
-
Sodium, 
potassium, 
creatinine, 
chloride, 
calcium, BUN, bicarbonate, albumin, LDH, 
AST, ALT, ALP, glucose, total bilirubin, 
indirect bilirubin
-
Serum pregnancy test (potential child-bearing 
females only)
-
Urinalysis: pH, protein, glucose, ketones, 
bilirubin, nitrites, urobilinogen, blood, leukocyte 
esterase (with microscopic examination of urine 
sediment if abnormal)

SC infusion diary: An SC/IgG infusion diary will be 
provided to each subject at Screening which may be 
used to record items including but not limited to: local 
infusion site reactions, concomitant medications 
(including antibiotics [prophylactic and therapeutic]), 
and details of IgG drug administration (location and 
number of sites, date/clock time of start and end of 
-  Note the IgG trough values drawn during the Previous 
Regimen Phase constitute the Pre-baseline trough 
values which will confirm the final eligibility for 
subjects entering the study (must be ≥ 500 mg/dL) 
with the exception of the pSC #2 trough result which 
will be reported after the Baseline visit.
Exception 
added 
for  
clarification
Removed 
requirement 
to 
repeat Screening safety labs 
as 
Screening/Pre-regimen 
Phase window is limited to 8 
weeks 
and 
such 
lab 
parameters 
are 
not 
anticipated to significantly 
change in this timeframe for 
the targeted study population
Moved initial use of the SC 
infusion 
diary 
from 
Screening to Baseline visit

Protocol GTI1503 - Amendment 2
22 Jul 2016
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Page 7 of 97
Sections
Change From:
(Version 1.2 dated 04 Dec 2015)
(Strikethrough is added to highlight deleted text)
Change To:
(Version 2.0, dated 22 Jul 2016)
(Underline is added to highlight new text)
Rationale:
infusion, dose/volume, duration and rates of infusion). 
All local infusion site reactions will be recorded in the 
eCRF. The subset of local infusion site reactions 
where 
the 
symptoms/signs 
lead 
to 
infusion 
interruption or discontinuation, require concomitant 
medication, or have an impact on the general 
condition of the subject as judged by the Investigator 
will be considered as AEs. The SC infusion diary may 
also 
be 
used 
to 
record 
days 
of 
missed 
work/school/daily activities due to infections and 
related treatment. For subjects entering study on 
IVIG, the infusion diary may be used to record 
concomitant medications and days of missed 
work/school/daily activities due to infections and 
related treatment.
-  Review of the SC infusion diary entries and 
infusion details will be undertaken with 
subjects/caregivers 
during 
the 
Previous 
Regimen Phase.

Record days lost from work/school/daily activities 
due to infections and treatment

AEs (including local infusion site reactions [see 
Section 4.3.1 for definitions]), prior and concomitant 
medications assessments (for antibiotics distinguish 
between prophylactic use and use for treatment of an 
episode of infection).

AEs (including infusion reactions [see Section 4.3.1 
for definitions]), prior and concomitant medications 
assessments (for antibiotics distinguish between 
prophylactic use and use for treatment of an episode 
of infection).
Expanded 
AE 
reporting 
criterion to include potential 
systemic infusion reactions
Section 3.6.2.2
Baseline Visit 
(week 1)

AEs (including local infusion site reactions [see 
section 4.3.1 for definitions] and clinical observation 
of signs and symptoms suggestive of any significant 
disease or condition [e.g., thrombosis, anemia, etc.])

Review SC infusion diary and infusion details with 
subjects/caregivers. All local infusion site reactions 
will be recorded in the eCRF. The subset of local 
infusion site reactions where the symptoms/signs lead 

AEs (including infusion reactions [see section 4.3.1 
for definitions] and clinical observation of signs 
and symptoms suggestive of any significant disease 
or condition [e.g., thrombosis, anemia, etc.])

SC infusion diaries: SC/IgG infusion diaries will be 
provided to each subject at the Baseline visit which 
may be used to record items including but not 
limited 
to: 
local 
infusion 
site 
reactions, 
Expanded 
AE 
reporting 
criterion to include potential 
systemic infusion reactions
Moved initial use of the SC 
infusion 
diary 
from 
Screening to Baseline visit

Protocol GTI1503 - Amendment 2
22 Jul 2016
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Page 8 of 97
Sections
Change From:
(Version 1.2 dated 04 Dec 2015)
(Strikethrough is added to highlight deleted text)
Change To:
(Version 2.0, dated 22 Jul 2016)
(Underline is added to highlight new text)
Rationale:
to infusion interruption or discontinuation, require 
concomitant medication, or have an impact on the 
general condition of the subject as judged by the 
Investigator will be considered as AEs. For subjects 
entering study on IVIG, the infusion diary may be 
used to record concomitant medications and days of 
missed work/school/daily activities due to infections 
and related treatment.
concomitant medications (including antibiotics 
[prophylactic and therapeutic]), and details of IgG 
drug administration (location and number of sites, 
date/clock time of start and end of infusion, 
dose/volume, duration and rates of infusion). All 
local infusion site reactions will be recorded in the 
eCRF. The subset of local infusion site reactions 
where the symptoms/signs lead to infusion 
interruption 
or 
discontinuation, 
require 
concomitant medication, or have an impact on the 
general condition of the subject as judged by the 
Investigator will be considered as AEs. The SC 
infusion diary may also be used to record days of 
missed 
work/school/daily 
activities 
due 
to 
infections and related treatment. 
Sections
3.6.2.3, 3.6.2.4, 
3.6.2.5, 3.6.2.6, 
3.6.2.7
Appendix 1

Record AEs including local infusion site reactions 
(see section 4.3.1 for definitions) and clinical 
observation of signs and symptoms suggestive of any 
significant disease or condition [e.g., thrombosis, 
anemia, etc.])

Record AEs including infusion reactions (see 
section 
4.3.1 
for 
definitions) 
and 
clinical 
observation of signs and symptoms suggestive of 
any 
significant 
disease 
or 
condition 
[e.g., 
thrombosis, anemia, etc.])
Expanded 
AE 
reporting 
criterion to include potential 
systemic infusion reactions
Table 3-1
Additional 
special tests a
DAT, serum free 
hemoglobin, 
haptoglobin
Central 
(central 
DAT if 
feasible)
Additional 
special tests a
DAT, serum free 
hemoglobin, 
haptoglobin
Central
Revised per Central Lab 
confirmation
Section 3.7

Pregnancy

Pregnancy (Note: Subject must be withdrawn from 
IP administration and the study prior to dosing with 
a commercially available IgG product.)
Revised for clarification on 
timing of withdrawal due to 
pregnancy
Section 4.4.1
Any SAE (see Section 4.3.6) 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 study drug. Each SAE must be fully 
recorded in the subject’s eCRF or SAE Report Form.
SAEs will be reported using the designated SAE Report 
Any SAE (see Section 4.3.6) 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 study drug. Each SAE 
must be fully recorded in the subject’s eCRF and SAE
Report Form.
Revised for internal 
consistency

Protocol GTI1503 - Amendment 2
22 Jul 2016
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Page 9 of 97
Sections
Change From:
(Version 1.2 dated 04 Dec 2015)
(Strikethrough is added to highlight deleted text)
Change To:
(Version 2.0, dated 22 Jul 2016)
(Underline is added to highlight new text)
Rationale:
Form. When the Investigator becomes aware of an SAE, 
she/he must submit electronically through the electronic 
data capture (EDC) system or when the EDC system is 
not available submit a completed, signed, and dated SAE 
Report Form (in English) within 24 hours to the Sponsor 
by email/fax.
All SAE Report Forms and Pregnancy Report Forms 
must be reported to Grifols electronically through the 
EDC system or when the EDC system is not available, 
reported to:
SAEs will be reported using the designated 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 (ie, medical records).
All SAE Report Forms must be reported by email to:
Section 4.4.2
In any case, a Pregnancy Report Form must be completed 
and sent as soon as possible to the Sponsor for any 
pregnancies that occur from time of consent through the 
Final Visit (i.e., end of study).
In any case, a Pregnancy Report Form must be 
completed and sent as soon as possible to the Sponsor 
for any pregnancies that occur in a female subject or 
partner of a male subject from time of consent through 
the Final Visit (i.e., end of study).
Revised for internal 
consistency
Appendix 1
Deleted row IgG level (random) if predose trough does 
not coincide with visit
Deleted
Screening, 
pIV#1/pSC#1,
and 
pIV#2 
assessments for Review SC Diary & infusion details with 
subject/caregiver
f
Record results of most recent chest X-ray within 12 
months (A chest X-ray will be necessary if not 
performed within 12 months of the Screening visit.)
g
Laboratory Assessments (chemistry, hematology, 
haptoglobin, & urinalysis) will be performed at the 
Screening and Baseline Visits. For subjects entering 
study on a prior IVIG regimen who do not have 
Screening Visit and pIV#1 coincide (pre-dose pIV#1) 
safety laboratory parameters (hematology, chemistry, 
urinalysis and serum pregnancy test) will be repeated 
during the Screening/Previous Regimen Phase.
f
Record results of most recent chest X-ray within 12 
months (A chest X-ray will be necessary if not 
performed within 12 months of the Screening visit 
for 
adult 
subjects 
as 
permitted 
per 
local 
requirements). 
g
Laboratory Assessments (chemistry, hematology, 
haptoglobin, & urinalysis) will be performed at the 
Screening and Baseline Visits. 
Removed IgG row to avoid 
an additional blood draw for 
certain subjects
Moved initial use of the SC 
infusion diary from 
Screening to Baseline visit;
Removed requirement for a 
Screening x-ray to limit 
radiation exposure for 
pediatric subjects and to 
comply with local 
requirements for adult 
subjects
Removed requirement to 
repeat Screening safety labs

Protocol GTI1503 - Amendment 2
22 Jul 2016
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Page 10 of 97
Investigator Signature Page
The undersigned confirms that he/she agrees to conduct the study under the conditions 
described in this protocol and comply with International Conference on Harmonization 
Good Clinical Practice (ICH GCP) and all applicable regulatory requirements:
___________________________________
______________________
INVESTIGATOR NAME (Please Print)
LOCATION
___________________________________
______________________
INVESTIGATOR SIGNATURE
DATE

Protocol GTI1503 - Amendment 2
22 Jul 2016
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Page 11 of 97
Protocol Synopsis
Title of Study:
A Multi-Center, Open-Label, Single-Arm Trial to Evaluate Efficacy, Pharmacokinetics, and 
Safety and Tolerability of IGSC 20% in Subjects with Primary Immunodeficiency
Study Number
GTI1503
Phase:
3
Number of Subjects Planned:
Approximately 60 subjects 
Study Centers Planned:
Approximately 40 study centers 
Study Objectives:
The primary efficacy objective of this Phase 3 study is to evaluate whether weekly 
administered Immune Globulin Subcutaneous (Human), 20% Caprylate/Chromatography 
Purified (IGSC 20%) over a one year period will achieve less than 1 serious bacterial 
infection (SBI) per subject per year in primary immunodeficiency (PI) subjects.
The secondary objective of this study is to determine if IGSC 20% replacement therapy 
maintains mean trough IgG levels that are comparable to the mean trough IgG levels with the 
previous IgG replacement regimen. Additional secondary objectives include determination of 
rate of infection of any kind (serious and non-serious), number of days on antibiotics, number 
of hospitalizations due to infection, and number of days of work/school/daily activities 
missed per subject year due to infections and their treatment.
The safety objectives are to assess the safety and tolerability of IGSC 20% as an IgG 
replacement therapy in subjects with PI.
Target Population:
Eligible participants for this study include male or female subjects who are 2 to 75 years of 
age and have a diagnosis of PI requiring IgG replacement treatment and who are currently 
receiving IgG replacement therapy via intravenous (IV) or subcutaneous (SC) infusion as a 
stable regimen for at least 3 consecutive months. A documented trough IgG level of       
≥500 mg/dL (within the previous 6 months) on this regimen is required.
For subjects receiving intravenous immune globulin (IVIG) at study entry, the dose must be 
at least 200 mg/kg per infusion administered every 3 or 4 weeks. For subjects receiving 
subcutaneously delivered immune globulin (SCIG) at study entry, there is no prerequisite 
minimum dose. Subjects who have never received IVIG or SCIG treatment (treatment naïve) 

Protocol GTI1503 - Amendment 2
22 Jul 2016
CONFIDENTIAL
Page 12 of 97
will not be eligible for entry into the study.
Overall Study Description:
This is a prospective, multi-center, open-label, single-arm, efficacy, pharmacokinetic (PK),
safety and tolerability study of the investigational product (IP), IGSC 20% in subjects with 
PI. Approximately 60 subjects will be enrolled in order to have approximately 20 adult 
subjects and 20 pediatric subjects treated with subcutaneously administered IGSC 20% who 
complete the entire study. This study will include 3 study stages: Screening/Previous 
Regimen Phase, IGSC 20% Treatment Stage 1 (13 IGSC 20% weekly doses), and IGSC 20% 
Treatment Stage 2 (39 IGSC 20% weekly doses).
A total of 52 doses of IGSC 20% will be administered with a final follow-up visit 1 week 
after the last dose at Week 53. Subjects/caregivers will be trained on self-administration of
IGSC 20% by the clinical site personnel.
Study Phases:
This is a prospective, multi-center, open-label, single-arm, efficacy, PK, safety and 
tolerability study of IGSC 20% in subjects with PI. Approximately 60 subjects will be 
enrolled in order to have approximately 20 adult subjects and 20 pediatric subjects treated 
with subcutaneously administered IGSC 20% who complete the entire study. This study will 
include 3 study stages: Screening/Previous Regimen Phase, IGSC 20% Treatment Stage 1 
(13 IGSC 20% weekly doses), and IGSC 20% Treatment Stage 2 (39 IGSC 20% weekly 
doses). 
Subjects who are receiving IVIG at a dose of at least 200 mg/kg per infusion every 3 or 
4 weeks at Screening must be on a stable IgG regimen (dose and dosing interval) for at least 
3 consecutive months prior to Screening. Subjects who are receiving SCIG must also be on a 
stable regimen for at least 3 consecutive months prior to Screening; there is no prerequisite 
minimum dose for subjects entering study on a SCIG regimen. Subjects who have never 
received IVIG or SCIG treatment (treatment naïve) will not be eligible for entry into the 
study. 
Previous Regimen Phase:   

Subjects will be infused with their current ongoing (“previous regimen”) IVIG/SCIG 
regimen (pIV/pSC) in the clinic (mandatory) to obtain 2 trough IgG levels (obtained prior 
to each pIV/pSC infusion) on each subject’s "previous regimen". For subjects entering 
study on SCIG, the second IgG trough level may be obtained at Baseline, immediately 
prior to starting the initial infusion of IGSC 20%.

The Screening Visit may coincide with the pIV/pSC infusion on the previous regimen 
(pIV#1/pSC#1). Product for the previous IgG regimen is not provided by Grifols. pIV 
subjects will be enrolled in IGSC 20% Treatment Stage 1 one week after completion of 
the last IgG trough sampling in the Previous Regimen Phase and therefore the subject 
must have 2 minimum concentration (Ctrough) samples on their pIV prior to the 
Baseline/Week 1 visit. pSC subjects will be enrolled in IGSC 20% Treatment Stage 1 
(Baseline) in accordance with the time interval that they are currently receiving SCIG 

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(i.e., if on a weekly SCIG regimen, Baseline will occur 1 week after completion of the 
last SCIG infusion and a second IgG trough level will be obtained at Baseline. If the 
interval between pSC infusions is 2 weeks (or more), then Baseline will occur after that 
time interval has elapsed, a trough IgG level will be obtained, and the eligible subject 
may commence IGSC 20% after Baseline assessments are complete).

Nonconsecutive Ctrough samples are acceptable for subjects on SCIG. The 4-week time 
allotment for the Screening/Previous Regimen Phase is necessary in order to ensure 
Screening human immunodeficiency virus (HIV) nucleic acid amplification technology 
(NAT) test results will be available before the Baseline Visit/Week 1 visit. 
20% IGSC Treatment Stage 1:

The first dose of the IP, IGSC 20%, will be administered immediately after Baseline 
assessments are complete (SC#1). Subjects will be infused with IGSC 20% at a 1:1 
dose-equivalent regimen (per equation in Section 3.3.2) from their previous regimen at 
the clinical site (or a minimum IGSC 20% dose of 100 mg/kg/week if the derived 1:1 
dose from the previous regimen is lower).

All subjects will receive 13 IGSC 20% infusions at weekly intervals and study visits at 
the clinical site will occur at Baseline/SC#1, SC#2, #3, #5, #9, and #13. IgG trough blood 
levels will be measured at all of these visits (except SC#3) occurring at the clinical site. 
All other doses of IGSC 20% may be infused at home (once properly trained) or in the 
clinic. 

The mg/kg dose of IGSC 20% (ratio of mg per kg) will be adjusted at clinic visits if the 
trough level in subjects is below 500 mg/dL, since this level is considered as insufficient 
to protect against SBI; the goal is to avoid repeated dose adjustments. The precise dose 
adjustment (mg/kg) should not be more than a 15% to 20% increase from the dose 
producing the low IgG trough, per the Investigator’s discretion. Any dose adjustments 
beyond this range will be completed in consultation with the Grifols Medical Monitor. 
The Treatment Stage 1 dose will continue into IGSC 20% Treatment Stage 2. After the 
13th IGSC 20% infusion in IGSC 20% Treatment Stage 1, subjects will enter IGSC 20% 
Treatment Stage 2 to receive an additional 39 weeks of IGSC 20% therapy.
IGSC 20% Treatment Stage 2:

In this treatment stage, the IGSC 20% dose (mg/kg) will remain constant with no dose 
adjustment permitted unless it is absolutely medically necessary to change the dose, and 
such change requires prior consultation with the Grifols Medical Monitor. Weight will be 
measured at every in-clinic visit and dosing will be based on the subject’s most current 
weight. For the subsequent at home IGSC 20% infusions between clinic visits, the dose 
will be the same as the total infusion dose calculated at the previous clinic study visit 
where weight was measured at the clinical site.

While all subjects will have an SC#17 clinic visit and associated standard assessments, 
serial PK sampling will be performed only in a subset of subjects: At SC#17, PK profiles 
in the first (where possible) 20 adult subjects will be measured by obtaining blood draws 

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for steady-state PK analyses over a period of 7 days just prior to and post the 17th IGSC 
20% infusion through SC#18. These subjects will constitute the PK subset in this study. 
-
Where possible, the PK subset will comprise the first 20 adult subjects enrolled. Any 
designated PK subject who undergoes a dose adjustment (mg/kg change in dose) at or 
after the ninth IGSC 20% infusion (SC#9) which corresponds to at or after Week 9 in
Treatment Stage 1 will be permitted to remain in the study, though he/she will not 
participate in PK profiling; however, an additional PK replacement subject may be 
recruited. 
-
Similarly, PK subjects who do not complete the full PK profile may be replaced if 
deemed necessary.
A total of 52 doses of IGSC 20% will be administered (13 doses of IGSC 20% in Treatment 
Stage 1 and 39 doses of IGSC 20% in Treatment Stage 2) with a final follow-up visit at 
Week 53 one week after the last dose at Week 52.
Final Visit (Week 53)/Early Termination Visit
One week post last SC infusion of IGSC 20%, a Final Visit will occur. If a subject 
discontinues at any point during the study after Baseline, the subject will be requested to 
return to the Investigator’s study site for Final Visit/Early Termination Visit (Appendix 1).
Key Assessments and Procedures:
The primary efficacy variable, SBI, is defined as described in Appendix 3.
IgG trough levels will be measured at least twice during the Screening/Previous Regimen 
Phase, and Baseline as detailed in Appendix 1 and Figure 3-1, just prior to the second 
IGSC 20% weekly infusion, at the SC#5 Visit, and then about every 4 weeks.
At SC#17, PK profiles in approximately 20 adult subjects will be measured by obtaining 
blood draws for steady-state PK analyses over a period of 7 days just prior to and post the 
17th IGSC 20% infusion as detailed in Appendix 2. An SC infusion diary will be provided to 
each subject at the Baseline visit which may be used to record items including but not limited 
to: local infusion site reactions, concomitant medications (including antibiotics [prophylactic 
and therapeutic]), and details of SC drug administration (location and number of sites, 
date/clock time of start and end of infusion, dose/volume, duration and rates of infusion). The 
SC infusion diary will also be used to record days of missed work/school/daily activities due 
to infections and related treatment.
Duration of Treatment:
The duration of the IGSC 20% treatment periods of the study is 12 months. A total of 52 
doses of IGSC 20% will be administered (13 doses of IGSC 20% in Treatment Stage 1 and 
39 doses of IGSC 20% in Treatment Stage 2).
Diagnosis and Main Eligibility Criteria:

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Inclusion Criteria:
A subject must meet all the following inclusion criteria to be eligible for participation in this 
study.
1. Adults and adolescents between the ages of 2 and 75 years (inclusive) at Screening.
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.
3. The subject has not had an SBI within the last 3 months prior to Screening and has no
SBIs up to the time of the Baseline Visit. 
Note: If an SBI occurs during the Screening/Previous Regimen Phase and prior to the 
first dose of Grifols IGSC 20%, the subject will be a Screen Failure).
4. Currently on IgG replacement therapy (stable regimen [dose and dosing interval] via IV 
or SC infusion) for ≥ 3 consecutive months. Subjects receiving IVIG prior to study must 
receive a dosage of at least 200 mg/kg per infusion.
5. Documentation (within previous 6 months) of an IgG trough level of ≥500 mg/dL on 
current IgG replacement therapy regimen.  
6. Screening/pre-Baseline trough IgG levels must be ≥500 mg/dL.
Note: If Screening and/or pre-Baseline trough levels (not including pSC#2 trough) are not 
above this threshold, the subject will be a Screen Failure, but may be re-screened 
following dose adjustment of their original IgG replacement therapy regimen and 
maintaining stable dosing for a period of at least 3 consecutive months prior to Screening 
a second time.
7. The medical records for all subjects should be available to document diagnosis, previous 
infections, and treatment.
8. The subject has signed an informed consent.
Note: The subject must sign the informed consent form (ICF) if at least 18 years old; for 
children of younger age, the subject’s parent or legal guardian must sign the ICF and if 
appropriate/applicable, the subject must sign a child assent form approved by the 
Institutional Review Board or Ethics Committee (IRB/EC) per their requirements (see 
Section 7.4).
Exclusion Criteria:
A subject meeting any of the following exclusion criteria is NOT eligible for participation in 
the study.
1. Clinical evidence of any significant acute or chronic disease that, in the opinion of the 
Investigator, may interfere with successful completion of the trial or place the subject at 
undue medical risk.

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2. The subject has had a known serious adverse reaction to immunoglobulin or any severe 
anaphylactic reaction to blood or any blood-derived product.
3. The subject has a history of blistering skin disease, clinically significant 
thrombocytopenia, bleeding disorder, diffuse rash, recurrent skin infections, or other 
disorders where SC therapy would be contraindicated during the study.
4. The subject has isolated IgG subclass deficiency, isolated specific antibody deficiency 
disorder, or transient hypogammaglobulinemia of infancy.
5. The subject has known Selective Immunoglobulin A (IgA) Deficiency (with or without 
antibodies to IgA). (Note: exclusion is for the specific diagnostic entity. It does not 
exclude other forms of humoral primary immunodeficiency which have decreased IgA in 
addition to decreased IgG requiring immune globulin [IgG] replacement).
6. Females of childbearing potential who are pregnant, have a positive pregnancy test at 
Screening (serum) or Baseline (urine) (human chorionic gonadotropin [HCG]-based 
assay), are breastfeeding, or unwilling to practice a highly effective method of 
contraception (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.)
7. The subject has significant proteinuria (dipstick proteinuria ≥ 3+, known urinary protein 
loss > 1 g/24 hours, or nephrotic syndrome), has a history of acute renal failure, has 
severe renal impairment (blood urea nitrogen [BUN] or creatinine more than 2.5 times 
the upper limit of normal [ULN]), and/or is on dialysis.
8. The subject has Screening Visit values of aspartate aminotransferase (AST) or alanine 
aminotransferase (ALT) levels exceeding 2.5 times the ULN for the expected normal 
range for the testing laboratory.
9. The subject has hemoglobin < 9 g/dL at Screening.
10. The subject has a known previous infection with or clinical signs and symptoms 
consistent with current hepatitis B virus (HBV) or hepatitis C virus (HCV) infection.  
11. The subject has a history of or current diagnosis of deep venous thrombosis or 
thromboembolism (e.g., myocardial infarction, cerebrovascular accident, or transient 
ischemic attack); history refers to an incident in the year prior to Screening or 2 episodes 
over lifetime.
12. The subject is currently receiving anti-coagulation therapy which would make SC
administration inadvisable (vitamin K antagonists, nonvitamin K antagonist oral 
anticoagulants [e.g., dabigatran etexilate targeting Factor IIa, rivaroxaban, edoxaban, and 
apixaban targeting Factor Xa], parenteral anticoagulants [e.g., fondaparinux]).
13. The subject currently has a known hyperviscosity syndrome.
14. The subject has an acquired medical condition that is known to cause secondary immune 
deficiency, such as chronic lymphocytic leukemia, lymphoma, multiple myeloma, 

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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). 
15. The subject is HIV positive by nucleic acid amplification technology (NAT) based on a 
Screening blood sample. The subject may enter the Previous Regimen Phase while the 
Screening blood sample is being tested, but will be a Screen Failure and will not undergo 
Baseline assessments if the HIV result is positive.
16. The subject (if < 18 years of age) has non-controlled arterial hypertension at a level of 
greater than or equal to the 90th percentile blood pressure (either systolic or diastolic) for 
their age and height (see Appendix 4) or the adult subject has non-controlled arterial 
hypertension (systolic blood pressure > 160 mmHg and/or diastolic blood pressure > 100 
mmHg).
17. The subject is 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 of corticosteroids of not more than 10 days would not exclude 
a subject. Inhaled or topical corticosteroids are allowed. 
18. The subject has known substance or prescription drug abuse.
19. The subject has participated in another clinical trial within 30 days prior to Screening 
(observational studies without investigative treatments [non-interventional] are 
permitted) or has received any investigational blood product, with the exception of other 
IgG products, within the previous 3 months.
20. The subject/caregiver is unwilling to comply with any aspect of the protocol, including 
the home SC infusions, blood sampling, and completion of an SC infusion diary for the 
duration of the study.
21. Mentally challenged subjects who cannot give independent informed consent.
22. In the opinion of the Investigator, the subject may have compliance problems with the 
protocol and the procedures of the protocol.
Investigational Product, Dose, and Mode of Administration:
The investigational product is Grifols Immune Globulin Subcutaneous (Human), 20% 
Caprylate/Chromatography Purified (IGSC 20%) which is a sterile liquid formulation of 
immunoglobulin that has been purified from human plasma via a multi-step process.
The IGSC 20% mg/kg/week dose to be utilized during Treatment Stage 1 will be calculated 
based on the subject’s prior (pre-study) pIV or pSC replacement regimen with a 1-to-1 (1:1) 
correspondence in dosage and a minimum dose of IGSC 20% of 100 mg/kg/week. During 
Treatment Stage 1, adjustment in the dose of IGSC 20% will be made if IgG Ctrough is less 
than 500 mg/dL.
The IV regimen to IGSC 20% dose conversion calculation formula is: 

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The alternative SC regimen to IGSC 20% dose conversion calculation formula is: 
For subjects on another SCIG regimen at study entry, if the dose is given weekly, the dose of 
IGSC 20% will be the same. However, if the pre-study SC regimen is dosed over a longer 
time interval, that dose will be divided by the number of weeks between doses to provide the 
IGSC 20% dose per week (see protocol Section 3.3.2). The minimum dose for IGSC 20% for 
either case of transition is 100 mg/kg/week.
During Treatment Stage 2, the mg/kg body weight dose of IGSC 20% is to be kept constant
unless it is absolutely medically necessary to change the dose, and such change requires prior
consultation with the Grifols Medical Monitor. Weight will be measured at every in-clinic 
visit and dosing will be based on the subject’s current weight.
This is an open-label study.
Study Variables:
Efficacy and Pharmacokinetic Variables:
Primary Efficacy Variable

The primary efficacy variable is the number of SBIs.
Secondary Variables

Trough concentrations of total IgG of previous regimen during the Screening/Previous 
Regimen Phase and the IGSC 20% Treatment Stages 1 and 2

Rate of infection of any kind (serious and non-serious) including acute sinusitis, 
exacerbation of chronic sinusitis, acute otitis media, pneumonia, acute bronchitis, and 
infectious diarrhea, which will be recorded as an AE with the Investigator answering the 
following question affirmatively in the eCRF: “is this an infection?” (verbatim term 
delineating nature of infection).

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
pSC dose mg/kg
previous pSC dosing interval in weeks between infusions
≥ 200 mg/kg (pIV dose)
3 or 4 (previous pIV dosing interval in weeks between infusions)

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Other Variables

Trough levels of IgG subclasses (IgG1, IgG2, IgG3, IgG4) in specific pre-dose blood 
samples in all subjects  

Antibody levels for Streptococcus pneumoniae, Hemophilus influenzae, and Clostridium
tetani (tetanus)

PK profile for total IgG (area under the concentration-time curve from 0 to 7 days 
[AUC0-7 days], maximum concentration [Cmax], and time to reach Cmax [tmax]) in adult PI 
subjects at steady state (after approximately 4 months [16 weeks]) of weekly 
administration of IGSC 20% 

Trough measles antibody titers (functional assay) are an exploratory variable for 
informational purposes

Number of 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])
Safety Variables:

Adverse events (AEs), suspected adverse drug reactions (suspected ADRs), serious AEs 
(SAEs), and discontinuations due to AEs and SAEs
Note: All local infusion site reactions will be recorded in the eCRF. The subset of local 
infusion site reactions where the symptoms/signs lead to infusion interruption or 
discontinuation, require concomitant medication, or have an impact on the general 
condition of the subject as judged by the Investigator will be considered as AEs.

Vital signs during clinic visits (temperature [T], respiratory rate [RR], heart rate [HR], 
systolic blood pressure [SBP] and diastolic blood pressure [DBP]).

Physical assessments: physical exams will be recorded as normal or abnormal, according 
to the physician’s judgment criteria, and findings will be recorded.

Laboratory assessments including chemistry, hematology, and urinalysis
Adverse Event Management
Subjects will be carefully monitored for AEs. This monitoring includes clinical and 
laboratory tests and physical signs. Adverse events should be assessed in terms of their 
seriousness, severity, and causal relationship to the IP.
Any AE that occurs at any time between the signature of the ICF and last day of the subject’s 
participation in the clinical trial must be reported and recorded in the AE eCRF.
For AEs that occur during infusions, the infusion rate in effect at the time of onset of the AE, 
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.
In so far as is possible, all individuals will be followed up until the AE or suspected ADR has 
resolved. If an AE/suspected ADR/SAE is present when the subject has completed the study, 

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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 pregnancy must be followed by the Investigator until delivery or to the end of 
pregnancy.
Statistical and Analytical Methods:
Determination of Sample Size
Assuming that the true rate of the SBIs is 0.25 per subject per year, 40 subjects treated for 
one year for IGSC 20% will provide at least 90% power to reject the null hypothesis of an
SBI rate greater than or equal to 1.0 per person per year, using a one-sided test at the 0.01 
level. 
In order to obtain a total of 40 PI subjects including 20 adult and 20 pediatric subjects who 
complete the study, approximately 60 subjects will be enrolled and treated in the study. This 
sample size is to allow for a moderate to high early discontinuation rate seen in other similar 
studies.
Safety Population
The safety population will include all subjects who have received any amount of IGSC 20% 
and will be used for safety analyses.
Efficacy Evaluable Population 
The efficacy evaluable population will include all subjects who have received at least one 
dose of IGSC 20% and will be used for efficacy analyses.
IgG Population
The IgG population will consist of all subjects who receive any amount of IGSC 20% and 
have total IgG concentration data to facilitate the comparison of mean trough IgG 
concentration during the IGSC 20% stage versus the pre-treatment phase. 
Pharmacokinetic Population
The PK population will consist of all adult subjects who have received IGSC 20% and have 
sufficient serial IgG concentration versus time data to facilitate calculation of area under the 
concentration vs. time curve (AUC) PK parameters.
Primary Efficacy Analyses
The primary efficacy variable of SBIs will be analyzed using the efficacy evaluable 
population. 
The number of SBIs from Week 1 to Week 53 during IGSC 20% treatment period and 
percentage of subjects with SBIs will be summarized. The SBI rate will be compared to the 
recommended standard rate of 1 SBI per person per year. The following hypothesis testing is 

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performed with one-sided test at alpha = 0.01 level: 
year
per
person
per
SBI
H
versus
year
per
person
per
SBI
H
A
1
:
1
:
0




Where λ is the SBI rate during IGSC 20% treatment. Occurrence of SBI is assumed to follow 
the Poisson distribution. The generalized linear model procedure for Poisson regression with 
log link will be used to estimate the SBI rate for IGSC 20% 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.
Secondary and Other Efficacy Analysis
Secondary and other efficacy variables (except the PK variables [discussed below]) will be 
summarized descriptively. Annualized rate of all infections, days of missed 
work/school/daily activities, days on antibiotics, and hospitalizations will be calculated and 
the 95% CI will be provided. 
Pharmacokinetic Analysis
Trough concentrations of total IgG during the Screening/Previous Regimen Phase and the 
IGSC 20% Treatment Stage will be summarized by week for the efficacy evaluable 
population. Mean trough for IGSC 20% treatment phase will be calculated as the average of 
all steady state trough concentrations measured during the IGSC 20% Treatment Stage 2 (i.e., 
IgG trough levels measured at the following visits: SC#17, #20, #24, #28, #32, #36, #40, 
#44, #48,  #52, and #53). Comparison will be made to the mean of 2 troughs for previous IgG 
treatment (either IVIG or other SCIG products) obtained from the Screening/Previous 
Regimen Phase. Mean trough data will be summarized. Mean trough summary and analysis 
will be based on the IgG population.
For samples collected after SC#14 infusion (start of Treatment Stage 2), total IgG 
concentrations will be summarized by time point. For subjects in the PK subset with an IgG 
PK profile, individual and mean/median IgG concentrations versus time curves will be 
plotted. PK parameters for total IgG including AUC0-7days, Cmax, and tmax will be determined 
by noncompartmental model using WinNonlin software. All PK parameters will be tabulated 
and summarized descriptively. The analyses will be based on the PK population. 
Summaries will be provided for average trough concentration of IgG subclasses (Screening, 
Baseline, before the 13th, 24th, 36th IGSC 20% infusion, and Final Visit). Summaries of 
average trough level concentration of antibody titers S. pneumoniae, H. influenzae, and C.
tetani (tetanus) will also be provided. 
Trough measles antibody titers (functional assay) are an exploratory variable for 

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informational purposes.
Safety Analysis

The safety analyses are based on the safety population. 

All AEs, suspected ADRs, SAEs, and discontinuations due to AEs and SAEs will be 
summarized by presenting the number of events and the number and percentage of 
subjects with events. The summaries will be presented by Medical Dictionary for 
Regulatory Activities (MedDRA) system organ class and preferred term. AE summaries 
by severity will also be provided. Local infusion site reactions will be similarly 
summarized.

Subjects with deaths, SAEs, and AEs leading to premature discontinuation from the study 
will be listed and presented in a narrative form. 

Adverse events temporally associated with SC administration of study drug will be 
defined as those occurring during or within 72 hours of completion of an infusion.

Local infusion site reactions will be tabulated and summarized for the total duration of 
the study and by IGSC 20% infusion week.

For all laboratory tests and vital signs, 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.

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TABLE OF CONTENTS
SUMMARY OF CHANGES FOR AMENDMENT 2 VERSION 2.0......................................3
GLOSSARY AND ABBREVIATIONS..................................................................................27
1
INTRODUCTION ...........................................................................................................30
1.1
Primary Immunodeficiency ...................................................................................30
1.2
Immunoglobulin Replacement Therapy ................................................................30
1.3
Immune Globulin Subcutaneous (Human), 20% Caprylate/Chromatography 
Purified (IGSC 20%)..............................................................................................31
1.4
Study Rationale and Dose Selection......................................................................31
1.4.1
Study Rationale............................................................................................31
1.4.2
Dose Rationale.............................................................................................32
2
STUDY OBJECTIVES....................................................................................................34
2.1
Efficacy and Pharmacokinetic Objectives .............................................................34
2.1.1
Primary Efficacy Objective..........................................................................34
2.1.2
Secondary Objectives...................................................................................34
2.1.3
Other Objectives ..........................................................................................34
2.2
Safety Objectives ...................................................................................................35
3
INVESTIGATIONAL PLAN..........................................................................................35
3.1
Study Design and Plan...........................................................................................35
3.2
Selection of Study Population................................................................................39
3.2.1
Inclusion Criteria .........................................................................................39
3.2.2
Exclusion Criteria ........................................................................................40
3.3
Treatments..............................................................................................................42
3.3.1
Treatments to Be Administered ...................................................................42
3.3.2
Selection of Dose and Interval for Each Subject .........................................42
3.3.2.1
Labeling of Investigational Product(s)
43
3.3.2.2
Storage of Investigational Products
44
3.3.2.3
Preparation
44
3.3.2.4
Accountability for Investigational Product(s)
44
3.3.3
Rationale for Selection of Doses and Dose Interval for Investigational  
Products in the Study ...................................................................................45
3.3.4
Method of Assigning Subjects to Treatment Groups...................................45
3.3.4.1
Subject Numbering
45
3.3.4.2
Randomization
45
3.3.4.3
Blinding
45
3.3.4.4
Administration and Timing of Investigational Product for Each 
Subject
45
3.3.4.5
Subcutaneous Administration Procedures of Investigational 
Product
46

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3.3.4.6
Treatment Compliance
47
3.4
Prior and Concomitant Therapy.............................................................................47
3.4.1
Prohibited Medications Prior to Study Participation ...................................47
3.4.2
Prohibited Concomitant Medications during the Study...............................47
3.4.3
Restricted Concomitant Medications during the Study ...............................48
3.4.4
Drug Interactions .........................................................................................48
3.5
Study Variables......................................................................................................48
3.5.1
Efficacy and Pharmacokinetic Variables.....................................................48
3.5.1.1
Primary Efficacy Variable
48
3.5.1.2
Secondary Variables
48
3.5.1.3
Other Variables
49
3.5.2
Safety Variables...........................................................................................49
3.6
Assessments...........................................................................................................50
3.6.1
Assessment Periods......................................................................................50
3.6.2
Observations and Measurements .................................................................50
3.6.2.1
Screening Visit and Previous Regimen Phase
50
3.6.2.2
Baseline/IGSC 20% SC#1/Week1 (Start of IGSC 20% Treatment 
Stage 1)
53
3.6.2.3
IGSC 20% Treatment Stage 1: Weeks 2 through 13; SC#2 
through SC#13
55
3.6.2.4
IGSC 20% Treatment Stage 2 (Weeks 14 through 52, SC#14 
through SC#52)
59
3.6.2.5
IGSC 20% Treatment Stage 2 – PK Subset Only
61
3.6.2.6
Final Visit – Week 53 (1 Week Post Final IGSC 20% Infusion) –
Visit in Clinic
62
3.6.2.7
Early Termination Visit
63
3.6.3
Description of Laboratory Tests and Procedures.........................................65
3.6.3.1
Virus Safety Testing
66
3.6.3.2
Immunoglobulin G Assessments
66
3.7
Removal of Subjects ..............................................................................................67
3.8
Follow-Up of Subjects Withdrawn from Study.....................................................67
3.9
Subject Recruitment...............................................................................................67
3.10
Premature Termination of Study/Closure of Center..............................................68
4
ADVERSE EVENTS.......................................................................................................68
4.1
Warnings/Precautions ............................................................................................68
4.2
Adverse Event Monitoring.....................................................................................68
4.3
Adverse Event Definitions.....................................................................................68
4.3.1
Adverse Events ............................................................................................68
4.3.2
Suspected Adverse Drug Reactions/Adverse Reactions..............................69
4.3.3
Causality of Adverse Event .........................................................................69
4.3.4
Severity of Adverse Event or Suspected Adverse Drug Reaction...............70

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4.3.5
Expectedness of Adverse Event or Suspected Adverse Drug Reaction ......70
4.3.6
Seriousness of Adverse Event or Suspected Adverse Drug Reaction; 
Serious Adverse Event.................................................................................70
4.3.7
Adverse Event Documentation ....................................................................71
4.3.8
Type and Duration of the Follow-Up of Subjects after Adverse Events.....72
4.4
Reporting of Serious Adverse Events or Pregnancy..............................................72
4.4.1
Reporting Serious Adverse Event................................................................72
4.4.2
Reporting Pregnancy....................................................................................73
5
STATISTICAL METHODS AND DETERMINATION OF SAMPLE  SIZE...............73
5.1
Statistical and Analytical Plans..............................................................................73
5.1.1
Subject Population(s) for Analysis ..............................................................74
5.1.2
Demographic and Baseline Characteristics .................................................74
5.1.3
Efficacy Analysis.........................................................................................74
5.1.4
Pharmacokinetic Analysis............................................................................75
5.1.5
Safety Analysis ............................................................................................76
5.2
Determination of Sample Size ...............................................................................77
6
ADMINISTRATIVE .......................................................................................................77
6.1
Investigator(s), Other Study Personnel and External Committees ........................77
6.2
Data Quality...........................................................................................................77
6.3
Documentation.......................................................................................................77
6.3.1
Record Retention .........................................................................................78
6.3.2
Access to Information for Monitoring.........................................................78
6.3.3
Access to Information for Audits or Inspections.........................................78
7
ETHICAL AND LEGAL ASPECTS...............................................................................79
7.1
Institutional Review Board/Ethics Committee ......................................................79
7.2
Ethical Conduct of the Study.................................................................................79
7.3
Regulatory Authority Approvals/Authorizations...................................................79
7.4
Subject Information and Consent...........................................................................79
7.5
Insurance................................................................................................................80
7.6
Confidentiality .......................................................................................................80
8
USE OF DATA AND PUBLICATION ..........................................................................80
9
REFERENCES ................................................................................................................82
10
APPENDICES .................................................................................................................87
LIST OF IN-TEXT TABLES
Table 1-1 Summary of IgG Trough Levels from 1:1 IV to SC Dosing Regimen 
Studies..........................................................................................................................33

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Table 3-1 Name, Description, and Location of Laboratory Tests and Procedures............65
LIST OF IN-TEXT FIGURES
Figure 3-1 Overall Study Schema......................................................................................38
LIST OF APPENDICES
Appendix 1
Schedule of Study Procedures ...........................................................88
Appendix 2
PK Subset Group Detail Commencing at SC#17 IGSC 20% 
Treatment Stage 2 (~20 adults)....................................................................................91
Appendix 3
Diagnostic Criteria for Serious Infection Types ................................92
Appendix 4
Blood Pressure Percentiles for Pediatric Patients ..............................94

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GLOSSARY AND ABBREVIATIONS
°C
Degrees Celsius
°F
Degrees Fahrenheit
ADR
Adverse drug reaction
AE
Adverse event
AIDS
Acquired immunodeficiency syndrome
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
ARC
Absolute reticulocyte count
AST
Aspartate aminotransferase
AUC
Area under the concentration vs. time curve
AUC0-7days
Area under the concentration-time curve from 0 to 7 days
B19V
Parvovirus B19
BUN
Blood urea nitrogen
Cmax
Maximum concentration
Ctrough
Minimum concentration
CI
Confidence interval
CRO
Contract research organization
CSF
Cerebrospinal fluid
CXR
Chest X-ray
DAT
Direct antiglobulin test
DBP
Diastolic blood pressure
DNA
Deoxyribonucleic acid
eCRF
Electronic case report form
EDC
Electronic data capture
EMA
European Medicines Agency
FDA
Food and Drug Administration
HAV
Hepatitis A virus
HBV
Hepatitis B virus
HCG
Human chorionic gonadotropin
HCV
Hepatitis C virus
HIV
Human immunodeficiency virus

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HR
Heart rate
IB
Investigator’s Brochure
ICF
Informed consent form
ICH GCP
International Conference on Harmonization Good Clinical Practice
IgA
Immunoglobulin A
IgG
Immunoglobulin G
IGIV-C 10%
Immune Globulin Injection (Human), 10% Caprylate/Chromatography 
Purified (Grifols)
IgM
Immunoglobulin M
IGSC 20%
Immune Globulin Subcutaneous (Human), 20% 
Caprylate/Chromatography Purified (Grifols)
IM
Intramuscular
IP
Investigational product
IRB/EC
Institutional Review Board/Ethics Committee
IUD
Intrauterine device
IUS
Intrauterine system
IV
Intravenous
IVIG
Intravenous Immune Globulin (generic terminology)
kg
Kilogram
LDH
Lactate dehydrogenase
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligram
mL
Milliliter
NAT
Nucleic acid amplification technology
p
Used as a prefix pIV or pSC to denote prior (pre-study) immune globulin 
replacement regimen
pH
Potential of hydrogen; acidity/alkalinity measure
PI
Primary immunodeficiency
PK
Pharmacokinetics
RNA
Ribonucleic acid
RR
Respiratory rate
SAE
Serious adverse event
SBI
Serious bacterial infection

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SBP
Systolic blood pressure
SC
Subcutaneous
SCIG
Subcutaneously delivered immune globulin or subcutaneous 
immunoglobulin (generic terminology)  
SD
Standard deviation
T
Temperature
tmax
Time to reach Cmax
TEAE
Treatment-emergent adverse event 
US
United States
WBC
White blood cell

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1
INTRODUCTION
1.1
Primary Immunodeficiency
Primary Immunodeficiency (PI) 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 (1). Results from a recent study suggest that in the 
United States (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 (2). Worldwide upper estimates suggest that six 
million people (638,000 in Europe) may be living with a PI, although orders of magnitude 
fewer patients have been identified in registries (3). 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 immunoglobulin G (IgG) replacement in 
the treatment of these disorders has been well established (4,5) since 1952 when the use of 
serum globulin fraction was reported to reduce the frequency of infections in a patient with 
agammaglobulinemia. The therapeutic management of PI has been carried out via 
intramuscular (IM), intravenous (IV), and subcutaneous (SC) injections of various IgG 
preparations (6,7).   
1.2
Immunoglobulin Replacement Therapy
Despite its widespread use, the infusion of IV immune globulin (IVIG) is problematic in 
some patients, especially those who have poor venous access or develop systemic adverse 
events (AEs), such as headaches, fever, chills, or myalgias from this route of administration 
(8,9). In children, difficulty in obtaining venous access can prevent or delay IVIG therapy 
(7,10,11). Over the last several years subcutaneously delivered immune globulin (SCIG) has 
been developed for administration in the home setting for treatment of PI and has become 
accepted in the clinical setting (10,11,12). 
The results of several adult PI studies with SCIG products have shown good efficacy of 
replacement therapy and control of bacterial infections (13,14,15). Additionally, the results 
of several pediatric studies also showed that SC infusion of IgG in children (ages 1-15 years) 
at home was feasible and safe and also resulted in maintenance of the IgG levels above 
500 mg/dL (12,16,17), a level that is considered as sufficient to protect against serious 
bacterial infection (SBI) in adults and pediatric PI patients. It is now generally accepted that 
repeated SC infusions of IgG cause few, if any, adverse systemic reactions, and for some 
patients, including children, the SC route has become a preferred route of administration 
(8,18-29). 
Advantages of home-based SCIG infusions in adults and children with PI include treatment 
satisfaction and quality-of-life improvement, specifically, greater independence, better 
control of the therapy situation, and an overall improvement in daily life afforded by 
home-based therapy. Moreover, the technique involved is deemed easy to learn by adults and 
children (6,7,24,30).

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1.3
Immune Globulin Subcutaneous (Human), 20% 
Caprylate/Chromatography Purified (IGSC 20%)
The investigational product (IP) is Immune Globulin Subcutaneous (Human), 20% 
Caprylate/Chromatography Purified (IGSC 20%), Grifols company designation GRF6017. 
Henceforth in this document this product will be referred to as IGSC 20%, which is a sterile 
liquid formulation containing 20% human immune globulin formulated in 0.16-0.26 M 
glycine and 10-40 parts per million polysorbate 80 at pH 4.1-4.8.
Grifols IGSC 20% is a 20% solution of purified human immunoglobulin (primarily IgG) 
made from large pools of human plasma via modifications of the Immune Globulin Injection
(Human), 10% Caprylate/Chromatography Purified (IGIV-C 10%) manufacturing process. 
The IGIV-C 10% process is licensed under BLA 125046 in the US (trade name Gamunex®-C
which is a 10% IgG product), in Europe (Gamunex®), and in a number of other countries 
around the world.
In addition to the information provided here, please also refer to the IGSC 20% Investigator’s 
Brochure (IB).
1.4
Study Rationale and Dose Selection
1.4.1
Study Rationale
IVIG infusions produce an immediate rise in the serum IgG levels with marked peak levels 
which gradually decline as the IgG redistributes, equilibration takes place, and the IgG 
moves into the extravascular space over the typical 3 to 4 week IV dosing regimen period. 
The IgG decay occurs with first order kinetics over a period of approximately 3-4 weeks 
(18,31). Consequently the patient experiences substantial IgG concentration variations rather 
than a steady IgG level throughout the IV dosing period. Maintenance of higher IgG trough 
levels may benefit patients receiving IgG via the SC route at more frequent intervals (18).
Recent studies with SCIG regimens have documented higher and more constant IgG trough 
levels with lower IgG peak levels despite the fact that the SC dosing regimen is typically at a 
lower dose per infusion (yet equates to an equivalent IVIG total monthly dose), using more 
frequent dosing. The SCIG regimen results in much less variability in IgG levels, and higher 
and more consistent trough levels when compared to the IVIG regimens (32). One possible 
reason for the stable blood concentrations is that the SC infused IgG probably remains in the 
SC fat layer as a depot with a slow and continuous release into the circulatory system (6) in 
addition to the increased frequency of dosing. It has been reported that the uptake of the 
antibodies from SC tissue is high and the antibodies are not locally destroyed (18,33), which 
results in IgG reaching the circulation intact. 
Several SCIG products, ranging in protein IgG concentrations from 10% to 20%, are 
currently being used to treat PI most commonly by either weekly or biweekly administration. 
IGIV-C 10%, a 10% immunoglobulin product, is licensed in the US and some other countries 
(e.g., IGIVnex in Canada) for both IV and SC administration. The advantages of higher 

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concentration SCIG products (20%) are primarily significantly reduced infusion volume and 
shorter infusion time thereby significantly increasing ease of administration.
The primary objective of this trial is to assess the overall incidence of SBI per subject per 
year (as defined in the Food and Drug Administration [FDA] Guidance 2008 and European
Medicines Agency [EMA] Guidance 2012 [34,35]) using a dose-equivalent dosing regimen
for the IP, IGSC 20%, which is common clinical practice in the US and EMA regions. Thus,
the data obtained from this trial will be relevant and directly applicable to treaters with regard 
to efficacy and safety of IGSC 20% in subjects aged 2 years to 75 years inclusive. The 
duration of the treatment period of the study is 12 months in order to avoid seasonal bias 
(34,35). Pharmacokinetic (PK) data will be obtained at steady state from a subset of 
approximately 20 adult (> 16 years) subjects after approximately 4 months (16 weeks) of 
IGSC 20% dosing. 
1.4.2
Dose Rationale
IGIV-C 10% (10% final IgG concentration) is currently approved for SC administration in PI
in various geographies. Study 060001 showed that weekly SC administration in 32 adult PI 
subjects (including 3 adolescent subjects) resulted in a relatively constant steady-state trough 
plasma concentration of total IgG (1140 mg/dL). There were no SBIs reported in the 24 week 
SC treatment period (36). In a recently completed pediatric study (T5004-4001), weekly SC 
administration of IGIV-C 10% in 11 pediatric subjects (age range 4-15 years) also resulted in 
relatively constant steady-state trough plasma concentration of total IgG (1330 mg/dL).
There was no SBI reported in the 12 weeks of the SC treatment period. These results 
demonstrated that IGIV-C 10% treatment provided protection against SBIs when 
administered via the SC route of administration.
A dose-equivalent strategy is being utilized for the IGSC 20% product in order to maintain 
the overall monthly IgG dose for subjects based on their previous regimen (IVIG or SCIG). It 
is known that physicians commonly optimize each subject’s IgG dose based on IgG trough 
levels, as well as clinical signs and symptoms of PI, and thus the intent of this study is to 
maintain each subject’s monthly dose of IgG. This dose-equivalent rationale is also based on 
results from several well-controlled clinical trials where dose-equivalent SCIG regimens 
were studied in patients with PI (reviewed in 14,19,26,27,32,37,38). All of these studies 
resulted in IgG trough levels on the SCIG regimen slightly higher than the previous IVIG
regimens without any loss of efficacy in preventing SBIs as illustrated in Table 1-1
(14,27,37,39).

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Table 1-1 Summary of IgG Trough Levels from 1:1 IV to SC Dosing Regimen Studies
Reference
Product
N
Mean pre-IV trough 
level (mg/dL)b
Time Point for 
SC IgG trough
Mean SC trough 
level (mg/dL)b
% Change in 
Trough (SC/IV)
Annualized 
SBI rate
Gardulf27
(2006)
16% SCIG 
(Vivaglobin)
n=15 on prior IVIG
age 2-11
780
Weeks 16-43 
920
18%
0.04
n=27 on prior IVIG 
adults
860
890
3.5%
Borte39
(2011)a
20% SCIG
(Hizentra)
n=11 on prior IVIG
age 2-11
647
Primary efficacy 
IgG trough 
infusions 12-17
792
22%
0.0
n=1 on prior IVIG 
adolescents
not provided
not provided
---
n=13 on prior IVIG
adults
715
814
14%
Jolles14
(2011)a
20% SCIG
(Hizentra)
n=27 on prior IVIG
678
798
18%
Desai37
(2009)
10% SCIG
(Gamunex)
n=11
age 5-59
1079
6 months
1160
8%
0.09 
Note: For studies by Gardulf et al., Borte et al., and Jolles et al., the data presented are from a subset who received IVIG initially. In the Desai et al. publication,
all patients initially received IVIG.
a
The Borte et al. and Jolles et al. publications represent different presentations of data from the same Phase 3 study of Hizentra; the publication by Jolles et al.
2011 does not summarize the pediatric and adult subjects separately whilst Borte et al. present data by age group with in-text detail regarding the subset 
entering study on IVIG.
b
For consistency within this table for cross-study comparison, this table uses units of mg/dL; however publications may have used other units such as g/L. 

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All of the studies summarized in Table 1-1 resulted in IgG trough levels on an SCIG
regimen higher than the previous IVIG regimens, with a range of increase on SCIG regimen 
from 4% to 22% when compared to previous IV regimen. In addition, there was no loss of 
efficacy in preventing SBIs (range from 0.0 to 0.09 annualized SBI rate). Accordingly, dose-
equivalent dosing (1:1 IV to SC [i.e., with no dose conversion factor]) will be employed in 
this study with a minimum dose of IGSC 20% set at 100 mg/kg/week.
2
STUDY OBJECTIVES
2.1
Efficacy and Pharmacokinetic Objectives
2.1.1
Primary Efficacy Objective
The primary objective of this Phase 3 study is to evaluate whether weekly administered 
IGSC 20% over a one year period will achieve less than 1 SBI per subject per year in PI 
subjects.
2.1.2
Secondary Objectives

To determine if IGSC 20% replacement therapy maintains mean trough IgG levels that 
are comparable to the mean trough blood levels with the previous IgG replacement 
regimen

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

To evaluate 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. 

To evaluate number of hospitalizations due to infection

To evaluate number of days of work/school/daily activities missed per subject year due to 
infections and  related treatment
2.1.3
Other Objectives

To evaluate trough levels of IgG subclasses (IgG1, IgG2, IgG3, IgG4) 

To evaluate antibody levels for Streptococcus pneumoniae, Hemophilus influenzae, and
Clostridium tetani (tetanus)

To evaluate the PK profile for total IgG (area under the concentration-time curve from 
0 to 7 days [AUC0-7 days], maximum concentration [Cmax], and time to reach Cmax [tmax]) in 
adult PI subjects at steady state (after approximately 4 months [16 weeks]) of weekly 
administration of IGSC 20% 

Trough measles antibody titers (functional assay) are an exploratory variable for 
informational purposes

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
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).
2.2
Safety Objectives

To assess the safety and tolerability of IGSC 20% as an IgG replacement therapy in 
subjects with PI.
3
INVESTIGATIONAL PLAN
3.1
Study Design and Plan
This is a prospective, multi-center, open-label, single-arm, efficacy, PK, safety and 
tolerability study of IGSC 20% in subjects with PI. Approximately 60 subjects will be 
enrolled in order to have approximately 20 adult subjects and 20 pediatric subjects treated 
with subcutaneously administered IGSC 20% who complete the entire study. This study will 
include 3 study stages: Screening/Previous Regimen Phase, IGSC 20% Treatment Stage 1 
(13 IGSC 20% weekly doses), and IGSC 20% Treatment Stage 2 (39 IGSC 20% weekly 
doses). 
Subjects who are receiving IVIG at a dose of at least 200 mg/kg per infusion every 3 or 
4 weeks at Screening must be on a stable IgG regimen (dose and dosing interval) for at least
3 consecutive months prior to Screening. Subjects who are receiving SCIG must also be on a 
stable regimen for at least 3 consecutive months prior to Screening; there is no prerequisite 
minimum dose for subjects entering study on an SCIG regimen. Subjects who have never 
received IVIG or SCIG treatment (treatment naïve) will not be eligible for entry into the 
study. 
Previous Regimen Phase:   

Subjects will be infused with their current ongoing (“previous regimen”) IVIG/SCIG
regimen (pIV/pSC) in the clinic (mandatory) to obtain 2 trough IgG levels (obtained prior 
to each pIV/pSC infusion) on each subject’s "previous regimen". For subjects entering 
study on SCIG, the second IgG trough level may be obtained at Baseline, immediately 
prior to starting the initial infusion of IGSC 20%.

The Screening Visit may coincide with the pIV/pSC infusion on the previous regimen 
(pIV#1/pSC#1). Product for the previous IgG regimen is not provided by Grifols. pIV
subjects will be enrolled in IGSC 20% Treatment Stage 1 one week after completion of 
the last IgG trough sampling in the Previous Regimen Phase and therefore the subject 
must have 2 minimum concentration (Ctrough) samples on their pIV prior to the 
Baseline/Week 1 visit. pSC subjects will be enrolled in IGSC 20% Treatment Stage 1 
(Baseline) in accordance with the time interval that they are currently receiving SCIG 
(i.e., if on a weekly SCIG regimen, Baseline will occur 1 week after completion of the 

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last SCIG infusion and a second IgG trough level will be obtained at Baseline. If the 
interval between pSC infusions is 2 weeks (or more), then Baseline will occur after that 
time interval has elapsed, a trough IgG level will be obtained, and the eligible subject 
may commence IGSC 20% after Baseline assessments are complete).

Nonconsecutive Ctrough samples are acceptable for subjects on SCIG. A minimum of 10 
days is anticipated for the Screening/Previous Regimen Phase to ensure Screening human 
immunodeficiency virus (HIV) nucleic acid amplification technology (NAT) test results 
will be available before the Baseline Visit/Week 1 visit.
20% IGSC Treatment Stage 1:

The first dose of the IP, IGSC 20%, will be administered immediately after Baseline 
assessments are complete (SC#1). Subjects will be infused with IGSC 20% at a 1:1 
dose-equivalent regimen (per equation in Section 3.3.2) from their previous regimen at 
the clinical site (or a minimum IGSC 20% dose of 100 mg/kg/week if the derived 1:1 
dose from the previous regimen is lower).

All subjects will receive 13 IGSC 20% infusions at weekly intervals and study visits at 
the clinical site will occur at Baseline/SC#1, SC#2, #3, #5, #9, and #13. IgG trough blood 
levels will be measured at all of these visits (except SC#3) occurring at the clinical site. 
All other doses of IGSC 20% may be infused at home (once properly trained) or in the 
clinic. 

The mg/kg dose of IGSC 20% (ratio of mg per kg) will be adjusted at clinic visits if the 
trough level in subjects is below 500 mg/dL, a level that is considered as insufficient to 
protect against SBI (40-43); the goal is to avoid repeated dose adjustments. The precise 
dose adjustment (mg/kg) should not be more than a 15% to 20% increase from the dose 
producing low IgG trough, per the Investigator’s discretion. Any dose adjustments 
beyond this range will be completed in consultation with the Grifols Medical Monitor. 
The Treatment Stage 1 dose will continue into IGSC 20% Treatment Stage 2. After the 
13th IGSC 20% infusion in IGSC 20% Treatment Stage 1, subjects will enter IGSC 20%
Treatment Stage 2 to receive an additional 39 weeks of IGSC 20% therapy.
IGSC 20% Treatment Stage 2:

The IGSC 20% dose (mg/kg) will remain constant with no dose adjustment permitted in 
this phase, unless it is absolutely medically necessary to change the dose, and such 
change requires prior consultation with the Grifols Medical Monitor. Weight will be 
measured at every in-clinic visit and dosing will be based on the subject’s most current 
weight. For the subsequent at home IGSC 20% infusions between clinic visits, the dose 
will be the same as the total infusion dose calculated at the previous clinic study visit 
where weight was measured at the clinical site.

While all subjects will have a SC#17 clinic visit and standard assessments, serial PK 
sampling will only be performed in a subset of adult subjects: At SC#17, PK profiles in 
the first (where possible) 20 adult subjects, will be measured by obtaining blood draws 

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for steady-state PK analyses over a period of 7 days just prior to and post the 17th IGSC 
20% infusion through SC#18. These subjects will constitute the PK subset in this study. 
-
Where possible, the PK subset will comprise the first 20 adult subjects enrolled. Any 
designated PK subject who undergoes a dose adjustment (mg/kg change in dose) at or 
after the ninth IGSC 20% infusion (SC#9) which corresponds to at or after Week 9 
Treatment Stage 1 will be permitted to continue within the study, though he/she will 
not participate in PK profiling; however, an additional PK replacement subject may 
be recruited. 
-
Similarly, PK subjects who do not complete the full PK profile may be replaced if 
deemed necessary.
A total of 52 doses of IGSC 20% will be administered (13 doses of IGSC 20% in Treatment 
Stage 1 and 39 doses of IGSC 20% in Treatment Stage 2) with a final follow-up visit at 
Week 53 one week after the last dose at Week 52.
The overall study schema and the specific time points for PK sampling for Previous Regimen 
Phase and IGSC 20% Treatment Stages are outlined in Figure 3-1, and the schedule of study 
procedures is provided in Appendix 1 with PK details in Appendix 2. Appendix 3 provides 
definitions for the primary endpoint variable, SBIs.

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Figure 3-1 Overall Study Schema

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3.2
Selection of Study Population
Eligible participants for this study include male or female subjects who are 2 to 75 years of 
age and have a diagnosis of PI requiring IgG replacement treatment. Subjects who initially 
fail to meet eligibility criteria may be re-screened once upon consultation with the Medical 
Monitor. Subjects who fail to meet eligibility criteria upon re-screen are Screen Failures and 
will not be eligible to participate in the study.
3.2.1
Inclusion Criteria
A subject must meet all the following inclusion criteria to be eligible for participation in this 
study:
1. Adults and adolescents between the ages of 2 and 75 years (inclusive) at Screening.
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-immunoglobin 
[IgM] immunodeficiency syndrome). Please also refer to Exclusion Criteria.
3. The subject has not had an SBI within the last 3 months prior to Screening and has no 
SBI up to the time of the Baseline Visit. 
Note: if an SBI occurs during the Screening/Previous Regimen Phase and prior to the first 
dose of Grifols IGSC 20%, the subject will be a Screen Failure
4. Currently on IgG replacement therapy (stable regimen [dose and dosing interval] via IV 
or SC infusion) for ≥ 3 consecutive months. Subjects receiving IVIG prior to study must 
receive a dosage of at least 200 mg/kg per infusion.
5. Documentation (within previous 6 months) of an IgG trough level of ≥ 500 mg/dL on 
current IgG replacement therapy regimen.
6. Screening/pre-Baseline trough IgG levels must be ≥500 mg/dL.
Note: If Screening and/or pre-Baseline trough levels (not including pSC#2 trough) are not 
above this threshold the subject will be a Screen Failure, but may be re-screened 
following dose adjustment of their original IgG replacement therapy regimen and 
maintaining stable dosing for a period of at least 3 consecutive months prior to Screening 
a second time.
7. The medical records for all subjects should be available to document diagnosis, previous 
infections and treatment.
8. The subject has signed an informed consent.
Note: The subject must sign the informed consent form (ICF) if at least 18 years old; for 
children of younger age the subject’s parent or legal guardian must sign the ICF and if 
appropriate/applicable, the subject must sign a Child Assent form approved by the 

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Institutional Review Board or Ethics Committee (IRB/EC) per their requirements (see 
Section 7.4).
3.2.2
Exclusion Criteria
A subject meeting any of the following exclusion criteria is NOT eligible for participation in 
the study.
1. Clinical evidence of any significant acute or chronic disease that, in the opinion of the 
Investigator, may interfere with successful completion of the trial or place the subject at 
undue medical risk
2. The subject has had a known serious adverse reaction to immunoglobulin or any severe 
anaphylactic reaction to blood or any blood-derived product
3. The subject has a history of blistering skin disease, clinically significant 
thrombocytopenia, bleeding disorder, diffuse rash, recurrent skin infections, or other 
disorders where SC therapy would be contraindicated during the study
4. The subject has isolated IgG subclass deficiency, isolated specific antibody deficiency 
disorder, or transient hypogammaglobulinemia of infancy.
5. The subject has known Selective Immunoglobulin A (IgA) Deficiency (with or without 
antibodies to IgA) (Note: exclusion is for the specific diagnostic entity. It does not 
exclude other forms of humoral primary immunodeficiency which have decreased IgA in 
addition to decreased IgG requiring immune globulin [IgG] replacement).
6. Females of childbearing potential who are pregnant, have a positive pregnancy test at 
Screening (serum) or Baseline (urine) (human chorionic gonadotropin [HCG]-based 
assay), are breastfeeding, or unwilling to practice a highly effective method of 
contraception (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.)
7. The subject has significant proteinuria (dipstick proteinuria ≥ 3+, known urinary protein 
loss > 1 g/24 hours, or nephrotic syndrome), has a history of acute renal failure, has 
severe renal impairment (blood urea nitrogen [BUN] or creatinine more than 2.5 times 
the upper limit of normal [ULN]), and/or is on dialysis
8. The subject has Screening Visit values of aspartate aminotransferase (AST) or alanine 
aminotransferase (ALT) levels exceeding 2.5 times the ULN for the expected normal 
range for the testing laboratory.
9. The subject has hemoglobin < 9 g/dL at Screening
10. The subject has a known previous infection with or clinical signs and symptoms 
consistent with current hepatitis B virus (HBV) or hepatitis C virus (HCV) infection  

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11. The subject has a history of or current diagnosis of deep venous thrombosis or 
thromboembolism (e.g., myocardial infarction, cerebrovascular accident, or transient 
ischemic attack); history refers to an incident in the year prior to Screening or 2 episodes 
over lifetime 
12. The subject is currently receiving anti-coagulation therapy which would make SC
administration inadvisable (vitamin K antagonists, nonvitamin K antagonist oral 
anticoagulants [e.g., dabigatran etexilate targeting Factor IIa, rivaroxaban, edoxaban, and 
apixaban targeting Factor Xa], parenteral anticoagulants [e.g., fondaparinux]). 
13. The subject currently has a known hyperviscosity syndrome
14. The subject 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 HIV infection/acquired immune deficiency syndrome (AIDS). 
15. The subject is HIV positive by NAT based on a Screening blood sample. The subject may 
enter the Previous Regimen Phase while the Screening blood sample is being tested, but 
will be a Screen Failure and will not undergo Baseline assessments if the HIV result is 
positive.
16. The subject (if < 18 years of age) has non-controlled arterial hypertension at a level of 
greater than or equal to the 90th percentile blood pressure (either systolic or diastolic) for 
their age and height (see Appendix 4) or the adult subject has non-controlled arterial 
hypertension (systolic blood pressure > 160 mmHg and/or diastolic blood pressure > 100 
mmHg)
17. The subject is 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 of corticosteroids of not more than 10 days would not exclude 
a subject. Inhaled or topical corticosteroids are allowed.
18. The subject has known substance or prescription drug abuse.
19. The subject has participated in another clinical trial within 30 days prior to Screening 
(observational studies without investigative treatments [non-interventional] are 
permitted) or has received any investigational blood product, with the exception of other 
IgG products, within the previous 3 months
20. The subject/caregiver is unwilling to comply with any aspect of the protocol, including 
the home SC infusions, blood sampling, and completion of an SC infusion diary for the 
duration of the study
21. Mentally challenged subjects who cannot give independent informed consent
22. In the opinion of the Investigator the subject may have compliance problems with the 
protocol and the procedures of the protocol.

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3.3
Treatments
3.3.1
Treatments to Be Administered
Grifols Immune Globulin Subcutaneous (Human), 20% Caprylate/Chromatography Purified 
(IGSC 20%) is a sterile liquid formulation of immunoglobulin that has been purified from 
human plasma via a multi-step process. IGSC 20% will be supplied in a 50 mL vial size 
containing a 20% solution of Immune Globulin, i.e., a concentration of 20 g/100 mL, with a 
nominal 10 grams Immune Globulin per vial.
3.3.2
Selection of Dose and Interval for Each Subject
Screening/Previous Regimen Phase
Subjects will continue their existing (“previous regimen”) IVIG or SCIG regimens (pIV or 
pSC) during the Screening/Previous Regimen Phase. Product for the Screening/Previous 
Regimen Phase is not provided by Grifols. Each subject’s established IVIG or SCIG 
replacement regimen will not be changed throughout the Previous Regimen Phase. Subjects 
receiving IVIG prior to Screening must receive a dosage of at least 200 mg/kg per infusion,
and all subjects must fulfill IgG trough level eligibility criteria ≥ 500 mg/dL (for subjects 
receiving SCIG prior to Screening, no minimum dosage is required).
The Previous Regimen Phase will include measurement of 2 IgG Ctrough levels on the 
subject’s existing IVIG/SCIG treatment regimen. For subjects receiving IVIG, the 2 IgG 
Ctrough levels will be obtained prior to each of the 2 IVIG infusions in this Phase (of up to 
8 weeks). For subjects receiving SCIG, the 2 IgG Ctrough levels obtained prior to each of the 2 
SC infusions (one week apart or longer interval based on existing previous regimen) will 
result in a shorter Screening/Previous Regimen Phase time interval of 4 weeks.
All measured Ctrough levels of IgG drawn pre-Baseline must be ≥ 500 mg/dL for the subject to 
qualify for Baseline and receipt of study drug (IGSC 20%). If the Ctrough levels of IgG are
< 500 mg/dL on the subject’s existing IVIG or SCIG regimen, the subject will be a Screen 
Failure. However, the subject may be re-screened once after adjustment in their IgG 
replacement regimen and maintaining stable dosing for 3 months.
IGSC 20% Treatment Stage 1 and Stage 2
Dosing: The IGSC 20% mg/kg/week dose to be utilized during Treatment Stage 1 will be
calculated based on the subject’s prior (pre-study) pIV or pSC replacement regimen with a    
1 to 1 (1:1) correspondence in dosage and a minimum dose of IGSC 20% of 100 mg/kg/week. 
Treatment Stage 1 will commence 7 days after the last IVIG dose or 7 days after the last SC 
dose of the subject’s previous IgG replacement regimen if on a weekly schedule. If SCIG is 
given on a biweekly schedule, the dosing interval would be 2 weeks (i.e., the timing of start 
of Treatment Stage 1 will match the SC dosing interval so that the second SCIG Ctrough can be 
obtained immediately prior to dosing with IGSC 20%). During Treatment Stage 1,
adjustment in the dose (mg/kg) of IGSC 20% (ratio of mg per kg) will be made at clinic visits

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if IgG Ctrough is less than 500 mg/dL so that adequate immunoglobulin levels are attained.
The precise IGSC 20% dose adjustment (mg/kg) should not be more than a 15% to 20% 
increase (relative to the dose producing low IgG trough), per the Investigator’s discretion. 
Any dose adjustments beyond this range will be completed in consultation with the Grifols 
Medical Monitor.
The IV regimen to IGSC 20% dose conversion calculation formula is: 
The alternative SC regimen to IGSC 20% dose conversion calculation formula is: 
For subjects on another SCIG regimen at study entry, if the dose is given weekly, the dose of 
IGSC 20% will be the same. However, if the pre-study SC regimen is dosed over a longer 
time interval, that dose will be divided by the number of weeks between doses to provide the 
IGSC 20% dose per week. The minimum dose for IGSC 20% for either case of transition is 
100 mg/kg/week.
Weight will be measured at every in-clinic visit and dosing will be based on the subject’s
most current weight. For the subsequent at home IGSC 20% infusions between clinic visits, 
the dose will be the same as the total infusion dose calculated at the previous clinic study 
visit where weight was measured at the clinical site.
During Treatment Stage 2, the mg/kg dose of IGSC 20% (ratio of mg per kg) is to be 
kept constant unless it is absolutely medically necessary to change the dose, and such 
change requires prior consultation with the Grifols Medical Monitor.
A total of 52 weekly doses of IGSC 20% will be administered with a final visit at Week 53 
one week after the last IGSC 20% infusion at Week 52.
3.3.2.1
Labeling of Investigational Product(s)
Grifols IGSC 20% will be labeled according to the requirements of local law and legislation. 
Label text will be approved according to agreed Grifols Therapeutics Inc. procedures, and a 
copy of the labels will be made available to the study site upon request.
pSC dose mg/kg
previous pSC dosing interval in weeks between infusions
≥ 200 mg/kg (pIV dose)
3 or 4 (previous pIV dosing interval in weeks between infusions)

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3.3.2.2
Storage of Investigational Products
IGSC 20% 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 
investigative product.
IGSC 20% must be stored at temperatures of 2°C to 8°C (36°F to 46°F) and protected from 
light. Do not freeze or partially freeze. Investigators, or designees, are responsible for 
maintaining storage temperature records and for immediately reporting deviations in 
temperature to the study monitor.
Details for the storage are located in the pharmacy manual provided to each site and 
instructions will also be provided to participating subjects.
3.3.2.3
Preparation
The volume (i.e., total infusion dose administered) of Grifols IGSC 20% to be prepared for 
each SC infusion will be individualized for each subject based on dose-equivalence with their 
previous (pre-study) regimen using body weight based dosing (≥100 mg/kg/week). 
IGSC 20% must be inspected visually before being administered. The solution must not be 
used if turbid or if it contains visible particles. Solution that has been frozen should not be 
used. The Investigator, or designee, is responsible for immediately reporting any issues noted 
with IGSC 20% to the study monitor.
Reference the pharmacy manual/study manual for detailed instructions for IGSC 20% 
preparation and administration.
3.3.2.4
Accountability for Investigational Product(s)
IGSC 20% is 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 IP 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 IGSC 20% for his/her site. IP inventory/dispensing documentation 
verifying the receipt, dispensing, and 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. IGSC 20% supplies must be accounted for by the monitor and 
inventory/dispensing logs must be verified by the monitor prior to IGSC 20% return or 
destruction. Written documentation of all 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 Therapeutics Inc.

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3.3.3
Rationale for Selection of Doses and Dose Interval for Investigational 
Products in the Study
The IP, IGSC 20%, is a liquid formulation. The planned dosage regimen for use in PI
subjects is to use a dose-equivalent strategy (1:1; i.e., with no dose conversion factor) for 
Grifols IGSC 20% product to maintain the overall monthly IgG dose for the subjects based 
on their prior (pre-study) IgG replacement regimen (IVIG or SCIG) administered weekly by 
SC infusion and evaluated over 12 months.
The minimum dose for the IGSC 20% will be set at 100 mg/kg/week. Data and references 
illustrating comparability of SC weekly replacement therapy utilizing a 1:1 dose conversion 
are provided in Section 1.4.2 and Table 1-1 .
The weekly dose of IGSC 20% (mg/kg) will be adjusted in Treatment Stage 1 if the trough
IgG blood level in subjects is below 500 mg/dL, which is considered as insufficient to protect
against SBI.
Subjects in this study will receive a total of 52 weekly SC infusions of IGSC 20%.
3.3.4
Method of Assigning Subjects to Treatment Groups
This is an open-label, single-arm study; all subjects will receive the same IP (IGSC 20%) via 
SC infusion.
3.3.4.1
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). For 
example, if the Investigator’s center number is 
, subject numbers will be 
, 
, 
, etc., in consecutive order. Subject numbers, once assigned, will not be 
reused at any center.
3.3.4.2
Randomization
This is a single-arm study with no randomization.
3.3.4.3
Blinding
This is an open-label, single-arm study with no blinding.
3.3.4.4
Administration and Timing of Investigational Product for Each Subject
Subjects will receive a total of 52 weekly SC infusions of IGSC 20% IP (13 weekly SC 
infusions in Treatment Stage 1 and 39 weekly SC infusions in Treatment Stage 2).  See 
Section 3.3.2 for details on Treatment Stage 1 dosing guidance and calculation. During 

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Treatment Stage 1, if considered medically necessary, weekly infusions may be given at the 
Investigator’s study site or, if deemed appropriate, at an alternate site under the care and 
supervision of trained healthcare personnel.
The first 3 IGSC 20% infusions in Treatment Period 1 (SC#1, SC#2, and SC#3) will be given 
under supervision at the study site before any subsequent IP SC infusions are administered 
away from the study site. Thereafter, IGSC 20% infusions may be at home except for 
designated clinic visits at which IGSC 20% will be infused in the clinic (SC#5, 9, 13, 17, 20, 
24, 28, 32, 36, 40, 44, 48, 52 [for those subjects who are in the PK subset, 5 additional blood 
samples for IgG level testing will also be required between SC#17 and #18]). A pump 
specifically designed for SC infusions will be provided for individual use to each subject 
prior to the beginning of IGSC 20% Treatment Stage 1. Subjects and, in the case of children,
parents or legal guardians will be trained thoroughly on its use. The exact IGSC 20% total 
infusion dose administered will be recorded for each infusion.
3.3.4.5
Subcutaneous Administration Procedures of Investigational Product 
Details regarding infusion rate and infusion administration are located in the pharmacy/study 
manual. Subjects may use the same anatomical area or rotate anatomical areas for SC 
infusions throughout the study. No more than 8 infusion sites per infusion will be used. The 
minimum distance between infusion sites is recommended to be no less than 2 inches
(5.1 cm). The target infusion rate will be no greater than 25 mL/hour/site as tolerated by the 
subject and per the Investigator’s discretion; the Investigator will tailor the infusion
configuration for each subject. Subjects who are naïve to SC infusion for IgG replacement 
(i.e., receiving IVIG at study entry) should start at a lower SC infusion rate per site initially 
while transitioning from the IV to SC route of administration. Once the target infusion rate is 
achieved, it should not be changed in the middle of an infusion unless the subject experiences 
tolerability issues at that infusion rate. In the event that the subject is not able to tolerate the 
set infusion rate, the rate may be decreased for better tolerability. Conversely, if the target 
infusion rate is well tolerated during 2 infusions an increase of 20% in infusion rate and 
volume per site is allowed at the discretion of the Investigator at the time of the clinic visit. 
The volume infused, infusion start date/time, infusion end date/time, and initial and final 
infusion rates will be recorded. 
The number of infusion sites, the location(s) and rate of infusion for each infusion site, and 
other SC infusion information will be recorded in the SC infusion diary by the 
subject/parents or legal guardians, site personnel as appropriate and subsequently recorded in 
the electronic case report form (eCRF). In addition, SC infusion local site reactions will be 
recorded in the diary. Full details regarding the SC infusion diary are in Section 3.6.2.2.
Refer to the pharmacy manual/study manual for detailed instructions for IGSC 20% 
preparation and administration.  

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3.3.4.6
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 
source documents.
3.4
Prior and Concomitant Therapy
Concomitant medications must be recorded in the subject’s source documents and in the
eCRF from time of consent, including the trade or generic names of the medication, the dose, 
the route of administration, duration, and frequency. All IgG treatments administered for the 
past 12 months prior to screening should be recorded.
3.4.1
Prohibited Medications Prior to Study Participation
Use of the following medications, as specified below, would exclude a subject from 
participating in this study:

At the time of Screening, receiving systemic corticosteroids (long-term daily doses of         
> 1 mg of prednisone equivalent/kg/day for > 30 days) (intermittent courses of not more 
than 10 days would not exclude subject). Note: Inhaled or topical corticosteroids are 
allowed.

At the time of Screening, receiving immunosuppressants including chemotherapeutic 
agents or immunomodulators

At the time of Screening, receiving anti-coagulation therapy which would make SC
administration inadvisable (vitamin K antagonists, nonvitamin K antagonist oral 
anticoagulants [e.g., dabigatran etexilate targeting Factor IIa, rivaroxaban, edoxaban, and 
apixaban targeting Factor Xa], parenteral anticoagulants [e.g., fondaparinux]). 
3.4.2
Prohibited Concomitant Medications during the Study
Use of the following during the study (from Screening to Week 53 Final Visit) is prohibited:

After the Previous Regimen Phase, any IgG replacement therapy other than IGSC 20% 
provided in this study

Corticosteroids in excess of stipulations delineated in Section 3.4.1

Anti-coagulant therapy as outlined in Section 3.4.1

Immunosuppressants including chemotherapeutic agents or immunomodulators

Investigational products not part of this study

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3.4.3
Restricted Concomitant Medications during the Study
For subjects receiving a permissible stable dose of systemic steroids (defined above), it is 
recommended to maintain the same dose throughout the study.
The medications listed below are not allowed during the study as premedication to an SC
infusion; however, these medications are allowed during the study for general use (e.g., to 
treat an AE):
Oral medications:

Ibuprofen

Acetaminophen

Antihistamines
Topical medications:

Steroids

Antihistamines
3.4.4
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 (Medical Advisory Committee of the Immune Deficiency Foundation [44]). 
Passive transfer of antibodies from IGSC 20% 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, particularly for children during the course of this protocol.
3.5
Study Variables
3.5.1
Efficacy and Pharmacokinetic Variables
3.5.1.1
Primary Efficacy Variable
The primary efficacy variable is the number of SBIs. Also, the percentage of subjects with 
SBIs will be summarized. SBI definitions (FDA/EMA diagnostic criteria) are provided in 
Appendix 3 (34,35).
3.5.1.2
Secondary Variables
One of the secondary endpoints of this study is trough concentrations of total IgG of previous 
regimen during the Screening/Previous Regimen Phase and the IGSC 20% Treatment Stages. 

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It is measured to determine if IGSC 20% replacement therapy maintains mean trough IgG 
levels that are comparable to the mean trough blood levels with the previous IgG replacement 
regimen.
Other secondary variables include the rate of infection of any kind (serious and non-serious),
antibiotic treatment (oral, parenteral, oral plus parenteral, prophylactic, and therapeutic), 
hospitalizations due to infection, and days lost from work/school/daily activities due to 
infections and related treatment. The infection of any kind includes 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 eCRF: “Is this an infection? (verbatim term delineating nature 
of infection).
3.5.1.3
Other Variables
Additional PK parameters include average trough concentration of IgG subclasses (IgG1, 
IgG2, IgG3, and IgG4), and concentration of antibody levels to S. pneumoniae, H. influenzae, 
and C. tetani (tetanus). Trough measles antibody titers (functional assay) are an exploratory 
variable for informational purposes.
For the adult (n~20) PK subset, serial samples will be collected immediately before and after 
SC#17 infusion at steady state. The PK profile will include total IgG concentrations at 
timepoints over a 7-day period. PK parameters including AUC0-7days, Cmax, and tmax will be 
determined by a noncompartmental model using WinNonlin.  
Another efficacy variable is 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 
analyzed separately. 
3.5.2
Safety Variables
The following safety variables will be assessed in this study:

AEs, suspected adverse drug reactions (suspected ADRs), serious AEs (SAEs), and 
discontinuations due to AEs and SAEs
Note: All local infusion site reactions will be recorded in the eCRF. The subset of local 
infusion site reactions where the symptoms/signs lead to infusion interruption or 
discontinuation, require concomitant medication, or have an impact on the general 
condition of the subject as judged by the Investigator will be considered as AEs.

Vital signs during clinic visits (temperature [T], respiratory rate [RR], heart rate [HR], 
systolic blood pressure [SBP] and diastolic blood pressure [DBP]).

Physical assessments: physical exams will be recorded as normal or abnormal, according 
to the physician’s judgment criteria, and findings will be recorded.

Laboratory assessments including chemistry, hematology, and urinalysis.

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3.6
Assessments
3.6.1
Assessment Periods
An overview of the study schedule is provided as Appendix 1. The study consists of 
Screening/Previous Regimen Phase of up to 8 weeks in duration, IGSC 20% Treatment Stage 
1 of 13 weeks duration, and IGSC 20% Treatment Stage 2 of 39 weeks duration, followed by 
a Final Visit at Week 53 one week after Week 52. The total duration of study participation 
may be up to 60 weeks.
3.6.2
Observations and Measurements
The following sections describe the procedures/assessments to take place at each study visit. 
See the Schedule of Study Procedures table in Appendix 1 for a summary of study visits and 
the procedures to be conducted at each visit. Visits occurring after the Baseline Visit should 
be scheduled at the protocol-specified week relative to the date of the Week 1 (Baseline) 
Visit; a ± 1 day window is allowed with the exception of the serial PK sampling (non-dosing) 
visits (only applicable to the PK subset). If there are logistical issues requiring schedule 
adjustment for weekly IGSC 20% administration, SC#1 may be scheduled 6 to 9 days after 
pIV#2. Schedule adjustment may also be made after SC#3 or later (± 2 days from last 
infusion) when home infusion is initiated. Unscheduled visits may be conducted if deemed 
necessary for the purpose of subject safety.
3.6.2.1
Screening Visit and Previous Regimen Phase
Subjects who initially fail to meet eligibility criteria may be re-screened once upon 
consultation with the Sponsor. Subjects who fail to meet eligibility criteria upon re-screen are 
screen failures and will not be eligible to participate in the study.
The Previous Regimen Phase for subjects may be between 4 weeks (for subjects entering 
study on SCIG) and up to 8 weeks (for subjects entering study on IVIG).  At the Screening 
Visit, if a prospective subject is also being dosed (mandatory in-clinic dosing) with their 
pIV/pSC infusion, in such instances the Screening Visit also becomes a pIV#1 or pSC#1
Visit which shortens the overall duration of this phase. The duration of this phase is also 
dependent on the need for the HIV screening results that are required prior to 
Baseline/Week 1 of Treatment Stage 1, which may take up to 2 weeks to report.  Another 
factor which may impact the duration of this phase is the previous IgG dosing frequency (i.e., 
weekly, biweekly, once every 3 or 4 weeks) in order to ensure 2 previous regimen Ctrough 
blood samples are obtained prior to initiation of IGSC 20% dosing in Treatment Stage 1.

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ASSESSMENTS AND PROCEDURES DURING SCREENING VISIT AND PREVIOUS REGIMEN PHASE
Screening Visit Assessments for all subjects

Informed consent

Assess inclusion and exclusion criteria (Section 3.2) to determine subject eligibility

Assign subject number

Medical history (record relevant medical history defined as any history impactful on the 
subject’s condition in terms of current functioning, disability, treatment, or management)

Demography

Record specific diagnosis of type of PI, date of diagnosis, and date and dose of current 
IgG replacement regimen initiated

AEs (including infusion reactions [see Section 4.3.1 for definitions]), prior and 
concomitant medications assessments (for antibiotics distinguish between prophylactic 
use and use for treatment of an episode of infection)

Full physical exam (excludes breast and genitourinary exam)

Record any SBIs (defined in Appendix 3) and hospitalizations due to infections (if this 
occurs during the Screening/Previous Regimen Phase, the subject will be a Screen 
Failure)

Record non-serious infections (by category) and antibiotic treatment.
These 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 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 eCRF.

Height and weight 

Vital signs (T, RR, HR, SBP, DBP)

Record results of most recent chest X-ray within 12 months (A chest X-ray will be 
necessary if not performed within 12 months of the Screening visit for adult subjects only 
as permitted per local requirements.) Note: at least one radiographic view (anterior-
posterior [AP] or posterior-anterior [PA] is required)

Sample for IgG subclass levels, and antibody titers for bacterial pathogens (H. influenzae, 
S. pneumoniae, C. tetani [tetanus])

Blood and urine samples for clinical laboratory assessments (e.g., clinical chemistry, 
hematology, urinalysis, pregnancy testing) (see Section 3.6.3). 
-
Hemoglobin, hematocrit, platelets, red blood cell count including red blood cell 
morphology, white blood cell count with differential; absolute reticulocyte count 
(ARC) 

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-
Additional Special Tests: haptoglobin
-
HIV NAT test sample   
-
Sodium, potassium, creatinine, chloride, calcium, BUN, bicarbonate, albumin, lactate 
dehydrogenase (LDH),  AST, ALT, alkaline phosphatase (ALP), glucose, total 
bilirubin, indirect bilirubin
-
Serum pregnancy test (potential child-bearing females only)
-
Urinalysis: pH, protein, glucose, ketones, bilirubin, nitrites, urobilinogen, blood, 
leukocyte esterase (with microscopic examination of urine sediment if abnormal)
For subjects who will also receive a previous regimen SCIG or IVIG dose at the 
Screening Visit, perform the following:

Blood sample for previous regimen IgG level (Ctrough for subjects receiving 
pIV#1/pSC#1)

pIV/pSC dose in the clinic (mandatory)
For subjects who will NOT receive a previous regimen SCIG or IVIG dose at the 
Screening Visit, schedule a pIV#1/pSC#1 Visit during this stage.
Previous Regimen Phase pIV or pSC Visit #1 or #2

Vital signs (T, RR, HR, SBP, DBP) 

Trough (pre-dose of previous IgG replacement regimen) PK IgG sampling at 2 time 
points.  Please note:
-
For subjects receiving SCIG therapy as their previous regimen, the pSC#1 dose will 
occur during the Screening/Previous Regimen Phase with an IgG trough level drawn 
pre-dose. The second IgG trough level may be drawn at Baseline prior to the first 
dose of IGSC 20% (a separate pSC#2 visit is not required). These samples do not 
have to be consecutive; however, they must be collected pre-dose. 
-
For subjects receiving IVIG therapy as their previous regimen, trough IgG levels will 
be drawn prior to each pIV dose. The pIV#1 dose can coincide with the Screening 
Visit. The pIV#2 dose will occur 3 to 4 weeks later during the Previous Regimen 
Phase. Please note a separate pIV#2 visit is required in all cases.
-
Note the IgG trough values drawn during the Previous Regimen Phase constitute the 
Pre-baseline trough values which will confirm the final eligibility for subjects 
entering the study (must be ≥ 500 mg/dL) with the exception of the pSC #2 trough 
result which will be reported after the Baseline visit.

Administration of the subject’s current (“previous”) IgG replacement regimen as 
detailed above and specifically in Sections 3.1 and 3.3.2

Record any SBIs (defined in Appendix 3) and hospitalizations due to infections (if this 
occurs during the Screening/Previous Regimen Phase the subject will be a Screen 
Failure)

Record non-serious infections (by category) and antibiotic treatment.

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These 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 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 eCRF.

AEs (including infusion reactions [see Section 4.3.1 for definitions]), prior and 
concomitant medications assessments (for antibiotics distinguish between prophylactic 
use and use for treatment of an episode of infection)
3.6.2.2
Baseline/IGSC 20% SC#1/Week1 (Start of IGSC 20% Treatment Stage 1)
All Screening laboratory results and assessments must be available and all inclusion and 
exclusion criteria must have been satisfied prior to initiating treatment. Eligible subjects will 
enter IGSC 20% Treatment Stage 1. There should be no interruption in IgG dosing. The 
IGSC 20% Treatment Stage 1 should commence 7 days (1 week) after the last previous 
regimen dose of IVIG or SCIG, except if SCIG is given on a biweekly schedule, the interval 
would be 2 weeks (i.e., the timing of start of Treatment Stage 1 will match the SC dosing 
interval so that an accurately reflective, previous regimen IgG Ctrough can be obtained at 
Baseline). 
The first 3 SC infusions of IGSC 20% will be performed under medical supervision in the 
Investigator’s clinic (SC#1, SC#2, and SC#3); weekly SC infusions may be administered at 
home thereafter, once the subject (or parent/guardian if the subject is a child) has been 
properly trained, and demonstrated to the treating physician his/her competence in 
administering infusion, use of the SC pump and collection of data on the SC diary.
BASELINE VISIT (WEEK 1)   
Assessments to be performed prior to IGSC 20% infusion

Re-assess inclusion and exclusion criteria (Section 3.2) to determine subject eligibility
(e.g., assure HIV NAT result is negative)

AEs (including infusion reactions [see Section 4.3.1 for definitions] and clinical 
observation of signs and symptoms suggestive of any significant disease or condition 
[e.g., thrombosis, anemia, etc.])

Prior and concomitant medications assessments (for antibiotics distinguish between 
prophylactic use and use for treatment of an episode of infection)

SC infusion diaries: SC/IgG infusion diaries will be provided to each subject at the 
Baseline visit which may be used to record items including but not limited to: local 
infusion site reactions, concomitant medications (including antibiotics [prophylactic and 
therapeutic]), and details of IgG drug administration (location and number of sites, 

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date/clock time of start and end of infusion, dose/volume, duration and rates of infusion).
All local infusion site reactions will be recorded in the eCRF. The subset of local infusion 
site reactions where the symptoms/signs lead to infusion interruption or discontinuation, 
require concomitant medication, or have an impact on the general condition of the subject 
as judged by the Investigator will be considered as AEs. The SC infusion diary may also 
be used to record days of missed work/school/daily activities due to infections and related 
treatment. 

Full physical exam (excludes breast and genitourinary exam)

Weight and height

Vital signs (T, RR, HR, SBP, DBP) 

Pre-dose PK IgG sampling which may also be the pSC#2 trough sample for subjects on a 
previous SC regimen.

Blood sample for IgG subclass levels, and antibody titers for bacterial pathogens
(H. influenzae, S. pneumoniae, C. tetani [tetanus])

Blood draw for trough measles antibody titer

Collection of virus safety retain samples as detailed in Table 3-1 and Section 3.6.3.1
(collect samples but test only if the subject exhibits clinical signs and symptoms 
consistent with hepatitis A, hepatitis B, hepatitis C, HIV, or parvovirus B19 [B19V]
infection while participating in the study.)
Note: For young pediatric subjects, at the discretion of the Investigator, virus safety retain 
samples may be drawn the day prior to Baseline instead of combining with other baseline 
blood draws on a single day.

Blood and urine samples for clinical laboratory assessments (clinical chemistry, 
hematology, urinalysis, additional special tests) (see Section 3.6.3):
-
Hemoglobin, hematocrit, platelets, red blood cell count including red blood cell 
morphology, white blood cell count with differential; ARC
-
Additional Special Test: haptoglobin
-
Sodium, potassium, creatinine, chloride, calcium, BUN, bicarbonate, albumin, LDH, 
AST, ALT, ALP, glucose, total bilirubin, indirect bilirubin
-
Urinalysis: pH, protein, glucose, ketones, bilirubin, nitrites, urobilinogen, blood, 
leukocyte esterase (with microscopic examination of urine sediment if abnormal)

Urine pregnancy test for women of childbearing potential (to be performed locally at the 
investigative site)

Record any SBIs (defined in Appendix 3), hospitalizations due to infections (if this 
occurs during the Screening/Previous Regimen Phase and prior to first dose of Grifols 
IGSC 20%, the subject will be a Screen Failure)

Record non-serious infections (by category) and antibiotic treatment.
These 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 eCRF: “Is this an infection? (verbatim term delineating 
nature of infection). Also record validated infections documented by positive radiograph, 

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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 eCRF.

Record days lost from work/school/daily activities due to infections and treatment
Following completion of Baseline assessments (pre-dose), the subject will receive the first 
IGSC 20% infusion (SC#1) at the Investigator’s site during the same visit.

IGSC 20% dosage (mg/kg) will be based on the subject’s prior (pre-study) IgG 
replacement regimen as described in Section 3.3 and will be ≥ 100 mg/kg/week

Site personnel will train subjects/caregivers to administer IGSC 20% during this visit
using an infusion SC pump

Document total infusion volume prepared, infusion start date/time and stop date/time, 
total volume infused, and, if necessary, any infusion interruption with explanation

Record AEs including infusion reactions (see Section 4.3.1 for definitions) and clinical 
observation of signs and symptoms suggestive of any significant disease or condition 
[e.g., thrombosis, anemia, etc.])

Record concomitant medications (for antibiotics distinguish between prophylactic use 
and use for treatment of an episode of infection)
3.6.2.3
IGSC 20% Treatment Stage 1: Weeks 2 through 13; SC#2 through SC#13
After SC#3 (Week 3), subsequent clinic visits will be at monthly intervals through SC#13 
and will include trough (pre-dose) PK IgG levels. The IGSC 20% mg/kg dose will be 
adjusted if the trough level is below 500 mg/dL since this level is considered as 
ineffective against bacterial infection.
IGSC 20% SC#2 – VISIT IN CLINIC
The second IGSC 20% infusion (SC#2) will be administered at the Investigator’s site 1 week 
post Baseline to provide additional training for the subject. The subject or caregiver should 
administer the infusion under supervision by site personnel. The following 
assessments/procedures will be performed: 

Pre-infusion: Draw trough (pre-dose) PK IgG sample 

IGSC 20% dosage will be based on the subject’s weight measured in the clinic at 
Baseline and any adjustment necessary based on the subject’s most recent IgG trough 
level from last visit

Site personnel will observe (or re-train) subjects/caregivers to self-administer IGSC 20% 
during this visit using an SC pump

Document total infusion volume prepared, infusion start date/time and stop date/time, 
total volume infused, and, if necessary, any infusion interruption with explanation

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
Record AEs including infusion reactions (see Section 4.3.1 for definitions) and clinical 
observation of signs and symptoms suggestive of any significant disease or condition 
[e.g., thrombosis, anemia, etc.])

Record concomitant medications (for antibiotics distinguish between prophylactic use 
and use for treatment of an episode of infection)

Record any SBIs (defined in Appendix 3) and hospitalizations due to infections. The 
evaluations performed to fulfill diagnostic categories specified in Appendix 3 must be 
recorded in the eCRF.

Record non-serious infections (by category) and antibiotic treatment.
These 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 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 eCRF.

Record days lost from work/school/daily activities due to infections and treatment
IGSC 20% SC#3 – VISIT IN CLINIC
The third IGSC 20% infusion (SC#3) will also be administered at the Investigator’s site to 
provide additional experience for the subject/caregiver. The subject or caregiver should 
administer the infusion under supervision by site personnel. The following 
assessments/procedures will be performed: 

IGSC 20% dosage will be based on the subject’s weight measured in the clinic at 
Baseline and any adjustment necessary based on the subject’s most recent IgG trough 
level from last visit

Site personnel will observe (or re-train) subjects/caregivers  to self-administer IGSC 20% 
during this visit using an SC pump

Document total infusion volume prepared, infusion start date/time and stop date/time, 
total volume infused, and, if necessary, any infusion interruption with explanation

Record AEs including infusion reactions (see Section 4.3.1 for definitions) and clinical 
observation of signs and symptoms suggestive of any significant disease or condition 
[e.g., thrombosis, anemia, etc.])

Record concomitant medications (for antibiotics distinguish between prophylactic use 
and use for treatment of an episode of infection)

Record any SBIs (defined in Appendix 3) and hospitalizations due to infections. The 
evaluations performed to fulfill diagnostic categories specified in Appendix 3 must be 
recorded in the eCRF. 

Record non-serious infections (by category) and antibiotic treatment.

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These 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 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 eCRF.

Record days lost from work/school/daily activities due to infections and treatment
IGSC 20% SC#5, 9, AND 13 – VISITS IN CLINIC
Assessments to be performed prior to IGSC 20% infusion at all Visits:

Full physical exam (excludes breast and genitourinary exam) at SC#13 Visit only

Weight

Vital signs (T, RR, HR, SBP, DBP) 

Trough (pre-dose) PK IgG sampling 

Review of trough (pre-dose) PK IgG level to assure Ctrough is not less than 500 mg/dL. 
Adjustment in dose of IGSC 20% will be necessary if IgG Ctrough is below this threshold. 
The dose adjustment (mg/kg) should not be more than a 15% to 20% increase from the 
dose producing the low IgG trough, per the Investigator’s discretion. Any dose 
adjustments beyond this range will require consultation with Grifols. Use weight from 
current visit to calculate the total dose of IGSC 20% to be administered on-site and 
subsequently at home at weekly intervals.

Review SC infusion diary and infusion details from IGSC 20% administered weekly at 
home with subjects/caregivers. All local infusion site reactions will be recorded in the 
eCRF. The subset of local infusion site reactions where the symptoms/signs lead to 
infusion interruption or discontinuation, require concomitant medication, or have an 
impact on the general condition of the subject as judged by the Investigator will be 
considered as AEs.

Record any SBIs (defined in Appendix 3) and hospitalizations due to infections. The 
evaluations performed to fulfill diagnostic categories in Appendix 3 must be recorded in 
the eCRF.

Record non-serious infections (by category) and antibiotic treatment.
These 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 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 

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antigen test). The specific evaluations performed to validate infections must be recorded 
in the eCRF.

Record days lost from work/school/daily activities due to infections and treatment
IP infusion in clinic at Visits SC#5, SC#9, and SC#13

IGSC 20% dose will be based on the subject’s weight measured in the clinic at SC#5, 
SC#9, and SC#13 Visits and any adjustment necessary based on the subject’s most recent 
IgG trough level from last visit

An infusion pump (designed for SC infusion) will be used to deliver IGSC 20%

Site personnel will observe subjects/caregivers administering IGSC 20% and retrain if 
needed. This will be documented.

Document total infusion volume prepared, infusion start date/time and stop date/time, 
total volume infused, and, if necessary, any infusion interruption with explanation

Record AEs including infusion reactions (see Section 4.3.1 for definitions) and clinical 
observation of signs and symptoms suggestive of any significant disease or condition 
[e.g., thrombosis, anemia, etc.])

Record concomitant medications (for antibiotics distinguish between prophylactic use 
and use for treatment of an episode of infection)
IP infusion may be administered at home for intervening weekly infusions, specifically 
infusion numbers SC#4, SC#6, SC#7, SC#8, SC#10, SC#11, and SC#12. The SC infusion
diary must be completed with all relevant information pertaining to infusion particulars as 
detailed in Section 3.6.2.2. The weight that will be used to determine the infusion dose will 
be the most recent weight obtained at the last clinic visit.
Laboratory draw and height at SC#13 visit only prior to IGSC 20% infusion:

Height

Sample for IgG subclass levels, and antibody titers for bacterial pathogens (H. influenzae, 
S. pneumoniae, C. tetani [tetanus]) 

Blood and urine samples for clinical laboratory assessments (clinical chemistry, 
hematology, urinalysis, additional special tests) (see Section 3.6.3):
-
Hemoglobin, hematocrit, platelets, red blood cell count including red blood cell 
morphology, white blood cell count with differential, ARC
-
Additional Special Tests: Direct antiglobulin test (DAT), serum free hemoglobin, 
haptoglobin 
-
Sodium, potassium, creatinine, chloride, calcium, BUN, bicarbonate, albumin, LDH, 
AST, ALT, ALP, glucose, total bilirubin, indirect bilirubin
-
Urinalysis: pH, protein, glucose, ketones, bilirubin, nitrites, urobilinogen, blood, 
leukocyte esterase (with microscopic examination of urine sediment if abnormal)

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3.6.2.4
IGSC 20% Treatment Stage 2 (Weeks 14 through 52, SC#14 through SC#52)
During IGSC 20% Treatment Stage 2, the mg/kg IGSC 20% dose (ratio of mg per kg) will 
now remain constant with no dose adjustment permitted, unless it is absolutely medically 
necessary to change the dose, and such change requires previous consultation with the 
Grifols Medical Monitor. Weight will be measured at every in-clinic visit and dosing will be 
based on the subject’s current weight. For the subsequent at home IGSC 20% infusions 
between clinic visits, the dose will be the same as the total infusion dose calculated at the 
previous clinic study visit where weight was measured at the clinical site. IgG trough levels 
will be measured monthly (every 4 weeks). After 16 weeks of IGSC 20% treatment 
(including Stage 1), at SC#17, PK profiles in approximately 20 adult subjects will be 
measured. Where possible, the first available 20 adult subjects reaching the visit designated 
SC#17 in this study will constitute the PK subset. Blood draws for steady-state PK analyses 
will be collected after the 17th SC dose for up to 7 days post dose. 
IGSC 20% SC# 17, 20, 24, 28, 32, 36, 40, 44, 48, AND 52 – VISITS IN CLINIC
Assessments to be performed prior to IGSC 20% infusion at all visits:

Full physical exam (excludes breast and genitourinary exam) at SC#24 and #36 only

Weight

Vital signs (T, RR, HR, SBP, DBP) 

Trough (pre-dose) PK IgG sampling for all subjects. Note for PK subset profiling IgG 
trough should be within 0.5 hour of start of infusion on SC#17. Review of trough 
(pre-dose) PK IgG level. Use weight from current visit to calculate total dose of IGSC 
20% to be administered on-site and subsequently at home at weekly intervals.

Blood draw for trough measles antibody titer at SC#20 and SC#52 only

Review SC infusion diary and infusion details from IGSC 20% administered weekly at 
home with subjects/caregivers. All local infusion site reactions will be recorded in the 
eCRF. The subset of local infusion site reactions where the symptoms/signs lead to 
infusion interruption or discontinuation, require concomitant medication, or have an 
impact on the general condition of the subject as judged by the Investigator, will be 
considered as AEs.

Record any SBIs (defined in Appendix 3) and hospitalizations due to infections. The 
evaluations performed to fulfill the diagnostic categories in Appendix 3 must be recorded 
in the eCRF.

Record non-serious infections (by category) and antibiotic treatment.
These 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 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 

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antigen test). The specific evaluations performed to validate infections must be recorded 
in the eCRF.

Record days lost from work/school/daily activities due to infections and treatment
Laboratory draw and height at SC#24 and SC#36 visits only prior to IGSC 20% infusion:

Height

Blood and urine samples for clinical laboratory assessments (clinical chemistry, 
hematology, urinalysis, additional special tests) (see Section 3.6.3):
-
Hemoglobin, hematocrit, platelets, red blood cell count including red blood cell 
morphology, white blood cell count with differential, ARC
-
Additional Special Tests: DAT, serum free hemoglobin, haptoglobin
-
Sodium, potassium, creatinine, chloride, calcium, BUN, bicarbonate, albumin, LDH, 
AST, ALT, ALP, glucose, total bilirubin, indirect bilirubin
-
Urinalysis: pH, protein, glucose, ketones, bilirubin, nitrites, urobilinogen, blood, 
leukocyte esterase (with microscopic examination of urine sediment if abnormal)

Sample for IgG subclass levels and antibody titers for bacterial pathogens (H. influenzae, 
S. pneumoniae, C. tetani [tetanus])
IP infusion in clinic at SC#17, 20, 24, 28, 32, 36, 40, 44, 48, and 52 visits:

IGSC 20% net total dose will be determined on the subject’s current weight 

Site personnel will observe (and re-train as needed) subjects administering IGSC 20%
using the SC pump

Document total infusion volume prepared, infusion start date/time and stop date/time, 
total volume infused, and, if necessary, any infusion interruption with explanation

Record AEs including infusion reactions (see Section 4.3.1 for definitions) and clinical 
observation of signs and symptoms suggestive of any significant disease or condition 
[e.g., thrombosis, anemia, etc.])

Record concomitant medications (for antibiotics distinguish between prophylactic use 
and use for treatment of an episode of infection)
IP infusion may be administered at home for intervening weekly infusions, specifically 
infusion numbers SC#14, SC#15, SC#16, (SC#18 except for PK subset see Section 3.6.2.5), 
SC#19, SC#21, SC#22, SC#23, SC#25, SC#26, SC#27, SC#29, SC#30, SC#31, SC#33, 
SC#34, SC#35, SC#37, SC#38, SC#39, SC#41, SC#42, SC#43, SC#45, SC#46, SC#47, 
SC#49, SC#50, and SC#51. The SC infusion diary must be completed with all relevant 
information pertaining to infusion particulars as detailed in Section 3.6.2.2. The weight that 
will be used to determine the infusion dose will be the most recent weight obtained at the last 
clinic visit.

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3.6.2.5
IGSC 20% Treatment Stage 2 – PK Subset Only
Subjects agreeing to participate in the serial PK sampling portion of the study (preferably the 
first 20 adults enrolled) will have additional PK profiling starting at SC#17 (Week 17) and 
ending at SC#18 (Week 18). While all subjects will have a SC#17 (Week 17) visit (described 
above), only subjects in the PK subset will have an additional clinic visit at SC#18. 
To participate in the PK subset, a subject must not have required an mg/kg dose level 
adjustment in IGSC 20% at or after SC#9. Details are provided in Appendix 2 and below.
ADDITIONAL IGSC 20% SC#17 AND SC#18 ASSESSMENTS – FOR PK SUBSET ONLY
After IGSC SC#17 visit infusion – Serial PK sampling to be done for PK subset only

PK serial blood samples for serial IgG levels will be drawn at the following time points 
after completion of the IGSC 20% SC#17 infusion:
-
Immediately at the completion of the 17th SC infusion
-
1 day ± 4 hours post SC#17 infusion
-
3 days ± 4 hours post SC#17 infusion
-
5 days ± 4 hours post SC#17 infusion
-
7 days ± 1 day post SC#17 infusion (within 0.5 hour prior to the SC#18 IGSC 20% 
infusion)
Assessments to be performed prior to IGSC 20% infusion at additional clinic visit at 
SC#18 (Week 18) for PK subset subjects only :

Weight

Vital signs (T, RR, HR, SBP, DBP) 

Trough (pre-dose) PK IgG sampling (within 0.5 hour of the start of infusion)

Review of trough (pre-dose) PK IgG level. Use weight from current visit to calculate 
total dose of IGSC 20% to be administered on-site and subsequently at home at weekly 
intervals. If a dose adjustment (in mg/kg dose) occurred at or after SC#9 then the 
subject is not appropriate for the PK subset study and should not undergo the PK 
profiling. An additional subject should be designated for PK profiling.

Record any SBIs (defined in Appendix 3) and hospitalizations due to infections. The 
evaluations performed to fulfill diagnostic categories in Appendix 3 must be recorded in 
the eCRF.

Record non-serious infections (by category) and antibiotic treatment.
These 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 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 

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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 eCRF.

Record days lost from work/school/daily activities due to infections and treatment
IP infusion in clinic for PK subset only (SC#18 Visit):

IGSC 20% dose will be based on the subject’s current weight 

An infusion pump (designed for SC infusion) will be used to deliver IGSC 20%

Site personnel will observe subjects/caregivers administering IGSC 20% and retrain if 
needed. This will be documented.

Document total infusion volume prepared, infusion start date/time and stop date/time, 
total volume infused, and, if necessary, any infusion interruption with explanation

Record AEs, including infusion reactions (see Section 4.3.1 for definitions) and clinical 
observation of signs and symptoms suggestive of any significant disease or condition 
[e.g., thrombosis, anemia, etc.])

Record concomitant medications (for antibiotics distinguish between prophylactic use 
and use for treatment of an episode of infection)
3.6.2.6
Final Visit – Week 53 (1 Week Post Final IGSC 20% Infusion) – Visit in Clinic
The final infusion of IGSC 20% will be SC#52. One week post last SC infusion a Final Visit 
will occur. 
The following assessments will be performed:

Full physical exam (excludes breast and genitourinary exam)

Height

Vital signs (T, RR, HR, SBP, DBP) 

Trough (pre-dose) PK IgG sampling 

Sample for IgG subclass levels and antibody titers for bacterial pathogens (H. influenzae, 
S. pneumoniae, C. tetani [tetanus])

Blood and urine samples for clinical laboratory assessments (clinical chemistry, 
hematology, urinalysis, additional special tests, pregnancy testing) (see Section 3.6.3):
-
Hemoglobin, hematocrit, platelets, red blood cell count including red blood cell 
morphology, white blood cell count with differential, ARC
-
Additional Special Tests: DAT, serum free hemoglobin, haptoglobin
-
Sodium, potassium, creatinine, chloride, calcium, BUN, bicarbonate, albumin, LDH, 
AST, ALT, ALP, glucose, total bilirubin, indirect bilirubin
-
Serum pregnancy test (potential child-bearing females only)
-
Urinalysis: pH, protein, glucose, ketones, bilirubin, nitrites, urobilinogen, blood, 
leukocyte esterase (with microscopic examination of urine sediment if abnormal)

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
Record AEs including infusion reactions (see Section 4.3.1 for definitions) and clinical 
observation of signs and symptoms suggestive of any significant disease or condition 
[e.g., thrombosis, anemia, etc.])

Record concomitant medications (for antibiotics distinguish between prophylactic use 
and use for treatment of an episode of infection)

Perform final SC infusion diary review for infusion details with subjects/caregivers. All
local infusion site reactions will be recorded in the eCRF. The subset of local infusion 
site reactions where the symptoms/signs lead to infusion interruption or discontinuation, 
require concomitant medication, or have an impact on the general condition of the subject 
as judged by the Investigator will be considered as AEs.

Record any SBIs (Appendix 3) and hospitalizations due to infections. The evaluations 
performed to fulfill diagnostic categories in Appendix 3 must be recorded in the eCRF.

Record non-serious infections (by category) and antibiotic treatment.
These 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 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 eCRF.

Record days lost from work/school/daily activities due to infections and treatment
3.6.2.7
Early Termination Visit
If a subject discontinues at any point during the study after Baseline, the subject will be 
requested to return to the Investigator’s study site for an Early Termination Visit. The 
assessments at this visit will be the same as the Final Visit in the case of a subject who 
prematurely discontinues the study.
The following procedures and assessments will be performed during the Early Termination
Visit:

Full physical exam (excludes breast and genitourinary exam)

Height

Vital signs (T, RR, HR, SBP, DBP) 

Trough PK IgG sampling 

Sample for IgG subclass levels, and antibody titers for bacterial pathogens (H. influenzae, 
S. pneumoniae, C. tetani [tetanus])

Blood and urine samples for clinical laboratory assessments (clinical chemistry, 
hematology, urinalysis, additional special tests, pregnancy testing) (see Section 3.6.3):

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-
Hemoglobin, hematocrit, platelets, red blood cell count including red blood cell 
morphology, white blood cell count with differential, ARC
-
Additional Special Tests: DAT, serum free hemoglobin, haptoglobin
-
Sodium, potassium, creatinine, chloride, calcium, BUN, bicarbonate, albumin, LDH, 
AST, ALT, ALP, glucose, total bilirubin, indirect bilirubin
-
Serum pregnancy test (potential child-bearing females only)
-
Urinalysis: pH, protein, glucose, ketones, bilirubin, nitrites, urobilinogen, blood, 
leukocyte esterase (with microscopic examination of urine sediment if abnormal)

Record AEs including infusion reactions (see Section 4.3.1 for definitions) and clinical 
observation of signs and symptoms suggestive of any significant disease or condition 
[e.g., thrombosis, anemia, etc.])

Record concomitant medications (for antibiotics distinguish between prophylactic use 
and use for treatment of an episode of infection)

Perform final SC infusion diary review for infusion details with subjects/caregivers. All 
local infusion site reactions will be recorded in the eCRF. The subset of local infusion 
site reactions where the symptoms/signs lead to infusion interruption or discontinuation, 
require concomitant medication, or have an impact on the general condition of the subject 
as judged by the Investigator will be considered as AEs.

Record any SBIs (Appendix 3) and hospitalizations due to infections. The evaluations 
performed to fulfill diagnostic categories in Appendix 3 must be recorded in the eCRF

Record non-serious infections (by category) and antibiotic treatment.
These 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 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 eCRF

Record days lost from work/school/daily activities due to infections and treatment

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3.6.3
Description of Laboratory Tests and Procedures
Detailed descriptions of laboratory test procedures are located in the study Laboratory 
Manual. Table 3-1 provides a summary of the laboratory tests conducted for this study.
Table 3-1 Name, Description, and Location of Laboratory Tests and Procedures
Test Panel
Description
Location
Hematology a
Hemoglobin, hematocrit, platelets, red blood cell count 
including red blood cell morphology, white blood cell count 
with differential, ARC
Central
Additional special tests a
DAT, serum free hemoglobin, haptoglobin
Central
Chemistry a
Sodium, potassium, creatinine, chloride, calcium, BUN, 
bicarbonate, albumin, LDH, AST, ALT, ALP, glucose, total 
bilirubin, indirect bilirubin
Central
IgG levels a
Total IgG levels will consist of trough (pre-dose) measurements 
in all subjects, and for the PK subset, serial PK sampling for PK 
profiling of IGSC 20%
Central
IgG subclass levels and 
antibody titers a
Measurement of IgG subclasses (IgG1, IgG2, IgG3, IgG4). 
Measurement of levels of selected specific antibodies against H.
influenzae, anti-pneumococcal polysaccharide (S. pneumoniae), 
and C. tetani [tetanus]
Specialty
Trough measles antibody 
titers (functional assay) a
Trough samples for measles antibody titer will be collected at 
Baseline (before the first infusion of Grifols IGSC 20%),
SC#20, and SC#52
Specialty
Serum pregnancy test a
Qualitative serum β-HCG for females of child-bearing potential
will be performed at Screening and Final Visit
Central
Urine pregnancy test a
Qualitative urine β-HCG will be performed at Baseline
Local
Viral NAT testing a, b, c
Screening:
HIV RNA testing
Central
Baseline:
Collect retain samples for hepatitis A virus (HAV) RNA, HBV 
DNA, HCV RNA, HIV RNA, and B19V DNA testing
Viral serology testing a, b, c
Baseline 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
Urinalysis a
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)
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
These samples will be retained until all analyses in support of the study are complete.
c
See Section 3.6.3.1. 

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3.6.3.1
Virus Safety Testing
At Screening, a sample for HIV NAT testing will be collected and tested for determination of
subject eligibility. The subject must be negative for HIV by NAT based on a Screening blood 
sample. The subject may enter the Previous Regimen Phase while the Screening blood 
sample is being tested, but will be a Screen Failure and will not undergo Baseline 
assessments if the HIV result is positive.
Virus safety (viral NAT and viral serology) retain samples collected at the Baseline Visit, 
prior to IGSC 20% infusion, will be tested only if the subject exhibits clinical signs and 
symptoms consistent with hepatitis A, hepatitis B, hepatitis C, HIV, or B19V infection while 
participating in the study. Virus safety samples will be retained until all analyses in support 
of the study are complete. Additional samples for viral NAT and viral serology testing may 
be collected and tested during the study only if the subject exhibits clinical signs and 
symptoms consistent with hepatitis A, hepatitis B, hepatitis C, HIV, or B19V infection while 
participating in the study.
Note: For young pediatric subjects, at the discretion of the Investigator, virus safety retain 
samples may be drawn the day prior to Baseline instead of combining with other baseline 
blood draws on a single day.
3.6.3.2
Immunoglobulin G Assessments
All subjects will have trough (pre-dose) total IgG measurements performed at each visit
(except SC#3). These measurements are important as a guide to dose level adjustment in 
Treatment Stage 1 to assure that adequate IgG levels are maintained at a sufficient 
concentration (not less than 500 mg/dL) to avoid serious infection. Samples will be retained 
until all analyses in support of the study are complete.
In addition, IgG subclass antibody levels (IgG1, IgG2, IgG3, and IgG4) will be measured at 
Screening, Baseline (prior to first dose of IGSC 20%), SC#13, SC#24, SC#36, and Final 
Visit in all subjects. Specific antibody levels to the following pathogens will also be 
measured at these time points: H. influenzae, anti-pneumococcal polysaccharide (S.
pneumoniae), and tetanus (C. tetani). Trough samples for measles antibody titer will be 
collected at Baseline (before the first infusion of Grifols IGSC 20%) at SC#20 and at SC#52. 
In the adult PK subset, total IgG PK profiling will be performed as described in Section 
3.6.2.5. Samples will be drawn at the following time points:

Trough (pre-dose) PK IgG sampling (within 0.5 hour of the start of the 17th SC infusion)

Immediately at the completion of the 17th SC infusion

1 day ± 4 hours post infusion

3 days ± 4 hours post infusion

5 days ± 4 hours post infusion

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
7 days ± 1 day post infusion (within 0.5 hour prior to the 18th IGSC 20% dose)
3.7
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 may be withdrawn from IP or the study for the following reasons: 

Subjects with an occurrence of a concomitant disease, or any medical condition which, 
either because of its severity or duration or necessary change in treatment, contravenes 
the condition of the study or puts the subject at unnecessary risk or harm

Subjects with an occurrence of an AE which in the opinion of the Investigator and/or 
subject requires termination of treatment

Subjects who are noncompliant with the protocol (including noncompliance with weekly 
IGSC 20% dosing) per the Investigator’s discretion

Pregnancy (Note: Subject must be withdrawn from IP administration and the study prior 
to dosing with a commercially available IgG product.) 
In all cases, the reason for withdrawal must be recorded in the eCRF and in the subject's 
source documentation. 
3.8
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 to have all assessments completed for the Early Termination Visit (see 
Section 3.6.2.7 and Appendix 1) as close as practical to 1 week after their last administration 
of the IP.
3.9
Subject Recruitment
A PK subject who undergoes a dose adjustment (in mg/kg) at or after SC#9 is not appropriate 
for the PK subset study and should not undergo the PK profiling. The subject will be 
permitted to continue within the study. However, an additional PK subject may be recruited; 
similarly an additional PK subject may be enrolled if a subject in the PK subset cannot 
adequately complete the PK profiling.

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3.10
Premature Termination of Study/Closure of Center
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 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 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 International Conference on Harmonization Good Clinical Practice 
(ICH GCP)
4
ADVERSE EVENTS 
4.1
Warnings/Precautions
For complete information on IGSC 20%, refer to the IB.
4.2
Adverse Event Monitoring
Subjects must be carefully monitored for AEs. This monitoring includes clinical and 
laboratory tests and physical signs. Adverse events should be assessed in terms of their 
seriousness, severity, and causal relationship to the IP.
4.3
Adverse Event Definitions
4.3.1
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.
Any AE that occurs at any time between the signing of the ICF and the last day of the 
subject’s participation in the clinical trial must be reported and recorded in the AE eCRF.

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All local infusion site reactions will be recorded in the eCRF. The subset of local infusion 
site reactions where the symptoms/signs lead to infusion interruption or discontinuation, 
require concomitant medication, or have an impact on the general condition of the subject as 
judged by the Investigator will be considered as AEs.
4.3.2
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. 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, that is, the relationship cannot be ruled out. 
4.3.3
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 for SAEs. Assessment of the causal relationship to the study drug will be 
made according to the following classifications based on Karch FE et al. (45):
Definite: An event that follows a reasonable temporal sequence from administration of the 
treatment or in which the treatment level has been established in body fluids or tissues; that 
follows a known response pattern to the suspected treatment and that is confirmed by 
improvement on stopping the treatment (dechallenge), and reappearance of the event on 
repeated exposure (rechallenge).
Probable: An event that follows a reasonable temporal sequence from administration of the 
treatment; that is confirmed by dechallenge; that follows a known response pattern to the 
suspected treatment; that is confirmed by dechallenge and that could not be reasonably 
explained by the known characteristics of the subject’s clinical state.
Possible: An event that follows a reasonable temporal sequence from administration of the 
treatment; that follows a known response pattern to the suspected treatment; but that could 
have been produced by the subject’s clinical state or other modes of therapy administered to 
the subject.
Doubtful/Unlikely: An event that follows a reasonable temporal sequence from 
administration of the treatment; that does not follow a known response pattern to the 
suspected treatment; but that could not be reasonably explained by the known characteristics 
of the subject’s clinical state.
Unrelated: Any event that does not meet the criteria above.
The operational tool to decide the AE causal relationship is based on algorithms by Karch FE 
et al. and Naranjo CA et al. (46,47).

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When an AE is classified, assessing causal relationship by the Investigator, as “definitive”, 
i.e., “probable”, “possible” or “doubtful/unlikely”, the event will be defined as a suspected 
ADR. When the causal relationship is labeled “unrelated”, then it will be considered that the 
AE is not imputable to the study treatment and it is not a suspected ADR.
In addition, when a causal relationship between the study treatment and the AE cannot be 
ruled out by the Investigator and/or Sponsor, it means that the AE cannot be labeled 
“unrelated”.
For any subject, all AEs that occur at any time from the beginning of IP administration until 
the final visit of the clinical trial will be considered as treatment emergent AEs (TEAEs).
4.3.4
Severity of Adverse Event or Suspected Adverse Drug Reaction
AEs and suspected ADRs will be classified depending on their severity according to the 
following definitions:
1. Mild: an AE which is well tolerated by the subject, causing minimum degree of malaise 
and without affecting normal activities.
2. Moderate: an AE that interferes with the subject’s normal activities.
3. Severe: an AE that prevents the subject from performing their normal activities.
AE and suspected ADR 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 clinical trial, taking into account current criteria included in this section.
4.3.5
Expectedness of Adverse Event or Suspected Adverse Drug Reaction
An AE or suspected ADR 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 (i.e., IB) for any 
serious ADRs (potentially related SAEs) for expedited safety reporting purposes.  
4.3.6
Seriousness of Adverse Event or Suspected Adverse Drug Reaction; 
Serious Adverse Event
An AE or suspected ADR is considered “serious” if, in the view of either the Investigator or 
Sponsor, it results in any of the following outcomes: 
1. Death

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2. 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)
3. In-patient hospitalization or prolongation of existing hospitalization
4. A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
5. A congenital anomaly/birth defect
6. 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).
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. 
A distinction should be drawn between serious and severe AEs. The term “severe” is used to 
describe the intensity (severity) of a specific event; the event itself, however, may be of 
relative minor medical significance (such as severe headache). This is not the same as 
“serious”, which is defined on subject/event outcome or action criteria usually associated 
with events that pose a threat to a subject’s life or functioning. Seriousness (not severity) is a 
medical term while severity is a subjective term. 
According to the medical criteria, an AE or a suspected ADR can be classified as serious, 
although it does not fulfill the conditions fixed in this section, if it is considered important 
from a medical point of view.
4.3.7
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 eCRF or SAE form and medical 
record. If no AE has occurred during the study period, 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 eCRF:

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1. The verbatim term (a diagnosis is preferred)
2. Date/time of onset
3. Date/time of resolution
4. Severity (mild, moderate, severe)
5. Causality (unrelated, doubtful/unlikely, possible, probable, definite)*
6. Seriousness (yes, no)
7. Action taken (with regard to IP)
8. Other action (to treat the event)
9. Outcome and sequel (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,
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.
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 relevant, e.g., causing the 
subject to withdraw from the study, requiring treatment or causing apparent clinical 
manifestations, or judged relevant by the Investigator, should be reported as an AE. Each 
event must be described in detail 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.
4.3.8
Type and Duration of the Follow-Up of Subjects after Adverse Events 
In so far as is possible, all individuals will be followed up until the AE or suspected ADR 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, no further change is expected, and the Investigator decides that no further 
follow-up is necessary.
4.4
Reporting of Serious Adverse Events or Pregnancy
4.4.1
Reporting Serious Adverse Event 
Any SAE (see Section 4.3.6) 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 study drug. Each SAE must be fully recorded in the subject’s eCRF and 
SAE Report Form. 

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SAEs will be reported using the designated 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 (ie, medical 
records).
Each SAE must be followed up until resolution or stabilization. After the initial report, all 
relevant information for SAE follow up and 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 
contract research organization (CRO) may request additional information and/or reports.
All SAE Report Forms must be reported by email to: 
Grifols Global Pharmacovigilance for Reporting SAEs and Pregnancy
Email: 
FAX (back-up only): 
(International)
When required, and according to local law and regulations, SAEs must be reported to the 
IRB/EC and regulatory authorities.
4.4.2
Reporting Pregnancy
Pregnancies occurring during the course of the study will not be considered an AE unless a 
relation to the study drug is suspected. In any case, a Pregnancy Report Form must be 
completed and sent as soon as possible to the Sponsor for any pregnancies that occur in a 
female subject or partner of a male subject from time of consent through the Final Visit (i.e., 
end of study). 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 defects 
observed in the child must be reported as an SAE (see email address or fax number in 
Section 4.4.1) within 24 hours of the Investigator or study personnel’s first knowledge.
5
STATISTICAL METHODS AND DETERMINATION OF SAMPLE 
SIZE
5.1
Statistical and Analytical Plans
Unless otherwise specified, descriptive statistics will include the number, 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.

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Data handling and evaluation procedures will be described as detailed in the Statistical 
Analysis Plan.
5.1.1
Subject Population(s) for Analysis
Safety Population
The safety population will include all subjects who have received any amount of IGSC 20%
and will be used for safety analysis.
Efficacy Evaluable Population
The efficacy evaluable population will include all subjects who have received at least one 
dose of IGSC 20% and will be used for efficacy analysis.
IgG Population
The IgG population will consist of all subjects who receive any amount of IGSC 20% and 
have total IgG concentration data to facilitate the comparison of mean trough IgG 
concentration during the IGSC 20% phase versus the pre-treatment phase. 
Pharmacokinetic Population
The PK population will consist of all adult subjects who have received IGSC 20% and have 
sufficient serial IgG concentration vs. time data to facilitate calculation of AUC PK
parameters.
5.1.2
Demographic and Baseline Characteristics
The 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. 
5.1.3
Efficacy Analysis
The primary efficacy variable of SBIs will be analyzed using the efficacy evaluable 
population. The number of SBIs from Week 1 to Week 53 during the IGSC 20% treatment 
period and percentage of subjects with SBIs will be summarized. 
The SBI rate will be compared to the recommended standard rate of 1 SBI per person per 
year. The following hypothesis testing is performed with one-sided test at alpha = 0.01 level: 

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year
per
person
per
SBI
H
versus
year
per
person
per
SBI
H
A
1
:
1
:
0




Where is the SBI rate during IGSC 20% treatment. Occurrence of SBI is assumed to 
follow the Poisson distribution. 
The generalized linear model procedure for Poisson regression with log link will be used to 
estimate the SBI rate for IGSC 20% 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. 
Secondary Efficacy Assessments:

All infections of any kind (serious/nonserious including 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 eCRF: “Is this an infection?” (verbatim term delineating 
infection).

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 
Other Efficacy Assessments

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)
The secondary and other efficacy variables will be summarized descriptively. Annualized 
rate of all infections, days missed work/school/daily activities, days on antibiotics, and 
hospitalizations will be calculated and the 95% CI will be provided. 
5.1.4
Pharmacokinetic Analysis
Trough concentrations of total IgG during the Screening/Previous Regimen Phase and the 
IGSC 20% Treatment Stages will be summarized by week for the efficacy evaluable 
population. Mean trough for IGSC 20% treatment phase will be calculated as the average of 

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all steady state trough concentrations measured during the IGSC 20% Treatment Stage 2, i.e., 
IgG trough levels measured at the following visits: SC#17, #18, #20, #24, #28, #32, #36, 
#40, #44, #48, #52, and #53. Comparison will be made to the mean of 2 troughs for previous 
IgG treatment (either IVIG or other SCIG products) obtained from the Screening/Previous 
Regimen Phase. Mean trough data will be summarized. Mean trough summary and analysis 
will be based on the IgG population.
For samples collected after SC#14 infusion (start of Treatment Stage 2), total IgG 
concentrations will be summarized by time point. For subjects in the PK subset with an IgG 
PK profile, individual and mean/median IgG concentrations vs. time curves will be plotted. 
PK parameters for total IgG including AUC0-7days, Cmax, and tmax will be determined by 
noncompartmental model using WinNonlin software. All PK parameters will be tabulated 
and summarized descriptively. The analyses will be based on the PK population. 
Summaries will be provided for average trough concentration of IgG subclasses (Screening, 
Baseline, before the 13th, 24th, 36th IGSC 20% infusion, and Final Visit). Summaries of 
average trough level concentration of antibody titers against S. pneumoniae, H. influenzae, 
and C. tetani (tetanus) will also be provided (collected at these same time points).
Trough measles antibody titers (functional assay at Baseline, SC#20 Visit, and SC#52 Visit) 
are an exploratory variable for informational purposes.
5.1.5
Safety Analysis
The safety analyses are based on the safety population. 
All AEs, suspected ADRs, SAEs and discontinuations due to AEs and SAEs will be 
summarized by presenting the number of events and the number and percentage of subjects 
with the events. The summaries will be presented by MedDRA system organ class and 
preferred term. AE summaries by severity will also be provided. Local infusion site reactions 
will be similarly summarized.
Subjects with deaths, SAEs, and AEs leading to premature discontinuation from the study 
will be listed and presented in a narrative form.  
Adverse events temporally associated with SC administration of study drug will be defined 
as those occurring during or within 72 hours of completion of an infusion. Additionally, local
infusion site reactions will be tabulated and summarized for the total duration of the study 
and by IGSC 20% infusion week.
For all laboratory tests and vital signs, 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.

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5.2
Determination of Sample Size
Assuming that the true rate of the SBIs is 0.25 per subject per year, 40 subjects treated for 
one year for IGSC 20% will provide at least 90% power to reject the null hypothesis of a SBI 
rate greater than or equal to 1.0 per person per year, using a one-sided test at the 0.01 level.
In order to obtain a total of 40 PI subjects including 20 adult and 20 pediatric evaluable 
subjects, approximately 60 subjects will be enrolled and treated in the study. This sample size 
is to allow for a moderate to high early discontinuation rate seen in other similar studies 
(13,36). 
6
ADMINISTRATIVE
6.1
Investigator(s), Other Study Personnel and External Committees
Information regarding additional key personnel 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 via an Investigators meeting, site initiation visit 
or other appropriate individual site training session(s).
6.2
Data Quality
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.
6.3
Documentation
The study data will be recorded and kept current in the 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 will be monitored at the site by Grifols Therapeutics Inc. 
representatives at regular intervals and reviewed for completeness and compared with the 
source documents. Examples of source documents include individual subject medical 
records, which are separate from the eCRFs.  

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All AEs and SAEs must be recorded. All SAEs must be recorded on the SAE form. The SAE 
form must be kept in the site records with a copy provided to the designated person as 
detailed in the study file.  
6.3.1
Record Retention
At study completion, all study data will be transferred to Grifols Therapeutics Inc. according 
to ICH GCP guidelines, local laws, regulations, and Grifols Therapeutics Inc. 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 Therapeutics 
Inc. 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.
6.3.2
Access to Information for Monitoring
The data will be recorded and kept current in eCRFs by the study site personnel directly 
responsible for the information and reviewed for completeness by the monitor. Grifols 
Therapeutics Inc. 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 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.
6.3.3
Access to Information for Audits or Inspections
Representatives of regulatory authorities or of Grifols Therapeutics Inc. may conduct audits 
or inspections 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 Therapeutics 
Inc. Medical Monitor immediately. The Investigator agrees to provide to representatives of a 
Regulatory Agency or Grifols Therapeutics Inc. access to records, facilities, and personnel 
for the effective conduct of an audit or inspection.

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7
ETHICAL AND LEGAL ASPECTS
7.1
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 IRB/EC is organized and operates according to ICH GCP 
guidelines and applicable laws and regulations.
7.2
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.
7.3
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.
7.4
Subject Information and Consent
Subject information, ICF, and Assent Form will be provided to Investigator sites. Prior to the 
beginning of the study, the Investigator must have the IRB/EC written approval/favorable 
opinion of the written ICF, Assent Form, and any other written information to be provided to 
subjects. The written approval of the IRB/EC together with the approved subject 

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information/Assent Form/ICF must be filed in the study files and a copy of the documents 
must also be provided to Sponsor by the Investigator site.
Written ICF by the subject or a parent and/or legal guardian along with subject assent, if
applicable, must be obtained before any study specific procedure takes place. Participation in 
the study and date of ICF given by the subject should be documented appropriately in the 
subject's files. A signed copy of the subject ICF and Assent Form, if applicable, will be 
provided to the subject or subject's authorized representative (i.e., parent or legal guardian).
7.5
Insurance
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 Sponsor, or as otherwise required by applicable laws and/or regulations.
7.6
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 number and subject 
initials will be recorded in the eCRF, and if the subject’s name appears on any other 
document (e.g., pathologist report), it must be obliterated 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 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.
8
USE OF DATA AND PUBLICATION
Sponsor is committed to honoring the principles of academic freedom while, at the same 
time, protecting its confidential information, the subjects, and the integrity of the study, and 
the study documentation all in compliance with applicable law. Institution and/or Investigator 
recognize that, with respect to any study that is part of a multi-site study, there is a need for a 
coordinated approach to any publication or presentation of results from the sites. 
Accordingly, the Institution/Investigator shall not publish or present any results from this 
study to any third parties until: (1) Sponsor publishes the results; (2) Institution and/or 
Investigator receives written notification from Sponsor that publication of the results is no 

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longer planned; or (3) twelve (12) months following the close of Study, whichever occurs 
first.  
Institution and/or Investigator shall submit to Sponsor for its review a copy of any proposed 
publication at least thirty (30) calendar days prior to the planned date of submission for 
publication or presentation. Institution and Investigator shall consider in good faith all 
comments received from Sponsor during the review period and shall delete Sponsor’s 
confidential information (other than study results). 
If Sponsor determines that the publication contains patentable subject matter which requires 
protection, Sponsor may require the delay of submission for publication or presentation for 
an additional period of time for the purpose of filing patent applications or otherwise take 
measures to protect such information.  
Institution and/or Investigator shall acknowledge Sponsor’s support in all publications and 
presentations.    

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9
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35. European Medicines Agency, Committee for Medicinal Products for Human Use 
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39. Borte M, Pac M, Serban M, Gonzalez-Quevedo T, Grimbacher B, Jolles S, et al.
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Working Group. European consensus proposal for immunoglobulin therapies. Eur J 
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intravenous immunoglobulin in human disease: a review of evidence by members of the 
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Immunology. J Allergy Clin Immunol. 2006;117(4):S525-S553.
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Allergy, Asthma & Immunology. 2005;94:S1-S63.
43. Shehata N, Palda V, Bowen T, Haddad E, Issekutz TB, Mazer B, et al. The use of 
immunoglobulin therapy for patients with primary immune deficiency: an evidence-based 
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Recommendations for live viral and bacterial vaccines in immunodeficient patients and 
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46. Karch FE, Lasagna L. Toward the operational identification of adverse drug reactions. 
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47. Naranjo CA, Busto U, Sellers EM et al. A method for estimating the probability of 
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48. Levy MM, Fink MP, Marshall JC et al. 2001 SCCM/ESICM/ACCP/ATS/SIS 
International Sepsis Definitions Conference. Crit Care Med. 2003;31:1250-1256.
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10 APPENDICES

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Appendix 1
Schedule of Study Procedures
Procedures and Evaluation
Previous Regimen Phase
IGSC 20% Treatment Stage 1
IGSC 20% Treatment Stage 2
Final Visit    
(Week 53)/ Early 
Termination
1 Week post last 
IGSC 20% Dose
Visit Designations:
Screeninga
pIV#1a
/pSC#1a
pIV#2
Baseline/
SC#1
SC#2 & 3
SC#5, 9, 13
SC#17 
SC#18 in clinic 
only         
for PK subset
SC#20, 24, 28, 32, 36, 
40, 44, 48, 52
Study Weeks
Week 1
Weeks 2&3 Weeks 5, 9, 13
Week 17
Week 18
Weeks 20, 24, 28, 32, 
36, 40, 44, 48, 52
Week 53
Informed consent/assent (if applicable)
X
Inclusion/exclusion criteria (confirm 
eligibility)b
X
Xc
Medical history, demography
X
Record specific diagnosis of type of PI
X
Full physical examd
X
Xc
SC#13c
SC#24c, SC#36c
X
Weighte
X
Xc
Xc
Xc
Xc
Xc
Height
X
X
SC#13
SC#24, SC#36
X
Record results of most recent chest X-
ray within 12 monthsf
Xf
Vital signs
X
X
X
Xc
Xc
Xc
Xc
Xc
X
Record any serious bacterial infections 
(defined in Appendix 3), hospitalizations 
due to infections
X
X
X
X
X
X
X
X
X
X
Record non-serious infections as AEs & 
antibiotic treatment
X
X
X
X
X
X
X
X
X
X
Record days lost from work/school/daily 
activities due to infections and treatment
X
X
X
X
X
X
X
X
X
Laboratory assessments (chemistry, 
hematology, special tests, urinalysis)g
X
Xc
SC#13c
SC#24c, SC#36c
Xc
Serum pregnancy testh
X
Xc, g
X
Urine pregnancy testh (at site)
Xc
Trough (pre-dose) PK IgG sampling
X
Xc
Xc
Xc
SC#2 onlyc
Xc
Xc
Xc
Xc
Xc
Sample for IgG subclass levels & 
antibody titers for bacterial pathogens 
(H. influenzae, S. pneumoniae, C. 
tetani [tetanus])
X
Xc
SC#13c
SC#24c, SC#36c
Xc

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Procedures and Evaluation
Previous Regimen Phase
IGSC 20% Treatment Stage 1
IGSC 20% Treatment Stage 2
Final Visit    
(Week 53)/ Early 
Termination
1 Week post last 
IGSC 20% Dose
Visit Designations:
Screeninga
pIV#1a
/pSC#1a
pIV#2
Baseline/
SC#1
SC#2 & 3
SC#5, 9, 13
SC#17 
SC#18 in clinic 
only         
for PK subset
SC#20, 24, 28, 32, 36, 
40, 44, 48, 52
Study Weeks
Week 1
Weeks 2&3 Weeks 5, 9, 13
Week 17
Week 18
Weeks 20, 24, 28, 32, 
36, 40, 44, 48, 52
Week 53
Blood draw for trough measles 
antibody titer
Xc
SC#20, SC#52c
HIV NAT testing
X
Collection of virus safety retain samplesi
Xc
Previous (p)IV/SC infusions
X
X
IGSC 20% infusion intervals
X
X
q weekly
4-13
q weekly
14-17
X
q weekly 18-52
IGSC 20% given in clinic infusion 
numberj
SC#1
SC#2, 3
SC#5, 9, 13
SC#17
SC#18
SC#20, 24, 28, 32, 36,
40, 44, 48, 52
Serial PK sampling
Xk----------------Xk
Prior and concomitant medicationsl
X
X
X
X
X
X
X
X
X
X
Adverse events including infusion 
reactions (see Section 4.3.1 for 
definitions) and clinical observation of 
signs and symptoms suggestive of any 
significant disease or condition [e.g., 
thrombosis, anemia, etc.])
X
X
X
X
X
X
X
X
X
X
Review SC infusion diary & infusion 
details with subjects/caregivers
X
X
X
X
X
Note: Please see Appendix 3 for serious bacterial infections diagnostic tests and requirements (e.g., chest X-ray, cultures) that are required per FDA Guidance to 
meet criteria for this primary endpoint. If a SBI occurs, additional testing is needed to validate and must be recorded in the eCRF. 
Similarly, for validated non-serious infections documented by positive radiograph, fever (> 38°C oral or > 39°C rectal), culture, or diagnostic testing for 
microorganisms the specific evaluations performed to validate infections must be recorded in the eCRF.
a
The Screening Visit can coincide with the previous (p)IV#1 or pSC#1 visit. After the pIV#1 infusion, subjects will receive the pIV#2 infusion. After 
previous (p)SC#1 infusion, subjects will enter IGSC 20% Treatment Stage 1 directly. 
b
Inclusion/exclusion criteria must be satisfied before the subject receives the first IGSC 20% infusion.
c
Must be performed prior to IgG replacement product administration at designated study visits.

Protocol GTI1503 - Amendment 2
22 Jul 2016
CONFIDENTIAL
Page 90 of 97
d
Excludes breast and genitourinary exam.
e
The recorded weight will be used to calculate the IGSC 20% dose for this study visit and subsequent weekly infusions until next in clinic study visit where 
weight is measured.  
f
Record results of most recent chest X-ray within 12 months (A chest X-ray will be necessary if not performed within 12 months of the Screening visit for 
adult subjects as permitted per local requirements). 
g
Laboratory Assessments (chemistry, hematology, haptoglobin, & urinalysis) will be performed at the Screening and Baseline Visits. Additional testing of all 
laboratory assessments will be prior to IGSC 20% infusion clinic visits coinciding with SC#13, #24, and #36, and the Final Visit. Laboratory testing includes 
Hematology: Hemoglobin, hematocrit, platelets, red blood cell count including red blood cell morphology, white blood cell count with differential; ARC. 
Additional Special Tests: DAT, serum free hemoglobin, haptoglobin (during Screening and Baseline, only haptoglobin will be measured. At all other time 
points specified, all additional special tests will be performed). Chemistry: Sodium, potassium, creatinine, chloride, calcium, BUN, bicarbonate, albumin, 
LDH, AST, ALT, ALP, glucose, total bilirubin, indirect bilirubin. Urinalysis: pH, protein, glucose, ketones, bilirubin, nitrites, urobilinogen, blood, 
leukocyte esterase (with microscopic examination of urine sediment if abnormal).
h
Potential child-bearing females only; results must be negative to participate in the study or continue on IP. Qualitative serum β-HCG will be performed at 
Screening Visit and repeated during the Screening/Previous Regimen Phase for subjects entering study on a prior IVIG regimen who do not have Screening 
Visit and pIV#1 coincide (pre-dose pIV#1) given the potential for an 8-week time interval before Baseline. A qualitative urine pregnancy test will be 
performed at Baseline at the investigative site.
i
Collect blood samples at Baseline, prior to IGSC 20% infusion but test only if the subject exhibits clinical signs and symptoms consistent with hepatitis A, 
hepatitis B, hepatitis C, HIV, or parvovirus B19 infection while participating in the study.  See Section 3.6.3 and Table 3-1 for details. Note: For young 
pediatric subjects, at the discretion of the Investigator, virus safety retain samples may be drawn the day prior to Baseline instead of combining 
with other baseline blood draws on a single day.
j
During Treatment Stage 1 and Treatment Stage 2 IGSC 20% infusions will be given in the clinic with observation of self-administration technique
(subject/caregiver) of SC infusion at Visit Designations SC#1, 2, 3, 5, 9, 13, 17, (18 for PK subset), 20, 24, 28, 32, 36, 40, 44, 48, and 52.  The remaining 
weekly IGSC 20% doses should be administered at home.
k
Blood draws for PK assessment will be taken in approximately 20 adults subjects at the following time points: prior to the 17th IGSC 20% infusion (within 
0.5 hour of the start of infusion); immediately at the completion of the 17th SC infusion; 1 day ± 4 hours post infusion; 3 days ± 4 hours post infusion; 5 days 
± 4 hours post infusion and 7 days ± 1 day post infusion (within 0.5 hour prior to the 18th IGSC 20% dose) for IgG trough level.
l
For antibiotics distinguish between prophylactic use and use for treatment of an episode of infection.

Protocol GTI1503 - Amendment 2
22 Jul 2016
CONFIDENTIAL
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Appendix 2
PK Subset Group Detail Commencing at SC#17 IGSC 20% 
Treatment Stage 2 (~20 adults)
SC#17
1 day
± 4 hours
post SC#17
3 days
± 4 hours
post SC#17
5 days
± 4 hours
post SC#17
SC#18
Serial PK 
profile total 
IgG post 
IGSC 20% 
SC#17 
X
prior to the 17th IGSC 20% 
infusion (within 0.5 hour of the 
start of infusion)
X
X 
X
X
7 days ± 1 day 
post SC#17 
(within 0.5 hour 
prior to the 18th 
IGSC 20% dose) 
for IgG trough 
level
X
immediately at the completion 
of the 17th SC infusion

Protocol GTI1503 - Amendment 2
22 Jul 2016
CONFIDENTIAL
Page 92 of 97
Appendix 3
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, 
oligouria, 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 culturec, 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 (48). 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 (49). 
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. 
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 (50).

Protocol GTI1503 - Amendment 2
22 Jul 2016
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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, MRI 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 (51).
e We recommend a deep expectorated sputum gram stain to demonstrate the presence of microorganisms on 
examination of 10-20 oil immersion microscopic fields and < 10 squamous epithelial cells and 
> 25 polymorphonuclear leukocytes at 10X low power magnification to determine suitability of sputum 
culture (51). 

Protocol GTI1503 - Amendment 2
22 Jul 2016
CONFIDENTIAL
Page 94 of 97
Appendix 4
Blood Pressure Percentiles for Pediatric Patients 

Protocol GTI1503 - Amendment 2
22 Jul 2016
CONFIDENTIAL
Page 95 of 97
Blood Pressure Levels for Boys by Age and Height Percentile (Conti111ued) 
BP 
Systolic BP (mmHg) 
Diastolic BP (mmHD) 
Age 
Percentile 
Percentile of Height 
Percentile of Height 
(Year) 
"' 
5th 
1Oth 
25th 
50th 
75th 
90th 
95th 
5th 
10th 
25th 
50th 
75th 
90th 
95th 
11 
501h 
99 
100 
102 
104 
105 
107 
107 
59 
59 
60 
61 
62 
63 
63 
12 
13 
14 
15 
16 
17 
901h 
951h 
991h 
501h 
901h 
951h 
991h 
501h 
901h 
951h 
991h 
501h 
901h 
951h 
991h 
501h 
901h 
951h 
991h 
501h 
901h 
951h 
991h 
501h 
901h 
951h 
991h 
BP, blood pressure 
113 
114 
115 
117 
119 
117 
118 
119 
121 
123 
124 
125 
127 
129 
130 
101 
102 
104 
106 
108 
115 
116 
118 
120 
121 
119 
120 
122 
123 
125 
126 
127 
129 
131 
133 
104 
105 
106 
108 
110 
117 
118 
120 
122 
124 
121 
122 
124 
126 
128 
128 
130 
131 
133 
135 
106 
107 
109 
111 
113 
120 
121 
123 
125 
126 
124 
125 
127 
128 
130 
131 
132 
134 
136 
138 
109 
110 
112 
113 
115 
122 
124 
125 
127 
129 
126 
127 
129 
131 
133 
134 
135 
136 
138 
140 
111 
112 
114 
116 
118 
125 
126 
128 
130 
131 
129 
130 
132 
134 
135 
136 
137 
139 
141 
143 
114 
115 
116 
118 
120 
127 
128 
130 
132 
134 
131 
132 
134 
136 
138 
139 
140 
141 
143 
145 
120 
121 
124 
125 
132 
132 
109 
110 
123 
123 
127 
127 
134 
135 
111 
112 
125 
126 
129 
130 
136 
137 
114 
115 
128 
128 
132 
132 
139 
140 
117 
117 
130 
131 
134 
135 
142 
142 
119 
120 
133 
134 
137 
137 
144 
145 
121 
122 
135 
136 
139 
140 
146 
147 
74 
78 
86 
59 
74 
78 
86 
60 
75 
79 
87 
60 
75 
80 
87 
61 
76 
81 
88 
63 
78 
82 
90 
65 
80 
84 
92 
74 
78 
86 
60 
75 
79 
87 
60 
75 
79 
87 
61 
76 
80 
88 
62 
77 
81 
89 
63 
78 
83 
90 
66 
80 
85 
93 
75 
79 
87 
61 
75 
80 
88 
61 
76 
80 
88 
62 
77 
81 
89 
63 
78 
82 
90 
64 
79 
83 
91 
66 
81 
86 
93 
76 
80 
88 
62 
76 
81 
89 
62 
77 
81 
89 
63 
78 
82 
90 
64 
79 
83 
91 
65 
80 
84 
92 
67 
82 
87 
94 
• The 90th percentile is 1.28 SO, 95th percentile is 1.645 SO, and the 99th percentile is 2.326 SO over the mean. 
77 
81 
89 
63 
77 
82 
90 
63 
78 
82 
90 
64 
79 
83 
91 
65 
80 
84 
92 
66 
81 
85 
93 
68 
83 
87 
95 
78 
82 
90 
63 
78 
82 
90 
64 
79 
83 
91 
65 
79 
84 
92 
66 
80 
85 
93 
67 
82 
86 
94 
69 
84 
88 
96 
78 
82 
90 
64 
79 
83 
91 
64 
79 
83 
91 
65 
80 
84 
92 
66 
81 
85 
93 
67 
82 
87 
94 
70 
84 
89 
97 
For research purposes, the standard deviations in Appendix Table B-1 allow one to compute BP Z-scores and percemliles for boys 
with heigh! percentiles given in Table 3 (i.e., the 5th,1 Oth, 251h, 50th, 75th, 90th, and 95th percentiles). These heigh! percentiles 
must be converted lo height Z-scores given by (5% = -1.645; 10% = -1.28; 25% = -0.68; 50% = 0; 75% = 0.68; 90% = 1.28%; 
95% = 1.645) and then computed according lo the methodology in steps 2-4 described in Appendix B. For children with height 
percentiles olh.er lhan these, follow steps 1-4 as described in Appendix B. 

Protocol GTI1503 - Amendment 2
22 Jul 2016
CONFIDENTIAL
Page 96 of 97
Blood Pressure L.evels for Girls by Age and Height Percentile 
BP 
Age 
Percentile 
(Year) 
.,_ 
I 
50th 
2 
3 
4 
5 
6 
7 
8 
9 
10 
90th 
951h 
99th 
50th 
90th 
951h 
99th 
50th 
90th 
951h 
99th 
50th 
90th 
951h 
99th 
50th 
90th 
951h 
99th 
50th 
90th 
951h 
99th 
50th 
90th 
951h 
99th 
50th 
90th 
951h 
99th 
50th 
90th 
951h 
99th 
50th 
90th 
951h 
99th 
5th 
83 
97 
Systolic BP (mmHg) 
Percentile of Height 
1Oth 
25th 
50th 
75th 
90th 
84 
85 
86 
88 
89 
97 
98 
100 
101 
102 
95th 
90 
103 
100 
101 
102 
104 
105 
106 
107 
108 
108 
109 
111 
112 
113 
114 
88 
88 
91 
91 
88 
w 
100 
101 
1ro 
104 
1m 
1ro 
104 
100 
109 
110 
111 
112 
114 
115 
116 
88 
88 
88 
91 
100 
100 
1m 
1ro 
104 
106 
106 
104 
104 
105 
107 
108 
109 
110 
111 
111 
113 
114 
115 
116 
117 
88 
88 
w 
91 
101 
102 
103 
104 
106 
107 
108 
105 
106 
107 
108 
110 
111 
112 
112 
113 
114 
115 
117 
118 
119 
88 
w 
91 
88 
1ro 
1ro 
106 
107 
107 
108 
110 
111 
112 
113 
114 
114 
116 
117 
118 
120 
120 
91 
88 
w 
88 
104 
105 
106 
108 
109 
110 
111 
108 
109 
110 
111 
113 
114 
115 
115 
116 
117 
119 
120 
121 
122 
88 
w 
w 
88 
106 
107 
108 
109 
111 
112 
113 
110 
111 
112 
113 
115 
116 
116 
117 
118 
119 
120 
122 
123 
124 
88 
88 
w 
100 
101 
108 
109 
110 
111 
113 
114 
114 
112 
112 
114 
115 
116 
118 
118 
119 
120 
121 
122 
123 
125 
125 
88 
w 
88 
100 
101 
1m 
1ro 
110 
110 
112 
113 
114 
116 
116 
114 
114 
115 
117 
118 
119 
120 
121 
121 
123 
124 
125 
127 
127 
88 
w 
100 
1m 
1ro 
104 
112 
112 
114 
115 
116 
118 
118 
116 
116 
117 
119 
120 
121 
122 
1D 
1D 
1ll 
5th 
38 
52 
56 
64 
43 
57 
61 
69 
47 
61 
65 
73 
50 
64 
68 
76 
52 
66 
70 
78 
68 
72 
80 
55 
69 
73 
81 
57 
71 
75 
82 
58 
72 
76 
83 
59 
73 
77 
84 
Diastolic BP (mmHg) 
Percentile of Height 
10th 
25th 
50th 
75th 
90th 
95th 
G 
41 
41 
G 
57 
64 
44 
58 
62 
69 
48 
62 
66 
73 
50 
64 
68 
76 
53 
67 
71 
78 
68 
72 
80 
56 
70 
74 
81 
57 
71 
75 
82 
58 
72 
76 
83 
59 
73 
77 
84 
57 
65 
44 
58 
62 
70 
48 
62 
66 
74 
51 
65 
69 
76 
53 
67 
71 
79 
55 
69 
73 
80 
56 
70 
74 
82 
57 
71 
75 
83 
58 
72 
76 
84 
59 
73 
77 
85 
58 
65 
45 
59 
63 
70 
49 
63 
67 
74 
52 
66 
70 
77 
68 
72 
79 
56 
70 
74 
81 
57 
71 
75 
82 
58 
72 
76 
83 
59 
73 
77 
84 
60 
74 
78 
86 
59 
66 
46 
60 
64 
71 
50 
64 
68 
75 
52 
67 
71 
78 
55 
69 
73 
80 
70 
74 
82 
58 
72 
76 
83 
59 
73 
77 
84 
60 
74 
78 
85 
61 
75 
79 
86 
59 
67 
46 
61 
65 
72 
50 
64 
68 
76 
53 
67 
71 
79 
55 
69 
73 
81 
57 
71 
75 
83 
58 
72 
76 
84 
60 
74 
78 
85 
61 
75 
79 
86 
62 
76 
80 
87 
60 
67 
47 
61 
65 
72 
51 
65 
69 
76 
68 
72 
79 
70 
74 
81 
58 
72 
76 
83 
59 
73 
77 
84 
60 
74 
78 
86 
61 
75 
79 
87 
62 
76 
80 
88 

Protocol GTI1503 - Amendment 2
22 Jul 2016
CONFIDENTIAL
Page 97 of 97
Blood Pressure L.evels for Girls by Age and Height Percentile (Continued) 
BP 
Systolic BP (mmHg) 
Diastolic BP (mmHg) 
Age 
Percentile 
Percentile of Height 
Percentile of Height 
(Year) 
.,_ 
5th 
1Oth 
25th 
50th 
75th 
90th 
95th 
5th 
10th 
25th 
50th 
75th 
90th 
95th 
11 
50th 
12 
13 
14 
15 
16 
17 
90th 
951h 
99th 
50th 
90th 
951h 
99th 
50th 
90th 
951h 
99th 
50th 
90th 
951h 
99th 
50th 
90th 
951h 
99th 
50th 
90th 
951h 
99th 
50th 
90th 
951h 
99th 
BP, blood pressure 
100 
101 
102 
t 03 
t 05 
t 06 
107 
114 
1t 4 
1t 6 
t 17 
t 18 
t 19 
120 
118 
1t 8 
1t 9 
t 21 
t 22 
t 23 
124 
125 
125 
126 
t 28 
t 29 
t 30 
13t 
1m 
1m 
t oo 
t 06 
116 
1t 6 
1t 7 
t 19 
t 20 
t 21 
122 
119 
120 
121 
t 23 
t 24 
t 25 
126 
1V 
1V 
13 
t 30 
1D 
104 
105 
106 
t 07 
t 09 
t 10 
110 
117 
1t 8 
1t 9 
t 21 
t 22 
t 23 
124 
12t 
122 
123 
t 24 
t 26 
t 27 
128 
13 
13 
130 
t n 
106 
106 
107 
t 09 
t 10 
t 11 
112 
119 
120 
121 
t 22 
t 24 
t 25 
125 
1D 
1D 
tV 
t 3 
13 
130 
131 
132 
t 33 
t 35 
t 36 
136 
107 
108 
109 
t 10 
t 11 
t 13 
113 
120 
121 
122 
t 23 
t 25 
t 26 
127 
124 
125 
126 
t 27 
t 29 
t 30 
13t 
13t 
132 
133 
t 36 
t 37 
138 
108 
108 
1t 0 
t 11 
t 12 
t 14 
114 
12t 
122 
123 
t 24 
t 26 
t 27 
128 
1V 
t 3 
t 30 
1D 
t 36 
108 
109 
1t 0 
t 11 
t 13 
t 14 
115 
122 
122 
1D 
tV 
13 
1V 
t 3 
t 30 
1D 
1D 
t 36 
t 36 
74 
78 
85 
6t 
75 
79 
86 
62 
76 
80 
87 
63 
77 
8t 
88 
64 
78 
82 
89 
64 
78 
82 
90 
64 
78 
82 
90 
74 
78 
85 
61 
75 
79 
86 
62 
76 
80 
87 
63 
77 
81 
88 
64 
78 
82 
89 
64 
78 
82 
90 
65 
79 
83 
90 
74 
78 
86 
61 
75 
79 
87 
62 
76 
80 
88 
63 
77 
81 
89 
64 
78 
82 
90 
65 
79 
83 
90 
65 
79 
83 
91 
75 
79 
87 
62 
76 
80 
88 
63 
77 
81 
89 
64 
78 
82 
90 
65 
79 
83 
91 
66 
80 
64 
91 
66 
80 
64 
91 
• The 90th percentile is 1.28 SO, 95th percentile is 1.645 SO, and the 99th percentile is 2.326 SO over the mean. 
76 
80 
87 
63 
77 
81 
88 
64 
78 
82 
89 
65 
79 
83 
90 
66 
80 
84 
91 
66 
81 
85 
92 
67 
81 
85 
92 
77 
81 
88 
64 
78 
82 
89 
65 
79 
83 
90 
66 
80 
84 
91 
67 
81 
85 
92 
67 
81 
85 
93 
67 
81 
85 
93 
77 
81 
89 
64 
78 
82 
90 
65 
79 
83 
91 
66 
80 
84 
92 
67 
81 
85 
93 
66 
82 
86 
93 
66 
82 
86 
93 
For research purposes, the standard deviations in Appendix Table 8-t allow one to compute BP Z-scores and percentiles for 
with height percentiles given in Table 4 (i.e., the 51h, 10th, 25th, 50th, 751h, 90th, and 95th percentiles). These height percentiles 
must be converted to height Z-scores given by (5% = -1.645; t O% = -1.28; 25% = -0.66; 50% = 0; 75% = 0.68; 90% = t .28%; 
95% = 1.645) and then computed according to the methodology in steps 2-4 described in Appendix B. For children with height 
percentiles other lhan these, follow steps 1-4 as described in Appendix B.