A Phase 3, Open-label, Non-controlled, Multi-dose, Extension Study to Evaluate the Long-term Safety and Tolerability of IGSC, 20% in Japanese Subjects With Primary Immunodeficiency Disease (PID)
Phase: PHASE3
Conditions: Primary Immunodeficiency Disease
Sponsor: Takeda

Clinical Study Protocol 
NCT Number: NCT04842643 
Title: A Phase 3, Open-label, Non-controlled, Multi-dose, Extension Study to Evaluate 
the Long-term Safety and Tolerability of IGSC, 20% in Japanese Subjects with Primary 
Immunodeficiency Disease (PID) 
Study Number: TAK-664-3002 
Document Version and Date: Amendment 3.0 / 28-Nov-2022 
Certain information within this document has been redacted (ie, specific content is 
masked irreversibly from view) to protect either personally identifiable information or 
company confidential information. 

TAKEDA PHARMACEUTICALS
PROTOCOL: TAK-664-3002
Title:
A Phase 3, Open-label, Non-controlled, Multi-dose, Extension Study 
to Evaluate the Long-term Safety and Tolerability of IGSC, 20% in
Japanese Subjects with Primary Immunodeficiency Disease (PID)
Short Title:
Long-term Safety and Tolerability of IGSC, 20% in Japanese 
Subjects with PID
Study Phase:
Phase 3
Acronym:
TAK-664-3002
Drug:
TAK-664, Immune Globulin Subcutaneous (Human), 20% Solution 
(IGSC, 20%)
IND Number:
Not Applicable
EUDRACT 
Number:
Not Applicable
Sponsor:
Takeda Pharmaceutical Company Limited
1-1, Doshomachi 4-Chome, Chuo-ku, Osaka-shi,
Osaka, Japan
Principal / 
Coordinating 
Investigator:
Multicenter
Protocol History:
Protocol Amendment 3.0: 28 Nov 2022
Protocol Amendment 2.0: 19 Jul 2022
Protocol Amendment 1.0: 02 Nov 2021
Original Protocol 1.0: 18 Jan 2021
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1. ADMINISTRATIVE INFORMATION AND PRINCIPLES OF CLINICAL STUDIES
1.1 Contacts and Responsibilities of Study-Related Activities
A separate contact information list will be provided to each site.
Takeda Development Center sponsored investigators per individual country requirements will be 
provided with emergency medical contact information cards to be carried by each subject.
General advice on protocol procedures should be obtained through the monitor assigned to the 
study site. Information on service providers is given and relevant guidelines provided to the site.
1.2 Principles of Clinical Studies
This study will be conducted with the highest respect for the individual participants in 
accordance with the requirements of this study protocol and also in accordance with the 
following:

The ethical principles that have their origin in the Declaration of Helsinki.

International Council for Harmonisation (ICH) E6 Good Clinical Practice (GCP):
Consolidated Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws,
clinical trial disclosure laws, and regulations.
After obtaining the marketing authorization of this drug in Japan, this clinical trial will continue 
as a post-marketing clinical trial, and will comply with the GCP Ministerial Ordinance and the 
Ministerial Ordinance on the criteria for conducting post-marketing surveillance and testing of 
pharmaceuticals. After the transition to post-marketing clinical trials, the term “clinical trial” in 
the “clinical trial protocol” will be replaced with “post-marketing clinical trial”.
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SIGNATURES
The signature of the responsible Takeda medical officer (and other signatories, as applicable) can 
be found on the signature page.
Electronic Signatures are provided on the last page of this document.
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INVESTIGATOR AGREEMENT
I confirm that I have read and that I understand this protocol, the Investigator’s Brochure, 
package insert and any other product information provided by the sponsor. I agree to conduct this 
study in accordance with the requirements of this protocol and also to protect the rights, safety, 
privacy, and well-being of study subjects in accordance with the following:

The ethical principles that have their origin in the Declaration of Helsinki.

International Council for Harmonisation, E6 Good Clinical Practice: Consolidated
Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws and
regulations.

Regulatory requirements for reporting serious adverse events defined in Section 10.2 of
this protocol.

Terms outlined in the study site agreement.

Responsibilities of the Investigator (Appendix B).
Signature of Investigator
Date
Investigator Name (print or type)
Investigator’s Title
Location of Facility (City, State/Provence)
Location of Facility (Country)
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1.3 Summary of Changes from Previous Protocol Version
Protocol Amendment
Summary of Changes Since the Last Version of the Approved Protocol
Protocol Amendment
3.0
Amendment Date
28 Nov 2022
Japan
Description of Change
Rationale for Change
Section Affected by Change
Interim analysis will be conducted 
during the study.
The interim analysis data will be 
submitted during Japanese New 
Drug Application process as 
requested by Pharmaceuticals and 
Medical Devices Agency 
(PMDA).
Synopsis and Section 13.2
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TABLE OF CONTENTS
1. ADMINISTRATIVE INFORMATION AND PRINCIPLES OF CLINICAL STUDIES . 2
1.1 Contacts and Responsibilities of Study-Related Activities ............................................. 2
1.2 Principles of Clinical Studies ............................................................................................. 2
SIGNATURES ...................................................................................................................... 3
INVESTIGATOR AGREEMENT...................................................................................... 4
1.3 Summary of Changes from Previous Protocol Version .................................................. 5
TABLE OF CONTENTS ............................................................................................................. 6
2. STUDY SUMMARY............................................................................................................... 11
3. LIST OF ABBREVIATIONS ................................................................................................ 15
4. INTRODUCTION................................................................................................................... 17
4.1 Background ....................................................................................................................... 17
4.1.1 Indication and Current Treatment Options............................................................ 17
4.1.2 Product Background and Clinical Information...................................................... 18
4.2 Rationale for the Proposed Study.................................................................................... 19
4.3 Benefit/Risk Profile........................................................................................................... 19
5. STUDY OBJECTIVES AND ENDPOINTS......................................................................... 21
5.1 Objectives .......................................................................................................................... 21
5.1.1 Primary Objective ..................................................................................................... 21
5.1.2 Secondary Objectives ................................................................................................ 21
5.2 Endpoints........................................................................................................................... 21
5.2.1 Primary Endpoint: Safety and Tolerability ............................................................ 21
5.2.2 Secondary Endpoints: Safety, Tolerability, PK, and Efficacy............................... 21
6. STUDY DESIGN AND DESCRIPTION .............................................................................. 23
6.1 Study Design...................................................................................................................... 23
6.2 Justification for Study Design, Dose, and Endpoints .................................................... 24
6.3 Premature Termination or Suspension of Study or Study Site.................................... 25
6.3.1 Criteria for Premature Termination or Suspension of the Study......................... 25
6.3.2 Criteria for Premature Termination or Suspension of Study Sites ...................... 25
6.3.3 Procedures for Premature Termination or Suspension of the Study or the 
Participation of Study Site(s).................................................................................... 25
7. SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS ............... 26
7.1 Inclusion Criteria.............................................................................................................. 26
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7.2 Exclusion Criteria............................................................................................................. 26
7.3 Excluded Medications....................................................................................................... 26
7.4 Criteria for Discontinuation or Withdrawal of a Subject............................................. 27
7.5 Procedures for Discontinuation or Withdrawal of a Subject ....................................... 28
8. CLINICAL STUDY MATERIAL MANAGEMENT.......................................................... 29
8.1 Study Drug and Materials................................................................................................ 29
8.1.1 Dosage Form, Manufacturing, Packaging, and Labeling ...................................... 29
8.1.1.1 Study Drug .......................................................................................................... 29
8.1.1.2 Packaging ............................................................................................................ 29
8.1.1.3 Labeling ............................................................................................................... 29
8.1.2 Storage ........................................................................................................................ 29
8.1.3 Dose and Regimen...................................................................................................... 30
8.1.4 Overdose ..................................................................................................................... 31
8.2 Study Drug Assignment and Dispensing Procedures.................................................... 32
8.3 Device-Used-in-Clinical-Trial/Device-related Defects................................................... 32
8.3.1 Marketing Approval.................................................................................................. 32
8.3.2 Indications for Use..................................................................................................... 32
8.3.3 Usage Instructions and Warnings............................................................................ 33
8.3.4 Device-related Defects ............................................................................................... 33
8.4 Accountability and Destruction of Sponsor-Supplied Drugs........................................ 33
9. STUDY PLAN......................................................................................................................... 35
9.1 Study Procedures .............................................................................................................. 35
9.1.1 Informed Consent Procedure ................................................................................... 35
9.1.2 Demographics, Medical History, and Medication History Procedure.................. 35
9.1.3 Physical Examination Procedure ............................................................................. 35
9.1.4 Vital Sign Procedure.................................................................................................. 36
9.1.5 Documentation of Concomitant Medications.......................................................... 36
9.1.6 Documentation of Concurrent Medical Conditions ............................................... 36
9.1.7 Procedures for Clinical Laboratory Samples.......................................................... 37
9.1.7.1 Hematology and Clinical Chemistry................................................................. 38
9.1.7.2 Urinalysis............................................................................................................. 38
9.1.7.3 Specialty Tests..................................................................................................... 38
9.1.7.4 Hemolysis Tests................................................................................................... 39
9.1.7.5 Specific Antibodies.............................................................................................. 39
9.1.8 Contraception and Pregnancy Avoidance Procedure ............................................ 39
9.1.8.1 Definitions and Procedures for Contraception and Pregnancy Avoidance .. 39
9.1.8.2 Contraceptive Guidance..................................................................................... 40
9.1.9 Pregnancy ................................................................................................................... 41
9.1.10 Pharmacokinetic ...................................................................................................... 41
9.1.10.1 Serum IgG Trough Levels................................................................................ 41
9.1.11 Efficacy ..................................................................................................................... 42
9.1.11.1 Acute Serious Bacterial Infection Rate........................................................... 42
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9.1.11.2 Infections ........................................................................................................... 42
9.1.11.3 Treatment Preference....................................................................................... 42
9.1.11.4 Healthcare Resource Utilization...................................................................... 43
9.1.12 Documentation of Screen Failure........................................................................... 43
9.1.13 Documentation of Study Entrance......................................................................... 43
9.2 Monitoring Subject Treatment Compliance .................................................................. 43
9.3 Schedule of Observations and Procedures ..................................................................... 44
9.3.1 Study Entrance........................................................................................................... 44
9.3.2 Treatment Phase ........................................................................................................ 44
9.3.3 End of Study Visit or Early Termination................................................................ 46
9.3.4 Post Study Care.......................................................................................................... 46
10. PRETREATMENT EVENTS AND ADVERSE EVENTS............................................... 47
10.1 Definitions........................................................................................................................ 47
10.1.1 Pretreatment Events................................................................................................ 47
10.1.2 AEs ............................................................................................................................ 47
10.1.3 Additional Points to Consider for AEs .................................................................. 47
10.1.4 SAEs.......................................................................................................................... 49
10.1.5 Unexpected Adverse Event ..................................................................................... 50
10.1.6 Suspected Unexpected Serious Adverse Reaction ................................................ 50
10.1.7 Intensity of AEs........................................................................................................ 51
10.1.8 Causality of AEs....................................................................................................... 51
10.1.9 Relationship to Study Procedures .......................................................................... 52
10.1.10 Start Date................................................................................................................ 52
10.1.11 Stop Date................................................................................................................. 52
10.1.12 Frequency ............................................................................................................... 52
10.1.13 Action Concerning Study Drug............................................................................ 53
10.1.14 Outcome.................................................................................................................. 53
10.2 Procedures ....................................................................................................................... 54
10.2.1 Collection and Reporting of AEs............................................................................ 54
10.2.1.1 AE Collection Period........................................................................................ 54
10.2.1.2 AE Reporting .................................................................................................... 55
10.2.2 Collection and Reporting of SAEs.......................................................................... 55
10.3 Follow-up of SAEs .......................................................................................................... 56
10.3.1 Safety Reporting to Investigators, IRBs, and Regulatory Authorities ............... 56
11. STUDY-SPECIFIC COMMITTEES.................................................................................. 56
12. DATA HANDLING AND RECORD KEEPING............................................................... 57
12.1 CRFs................................................................................................................................. 57
12.2 Record Retention ............................................................................................................ 58
13. STATISTICAL METHODS ................................................................................................ 59
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13.1 Statistical and Analytical Plans ..................................................................................... 59
13.1.1 Analysis Sets............................................................................................................. 59
13.1.2 Analysis of Demographics and Other Baseline Characteristics.......................... 59
13.1.3 Safety Analysis ......................................................................................................... 59
13.1.3.1 Analysis of Adverse Events.............................................................................. 60
13.1.3.2 Clinical Laboratory Data................................................................................. 62
13.1.3.3 Vital Signs.......................................................................................................... 62
13.1.4 Serum IgG Concentrations ..................................................................................... 63
13.1.5 Efficacy Analysis...................................................................................................... 63
13.1.6 Other Analyses......................................................................................................... 63
13.1.6.1 Treatment Preference Analyses....................................................................... 63
13.2 Interim Analysis.............................................................................................................. 63
13.3 Determination of Sample Size........................................................................................ 64
14. QUALITY CONTROL AND QUALITY ASSURANCE.................................................. 65
14.1 Study Site Monitoring Visits.......................................................................................... 65
14.2 Protocol Deviations......................................................................................................... 65
14.3 Quality Assurance Audits and Regulatory Agency Inspections................................. 65
15. ETHICAL ASPECTS OF THE STUDY............................................................................. 66
15.1 IRB Approval.................................................................................................................. 66
15.2 Subject Information, Informed Consent, and Subject Authorization....................... 67
15.3 Subject Confidentiality................................................................................................... 68
15.4 Publication, Disclosure, and Clinical Trial Registration Policy................................. 68
15.4.1 Publication and Disclosure...................................................................................... 68
15.4.2 Clinical Trial Registration ...................................................................................... 69
15.4.3 Clinical Trial Results Disclosure............................................................................ 69
15.5 Insurance and Compensation for Injury...................................................................... 69
16. REFERENCES...................................................................................................................... 70
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2. STUDY SUMMARY
Name of Sponsor:
Takeda Pharmaceutical Company Limited
Compound:
TAK-664, Immune Globulin Subcutaneous
(Human), 20% Solution (IGSC, 20%)
Title of Protocol: A Phase 3, Open-label, Non-controlled, 
Multi-dose, Extension Study to Evaluate the Long-term 
Safety and Tolerability of IGSC, 20% in Japanese Subjects 
with Primary Immunodeficiency Disease (PID).
IND No.:
Not Applicable
EudraCT No.:
Not Applicable
Study Number: TAK-664-3002
Phase: 3
Rationale:
This is an open-label extension study, following completion of Study TAK-664-3001. It will provide data on 
the long-term safety and tolerability of IGSC, 20% in Japanese subjects with PID who successfully complete 
study TAK-664-3001 and wish to continue treatment with IGSC, 20%. The results from these 2 studies will 
extend/support the data obtained from 2 global (United States and European Union) pivotal studies for 
IGSC, 20% in PID, to Japanese patients with PID.
Study Design:
This is a Phase 3, prospective, multicenter, open-label, non-controlled, single-arm extension study.
This study will enroll Japanese subjects with PID who complete Study TAK-664-3001 successfully.
Subjects are considered to have completed Study TAK-664-3001 successfully if they fulfill the following 
criterion:

Completed Epoch 2, in which IGSC, 20% is administered weekly (completion of Epoch 3, in which
IGSC, 20% is administered biweekly, is not mandatory for participation in TAK-664-3002 study).
Schematic of study design:
Abbreviations: EOS=End of Study, IgG= immunoglobulin G, IGSC= subcutaneous immunoglobulin, SC=subcutaneous.
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Screening/Baseline Period
Informed consent is expected to be obtained at last visit or prior to last visit of Study TAK-664-3001.
The subjects will undergo screening/baseline procedures for determination of eligibility before infusion of 
IGSC, 20%. 
IGSC, 20% Treatment Period
Eligible subjects will receive IGSC, 20% until the commercial IGSC, 20% is available at each study site or study 
termination (estimated duration: approximately 3 years).
Visit Schedule
The number of infusion visits and study site visits during the subcutaneous (SC) treatment period will depend 
on where the SC injection is administered. Infusions may be performed at home or at the study site, at the 
investigator’s discretion. The decision where the SC injection is administered is made during Study 
TAK-664-3001, however the location of injection administration can be changed based on the investigator’s 
and subject’s agreement.
Subjects should come to the study site for visits when laboratory test samples are to be collected every 12 weeks. 
Subjects are not required to come to the study site if all procedures/assessments can be performed at home.
Primary Objectives:
To evaluate the long-term safety and tolerability of IGSC, 20% in Japanese subjects with PID.
Secondary Objectives:

To assess serum trough immunoglobulin G (IgG) and subclasses concentrations following weekly or
biweekly administration of IGSC, 20% in Japanese subjects with PID.

To evaluate the efficacy of IGSC, 20% in Japanese subjects with PID.

To assess treatment preference of Japanese subjects with PID.
Subject Population: Japanese subjects aged 2 years or older with PID.
Number of Subjects:
Approximately 10 subjects. A total of 16 subjects will be 
enrolled in Study TAK-664-3001, of whom 12 subjects are 
expected to complete Epoch 2. The subjects who successfully 
complete Epoch 2 are eligible to enter this extension study.
Number of Sites: 
Approximately 10 to 15 study sites planned, 
located in Japan.
Dosage Form:
The dose of IGSC, 20% infusion was established in Study 
TAK-664-3001, and is assumed to maintain the target IgG 
trough level ≥5 g/L (Epoch 2: approximately between 50 and 
200 mg/kg of IGSC, 20% weekly, Epoch 3: approximately 
between 100 and 400 mg/kg of IGSC, 20% biweekly).
When the IgG trough level is found not to be maintained at 
≥5 g/L during the study, adjustment of the dose is allowed at 
the discretion of the investigator.
Route of Administration:
Subcutaneous infusion, weekly or biweekly.
Duration of Treatment:
Eligible subjects will receive IGSC, 20% until the 
commercial IGSC, 20% is available at each study site or 
study termination (estimated duration: approximately 
3 years).
Period of Evaluation:
Subjects should come to the study site for visits 
when laboratory test samples are to be collected
every 12 weeks. Subjects are not required to come 
to the study site if all the procedures/assessments 
can be performed at home (estimated duration: 
approximately 3 years).
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Criteria for Inclusion:
Each subject must meet all the following criteria to enroll in the study:
1.
Subject has completed or is about to complete Takeda Clinical Study TAK-664-3001.
A subject is considered to have completed Study TAK-664-3001 successfully if they fulfill the following
criterion:

Completed Epoch 2, in which IGSC, 20% is administered weekly (completion of Epoch 3, in which
IGSC, 20% is administered biweekly, is not mandatory for participation in TAK-664-3002 study).
2.
Written informed consent is obtained from either the subject or the subject's legally authorized
representative prior to any study-related procedures and study product administration.
3.
Subject is willing and able to comply with the requirements of the protocol.
Criteria for Exclusion:
Subjects who meet any of the following criteria will be excluded from the study:
1.
Subject has developed a new serious medical condition during participation in Study TAK-664-3001 such
that the subject’s safety or medical care would be impacted by participation in the extension study
TAK-664-3002.
2.
Subject is scheduled to participate in another non-Takeda clinical study involving an Investigational
Product or device-used-in-clinical-trial in the course of this study.
3.
If a female of childbearing potential, subject is pregnant or has a negative pregnancy test but does not
agree to employ adequate birth control measures for the duration of the study.
Criteria for Evaluation and Analyses:
The primary endpoint for this study is safety and tolerability.
Safety and tolerability endpoints/outcome measures:

Occurrence of treatment-emergent adverse events (TEAEs), including but not limited to: investigation
product-related and non-related*, serious, nonserious, severe, local and systemic TEAEs, as well as
TEAEs leading to premature discontinuation from study, and infusion-associated TEAEs.
*Any TEAE that is recorded by the investigator as “probably related” or “possibly related” to study drug
will be considered as IGSC, 20%-related adverse event (AE), and any AE recorded as “unlikely related”
or “not related” will be considered as unrelated AE.
Secondary endpoints for this study are safety, tolerability, pharmacokinetic (PK), and efficacy.
Pharmacokinetic endpoint/outcome measure: 

Measurement of serum trough IgG and subclasses concentrations following weekly or biweekly
administration of IGSC, 20% in Japanese subjects with PID.
Efficacy endpoints/outcome measures: 

Annual rate of validated acute serious bacterial infections per subject.

Annual rate of all infections per subject.

Health Resource Utilization:

Days not able to attend school/work or to perform normal daily activities due to illness/infection

Days on antibiotics

Number of hospitalizations due to illness/infection and length of stay (in days)

Number of acute (urgent or unscheduled) physician visits due to illness/infection.

Treatment preference.
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Safety endpoints/outcome measures:

Clinical laboratory outcomes: raw (actual) values and change from baseline.
Clinically significant, treatment-emergent changes in clinical laboratory measurements will be recorded in
the study database (internal or external) as TEAEs.

Vital signs: raw (actual) values and change from baseline and change from pre-infusion to post-infusion.
Baseline is defined as the last non-missing value before the time of participation in TAK-664-3001 study.
Tolerability endpoints/outcome measures:

Occurrence of tolerability events related to the infusion of study drug.
*An infusion is considered tolerable if the infusion rate was not reduced, or the infusion was not
interrupted or stopped, due to a TEAE related to study drug infusion. A tolerability event is considered
to have occurred if an infusion was not tolerable. Tolerability events will be measured in terms of the
number and percentage of subjects for which the infusion was not tolerable.
Statistical Considerations:
Analysis Sets

All-Treated Set: All enrolled subjects who received IGSC, 20% administration at least once in this
study, this will be the efficacy analysis set.

Safety analysis set (SAS): All enrolled subjects who received at least 1 dose of study drug (IGIV) in
TAK-664-3001 study, this will be SAS.
Safety analysis will be performed using the SAS.
The number and percentage of subjects with TEAEs will be summarized by Medical Dictionary for Regulatory 
Activities (MedDRA) System Organ Class and Preferred Term overall, by severity, and by relationship to study 
drug. Separate summaries will also be generated for TEAEs overall and by severity. Change from baseline in 
clinical laboratory tests, and vital signs will be summarized.
Efficacy and treatment preference endpoints will be summarized descriptively using the All-Treated Set.
Continuous endpoints/outcome measures (eg, change from baseline) will be summarized using the following 
descriptive statistics: number of subjects (n), mean, median, standard deviation, minimum value, maximum 
value. Categorical endpoints/outcome measures (eg, AEs) will be summarized in terms of number and percent of 
subjects and number of occurrences in each category.
For serum IgG concentrations, descriptive statistics will also include geometric mean and the corresponding 
2-sided 95% confidence interval. Confidence intervals are for descriptive purposes. Caution should be exhibited
in their interpretation as this study is not designed for hypothesis testing.
An interim analysis of study data will be undertaken to support the Japanese New Drug Application submission. 
It will summarize PK (Serum IgG trough levels), safety, efficacy, and tolerability of treatment with IGSC, 20% 
in all subjects with PID in this study. The snapshot date will be stated in the statistical analysis plan. The target 
data will be all subject data obtained at snapshot date in this study.
Sample Size Justification: No formal sample size calculation has been performed in this extension study. 
A sample size of approximately 16 subjects is the estimated maximal number of subjects who can enroll from 
the previous TAK-664-3001 study.
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3. LIST OF ABBREVIATIONS
Abbreviation
Definition
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ASBI
acute serious bacterial infection
AST
aspartate aminotransferase
-hCG
beta-human chorionic gonadotropin
BUN
blood urea nitrogen
B19V
Parvovirus B19
CRO
contract research organization
CSF
cerebrospinal fluid
CT
computed tomography 
eCRF
electronic case report form 
EOS
End of Study
ERCSI
Emergency Reception Center for Safety Information
EU
European Union
EudraCT
European Union clinical trials database
FDA
Food and Drug Administration 
GCP
Good Clinical Practice
HAV
hepatitis A virus
HBV
hepatitis B virus
HCV
hepatitis C virus
HEV
hepatitis E virus
HIV
human immunodeficiency virus
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonisation 
Ig
immunoglobulin
IgG
immunoglobulin G
IGIV
intravenous immunoglobulin
IGSC
subcutaneous immunoglobulin
IGSC, 20%
Immune Globulin Subcutaneous (Human), 20% Solution
IP
investigational product
IRB
institutional review board
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Abbreviation
Definition
IRT
interactive response technology
IV
intravenous 
LDH
lactate dehydrogenase
MedDRA
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging
PCR
polymerase chain reaction
PID
primary immunodeficiency disease
PK
Pharmacokinetic
PT
preferred term
QoL
quality of life
RSI
Reference Safety Information
SAE
serious adverse event 
SAP
statistical analysis plan
SAS
Safety Analysis Set
SC
subcutaneous
SOC
system organ class
SUSAR
suspected unexpected serious adverse reaction
SY
subject-year
TEAE
treatment-emergent adverse event
TFLs
tables, figures, and listings
US
United States
WBC
white blood cell 
WHO
World Health Organization
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4. INTRODUCTION
4.1 Background
4.1.1 Indication and Current Treatment Options
Primary immunodeficiency diseases (PID) are disorders that result in increased susceptibility
to recurrent infections, secondary to the underlying defects in adaptive (humoral and/or
cell-mediated immunity) and/or innate immune system (Hernandez-Trujillo, 2014, Picard et al.,
2018, Rosen et al., 1995). The number of known PID defects has increased in the last 20 years
and the World Health Organization (WHO) currently recognizes more than 406 distinct disorders
(with >430 gene defects) (Bousfiha et al., 2020). The most recent classification of molecularly
defined PIDs issued by the Expert Committee of the International Union of Immunological
Societies (Picard et al., 2018) distinguishes 9 PID categories according to common disease
phenotypes.
Therapeutic options for the treatment of infections in PID with antibody production defects 
include standard antibiotic treatment and administration of immunoglobulin G (IgG) as a 
replacement therapy. Antibody replacement can be administered either intravenously or 
subcutaneously (Melamed et al., 2012). Therapeutic options for treatment of PID itself to 
correct the defect are transplantation of bone marrow-derived stem cells, and recently, 
gene therapy (de la Morena and Nelson, 2014, Hernandez-Trujillo, 2014, Kuo, 2018, Picard et 
al., 2018, Sauer et al., 2014). 
Currently, the majority of IgG products are licensed for intravenous (IV) administration, 
though in the past several years, subcutaneous (SC) administration has gained popularity. 
When given weekly or every other week, subcutaneous immunoglobulin (IGSC) leads to higher 
trough serum IgG concentrations than monthly IV infusions (Berger, 2011, Gardulf et al., 1995, 
Gardulf et al., 1991). 
Immunoglobulin (Ig) replacement therapy administered by the SC route (IGSC) is considered to 
be effective, safe, and is also well accepted by subjects with PID (Gardulf and Hammarström, 
1996). This route of administration may be of particular interest in patients with poor venous 
access such as pediatric patients (Melamed et al., 2012, Wasserman, 2012) and those patients 
interested in home-based therapy since it can be self-administered (Abolhassani et al., 2012, 
Wasserman, 2012, Zuizewind et al., 2018). Another major potential benefit of IGSC is the 
lower incidence of systemic adverse events (AEs) compared to intravenous immunoglobulin 
(IGIV) (Berger, 2013, Suez et al., 2016). The Ig preparations currently approved for SC 
use in the United States (US), Canada, and the European Union (EU) are formulated at 
10% to 20% (only the 20% IGSC formulation Hizentra® is available in Japan). 
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The higher concentration products allow for a relatively smaller infusion volume, which may 
reduce the number of infusion sites and/or duration of infusion, thereby improving patient quality 
of life (QoL) (Wasserman, 2012).
4.1.2 Product Background and Clinical Information
A major disadvantage of conventional SC administration is that only small volumes can be 
infused at each site, necessitating the use of multiple sites on a weekly or biweekly (every other
week) basis. Generally, using a 16% solution, approximately 20 mL can be infused per site; an 
adult patient receiving 400 mg/kg body weight every 4 weeks thus would require at least 3 sites 
per week or 12 sites per month. Even though weekly or biweekly administration has the added 
advantage of maintaining better trough levels than monthly IV infusions, the requirement of 
multiple needle insertions has been a deterrent for many patients. 
The pharmacokinetics (PK) of SC administration are different from that of IV infusions, and 
bioavailability of Ig administered subcutaneously may be less than after IV infusions. This 
reduced bioavailability after SC administration may be due to the mode of absorption of large 
protein molecules, which cannot readily diffuse through the capillary walls and must be absorbed 
via the lymphatics (Supersaxo et al., 1990).
Subcutaneous immunoglobulin, 20%, a new Ig preparation for SC use, is formulated as a 
20% solution. The manufacturing process for Immune Globulin Subcutaneous (Human), 
20% Solution (IGSC, 20%) shares common manufacturing steps with IGI, 10%, with the 
exception of the final ultra-/diafiltration and formulation steps. The IgG subclass distribution is 
within the normal range for human serum, and the product comprises antibodies to specific 
bacterial and viral pathogens. The preparation retains all Fab and Fc mediated functions of the 
native IgG molecule. The higher protein concentration leads to smaller infusion volumes 
compared with less concentrated products.
The clinical development program of IGSC, 20% is based on the European Medicines agency
Guidelines for human normal Ig for SC and IV use (Committee for Human Medicinal Products, 
2010, Committee for Proprietary Medicinal Products, 2002) and the Food and Drug 
Administration (FDA) guidance to industry (Food and Drug Administration, 2008). The safety, 
tolerability, and efficacy of IGSC, 20% in primary immunodeficiency have been demonstrated in 
adult and pediatric patients in 2 Phase 2/3 studies in Europe (Study 170903) (Borte et al., 2017)
and in North America (Study 170904) (Suez et al., 2016).
Refer to the latest version of the IGSC, 20% Investigator’s Brochure (IB) for detailed 
information on product properties and nonclinical and clinical studies.
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4.2 Rationale for the Proposed Study
Approximately 2,900 to 3,500 people are diagnosed with PID in Japan, and the number of 
diagnosed patients is increasing. Furthermore, in Japan, the administration route for Ig
replacement therapy was historically mostly IV. The Study TAK-664-3001 evaluates serum 
trough IgG levels, safety and tolerability, and efficacy of IGSC, 20% (SC administration), and 
assesses disease activity and health-related QoL in Epoch 1, Epoch 2, and Epoch 3, in subjects 
with PID in Japan. It aims to demonstrate maintenance of total IgG trough levels on IGSC, 20% 
(Epoch 2, Epoch 3) relative to IGIV (Epoch 1). TAK-664-3002 is an open-label extension study, 
following completion of Study TAK-664-3001. It will provide data on the long-term safety and 
tolerability of IGSC, 20% in Japanese subjects with PID who successfully complete Study 
TAK-664-3001 and wish to continue treatment with IGSC, 20%. The results from these 2 studies 
will extend/support the data obtained from 2 global (US and EU) pivotal studies for IGSC, 20% 
in PID, to Japanese patients with PID. 
4.3 Benefit/Risk Profile 
Subcutaneous immunoglobulin, 20% is a new Ig preparation supplied as a 20% solution for SC 
use that contains functionally intact IgG. The IgG subclass distribution for the final product is 
within the normal range for human serum and comprises antibodies to specific bacterial and viral 
pathogens. Subcutaneous immunoglobulin, 20% is a benefit to patients with poor vein access, to 
pediatric patients because of the low volume to be administered, and to those patients interested 
in home-based therapy since it can be self-administered. The higher concentration allows for a 
smaller infusion volume, which may reduce the number of infusion sites and/or duration of 
infusion.
Final results from Study 170904 and Study 170903 indicate that IGSC, 20% administered SC is 
efficacious and well tolerated in adult and pediatric subjects with PID. Results of the integrated 
safety analysis support the similarity of IGSC, 20% safety profile to the licensed IGIV, 10% 
administered SC.
Tolerability was demonstrated by the high rate of IGSC, 20% infusions completed without 
interruption (>99.9%). In Study 170904, a median maximum infusion rate of 60 mL/hour per site 
and a median maximum infusion volume of 39.5 mL per site were tolerated without an increase 
in the rate of local or systemic AEs. 
Efficacy was demonstrated by the low annual rate of validated acute serious bacterial infections 
(ASBI), meeting the predefined criteria of 1 or less validated ASBI per year in subjects with PID 
treated with IGSC, 20% either at the same weekly-equivalent dose as with the previously used Ig
product (170903) or at a dose adjusted to achieve the bioavailability of IGIV 10% (170904). 
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The low total infection rates and the maintenance of protective trough levels of total IgG and 
pathogen-specific antibodies in both studies conducted with IGSC, 20% are further evidence 
of the effectiveness of IGSC, 20% treatment as replacement therapy in subjects with PID. 
Quality of life assessments and other patient-outcome assessments suggest that subjects 
appreciate the treatment convenience offered by IGSC, 20% preparation.
Immunoglobulin preparations have been used extensively in clinical practice for more than 
25 years, to treat a variety of disorders, including PID. The incidence of systemic reactions 
following administration of currently available SC preparations is much less than with IV 
administration as documented in numerous studies (Chapel et al., 2000, Gardulf et al., 1995). 
The safety profile of IGSC, 20% was consistent with expected adverse reactions for 
GAMMAGARD LIQUID administered SC. Across IGSC, 20% studies, the incidence of related 
systemic AEs was low (0.029 events/infusion). Headache, the most common systemic adverse 
reaction during the IGSC, 20% development program occurred in 1% to less than 10% of 
subjects.
Potential risks with IGSC, 20% replacement therapy such as hypersensitivity, transmission of 
infectious agents, hemolysis, thrombotic and thromboembolic events, renal adverse reaction, and 
aseptic meningitis syndrome were not observed during clinical development with IGSC, 20%. 
Therefore, the benefits of IGSC, 20% for treatment of patients with PID outweigh the risks.
Always refer to the latest version of the IGSC, 20% IB for the overall benefit/risk assessment 
and the most accurate and current information regarding drug metabolism, PK, efficacy, and 
safety of IGSC, 20%.
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5. STUDY OBJECTIVES AND ENDPOINTS
5.1 Objectives
5.1.1 Primary Objective
To evaluate the long-term safety and tolerability of IGSC, 20% in Japanese subjects with PID.
5.1.2 Secondary Objectives

To assess serum trough IgG and subclasses concentrations following weekly or biweekly
administration of IGSC, 20% in Japanese subjects with PID.

To evaluate the efficacy of IGSC, 20% in Japanese subjects with PID.

To assess treatment preference of Japanese subjects with PID.
5.2 Endpoints
5.2.1 Primary Endpoint: Safety and Tolerability

Occurrence of treatment-emergent adverse events (TEAEs), including but not limited to:
study drug-related and non-related*, serious, nonserious, severe, local and systemic
TEAEs, as well as TEAEs leading to premature discontinuation from study, and
infusion-associated TEAEs.
*Any TEAE that is recorded by the investigator as “probably related” or “possibly related”
to study drug will be considered as IGSC, 20%-related AE, and any AE recorded as
“unlikely related” or “not related” will be considered as unrelated AE.
5.2.2 Secondary Endpoints: Safety, Tolerability, PK, and Efficacy
Pharmacokinetic endpoint/outcome measure: 

Measurement of serum trough IgG and subclasses concentrations following weekly or
biweekly administration of IGSC, 20% in Japanese subjects with PID.
Efficacy endpoints/outcome measures:

Annual rate of validated ASBI per subject.

Annual rate of all infections per subject.

Health Resource Utilization:

Days not able to attend school/work or to perform normal daily activities due to
illness/infection

Days on antibiotics

Number of hospitalizations due to illness/infection and length of stay (in days)
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
Number of acute (urgent or unscheduled) physician visits due to illness/infection.

Treatment preference.
Safety endpoints/outcome measures:

Clinical laboratory outcomes: raw (actual) values and change from baseline.
Clinically significant, treatment-emergent changes in clinical laboratory measurements will
be recorded in the study database (internal or external) as TEAEs.

Vital signs: raw (actual) values and change from baseline and change from pre-infusion to
post-infusion.
Baseline is defined as the last non-missing value before the time of participation in the
TAK-664-3001 study.
Tolerability endpoints/outcome measures:

Occurrence of tolerability events related to the infusion of study drug.
*An infusion is considered tolerable if the infusion rate was not reduced, or the infusion was
not interrupted or stopped, due to a TEAE related to study drug infusion. A tolerability
event is considered to have occurred if an infusion was not tolerable. Tolerability events
will be measured in terms of the number and percentage of subjects for which the infusion
was not tolerable.
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6. STUDY DESIGN AND DESCRIPTION
6.1 Study Design
This is a Phase 3, prospective, multicenter, open-label, non-controlled, single-arm extension
study.
Approximately 10 to 15 study sites planned, located in Japan. Number of subjects are 
approximately 10. A total of 16 subjects will be enrolled in Study TAK-664-3001, of whom 
12 subjects are expected to complete Epoch 2. The subjects who successfully complete Epoch 2 
are eligible to enter this extension study.
This study will enroll Japanese subjects with PID who complete Study TAK-664-3001
successfully.
Subjects are considered to have completed Study TAK-664-3001 successfully if they fulfill the 
following criterion:

Completed Epoch 2, in which IGSC, 20% is administered weekly (completion of Epoch 3,
in which IGSC, 20% is administered biweekly, is not mandatory for participation in
TAK-664-3002 study).
Screening/Baseline Period
Informed consent is expected to be obtained at last visit or prior to last visit of 
Study TAK-664-3001.
The subjects will undergo screening/baseline procedures for determination of eligibility before 
infusion of IGSC, 20% (see Appendix-Table 1 for Schedule of Study Procedures).
IGSC, 20% Treatment Period
Eligible subjects will receive IGSC, 20% until the commercial IGSC, 20% is available at each 
study site or study termination (estimated duration: approximately 3 years).
Visit Schedule
The number of infusion visits and study site visits during the SC treatment period will depend on 
where the SC injection is administered. Infusions may be performed at home or at the study site, 
at the investigator’s discretion. The decision where the SC injection is administered is made 
during the Study TAK-664-3001, however the location of injection administration can be 
changed based on the investigator’s and subject’s agreement. Subjects should come to the study 
site for visits when laboratory test samples are to be collected every 12 weeks. Subjects are not 
required to come to the study site if all procedures/assessments can be performed at home.
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A schematic of the study design is included as In-Text Figure 6-1. A schedule of assessments is 
listed in Appendix A.
In-Text Figure 6-1. Schematic of Study Design
Abbreviations: EOS=End of study, IgG= immunoglobulin G, IGSC= subcutaneous immunoglobulin, 
SC=subcutaneous.
6.2 Justification for Study Design, Dose, and Endpoints
For all study subjects, the Ig dose during the pre-study period (equivalent to approximately 
200 mg/kg to 600 mg/kg body weight at 3- or 4-week intervals, as according to the product 
package insert) was maintained upon study entry into Study TAK-664-3001. In replacement 
therapy, the dose may need to be individualized for each subject dependent on the serum trough 
levels of IgG and clinical response. The dose regimen should achieve a trough level of IgG 
(measured before the next infusion) of at least 5 g/L and aim to be within the reference interval 
of serum IgG for age.
This is an extension study for Study TAK-664-3001 and has been designed to primarily 
evaluate long-term safety and tolerability. Serum trough IgG concentrations, rate of bacterial 
infections, Health Resource Utilization, QoL, treatment preference, and treatment satisfaction 
questionnaires were all endpoints in TAK-664-3001 and these data (except the QoL and 
treatment satisfaction) will continue to be collected in this extension study.
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In principle, the dose regimen as established in Study TAK-664-3001 should be maintained 
during the extension study. Subjects who complete Epoch 2 will start weekly dosing, and 
subjects who complete Epoch 3 will start biweekly dosing. The dose interval may be switched to 
weekly or biweekly on a case-by-case basis for the subjects if needed. For subjects who 
discontinue Epoch 3 and enter Study TAK-664-3002, the dose regimen will be determined on a 
case-by-case basis.
The dose of IGSC, 20% infusion was established in Study TAK-664-3001 and is assumed to 
maintain the target IgG trough level ≥5 g/L (Epoch 2: approximately between 50 and 200 mg/kg 
of IGSC, 20% weekly, Epoch 3: approximately between 100 and 400 mg/kg of IGSC, 20% 
biweekly).
When the IgG trough level is found not to be maintained at ≥5 g/L during the study, adjustment 
of the dose is allowed at the discretion of the investigator.
6.3 Premature Termination or Suspension of Study or Study Site
6.3.1 Criteria for Premature Termination or Suspension of the Study
The study will be completed as planned unless 1 or more of the following criteria are satisfied,
which will require temporary suspension or early termination of the study.

New information or other evaluation regarding the safety or efficacy of the study drug that
indicates a change in the known risk/benefit profile for the TAK-664, such that the risk is
no longer acceptable for subjects participating in the study.

Significant violation of Good Clinical Practice (GCP) that compromises the ability to
achieve the primary study objectives or compromises subject safety.
6.3.2 Criteria for Premature Termination or Suspension of Study Sites
A study site may be terminated prematurely or suspended if the study site (including the 
investigator) is found in significant violation of GCP, protocol, or contractual agreement, is 
unable to ensure adequate performance of the study, or as otherwise permitted by the contractual 
agreement.
6.3.3 Procedures for Premature Termination or Suspension of the Study or the 
Participation of Study Site(s)
In the event that the sponsor, an institutional review board (IRB) or regulatory authority elects to 
terminate or suspend the study or the participation of a study site, a study-specific procedure for 
early termination or suspension will be provided by the sponsor; the procedure will be followed 
by applicable study sites during the course of termination or study suspension.
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7. SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS
Japanese subjects aged 2 years or older with PID are enrolled in this study. All entry criteria,
including test results, need to be confirmed prior to first dose.
7.1 Inclusion Criteria
Each subject must meet all the following criteria to enroll in the study:
1.
Subject has completed or is about to complete Takeda Clinical Study TAK-664-3001.
A subject is considered to have completed Study TAK-664-3001 successfully if they fulfill
the following criterion:

Completed Epoch 2, in which IGSC, 20% is administered weekly (completion of
Epoch 3, in which IGSC, 20% is administered biweekly, is not mandatory for
participation in TAK-664-3002 study).
2.
Written informed consent is obtained from either the subject or the subject's legally
authorized representative prior to any study-related procedures and study product
administration.
3.
Subject is willing and able to comply with the requirements of the protocol.
7.2 Exclusion Criteria
Any subject who meets any of the following criteria will not qualify for entry into the study:
1.
Subject has developed a new serious medical condition during participation in
Study TAK-664-3001 such that the subject’s safety or medical care would be impacted by
participation in the extension study TAK-664-3002.
2.
Subject is scheduled to participate in another non-Takeda clinical study involving an
Investigational Product or device-used-in-clinical-trial in the course of this study.
3.
If a female of childbearing potential, subject is pregnant or has a negative pregnancy test
but does not agree to employ adequate birth control measures for the duration of the study.
7.3 Excluded Medications 
The following medications are not permitted during the course of the study:

Other IgG products after first exposure to study drug.

Hyper immune serum.

Immunosuppressive drugs following transplantation.
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Pre-medication on the Day of Product Administration:
In this study, subjects should not receive pre-medication for SC infusions unless an adverse 
reaction of at least moderate severity, not resolving with a reduction in the infusion rate, occurs 
during or after at least 2 infusions. Should this occur, subjects may be pretreated with 
antipyretics, corticosteroids or antihistamines at the discretion of the investigator. Topical local 
anesthetics may be used if the needle insertion was intolerable in prior infusions. Subjects who 
have a history of using topical anesthetics may use these topical anesthetics for SC infusions. 
The use of such pre-medications must be recorded on the concomitant medication record.
Treatments not listed above are considered allowable.
7.4 Criteria for Discontinuation or Withdrawal of a Subject
The primary reason for discontinuation or withdrawal of the subject from the study or study drug 
should be recorded in the electronic case report form (eCRF) using the following categories. For 
screen failure subjects, see Section 9.1.12.
1.
AE: The subject has experienced an AE that requires early termination because continued
participation imposes an unacceptable risk to the subject’s health or the subject is unwilling
to continue because of the AE.
2.
Lack of efficacy: The investigator has determined that the subject is not benefiting from
study treatment; and continued participation would pose an unacceptable risk to the
subject.
3.
Non-compliance with study drug.
4.
Non-compliance with study procedures.
5.
Physician decision.
6.
Pregnancy: The subject is found to be pregnant.
Note: If the subject is found to be pregnant, the subject must be withdrawn immediately.
The procedure is described in Section 9.1.9.
7.
Progressive disease.
8.
Significant protocol deviation: The discovery after the first dose of study drug that the
subject failed to meet protocol entry criteria or did not adhere to protocol requirements, and
continued participation poses an unacceptable risk to the subject’s health.
9.
Withdrawal by parent/guardian.
10. Withdrawal by subject: The subject (or subject’s legally acceptable representative) wishes
to withdraw from the study. The reason for withdrawal, if provided, should be recorded in
the eCRF.
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Note: All attempts should be made to determine the underlying reason for the withdrawal 
and, where possible, the primary underlying reason should be recorded (ie, withdrawal due 
to an AE should not be recorded in the “voluntary withdrawal” category).
11. Lost to follow-up: The subject did not return to the clinic and 3 attempts to contact the
subject were unsuccessful. The 3 attempts should be documented. At least 1 of these
documented attempts must include a written communication sent to the subject’s last
known address via courier or mail (with an acknowledgment of receipt request) asking that
the subject return to the study site for final safety evaluations and return any unused study
drug.
12. Death.
13. Study site terminated by the sponsor.
14. Study termination: The sponsor, IRB or regulatory agency terminates the study.
15. Other.
7.5 Procedures for Discontinuation or Withdrawal of a Subject
The investigator may discontinue a subject’s study participation at any time during the study 
when the subject meets the study termination criteria described in Section 7.4. In addition, a 
subject may discontinue his or her participation without giving a reason at any time during the 
study. Should a subject’s participation be discontinued, the primary criterion for termination 
must be recorded by the investigator. In addition, efforts should be made to perform all 
procedures scheduled for the Early Termination Visit. Discontinued or withdrawn subjects will 
not be replaced.
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8. CLINICAL STUDY MATERIAL MANAGEMENT
This section contains information regarding all medications and materials provided directly by
the sponsor, and/or sourced by other means, that are required by the study protocol, including
important sections describing the management of study material.
8.1 Study Drug and Materials
8.1.1 Dosage Form, Manufacturing, Packaging, and Labeling
8.1.1.1 Study Drug
The study drug IGSC, 20% is a liquid formulation of IgG. At least 95% (EU specifications)/96% 
(US specifications) of the protein in the study drug is gamma globulin. The product is isotonic 
and has a pH of 4.6 to 5.1 (diluted at 1% in saline). It contains 18.0 to 22.0 g of protein per 
100 mL and approximately 0.2 to 0.3 M glycine. The liquid preparation is clear and colorless or 
pale yellow or light brown. It contains no preservatives. 
Additional information is provided in the current IB.
Immune Globulin Subcutaneous (Human), 20% Solution (IGSC, 20%) will be provided by the 
sponsor and will be labeled as investigational product (IP).
8.1.1.2 Packaging
Immune Globulin Subcutaneous (Human), 20% Solution is supplied in single-dose glass vials 
that nominally contain 4 g and 8 g of protein per vial.
Changes to sponsor-supplied packaging prior to dosing may not occur without full agreement in 
advance by the sponsor.
8.1.1.3 Labeling
Labels containing study information and pack identification are applied to the study drug vial 
and carton. The product will be labeled according to the valid regulatory requirements for 
clinical studies.
8.1.2 Storage
The investigator has overall responsibility for ensuring that study drug is stored in a secure, 
limited-access location. Limited responsibility may be delegated to the pharmacist or member of 
the study team, but this delegation must be documented. Immune Globulin Subcutaneous 20% is 
distributed or administered by the pharmacist or nominated member of the study team. The 
pharmacist/nominated team member will enter the subject identifier on the study drug vial/carton 
labels as they are distributed or administered.
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Study drug must be stored in accordance with labeled storage conditions. Temperature 
monitoring is required at the storage location to ensure that the study drug is maintained within 
an established temperature range. The investigator is responsible for ensuring that the 
temperature is monitored throughout the duration of the study and that records are maintained; 
the temperature should be monitored continuously by using either an in-house system, a 
mechanical recording device such as a calibrated chart recorder, or by manual means, such that 
both minimum and maximum thermometric values over a specific time period can be recorded 
and retrieved as required. The sponsor must be notified immediately upon discovery of any 
excursion from the established range. Temperature excursions will require study site 
investigation as to cause and remediation. The sponsor will determine the ultimate impact of 
excursions on the study drug and will provide supportive documentation as necessary. Under no 
circumstances should the product be dispensed to subjects until the impact has been determined 
and the product is deemed appropriate for use by the sponsor.
The sponsor should be notified immediately if there are any changes to the storage area of the 
study drug that could affect the integrity of the product(s), eg, fumigation of a storage room.
All study drug for the sponsor’s studies must be stored in a securely locked, substantially 
constructed room or cabinet according to all applicable local, state, and/or national laws. 
Limited, controlled access to these study drugs must be maintained, as well as chain of custody, 
for all study drug movement.
8.1.3 Dose and Regimen
In principle, the dose regimen established in TAK-664-3001 should be maintained during the 
extension study. Subjects who complete Epoch 2 will start weekly dosing, and subjects who 
complete Epoch 3 will start biweekly dosing. The dose interval may be switched to weekly or 
biweekly on a case-by-case basis for the subjects if needed. For subjects who discontinue 
Epoch 3 and enter Study TAK-664-3002, the dose regimen will be determined on a case-by-case 
basis.
The dose of IGSC, 20% infusion was established in Study TAK-664-3001 and is assumed to 
maintain the target IgG trough level ≥5 g/L (Epoch 2: approximately between 50 and 200 mg/kg 
of IGSC, 20% weekly, Epoch 3: approximately between 100 and 400 mg/kg of IGSC, 20% 
biweekly). The dose can be modified based on subject’s IgG level/condition/body weight.
Infusion Volumes and Rates
The infusion rate and volume that was tolerated in the TAK-664-3001 study and as 
recommended by the investigator will be followed in this study. Multiple infusion sites 
can be used for infusion simultaneously as determined by the subject and investigator. 
Infusions will be conducted with a pump. It is suggested to complete the administration 
within 2 hours due to the potential formation of particles caused by siliconized syringes.
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The study subject should be well trained for self-infusion process before they will do 
self-infusion at home. Investigator should confirm that the subject has enough knowledge and 
skill for self-infusion and need to record it. In-Text Table 8-1 presents the volume and rate of 
infusion, (when tolerated well by the subject).
In-Text Table 8-1. Infusion Volume and Rate
Infusion Parameters
Subsequent Infusions
Subjects <40 kg
Subjects ≥40 kg
Volume (mL/site)
≤60
Rate (mL/h/site)
≤60
Site of Administration
The infusion site should be selected in an area that is free of tenderness, erythema, or induration, 
and the overlying skin should be intact. It is recommended that the infusion sites be rotated to 
avoid any single infusion site being used repeatedly within a short time interval. In addition, 
when 2 or more SC infusion sites are to be used during an infusion, each site should be at least 
10 cm (4 inches) apart.
Multiple infusion sites can be used simultaneously. The number of infusion sites will depend on 
the subject’s total dose in mL; there is no maximum to the number of infusion sites. To calculate 
the number of sites to be used, divide the total volume to be infused by the maximum 
volume/site to be infused. Up to 10% average per site is permitted, if necessary, to avoid starting 
a new site for only a few milliliters. For example, if the dose is 124 mL, and 2 sites are to be 
used, the dose per site can be 62 mL per site rather than using 3 sites.
8.1.4 Overdose
An overdose is defined as a known deliberate or accidental administration of study drug, to or by 
a study subject, at a dose above that which is assigned to that individual subject according to the 
study protocol.
All cases of overdose (with or without associated AEs) will be documented on an Overdose page
of the eCRF, in order to capture this important safety information consistently in the database.
An overdose should be reported to the sponsor according to the serious adverse event (SAE)
reporting procedure whether or not they result in an AE/SAE according to the procedure outlined 
in Section 10.2.2.
Note: The 24-hour reporting requirement for SAEs does not apply to reports of overdose unless 
it results in an SAE.
In the event of drug overdose, the subject should be treated symptomatically.
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8.2 Study Drug Assignment and Dispensing Procedures
This is an open-label, non-controlled study where all subjects will be enrolled to receive 
IGSC, 20%. Individual subject numbers are automatically assigned to all subjects via the 
interactive response technology (IRT) as they consent to take part in the study. Within each study 
site (numbered uniquely within a protocol), the subject number is assigned according to the 
sequence of subject presentation for study participation.
Interactive response technology will be used for study drug supply management, inventory 
management, supply ordering, study drug expiration tracking, temperature excursion reporting, 
and return of study drug. 
Details for the handling of study drug will be described in the pharmacy manual.
8.3 Device-Used-in-Clinical-Trial/Device-related Defects
In this study, ʻDevice-Used-in-Clinical-Trialʼ is defined as below:
Device name 
FREEDOM60® Integrated Syringe Infusion System
Type
Infusion Pump Syringe Driver
Manufacturer
KORU Medical Systems
Version
Not Applicable
8.3.1 Marketing Approval
The FREEDOM60 Syringe Driver® is US FDA 510(k) Class 2 device under K200176. 
Further, the device is CE marked as a Class 2a, in accordance with EU Medical Device Directive 
93/42/EEC.
The FREEDOM60 Integrated Syringe Infusion System consists of the following components: 

FREEDOM60 Syringe Driver

Precision Flow Rate Tubing™

HIgH-Flo SC Safety Needle Sets™.
The FREEDOM60 Integrated Syringe Infusion System has not yet been approved for marketing 
in Japan.
8.3.2 Indications for Use
The FREEDOM60 Syringe Driver is indicated for use with Becton Dickinson & Co. BD®
Plastipak™ Luer-Lok® 50 mL (EU Reference #300865, US Reference #309653).
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The FREEDOM60 Syringe Driver is an ambulatory device designed to accommodate a BD 
Plastipak Luer-Lok 60 mL Syringe (Catalog No.: 8881-560125, BD 309653), and fluid volumes 
ranging from 10 to 60 cc. The pump uses a constant force spring mechanism to apply pressure to 
the plunger-end syringe. 
The FREEDOM60 Integrated Syringe Infusion System is assembled by loading the prefilled 
syringe with tubing into the FREEDOM60 Syringe Driver.
The infusion system is indicated for continuous delivery at controlled infusion rates via IV and 
SC route. The infusion system is indicated to deliver SC infusion of immune globulin human 
plasma derived Igs, electrolyte solutions, iron chelating agents, and infusible selective 
immunosuppressants; and IV infusion of beta lactamase resistant penicillin’s, other 
aminoglycosides, and carbapenems.
The infusion system is indicated for continuous delivery of SC infusion of TAK-664 at 
controlled rate.
8.3.3 Usage Instructions and Warnings
For the usage instructions and warnings, please refer to Site Infusion Manual and Subject 
Infusion Manual.
8.3.4 Device-related Defects
Investigators are required to report device-related defects to sponsor within 24 hours. Please 
report the device-related defects using the “Clinical Trial Material Complaint Form” via the 
email address: 
The Reference Safety Information (RSI) for the Devise-Used-in-the-Clinical-Trial is the 
Instructions For Use, which the sponsor has provided under separate cover to all investigators in 
Japan.
8.4 Accountability and Destruction of Sponsor-Supplied Drugs
Investigators will be provided with sufficient amounts of the study drug to carry out this protocol 
for the agreed number of subjects. The investigator or designee will acknowledge receipt of the 
study drug, documenting shipment content and condition. Accurate records of all study drug
dispensed, used, returned, and/or destroyed must be maintained as detailed further in this section.
The investigator has overall responsibility for administering/dispensing IP. Where permissible, 
tasks may be delegated to a qualified designee (eg, a pharmacist) who is adequately trained in the 
protocol and who works under the direct supervision of the investigator. This delegation must be 
documented in the applicable study delegation of authority form.
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The investigator or his/her designee (as documented by the investigator in the applicable study
delegation of authority form) will administer/dispense the study drug only to subjects included in
this study following the procedures set out in the study protocol. Each subject will be given only 
the study drug carrying his/her treatment assignment. All administered/dispensed medication will 
be documented in the subject’s source and/or other study drug record. The investigator is
responsible for ensuring the retrieval of all study supplies from subjects. Due to the health/safety 
concerns with returning the study drug container, the investigator must request that subjects keep 
the empty study drug packaging after use and return it to the study site for drug accountability 
purposes.
The site may use an alternative method for dispensing. If permitted by country or local 
regulations and IRBs, the IP can be shipped from the site directly to the subject’s home address. 
Subjects must be provided with instructions on how to receive, store, and ultimately return the 
IP/sponsor-supplied treatments.
No study drug stock or returned inventory from a Takeda-sponsored study may be removed from 
the study site where originally shipped without prior knowledge and consent by the sponsor. If 
such transfer is authorized by the sponsor, all applicable local, state, and national laws must be 
adhered to for the transfer.
The sponsor or its representatives must be permitted access to review the supplies storage and 
distribution procedures and records.
At the end of the study, or as instructed by the sponsor, all unused stock, subject-returned study 
drug, and empty/used study drug packaging are to be sent to a nominated contractor on behalf of 
the sponsor. Study drug being returned to the sponsor’s designated contractors must be counted 
and verified by study site personnel and the sponsor (or designated contract research 
organization [CRO]). For unused supplies where the original supplied tamper-evident feature is 
verified as intact, the tamper-evident feature must not be broken and the labeled amount is to be 
documented in lieu of counting. Shipment return forms, when used, must be signed prior to 
shipment from the site. Validated electronic return systems (ie, IRT) do not require a shipment 
form. Returned study drug must be packed in a tamper-evident manner to ensure product 
integrity. Contact the sponsor for authorization to return any study drug prior to shipment. 
Shipment of all returned study drug must comply with local, state, and national laws.
Based on entries in the study site drug accountability forms, it must be possible to reconcile IPs 
delivered with those used and returned. All IPs must be accounted for and all discrepancies 
investigated and documented to the sponsor’s satisfaction.
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9. STUDY PLAN
9.1 Study Procedures
The following sections describe the study procedures and data to be collected. For each
procedure, subjects are to be assessed by the same investigator or study site personnel whenever
possible. The Schedule of Study Procedures is located in Appendix-Table 1.
9.1.1 Informed Consent Procedure
The requirements of the informed consent are described in Section 15.2.
Informed consent must be obtained prior to the subject entering into the study, and before any 
protocol-directed procedures are performed. In this study, informed consent is expected to be 
obtained at the last visit or prior to the last visit of Study TAK-664-3001.
A subject identification number (subject number) will be assigned to each subject via the IRT at 
the time that informed consent is obtained; this subject number will be used throughout the 
study.
9.1.2 Demographics, Medical History, and Medication History Procedure
Subject demographic information including gender, age, and race will be collected in the main 
study (TAK-664-3001).
Medical and medication history will be collected and recorded in the subject’s source documents. 
When the evaluation is performed in the Study TAK-664-3001, the medical and medication 
history will not be collected in this study at the Baseline Visit.
All medications taken and non-drug therapies received from 30 days prior to the date the 
informed consent document is signed until completion/termination will be recorded on the 
concomitant medications and non-drug therapies eCRFs.
9.1.3 Physical Examination Procedure
At baseline and subsequent scheduled study visits at the site (see Appendix-Table 1), a physical 
examination will be performed on the following body systems being described as normal or 
abnormal: general appearance, head and neck, eyes and ears, nose and throat, chest, lungs, heart, 
abdomen, extremities and joints, lymph nodes, skin, and neurological. 
At baseline, if an abnormal condition is detected, the condition will be described on the medical 
history eCRF. At study visits, if a new abnormal or worsened abnormal pre-existing condition is 
detected, the condition will be described on the AE eCRF. If the abnormal value was not deemed 
an AE because it was due to an error, due to a preexisting disease, not clinically significant, a 
symptom of a new/worsened condition already recorded as an AE, or due to another issue that 
will be specified, the investigator will record the justification on the source record.
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9.1.4 Vital Sign Procedure
Vital signs will include height (in or cm), weight (lb or kg), body temperature (°C or °F), 
respiratory rate (breaths/minute), pulse rate (beats/minute), and systolic and diastolic blood 
pressure (mmHg). Blood pressure measurements will be taken after subjects remain sitting in an 
upright position for at least 1 minute. Vital signs can be measured at subject’s home as described 
in Section 9.3.2.
Vital sign values are to be recorded on the appropriate eCRF. Additional tests and other 
evaluations required to establish the significance or etiology of an abnormal result or to monitor 
the course of an AE should be obtained when clinically indicated. Any abnormal value that 
persists should be followed at the discretion of the investigator.
The investigator will assess whether a change from baseline (as determined at the 
Screening/Baseline Visit) in vital signs may be deemed clinically significant and whether the 
change should be considered and recorded as an AE. Vital signs at home will be recorded in 
subject diary and will be reviewed by investigators.
9.1.5 Documentation of Concomitant Medications
Concomitant medication is any drug given in addition to the study drug. These may be 
prescribed by a physician or obtained by the subject over the counter. Concomitant medication is 
not provided by the sponsor. At each study visit, subjects will be asked whether they have taken 
any medication other than the study drug (used from signing of informed consent through the 
end of the study), and all medication including vitamin supplements, over-the-counter 
medications, and oral herbal preparations, must be recorded in the eCRF. This information can 
be taken from subjects at home by the procedure determined by each study site (eg, telephone, 
telemedicine to subject’s home) as described in Section 9.3.2.
Requirement for all antibiotic therapy must be documented as an AE. Prophylactic treatment 
with systemic antibacterial antibiotics is allowed during the study. The use of antibiotics should 
be recorded as concomitant medication.
9.1.6 Documentation of Concurrent Medical Conditions
Concurrent medical conditions are those significant ongoing conditions or diseases that are 
present at signing of informed consent. This includes clinically significant laboratory, or physical 
examination abnormalities noted at baseline examination, according to the judgment of the 
investigator. As subjects are from the preceding study (TAK-664-3001), concurrent medical 
conditions will be those recorded in TAK-664-3001.
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9.1.7 Procedures for Clinical Laboratory Samples
All clinical laboratory tests will be performed according to the laboratory’s standard procedures. 
Reference ranges will be supplied by the laboratory and used to assess the results for clinical 
significance and out-of-range changes which may be associated with, or constitute, an AE. 
The investigator should assess out-of-range clinical laboratory values for clinical significance, 
indicating if the value(s) is/are not clinically significant or clinically significant. Abnormal 
clinical laboratory values, which are unexpected or not explained by the subject’s clinical 
condition, may, at the discretion of the investigator or sponsor, be repeated as soon as possible 
until confirmed, explained, or resolved.
Laboratory tests including assessment of IgG trough levels will be performed every 12 weeks
from Visit 1.
The investigator will assess each abnormal laboratory value as described in this section. In 
addition, the sponsor will evaluate laboratory values for abnormalities according to a 5-point 
(Grades 0 - 4) toxicity grading scale provided in Appendix D.
The Common Toxicity Criteria of the (Eastern Cooperative Oncology Group, 2006) will be used
to grade the following laboratory values: alkaline phosphatase (ALP), alanine aminotransferase 
(ALT), aspartate aminotransferase (AST), blood urea nitrogen (BUN), hemoglobin, 
lymphocytes, neutrophils, platelet count, serum creatinine, serum total bilirubin, and white blood 
cell (WBC) count. Grading for lactate dehydrogenase (LDH) will use the same thresholds as 
defined for ALT and AST. Sodium and potassium will be graded using the thresholds taken from 
the WHO toxicity grading system (World Health Organization, 2003). 
The investigator’s assessment of each abnormal laboratory value (with the exception of total 
IgG, IgG subclasses and specific antibodies) is to be recorded on the laboratory form. For each 
abnormal laboratory value, the investigator will determine whether the value is also considered 
an AE (see definition in Section 10.1). If yes, the sign, symptom, or medical diagnosis will be 
recorded on the AE eCRF. If the abnormal value was not deemed an AE because it was due to a 
laboratory error, was due to a pre-existing disease (see Section 10.1.3), was not clinically 
significant, was a symptom of a new/worsened condition already recorded as an AE, or was due 
to another issue that will be specified, the investigator will record the justification on the 
laboratory form. Additional tests and other evaluations required to establish the significance or 
etiology of an abnormal result or to monitor the course of an AE should be obtained when 
clinically indicated. Any abnormal value that persists should be followed at the discretion of the 
investigator. Any positive seroconversion result shall be re-tested and confirmed.
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9.1.7.1 Hematology and Clinical Chemistry
The hematology panel will consist of complete blood count (hemoglobin, hematocrit, 
erythrocytes [ie, red blood cell count], and leukocytes [ie, WBC]) with differential (ie, basophils, 
eosinophils, lymphocytes, monocytes, neutrophils), and platelet counts. In addition, absolute 
neutrophil counts will be determined by laboratory calculation.
The clinical chemistry panel will consist of sodium, potassium, chloride, bicarbonate, protein, 
albumin, ALT, serum total bilirubin, AST, ALP, LDH, BUN, serum creatinine, creatinine 
phosphokinase, glucose, haptoglobin, and lipase.
Immunoglobulin G and IgG subclasses (IgG1, IgG2, IgG3, and IgG4) will be measured for 
assessment of trough levels.
Blood will be obtained for assessment of hematology and clinical chemistry including IgG and 
IgG subclasses at baseline, distinct study visits, and at study completion/termination. For a 
schedule of laboratory test blood drawings, see Appendix-Table 2. These assessments will be 
performed on Ethylenediamine tetraacetic acid (EDTA)-anticoagulated whole blood and serum, 
respectively, processed through a central laboratory. 
9.1.7.2 Urinalysis 
Urinalysis includes: color, specific gravity, pH, protein, glucose, ketones, bilirubin, urobilinogen, 
blood, nitrite, leukocyte esterase, and microscopic examination. 
For a schedule of laboratory test sample drawings, see Appendix-Table 2. These assessments 
will be performed at the central laboratory. Local laboratory can be used if deemed necessary.
A urine pregnancy test will be performed at the study site for females of childbearing potential 
which is indicated in Appendix-Table 2 (see also Section 9.1.9).
9.1.7.3 Specialty Tests
Specialty tests include: hepatitis B surface antigen, polymerase chain reaction (PCR) for 
hepatitis C virus (HCV) and PCR for human immunodeficiency virus (HIV)-1/2. For a schedule 
of laboratory test blood drawings, see Appendix-Table 2. These assessments will be performed at 
the central laboratory.
Additional specialty tests may be performed if required to establish the etiology of an AE or of 
abnormal laboratory results, such as tests for HIV, hepatitis A virus (HAV), hepatitis B virus 
(HBV), HCV, hepatitis E virus (HEV), or Parvovirus B19 (B19V).
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9.1.7.4 Hemolysis Tests
Scheduled tests will only be performed in subjects aged 12 years and older, in order to avoid 
multiple blood drawings in small children.
Tests for hemolysis:

direct antiglobin test (Coombs-test or antiglobin test)

urine hemosiderin
In addition, these assessments should be performed within 72 hours of being informed of the 
hemoglobin level if there is a decrease of hemoglobin ≥2 g/dL compared to the previous visit, 
unless there is a clear alternative explanation (which has been documented on the appropriate
eCRF).
Hemolysis test will be done every 24 weeks from Visit 1. For a schedule of laboratory test blood 
drawings, see Appendix-Table 2.
9.1.7.5 Specific Antibodies
Specific antibody tests (quantitative method) to clinically relevant pathogens (Clostridium tetani
toxoid, Haemophilus influenzae Type B [HIB] and HBV) will be performed.
For a schedule of specific antibody testing see Appendix-Table 2.
9.1.8 Contraception and Pregnancy Avoidance Procedure
9.1.8.1 Definitions and Procedures for Contraception and Pregnancy Avoidance
Sexually active females of childbearing potential should use an acceptable form of contraception. 
Females of childbearing potential must be advised to use acceptable contraceptives throughout 
the study period and for 30 days following the last dose of the study drug. If used, hormonal 
contraceptives should be administered according to the package insert. Any female of 
childbearing potential who is not currently sexually active must agree to use acceptable 
contraception, as defined below, if she becomes sexually active during the study and for 30 days 
following the last dose of the study drug. 
Female subjects should be either:

Premenarchal and either Tanner stage 1 or less than age 9 years, or

Postmenopausal (12 consecutive months of spontaneous amenorrhea and age ≥51 years)

Surgically sterile (having undergone 1 of the following surgical acts: hysterectomy,
bilateral tubal ligation, bilateral oophorectomy or bilateral salpingectomy) and at least
6 weeks post-sterilization, or
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
Of childbearing potential with a negative urine human chorionic gonadotropin (hCG) or
serum beta-hCG (β-hCG) pregnancy test at the Baseline Visit. Females of childbearing
potential must agree to abstain from sexual activity that could result in pregnancy or agree
to use acceptable methods of contraception.
Acceptable methods of contraception include the following:

Intrauterine devices plus condoms

Double-barrier methods (eg, condoms and diaphragms with spermicidal gel or foam)

Hormonal contraceptives (oral, depot, or vaginal ring), stabilized for at least 30 days prior
to the Baseline Visit, plus condoms. Note: If the subject becomes sexually active during
the study, she should use 1 of the other acceptable methods noted above in addition to the
hormonal contraceptive until it has been stabilized for 30 days.
9.1.8.2 Contraceptive Guidance
Female participants of childbearing potential are eligible to participate if they agree to use a 
highly effective method of contraception consistently and correctly as described below.
Highly Effective Contraceptive Methods That Are User Dependent a
Failure rate of <1% per year when used consistently and correctly. 

Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of
ovulationb

Oral
Highly Effective Methods That Are User Independent a

Implantable progestogen only hormonal contraception associated with inhibition of ovulationb

Intrauterine device

Intrauterine hormone-releasing system
Bilateral tubal occlusion

Vasectomized partner
A vasectomized partner is a highly effective contraception method provided that the partner is the sole male sexual
partner of the woman of childbearing potential and the absence of sperm has been confirmed. If not, an additional
highly effective method of contraception should be used.

Sexual abstinence
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual
intercourse during the entire period of risk associated with the study treatment. The reliability of sexual abstinence
needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of the participant.
NOTES: 
a) Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent
with local regulations regarding the use of contraceptive methods for participants participating in clinical studies. 
b) Hormonal contraception may be susceptible to interaction with the study treatment, which may reduce the
efficacy of the contraceptive method. In this case, 2 highly effective methods of contraception should be utilized
during the treatment period and for at least 30 days after the last dose of study treatment
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9.1.9 Pregnancy
A urine pregnancy test will be performed at the study site for females of childbearing potential 
which is indicated in Appendix-Table 2.
All pregnancies are reported from the time informed consent is signed until the End of Study 
(EOS)/Early Termination Visit.
Any report of pregnancy for any female study participant must be reported within 24 hours of the 
investigator’s awareness, using a pregnancy notification form (see Appendix F).
A copy of the Pregnancy Report Form (and any applicable follow-up reports) must also be sent 
to the CRO medical monitor using the details specified in the Appendix F. The pregnant female 
subject must be withdrawn from the study.
Every effort should be made to gather information regarding the pregnancy outcome and 
condition of the infant. It is the responsibility of the investigator to obtain this information within 
30 calendar days after the initial notification and approximately 30 calendar days and 1 year 
post-partum.
Pregnancy complications such as spontaneous abortion/miscarriage, elective abortion or 
congenital abnormality are considered SAEs and must be reported using the Safety Report Form.
In addition to the above, if the investigator determines that the pregnancy meets serious criteria, 
it must be reported in the Safety Report Form as well in the Pregnancy Report Form. The test 
date of the first positive urine hCG or serum β-hCG test or ultrasound result will determine the 
pregnancy onset date.
9.1.10 Pharmacokinetic
9.1.10.1 Serum IgG Trough Levels
Serum IgG trough levels (total serum levels of IgG and IgG subclasses IgG1, IgG2, IgG3, and 
IgG4) will be determined according to the schedule described in Appendix-Table 2 by using 
standard assay methods for the determination of total IgG concentration and IgG subclasses.
The blood drawing for the IgG determination will always take place before the infusion is 
administered.
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9.1.11 Efficacy
9.1.11.1 Acute Serious Bacterial Infection Rate 
Infections will be reported as AEs and the number and types of infections will be determined. 
Acute serious bacterial infections will include bacteremia/sepsis, bacterial meningitis, 
osteomyelitis/septic arthritis, bacterial pneumonia, and visceral abscess that are caused by a 
recognized bacterial pathogen. 
The diagnostic criteria for ASBIs are included in Appendix E.
The ASBI rate will be calculated as the mean number of ASBI per subject per year in the
All-Treated Set.
9.1.11.2 Infections
1.
The annual rate of all infections per subject.
All infections will be reported as AEs and the number and types of infections will be
determined.
2.
Days not able to attend school/work or to perform normal daily activities due to
illness/infection.
This information will be collected using diaries or other source data options throughout the
study and will be transcribed to eCRFs.
3.
Days on antibiotics
Days on antibiotics will be collected using diaries or other source data options throughout
the study and will be transcribed to eCRFs.
4.
Number of hospitalizations due to illness/infection and length of stay (in days)
Admissions to a hospital as an inpatient and the number of days in hospital will be
collected using diaries or other source data options throughout the study and will be
transcribed to eCRFs.
5.
Number of acute (urgent or unscheduled) physician visits due to illness/infection
Acute (urgent or unscheduled) physician visits due to illness/infection, will be collected
using diaries or other source data options throughout the study and will be transcribed to
eCRFs.
9.1.11.3 Treatment Preference
Treatment preference will be assessed at the Baseline Visit and the EOS/Early Termination Visit
in this study. 
Treatment preference will be analyzed separately for the age groups 2 to 13 years 
(observer: parent) and 14 years and older (observer: subject). Age will be defined as the age at 
baseline.
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9.1.11.4 Healthcare Resource Utilization 
Days not able to attend school/work or to perform normal daily activities due to illness/infection, 
days on antibiotics, number of hospitalizations due to illness/infection and length of stay (in 
days) and number of acute (urgent or unscheduled) physician visits due to illness/infection will 
be collected as described in Section 9.1.11.2.
9.1.12 Documentation of Screen Failure
Investigators must account for all subjects who sign informed consent.
The primary reason for screen failure should be recorded in the eCRF using the following 
categories:

AE

Did not meet eligibility criteria

Significant protocol deviation

Lost to follow-up

Voluntary withdrawal

Study termination

Other.
Subject identification numbers assigned to subjects who fail screening should not be reused.
9.1.13 Documentation of Study Entrance
Only subjects who meet all of the inclusion criteria and none of the exclusion criteria are eligible 
for entrance into the treatment phase.
If the subject is found to be not eligible for treatment phase, the investigator should record the 
primary reason for failure on the applicable eCRF.
9.2 Monitoring Subject Treatment Compliance
Subjects must be instructed to bring unused study drug and empty/used study drug packaging at
every visit. Drug accountability must be assessed at the container/packaging level for unused 
study drug that is contained within the original tamper-evident sealed container (eg, bottles, 
trays, vials) or at the individual count level for opened containers/packaging. The 
pharmacist/nominated person will record details on the drug accountability form.
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9.3 Schedule of Observations and Procedures
The schedule for all study-related procedures for all evaluations is shown in Appendix A. 
Assessments should be completed at the designated visit/time point(s).
9.3.1 Study Entrance
Informed consent is expected to be obtained at last visit or prior to last visit of 
Study TAK-664-3001. The subjects will undergo screening/baseline procedures for 
determination of eligibility. Baseline can correspond to the EOS Visit of Study TAK-664-3001. 
In such case, the Screening/Baseline Visit and Visit 1 can be on the same day. The following 
procedures will be performed and documented:

Informed consent

Eligibility criteria

Physical examination

Vital signs

Laboratory assessments as per Appendix-Table 2

Assessment of non-drug therapies

Assessment of concomitant medication

Assessment of AEs

Collection/Review of Diary (Diary of Study-TAK-664-3001)

Treatment Preference

Healthcare Resource Utilization.
9.3.2 Treatment Phase
Eligible subjects will receive IGSC, 20% until the commercial IGSC, 20% is available at each 
study site or study termination (estimated duration: approximately 3 years).
The number of infusion visits and study site visits during the SC treatment period will depend on 
where the SC injection is administered. Infusions may be performed at home or at the study site, 
at the investigator’s discretion. The decision where the SC injection is administered is made 
during Study TAK-664-3001, however the location of injection administration can be changed 
based on the investigator’s and subject’s agreement. 
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Subjects should come to the study site for visits when laboratory test samples are to be collected
every 12 weeks. Subjects are not required to come to the study site if all procedures/assessments 
can be performed at home. The following procedures will be performed and documented:

Physical examination
Physical examination will be performed only on subject’s study site visits.

Vital signs
Height will be measured at every 24-week visit starting from Visit 1 and it will not be
required at other visits. Respiratory rate will be measured when the subjects come to study
site, and it will not be required at visits from home. Weight, body temperature, pulse rate,
systolic and diastolic blood pressure will be measured at all visits. At home, these will be
measured with equipment provided by the sponsor and the measurement results should be
recorded in subject diaries.

Laboratory assessments as per Appendix-Table 2

Assessment of non-drug therapies
At Visit 2 or Visit 3, this information will be taken with procedure determined by each
study site (eg, telephone, telemedicine) from subjects at home. At the time of weekly or
biweekly treatment other than site visits, subjects will record this information in subject’s
diary.

Assessment of concomitant medication
At Visit 2 or Visit 3, this information will be taken with procedure determined by each
study site (eg, telephone, telemedicine) from subjects at home. At the time of weekly or
biweekly treatment other than site visits, subjects will record this information in subject’s
diary.

Assessment of AEs
At Visit 2 or Visit 3, this information will be taken with procedure determined by each
study site (eg, telephone, telemedicine) from subjects at home. At the time of weekly or
biweekly treatment other than site visits, subjects will record this information in subject’s
diary.

Collection/Review of diary
During the study site visit and home visit, the investigator or designee will inquire about
subject diaries for pages of changes in subject’s condition, administration status (including
healthcare resource utilization) and vital sign results. Subject diaries will be collected when
the subjects visit the study sites.

Administration of study drug
Infusions may be performed at home or at the study site, at the investigator’s discretion
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
Healthcare Resource Utilization.
At Visit 2 or Visit 3, this information will be taken with procedure determined by each
study site (eg, telephone, telemedicine) from subjects at home. At the time of weekly or
biweekly treatment other than site visits, subjects will record this information in subject’s
diary.
9.3.3 End of Study Visit or Early Termination
The following procedures will be performed and documented:

Physical examination

Vital signs

Laboratory assessments

Assessment of non-drug therapies

Assessment of concomitant medication

Assessment of AEs

Collection/Review of diary

Treatment Preference

Healthcare Resource Utilization.
For all subjects receiving study drug, the investigator must complete the EOS eCRF page.
9.3.4 Post Study Care
Study drug will not be available upon completion of the subject’s participation in the study. 
The subject should be returned to the care of a physician and standard therapies as required.
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10. PRETREATMENT EVENTS AND ADVERSE EVENTS
10.1 Definitions
10.1.1 Pretreatment Events
Not applicable.
10.1.2 AEs
An AE is defined as any untoward medical occurrence in a clinical investigation subject 
administered a drug; it does not necessarily have to have a causal relationship with this 
treatment.
An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant 
abnormal laboratory value), symptom, or disease temporally associated with the use of a drug 
whether or not it is considered related to the drug.
10.1.3 Additional Points to Consider for AEs
An untoward finding generally may:

Indicate a new diagnosis or unexpected worsening of a pre-existing condition. (Intermittent
events for pre-existing conditions or underlying disease should not be considered AEs.)

Necessitate therapeutic intervention.

Require an invasive diagnostic procedure.

Require discontinuation or a change in dose of study drug or a concomitant medication.

Be considered unfavorable by the investigator for any reason.
AEs caused by a study procedure (eg, a bruise after blood draw) should be recorded as an AE.
Diagnoses versus signs and symptoms:

Each event should be recorded to represent a single diagnosis. Accompanying signs
(including abnormal laboratory values) or symptoms should NOT be recorded as additional
AEs. If a diagnosis is unknown, sign(s) or symptom(s) should be recorded appropriately as
an AE(s).
Laboratory values:

Changes in laboratory values are only considered to be AEs if they are judged to be
clinically significant (ie, if some action or intervention is required or if the investigator
judges the change to be beyond the range of normal physiologic fluctuation). A laboratory
re-test and/or continued monitoring of an abnormal value or finding are not considered an
intervention. In addition, repeated or additional noninvasive testing for verification,
evaluation or monitoring of an abnormality is not considered an intervention.
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
If abnormal laboratory values are the result of pathology for which there is an overall
diagnosis (eg, increased creatinine in renal failure), the diagnosis only should be reported
appropriately as an AE.
Pre-existing conditions:

Pre-existing conditions (present at the time of signing of informed consent) are considered
concurrent medical conditions and should NOT be recorded as AEs. Baseline evaluations
(eg, laboratory tests, X-rays etc.) should NOT be recorded as AEs unless related to study
procedures. However, if the subject experiences a worsening or complication of such a
concurrent medical condition, the worsening or complication should be recorded
appropriately as an AE (worsening or complication occurs after start of study drug).
Investigators should ensure that the event term recorded captures the change in the
condition (eg, “worsening of…”).

If a subject has a pre-existing episodic concurrent medical condition (eg, asthma, epilepsy)
any occurrence of an episode should only be captured as an AE if the condition becomes
more frequent, serious or severe in nature. Investigators should ensure that the AE term
recorded captures the change in the condition from baseline (eg, “worsening of…”).

If a subject has a degenerative concurrent medical condition (eg, cataracts, rheumatoid
arthritis), worsening of the condition should only be recorded as AE if occurring to a
greater extent to that which would be expected. Investigators should ensure that the AE
term recorded captures the change in the condition (eg, “worsening of…”).
Worsening of AEs:

If the subject experiences a worsening or complication of an AE after any change in study
drug, the worsening or complication should be recorded as a new AE. Investigators should
ensure that the AE term recorded captures the change in the condition (eg, “worsening
of…”).
Changes in intensity of AEs:

If the subject experiences changes in intensity of an AE, the event should be captured once
with the maximum intensity recorded.
Preplanned procedures (surgeries or interventions):

Preplanned procedures (surgeries or therapies) that were scheduled prior to signing of
informed consent are not considered AEs. However, if a preplanned procedure is
performed early (eg, as an emergency) due to a worsening of the pre-existing condition, the
worsening of the condition should be recorded as an AE. Complications resulting from any
planned surgery should be reported as AEs.
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Elective surgeries or procedures:

Elective procedures performed where there is no change in the subject’s medical condition
should not be recorded as AEs, but should be documented in the subject’s source
documents. Complications resulting from an elective surgery should be reported as AEs.
Insufficient clinical response (lack of efficacy):

Insufficient clinical response, efficacy, or pharmacologic action, should NOT be recorded
as an AE. The investigator must make the distinction between exacerbation of pre-existing
illness and lack of therapeutic efficacy.
10.1.4 SAEs
An SAE is defined as any untoward clinical manifestation of signs, symptoms or outcomes 
(whether considered related to study treatment or not at any dose):
1.
Results in DEATH.
2.
Is LIFE-THREATENING.
Note: The term “life-threatening” refers to an event in which the subject was at risk of
death at the time of the event; it does not refer to an event that hypothetically might have
caused death if it were more severe.
3.
Requires inpatient HOSPITALIZATION or prolongation of existing hospitalization.
Note: Hospitalizations that are the result of elective or previously scheduled investigations
procedures or surgery for pre-existing conditions and have not worsened after initiation of
treatment should not be classified as SAEs.
For example, an admission for a previously scheduled ventral hernia repair would not be
classified as an SAE; however, complication(s) resulting from a hospitalization for an
elective or previously scheduled surgery that meet(s) serious criteria must be reported as
SAE(s).
4.
Results in persistent or significant DISABILITY/INCAPACITY.
5.
Leads to a CONGENITAL ANOMALY/BIRTH DEFECT.
6.
Is an IMPORTANT MEDICAL EVENT.
Note: Important medical events that may not result in death, be life-threatening, or require
hospitalization may be considered an SAE when, based upon appropriate medical
judgment, they may jeopardize the subject and may require medical or surgical
intervention to prevent 1 of the outcomes listed in this definition. Examples of such
medical events include:
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
Bronchospasm associated with anaphylaxis requiring intensive treatment in an
emergency room or at home; blood dyscrasias or convulsions that do not result in
inpatient hospitalization; or the development of drug dependency or drug abuse.

Reviewed and confirmed seroconversion for HIV, HAV, HBV, HCV, HEV, or B19V.
Adverse events that fulfill 1 or more of the serious criteria above are also to be considered SAEs 
and should be reported and followed up in the same manner (see Sections 10.2.2 and 10.3).
10.1.5 Unexpected Adverse Event
An unexpected AE is an AE whose nature, severity, specificity, or outcome is not consistent with 
the term, representation, or description used in the RSI. “Unexpected” also refers to the AEs that 
are mentioned in the IB and/or prescribing information as occurring with a class of drugs or as 
anticipated from the pharmacological properties of the product, but are not specifically 
mentioned as occurring with the particular product under investigation.
The expectedness of AEs will be determined by the sponsor using the IGSC, 20% IB and/or 
prescribing information as the RSI. This determination will include considerations such as the 
number of AEs previously observed, but not on the basis of what might be anticipated from the 
pharmacological properties of a product.
10.1.6 Suspected Unexpected Serious Adverse Reaction
A Suspected Unexpected Serious Adverse Reaction (SUSAR) is defined as any suspected 
adverse reaction to study treatment (ie, including active comparators) that is both serious and 
unexpected.
The event(s) must meet all of the following:

Suspected adverse reaction

Serious

Unexpected

Assessed as related to study treatment.
Symptoms of the Disease under study
Symptoms of the disease under study should not be classed as AEs as long as they are within the 
normal day-to-day fluctuation or expected disease progression and are part of the efficacy or 
effectiveness data collected in the study. Significant worsening of symptoms should be recorded 
as an AE.
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Pre-existing conditions prior to randomization or initiation of study medication are described in 
the medical history, and those that manifest with the same severity, frequency, or duration after 
drug exposure, are not be recorded as AEs. However, when there is an increase in the severity, 
duration or frequency of a pre-existing condition, the event must be described on the AE CRF.
10.1.7 Intensity of AEs
The different categories of intensity (severity) are characterized as follows:

Mild: The event is transient and easily tolerated by the subject.

Moderate: The event causes the subject discomfort and interrupts the subject’s usual
activities

Severe: The event causes considerable interference with the subject’s usual activities.
10.1.8 Causality of AEs
An investigator must make the assessment of relationship to study drug for each AE. The 
investigator should decide whether, in his or her medical judgment, there is a reasonable 
possibility that the event may have been caused by the study drug. 
If there is no valid reason for suggesting a relationship, then the AE should be classified as 
“unlikely related” or “not related”. Otherwise, if there is any valid reason, even if undetermined 
or untested, for suspecting a possible cause-and-effect relationship between the study drug and 
the occurrence of the AE, then the AE should be considered “probably related” or “possibly 
related”. The causality assessment must be documented in the source.
The relationship of each AE to study drug will be assessed using the following categories:
In-Text Table 10-1. Relationship of AE to Study Drug
Probably related
The temporal relationship between the event and the administration of the study drug is 
compelling enough and/or follows a known or suspected response pattern to that product, and 
the event cannot be explained by the subject’s medical condition, other therapies, or accident.
Possibly related
Suggests that a reasonable temporal sequence of the event with the study drug administration 
exists and the likely causal association of the event with the study drug. This will be based 
upon the known pharmacological action of the study drug, known or previously reported 
adverse reactions to the study drug or class of drugs, or judgment based on the investigator’s 
clinical experience.
Unlikely related
Suggests that the clinical picture is highly consistent with a cause other than the study drug, 
but attribution cannot be made with absolute certainty and a relationship between the study 
drug and adverse event cannot be excluded with complete confidence.
Not related
The event can be readily explained by other factors such as the subject’s underlying medical 
condition, concomitant therapy, or accident and no plausible temporal or biologic relationship 
exists between the study drug and the event.
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10.1.9 Relationship to Study Procedures
Relationship (causality) to study procedures should be determined for all AEs.
The relationship should be assessed as Related if the investigator considers that there is 
reasonable possibility that an event is due to a study procedure. Otherwise, the relationship 
should be assessed as Not Related. 
10.1.10 Start Date
The start date of the AE is the date that the first signs/symptoms were noted by the subject and/or 
investigator.
The start date of AEs will be determined using the following criteria:
In-Text Table 10-2. Criteria for Start Date of Adverse events
Adverse events
Start Date
Any signs/symptoms/diseases (diagnosis)
The date that the first signs/symptoms/diseases were noted by the 
subject and/or the investigator should be recorded.
Asymptomatic diseases
The date when examination was performed for diagnosis and 
diagnosis was confirmed should be recorded.
The date when diagnosis was confirmed should also be recorded even 
when values or findings showed previous values or findings or the 
onset time can be estimated.
Worsening or complication of concurrent 
medical conditions or any 
signs/symptoms/diseases before 
treatment
The date that a worsening or complication of the condition was noted 
first by the subject and/or the investigator should be recorded.
The examination after start of the study 
drug showed abnormal values/findings
The date of examination when an abnormal value or findings that was 
judged to be clinically significant was noted should be recorded.
The examination at the start of the study 
drug showed abnormal values/findings 
and the subsequent examinations showed 
worsening of the symptoms
The date of examination when apparent elevation, reduction, increase 
or decrease was confirmed in judgment according to the trends in 
those values or findings should be recorded.
10.1.11 Stop Date 
The stop date of the AE is the date at which the subject recovered, the event resolved but with 
sequelae or the subject died.
10.1.12 Frequency 
Episodic AEs (eg, vomiting) or those which occur repeatedly over a period of consecutive days 
are intermittent. All other events are continuous.
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10.1.13 Action Concerning Study Drug 

Drug withdrawn – a study drug is stopped due to the particular AE.

Dose not changed – the particular AE did not require stopping a study drug.

Unknown – only to be used if it has not been possible to determine what action has been
taken.

Not Applicable – a study drug was stopped for a reason other than the particular AE eg, the
study has been terminated, the subject died, dosing with study drug was already stopped
before the onset of the AE.

Dose Reduced – the dose was reduced due to the particular AE.

Dose Increased – the dose was increased due to the particular AE.

Dose Interrupted – the dose was interrupted due to the particular AE.
10.1.14 Outcome

Recovered/Resolved – subject returned to first assessment status with respect to the AE.

Recovering/Resolving – the intensity is lowered by 1 or more stages: the diagnosis or
signs/symptoms has almost disappeared; the abnormal laboratory value improved but has
not returned to the normal range or to baseline; the subject died from a cause other than the
particular AE with the condition remaining “recovering/resolving”.

Not recovered/not resolved – there is no change in the diagnosis, signs or symptoms; the
intensity of the diagnosis, signs/symptoms or laboratory value on the last day of the
observed study period has got worse than when it started; is an irreversible congenital
anomaly; the subject died from another cause with the particular AE state remaining “Not
recovered/not resolved”.

Resolved with sequelae – the subject recovered from an acute AE but was left with
permanent/significant impairment (eg, recovered from a cardiovascular accident but with
some persisting paresis).

Fatal – the AEs which are considered as the cause of death.
Any SAE that results in the subject’s death (eg, the SAE was noted as the primary
cause of death) must have fatal checked as an outcome with the date of death
recorded as the resolution date. For all other events ongoing at the time of death that
did not contribute to the subject’s death, the outcome should be considered not
resolved, without a resolution date recorded.
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For any SAE that results in the subject’s death or any ongoing events at the time of
death, unless another study drug (IGSC, 20%) action was previously taken (eg, drug
interrupted, reduced, withdrawn), the action taken with the study drug (IGSC, 20%)
should be recorded as “dose not changed” or “not applicable” (if the subject never
received study drug [IGSC, 20%]). The study drug action of withdrawn should not be
selected solely as a result of the subject’s death.

Unknown – the course of the AE cannot be followed up due to hospital change or
residence change at the end of the subject’s participation in the study.
10.2 Procedures
10.2.1 Collection and Reporting of AEs
10.2.1.1 AE Collection Period
Collection of AEs will commence from the time that the subject is first administered study drug. 
Routine collection of AEs will continue until EOS/Early Termination Visit. All AEs must be 
followed until closure (the subject’s health has returned to his/her baseline status or all variables 
have returned to baseline) or until 30 days after EOS/Early Termination Visit, whichever comes 
first. Closure indicates that an outcome is reached, stabilization achieved (the investigator does 
not expect any further improvement or worsening of the event), or the event is otherwise 
explained.
Clinical Laboratory and Other Safety Assessment
A change in the value of a clinical laboratory parameter or vital sign measure, can represent an 
AE if the change is clinically relevant or if, during administration of study drug, a shift of a 
parameter is observed from a value in the normative range to a value that is outside the normal 
range and considered clinically significant, or a further waning of an already clinically 
significant value. When evaluating such changes, the extent of deviation from the reference 
range, the duration until return to the reference range, either while continuing administration or 
after the end of administration of the study drug, and the range of variation of the respective 
parameter within its reference range, should also be considered.
If, at the end of the treatment phase, there are abnormal clinical laboratory (such as hematology 
panel or clinical chemistry panel), vital sign, which were not present at the start of study 
treatment, further investigations should be performed until the values return to within the 
reference range or until a plausible explanation (eg, concomitant disease or expected disease 
evolution) is found for the abnormal values.
The investigator should assess, based on the above criteria and the clinical condition of the 
subject, whether a change in a clinical laboratory value, or vital sign parameter is clinically 
significant and represents an AE.
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10.2.1.2 AE Reporting
At each study visit, the investigator will assess whether any subjective AEs have occurred. A 
neutral question, such as “How have you been feeling since your last visit?” may be asked. 
Subjects may report AEs occurring at any other time during the study. 
All subjects experiencing AEs, whether considered associated with the use of the study drug or 
not, must be monitored until the symptoms subside and any clinically relevant changes in 
laboratory values have returned to baseline or until 30 days after EOS/Early Termination Visit. 
All AEs will be documented in the AE page of the eCRF, whether or not the investigator 
concludes that the event is related to the drug treatment. The following information will be 
documented for each event:

Event term.

Start and stop date.

Frequency.

Intensity.

Investigator’s opinion of the causal relationship between the event and administration of
study drug(s) (probably related, possibly related, unlikely related, or not related).

Investigator’s opinion of the causal relationship to study procedure(s), including the details
of the suspected procedure.

Action concerning study drug.

Outcome of event.

Seriousness.
10.2.2 Collection and Reporting of SAEs
When an SAE occurs through the AE collection period, it should be reported according to the 
following procedure:
An SAE should be reported by the investigator to the sponsor/the Emergency Reception Center 
for Safety Information (ERCSI) (see Appendix F) within 24 hours/1 business day of the SAE 
occurrence, along with any relevant information. The investigator should submit the detailed 
Safety Report Form to the sponsor/the ERCSI appropriate personnel within 10 calendar days. 
The information should be completed as fully as possible but contain, at a minimum:
A short description of the event and the reason why the event is categorized as serious.

Subject identification number.
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
Investigator’s name.

Name of the study drug(s).

Causality assessment.
The investigator should submit the original copy of the Safety Report Form to the sponsor
(Note: Source documents are not to be sent unless requested).
Any SAE spontaneously reported to the investigator following the AE collection period should 
be reported to the sponsor if considered related to study participation.
10.3 Follow-up of SAEs
If information not available at the time of the first report becomes available at a later date, the 
investigator should complete a follow-up Safety Report Form (copy) or provide other written 
documentation and fax it immediately. Copies of any relevant data from the hospital notes 
(eg, laboratory tests, discharge summary, postmortem results) should be sent to the addressee, if 
requested.
All SAEs should be followed up until resolution or permanent outcome of the event. The 
timelines and procedure for follow-up reports are the same as those for the initial report.
10.3.1 Safety Reporting to Investigators, IRBs, and Regulatory Authorities
The sponsor will be responsible for reporting all SUSARs and any other applicable SAEs to 
regulatory authorities, investigators, and IRBs, as applicable. 
Relative to the first awareness of the event by/or further provision to the sponsor or sponsor’s 
designee, SUSARs will be submitted to the regulatory authorities as expedited report within 
7 days for fatal and life-threatening events and 15 days for other serious events, unless otherwise 
required by national regulations. The sponsor will also prepare an expedited report for other 
safety issues where these might materially alter the current benefit-risk assessment of a study 
drug/sponsor-supplied drug or that would be sufficient to consider changes in the study 
drug/sponsor-supplied drug administration or in the overall conduct of the trial. The study site 
also will forward a copy of all expedited reports to his or her IRB.
11. STUDY-SPECIFIC COMMITTEES
No steering committee, data safety monitoring committee, or clinical endpoint committee will be
used in this study.
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12. DATA HANDLING AND RECORD KEEPING
The full details of procedures for data handling will be documented in the Data Management
Plan. Adverse events, medical history, and concurrent medical conditions will be coded using the
Medical Dictionary for Regulatory Activities (MedDRA). Drugs will be coded using the WHO
Drug Dictionary.
12.1 CRFs
Completed eCRFs are required for each subject who signs an informed consent.
A subject diary will be provided to each subject at enrollment to record the information. The 
subject diary will serve as a source record and remain at the study site. Entries in the subject 
diaries will be transcribed or entered into the appropriate collection device. Any entry on the 
eCRF that does not correspond with an entry in the subject diary will be explained by the 
investigator in source documentation.
The sponsor or its designee will supply study sites with access to eCRFs. The sponsor will make 
arrangements to train appropriate study site staff in the use of the eCRF. These forms are used to 
transmit the information collected in the performance of this study to the sponsor and regulatory 
authorities. Electronic CRFs must be completed in English.
After completion of the entry process, computer logic checks will be run to identify items, such 
as inconsistent dates, missing data, and questionable values. Queries may be issued by Takeda 
personnel (or designees) and will be answered by the site. 
Corrections to eCRFs are recorded in an audit trail that captures the old information, the new 
information, identification of the person making the correction, the date the correction was made, 
and the reason for change. Reasons for significant corrections should additionally be included. 
All new additions are to be made with the date and sign.
The principal investigator must review the eCRFs for completeness and accuracy and must sign 
and date the appropriate eCRFs as indicated. Furthermore, the investigator must retain full 
responsibility for the accuracy and authenticity of all data entered on the eCRFs.
After the lock of the study database, any change of, modification of or addition to the data on the 
eCRFs should be made by the investigator with use of change and modification records of the 
eCRFs (Data Clarification Form) provided by the sponsor. The principal investigator must 
review the data change for completeness and accuracy, and must sign, or sign and seal, and date.
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Electronic CRFs will be reviewed for completeness and acceptability at the study site during 
periodic visits by the sponsor or its designee. The sponsor or its designee will be permitted to 
review the subject’s medical and hospital records pertinent to the study to ensure accuracy of the 
eCRFs. The completed eCRFs are the sole property of the sponsor and should not be made 
available in any form to third parties, except for authorized representatives of appropriate 
governmental health or regulatory authorities, without written permission of the sponsor. 
12.2 Record Retention
The investigator and the head of the study site agree to keep the records stipulated in 
Section 12.1 and those documents that include (but are not limited to) the study-specific 
documents, the identification log of all participating subjects, medical records, all original signed 
and dated informed consent forms (ICFs), electronic copy of CRFs, including the audit trail, and 
detailed records of drug disposition to enable evaluations or audits from regulatory authorities, 
the sponsor or its designees. 
The investigator and the head of the study site are required to retain essential relevant documents 
until the day specified as 1) or 2) below, whichever comes later. However, if the sponsor 
requests a longer time period for retention, the head of the study site should discuss how long 
and how to retain those documents with the sponsor. 
1)
The day on which marketing approval of the study drug is obtained (or the day 3 years
after the date of notification in the case that the investigation is discontinued).
2)
The day 3 years after the date of early termination or completion of the study.
In addition, the investigator and the head of the study site should retain the essential relevant 
documents until the receipt of a sponsor-issued notification to state the retention is no longer 
required. 
Since the investigational drug (IGSC, 20%) in this study is equivalent to the specified biological 
products, the records regarding the administration of IGSC, 20% at the study sites must be 
maintained for 20 years according to the regulation of the product of specified biological 
products “Explanation of the use of specified biological products to the target person and 
records and preservation of specified biological products” (Pharmaceutical Affairs No. 0515012 
May 15, 2003).
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13. STATISTICAL METHODS
13.1 Statistical and Analytical Plans
A statistical analysis plan (SAP) will be prepared and finalized prior to database lock. This
document will provide further details regarding the definition of analysis variables and analysis
methodology to address all study objectives. Specifications for the corresponding tables, figures,
and listings (TFLs) will be provided separately, in the study TFL shells document.
Continuous endpoints/outcome measures (eg, change from baseline) will be summarized using 
the following descriptive statistics: number of subjects (n), mean, median, standard deviation, 
minimum value, maximum value. Categorical endpoints/outcome measures (eg, AEs) will be 
summarized in terms of number and percent of subjects and number of occurrences in each 
category.
13.1.1 Analysis Sets

All-Treated Set: All enrolled subjects who received IGSC, 20% administration at least
once in this study, this will be efficacy analysis set.

Safety Analysis Set (SAS): All enrolled subjects who received at least 1 dose of study drug
(IGIV) in TAK-664-3001 study, this will be SAS.
13.1.2 Analysis of Demographics and Other Baseline Characteristics
Demographic and other baseline characteristics will be summarized descriptively. As noted 
above, the analysis process will be detailed in the study SAP, meaning the study SAP will 
provide a technical and detailed elaboration of the analyses of study endpoints and further 
document the planned summary of other study information, including but is not limited to: 
subject disposition, demographics and baseline characteristics, exposure to study drug, and prior 
and concomitant medications.
13.1.3 Safety Analysis
Safety analysis will be performed using the SAS.
The primary objective of the study is to assess the long-term safety and tolerability. Safety and 
tolerability endpoints (defined in Sections 5.2.1 and 5.2.2) will be analyzed using descriptive 
statistics.
For laboratory and vital sign analyses, baseline will be defined as the last non-missing value 
before the time of participation in the TAK-664-3001 study.
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13.1.3.1 Analysis of Adverse Events
13.1.3.1.1 Definitions
Treatment emergent adverse events are defined as AEs with onset after date/time of first dose of 
study drug (IGIV) in Study TAK-664-3001, or medical conditions present prior to the start of 
study drug (IGIV) in Study TAK-664-3001 but increased in severity or relationship after 
date/time of first dose of study drug (IGIV) in Study TAK-664-3001.
Related TEAEs are defined as causally related TEAEs.
13.1.3.1.2 Handling of Recurrent AEs and Other AE situations
Multiple Severities and Relationships: For subject with multiple severities of the same AE, the 
maximum severity (most serious severity) will be used in analysis, and similarly with multiple 
relationships of the same AE, the worst relationship will be used.
Related AEs: Any AE that is recorded as “probably related” or “possibly related” to study drug 
will be considered a “related” AE, and any AE recorded as “unlikely related” or “not related” 
will be considered an “unrelated” AE.
Recurrent AEs: If more than 1 AE occurs within the same Preferred Term (PT) for the same 
subject, then the subject will be counted only once for that PT using the most severe and most 
related occurrence for the summarization by severity and by relationship to the study drug. For 
example, if a subject experienced a mild headache not related to the study drug, and a moderate 
headache related to the study drug, then the subject will be counted once for headache using the 
moderate headache related to the study drug.
Details on data handling conventions will be provided in the study SAP.
13.1.3.1.3 Occurrence and Numbers of Adverse Events
All AEs will be summarized by MedDRA System Organ Class (SOC) and PT. Only TEAEs will 
be analyzed. 
Note: Hereafter, TEAE and AE are used interchangeably. 
The following summaries will be provided:

Number and percentage of subjects with TEAEs by SOC and PT, and overall

Number of TEAEs by SOC and PT, and overall

These summaries will be repeated by severity and relationship
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The following approaches will be used, where applicable:

Overall summary: Overall summary will include, but not limited to: Any TEAE, local
TEAE, systemic TEAE, related TEAE, unrelated TEAE, severe TEAE, severe related
TEAE, serious TEAE, serious related TEAE, TEAE leading to discontinuation from study,
infusion-associated TEAE and any TEAE leading to death.

Summaries by SOC and PT: In the summaries, SOC will be sorted alphabetically, and PT
will be sorted within each SOC in descending frequency.

Summaries by PT only: In the summaries, PT will be sorted in decreasing frequency.

In AE incidence summaries, subjects with multiple events in the same category will be
counted only once in the AE category. Subjects with events in more than 1 category will be
counted once in each of the categories.

In AE count summaries, multiple occurrences of the same AE will be counted multiple
times.
13.1.3.1.4 Adverse Events per Infusion, per Subject, per Subject-Year
The following summaries will be provided: 

Number of AEs per infusion, by SOC and PT

Number of AEs per subject, by SOC and PT

Number of AEs per subject-year (SY), by SOC and PT
Per infusion is the number of events divided by total number of infusions administered; per 
subject is the number of events divided by total number of subjects; per SY is number of events 
divided by total number of days of exposure, converted into years.
Adverse events per SY summary adjusts for differences in subjects’ durations in the study. 
For number of AEs, multiple occurrences of the same AE in the same subject will be counted 
multiple times.
Number of AEs, AEs per SY, and AEs per 1000 SYs will be provided for all AEs (if analyzable), 
by primary SOC and PT. 
The following calculations apply, where applicable:

AEs per infusion = number of AEs/total number of infusions administered to subjects in
the analysis set.

AE per subject = number of AEs/total number of subjects in the analysis set.
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
AEs per SY = number of AEs/total number of days of exposure, ie., the sum of duration of
treatment for all subjects in the analysis set, converted into years.

AEs per 1000 SYs = 1000 × (Total Number of AEs in the study for all subjects/Total SYs
in the study).
Total SYs will be calculated by summing subjects’ durations in the study. Each subject’s 
duration will be calculated as: (last date in study – date of initial dose of study drug in this 
study)/365.25. If the subject’s last date is missing, then the date of last dose of study drug will be 
used if available.
13.1.3.1.5 Tolerability
The following summaries will be provided:

Number (percentage) of subjects for whom the infusion rate was reduced for tolerability
concerns or for AEs

Number (percentage) of subjects for whom the infusion was interrupted for tolerability
concerns or for AEs

Number (percentage) of subjects for whom the infusion was stopped for tolerability
concerns or for AEs

Number (percentage) of subjects for whom the infusion rate was reduced or interrupted or
stopped for tolerability concerns or for AEs.
13.1.3.2 Clinical Laboratory Data
Raw (actual) values and change from baseline in clinical laboratory tests and vital signs will be 
summarized at each post-baseline assessment time point as continuous variables.
Shift from baseline (shift table) to each post-baseline assessment time point will be provided for 
laboratory categorical variables. 
Summaries of shift from baseline will be produced for each laboratory parameter that has a 
reference range, using the categories: low (below the lower limit of the reference range), normal 
(within the reference range), high (above the upper limit of the reference range), and missing.
Missing data will not be imputed.
13.1.3.3 Vital Signs
Raw (actual) values and change from baseline in vital sign tests will be summarized at each 
post-baseline assessment time point as continuous variables.
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13.1.4 Serum IgG Concentrations
Serum IgG concentrations will be summarized using descriptive statistics which will also include 
geometric mean and the corresponding 2-sided 95% confidence interval. Confidence intervals
are for descriptive purposes. Caution should be exhibited in their interpretation as this study is 
not designed for hypothesis testing.
13.1.5 Efficacy Analysis
Efficacy analysis will be performed using the All-Treated Set. Assessment of efficacy is a 
secondary objective of the study. Efficacy endpoints are:

Annual rate of validated ASBI per subject

Annual rate of all infections per subject

Health Resource Utilization

Days not able to attend school/work or to perform normal daily activities due to
illness/infection

Days on antibiotics

Number of hospitalizations due to illness/infection and length of stay (in days)

Number of acute (urgent or unscheduled) physician visits due to illness/infection.
Efficacy endpoint data will be analyzed using descriptive statistics.
13.1.6 Other Analyses
13.1.6.1 Treatment Preference Analyses
Treatment preference data will be listed in the subject data listing(s). The following endpoint will 
be analyzed using descriptive statistics, as planned for the efficacy endpoints.

Treatment Preference (EOS/Early Termination).
Endpoint details will be provided in the study SAP.
13.2 Interim Analysis 
An interim analysis of study data will be undertaken to support the Japanese New Drug 
Application submission as described below. 
It will summarize PK (Serum IgG trough levels), safety, efficacy, and tolerability of treatment 
with IGSC, 20% in all subjects with PID in this study. The snapshot date will be stated in the 
SAP. The target data will be all subject data obtained at snapshot date in this study. No adaptive 
design or data monitoring committee is planned for this study.
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13.3 Determination of Sample Size
No formal sample size calculation has been performed in this extension study. A sample size of 
approximately 16 subjects is the estimated maximal number of subjects who can enroll from the 
previous TAK-664-3001 study.
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14. QUALITY CONTROL AND QUALITY ASSURANCE
14.1 Study Site Monitoring Visits
The study monitor is responsible for ensuring and verifying that each study site conducts the
study according to the protocol, standard operating procedures, other written
instructions/agreements, International Council for Harmonisation (ICH) GCP, and applicable
regulatory guidelines/requirements. The investigator will permit the study monitor to visit the
study site at appropriate intervals, as described in the Clinical Study Agreement. Monitoring
processes specific to the study will be described in the clinical monitoring plan.
Alternative Approaches to Monitoring Due to Coronavirus Disease-2019 (COVID-19) or Other 
Unavoidable Circumstances
In unavoidable circumstances (eg, a widespread disease outbreak or natural disaster) that impact 
study procedures, data monitoring may be conducted remotely. The Remote Monitoring strategy 
is provided in the Clinical Operation Plan.
14.2 Protocol Deviations
The investigator may deviate from the protocol to eliminate an apparent immediate hazard to the 
subject. In the event(s) of an apparent immediate hazard to the subject, the investigator will 
notify the sponsor immediately by phone and confirm notification to the sponsor in writing as 
soon as possible, but within 1 calendar day after the change is implemented. The sponsor will 
also ensure the responsible IRB is notified of the urgent measures taken in such cases according 
to local regulations. 
If monitoring and/or auditing identify serious and/or persistent non-compliance with the 
protocol, the sponsor may terminate the investigator’s participation. The sponsor will notify the 
IRB and applicable regulatory authorities of any investigator termination.
14.3 Quality Assurance Audits and Regulatory Agency Inspections
The sponsor and/or sponsor’s representatives may conduct audits to evaluate study conduct and 
compliance with the protocol, standard operating procedures, other written 
instructions/agreements, ICH GCP, and applicable regulatory guidelines/requirements. The 
investigator will permit auditors to visit the study site, as described in the Clinical Study 
Agreement. Auditing processes specific to the study will be described in the auditing plan.
To ensure compliance with relevant regulations, data generated by this study must be available 
for inspection upon request by representatives of, for example, the Pharmaceuticals and Medical 
Devices Agency of Japan, other regulatory authorities, the sponsor or its representatives, and the 
IRB for each site.
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15. ETHICAL ASPECTS OF THE STUDY
This study will be conducted with the highest respect for the individual participants (ie, subjects)
according to the protocol, the ethical principles that have their origin in the Declaration of
Helsinki, and the ICH Harmonised Tripartite Guideline for GCP. Each investigator will conduct
the study according to applicable local or regional regulatory requirements and align his or her
conduct in accordance with the “Responsibilities of the Investigator” that are listed in
Appendix B. The principles of Helsinki are addressed through the protocol and through
appendices containing requirements for informed consent and investigator responsibilities.
15.1 IRB Approval
Institutional Review Boards must be constituted according to the applicable local requirements 
of each participating region. The sponsor or designee will require documentation noting all 
names and titles of members who make up the respective IRB. If any member of the IRB has 
direct participation in this study, written notification regarding his or her abstinence from voting 
must also be obtained.
The sponsor or designee will supply relevant documents for submission to the respective IRB for 
the protocol’s review and approval. This protocol, the IB, a copy of the ICF, and, if applicable, 
subject recruitment materials and/or advertisements and other documents required by all 
applicable laws and regulations, must be submitted to a central or local IRB or ethics committee 
for approval. The IRB’s written approval of the protocol and subject informed consent must be 
obtained and submitted to the sponsor or designee before commencement of the study (ie, before 
shipment of the sponsor-supplied drug or study-specific screening activity/signing a contract for 
the clinical study). The IRB approval must refer to the study by exact protocol title, number, and 
version date; identify versions of other documents (eg, ICF) reviewed; and state the approval 
date. The sponsor will notify the study site once the sponsor has confirmed the adequacy of study 
site regulatory documentation. Until the study site receives notification no protocol activities, 
including screening may occur.
Study sites must adhere to all requirements stipulated by their respective IRB. This may include 
notification to the IRB regarding protocol amendments, updates to the ICF, recruitment materials 
intended for viewing by subjects, local safety reporting requirements, reports and updates 
regarding the ongoing review of the study at intervals specified by the respective IRB, and 
submission of the investigator’s final status report to IRB. All IRB approvals and relevant 
documentation for these items must be provided to the sponsor or its designee.
Subject incentives should not exert undue influence for participation. Payments to subjects must 
be approved by the IRB and sponsor.
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15.2 Subject Information, Informed Consent, and Subject Authorization
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
applicable laws and regulations. The ICF, subject authorization form (if applicable), and subject 
information sheet (if applicable) describe the planned and permitted uses, transfers, and 
disclosures of the subject’s personal and personal health information for purposes of conducting 
the study. The ICF and the subject information sheet (if applicable) further explain the nature of 
the study, its objectives, and potential risks and benefits, as well as the date informed consent is 
given. The ICF will detail the requirements of the participant and the fact that he or she is free to 
withdraw at any time without giving a reason and without prejudice to his or her further medical 
care.
The investigator is responsible for the preparation, content, and IRB approval of the ICF and if 
applicable, the subject authorization form. The ICF, subject authorization form (if applicable), 
and subject information sheet (if applicable) must be approved by both the IRB and the sponsor 
prior to use.
The ICF, subject authorization form (if applicable), and subject information sheet (if applicable) 
must be written in a language fully comprehensible to the prospective subject. It is the 
responsibility of the investigator to explain the detailed elements of the ICF, subject 
authorization form (if applicable), and subject information sheet (if applicable) to the subject. 
Information should be given in both oral and written form whenever possible and in the manner 
deemed appropriate by the IRB. In the event the subject is not capable of rendering adequate 
written informed consent, then the subject’s legally acceptable representative may provide such 
consent for the subject in accordance with applicable laws and regulations.
The subject, or the subject’s legally acceptable representative, must be given ample opportunity 
to: (1) inquire about details of the study and (2) decide whether or not to participate in the study. 
If the subject, or the subject’s legally acceptable representative, determines he or she will 
participate in the study, then the ICF and subject authorization form (if applicable) must be 
signed and dated by the subject, or the subject’s legally acceptable representative, at the time of 
consent and prior to the subject entering into the study. The subject or the subject’s legally 
acceptable representative should be instructed to sign using their legal names, not nicknames, 
using blue or black ballpoint ink. The investigator must also sign and date the ICF and subject 
authorization (if applicable) at the time of consent and prior to subject entering into the study.
Once signed, the original ICF, subject authorization form (if applicable), and subject 
information sheet (if applicable) will be stored in the investigator’s site file. The investigator 
must document the date the subject signs the informed consent in the subject’s medical record. 
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Copies of the signed ICF, the signed subject authorization form (if applicable), and subject 
information sheet (if applicable) shall be given to the subject.
All revised ICFs must be reviewed and signed by relevant subjects or the relevant subject’s 
legally acceptable representative in the same manner as the original informed consent. The date 
the revised consent was obtained should be recorded in the subject’s medical record, and the 
subject should receive a copy of the revised ICF.
15.3 Subject Confidentiality
The sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this study, a subject’s source data will only be linked to 
the sponsor’s clinical trial database or documentation via a subject identification number. As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, age, or 
date of birth may be used to verify the subject and accuracy of the subject’s identification 
number.
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the 
sponsor requires the investigator to permit the monitor or the sponsor’s designee, representatives 
from any regulatory authority (eg, Pharmaceuticals and Medical Devices Agency), the sponsor’s 
designated auditors, and the appropriate IRBs to review the subject’s original medical records 
(source data or documents), including, but not limited to, laboratory test result reports, admission 
and discharge summaries for hospital admissions occurring during a subject’s study 
participation, and autopsy reports. Access to a subject’s original medical records requires the 
specific authorization of the subject as part of the informed consent process (see Section 15.2).
Copies of any subject source documents that are provided to the sponsor must have certain 
personally identifiable information removed (ie, subject name, address, and other identifier fields 
not collected on the subject’s eCRF).
15.4 Publication, Disclosure, and Clinical Trial Registration Policy
15.4.1 Publication and Disclosure
The investigator is obliged to provide the sponsor with complete test results and all data derived 
by the investigator from the study. During and after the study, only the sponsor may make study 
information available to other study investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the study site agreement, any public 
disclosure (including publicly accessible websites) related to the protocol or study results, is the 
sole responsibility of the sponsor.
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The sponsor may publish any data and information from the study (including data and 
information generated by the investigator) without the consent of the investigator. 
The investigator needs to obtain a prior written approval from the sponsor to publish any 
information from the study externally such as to a professional association.
15.4.2 Clinical Trial Registration
In order to ensure that information on clinical trials reaches the public in a timely manner and to 
comply with applicable laws, regulations and guidance, Takeda will, at a minimum register all 
interventional clinical trials it sponsors anywhere in the world on ClinicalTrials.gov and/or other 
publicly accessible websites before start of study, as defined in Takeda Policy/Standard. Takeda 
contact information, along with facility name, investigator’s city, state (for Americas 
investigators), country, and recruiting status will be registered and available for public viewing.
For some registries, Takeda will assist callers in locating study sites closest to their homes by 
providing the investigator name, address, and phone number to the callers requesting trial 
information. Once subjects receive investigator contact information, they may call the study site 
requesting enrollment into the trial. The investigative sites are encouraged to handle the trial 
inquiries according to their established subject screening process. If the caller asks additional 
questions beyond the topic of trial enrollment, they should be referred to the sponsor.
Any investigator who objects to the sponsor providing this information to callers must provide 
the sponsor with a written notice requesting that their information not be listed on the registry 
site. 
15.4.3 Clinical Trial Results Disclosure
Takeda will post the results of clinical trials on ClinicalTrials.gov and/or other publicly 
accessible websites, as required by Takeda Policy/Standard, applicable laws and/or regulations.
15.5 Insurance and Compensation for Injury
Each subject in the study must be insured in accordance with the regulations applicable to the 
study site where the subject is participating. If a local underwriter is required, then the sponsor or 
sponsor’s designee will obtain clinical study insurance against the risk of injury to study 
subjects. Refer to the study site agreement regarding the sponsor’s policy on subject 
compensation and treatment for injury. If the investigator has questions regarding this policy, 
he or she should contact the sponsor or sponsor’s designee.
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APPENDIX G. PROTOCOL HISTORY
Document
Date
Global/Country/Site Specific
Protocol Amendment 3.0
28 Nov 2022
Japan
Protocol Amendment 2.0
19 Jul 2022
Japan
Protocol Amendment 1.0
02 Nov 2021
Japan
Original Protocol
18 Jan 2021
Japan
Summary of Changes Protocol Amendment 2.0
Protocol Amendment
Summary of Changes Since the Last Version of the Approved Protocol
Protocol Amendment
2.0
Amendment Date
19 Jul 2022
Japan
Description of Change
Rationale for Change
Section(s) Affected by Change
Relationship of adverse event to 
study drug.
The order and definitions for 
probably related and possibly 
related updated in order to clarify 
strength of relationship of adverse 
event to study drug.
Section 2
Section 5.2.1
Section 10.1.8
In-Text Table 10-1
Section 10.2.1.2
Section 13.1.3.1.2
Investigational device term was 
replaced with device-used-in-clinical-
trial
To ensure consistency due to the 
modification of Japanese GCP
Section 2
Section 7.2
A new section for description of 
‘Device-used-in-clinical-trial’ is 
added.
The section also includes information 
regarding reporting of device related 
defects.
Due to the modification of 
Japanese GCP, information 
required for the ‘Device-used-in-
clinical-trial’ is added.
Section 8.3
The study schema is updated
To indicate home visits
Section 2
Section 6.1
The following revision was done:
Infusions may be performed at home 
or at the study site, at the 
investigator’s discretion. 
To allow administration of 
investigation product at home or 
study site.
Section 2
Section 6.1
Section 9.3.2
Appendix-Table 1 Schedule of 
Study Procedures
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Protocol Amendment
Summary of Changes Since the Last Version of the Approved Protocol
Protocol Amendment
2.0
Amendment Date
19 Jul 2022
Japan
Description of Change
Rationale for Change
Section(s) Affected by Change
The following revision was done:
Subjects should come to the study 
sites for visits when laboratory test 
samples are to be collected every 
12 weeks. Subjects are not required 
to come to the study site if all 
procedures/assessments can be 
performed at home.
Allow some visits to be done at 
subject’s home without visiting 
the study site.
Section 2
Section 6.1
Section 9.3.2
Appendix-Table 1 Schedule of 
Study Procedures
The following sentence was amended 
to:
The decision where the SC injection is 
administered is made during the Study 
TAK-664-3001, however the location 
of injection administration can be 
changed based on the Investigator’s 
and subject’s agreement
Statement added to provide 
flexibility to change the location 
of injection administration
Section 2
Section 6.1
Section 9.3.2
Appendix-Table 1 Schedule of 
Study Procedures
Added ‘body weight’ in the below 
sentence:
“The dose can be modified based on 
subject’s IgG level/condition/body 
weight”
To clarify ‘body weight’, is to be 
taken into consideration while 
calculating the dose.
Section 8.1.3
The following sentence is added:
“The site may use an alternative 
method for dispensing. If permitted 
by country or local regulations and 
IRBs, the IP can be shipped from the 
site directly to the subject’s home 
address. Subjects must be provided 
with instructions on how to receive, 
store, and ultimately return the 
IP/sponsor-supplied treatments.”
Statement added for clarifying 
provision of IP to subject’s home.
Section 8.4
The following sentences were added 
in Section 9.1.4
Vital signs can be measured at 
subject’s home as described in 
Section 9.3.2.
Vital signs at home will be recorded 
in subject diary and will be reviewed 
by investigators.
To specify what will be done 
during home visits.
Section 9.1.4
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Protocol Amendment
Summary of Changes Since the Last Version of the Approved Protocol
Protocol Amendment
2.0
Amendment Date
19 Jul 2022
Japan
Description of Change
Rationale for Change
Section(s) Affected by Change
The following statement was added 
in Section 9.1.5:
This information can be taken from 
subjects at home by the procedure 
determined by each study site (eg, 
telephone, telemedicine to subject’s 
home) as described in Section 9.3.2.
Statement added to clarify how 
information on intake of 
concomitant medication should be 
obtained during home visit.
Section 9.1.5
Visit 1 was added to the following 
statement
Laboratory tests including assessment 
of IgG trough levels will be 
performed every 12 weeks from 
Visit 1
To clarify timing of laboratory 
testing
Section 9.1.7
Visit 1 was added to the following 
statement
Hemolysis test will be done every 
24 weeks from Visit 1.
To clarify timing of hemolysis 
testing
Section 9.1.7.4
Text added for physical examination, 
vital signs, assessment of non-drug 
therapies, assessment of concomitant 
medications, assessment of AEs, 
collection/review of diary, 
administration of study drug, and 
healthcare resource utilization 
To specify what will be done 
during site and home visits.
Section 9.3.2
Appendix-Table 1. Schedule of Study 
Procedures is updated
The table and footnotes are 
updated to reflect the provision of 
home visits.
Appendix-Table 1 Schedule of 
Study Procedures.
Appendix-Table 2. Clinical 
laboratory assessments is updated
The table and footnote is updated 
to reflect the provision of home 
visits as well as study site visits.
Appendix-Table 2 heading: Clinical 
Laboratory Assessments at Study 
Site and Home Visits.
Minor grammatical, editorial and/or 
administrative changes have been 
made.
To improve the readability and/or 
clarity of the protocol.
Throughout the document
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