A Phase 3, Open-label, Non-controlled, Multi-dose Study to Evaluate the Pharmacokinetics, Safety and Tolerability, and Efficacy of Immune Globulin Subcutaneous (Human), 20% Solution (IGSC, 20%) in Japanese Subjects With Primary Immunodeficiency Diseases (PID)
Phase: PHASE3
Conditions: Primary Immunodeficiency Diseases (PID)
Sponsor: Baxalta now part of Shire

 
 
Title: A Phase 3, Open-label, Non-controlled, Multi-dose Study to Evaluate the 
Pharmacokinetics, Safety and Tolerability, and Efficacy of Immune Globulin 
Subcutaneous (Human), 20% Solution (IGSC, 20%) in Japanese Subjects with Primary 
Immunodeficiency Diseases (PID) 
 
NCT Number: NCT04346108 
Protocol Approve Date: 27-OCT-2020 
 
Certain information within this protocol has been redacted (ie, specific content is masked 
irreversibly from view with a black/blue bar) to protect either personally identifiable 
information or company confidential information. 
 
This may include, but is not limited to, redaction of the following: 
 
Named persons or organizations associated with the study. 
 
Patient identifiers within the text, tables, or figures or in by-patient data listings. 
 
Proprietary information, such as scales or coding systems, which are considered 
confidential information under prior agreements with license holder. 
 
Other information as needed to protect confidentiality of Takeda or partners, 
personal information, or to otherwise protect the integrity of the clinical study. 
 
If needed, certain appendices that contain a large volume of personally identifiable 
information or company confidential information may be removed in their entirety if it 
is considered that they do not add substantially to the interpretation of the data (eg, 
appendix of investigator’s curriculum vitae). 
 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Shire
Page 9
TAK-664-3001 Protocol
IGSC, 20%
27 OCT 2020
PRODUCT QUALITY COMPLAINTS
Investigators are required to report investigational product quality complaints or non-medical 
complaints to Shire within 24 hours. If requested, defective product(s) will be returned to the 
sponsor for inspection and analysis.
A product quality complaint includes any instances where there is an allegation or report relating 
to Shire licensed or investigational products, received in writing, electronically, or orally, which 
indicates an impact to a product’s strength, identity, safety, purity, or quality, or which suggests 
that a product did not meet the criteria defined in the regulatory applications, licenses, or 
marketing authorizations for the product. Examples of investigational product quality complaints 
include, but are not limited to, the following:
Unit issues
Capsule fill empty or overage
Bottle/vial fill shortage or overage
Capsule/tablet damaged/broken
Syringe/vial cracked/broken
Syringe leakage
Missing components
Product discoloration
Device malfunction
Labeling
Label missing
Leaflet or Instructions For Use (IFU)
missing
Label illegible
Incomplete, inaccurate, or
misleading labeling
Lot number or serial
number missing
Packaging
Damaged packaging (e.g.,
secondary, primary, bag/pouch)
Tampered seals
Inadequate or faulty closure
Missing components within
package
Foreign material
Contaminated product
Particulate in bottle/vial
Particulate in packaging
Please report the product quality complaint using the “Product Complaint Data Collection Form” 
via the email address:
CTMCOMPLAINT@TAKEDA.com
For instructions on reporting AEs related to product complaints, see Appendix 3.4.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Shire
Page 10
TAK-664-3001 Protocol
IGSC, 20%
27 OCT 2020
TABLE OF CONTENTS
PROTOCOL SIGNATURE PAGE............................................................................................. 2
SUMMARY OF CHANGES FROM PREVIOUS PROTOCOL VERSION.......................... 3
EMERGENCY CONTACT INFORMATION .......................................................................... 8
PRODUCT QUALITY COMPLAINTS..................................................................................... 9
TABLE OF CONTENTS ........................................................................................................... 10
1. PROTOCOL SUMMARY ..................................................................................................... 15
1.1 Synopsis.............................................................................................................................. 15
1.2 Schema ............................................................................................................................... 24
1.3 Schedule of Activities........................................................................................................ 25
2. INTRODUCTION................................................................................................................... 29
2.1 Indication and Current Treatment Options................................................................... 29
2.2 Product Background and Clinical Information............................................................. 30
2.3 Study Rationale................................................................................................................. 31
2.4 Benefit/Risk Assessment................................................................................................... 31
2.5 Compliance Statement...................................................................................................... 32
3. OBJECTIVES AND ENDPOINTS ....................................................................................... 33
3.1 Study Objectives ............................................................................................................... 33
3.1.1 Primary Objective ..................................................................................................... 33
3.1.2 Secondary Objectives ................................................................................................ 33
3.2 Study Endpoints................................................................................................................ 33
3.2.1 Primary Endpoint...................................................................................................... 33
3.2.2 Secondary Endpoints................................................................................................. 33
4. STUDY DESIGN..................................................................................................................... 37
4.1 Overall Design................................................................................................................... 37
4.2 Scientific Rationale for Study Design.............................................................................. 39
4.3 Justification for Dose........................................................................................................ 39
4.4 Duration of Subject Participation and Study Completion Definition.......................... 39
4.5 Sites and Regions .............................................................................................................. 39
5. STUDY POPULATION ......................................................................................................... 40
5.1 Inclusion Criteria.............................................................................................................. 40
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Shire
Page 11
TAK-664-3001 Protocol
IGSC, 20%
27 OCT 2020
5.2 Exclusion Criteria............................................................................................................. 40
5.3 Restrictions........................................................................................................................ 42
5.4 Reproductive Potential..................................................................................................... 42
5.4.1 Female Contraception ............................................................................................... 42
6. STUDY INTERVENTION..................................................................................................... 44
6.1 Investigational Product .................................................................................................... 44
6.2 IGIV (Non-Investigational Product) ............................................................................... 44
6.3 Blinding the Treatment Assignment ............................................................................... 44
6.4 Administration .................................................................................................................. 44
6.4.1 Interactive Response Technology for Investigational Product Management ...... 44
6.4.2 Allocation of Subject Numbers................................................................................. 45
6.4.3 Dosing.......................................................................................................................... 45
6.4.4 Infusions/Description of Treatment ......................................................................... 46
6.4.5 Unblinding the Treatment Assignment ................................................................... 47
6.4.6 Dose Modification ...................................................................................................... 47
6.5 Labeling, Packaging, Storage, and Handling of Investigational Product.................... 47
6.5.1 Packaging.................................................................................................................... 47
6.5.2 Labeling ...................................................................................................................... 47
6.5.3 Storage ........................................................................................................................ 47
6.6 Drug Accountability ......................................................................................................... 48
6.7 Subject Compliance.......................................................................................................... 49
6.8 Prior and Concomitant Therapy..................................................................................... 50
6.8.1 Prior Treatment......................................................................................................... 50
6.8.2 Concomitant Treatment............................................................................................ 50
6.8.3 Permitted Treatment................................................................................................. 50
6.8.4 Prohibited Treatment................................................................................................ 50
7. DISCONTINUATION OF STUDY INTERVENTION AND SUBJECT
DISCONTINUATION/WITHDRAWAL............................................................................. 52
7.1 Discontinuation of Study Treatment............................................................................... 52
7.2 Reasons for Discontinuation ............................................................................................ 52
7.3 Withdrawal from the Study............................................................................................. 52
7.4 Subjects “Lost to Follow-up” Prior to the Last Scheduled Visit.................................. 53
8. STUDY ASSESSMENTS AND PROCEDURES................................................................. 54
8.1 Study Periods..................................................................................................................... 54
8.1.1 Screening / Baseline Visit.......................................................................................... 54
8.1.2 Treatment Period....................................................................................................... 55
8.1.2.1 Study Epoch 1 ..................................................................................................... 55
8.1.2.2 Study Epoch 2 ..................................................................................................... 56
8.1.2.3 Study Epoch 3 ..................................................................................................... 56
8.1.2.4 End-of-Study Visit/Early Termination Visit.................................................... 57
8.1.3 Follow-up Period........................................................................................................ 57
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Shire
Page 12
TAK-664-3001 Protocol
IGSC, 20%
27 OCT 2020
8.1.4 Additional Care of Subjects after the Study ........................................................... 57
8.2 Study Assessments ............................................................................................................ 58
8.2.1 Demographic and Other Baseline Characteristics ................................................. 58
8.2.1.1 Height and Weight.............................................................................................. 58
8.2.1.2 Medical and Medication History....................................................................... 58
8.2.2 Pharmacokinetics....................................................................................................... 58
8.2.2.1 Serum IgG Trough Levels ................................................................................. 58
8.2.2.2 Pharmacokinetic Profiles................................................................................... 58
8.2.2.3 Specific Antibodies.............................................................................................. 59
8.2.3 Efficacy ....................................................................................................................... 59
8.2.3.1 Acute Serious Bacterial Infection Rate............................................................. 59
8.2.3.2 Infections ............................................................................................................. 59
8.2.4 Safety........................................................................................................................... 60
8.2.4.1 Physical Examination......................................................................................... 60
8.2.4.2 Adverse Events.................................................................................................... 60
8.2.4.3 Vital Signs............................................................................................................ 60
8.2.4.4 Clinical Laboratory Tests .................................................................................. 61
8.2.4.5 Pregnancy Test.................................................................................................... 64
8.2.5 Other ........................................................................................................................... 64
8.2.5.1 Pharmacodynamics............................................................................................. 64
8.2.5.2 Genetics................................................................................................................ 64
8.2.5.3 Health-related Quality of Life (QoL)................................................................ 64
8.2.5.4 Treatment Satisfaction....................................................................................... 64
8.2.5.5 Treatment Preference......................................................................................... 65
8.2.5.6 Healthcare Resource Utilization........................................................................ 65
8.2.6 Volume of Blood to Be Drawn from Each Subject ................................................. 65
8.2.7 Retention of Bioavailability and Bioequivalence Testing Samples ....................... 65
8.2.8 Subject Diary.............................................................................................................. 65
9. STATISTICAL CONSIDERATIONS .................................................................................. 67
9.1 Statistical Analysis Process .............................................................................................. 67
9.2 Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee......... 68
9.3 Sample Size and Power Considerations.......................................................................... 68
9.4 Statistical Analysis Set(s).................................................................................................. 69
9.5 Pharmacokinetic Analyses ............................................................................................... 69
9.5.1 Primary Pharmacokinetic Endpoint........................................................................ 70
9.5.2 Secondary Pharmacokinetic Endpoints................................................................... 70
9.6 Efficacy Analyses .............................................................................................................. 70
9.6.1 Efficacy Endpoints..................................................................................................... 70
9.7 Safety Analyses.................................................................................................................. 71
9.7.1 Analysis of Adverse Events....................................................................................... 71
9.7.1.1 Definitions............................................................................................................ 71
9.7.1.2 Handling of Recurrent AEs and Other AE Situations.................................... 72
9.7.1.3 Occurrence and Number of Adverse Events.................................................... 72
9.7.1.4 Adverse Events per Infusion, per Subject, per Subject-Year......................... 73
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Shire
Page 14
TAK-664-3001 Protocol
IGSC, 20%
27 OCT 2020
Tables
Table 1. Schedule of Study Procedures and Assessments  SCREENING and STUDY EPOCH 1 
IV Treatment 3-Week (± 1 Day)a Treatment Interval........................................................... 25
Table 2. Schedule of Study Procedures and Assessments  SCREENING and STUDY EPOCH 1 
IV Treatment 4-Week (± 1 Day)a Treatment Interval........................................................... 26
Table 3. Schedule of Study Procedures and Assessments  STUDY EPOCH 2 SC Treatment 7 
Day (± 1 Day)a Treatment Interval ....................................................................................... 27
Table 4. Schedule of Study Procedures and Assessments  STUDY EPOCH 3 SC Treatment 14 
Day (± 1 Day)a Treatment Interval ....................................................................................... 28
Table 5. Objectives and Endpoints ............................................................................................... 35
Table 6. Clinical Laboratory Assessments  SCREENING and STUDY EPOCH 1  IV Treatment 
3-Week (± 1 Day)a Treatment Interval ................................................................................. 86
Table 7. Clinical Laboratory Assessments  SCREENING and STUDY EPOCH 1 IV Treatment 
4-Week (± 1 Day)a Treatment Interval ................................................................................. 87
Table 8. Clinical Laboratory Assessments at site visits STUDY EPOCH 2 g SC Treatment 7 Day 
(± 1 Day)a Treatment Interval............................................................................................... 88
Table 9. PK Assessment Period in Epoch 2 (Subjects Aged 12 Years and Older Only).............. 89
Table 10. Clinical Laboratory Assessments at site visits,  STUDY EPOCH 3 SC Treatment 14 
Day (± 1 Day) Treatment Interval ........................................................................................ 90
Table 11. Adverse Event Relationship Categorization................................................................. 95
Table 12. Grading of Laboratory Parameters ............................................................................ 106
Figures
Figure 1. Study Design ................................................................................................................. 18
Figure 2. Study Schematic Diagram ............................................................................................. 24
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Shire
Page 15
TAK-664-3001 Protocol
IGSC, 20%
27 OCT 2020
1. PROTOCOL SUMMARY
1.1 Synopsis
Protocol number: TAK-664-3001
Drug: IGSC, 20%
Title of the study: A Phase 3, Open-label, Non-controlled, Multi-dose Study to Evaluate the Pharmacokinetics, 
Safety and Tolerability, and Efficacy of Immune Globulin Subcutaneous (Human), 20% Solution (IGSC, 20%) in 
Japanese Subjects with Primary Immunodeficiency Diseases (PID)
Short title: Pharmacokinetics, Safety and Tolerability, and Efficacy Evaluation of Immune Globulin Subcutaneous 
(Human), 20% Solution (IGSC, 20%) in Japanese Subjects with PID
Study phase: Phase 3
Number of subjects (total and per treatment arm):
The planned total sample size for this study is 16 subjects.
Of the 16 subjects to be enrolled, 12 subjects are expected to complete Epoch 2 of the study, assuming a 
conservative dropout rate of 25% (overall dropout rates assumed for previous IGSC, 20% PID studies and other PID 
studies are generally 10%-15%). Subjects who prematurely discontinue the study will not be replaced. The number 
of subjects expected to complete Epoch 2 (12) is considered adequate for the evaluation of serum trough levels, 
safety and tolerability, and efficacy of IGSC, 20%, as well as for the assessment of disease activity and health-
related quality of life (HRQoL).
This study is not designed for statistical hypothesis testing and therefore the sample size is not based on statistical
considerations such as study power, but instead mainly on consideration of the small size of the Japanese patient 
population with PID, a group of rare diseases. In Japan, the estimated prevalence of PIDs is 2 to 3 per 100,000 
people and the estimated number of people affected is 2,900-3,500. Of the number of PID patients (2,900-3,500), an 
estimated 1,450-1,750 would be potential targets for immunoglobulin replacement therapy. In clinical practice, most 
patients requiring a switch to subcutaneous immunoglobulin (IGSC) (as is required by the study design) are already 
being treated with the approved IGSC product (Hizentra®). For example, in the Hizentra® New Drug Application 
(NDA) review report, the estimated number of patients who could receive immunoglobulin replacement therapy was 
1,155, which is lower than the estimated 1,450-1,750 patients. Therefore, the number of potentially eligible patients 
for the planned study is extremely limited, making it infeasible to enroll a large sample size. Based on feasibility and 
the Sponsor’s clinical experience with immunoglobulin G (IgG) products, a total sample size of 16 subjects 
(12 completers) is considered adequate for providing reliable estimates of trough levels (study primary objective), as 
well as reliable estimates of safety and tolerability, efficacy, disease activity and HRQoL (secondary objectives). 
Investigator(s): multicenter study 
Site(s) and region(s): 
Japan – 10-15 sites planned
Study period (planned):
Approximately 2 years 
Clinical phase:
Phase 3
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Shire
Page 19
TAK-664-3001 Protocol
IGSC, 20%
27 OCT 2020
Inclusion and Exclusion Criteria: 
Inclusion Criteria:
Each subject must meet all the following criteria to enroll in the study:
1.
Be of Japanese descent, defined as born in Japan and having Japanese parents and Japanese maternal and
paternal grandparents.
2.
Subject must have a documented diagnosis of a form of primary humoral immunodeficiency involving
antibody formation and requiring gammaglobulin replacement, as defined according to the International
Union of Immunological Societies (IUIS) Committee 2017 (Picard et al., 2018). The diagnosis must be
confirmed by the Medical Director prior to treatment with IGIV.
3.
Subject is 2 years or older at the time of screening.
4.
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.
5.
Subject has been receiving a consistent dose of IGIV over a period of at least 3 months prior to screening
equivalent to approximately 200 - 600 mg/kg BW per 3 - 4 week period, as according to the product package
insert.
6.
Subject has a serum trough level of IgG ≥5 g/L at screening.
7.
Subject has not had a serious bacterial infection within the 3 months prior to screening.
8.
Subject is willing and able to comply with the requirements of the protocol.
Exclusion Criteria:
Subjects who meet any of the following criteria will be excluded from the study: 
1.
Subject has a known history of or is positive at screening for one or more of the following: hepatitis B
surface antigen (HBsAg), polymerase chain reaction (PCR) for hepatitis C virus (HCV), PCR for human
immunodeficiency virus (HIV) Type 1/2.
2.
Abnormal laboratory values at screening meeting any one of the following criteria (abnormal tests may be
repeated once to determine if they are persistent):
a. Persistent alanine aminotransferase (ALT) and aspartate amino transferase (AST) >2.5 times the upper
limit of normal (ULN) for the testing laboratory
b. Persistent severe neutropenia (defined as an absolute neutrophil count [ANC] ≤500/mm3)
3.
Subject has presence of renal function impairment defined by estimated glomerular filtration rate (eGFR)
<60 mL/min/1.73m2.
4.
Subject has been diagnosed with or has a malignancy (other than adequately treated basal cell or squamous
cell carcinoma of the skin or carcinoma in situ of the cervix), unless the disease-free period prior to screening
exceeds 5 years.
5.
Subject is receiving anti-coagulation therapy or has a history of thrombotic episodes (including deep vein
thrombosis, myocardial infarction, cerebrovascular accident, pulmonary embolism) within 12 months prior to
screening or a history of thrombophilia.
6.
Subject has abnormal protein loss (protein losing enteropathy, nephrotic syndrome).
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Shire
Page 20
TAK-664-3001 Protocol
IGSC, 20%
27 OCT 2020
7.
Subject has anemia that would preclude phlebotomy for laboratory studies according to standard practice at
the site.
8.
Subject has an ongoing history of hypersensitivity or persistent reactions (urticaria, breathing difficulty,
severe hypotension, or anaphylaxis) following IV immunoglobulin, SC immunoglobulin, and/or Immune
Serum Globulin (ISG) infusions.
9.
Subject has immunoglobulin A (IgA) deficiency (IgA less than 0.07g/L), known anti IgA antibodies, and a
history of hypersensitivity.
10.
Subject is on preventative (prophylactic) systemic antibacterial antibiotics at doses sufficient to treat or
prevent bacterial infections, and cannot stop these antibiotics at the time of screening.
11.
Subject has active infection and is receiving antibiotic therapy for the treatment of infection at the time of
screening.
12.
Subject has a bleeding disorder, or a platelet count less than 20,000/μL, or, in the opinion of the investigator,
would be at significant risk of increased bleeding or bruising as a result of subcutaneous therapy.
13.
Subject has total protein >9 g/dL or myeloma, or macroglobulinemia (IgM) or paraproteinemia.
14.
Women of childbearing potential meeting any one of the following criteria:
a. Subject presents with a positive pregnancy test.
b. Subject is breast feeding.
c. Subject intends to begin nursing during the course of the study.
d. Subject does not agree to employ adequate birth-control measures (e.g. intrauterine device, diaphragm
or condom [for male partner] with spermicidal jelly or foam, or birth control pills/patches) throughout
the course of the study.
15.
Subject has participated in another clinical study and has been exposed to an IP or device within 30 days
prior to study enrollment.
16.
Subject is scheduled to participate in another non-observational (interventional) clinical study involving an
IP or device during the course of the study (exception: an extension study of TAK-664-3001).
17.
Subject has severe dermatitis that would preclude adequate sites for safe product administration.
Maximum duration of subject participation in the study:

Screening: 2 to 8 weeks before the IGIV treatment period

Epoch 1: IGIV treatment period: 13 weeks

Epoch 2: IGSC, 20% treatment period 1: 12 weeks

Epoch 2: IGSC, 20% treatment period 2: 12 weeks

Epoch 3: IGSC, 20%: 12 weeks
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Shire
Page 21
TAK-664-3001 Protocol
IGSC, 20%
27 OCT 2020
Endpoints and statistical analysis:
Analysis Populations /Analysis Sets:
Analysis of serum trough levels of IgG, efficacy, safety and tolerability, and disease activity and HRQoL data will 
be based on the following analysis sets (analysis populations), as defined:

Enrolled Set: All screened subjects for whom an enrollment number has been assigned. Screened subjects
will consist of all subjects who have signed informed consent. Background summaries (e.g., subject
disposition) will be based on the Enrolled Set.

All-Treated Set: All enrolled subjects who received at least 1 dose of study drug (IGIV or IGSC). Analysis of
efficacy, safety and tolerability, and disease activity and HRQoL will be based on the All-Treated Set. Since
this study is non-randomized, the Safety Set (defined as all dosed subjects) and Full Analysis Set (defined as
all randomized and dosed) are identical, and therefore simply referred to as All-Treated Set for this study.

Pharmacokinetic Analysis Set (PKAS): All-Treated Set who have had at least 1 evaluable serum IgG
concentration value and have had no major protocol deviations or events that would affect the serum IgG
concentration analysis results. Analysis of PK data (serum IgG trough concentrations and PK profiles) will
be based on the PKAS.
Primary Endpoint:
Total serum trough levels of IgG (total serum trough IgG antibodies) measured during Period 2 of Study Epoch 2 
(weekly administration of IGSC, 20%) and during Epoch 3 (biweekly administration of IGSC, 20%).
Secondary Endpoints:
Endpoints cover PK, safety and tolerability, efficacy, and disease activity and HRQoL.
Pharmacokinetic endpoints and parameters in Epoch 1, Epoch 2 and Epoch 3, as indicated:

Total serum trough levels of IgG (total serum trough IgG antibodies) measured during Epoch 1 (every
3 weeks or every 4 weeks administration of IGIV)

PK parameters for total serum levels of IgG and for IgG subclasses (Epoch 2): AUC, CL/F, Cmax, Cmin, and
Tmax

Trough levels of specific antibodies to clinically relevant pathogens (Clostridium tetani toxoid, Haemophilus
influenzae [HIB], Hepatitis B Virus [HBV]) (Epoch 1, Epoch 2, Epoch 3)
Safety and Tolerability Endpoint(s): 
Safety endpoints/outcome measures in Epoch 1, Epoch 2 and Epoch 3:

Occurrence of treatment-emergent adverse events (TEAEs), including but not limited to: study drug (IGIV or
IGSC)-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 “possibly related” or “probably related” to study drug
(IGIV or IGSC) will be considered a related adverse event (AE), and any AE recorded as “unlikely
related” or “not related” will be considered an unrelated AE.

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
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Shire
Page 22
TAK-664-3001 Protocol
IGSC, 20%
27 OCT 2020
Baseline is defined as the last non-missing value before the initial dose of study drug (IGIV or IGSC).
Tolerability endpoints/outcome measures in Epoch 1, Epoch 2 and Epoch 3:

Occurrence of tolerability events related to the infusion of study drug (IGIV or IGSC)
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 (IGIV or IGSC) 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.
Efficacy endpoints/outcome measures in Epoch 1, Epoch 2 and Epoch 3:

Annual rate of validated acute serious bacterial infections per subject

Annual rate of all infections per subject

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
Disease activity and HRQoL endpoints in Epoch 1, Epoch 2 and Epoch 3:

QoL: PEDS-QL (Varni et al., 1999), SF-36 (Ware and Sherbourne, 1992), EQ-5D-3L Health Questionnaire
(Shaw et al., 2005)

Treatment Satisfaction (Life Quality Index, TSQM-9) (Daly et al., 1991)

Treatment Preference (End-of-Study [EOS]/Early Termination)
Endpoint details will be provided in the study Statistical Analysis Plan (SAP).
Statistical analysis
Statistical details will be provided in the SAP.
The primary objective of this study is to assess serum trough IgG concentrations following weekly administration of 
IGSC, 20% and serum trough IgG concentration after biweekly administration of IGSC, 20%, in Japanese subjects 
with PID, covering Epoch 2 and Epoch 3. 
The secondary objectives focus on PK, safety and tolerability, efficacy, and disease activity and HRQoL and cover 
Epoch 1, Epoch 2 and Epoch 3 (see Section 3.1).
PK analysis will be based on the PKAS, and safety and tolerability, efficacy, and disease activity and HRQoL 
analyses on the All-Treated Set. 
Study endpoint data (serum IgG trough levels, safety and tolerability, and efficacy, as well as disease activity and 
HRQoL) will be analyzed using descriptive statistics. No statistical hypothesis testing will be performed, and no 
interim analysis is planned.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Shire
Page 23
TAK-664-3001 Protocol
IGSC, 20%
27 OCT 2020
Statistical summaries will be presented, as appropriate, by epoch, by treatment period, by treatment period and 
visit/timepoint, and overall. 
Baseline is defined as the last non-missing value before initial dose of study drug (IGIV or IGSC). Continuous 
endpoints/outcome measures (e.g., change from baseline) will be summarized using the following descriptive 
statistics: number of subjects (n), mean, median, standard deviation (SD), minimum value, maximum value. 
Categorical endpoints/outcome measures (e.g., adverse events) will be summarized in terms of number and percent 
of subjects and number of occurrences in each category. 
For serum IgG trough levels, descriptive statistics will also include geometric mean (GM) and the corresponding 
2-sided 95% confidence interval (CI). No formal statistical comparison (hypothesis testing) of treatments will be
performed. CIs are for descriptive purposes. Caution should be exhibited in their interpretation as this study is not
designed for hypothesis testing.
For disease activity and HRQoL data, raw (actual) and change from baseline values will be summarized 
descriptively, and summaries will be provided by treatment period and pre-defined age group.
For the QoL endpoint: 2-7 years (PEDS-QL, observer: parent), 8-13 years (PEDS-QL, observer: subject), and 
14 years and older (SF 36, observer: subject); EQ-5D-3L Health Questionnaire: 2-11 years EQ-5D-3L (observer: 
parent) and 12 years and older EQ-5D-3L (observer: subject).
For the Treatment Satisfaction (Life Quality Index) endpoint: 2-13 years (observer: parent) and 14 years and older 
(observer: subject). Treatment Satisfaction Questionnaire for Medication (TSQM-9): 2-12 years (observer: parent) 
and 13 years and older (observer: subject).
For the Treatment Preference endpoint: 2-13 years (observer: parent) and 14 years and older (observer: subject). 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Shire
Page 25
TAK-664-3001 Protocol
IGSC, 20%
27 OCT 2020
1.3 Schedule of Activities
Table 1. Schedule of Study Procedures and Assessments 
SCREENING and STUDY EPOCH 1
IV Treatment 3-Week (± 1 Day)a Treatment Interval
Procedure/Assessment
Screening/
Baseline Visit
Visit No./Week in Study Epoch 1e
(One Week 
Later Start 
Study 
Epoch 2)
Visit 1
Week 1
Visit 2
Week 4
Visit 3
Week 7
Visit 4
Week 10
Visit 5
Week 13
Location
Site
Site
Site
Site
Site
Site
Informed Consent
X
Eligibility Criteria
X
Medical History
X
Physical Exam
X
X
X
Vital Signs
X
X
X
X
X
X
Laboratory Assessmentsb
Xc
X
X
X
X
X
Concomitant Medication and Non-Drug Therapies
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
Collection/Review Diaries
X
X
X
X
X
Study Product Treatment
Xd
Xd
Xd
X
X
Quality of Life Assessments
X
Treatment Satisfaction Assessment
X
Healthcare Resource Utilization
X
X
X
X
X
a
For the treatment interval. Dosing date should be 21 days (±1 day) after the last dose.
b
For laboratory assessments specific to the visits, see Table 6. At an infusion visit the assessments are to be taken pre-infusion, unless specified otherwise. 
c
Including retention samples to be taken at screening or prior to the first infusion. For subject 12 years or older approximately 2.5 mL serum and 2 mL plasma. For children 
younger than 12 years of age, approximately 2 mL plasma will be obtained.
d
Follow-up contact with the subject/caregiver by the investigator/designee will be necessary 3-5 days after completion of the first 3 infusions of each epoch in order to 
document AEs that may have occurred.
e
Any early discontinuation during Epoch 1 should complete End-of-Study procedures as described in Table 4, but excluding the quality of life, treatment satisfaction and 
treatment preference assessments
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Shire
Page 28
TAK-664-3001 Protocol
IGSC, 20%
27 OCT 2020
a
For the treatment interval. Visit date should be 28 days (±1 day) after the last visit.
b
Mandatory site visit at least once every 4 weeks. 
c
For laboratory assessments specific to the mandatory site visits, see Table 10. At an infusion visit the assessments are to be taken pre-infusion unless specified otherwise.
d
Infusions between mandatory site visits are to be home treatments, if possible - if investigator confirms (and documents) that subject/caregiver is capable of administering 
infusions
e
At mandatory site visits only. 
f 
All study subjects completing or exiting the study should complete the End of Study/Early Termination Procedures as described above.
g
Follow-up contact with the subject/caregiver by the investigator/designee (irrespective of whether the infusion was performed at the study site or at home) will be necessary 
3-5 days after completion of the first 3 infusions of each epoch in order to document AEs that may have occurred.
Table 4. Schedule of Study Procedures and Assessments 
STUDY EPOCH 3 
SC Treatment 14 Day (± 1 Day)a Treatment Interval
Procedure/Assessment
Visit No./Week in Study Epoch 3
Treatment at Study Siteb
Treatment at Homed
Location
Site Visit 1
Week 1
Site Visit 2
Week 5
Site Visit 3
Week 9
End-of-Study/Early 
Termination Visitf
Site Visit 4
Week 13
Home
Informed Consent
Inclusion/Exclusion
Medical History
Physical Exame
X
X
X
X
Vital Signs
X
X
X
X
Laboratory Assessmentsc
X
X
X
X
X
Concomitant Medication and Non-Drug Therapies
X
X
X
X
X
Adverse Events
X
X
X
X
X
Collection/Review Diaries
X
X
X
X
Study Product Treatment
Xg
Xg
X
Xg
Quality of Life Assessments
X
X
Treatment Satisfaction Assessment
X
X
Treatment Preference Assessment
X
Healthcare Resource Utilization
X
X
X
X
X
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Shire
Page 29
TAK-664-3001 Protocol
IGSC, 20%
27 OCT 2020
2. INTRODUCTION
2.1 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 354 distinct disorders (with
344 gene defects) (Picard et al., 2018). The most recent classification of molecularly defined
PIDs issued by the Expert Committee of the International Union of Immunological Societies
(IUIS) (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 IgG as a replacement therapy. 
Antibody replacement can be administered either intravenously (IV) or subcutaneously (SC) 
(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 IV administration, though in the past 
several years, SC administration has gained popularity. When given weekly or every other week, 
IGSC leads to higher trough serum IgG concentrations than monthly IV infusions (Berger, 2011, 
Gardulf et al., 1995, Gardulf et al., 1991). 
Immunoglobulin replacement therapy administered by the subcutaneous 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 compared to 
IGIV (Berger, 2013, Suez et al., 2016). The immunoglobulin preparations currently approved for 
SC use in the US, Canada and the European Union (EU) are formulated at 10% to 20% (only the 
20% IGSC formulation Hizentra® is available in Japan). 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 (Wasserman, 2012). 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Shire
Page 30
TAK-664-3001 Protocol
IGSC, 20%
27 OCT 2020
2.2 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 BW 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 of SC administration are different from that of IV infusions, and 
bioavailability of immunoglobulin 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).
IGSC, 20%, a new immunoglobulin preparation for SC use, is formulated as a 20% solution. The 
manufacturing process for 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 EMEA Guidelines for 
normal human normal immunoglobulin 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 two 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.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Shire
Page 31
TAK-664-3001 Protocol
IGSC, 20%
27 OCT 2020
2.3 Study Rationale
Approximately 2,900-3,500 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 intravenous. This study (TAK-664-3001) evaluates 
serum trough IgG levels, safety and tolerability, and efficacy of IGSC, 20% (subcutaneous 
administration), and assesses disease activity and HRQoL 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). The results from this study will 
extend/support the data obtained from two global (USA and EU) pivotal studies for IGSC, 20% 
in PID, to Japanese patients with PID. Data from this study will be used to support regulatory 
submission for the approval of IGSC, 20% in Japan.
2.4 Benefit/Risk Assessment 
IGSC, 20% is a new immunoglobulin 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. IGSC, 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 IGI, 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/hr 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). 
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. 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Shire
Page 32
TAK-664-3001 Protocol
IGSC, 20%
27 OCT 2020
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, pharmacokinetics, 
efficacy, and safety of IGSC, 20%. 
2.5 Compliance Statement
This study will be conducted in accordance with this protocol, the International Council for 
Harmonisation Guideline for Good Clinical Practice E6 (Integrated Addendum to ICH E6[R1]: 
Guideline for Good Clinical Practice E6[R2] Current Step 4 version, 9 November 2016), Title 21 
of the US Code of Federal Regulations (US CFR), the EU Directives (2001/20/EC; 2005/28/EC), 
and applicable national and local regulatory requirements.
The responsibilities of the study sponsor and investigator(s) are described fully in Appendix 1.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Shire
Page 34
TAK-664-3001 Protocol
IGSC, 20%
27 OCT 2020

PK parameters for total serum levels of IgG and for IgG subclasses (Epoch 2): AUC, CL/F,
Cmax, Cmin, and Tmax

Trough levels of specific antibodies to clinically relevant pathogens (Clostridium tetani
toxoid, HIB, HBV) (Epoch 1, Epoch 2, Epoch 3)
Safety and Tolerability Endpoint(s):
Safety endpoints/outcome measures in Epoch 1, Epoch 2 and Epoch 3:

Occurrence of TEAEs, including but not limited to: study drug (IGIV or IGSC)-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 “possibly related” or “probably
related” to study drug (IGIV or IGSC) will be considered a related AE, and any AE
recorded as “unlikely related” or “not related” will be considered an unrelated AE.

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 initial dose of study drug (IGIV or 
IGSC).
Tolerability endpoints/outcome measures in Epoch 1, Epoch 2 and Epoch 3:

Occurrence of tolerability events related to the infusion of study drug (IGIV or IGSC)
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 (IGIV or IGSC) 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.
Efficacy endpoints/outcome measures in Epoch 1, Epoch 2 and Epoch 3:

Annual rate of validated acute serious bacterial infections per subject

Annual rate of all infections per subject
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Shire
Page 35
TAK-664-3001 Protocol
IGSC, 20%
27 OCT 2020

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
Disease activity and HRQoL endpoints in Epoch 1, Epoch 2 and Epoch 3:

QoL: PEDS-QL (Varni et al., 1999), SF-36 (Ware and Sherbourne, 1992), EQ-5D-3L
Health Questionnaire (Shaw et al., 2005)

Treatment Satisfaction (Life Quality Index, TSQM-9) (Daly et al., 1991)

Treatment Preference (EOS/Early Termination)
Endpoint details will be provided in the study SAP.
Table 5. Objectives and Endpoints
Objective
Endpoint(s)
Primary

To assess serum trough IgG concentrations
following weekly administration of IGSC, 20%
(Epoch 2) and serum trough IgG concentration
after biweekly administration of IGSC, 20%
(Epoch 3) in Japanese subjects with PID.

Total serum trough levels of IgG (total serum trough
IgG antibodies) measured during Period 2 of Study
Epoch 2 (weekly administration of IGSC, 20%),
and during Epoch 3 (biweekly administration of
IGSC, 20%)
Secondary

To assess serum trough IgG concentrations
following every 3-week or every 4-week
administration of IGIV (Epoch 1) in Japanese
subjects with PID.

To characterize the PK profiles of IGSC, 20%
in Japanese subjects with PID following weekly
SC administration (Epoch 2).

Total serum trough levels of IgG (total serum trough
IgG antibodies) measured during Epoch 1 (every
3 weeks or every 4 weeks administration of IGIV)

PK parameters for total serum levels of IgG and for
IgG subclasses (Epoch 2): AUC, CL/F, Cmax, Cmin,
and Tmax

Trough levels of specific antibodies to clinically
relevant pathogens (Clostridium tetani toxoid, HIB,
HBV) (Epoch 1, Epoch 2, Epoch 3)
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Shire
Page 36
TAK-664-3001 Protocol
IGSC, 20%
27 OCT 2020
Table 5. Objectives and Endpoints
Objective
Endpoint(s)

To evaluate the safety and tolerability of
IGSC, 20% (Epoch 2, Epoch 3) and of IGIV
(Epoch 1) in Japanese subjects with PID.

Occurrence of TEAEs, including but not limited to:
study drug (IGIV or IGSC)-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
“possibly related” or “probably related” to study
drug (IGIV or IGSC) will be considered a related
AE, and any AE recorded as “unlikely related” or
“not related” will be considered an unrelated AE.

Clinical laboratory outcomes: raw (actual) values and
change from baseline

Vital signs: raw (actual) values and change from
baseline, and change from pre-infusion to post-
infusion

Occurrence of tolerability events related to the
infusion of study drug (IGIV or IGSC)

To evaluate the efficacy of IGSC, 20%
(Epoch 2, Epoch 3) and of IGIV (Epoch 1) in
Japanese subjects with PID.

Annual rate of validated acute serious bacterial
infections per subject

Annual rate of all infections per subject

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

To assess quality of life aspects, treatment
satisfaction, and treatment preference of
Japanese subjects with PID (Epoch 1, Epoch 2,
Epoch 3).

QoL: PEDS-QL, SF-36, EQ-5D-3L Health
Questionnaire

Treatment Satisfaction (Life Quality Index, TSQM-9)

Treatment Preference (EOS/Early Termination)
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Shire
Page 37
TAK-664-3001 Protocol
IGSC, 20%
27 OCT 2020
4. STUDY DESIGN
4.1 Overall Design
This is a phase 3, open-label, non-controlled, 3-epoch, multi-dose, multi-center study to evaluate
serum trough levels of IgG, PK, efficacy, safety and tolerability of IGSC, 20% (Epoch 2 and
Epoch 3) and of IGIV (Epoch 1) in Japanese subjects with PID, as well as to assess disease
activity and HQoL. A total of 16 subjects will be enrolled, of whom 12 subjects are expected to
complete Epoch 2 of the study.
A schematic of the study design is provided in Figure 1. Each subject will receive IGIV 
treatment in Epoch 1 for a total of 13 weeks, then switch to weekly SC treatment with 
IGSC, 20% in Epoch 2 for a total of 24 weeks; a subset of 7 subjects (of whom 5 subjects are 
expected to complete, assuming 25% dropout) will continue into Epoch 3 for a total of 12 weeks 
of biweekly SC treatment with IGSC, 20%.
The study consists of the following evaluation periods: 

Screening: 2 to 8 weeks before the IGIV treatment period

Epoch 1: IGIV treatment period: 13 weeks

All subjects will receive either 4 IGIV infusions at 4-week intervals, or 5 IGIV infusions at
3-week intervals, during Epoch 1.

Epoch 2: IGSC treatment period: 24 weeks (total); PK, safety, tolerability, efficacy and
HRQoL, per Schedule of Activities in Section 1.3
Epoch 2, IGSC treatment period 1: 12 weeks of weekly IGSC, 20% dose adjustment
period (infusion training will be performed during this period)
All subjects from Epoch 1 will receive IGSC, 20% infusion every week during
Epoch 2, as illustrated in Figure 1. If self-infusion is planned, self-infusion training
must be provided at the study sites, i.e. weekly visits for self-infusion training are
acceptable during the first 8 weeks of the treatment period. It is preferable that
subsequent infusions between scheduled site infusion visits be performed at home, by
the subject/caregiver, if in the opinion of the investigator, such treatment is safe and
appropriate. In that case, the investigator/designee must have trained the subject or
caregiver (documented the training), and must be satisfied that the subject or
caregiver is capable of self-administration of SC infusions at home, before the subject
or caregiver will be permitted to conduct the SC infusion at home.
The dose of IGSC, 20% infusion will be adjusted if necessary, to maintain the target
IgG trough level ≥5 g/L.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Shire
Page 38
TAK-664-3001 Protocol
IGSC, 20%
27 OCT 2020
Epoch 2, IGSC treatment period 2: 12 weeks of weekly IGSC, 20% efficacy
evaluation period (serum IgG trough levels and PK assessment)
All subjects will continue to receive IGSC, 20% infusion every week (see Figure 1) at
the dose established in the preceding study period. IgG trough level sampling for the
efficacy assessments will be performed during the efficacy evaluation period. The
IgG trough level will be assessed at Epoch 2, Week/Infusion numbers 17, 21 and
25 for all subjects.
A PK assessment will be performed in 5-7 subjects aged 12 years and older, within
the last month on weekly IGSC treatment (in Epoch 2 period 2, see Figure 1). The
following PK parameters will be assessed: AUC, CL/F, Cmax, Cmin, and Tmax. PK
serial sampling will start at Epoch 2 SC infusion number 21 ± 1. If the PK assessment
cannot start at SC infusion number 21 (which is at Week 21), it may alternatively start
at the infusion ± 1 week from infusion number 21, however the infusion at the start of
the PK must be performed as a site infusion visit.
Serum samples will be collected at the following time points:
o
Pre-infusion (i.e., trough level of previous infusion within 1 hour before infusion)
(Day 0 of PK)
o
Day 1 (± 6 hours, from infusion start time of Day 0)
o
Day 3 (± 6 hours, from infusion start time of Day 0)
o
Day 5 (± 6 hours, from infusion start time of Day 0)
o
Day 7 (± 6 hours, from infusion start time of Day 0, pre-infusion to the next
SC infusion)

Epoch 3: IGSC, 20% treatment period: 12 weeks of biweekly IGSC, 20%; PK (serum IgG
trough only), safety, tolerability, efficacy and HRQoL, per Schedule of Activities in
Section 1.3
At the discretion of the investigator and with agreement of the subject, a subset of
7 subjects in Epoch 2 treatment period 2 will continue for an additional 12 weeks of
biweekly SC treatment with IGSC, 20%, in Epoch 3, at an equivalent dose (the dose in
Epoch 3 will be twice the dose in Epoch 2). The serum IgG trough level will be assessed in
Epoch 3 at Weeks 5, 9 and 13 for all subjects.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Shire
Page 39
TAK-664-3001 Protocol
IGSC, 20%
27 OCT 2020
4.2 Scientific Rationale for Study Design
This phase 3, open-label study is designed to evaluate serum trough levels of IgG, efficacy, and 
safety and tolerability of Immune Globulin Subcutaneous (Human), 20% Solution (IGSC, 20%) 
in Japanese Subjects with PID, as well as to assess disease activity and HRQoL. The clinical data 
in Japanese subjects with PID from study TAK-664-3001 will be evaluated with the clinical data 
of 122 subjects from the overseas pivotal clinical studies (Study 170903 and Study 170904). 
4.3 Justification for Dose
For all study subjects, the immunoglobulin dose during the pre-study period (equivalent to 
approximately 200 - 600 mg/kg BW at 3- or 4-week intervals, as according to the product 
package insert) will be maintained upon study entry into study TAK-664-3001. In replacement 
therapy, the dose may need to be individualized for each patient 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. 
4.4 Duration of Subject Participation and Study Completion Definition
The subject’s maximum duration of participation is expected to be approximately 55 weeks. The 
study will be completed in approximately 2 years. Subjects who wish to enroll in the Extension 
Study, and complete Study TAK-664-3001 prior to the approval and implementation of the 
Extension Study, may extend participation in Epoch 2 or Epoch 3 at the same dose and treatment 
interval as they were last receiving (for a maximum of 4 months), to enable roll-over. The EOS 
visit will be postponed for such subjects until they enroll in the Extension Study.
The Study Completion Date is defined as the date on which the last subject in the study 
completes the final protocol-defined assessment(s).
4.5 Sites and Regions
The study will be conducted in Japan at approximately 10 to 15 sites.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Shire
Page 41
TAK-664-3001 Protocol
IGSC, 20%
27 OCT 2020
b. Persistent severe neutropenia (defined as an absolute neutrophil count [ANC]
≤500/mm3)
3.
Subject has presence of renal function impairment defined by estimated glomerular
filtration rate (eGFR) <60 mL/min/1.73m2.
4.
Subject has been diagnosed with or has a malignancy (other than adequately treated basal
cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix), unless the
disease-free period prior to screening exceeds 5 years.
5.
Subject is receiving anti-coagulation therapy or has a history of thrombotic episodes
(including deep vein thrombosis, myocardial infarction, cerebrovascular accident,
pulmonary embolism) within 12 months prior to screening or a history of thrombophilia.
6.
Subject has abnormal protein loss (protein losing enteropathy, nephrotic syndrome).
7.
Subject has anemia that would preclude phlebotomy for laboratory studies according to
standard practice at the site.
8.
Subject has an ongoing history of hypersensitivity or persistent reactions (urticaria,
breathing difficulty, severe hypotension, or anaphylaxis) following IV immunoglobulin,
SC immunoglobulin, and/or Immune Serum Globulin (ISG) infusions.
9.
Subject has immunoglobulin A (IgA) deficiency (IgA less than 0.07g/L), known anti IgA
antibodies, and a history of hypersensitivity.
10. Subject is on preventative (prophylactic) systemic antibacterial antibiotics at doses
sufficient to treat or prevent bacterial infections, and cannot stop these antibiotics at the
time of screening.
11. Subject has active infection and is receiving antibiotic therapy for the treatment of
infection at the time of screening.
12. Subject has a bleeding disorder, or a platelet count less than 20,000/μL, or, in the opinion
of the investigator, would be at significant risk of increased bleeding or bruising as a result
of subcutaneous therapy.
13. Subject has total protein >9 g/dL or myeloma, or macroglobulinemia (IgM) or
paraproteinemia.
14. Women of childbearing potential meeting any one of the following criteria:
a. Subject presents with a positive pregnancy test.
b. Subject is breast feeding.
c. Subject intends to begin nursing during the course of the study.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Shire
Page 42
TAK-664-3001 Protocol
IGSC, 20%
27 OCT 2020
d. Subject does not agree to employ adequate birth-control measures (e.g. intrauterine
device, diaphragm or condom [for male partner] with spermicidal jelly or foam, or
birth control pills/patches) throughout the course of the study.
15. Subject has participated in another clinical study and has been exposed to an IP or device
within 30 days prior to study enrollment.
16. Subject is scheduled to participate in another non-observational (interventional) clinical
study involving an IP or device during the course of the study (exception: an extension
study of TAK-664-3001).
17. Subject has severe dermatitis that would preclude adequate sites for safe product
administration.
5.3 Restrictions 
Not applicable.
5.4 Reproductive Potential
There are no adequate data from the use of IGSC, 20% in pregnant or lactating women. 
Maternally administered IGIV products have been shown to cross the placenta, increasingly 
during the third trimester. 
The effects of IGSC, 20% on fertility have not been established.
5.4.1 Female Contraception
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 IP. 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 
IP. 
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 one of the following surgical acts: hysterectomy,
bilateral tubal ligation, bilateral oophorectomy or bilateral salpingectomy) and at least
6 weeks post-sterilization, or
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Shire
Page 43
TAK-664-3001 Protocol
IGSC, 20%
27 OCT 2020

Of childbearing potential with a negative urine human chorionic gonadotropin (hCG) or
serum beta-hCG (-hCG) pregnancy test at the Screening 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 (e.g., condoms and diaphragms with spermicidal gel or foam)

Hormonal contraceptives (oral, depot, patch, injectable, or vaginal ring), stabilized for at
least 30 days prior to the screening visit (baseline visit), plus condoms. Note: If the subject
becomes sexually active during the study, she should use one of the other acceptable
methods noted above in addition to the hormonal contraceptive until it has been stabilized
for 30 days.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Shire
Page 44
TAK-664-3001 Protocol
IGSC, 20%
27 OCT 2020
6. STUDY INTERVENTION
6.1 Investigational Product
The IP Immune Globulin Subcutaneous (Human), 20% Solution (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 0.2-0.3 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 Investigator’s Brochure. 
Immune Globulin Subcutaneous (Human), 20% Solution (IGSC, 20%) will be provided by the 
sponsor and will be labeled as IP.
6.2 IGIV (Non-Investigational Product)
The IGIV product administered during Epoch 1 is an approved IV immunoglobulin procured 
locally, which is administered as per local product label. Additional information is provided in 
the appropriate product package label. IGIV will not be managed by interactive response 
technology (IRT) and will not be provided by the sponsor as IP.
The IGIV used in Epoch 1 will be the same IGIV preparation being administered to the patient 
prior to enrollment in the study and will be sourced by the sites. The lot number of IGIV used for 
the study should be recorded in eCRF by clinical site personnel. 
6.3 Blinding the Treatment Assignment
Not applicable.
6.4 Administration 
6.4.1 Interactive Response Technology for Investigational Product Management
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 IRT as 
they consent to take part in the study. Within each site (numbered uniquely within a protocol), 
the subject number is assigned according to the sequence of subject presentation for study 
participation.
IRT will be used for IP supply management in Epoch 2 and Epoch 3 (not Epoch 1), inventory 
management, supply ordering, IP expiration tracking, temperature excursion reporting, and 
return of IP. 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Shire
Page 45
TAK-664-3001 Protocol
IGSC, 20%
27 OCT 2020
Details for the handling of IP will be described in the pharmacy manual.
6.4.2 Allocation of Subject Numbers 
Subject numbers are assigned to all subjects as they consent to take part in the study. Within each 
site (numbered uniquely within a protocol), the subject number is assigned to subjects according 
to the sequence of presentation for study participation. 
Once a unique identifier has been assigned, that number must not be used again if, for example, a 
subject is withdrawn from the study. If a unique identifier is allocated incorrectly, the clinical 
research associate (CRA)/study monitor must be notified as soon as the error is discovered. 
6.4.3 Dosing
In Epoch 1, IGIV will be administered via IV infusions every 3 or 4 weeks, as per local product 
label, at the same dose as during pre-study period (equivalent to approximately 200 - 600 mg/kg 
at 3- or 4-week intervals). 
In Epoch 2 (24 weeks), approximately 50 - 200 mg/kg of IGSC, 20% will be administered 
subcutaneously once a week. The dose in Epoch 2 will be adjusted so that it is an equivalent 
weekly dose of the dose administered in Epoch 1. 

In Epoch 2, Period 1 (dose adjustment period, the first 12 weeks), the dose will be
adjusted, if needed, to maintain an IgG trough level ≥5 g/L.

In Epoch, 2 Period 2 (including IgG trough evaluation period, the second 12 weeks), the
dose established during the dose adjustment period will be administered.
In Epoch 3, approximately 100 - 400 mg/kg of IGSC, 20% will be administered subcutaneously 
once every 2 weeks in a sub-set of 7 subjects. The dose in Epoch 3 will be twice the dose in 
Epoch 2.
For the duration of the study: In order to maintain the same dose in mg/kg when there has been 
an increase in BW (kg), it will be necessary to increase the absolute dose (in g or mg) 
administered. The IGSC, 20% dose should be based on the most current weight measurement 
(taken at a site visit) - if the subject´s weight has increased by more than 5%, the absolute dose 
(in g or mg) should be adjusted at the next possible infusion. If there is a weight decrease, 
regardless of the percentage, the IGSC, 20% dose should not be changed.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Shire
Page 46
TAK-664-3001 Protocol
IGSC, 20%
27 OCT 2020
6.4.4 Infusions/Description of Treatment
Infusion Volumes
For subjects with a BW >= 40 kg, up to 60 mL should be administered per infusion site if well 
tolerated. For subjects with a BW <40 kg it is recommended that for the initial two infusions the 
volume be limited to 20 mL per infusion site, but if well tolerated the volume should be 
increased to a maximum of 60 mL for subsequent infusions.
Infusion Rates
For the initial two infusions, the infusion rate should be approximately 10-20 mL/h/site, and 
appropriate pump tubing set should be used. Especially for the first infusion, the pump tubing set 
for approximately 10 mL/h/site is recommended. For subsequent infusions, if well tolerated, the 
pump tubing set up to 60 ml/h/site can be used. It is suggested to complete the administration 
within 2 hours due to the potential formation of particles caused by siliconized syringes.
Multiple infusion sites can be used for infusion simultaneously as determined by the subject and 
investigator. Infusions will be conducted with a pump.
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.
Infusion Parameters
First 2 Infusions
Subsequent Infusions
Patients <40 kg
Patients ≥ 40kg
Patients < 40kg
Patients ≥ 40kg
Volume (mL/site)
≤20
≤60
≤60
Rate (mL/h/site)
10-20
≤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 two 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% overage 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.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Shire
Page 47
TAK-664-3001 Protocol
IGSC, 20%
27 OCT 2020
6.4.5 Unblinding the Treatment Assignment
Not applicable. 
6.4.6 Dose Modification
In Epoch 2, Period 1 (dose adjustment period), subjects will receive weekly SC infusions of 
IGSC, 20% at a weekly dosage calculated based on the dosage in Epoch 1 (which is based on 
pre-study IGIV treatment). The dose of IGSC, 20% (in mg/kg) will be adjusted if needed to 
maintain IgG trough level ≥5 g/L.
In Epoch 2, Period 2, the dosage established during the dose adjustment period (Period 1) will be 
administered.
In Epoch 3, the dose will be twice the dose in Epoch 2. 
The dose in mg/kg may be increased during the study if clinically indicated (e.g. increased 
incidence of infections, low IgG trough level [<5 g/L]) at the investigator´s discretion. If such an 
event arises, the sponsor should be informed, the rationale for such dose adjustment should be 
documented in the patient file, and the adjusted dose should be entered in the case report forms 
(CRFs).
6.5 Labeling, Packaging, Storage, and Handling of Investigational Product
6.5.1 Packaging
IGSC, 20% 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.
6.5.2 Labeling
Labels containing study information and pack identification are applied to the IP vial and carton. 
The product will be labeled according to the valid regulatory requirements for clinical studies.
6.5.3 Storage
The investigator has overall responsibility for ensuring that IP is stored in a secure, limited-
access location. Limited responsibility may be delegated to the pharmacy or member of the study 
team, but this delegation must be documented. IGSC 20% is distributed or administered by the 
pharmacy or nominated member of the study team. The pharmacist/nominated team member will 
enter the unique subject identifier on the IP vial/carton labels as they are distributed or 
administered.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Shire
Page 49
TAK-664-3001 Protocol
IGSC, 20%
27 OCT 2020
Due to the health/safety concerns with returning the IP container, the investigator must request 
that subjects keep the empty IP packaging after use and return it to the site for drug 
accountability purposes.
No IP stock or returned inventory from a Shire-sponsored study may be removed from the 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 IP, and 
empty/used IP packaging are to be sent to a nominated contractor on behalf of the sponsor. IP 
being returned to the sponsor’s designated contractors must be counted and verified by clinical 
site personnel and the sponsor (or designated 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 
(i.e., IRT) do not require a shipment form. Returned IP must be packed in a tamper-evident 
manner to ensure product integrity. Contact the sponsor for authorization to return any IP prior to 
shipment. Shipment of all returned IP must comply with local, state, and national laws.
Based on entries in the 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.
6.7 Subject Compliance
Subjects must be instructed to bring unused IP and empty/used IP packaging to every visit. Drug 
accountability must be assessed at the container/packaging level for unused IP that is contained 
within the original tamper-evident sealed container (e.g., 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.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Shire
Page 50
TAK-664-3001 Protocol
IGSC, 20%
27 OCT 2020
6.8 Prior and Concomitant Therapy
All non-study treatment (including but not limited to herbal treatments, vitamins, behavioral 
treatment, non-pharmacological treatment, such as psychotherapy, as appropriate) received 
within 30 days prior to the date the informed consent document is signed until the EOS/Early 
Termination Visit, and must be recorded in the subject’s source document.
6.8.1 Prior Treatment
Prior treatment includes all treatment (including but not limited to herbal treatments, vitamins, 
non-pharmacological treatment such as psychotherapy as appropriate) received within 30 days 
prior to the date the informed consent document is signed. Prior treatment information must be 
recorded in the subject’s source document.
6.8.2 Concomitant Treatment 
Concomitant treatment refers to all treatment taken between the date the informed consent 
document is signed until the EOS/Early Termination Visit. Concomitant treatment information 
must be recorded in the subject’s source document.
6.8.3 Permitted Treatment
Treatments not listed in Section 6.8.4 are considered allowable.
6.8.4 Prohibited Treatment
The following medications are not permitted during the course of the study:

Requirement for all antibiotic therapy must be documented as an AE. Prophylactic
treatment with systemic antibacterial antibiotics is not allowed during the study (except for
a period of up to 72 hours if required due to trauma or a scheduled procedure). The use of
systemic prophylactic antibacterial antibiotics by a subject will be considered a protocol
deviation (except for trauma or a scheduled procedure as described above). However,
prophylaxis for viral, fungal or protozoal infections (e.g. trimethoprim/sulfamethoxazole
twice a week for pneumocystis) which are not treated by immunoglobulin can be used and
should be recorded as concomitant medication.

Other IgG products after first exposure to study drug.

Hyper immune serum

Immunosuppressive drugs following transplantation
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Shire
Page 51
TAK-664-3001 Protocol
IGSC, 20%
27 OCT 2020
Pre-medication on the Day of Product Administration:

IV-Product Administration
Subjects who are prone to AEs occurring in conjunction with infusions of IGIV products
are often pre-medicated with antihistamines, antipyretics, and/or steroids. In this study,
however, pre-medications should be avoided, if possible, for both IV and SC infusions.
Subjects should only receive pre-medication (acetaminophen/non-steroidal anti-
inflammatory drugs [NSAIDs], corticosteroids, and antihistamines) prior to IV infusions if
the same AE(s) were seen prior to the study with 2 or more IGIV preparations. In addition,
should an AE occur during or following 2 or more infusions during this study, pre-
medications can be used for subsequent IV or SC infusions. The use of these medications
must be recorded in the concomitant medication record. Reactions that occur during the
IV infusions do not necessitate automatic pretreatment for the SC infusions.

SC-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.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Shire
Page 53
TAK-664-3001 Protocol
IGSC, 20%
27 OCT 2020
7.4 Subjects “Lost to Follow-up” Prior to the Last Scheduled Visit
A minimum of 3 documented attempts must be made to contact any subject who is lost to 
follow-up at any time point prior to the last scheduled contact (office visit or telephone contact). 
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 acknowledgement of receipt request) 
asking that the subject return to the site for final safety evaluations and return any unused IP.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Shire
Page 54
TAK-664-3001 Protocol
IGSC, 20%
27 OCT 2020
8. STUDY ASSESSMENTS AND PROCEDURES
8.1 Study Periods
The study will consist of 3 epochs. A tabulated schedule of study procedures and assessments is
provided for Study Epoch 1 in Table 1 (IV treatment 3-week treatment interval) and Table 2 (IV
treatment 4-week treatment interval), for Study Epoch 2 in Table 3, and for Study Epoch 3 in
Table 4. Clinical laboratory assessments are detailed in Section 8.2.
Follow-up contact with the subject/caregiver by the investigator/designee (irrespective of 
whether the infusion was performed at the study site or at home) will be necessary 3-5 days after 
completion of the first 3 infusions of each epoch in order to ensure that the documentation of 
AEs that may have occurred is being completed correctly.
8.1.1 Screening / Baseline Visit
Any subject who provides informed consent (i.e., signs and dates the informed consent form 
[ICF]) is considered a subject in the study. 
The written informed consent for all procedures and assessments for the conduct of the study 
must be obtained prior to any study related procedure.
Every single subject who enters the study will get a unique subject identification code (SIC). 
The following procedures and assessments will be performed at the Screening / Baseline Visit 
(see Table 1 and Table 2):

Availability of signed informed consent

Assessment of eligibility

Medical history

Physical exam

Vital signs (see Section 8.2.4.3)

Clinical laboratory assessments (see Table 6 for Epoch 1 3-week interval treatment and
Table 7 for Epoch 1 4-week interval treatment)

Retention samples should be taken at screening or prior to the first infusion. For subjects
12 years or older approximately 2.5 mL serum and 2 mL plasma will be taken and stored
frozen at –70°C or below at the central lab in the event further testing is needed. For
children younger than 12 years of age, approximately 2 mL of plasma will be obtained.

Concomitant medication and non-drug therapies
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Shire
Page 55
TAK-664-3001 Protocol
IGSC, 20%
27 OCT 2020
A screen failure is a subject who has given informed consent and failed to meet the inclusion 
and/or met at least 1 of the exclusion criteria and has not been administered study drug (IGIV or 
IGSC). The study site is responsible for maintaining an enrollment/screening log that includes all 
subjects enrolled. The log also will serve to document the reason for screening failure. All 
relevant screening data will be collected and reported, regardless of screening outcome.
Subjects who fail to meet eligibility criteria may be re-screened; they will be assigned a different 
SIC at re-screening. 
8.1.2 Treatment Period 
8.1.2.1 Study Epoch 1
During Epoch 1, subjects will receive either 5 IGIV infusions at 3-week intervals or 4 IGIV 
infusions at 4-week intervals.
The following procedures and assessments will be performed at the study site (detailed 
scheduled provided in Table 1 for 3-week interval treatment and in Table 2 for 4-week interval 
treatment):

Physical exam

Vital signs (see Section 8.2.4.3)

Clinical laboratory assessments (see Table 6 for 3-week interval treatment and Table 7 for
4-week interval treatment)

Concomitant medication and non-drug therapies

Adverse events

Collection/review of patient diaries

Quality of life and treatment satisfaction assessments (see Section 8.2.5.3 and
Section 8.2.5.4)

Healthcare Resource Utilization

Study Product Treatment
Collection of Infusion related data e.g.: lot number, start and stop time, infusion site,
infusion rate (mL/h) and changed rate if there is, total infusion volume (mL), infusion
completion, and the reason if infusion is not completed as planned.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Shire
Page 56
TAK-664-3001 Protocol
IGSC, 20%
27 OCT 2020
8.1.2.2 Study Epoch 2
During Epoch 2, subjects will receive weekly IGSC, 20% infusions.
The following procedures and assessments will be performed at the study site or during treatment 
at home, if applicable (detailed schedule provided in Table 3):

Physical exam

Vital signs (see Section 8.2.4.3)

Clinical laboratory assessments (see Table 8)

Concomitant medication and non-drug therapies

Adverse events

Collection/review of patient diaries

Quality of life and treatment satisfaction assessments (see Section 8.2.5.3 and
Section 8.2.5.4). (Treatment Preference at the EOS/Early Termination Visit, for subjects
completing the study in Epoch 2.)

Healthcare Resource Utilization

Study Product Treatment
Collection of Infusion related data e.g.: Med ID number (six digit), start and stop time,
infusion site, infusion rate (mL/h) and changed rate if there is, total infusion volume (mL),
infusion completion, and the reason if infusion is not completed as planned.
8.1.2.3 Study Epoch 3
During Epoch 3, subjects will receive biweekly IGSC, 20% infusions.
The following procedures and assessments will be performed at the study site or during treatment 
at home, if applicable (detailed schedule provided in Table 4):

Physical exam

Vital signs (see Section 8.2.4.3)

Clinical laboratory assessments (see Table 10)

Concomitant medication and non-drug therapies

Adverse events

Collection/review of patient diaries
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Shire
Page 57
TAK-664-3001 Protocol
IGSC, 20%
27 OCT 2020

Quality of life, treatment satisfaction and treatment preference assessments
(see Section 8.2.5.3, Section 8.2.5.4 and Section 8.2.5.5)

Healthcare Resource Utilization

Study Product Treatment
Collection of Infusion related data e.g.: Med ID number (six digit), start and stop time,
infusion site, infusion rate (mL/h) and changed rate if there is, total infusion volume (mL),
infusion completion, and the reason if infusion is not completed as planned.
8.1.2.4 End-of-Study Visit/Early Termination Visit
The EOS Visit will be conducted 1 week following the last IP infusion (subject in Epoch 2) or 
2 weeks following the last IP infusion (subject in Epoch 3). The following procedures and 
assessments should also be completed in the event of an early termination visit (if the subject 
need to terminate the study before study completion).
The following procedures and assessments will be performed at the study site (see Table 4):

Physical exam

Vital signs (see Section 8.2.4.3)

Clinical laboratory assessments (see Table 10)

Concomitant medication and non-drug therapies

Adverse events

Collection/review of patient diaries

Quality of life, treatment satisfaction and treatment preference assessments
(see Section 8.2.5.3, Section 8.2.5.4 and Section 8.2.5.5)

Healthcare Resource Utilization
8.1.3 Follow-up Period
There is no follow-up period.
8.1.4 Additional Care of Subjects after the Study
An extension study is planned, to offer continuation of treatment and for the additional collection 
of treatment-related data. The subjects who complete Epoch 2 or Epoch 3 can be enrolled in the 
Extension Study.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Shire
Page 58
TAK-664-3001 Protocol
IGSC, 20%
27 OCT 2020
8.2 Study Assessments 
8.2.1 Demographic and Other Baseline Characteristics
Subject demographic information including gender, age, and race will be collected prior to the 
subject receiving the first dose of study drug (IGIV or IGSC). 
8.2.1.1 Height and Weight
Height and weight will be measured and recorded in the subject’s source documents. 
8.2.1.2 Medical and Medication History
Medical and medication history will be collected and recorded in the subject’s source documents. 
At screening, the subject’s medical history will be described for the following body systems or 
surgery, and start and end dates, if known: eyes, ears, nose, and throat; respiratory; 
cardiovascular; gastrointestinal; musculoskeletal; neurological; endocrine; 
hematopoietic/lymphatic; dermatological; and genitourinary.
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 electronic case report forms (eCRFs).
8.2.2 Pharmacokinetics
8.2.2.1 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 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.
8.2.2.2 Pharmacokinetic Profiles
PK parameters for total serum levels of IgG and for IgG subclasses (IgG1, IgG2, IgG3, and 
IgG4) will be evaluated during Study Epoch 2 in a subset of 5-7 subjects aged 12 years and older 
only. 
The following parameters will be assessed: AUC, CL/F, Cmax, Cmin, and Tmax.
For a schedule of pharmacokinetic testing see Appendix 2.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Shire
Page 59
TAK-664-3001 Protocol
IGSC, 20%
27 OCT 2020
8.2.2.3 Specific Antibodies
Specific antibody tests (quantitative method) to Clostridium tetani toxoid, HIB and HBV will be 
performed.
For a schedule of specific antibody testing see Appendix 2.
8.2.3 Efficacy
8.2.3.1 Acute Serious Bacterial Infection Rate 
Infections will be reported as AEs and the number and types of infections will be determined. 
ASBIs 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 5.
The ASBI rate will be calculated as the mean number of acute serious bacterial infections per 
subject per year in the All-Treated Set. 
8.2.3.2 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.
Days not able to attend school/work or to perform normal daily activities due to
illness/infection, will be collected using diaries or other source data options throughout the
study and will be transcribed to CRFs.
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 CRFs.
4.
Number of hospitalizations due to illness/infection and length of stay (in days)
Admissions to a hospital as an in-patient 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 CRFs.
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
CRFs.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Shire
Page 60
TAK-664-3001 Protocol
IGSC, 20%
27 OCT 2020
8.2.4 Safety
8.2.4.1 Physical Examination
At screening and subsequent scheduled study visits at the site (as described in Section 1.3, 
Section 8.1.1 and Section 8.1.2), 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 screening, if an abnormal condition is detected, the condition will be 
described on the medical history CRF. At study visits, if a new abnormal or worsened abnormal 
pre-existing condition is detected, the condition will be described on the AE CRF. If the 
abnormal value was not deemed an AE because it was due to an error, due to a preexisting 
disease (described in Appendix 3), 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. 
8.2.4.2 Adverse Events
At each study visit, subjects will be questioned in a general way to ascertain if AEs have 
occurred since the previous visit (e.g., “Have you had any health problems since your last 
visit?”). Adverse events are collected from the time informed consent is signed. Refer to 
Appendix 3 for AE definitions, assessment, collection time frame, and reporting procedures. 
8.2.4.3 Vital Signs
Vital signs will include height (in or cm), weight (lb or kg), body temperature (°C or °F), 
respiratory rate (breaths/min), pulse rate (beats/min), and systolic and diastolic blood pressure 
(mmHg). Blood pressure measurements will be taken after subjects remain sitting in an upright 
position for at least one minute.
Vital signs will be measured as described below:
1.
Screening
All vital signs
2.
Infusion at Study Site

Within 30 min prior to infusion.
All vital signs except height. Weight can be taken at any time at the site visit.

30 (± 10) min after initiation of infusion
All vital signs except height and weight

During the infusion if a systemic AE occurs, to be assessed as needed:
All vital signs except height and weight
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Shire
Page 61
TAK-664-3001 Protocol
IGSC, 20%
27 OCT 2020

Within 30 min of completion of the infusion
All vital signs except height and weight
3.
Infusion at home
No assessment of vital signs
4.
End-of-Study
All vital signs
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.
8.2.4.4 Clinical Laboratory Tests
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.
A complete list of the clinical laboratory tests to be performed is provided in Appendix 2.
8.2.4.4.1 Hematology and Clinical Chemistry
The hematology panel will consist of complete blood count (hemoglobin, hematocrit, 
erythrocytes [i.e., red blood cell count], and leukocytes [i.e., white blood cell count {WBC}]) 
with differential (i.e., basophils, eosinophils, lymphocytes, monocytes, neutrophils) and platelet 
counts. In addition, absolute neutrophil counts (ANCs) will be determined by laboratory 
calculation.
The clinical chemistry panel will consist of sodium, potassium, chloride, bicarbonate, protein, 
albumin, ALT, serum total bilirubin, AST, alkaline phosphatase (ALP), lactate dehydrogenase 
(LDH), blood urea nitrogen (BUN), serum creatinine, creatinine phosphokinase (CPK), glucose, 
haptoglobin, lipase.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Shire
Page 62
TAK-664-3001 Protocol
IGSC, 20%
27 OCT 2020
IgG and IgG subclasses (IgG1, IgG2, IgG3, and IgG4) will be measured for assessment of trough 
levels.
IgG and IgG subclasses will also be measured for PK purposes. This will only be performed in 
subjects aged 12 years and older.
Blood will be obtained for assessment of hematology and clinical chemistry including IgG and 
IgG subclasses at screening/baseline, distinct study visits, and at study completion/termination. 
For a schedule of laboratory test blood drawings, see Appendix 2. These assessments will be 
performed on EDTA-anticoagulated whole blood and serum, respectively, processed through a 
central laboratory. 
8.2.4.4.2 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 2. These assessments will be 
performed at the central laboratory.
A urine pregnancy test will be performed at the study site for females of childbearing potential as 
indicated in Appendix 2 (see also Section 8.2.4.5). 
8.2.4.4.3 Specialty Tests
Specialty tests include: HBsAg, PCR for HCV and PCR for HIV-1/2. For a schedule of 
laboratory test blood drawings, see Appendix 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, HAV, HBV, HCV, HEV (hepatitis E virus), 
or B19V (Parvovirus B19) (see also Section 8.2.4.4.5.2).
8.2.4.4.4 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:
1.
If hemolysis tests are scheduled when routine hematology and clinical chemistry are
already being assessed at the visit, then tests for hemolysis will consist of:

direct antiglobin test (Coombs-test or AGT)
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Shire
Page 63
TAK-664-3001 Protocol
IGSC, 20%
27 OCT 2020

urine hemosiderin
2.
If hemolysis tests are scheduled when routine hematology and clinical chemistry are not
being assessed at the visit, then tests for hemolysis will consist of:

direct antiglobin test (Coombs-test or AGT)

urine hemosiderin

hemoglobin

LDH

serum haptoglobin
In addition, these assessments (item 2 above) 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).
For a schedule of laboratory test blood drawings, see Appendix 2.
8.2.4.4.5 Assessment of Laboratory Values
8.2.4.4.5.1 Toxicity Grading Scale
The investigator will be asked to assess each abnormal laboratory value as described in 
Section 8.2.4.4.5.2. In addition, the sponsor will evaluate laboratory values for abnormalities 
according to a 5-point (Grades 0-4) toxicity grading scale provided in Appendix 6.
The Common Toxicity Criteria of the (Eastern Cooperative Oncology Group, 2006) will be 
used to grade the following laboratory values: ALP, ALT, AST, BUN, hemoglobin, 
lymphocytes, neutrophils, platelet count, serum creatinine, serum total bilirubin, and WBC 
count. Grading for 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). 
8.2.4.4.5.2 Assessment of Abnormal Laboratory Values
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 Appendix 3). 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 
lab error, was due to a preexisting disease (described in Appendix 3.1), was not clinically 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Shire
Page 65
TAK-664-3001 Protocol
IGSC, 20%
27 OCT 2020
All subjects will complete the Treatment Satisfaction Questionnaire for Medication (TSQM-9), 
analyzed separately for the age groups: 2-12 years (observer: parent) and 13 years and older 
(observer: subject). Age will be defined as the age at screening. The observer should remain 
constant for the duration of subject participation. In the event that the language/age group is not 
available, the assessment in the closest language/age group will be used.
8.2.5.5 Treatment Preference
Treatment preference will be assessed at the EOS/Early Termination Visit.
Treatment preference will be analyzed separately for the age groups 2-13 years (observer: 
parent) and 14 years and older (observer: subject). Age will be defined as the age at screening.
8.2.5.6 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 8.2.3.2.
8.2.6 Volume of Blood to Be Drawn from Each Subject
The volume of blood to be drawn from each subject for laboratory assessments will be specified 
in the laboratory manual.
8.2.7 Retention of Bioavailability and Bioequivalence Testing Samples
Retention samples should be taken at screening or prior to the first infusion. For subjects 
12 years or older approximately 2.5 mL serum and 2 mL plasma will be taken and stored frozen 
at –70°C or below at the central lab in the event further testing is needed. For children younger 
than 12 years of age, approximately 2 mL of plasma will be obtained. 
8.2.8 Subject Diary
A subject diary will be provided to each subject at enrollment to record the following 
information, in addition to the information specified in Section 8.1.2, throughout the study 
period:

Occurrence of AEs (including infections). The investigator will provide guidance for the
subject/caregiver regarding identification and documentation of AEs

Concomitant medication use

Days not able to attend school/work or to perform normal daily activities due to
illness/infection
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Shire
Page 66
TAK-664-3001 Protocol
IGSC, 20%
27 OCT 2020

Non-study-required out-patient visits (including urgent care visits to see healthcare
providers), and hospitalizations, due to illness/infection

Infusion related data e.g.: Med Number (six digit), start and stop time, infusion site,
infusion rate (mL/h) and changed rate if there is, total infusion volume (mL), infusion
completion, and the reason if infusion is not completed as planned.
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.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Shire
Page 68
TAK-664-3001 Protocol
IGSC, 20%
27 OCT 2020
As noted above in this section, 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 (IGIV or IGSC), and prior and concomitant medications. In addition, the SAP will 
also include a description of how missing, unused and spurious data will be addressed.
In order to preserve the integrity of the statistical analysis and study conclusions, the SAP will be 
finalized prior to study database lock. Specifications for the corresponding tables, figures, and 
listings (TFLs) will be provided separately, in the study TFL shells document.
There are no statistical stopping criteria (go/no-go decision criteria) for this study.
9.2 Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee
Not applicable. No interim analysis, adaptive design, or data monitoring committee (DMC) is 
planned for this study. 
9.3 Sample Size and Power Considerations
The planned total sample size for this study is 16 subjects.
Of the 16 subjects to be enrolled, 12 subjects are expected to complete Epoch 2 of the study, 
assuming a conservative dropout rate of 25% (overall dropout rates assumed for previous 
IGSC, 20% PID studies and other PID studies are generally 10%-15%). Subjects who 
prematurely discontinue the study will not be replaced. The number of subjects expected to 
complete Epoch 2 (12) is considered adequate for the evaluation of serum trough levels, safety 
and tolerability, and efficacy of IGSC, 20%, as well as for the assessment of disease activity and 
HRQoL. 
This study is not designed for statistical hypothesis testing and therefore the sample size is not 
based on statistical considerations such as study power, but instead mainly on consideration of 
the small size of the Japanese patient population with PID, a group of rare diseases. In Japan, 
the estimated prevalence of PIDs is 2 to 3 per 100,000 people and the estimated number of 
people affected is 2,900-3,500. Of the number of PID patients (2,900-3,500), an estimated 
1,450-1,750 would be potential targets for immunoglobulin replacement therapy. In clinical 
practice, most patients requiring a switch to IGSC (as is required by the study design) are already 
being treated with the approved IGSC product (Hizentra®). For example, in the Hizentra® NDA 
review report, the estimated number of patients who could receive immunoglobulin replacement 
therapy was 1,155, which is lower than the estimated 1,450-1,750 patients. 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Shire
Page 69
TAK-664-3001 Protocol
IGSC, 20%
27 OCT 2020
Therefore, the number of potentially eligible patients for the planned study is extremely limited, 
making it infeasible to enroll a large sample size. Based on feasibility and the Sponsor’s clinical 
experience with IgG products, a total sample size of 16 subjects (12 completers) is considered 
adequate for providing reliable estimates of trough levels (study primary objective), as well as 
reliable estimates of safety and tolerability, efficacy, disease activity and HRQoL (secondary 
objectives).
9.4 Statistical Analysis Set(s)
Analysis of serum trough levels of IgG, efficacy, safety and tolerability, and disease activity and 
HRQoL data will be based on the following analysis sets (analysis populations), as defined:

Enrolled Set: All screened subjects for whom an enrollment number has been assigned.
Screened subjects will consist of all subjects who have signed informed consent.
Background summaries (e.g., subject disposition) will be based on the Enrolled Set.

All-Treated Set: All enrolled subjects who received at least 1 dose of study drug (IGIV or
IGSC).
Analysis of efficacy, safety and tolerability, and disease activity and HRQoL will be based
on the All-Treated Set. Since this study is non-randomized, the Safety Set (defined as all
dosed subjects) and Full Analysis Set (defined as all randomized and dosed) are identical,
and therefore simply referred to as All-Treated Set for this study.

Pharmacokinetic Analysis Set (PKAS): All-Treated Set who have had at least 1 evaluable
serum IgG concentration value and have had no major protocol deviations or events that
would affect the serum IgG concentration analysis results.
Analysis of PK data (serum IgG trough concentrations and PK profiles) will be based on
the PKAS.
9.5 Pharmacokinetic Analyses
The primary objective of the study is to assess serum trough IgG concentrations following 
weekly administration of IGSC, 20% (Epoch 2) and serum trough IgG concentration after 
biweekly administration of IGSC, 20% (Epoch 3), in Japanese subjects with PID. All PK data 
will be analyzed using descriptive statistics. Descriptive statistics will also include geometric 
mean (GM) and the corresponding 2-sided 95% confidence interval (CI). No formal statistical 
comparison (hypothesis testing) of treatments will be performed. Note that CIs are for 
descriptive purposes, and therefore caution should be exhibited in their interpretation as this 
study is not designed for hypothesis testing.
Analysis details will be provided in the study SAP.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Shire
Page 70
TAK-664-3001 Protocol
IGSC, 20%
27 OCT 2020
9.5.1 Primary Pharmacokinetic Endpoint
The primary PK endpoint is the total serum trough levels of IgG (total serum trough IgG 
antibodies) measured during Period 2 of Study Epoch 2 (weekly administration of IGSC, 20%), 
and Study Epoch 3 (biweekly administration of IGSC, 20%).
9.5.2 Secondary Pharmacokinetic Endpoints
Secondary PK endpoints and parameters in Epoch 1, Epoch 2 and Epoch 3, as indicated:

Total serum trough levels of IgG (total serum trough IgG antibodies) measured during
Epoch 1 (every 3 weeks or every 4 weeks administration of IGIV)

PK parameters estimated based on PK profiles in Epoch 2 using non-compartmental
analysis for total serum levels of IgG and for IgG subclasses (Epoch 2): AUC, CL/F, Cmax,
Cmin, and Tmax

Trough levels of specific antibodies to clinically relevant pathogens (e.g. Clostridium tetani
toxoid, HIB, HBV) (Epoch 1, Epoch 2, Epoch 3)
9.6 Efficacy Analyses
Assessment of efficacy is a secondary objective of the study. Efficacy endpoint data (defined 
below) will be analyzed using descriptive statistics. 
9.6.1 Efficacy Endpoints
Efficacy endpoints/outcome measures in Epoch 1, Epoch 2 and Epoch 3:

Annual rate of validated acute serious bacterial infections per subject

Annual rate of all infections per subject

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
Days will be standardized to per week, per month, or per year to adjust for the differential 
durations of the epochs.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Shire
Page 71
TAK-664-3001 Protocol
IGSC, 20%
27 OCT 2020
9.7 Safety Analyses
Assessment of safety and tolerability is a secondary objective of this study. Safety and 
tolerability endpoints (defined below) will be analyzed using descriptive statistics. 
Safety and tolerability endpoints/outcome measures in Epoch 1, Epoch 2 and Epoch 3 include:

Occurrence of TEAEs, including but not limited to: study drug (IGIV or IGSC)-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 “possibly related” or “probably
related” to study drug (IGIV or IGSC) will be considered a related AE, and any AE
recorded as “unlikely related” or “not related” will be considered an unrelated AE.

Occurrence of tolerability events related to the infusion of study drug (IGIV or IGSC)
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 (IGIV or IGSC) 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.

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 initial dose of study drug (IGIV or 
IGSC).
9.7.1 Analysis of Adverse Events
9.7.1.1 Definitions
TEAEs, defined as: AEs with onset after date-time of first dose of study drug (IGIV or IGSC), or 
medical conditions present prior to the start of study drug (IGIV or IGSC) but increased in 
severity or relationship after date-time of first dose of study drug (IGIV or IGSC).
Non-TEAEs, defined as: AEs with onset before date-time of first dose of study drug (IGIV or 
IGSC), or medical conditions present prior to the start of study drug (IGIV or IGSC) but did not 
increase in severity or relationship after date-time of first dose of study drug (IGIV or IGSC).
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Shire
Page 72
TAK-664-3001 Protocol
IGSC, 20%
27 OCT 2020
Related TEAEs, defined as causally related TEAEs.
9.7.1.2 Handling of Recurrent AEs and Other AE Situations
Multiple Severities and Relationships: 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. If a subject experiences 
multiple severities of the same AE (e.g., 3 occurrences: 1 mild, 1 moderate, 1 severe) all 
categorized under the same causality assessment (e.g., all related to study drug [IGIV or IGSC]), 
the AE with the maximum severity (AE that is severe) will be used in analysis.
Related AEs: Any AE that is recorded as “possibly related” or “probably related” to study drug 
(IGIV or IGSC) 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 study drug (IGIV or 
IGSC). For example, if a subject experienced a mild headache not related to the IP, and a 
moderate headache related to IP, then the subject will be counted once for headache using the 
moderate headache related to IP.
Details on data handling conventions will be provided in the study SAP.
9.7.1.3 Occurrence and Number of Adverse Events
All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA), 
version 18.1 or higher and then reported by MedDRA system organ class (SOC) and PT, and 
overall. Only TEAEs will be analyzed. Non-TEAEs will be listed only.
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
The following approaches will be used, where applicable:

Overall summary: Overall summary will include, but not limited to: Any TEAE, local
TEAE, related TEAE, severe TEAE, severe related TEAE, serious TEAE, serious related
TEAE, and TEAE leading to discontinuation for the epoch, and any TEAE leading to
death.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Shire
Page 73
TAK-664-3001 Protocol
IGSC, 20%
27 OCT 2020

Summaries by SOC and PT: In the summaries, SOC will be sorted alphabetically, and PT
will be sorted within each SOC in descending frequency in the Total column (i.e., the Total
column will be sorted in descending order after the sorting by SOC and PT).

Summaries by PT only: In the summaries, PT will be sorted in decreasing frequency in the
table Total column.

If more than 1 TEAE occurs within the same 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 study drug (IGIV or IGSC). For example,
if a subject experienced a mild headache not related to the IP, and a moderate headache
related to IP, then the subject will be counted once for headache using the moderate
headache related to IP.

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 one 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.
9.7.1.4 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, by SOC and PT
Per infusion is number of events divided by total number of infusions administered; per subject 
is number of events divided by total number of subjects; per subject-year is number of events 
divided by total number of days of exposure, converted into years.
AEs per subject-year summary adjusts for differences in subjects’ durations in the study and the 
potential differential dropout rates between epochs.
For number of AEs, multiple occurrences of the same AE in the same subject will be counted 
multiple times.
Number of AEs and AEs per 1000 subject-years (SYs) will be provided for all AEs (if 
analyzable), by primary SOC and PT for each epoch and overall. 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Shire
Page 74
TAK-664-3001 Protocol
IGSC, 20%
27 OCT 2020
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

AEs per subject-year = number of AEs / total number of days of exposure, i.e., 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 (IGIV or 
IGSC) + 1) / 365.25. If the subject’s last date is missing, then the date of last dose of study drug 
(IGIV or IGSC) will be used if available.
9.7.1.5 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
9.7.2 Clinical Laboratory Data
Baseline is defined as the last non-missing value before initial dose of study drug (IGIV or 
IGSC).
Raw (actual) clinical laboratory values (in SI units) and changes in raw values from baseline at 
each post-baseline assessment time point will be summarized as continuous variables. 
Shift from baseline (shift table) to each post-baseline assessment time point will be provided for 
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 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Shire
Page 112
TAK-664-3001 Protocol
IGSC, 20%
27 OCT 2020
11. REFERENCES
Abolhassani, H., Sadaghiani, M. S., Aghamohammadi, A., Ochs, H. D. & Rezaei, N. 2012. 
Home-based subcutaneous immunoglobulin versus hospital-based intravenous 
immunoglobulin in treatment of primary antibody deficiencies: Systematic review and 
meta analysis. J. Clin. Immunol, 32, 1180-1192.
Berger, M. 2011. Choices in IgG replacement therapy for primary immune deficiency diseases: 
subcutaneous IgG vs. intravenous IgG and selecting an optimal dose. Curr. Opin. Allergy 
Clin. Immunol, 11, 532-538.
Berger, M. 2013. Adverse effects of IgG therapy. J Allergy Clin Immunol Pract, 1, 558-566.
Borte, M., Krivan, G., Derfalvi, B., Marodi, L., Harrer, T., Jolles, S., Bourgeois, C., Engl, W., 
Leibl, H., McCoy, B., Gelmont, D. & Yel, L. 2017. Efficacy, safety, tolerability and 
pharmacokinetics of a novel human immune globulin subcutaneous, 20%: a Phase 2/3 
study in Europe in patients with primary immunodeficiencies. Clin Exp Immunol, 187,
146-159.
Chapel, H. M., Spickett, G. P., Ericson, D., Engl, W., Eibl, M. M. & Bjorkander, J. 2000. The 
comparison of the efficacy and safety of intravenous versus subcutaneous 
immunoglobulin replacement therapy. J. Clin. Immunol, 20, 94-100.
Committee for Human Medicinal Products 2010. Guideline on the clinical investigation of 
human normal immunoglobulin for intravenous administration (IVIg) - Draft. 
London.Web Link: 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/03/
WC500078472.pdf
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Shire
Page 113
TAK-664-3001 Protocol
IGSC, 20%
27 OCT 2020
Committee for Proprietary Medicinal Products 2002. Note for guidance on the clinical 
investigation of human normal immunoglobulin for subcutaneous and intramuscular use. 
CPMP/BPWG/283/00. 8. 07-2002. London, European Agency for the Evaluation of 
Medicinal Products (EMEA),.Web Link: 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/10/
WC500004255.pdf
Daly, P. B., Evans, J. H., Kobayashi, R. H., Kobayashi, A. L., Ochs, H. D., Fischer, S. H., 
Pirofsky, B. & Sprouse, C. 1991. Home-based immunoglobulin infusion therapy: quality 
of life and patient health perceptions. Ann Allergy, 67, 504-510.
de la Morena, M. T. & Nelson, R. P., Jr. 2014. Recent advances in transplantation for primary 
immune deficiency diseases: a comprehensive review. Clin Rev Allergy Immunol, 46,
131-144.
Eastern Cooperative Oncology Group 2006. Common toxicity criteria of the Eastern Cooperative 
Oncology Group.Web Link: http://www.ecog.org/general/ctc.pdf
Food and Drug Administration 2008. U.S.Department of Health and Human Services, Center for 
Biologics Evaluation and Research, Guidance for industry: Safety, efficacy, and 
pharmacokinetic studies to support marketing of immune globulin intravenous (human) 
as replacement therapy for primary humoral immunodeficiency.Web Link: 
https://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulator
yInformation/Guidances/Blood/ucm078526.pdf
Gardulf, A., Andersen, V., Björkander, J., Ericson, D., Frøland, S. S., Gustafson, R., 
Hammarström, L., Jacobsen, M. B., Jonsson, E., Möller, G., Nyström, T., Søeberg, B. & 
Smith, C. I. E. 1995. Subcutaneous immunoglobulin replacement in patients with primary 
antibody deficiencies: safety and costs. Lancet, 345, 365-369.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Shire
Page 114
TAK-664-3001 Protocol
IGSC, 20%
27 OCT 2020
Gardulf, A. & Hammarström, L. 1996. Subcutaneous administration of immunoglobulins.  What 
are the advantages? Clin Immunother, 6, 108-116.
Gardulf, A., Hammarström, L. & Smith, C. I. 1991. Home treatment of 
hypogammaglobulinaemia with subcutaneous gammaglobulin by rapid infusion. Lancet,
338, 162-166.
Goldstein, B., Giroir, B. & Randolph, A. 2005. International pediatric sepsis consensus 
conference: definitions for sepsis and organ dysfunction in pediatrics. Pediatr Crit Care 
Med, 6, 2-8.
Hernandez-Trujillo, V. 2014. New genetic discoveries and primary immune deficiencies. Clin 
Rev Allergy Immunol, 46, 145-153.
Kuo, C. Y. 2018. Advances in site-specific gene editing for primary immune deficiencies. Curr 
Opin Allergy Clin Immunol, 18, 453-458.
Melamed, I., Testori, A. & Spirer, Z. 2012. Subcutaneous immunoglobulins: Product 
characteristics and their role in primary immunodeficiency disease. Int. Rev. Immunol,
31, 451-461.
Picard, C., Bobby Gaspar, H., Al-Herz, W., Bousfiha, A., Casanova, J. L., Chatila, T., Crow, Y. 
J., Cunningham-Rundles, C., Etzioni, A., Franco, J. L., Holland, S. M., Klein, C., Morio, 
T., Ochs, H. D., Oksenhendler, E., Puck, J., Tang, M. L. K., Tangye, S. G., Torgerson, T. 
R. & Sullivan, K. E. 2018. International Union of Immunological Societies: 2017
Primary Immunodeficiency Diseases Committee Report on Inborn Errors of Immunity. J
Clin Immunol, 38, 96-128.
Rosen, F. S., Cooper, M. D. & Wedgwood, R. J. 1995. The primary immunodeficiencies. N Engl 
J Med, 333, 431-440.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Shire
Page 115
TAK-664-3001 Protocol
IGSC, 20%
27 OCT 2020
Sauer, A. V., Di Lorenzo, B., Carriglio, N. & Aiuti, A. 2014. Progress in gene therapy for 
primary immunodeficiencies using lentiviral vectors. Curr Opin Allergy Clin Immunol,
14, 527-534.
Shaw, J. W., Johnson, J. A. & Coons, S. J. 2005. US valuation of the EQ-5D health states: 
development and testing of the D1 valuation model. Med Care, 43, 203-220.
Suez, D., Stein, M., Gupta, S., Hussain, I., Melamed, I., Paris, K., Darter, A., Bourgeois, C., 
Fritsch, S., Leibl, H., McCoy, B., Gelmont, D. & Yel, L. 2016. Efficacy, safety, and 
pharmacokinetics of a novel human immune globulin subcutaneous, 20 % in patients 
with primary immunodeficiency diseases in North America. J Clin Immunol, 36, 700-
712.
Supersaxo, A., Hein, W. R. & Steffen, H. 1990. Effect of molecular weight on the lymphatic 
absorption of water-soluble compounds following subcutaneous administration. Pharm. 
Res, 7, 167-169.
Varni, J. W., Seid, M. & Rode, C. A. 1999. The PedsQL: measurement model for the pediatric 
quality of life inventory. Med. Care, 37, 126-139.
Ware, J. E., Jr. & Sherbourne, C. D. 1992. The MOS 36-item short-form health survey (SF-36). 
I. Conceptual framework and item selection. Med. Care, 30, 473-483.
Wasserman, R. L. 2012. Progress in gammaglobulin therapy for immunodeficiency: From 
subcutaneous to intravenous infusions and back again. J. Clin. Immunol, 32, 1153-1164.
World Health Organization 2003. Toxicity grading scale for determining the severity of adverse 
events.Web Link: 
http://www.icssc.org/Documents/Resources/AEManual2003AppendicesFebruary_06_20
03%20final.pdf
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Shire
Page 116
TAK-664-3001 Protocol
IGSC, 20%
27 OCT 2020
Zuizewind, C. A., van Kessel, P., Kramer, C. M., Muijs, M. M., Zwiers, J. C. & Triemstra, M. 
2018. Home-Based Treatment with Immunoglobulins: an Evaluation from the 
Perspective of Patients and Healthcare Professionals. J Clin Immunol.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use