Conditions: Primary Immunodeficiency Diseases (PID)
Allocation: NON_RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 16
Healthy volunteers: no

Brief summary:
The main aim of the study is to check how much TAK-771 stays in their blood over time, side effect from the study treatment or TAK-771, how much TAK-771 participants can receive without getting side effects from it, and if TAK-771 improves symptoms of primary immunodeficiency diseases (PID). This will help the study sponsor (Takeda) to work out the best dose to give people in the future.

The participants will be treated with TAK-771 for totally 27 or 30 weeks. Treatment period is consist of two periods called Epoch 1 and Epoch 2. In Epoch 1, different groups of participants will receive lower to higher doses of TAK-771 for 3 to 6 weeks. The study doctors will check for side effects from each dose of TAK-771. In Epoch 2, participants will receive TAK-771 once a 3 or 4 weeks until the end of 24 weeks.

There will be many clinic visits. The number of visits will depend on the infusion cycles of study drug (every 3, or 4 weeks).

Detailed description:

Arms:
arm 1: TAK-771 included IGI 10% and Recombinant Human Hyaluronidase (rHuPH20). Participants received subcutaneous infusion of rHuPH20 solution at a dose of 80 U/g IgG first, followed by SC infusion of 10% IGI within 10 minutes of completion of the infusion of rHuPH20 solution. The dose of 10% IGI was increased from 1/3 of full dose to full dose in 3 weeks for participants who received TAK-771 once every 3 weeks, or from 1/4 of full dose to full dose in 6 weeks for participants who received TAK-771 once every 4 weeks. arm 2: TAK-771 included Immune Globulin Infusion (IGI) 10% and Recombinant Human Hyaluronidase (rHuPH20). Participants received subcutaneous infusion of rHuPH20 solution at a dose of 80 U/g IgG first, followed by SC infusion of 10% IGI within 10 minutes of completion of the infusion of rHuPH20 solution, every 3, or 4 weeks for up to Week 27 for participants with 4-Week dosing interval or Week 25 for participants with 3-Week dosing interval.

Interventions: intervention 1: TAK-771
Intervention descriptions: intervention 1: Intervention description; Immune Globulin Infusion (IGI) 10% and Recombinant Human Hyaluronidase (rHuPH20)

Protocol document:
Prot_000.pdf: 
Clinical Study Protocol 
NCT Number: NCT05150340 
Title: A Phase 3, Open-label, Non-controlled Study to Evaluate the Pharmacokinetics, 
Safety and Tolerability, and Efficacy of TAK-771 in Japanese Subjects with Primary 
Immunodeficiency Diseases (PID) 
Study Number: TAK-771-3004 
Document Version and Date: Amendment 1 / 19-May-2022 
Certain information within this document has been redacted (ie, specific content is 
masked irreversibly from view) to protect either personally identifiable information or 
company confidential information. 


TAKEDA PHARMACEUTICALS
PROTOCOL:
TAK-771-3004
Title:
A Phase 3, Open-label, Non-controlled Study to Evaluate the 
Pharmacokinetics, Safety and Tolerability, and Efficacy of TAK-771 in 
Japanese Subjects with Primary Immunodeficiency Diseases (PID)
Short Title:
Pharmacokinetics, Safety and Tolerability, and Efficacy Evaluation of 
TAK-771 in Japanese Subjects with PID
Study Phase:
Phase 3
Drug:
TAK-771
Immune Globulin Infusion 10% (Human) [10% IGI] with Recombinant 
Human Hyaluronidase [rHuPH20]
IND Number:
Not Applicable
EUDRACT 
Number:
Not Applicable
Sponsor:
Takeda Pharmaceutical Company Limited 
1-1, Doshomachi 4-Chome, Chuo-ku, Osaka-shi, Osaka, Japan
Principal / 
Coordinating 
Investigator:
TBD
Protocol History:
Protocol Amendment 1 (version date: 19 May 2022)
replaces
Original Protocol (version date: 13 Jul 2021)
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Page 2
TAK-771 (10%IGI with rHuPH20)
Clinical Study Protocol: TAK-771-3004
19 May 2022
PROTOCOL SIGNATURE PAGE
Sponsor’s (Takeda) Approval
Signature:
Date:
Investigator’s Acknowledgement
I have read this protocol for Study TAK-771-3004.
Title: A Phase 3, Open-label, Non-controlled Study to Evaluate the Pharmacokinetics, Safety 
and Tolerability, and Efficacy of TAK-771 in Japanese Subjects with Primary Immunodeficiency 
Diseases (PID)
I have fully discussed the objective(s) of this study and the contents of this protocol with the 
sponsor’s representative.
I understand that the information in this protocol is confidential and should not be disclosed, 
other than to those directly involved in the execution or the scientific/ethical review of the study, 
without written authorization from the sponsor. It is, however, permissible to provide the 
information contained herein to a subject in order to obtain their consent to participate.
I agree to conduct this study according to this protocol and to comply with its requirements, 
subject to ethical and safety considerations and guidelines, and to conduct the study in 
accordance with International Council for Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use guidelines on Good Clinical Practice and with 
the applicable regulatory requirements.
I understand that failure to comply with the requirements of the protocol may lead to the 
termination of my participation as an investigator for this study.
I understand that the sponsor may decide to suspend or prematurely terminate the study at any 
time for whatever reason; such a decision will be communicated to me in writing. Conversely, 
should I decide to withdraw from execution of the study I will communicate my intention 
immediately in writing to the sponsor.
Investigator Name and Address:
(please hand print or type)
Signature:
Date:
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Page 3
TAK-771 (10%IGI with rHuPH20)
Clinical Study Protocol: TAK-771-3004
19 May 2022
SUMMARY OF CHANGES FROM PREVIOUS PROTOCOL VERSION
Protocol Amendment Summary and Rationale:
The following is a summary of the changes made in the amendment 1.
Protocol Amendment 
Summary of Change(s) Since the Last Version of the Approved Protocol
Amendment 1
Amendment Date:
19 May 2022
Global/Region/Country/
Site Specific: Japan
Description of Each Change and Rationale 
Section(s) Affected by Change
1
Descriptions of ‘Device used in 
clinical trial’ were added.
Due to the modification of 
Japanese GCP, information 
required for the ‘Device used in 
clinical trial’ was added.
PRODUCT QUALITY 
COMPLAINTS
Section 1.1 Mode of 
administration 
Section 6.3.3.2.2
Section 6.9
Section 10
Appendix 3.4
2
Infusion rate of 10%IGI was 
added
It was added to present enough 
information in the synopsis
Section 1.1 Mode of 
administration
3
Inclusion criteria 4 and relative 
description were modified.
It was modified due to the 
Japanese law which has been 
changed to recognize 18 years old 
as an adult
Section 1.1 Inclusion criteria
Section 5.1
Section 8.1.1
4
Exclusion criteria 9 was 
modified. 
It was modified since the 
assessment of anti-IgA antibodies 
is not commercially available in 
clinical practice in Japan. 
Section 1.1 Exclusion criteria
Section 5.2
5
Description in endpoints and 
analysis for Safety were 
modified.
For consistency between protocol 
and SAP
Section 1.1 Endpoints
Section 3.2 Table 5
Section 3.2.2
Section 9.7
6
HRQoL index for Treatment 
satisfaction (Life Quality Index) 
was removed.
Due to a difficulty in use of Life 
Quality Index, it was not 
implemented in this study.
Section 1.1 Endpoints
Section 3.2 Table 5
Section 3.2.2
Section 8.2.5.3.2
Section 9.8.1
7
Additional items to be 
summarized descriptively were 
included.
For consistency with tables to be 
produced.
Section 1.1 Statistical analysis
Section 9.6
Section 9.7
8
Analysis for treatment 
preference was corrected
Error in summarization of 
treatment preference was 
corrected.
Section 1.1 Statistical analysis
Section 9.8.1
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TAK-771 (10%IGI with rHuPH20)
Clinical Study Protocol: TAK-771-3004
19 May 2022
Protocol Amendment 
Summary of Change(s) Since the Last Version of the Approved Protocol
Amendment 1
Amendment Date:
19 May 2022
Global/Region/Country/
Site Specific: Japan
Description of Each Change and Rationale 
Section(s) Affected by Change
9
Screening visits column for 
subjects switching from 
IVIG/cSCIG treatment shown in 
schedule of activities and 
clinical laboratory tests were 
modified. The description in the 
body was also modified 
accordingly.
For administrative clarification
Section 1.3 Table 1, Table 3
Section 4.1
Appendix 2 Table 9, Table 11
10
Description of self-measurement 
of vital signs was added.
It was added to clarify the 
procedure of data collection when 
a subject chooses to have a self-
infusion at home.
Section 1.3 Table 1, Table 2, 
Table 3, Table 4
Section 8.2.4.4
Section 8.2.8
11
An instruction for dose 
modification based on weight 
changes was added.
It was added to clarify the level of 
weight changes which require the 
dose modifications.
Section 6.3.4 
12
The timing of specific antibody 
testing described in the body 
text was corrected, and it was 
added that the testing at PK 
troughs is not required for those 
who are not in the PK 
assessment.
It was added to clarify who don’t 
need to have the test at PK 
troughs and correct the 
inconsistency between the text 
description in the body and 
appendix tables.
Section 8.2.2.3
Appendix 2 Table 9, Table 10, 
Table 11, Table 12
13
Information regarding analysis 
of antibody titer was added. 
It was added to clarify how to 
analyze the antibody when there 
is more than one samples from a 
same subject. 
Section 8.2.4.5.3
14
Information regarding 
QoL/treatment satisfaction data 
capturing was added.
For clarification
Section 8.2.5.3
15
Version number of SAS to be 
used in this study was added
For clarification
Section 9.1
16
Description of SAE reporting 
was modified.
It was modified to reflect the 
actual procedure accurately.
CONTACT
Appendix 3.4
17
Description for reporting of 
abuse, misuse, overdose, or 
medication error was modified
It was modified to reflect the 
actual procedure accurately.
Appendix 3.9
18
The list of abbreviations was 
modified
For update
Appendix 8
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TAK-771 (10%IGI with rHuPH20)
Clinical Study Protocol: TAK-771-3004
19 May 2022
Protocol Amendment 
Summary of Change(s) Since the Last Version of the Approved Protocol
Amendment 1
Amendment Date:
19 May 2022
Global/Region/Country/
Site Specific: Japan
Description of Each Change and Rationale 
Section(s) Affected by Change
19
Correction of error
Typos and errors were corrected.
Section 1.1 Endpoints
Section 3.2 Table 5
Section 6.3.3.2.4
Section 8.2.4.5.2
Section 9.3
Section 9.4
Section 9.7.4
Section 9.8.1
Appendix 2 Table 14
See Appendix 9 for protocol history, including all previous amendments.
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TAK-771 (10%IGI with rHuPH20)
Clinical Study Protocol: TAK-771-3004
19 May 2022
CONTACTS
Contacts and Responsibilities for Study-Related Activities
Certain events and study-related activities will require the investigator and/or patient to have 
appropriate contact information. The sponsor or contract research organization (CRO) will 
provide investigators with emergency medical contact information cards to be carried by each 
subject, per individual country requirements.
Serious Adverse Event Reporting
If a subject experiences a serious adverse event (SAE) or a non-serious adverse event (AE) 
requiring expedited reporting per the protocol, the investigator must report the event to the 
sponsor or CRO within 24 hours via the Electronic Data Capture (EDC) system, if possible. 
If the event cannot be reported via EDC during the required period, it should be reported to 
BELLSYSTEM 24 shown below via e-mail or fax using an SAE Form in the same time frame:
Serious Adverse Event Reporting Contact Information for Japan:
BELLSYSTEM24, Inc.
Protocol and Safety-Related Questions or Concerns
For protocol- or safety-related questions or concerns during normal business hours 9:00 AM 
through 5:00 PM Japan, the investigator must contact the CRO medical monitor:
 
For protocol- or safety-related questions or concerns outside of normal business hours, the 
investigator must contact the CRO local medical monitor:
 
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TAK-771 (10%IGI with rHuPH20)
Clinical Study Protocol: TAK-771-3004
19 May 2022
PRODUCT QUALITY COMPLAINTS
Investigators are required to report investigational product/device-used-in-clinical-trial quality 
complaints or non-medical complaints to Takeda 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 Takeda licensed or investigational products, as well as device-used-in-clinical-trial defined in 
this protocol, received in writing, electronically, or orally, which indicates an impact to a 
product’s strength, identity, safety, purity, or quality, or which suggests that the product did not 
meet the criteria defined in the regulatory applications, licenses, or marketing authorizations for 
the product. Examples of investigational product/device-used-in-clinical-trial 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 (eg, 
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 (including the device-used-in-clinical-trial quality 
issues) using “Clinical Trial Material Complaint Form” via the e-mail address:
For instructions on reporting AEs related to product complaints, see Appendix 3.4.
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TAK-771 (10%IGI with rHuPH20)
Clinical Study Protocol: TAK-771-3004
19 May 2022
TABLE OF CONTENTS
PROTOCOL SIGNATURE PAGE............................................................................................. 2
SUMMARY OF CHANGES FROM PREVIOUS PROTOCOL VERSION.......................... 3
CONTACTS .................................................................................................................................. 6
PRODUCT QUALITY COMPLAINTS..................................................................................... 7
TABLE OF CONTENTS ............................................................................................................. 8
1. PROTOCOL SUMMARY ..................................................................................................... 13
1.1 Synopsis.............................................................................................................................. 13
1.2 Schema ............................................................................................................................... 20
1.3 Schedule of Activities........................................................................................................ 21
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...................................................................................................... 33
3. OBJECTIVES AND ENDPOINTS ....................................................................................... 34
3.1 Study Objectives ............................................................................................................... 34
3.1.1 Primary Objective ..................................................................................................... 34
3.1.2 Secondary Objectives ................................................................................................ 34
3.2 Study Endpoints................................................................................................................ 34
3.2.1 Primary Endpoint...................................................................................................... 34
3.2.2 Secondary Endpoints................................................................................................. 34
4. STUDY DESIGN..................................................................................................................... 39
4.1 Overall Design................................................................................................................... 39
4.2 Scientific Rationale for Study Design.............................................................................. 41
4.3 Justification for Dose........................................................................................................ 41
4.4 Duration of Subject Participation and Study Completion Definition.......................... 41
4.5 Sites and Regions .............................................................................................................. 41
5. STUDY POPULATION ......................................................................................................... 42
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Clinical Study Protocol: TAK-771-3004
19 May 2022
5.1 Inclusion Criteria.............................................................................................................. 42
5.2 Exclusion Criteria............................................................................................................. 43
5.3 Restrictions........................................................................................................................ 45
5.4 Reproductive Potential..................................................................................................... 45
5.4.1 Female Contraception ............................................................................................... 45
6. STUDY INTERVENTION..................................................................................................... 47
6.1 Investigational Product .................................................................................................... 47
6.1.1 Identity of Investigational Product .......................................................................... 47
6.2 Non-investigational Product ............................................................................................ 48
6.3 Administration of Investigational Product..................................................................... 48
6.3.1 Interactive Response Technology for Investigational Product Management ...... 48
6.3.2 Allocation of Subjects to Treatment ........................................................................ 48
6.3.3 Dosing.......................................................................................................................... 48
6.3.3.1 Dosing in Epoch 1 (Ramp-up Period)............................................................... 49
6.3.3.2 Dosing in Epoch 2 ............................................................................................... 50
6.3.4 Dose Modification ...................................................................................................... 52
6.4 Labeling, Packaging, Storage, and Handling of Investigational Product.................... 53
6.4.1 Labeling ...................................................................................................................... 53
6.4.2 Packaging.................................................................................................................... 53
6.4.3 Storage ........................................................................................................................ 53
6.5 Drug Accountability ......................................................................................................... 54
6.6 Training ............................................................................................................................. 56
6.7 Subject Compliance.......................................................................................................... 56
6.8 Prior and Concomitant Therapy..................................................................................... 56
6.8.1 Prior Treatment......................................................................................................... 56
6.8.2 Concomitant Treatment............................................................................................ 56
6.8.3 Permitted Treatment................................................................................................. 56
6.8.4 Prohibited Treatment................................................................................................ 57
6.9 Devices Used in Clinical Trial.......................................................................................... 58
6.9.1 Marketing approval................................................................................................... 58
6.9.2 Indications for Use..................................................................................................... 58
6.9.3 Usage Instructions and Warnings............................................................................ 58
7. DISCONTINUATION OF STUDY INTERVENTION AND SUBJECT
DISCONTINUATION/WITHDRAWAL............................................................................. 59
7.1 Discontinuation of Study Treatment............................................................................... 59
7.2 Reasons for Discontinuation ............................................................................................ 59
7.3 Withdrawal from the Study............................................................................................. 59
7.4 Subjects “Lost to Follow-up” Prior to the Last Scheduled Visit.................................. 60
8. STUDY ASSESSMENTS AND PROCEDURES................................................................. 61
8.1 Study Periods..................................................................................................................... 61
8.1.1 Screening .................................................................................................................... 61
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Clinical Study Protocol: TAK-771-3004
19 May 2022
8.1.2 Treatment Period....................................................................................................... 62
8.1.2.1 Epoch 1 (Ramp-up Period) ................................................................................ 62
8.1.2.2 Epoch 2 (24-week Treatment Period) ............................................................... 64
8.1.3 End-of-Study/Early Termination Visit.................................................................... 64
8.1.4 Follow-up Period........................................................................................................ 65
8.1.5 Additional Care of Subjects After the Study .......................................................... 65
8.2 Study Assessments ............................................................................................................ 65
8.2.1 Demographic and Other Baseline Characteristics ................................................. 65
8.2.1.1 Demographics...................................................................................................... 65
8.2.1.2 Medical and Medication History....................................................................... 66
8.2.2 Pharmacokinetics....................................................................................................... 66
8.2.2.1 Serum IgG Trough Levels ................................................................................. 66
8.2.2.2 Pharmacokinetic Profiles................................................................................... 66
8.2.2.3 Specific Antibodies.............................................................................................. 67
8.2.3 Efficacy ....................................................................................................................... 67
8.2.3.1 Acute Serious Bacterial Infection Rate............................................................. 67
8.2.3.2 Infections ............................................................................................................. 67
8.2.4 Safety........................................................................................................................... 68
8.2.4.1 Physical Examination......................................................................................... 68
8.2.4.2 Body Height and Weight.................................................................................... 68
8.2.4.3 Adverse Events.................................................................................................... 68
8.2.4.4 Vital Signs............................................................................................................ 68
8.2.4.5 Clinical Laboratory Tests .................................................................................. 69
8.2.4.6 Pregnancy Test.................................................................................................... 73
8.2.5 Other ........................................................................................................................... 73
8.2.5.1 Pharmacodynamics............................................................................................. 73
8.2.5.2 Genetics................................................................................................................ 73
8.2.5.3 Disease Activity and Health-related Quality of Life........................................ 73
8.2.5.4 Healthcare Resource Utilization........................................................................ 74
8.2.6 Volume of Blood to Be Drawn from Each Subject ................................................. 74
8.2.7 Retention of Bioavailability and Bioequivalence Testing Samples ....................... 74
8.2.8 Subject Diary.............................................................................................................. 74
8.2.9 Product Administration ............................................................................................ 75
9. STATISTICAL CONSIDERATIONS .................................................................................. 76
9.1 Statistical Analysis Process .............................................................................................. 76
9.2 Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee......... 76
9.3 Sample Size and Power Considerations.......................................................................... 76
9.4 Statistical Analysis Set(s).................................................................................................. 77
9.5 Pharmacokinetic Analyses ............................................................................................... 78
9.6 Efficacy Analysis............................................................................................................... 78
9.7 Safety Analyses.................................................................................................................. 79
9.7.1 Analysis of Adverse Events....................................................................................... 79
9.7.1.1 Definitions............................................................................................................ 79
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19 May 2022
9.7.1.2 Handling of Recurrent Adverse Events and Other Adverse Event Situations
.............................................................................................................................. 80
9.7.1.3 Occurrence and Number of Adverse Events.................................................... 80
9.7.1.4 Adverse Events per Infusion, per Subject, per Subject-Year......................... 81
9.7.1.5 Tolerability.......................................................................................................... 82
9.7.2 Clinical Laboratory Data.......................................................................................... 83
9.7.3 Vital Signs and Body Weight.................................................................................... 83
9.7.4 Antibodies................................................................................................................... 83
9.8 Other Analyses.................................................................................................................. 84
9.8.1 Disease Activity and Health-related Quality of Life Analyses............................... 84
9.8.2 Product Administration ............................................................................................ 84
10. REFERENCES...................................................................................................................... 85
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TAK-771 (10%IGI with rHuPH20)
Clinical Study Protocol: TAK-771-3004
19 May 2022
1. PROTOCOL SUMMARY
1.1 Synopsis
Protocol number: TAK-771-3004
Drug: TAK-771
Immune Globulin Infusion 10% (Human) [10% IGI] with 
Recombinant Human Hyaluronidase [rHuPH20]
Title of the study: A Phase 3, Open-label, Non-controlled Study to Evaluate the Pharmacokinetics, Safety and 
Tolerability, and Efficacy of TAK-771 in Japanese Subjects with Primary Immunodeficiency Diseases (PID)
Short title: Pharmacokinetics, Safety and Tolerability, and Efficacy Evaluation of TAK-771 in Japanese Subjects 
with PID
Study phase: Phase 3
Number of subjects (total and per treatment arm):
15 subjects will be enrolled.
Investigator(s): 
Multicenter study
Site(s) and Region(s): 
This study is planned to be conducted in 10 to 15 sites in Japan
Study period (planned):
Approximately 2 years
Clinical phase:
3
Objectives:
Primary: 
To assess serum trough levels of total immunoglobulin G (IgG) when using TAK-771 as maintenance therapy in 
Japanese subjects with PID.
Secondary: 

To characterize the pharmacokinetic (PK) profiles of TAK-771 in Japanese subjects with PID following
TAK-771 administration.

To evaluate the safety and tolerability of TAK-771 in Japanese subjects with PID.

To evaluate the efficacy of TAK-771 in Japanese subjects with PID.

To assess disease activity and health-related quality of life (HRQoL) in Japanese subjects with PID
following TAK-771 administration.
Rationale:
Approximately 2,900 to 3,500 people are diagnosed with PID in Japan, and the number of diagnosed patients is 
increasing (Ishimura et al., 2011). Immunoglobulin (IG) replacement therapy has been widely used for patients 
with PID and the administration route is commonly either monthly intravenous (IV) or weekly subcutaneous (SC) 
injection. TAK-771 has been developed to address the major limitation of conventional subcutaneous 
immunoglobulin (cSCIG) therapy and it significantly enhances SC administration in PID by offering improved 
bioavailability (as compared to cSCIG therapy) without requiring greater doses than those administered 
intravenously. TAK-771 allows the SC administration of standard PID monthly dosing volumes, and the 
utilization of infusion rates equal to IV administration while preserving the advantages of SC administration. 
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TAK-771 (10%IGI with rHuPH20)
Clinical Study Protocol: TAK-771-3004
19 May 2022
This proposed study is designed to evaluate serum trough IgG levels, safety and tolerability, and efficacy of 
TAK-771 which will be administered subcutaneously at 3- or 4-week intervals, and assesses disease activity and 
HRQoL in subjects with PID in Japan. It aims to demonstrate maintenance of total IgG trough levels in PID 
patients after being on stable doses of TAK-771. The results from this study will extend/support the data obtained 
in the global pivotal study (Study 160603) and the extension study (Study 160902), in which switching from 
intravenous immunoglobulin (IVIG) to TAK-771 in patients with PID was evaluated. Data from these global 
studies will be used for the regulatory submission for the approval of TAK-771 in Japan.
Investigational product, dose, and mode of administration:
Investigational product: TAK-771 (10% IGI with rHuPH20)
Dosage form: injectable SC solution
Dose: [rHuPH20] 80 U/g IgG (rHuPH20 drug product: 160 U/mL)
[10% IGI] equivalent IgG amount to previous treatment of each patient (after the initial ramp-up) (In the case of 
switching from subcutaneous immunoglobulin (SCIG), to be calculated on the basis of weekly equivalents from 
SCIG treatment, that is to say the TAK-771 doses at  3- or 4-week intervals are calculated by multiplying SCIG 
weekly dose by 3 or 4.) 
Dosage frequency: starting with a ramp-up: dosing interval of 1 week, then 2 weeks, then 3 weeks; then once 
every 3 or 4 weeks (as tolerated and as scheduled during pre-study period)
Subjects with 4-week Dosing Interval Regimen with TAK-771
Week
Infusion Number
Dose of 10% IGI
Week 1
1st. infusion
1/4 of full dose
Week 2
2nd. infusion
1/2 of full dose
Week 4
3rd. infusion
3/4 of full dose
Week 7 and the following 4-week intervals
4th. infusion and the following infusions
full dose
Subjects with 3-week Dosing Interval Regimen with TAK-771
Week
Infusion Number
Dose of 10% IGI
Week 1
1st. infusion
1/3 of full dose
Week 2
2nd. infusion
2/3 of full dose
Week 4 and the following 3-week intervals
3rd. infusion and the following infusions
full dose
Mode of Administration: SC infusion of rHuPH20 solution at a dose of 80 U/g IgG will be administered first, to 
be followed by SC infusion of 10% IGI within 10 minutes of completion of the infusion of rHuPH20 solution. 
For the initial 2 administrations of rHuPH20 in the study, it will be infused at 60 to 120 mL/h/site as tolerated and 
the rate may be increased as tolerated by the subject and at the discretion of the investigator, but not to exceed 
300 mL/h/site. SC infusion of 10% IGI will be administered via an infusion pump (SapphireTM Multi-Therapy)
at 1, 2, or 3 infusion sites per infusion day. For the initial 2 infusions in the study, the maximum infusion 
rate should be 80 mL/h and 240 mL/h per site, for subjects <40 kg and ≥40 kg body weight, respectively. 
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TAK-771 (10%IGI with rHuPH20)
Clinical Study Protocol: TAK-771-3004
19 May 2022
Step-wise increases are suggested in subsequent infusions with rate increases of up to 160 mL/h and 300 mL/h 
per site, for subjects <40 kg and ≥40 kg body weight, respectively.
Methodology:
This is a phase 3, open-label, non-controlled, multi-dose, multicenter study to evaluate PK, efficacy, safety and 
tolerability of TAK-771 in Japanese subjects with PID, as well as to assess disease activity and HRQoL. The 
patients who have been treated with IVIG, cSCIG, or TAK-664 can be enrolled in this study. After confirmation 
of eligibility, subjects will receive SCIG of TAK-771 in the treatment period. The TAK-771 administration is 
started with ramp-up infusion and subsequently in 3- or 4-weeks dosing frequency continued for 24 weeks. 
A schematic of the study design is included as Figure 1.
Inclusion and Exclusion Criteria: 
Inclusion Criteria:
The subject will not be considered eligible for the study without meeting all of the criteria below. 
1. Be a Japanese person.
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. The diagnosis must be confirmed by the
Medical Director prior to TAK-771 treatment.
3. Subject is 2 years or older at the time of screening/enrollment.
4. Written and/or electronic 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. If a
subject is <18 years of age, written and/or electronic informed consent should also be obtained from the
subject's legally authorized representative in addition to written informed assent by a subject if appropriate.
5. Subject has been receiving a stable clinical dose of IVIG or cSCIG, which is equivalent to approximately
200 to 600 mg/kg body weight per 3 to 4 week period for IVIG and approximately 50 to 200 mg/kg body
weight per week for cSCIG based on the description in the package insert, consistently over a period of at
least 3 months prior to screening, or
Subject has been receiving of TAK-664 with fixed dose and dosing frequency at least 3 months prior
to enrollment. That is, subject is about to complete Study TAK-664-3001 or participating in Study
TAK-664-3002.
6. Subject who has been receiving IVIG or cSCIG had all serum trough levels of IgG ≥5 g/L within 1 month
prior to the screening/enrollment.
7. Serum trough levels at screening/enrollment meet one of the following:
a.
IVIG-treated, cSCIG-treated subjects
Subject who had serum trough levels of IgG ≥5 g/L at the last 2 points in screening procedure before
the first administration of TAK-771.
b.
TAK-664-treated subjects
Subject who had serum trough levels of IgG ≥5 g/L at the last 2 points in Study TAK-664-3001 or
Study TAK-664-3002 (TAK-664 studies, hereafter) before the first administration of TAK-771
8. Subject is willing and able to comply with the requirements of the protocol.
9. Subject is willing and able to comply with use of digital tools and applications
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TAK-771 (10%IGI with rHuPH20)
Clinical Study Protocol: TAK-771-3004
19 May 2022
Exclusion Criteria:
The subject will be excluded from the study if any of the following exclusion criteria are met.
1.
Subject has a known history of or is positive at screening/enrollment 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.
For subjects who are switching from TAK-664 studies, the eligibility will be reconfirmed after the result of
the specialty test conducted at Week 1 become available.
2.
Abnormal laboratory values at screening/enrollment 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 aminotransferase (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 eGFR <60 mL/min/1.73m2.*
4.
Subject has been diagnosed with, or had 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/enrollment 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 IVIG, SCIG, and/or Immune Serum Globulin infusions
9.
Subject has immunoglobulin A (IgA) deficiency (serum IgA less than 0.07 g/L) and history of
hypersensitivity, or history of confirmed anti-IgA antibodies, or both.
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/enrollment**.
11. Subject has active infection and is receiving antibiotic therapy for the treatment of infection at the time of
screening/enrollment** or had a serious bacterial infection within the 3 months prior to
screening/enrollment.
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 SC therapy.
13. Subject has total protein >9 g/dL* or myeloma, or macroglobulinemia (IgM) or paraproteinemia.
14. Subject has a known allergy to hyaluronidase.
15. Women of childbearing potential who meet 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.
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TAK-771 (10%IGI with rHuPH20)
Clinical Study Protocol: TAK-771-3004
19 May 2022
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.
16. Subject has participated in another clinical study and has been exposed to an investigational product or
device within 30 days prior to study enrollment, (exception: TAK-664 studies).
17. Subject is scheduled to participate in another non-observational (interventional) clinical study involving an
investigational product or device during the course of the study.
18. Subjects who experiences clinically significant adverse events (AEs) in TAK-664 studies and it may worsen
by participating in this study.
19. Subject has severe dermatitis that would preclude adequate sites for safe product administration.*: For
subjects who are switching from TAK-664 studies, the latest laboratory data obtained in the TAK-664
studies will be used to determine the eligibility.
**: The exceptional use of antibiotics is allowed. See Section 6.8.4 for the details.
Maximum duration of subject participation in the study:

Screening period: up to 13 weeks

Treatment period [TAK-771 SCIG treatment period]:
-
Epoch 1: 3 weeks (3-week interval infusion) or 6 weeks (4-week interval infusion) of ramp-up dosing
period
-
Epoch 2: 12 weeks of dose adjustment period and 12 weeks of trough evaluation period
Endpoints
Analysis Populations /Analysis Sets:

Enrolled Set: All enrolled subjects who have signed informed (e)Consent and are assigned to subject
identification codes. Background summaries (e.g., subject disposition) will be based on the Enrolled Set.

Full Analysis Set (FAS): All enrolled subjects who received investigational drug at least once. Analysis of
efficacy, disease activity and HRQoL will be based on the FAS.

Safety Analysis Set (SAS): All enrolled subjects who received investigational drug at least once. Analysis
of safety, tolerability and product administration will be based on the SAS.

Pharmacokinetic Analysis Set (PKAS): All enrolled subjects who received investigational drug at least
once, have had at least 1 evaluable serum IgG concentration, and no major protocol deviations or events
that would affect the serum IgG concentration analysis results. Analysis of serum IgG trough concentrations
will be based on the PKAS and analysis of PK profiles will be based on the subset of 5 to 7 subjects aged
12 years and older in the PKAS.
Primary Endpoint:
Serum trough levels of total IgG (total serum trough IgG antibodies) measured during the trough evaluation 
period of Epoch 2 (administration of TAK-771).
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TAK-771 (10%IGI with rHuPH20)
Clinical Study Protocol: TAK-771-3004
19 May 2022
Secondary Endpoints:
Endpoints cover PK, safety and tolerability, efficacy, and disease activity and HRQoL.
Pharmacokinetic endpoints and parameters:

PK parameters for total serum levels of IgG and for IgG subclasses in the PK assessment period of Epoch 2
(in a subset of 5 to 7 subjects aged 12 years and older), which may include but not limited to the following:
maximum concentration (Cmax), time to maximum concentration (Tmax), area under the curve (AUC), half-
life, apparent total clearance (CL/F), apparent volume of distribution (Vz/F), minimum concentration (Cmin)

Serum trough levels of IgG subclasses in the trough evaluation period of Epoch 2

Trough levels of specific antibodies to clinically relevant pathogens (Clostridium tetani toxoid,
Haemophilus influenzae [HIB], Hepatitis B virus [HBV]) in Epoch 1 and 2
Safety and Tolerability Endpoints:

Occurrence of treatment-emergent adverse events (TEAEs) in Epoch 1 and 2, including but not limited to:
TAK-771-related and non-related, serious, non-serious, severe, local and systemic TEAEs, as well as
TEAEs leading to premature discontinuation from study, and infusion-associated TEAEs

Changes in clinical laboratory parameters in Epoch 1 and 2

Changes in vital signs and body weight in Epoch 1 and 2
Change from baseline in vital signs and body weight, and change from pre-infusion to post-infusion in vital
signs

Development of positive titer (≥ 1:160) binding antibodies, and development of neutralizing antibodies, to
rHuPH20 in Epoch 2
Number and percentage of subjects who develop anti-rHuPH20 binding antibody titers of ≥1:160
Number and percentage of subjects who develop neutralizing antibodies to rHuPH20

Occurrence of tolerability events related to the infusion of TAK-771 in Epoch 1 and 2
A tolerability event is considered to have occurred if an infusion was not tolerable, which is defined as
any changes in dosing of TAK-771 such as reduction of infusion rate, interruption or discontinuation of
TAK-771 due to TEAEs related to TAK-771. Number and percentage of subjects who experienced
tolerability events will be measured.

Number of weeks to reach final dose interval (3 weeks or 4 weeks) in Epoch 1

Percentage of subjects who achieve a treatment interval of 3 or 4 weeks in Epoch 2

Percentage of subjects who maintain a treatment interval of 3 or 4 weeks in Epoch 2
Efficacy endpoints:

Annual rate of validated acute serious bacterial infections (ASBIs) per subject in Epoch 1 and 2

Annual rate of all infections per subject in Epoch 1 and 2

Healthcare Resource Utilization in Epoch 1 and 2
-
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
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TAK-771 (10%IGI with rHuPH20)
Clinical Study Protocol: TAK-771-3004
19 May 2022

Infusion parameters in Epoch 2 including but not limited to: number of infusions per month, number of
infusion sites per infusion, number of infusion sites per month, duration of individual infusions, maximum
infusion rate/site, and infusion volume/site
Disease activity and health-related quality of life endpoints:

QoL: PEDS-QL (Varni et al., 1999), SF-36 v2 (Ware and Sherbourne, 1992), EQ-5D-3L Health
Questionnaire (Shaw et al., 2005) in Epoch 1 and 2

Treatment Satisfaction (TSQM-9) (Daly et al., 1991) in Epoch 1 and 2

Treatment Preference at end-of-study (EOS)/Early termination
Statistical analysis
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. In addition, 1st quartile (Q1) and 3rd quartile (Q3) will be summarized for safety and efficacy tables. 
Categorical endpoints/outcome measures (e.g., AEs) will be summarized in terms of number and percent of 
subjects and number of occurrences in each category.
For serum IgG, IgG subclasses (IgG1, IgG2, IgG3, and IgG4) and specific antibodies 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, number and percentage of subjects in each category will be summarized for 
the endpoint of Treatment Preference at EOS/Early Termination, and raw (actual) and change from baseline 
values will be summarized descriptively and summaries will be provided for other endpoints.
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TAK-771 (10%IGI with rHuPH20)
Clinical Study Protocol: TAK-771-3004
19 May 2022
1.3 Schedule of Activities
Table 1. Schedule of Activities for Subjects Switching from IVIG/cSCIG Treatment: 4-week Dosing Interval
Procedure
Screening period
Treatment period
Epoch 1
(Ramp-up)
Epoch 2
(4-week dosing interval)
EOS/Early 
termination 
visit
Visit No.
Screening 
visit 1a
Screening 
visit 2a
R-1
R-2
R-3
Visit 1b
Visit 2 b Visit 3 b Visit 4 b Visit 5 b Visit 6 b
Week
up to 13 weeks 
before Week 1
Week 
1
Week 
2
Week 
4
Week 
7
Week 
11
Week 
15
Week 
19
Week 
23
Week 
27
Week 31
Visit allowance
-
-
±0 day
±0 day ±0 day
±3 days
±3 days ±3 days ±3 days ±3 days
±3 days
±3 days
Informed consentc
X
Assessment of eligibility
X
Demographic information
X
Medical and medication history
X
Body height
X
Body weight
X
Xd
X
X
X
X
X
X
X
X
X
X
Physical examination
X
Xd
X
X
X
X
X
X
X
X
X
X
Concomitant medication, non-drug 
therapies
X
Xd
X
X
X
X
X
X
X
X
X
X
Clinical laboratory assessmentse
X
Xd
X
X
X
X
X
X
X
X
PK assessmentsf
X
Subject's own IVIG/cSCIG treatment
X
Xd
Investigational product treatmentg
X
X
X
X
X
X
X
X
X
Vital signsh
X
Xd
X
X
X
X
X
X
X
X
X
X
Adverse events review
X
Collection/Review diaries
X
X
X
X
X
X
X
X
X
X
Quality of life assessments
X
X
X
Treatment satisfaction assessment
X
X
X
Treatment preference
X
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TAK-771 (10%IGI with rHuPH20)
Clinical Study Protocol: TAK-771-3004
19 May 2022
Table 1. Schedule of Activities for Subjects Switching from IVIG/cSCIG Treatment: 4-week Dosing Interval
Procedure
Screening period
Treatment period
Epoch 1
(Ramp-up)
Epoch 2
(4-week dosing interval)
EOS/Early 
termination 
visit
Visit No.
Screening 
visit 1a
Screening 
visit 2a
R-1
R-2
R-3
Visit 1b
Visit 2 b Visit 3 b Visit 4 b Visit 5 b Visit 6 b
Week
up to 13 weeks 
before Week 1
Week 
1
Week 
2
Week 
4
Week 
7
Week 
11
Week 
15
Week 
19
Week 
23
Week 
27
Week 31
Visit allowance
-
-
±0 day
±0 day ±0 day
±3 days
±3 days ±3 days ±3 days ±3 days
±3 days
±3 days
Healthcare resource utilization
X
Self-administration proficiencyi
X
X
X
X
X
X
X
X
X
Abbreviations: AE=adverse event, cSCIG=conventional subcutaneous immunoglobulin, EOS=end-of-study, IgG=immunoglobulin G, 
IVIG=intravenous immunoglobulin,  PK= pharmacokinetic, SC= subcutaneous
a.
Visit frequency is dependent on the dosing frequency of subject’s own IVIG/cSCIG treatment. The interval from Screening Visit 1 to Screening Visit 2 should be at
least 3 weeks.
b. When TAK-771 dose is administered over multiple days as divided doses with 48 to 72 hours between doses due to the infusion volume, assessments don’t need to be
repeated on the second day of infusion.
c.
Written and/or electronic informed consent must be obtained prior to any study procedures including screening.
d. Assessments are conducted at every visit during the screening period.
e.
For laboratory assessments specific to the visits, see Table 9 in Appendix 2.
f.
Alternatively, PK assessment can be started at 1 visit earlier and completed just before the last SC infusion at the discretion of investigator. See Table 13 in Appendix 2
for PK assessment schedule.
g. Subcutaneous infusion of rHuPH20 solution will be administered first, followed by SC infusion of 10% IGI within 10 minutes of completion of the infusion of
rHuPH20 solution in a sequential order at the same location. The recommended site(s) for SC infusion are the middle to upper abdomen and thighs. If more than one
site are used, the infusion sites should be rotated by choosing opposite sides of the body. Avoid bony prominences, or scarred areas. The product should not be infused
at or around an infected or acutely inflamed area due to the potential risk of spreading a localized infection. Self-administration of SC infusions at home may be allowed
at the discretion of investigator after the training, evaluation and verification of subject’s (and/or caregiver’s) proficiency in self-infusion procedures are completed.
h. Blood pressure measurements will be taken after subjects remain sitting in an upright position for at least one minute. For the initial 3 SC infusions, vital signs are to be
monitored and recorded at any time prior to infusion, in the event of occurrence of AE(s), and within 60 minutes of completion of an infusion. During subsequent
infusion visits, vital signs will be taken once per administration, but will be recorded multiple times if an AE occurs. When subjects have self-infusion at home and an
AE occurs, subjects (and/or caregiver) should measure vital signs by themselves and record the values on subject diary.
i.
Subcutaneous infusions will be administered by an appropriately trained healthcare professional (eg, infusion nurse) or, if applicable, can be administered by the subject
and/or a caregiver. Training, evaluation, and verification of the subject’s (and/or caregiver’s) proficiency in performing self-infusion procedures by the
investigator/designee must be documented as a prerequisite before the subject (and/or caregiver) will be allowed to begin self-administration of SC infusions at sites,
home or other suitable locations. A proficiency checklist will be completed by the investigator/designee once training begins and until the subject’s (and/or caregiver’s)
proficiency is demonstrated. The proficiency check will not be required when subject has self-administration of SC infusions at home.
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TAK-771 (10%IGI with rHuPH20)
Clinical Study Protocol: TAK-771-3004
19 May 2022
Table 2. Schedule of Activities for Subjects Switching from TAK-664 Treatment: 4-week Dosing Interval
Procedure
Treatment period
Epoch 1
(Ramp-up)
Epoch 2
(4-week dosing interval)
EOS/Early 
termination 
visit
Visit No.
R-1
R-2
R-3
Visit 1b
Visit 2b
Visit 3b
Visit 4b
Visit 5b
Visit 6b
Week
Week 1a
Week 2
Week 4
Week 7
Week 11
Week 15
Week 19
Week 23
Week 27
Week 31
Visit allowance
±0 day
±0 day
±0 day
±3 days
±3 days
±3 days
±3 days
±3 days
±3 days
±3 days
Informed consentc
X
Assessment of eligibilityd
X
Demographic information
Xe
Medical and medication history
Xe
Body height
Xe
Body weight
X
X
X
X
X
X
X
X
X
X
Physical examination
X
X
X
X
X
X
X
X
X
X
Concomitant medication, non-drug 
therapies
Xe
X
X
X
X
X
X
X
X
X
Clinical laboratory assessmentsf
X
X
X
X
X
X
X
X
PK assessmentsg
X
Investigational product treatmenth
X
X
X
X
X
X
X
X
X
Vital signsi
X
X
X
X
X
X
X
X
X
X
Adverse events review
X
Collection/Review diaries
X
X
X
X
X
X
X
X
X
X
Quality of life assessments
X
X
X
Treatment satisfaction assessment
Xe
X
X
Treatment preference
X
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TAK-771 (10%IGI with rHuPH20)
Clinical Study Protocol: TAK-771-3004
19 May 2022
Table 2. Schedule of Activities for Subjects Switching from TAK-664 Treatment: 4-week Dosing Interval
Procedure
Treatment period
Epoch 1
(Ramp-up)
Epoch 2
(4-week dosing interval)
EOS/Early 
termination 
visit
Visit No.
R-1
R-2
R-3
Visit 1b
Visit 2b
Visit 3b
Visit 4b
Visit 5b
Visit 6b
Week
Week 1a
Week 2
Week 4
Week 7
Week 11
Week 15
Week 19
Week 23
Week 27
Week 31
Visit allowance
±0 day
±0 day
±0 day
±3 days
±3 days
±3 days
±3 days
±3 days
±3 days
±3 days
Healthcare resource utilization
X
Self-administration proficiencyj
X
X
X
X
X
X
X
X
X
Abbreviations: AE=adverse event, EOS=end-of-study, IgG=immunoglobulin G, PK= pharmacokinetic, SC= subcutaneous
a. The assessments for the Week 1 in TAK-771-3004 can be combined with the EOS/Early termination visit assessments in TAK-664 studies.
b. When TAK-771 dose is administered over multiple days as divided doses with 48 to 72 hours between doses due to the infusion volume, assessments don’t
need to be repeated on the second day of infusion.
c. Written and/or electronic informed consent must be obtained prior to any study procedures.
d. The latest laboratory data obtained in the TAK-664 studies will be used to determine the eligibility.
e. Data collected in the TAK-664 studies can be used if available.
f.
For laboratory assessments and PK assessments specific to the visits, see Table 10 in Appendix 2.
g. Alternatively, PK assessment can be started at 1 visit earlier and completed just before the last SC infusion at the discretion of investigator. See Table 13 in
Appendix 2 for PK assessment schedule.
h. Subcutaneous infusion of rHuPH20 solution will be administered first, followed by SC infusion of 10% IGI within 10 minutes of completion of the infusion
of rHuPH20 solution in a sequential order at the same location. The recommended site(s) for SC infusion are the middle to upper abdomen and thighs. If more
than one site are used, the infusion sites should be rotated by choosing opposite sides of the body. Avoid bony prominences, or scarred areas. The product
should not be infused at or around an infected or acutely inflamed area due to the potential risk of spreading a localized infection. Self-administration of SC
infusions at home may be allowed at the discretion of investigator after the training, evaluation and verification of subject’s (and/or caregiver’s) proficiency
in self-infusion procedures are completed.
i.
Blood pressure measurements will be taken after subjects remain sitting in an upright position for at least one minute. For the initial 3 SC infusions, vital
signs are to be monitored and recorded at any time prior to infusion, in the event of occurrence of AE(s), and within 60 minutes of completion of an infusion.
During subsequent infusion visits, vital signs will be taken once per administration, but will be recorded multiple times if an AE occurs. When subjects have
self-infusion at home and an AE occurs, subjects (and/or caregiver) should measure vital signs by themselves and record the values on subject diary.
j.
Subcutaneous infusions will be administered by an appropriately trained healthcare professional (eg, infusion nurse) or, if applicable, can be administered by
the subject and/or a caregiver. Training, evaluation, and verification of the subject’s (and/or caregiver’s) proficiency in performing self-infusion procedures
by the investigator/designee must be documented as a prerequisite before the subject (and/or caregiver) will be allowed to begin self-administration of SC
infusions at sites, home or other suitable locations. A proficiency checklist will be completed by the investigator/designee once training begins and until the
subject’s (and/or caregiver’s) proficiency is demonstrated. The proficiency check will not be required when subject has self-administration of SC infusions at
home.
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Page 25
TAK-771 (10%IGI with rHuPH20)
Clinical Study Protocol: TAK-771-3004
19 May 2022
Table 3. Schedule of Activities for Subjects Switching from IVIG/cSCIG Treatment: 3-Week Treatment Interval
Procedure
Screening period
Treatment period
Epoch 1
(Ramp-up)
Epoch 2
(3-week dosing interval)
EOS/Early 
termination 
visit
Visit No.
Screening 
visit 1a
Screening 
visit 2a
R-1
R-2
Visit 1b Visit 2b Visit 3b Visit 4b Visit 5b Visit 6b Visit 7b Visit 8b
Week
up to 13 weeks 
before Week 1
Week 
1
Week 
2
Week 
4
Week 
7
Week 
10
Week 
13
Week 
16
Week 
19
Week 
22
Week 
25
Week 28
Visit allowance
-
-
±0 day ±0 day ±3 days ±3 days ±3 days ±3 days ±3 days ±3 days ±3 days ±3 days
±3 days
Informed consentc
X
Assessment of eligibility
X
Demographic information
X
Medical and medication history
X
Body height
X
Body weight
X
Xd
X
X
X
X
X
X
X
X
X
X
X
Physical examination
X
Xd
X
X
X
X
X
X
X
X
X
X
X
Concomitant medication, non-
drug therapies
X
Xd
X
X
X
X
X
X
X
X
X
X
X
Clinical laboratory assessmentse
X
Xd
X
X
X
X
X
X
X
X
X
X
PK assessmentsf
X
Subject's own IVIG/cSCIG 
treatment
X
Xd
Investigational product treatmentg
X
X
X
X
X
X
X
X
X
X
Vital signsh
X
Xd
X
X
X
X
X
X
X
X
X
X
X
Adverse events review
X
Collection/Review diaries
X
X
X
X
X
X
X
X
X
X
X
Quality of life assessments
X
X
X
Treatment satisfaction assessment
X
X
X
Treatment preference
X
Healthcare resource utilization
X
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TAK-771 (10%IGI with rHuPH20)
Clinical Study Protocol: TAK-771-3004
19 May 2022
Table 3. Schedule of Activities for Subjects Switching from IVIG/cSCIG Treatment: 3-Week Treatment Interval
Procedure
Screening period
Treatment period
Epoch 1
(Ramp-up)
Epoch 2
(3-week dosing interval)
EOS/Early 
termination 
visit
Visit No.
Screening 
visit 1a
Screening 
visit 2a
R-1
R-2
Visit 1b Visit 2b Visit 3b Visit 4b Visit 5b Visit 6b Visit 7b Visit 8b
Week
up to 13 weeks 
before Week 1
Week 
1
Week 
2
Week 
4
Week 
7
Week 
10
Week 
13
Week 
16
Week 
19
Week 
22
Week 
25
Week 28
Visit allowance
-
-
±0 day ±0 day ±3 days ±3 days ±3 days ±3 days ±3 days ±3 days ±3 days ±3 days
±3 days
Self-administration proficiencyi
X
X
X
X
X
X
X
X
X
X
Abbreviations: AE=adverse event, cSCIG=conventional subcutaneous immunoglobulin, EOS=end-of-study, IgG=immunoglobulin G, 
IVIG=intravenous immunoglobulin, PK= pharmacokinetic, SC=subcutaneous
a. Visit frequency is dependent on the dosing frequency of subject’s own IVIG/cSCIG treatment. The interval from Screening Visit 1 to Screening Visit 2 should be at
least 3 weeks.
b. When TAK-771 dose is administered over multiple days as divided doses with 48 to 72 hours between doses due to the infusion volume, assessments don’t need to be
repeated on the second day of infusion.
c. Written and/or electronic informed consent must be obtained prior to any study procedures including screening.
d. Assessments are conducted at every visit during the screening period.
e. For laboratory assessments and PK assessments specific to the visits, see Table 11 in Appendix 2.
f. Alternatively, PK assessment can be started at 1 visit earlier and completed just before the last SC infusion at the discretion of investigator. See Table 14 in Appendix 2
for PK assessment schedule.
g. Subcutaneous infusion of rHuPH20 solution will be administered first, followed by SC infusion of 10% IGI within 10 minutes of completion of the infusion of
rHuPH20 solution in a sequential order at the same location. The recommended site(s) for SC infusion are the middle to upper abdomen and thighs. If more than one
site are used, the infusion sites should be rotated by choosing opposite sides of the body. Avoid bony prominences, or scarred areas. The product should not be infused
at or around an infected or acutely inflamed area due to the potential risk of spreading a localized infection. Self-administration of SC infusions at home may be
allowed at the discretion of investigator after the training, evaluation and verification of subject’s (and/or caregiver’s) proficiency in self-infusion procedures are
completed.
h. Blood pressure measurements will be taken after subjects remain sitting in an upright position for at least one minute. For the initial 3 SC infusions, vital signs are to be
monitored and recorded at any time prior to infusion, in the event of occurrence of AE(s), and within 60 minutes of completion of an infusion. During subsequent
infusion visits, vital signs will be taken once per administration, but will be recorded multiple times if an AE occurs. When subjects have self-infusion at home and an
AE occurs, subjects (and/or caregiver) should measure vital signs by themselves and record the values on subject diary.
i. Subcutaneous infusions will be administered by an appropriately trained healthcare professional (eg, infusion nurse) or, if applicable, can be administered by the
subject and/or a caregiver. Training, evaluation, and verification of the subject’s (and/or caregiver’s) proficiency in performing self-infusion procedures by the
investigator/designee must be documented as a prerequisite before the subject (and/or caregiver) will be allowed to begin self-administration of SC infusions at sites,
home or other suitable locations. A proficiency checklist will be completed by the investigator/designee once training begins and until the subject’s (and/or caregiver’s)
proficiency is demonstrated. The proficiency check will not be required when subject has self-administration of SC infusions at home.
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TAK-771 (10%IGI with rHuPH20)
Clinical Study Protocol: TAK-771-3004
19 May 2022
Table 4. Schedule of Activities for Subjects Switching from TAK-664 Treatment: 3-Week Treatment Interval
Procedure
Treatment period
Epoch 1
(Ramp-up)
Epoch 2
(3-week dosing interval)
EOS/Early 
termination 
visit
Visit No.
R-1
R-2
Visit 1b
Visit 2b
Visit 3b
Visit 4b
Visit 5b
Visit 6b
Visit 7b
Visit 8b
Week
Week 1a Week 2 Week 4
Week 7 Week 10 Week 13 Week 16 Week 19 Week 22 Week 25
Week 28
Visit allowance
±0 day
±0 day
±3 day
±3 days
±3 days
±3 days
±3 days
±3 days
±3 days
±3 days
±3 days
Informed consentc
X
Assessment of eligibilityd
X
Demographic information
Xe
Medical and medication history
Xe
Body height
Xe
Body weight
X
X
X
X
X
X
X
X
X
X
X
Physical examination
X
X
X
X
X
X
X
X
X
X
X
Concomitant medication, non-drug therapies
Xe
X
X
X
X
X
X
X
X
X
X
Clinical laboratory assessmentsf
X
X
X
X
X
X
X
X
X
X
PK assessmentsg
X
Investigational product treatmenth
X
X
X
X
X
X
X
X
X
X
Vital signsi
X
X
X
X
X
X
X
X
X
X
X
Adverse events review
X
Collection/Review diaries
X
X
X
X
X
X
X
X
X
X
X
Quality of life assessments
X
X
X
Treatment satisfaction assessment
Xe
X
X
Treatment preference
X
Healthcare resource utilization
X
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TAK-771 (10%IGI with rHuPH20)
Clinical Study Protocol: TAK-771-3004
19 May 2022
Table 4. Schedule of Activities for Subjects Switching from TAK-664 Treatment: 3-Week Treatment Interval
Procedure
Treatment period
Epoch 1
(Ramp-up)
Epoch 2
(3-week dosing interval)
EOS/Early 
termination 
visit
Visit No.
R-1
R-2
Visit 1b
Visit 2b
Visit 3b
Visit 4b
Visit 5b
Visit 6b
Visit 7b
Visit 8b
Week
Week 1a Week 2 Week 4
Week 7 Week 10 Week 13 Week 16 Week 19 Week 22 Week 25
Week 28
Visit allowance
±0 day
±0 day
±3 day
±3 days
±3 days
±3 days
±3 days
±3 days
±3 days
±3 days
±3 days
Self-administration proficiencyj
X
X
X
X
X
X
X
X
X
X
Abbreviations: AE=adverse event, EOS=end-of-study, IgG=immunoglobulin G, PK= pharmacokinetic, SC= subcutaneous
a. The assessments for the Week 1 in TAK-771-3004 can be combined with the EOS/Early termination visit assessments in TAK-664 studies.
b. When TAK-771 dose is administered over multiple days as divided doses with 48 to 72 hours between doses due to the infusion volume, assessments don’t
need to be repeated on the second day of infusion.
c. Written and/or electronic informed consent must be obtained prior to any study procedures.
d. The latest laboratory data obtained in the TAK-664 studies will be used to determine the eligibility.
e. Data collected in the TAK-664 studies can be used if available.
f.
For laboratory assessments and PK assessments specific to the visits, see Table 12 in Appendix 2.
g. Alternatively, PK assessment can be started at 1 visit earlier and completed just before the last SC infusion at the discretion of investigator. See Table 14 in
Appendix 2 for PK assessment schedule.
h. Subcutaneous infusion of rHuPH20 solution will be administered first, followed by SC infusion of 10% IGI within 10 minutes of completion of the infusion
of rHuPH20 solution in a sequential order at the same location. The recommended site(s) for SC infusion are the middle to upper abdomen and thighs. If more
than one site are used, the infusion sites should be rotated by choosing opposite sides of the body. Avoid bony prominences, or scarred areas. The product
should not be infused at or around an infected or acutely inflamed area due to the potential risk of spreading a localized infection. Self-administration of SC
infusions at home may be allowed at the discretion of investigator after the training, evaluation and verification of subject’s (and/or caregiver’s) proficiency
in self-infusion procedures are completed.
i.
Blood pressure measurements will be taken after subjects remain sitting in an upright position for at least one minute. For the initial 3 SC infusions, vital
signs are to be monitored and recorded at any time prior to infusion, in the event of occurrence of AE(s), and within 60 minutes of completion of an infusion.
During subsequent infusion visits, vital signs will be taken once per administration, but will be recorded multiple times if an AE occurs. When subjects have
self-infusion at home and an AE occurs, subjects (and/or caregiver) should measure vital signs by themselves and record the values on subject diary.
j.
Subcutaneous infusions will be administered by an appropriately trained healthcare professional (eg, infusion nurse) or, if applicable, can be administered by
the subject and/or a caregiver. Training, evaluation, and verification of the subject’s (and/or caregiver’s) proficiency in performing self-infusion procedures
by the investigator/designee must be documented as a prerequisite before the subject (and/or caregiver) will be allowed to begin self-administration of SC
infusions at sites, home or other suitable locations. A proficiency checklist will be completed by the investigator/designee once training begins and until the
subject’s (and/or caregiver’s) proficiency is demonstrated. The proficiency check will not be required when subject has self-administration of SC infusions at
home.
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TAK-771 (10%IGI with rHuPH20)
Clinical Study Protocol: TAK-771-3004
19 May 2022
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) (Tangye et al., 2020) distinguishes 10 PID categories according to common disease
phenotypes.
Considered rare diseases until recently, PIDs may affect up to 1/1200 people worldwide 
according to current estimates (Bousfiha et al., 2013). In Japan, the prevalence of PIDs and 
number of patients are estimated as 2 to 3 per 100,000 people and 2,900 to 3,500 patients, 
respectively, though the accurate prevalence is not well known (Ishimura et al., 2011). In 
addition, it is well known that patients with PID are at high risk of developing malignancy, 
and, it is reported that 3.2% of patients with PID have developed malignant diseases 
(de la Morena and Nelson, 2014). Primary immunodeficiency diseases are specified as a 
designated intractable disease by Ministry of Health, Labour and Welfare in Japan.
Therapeutic options for the treatment of infections in PID with antibody production defects 
include standard antibiotic treatment and administration of immunoglobulin G (IgG) as a 
replacement therapy. Antibody replacement can be administered either intravenously or 
subcutaneously (Melamed et al., 2012). Therapeutic options for treatment of PID itself to 
correct the defect are transplantation of bone marrow-derived stem cells, and recently, gene 
therapy (de la Morena and Nelson, 2014, Hernandez-Trujillo, 2014, Kuo, 2018, Picard et al., 
2018, Sauer et al., 2014).
Currently, the majority of IgG products are licensed for intravenous (IV) administration, 
though in the past several years, subcutaneous (SC) administration has gained popularity. 
When given weekly or every other week, subcutaneous immunoglobulin (SCIG) leads to higher 
trough serum IgG concentrations than monthly IV infusions (Berger, 2011, Gardulf et al., 1995, 
Gardulf et al., 1991). Immunoglobulin (IG) replacement therapy administered by the SC 
route 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). 
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Clinical Study Protocol: TAK-771-3004
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Another major potential benefit of SCIG is the lower incidence of systemic adverse events (AEs) 
compared to intravenous immunoglobulin (IVIG) (Berger, 2013, Suez et al., 2016). The IG 
preparations currently approved for SC use in the United States (US), Canada and the European 
Union (EU) are formulated at 10% to 20%. The higher concentration products allow for a 
relatively smaller infusion volume, which may reduce the number of infusion sites and/or 
duration of infusion, thereby improving patient quality of life (QoL) (Wasserman, 2012).
Currently in Japan, only one product of IgG formulation for SC use (20% SCIG formulation 
Hizentra®) is available. The availability of additional alternative IgG formulation for SC use is 
highly needed for patients who do not tolerate their current SCIG. In addition, to be prepared in 
the event of product shortages, due to manufacturing constraints or natural disasters, stable 
supply of SCIG products should be secured by several companies.
2.2 Product Background and Clinical Information
The pharmacokinetics (PK) of SC administration are different from that of IV infusions, and 
bioavailability of IG administered subcutaneously may be lower 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).
A major disadvantage of conventional SC administration is that only small volumes can be 
infused at each injection site, necessitating the use of multiple sites on a weekly or bi-weekly 
(every other week) basis. Generally, using a 16% solution, approximately 20 mL can be infused 
per site; an adult patient receiving 400 mg/kg body weight every 4 weeks thus would require at 
least 3 sites per week or 12 sites per month. Even though weekly or bi-weekly administration has 
the added advantage of maintaining better trough levels than monthly IV infusions, since SCIG 
which is currently available in Japan requires weekly injections, the requirement of multiple 
needle insertions in a lifelong treatment has been a deterrent for many patients with PID.
TAK-771 (10% immune globulin infusion [IGI] with rHuPH20) has been developed to address 
the major limitation of conventional SCIG (cSCIG) therapy and it significantly enhances SC 
administration in PID by offering improved bioavailability (as compared to cSCIG therapy) 
without requiring greater doses than those administered intravenously (Schiff et al., 2008). 
In addition, TAK-771 allows the SC administration of standard PID monthly dosing volumes, 
and the utilization of infusion rates equal to IV administration while preserving the advantages 
of SC administration (Schiff et al., 2008).
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Clinical Study Protocol: TAK-771-3004
19 May 2022
2.3 Study Rationale
Approximately 2,900 to 3,500 people are diagnosed with PID in Japan, and the number of 
diagnosed patients is increasing. Immunoglobulin replacement therapy has been widely used for 
patients with PID, and the administration route is commonly either monthly IV or weekly SC 
injection in Japan. This proposed study is designed to evaluate serum trough IgG levels, safety 
and tolerability, and efficacy of TAK-771 administered subcutaneously at 3- or 4-week intervals, 
and assesses disease activity and health-related quality of life (HRQoL) in subjects with PID in 
Japan. It aims to demonstrate maintenance of total IgG trough levels in PID patients after being 
on stable doses of TAK-771. The results from this study will extend/support the data obtained in 
the global pivotal study (Study 160603) and the extension study (Study 160902), in which 
switching from IVIG to TAK-771 in patients with PID was evaluated. Data from these global 
studies will be used for the regulatory submission for the approval of TAK-771 in Japan.
2.4 Benefit/Risk Assessment
The clinical program for TAK-771 includes 7 completed interventional clinical studies (160601, 
160602, 160603, 160902, 161101, 170901, and 161001) in subjects with PID and healthy 
volunteers, and 1 completed non-interventional registry study (161301) in women exposed to 
treatment before or during pregnancy (pregnancy registry). These studies provide evidence 
demonstrating the efficacy, PK, safety and tolerability of TAK-771 in subjects with PID, healthy 
volunteers and pregnant women. rHuPH20 increased the bioavailability of 10% IGI administered 
SC normalized by area under the curve (AUC)/dose/kg body weight by approximately 20%, thus 
reducing the clinically effective dose. When administered at 108% of the IV dose, TAK-771 was 
pharmacokinetically equivalent to 10% IGI administered IV with respect to area under the curve 
from time 0 to time τ (AUC0-τ) and resulted in comparable trough IgG levels. The IgG trough 
levels were well above 5.0 g/L, the accepted minimum level for effective prophylaxis against 
infections in patients with PID (Orange et al., 2006).
TAK-771 administered over 3 years at a similar frequency to IVIG was safe with a comparable 
AE profile to SCIG at infusion volumes and rates equivalent to IVIG, and effectively maintained 
low rates of infection in patients with PID (Wasserman et al., 2015). Large infusion volumes up
to 600 mL/site were well-tolerated, enabling treatment of pediatric and adult patients with PID at 
the same interval used for 10% IGI administered IV. When administered at 108% of the IV dose, 
TAK-771 resulted in a somewhat lower rate of infections per subject-year (SY) than 10% IGI 
administered IV or SC. Trough IgG levels were comparable for TAK-771 and 10% IGI 
administered IV. Protective trough levels were maintained during long-term treatment with 
TAK-771. TAK-771 reduced the clinically effective SC dose of 10% IGI compared to SC 
administration alone and resulted in decreased frequency, severity and duration of local 
induration. A decline in the rate of related local AEs per subject per year was observed 
during long-term replacement therapy with TAK-771 in subjects with PID.
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Clinical Study Protocol: TAK-771-3004
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TAK-771 was shown to be effective in preventing infections in patients with PID. 
The primary endpoint of the pivotal study 160603 was met with respect to the frequency 
of validated acute serious bacterial infections (ASBIs) during TAK-771 treatment. Studies 
160902 and 161101 confirmed the efficacy outcomes in terms of validated ASBIs and overall 
infection rate. In these studies, the rate of validated ASBIs/subject/year were well below 
1.0 validated ASBI/subject/year, the threshold specified as providing substantial evidence of 
efficacy by the Food and Drug Administration (FDA) Guidance (Food and Drug Administration, 
2008) and also complies with the European Medicines Agency (EMA) Guidance (Committee for 
Proprietary Medicinal Products, 2002). Protection against infection was maintained during long-
term TAK-771 in pivotal study 160603 and extension study 160902. The overall annual rate of 
infections per SY while on TAK-771 treatment in the 2 studies was 2.99 (95% CI: 2.60 to 3.42). 
It compare favorably to published data; 4.1 infections per SY reported from SC treatment with 
another 10% IgG preparation (Wasserman et al., 2010), 3.4 to 5.6 infections per SY reported in 
3 studies with SC administration of 16% IgG preparation (Berger et al., 2010, Borte et al., 2011, 
Ochs et al., 2006), and 2.4, 2.76 and 3.3 infections per SY were reported from long-term SC 
treatment with a 20% IgG preparation (Borte et al., 2012, Borte et al., 2013, Hagan et al., 2010).
Overall, the clinical program for TAK-771 demonstrated the positive safety profile. 
In Study 160603, subjects received TAK-771 treatment for at least 1 year, and majority of 
subjects who received TAK-771 were treated at the same interval used previously for IV 
treatment (3 or 4 weeks). TAK-771 was well-tolerated at large volumes (up to 600 mL/site) and 
utilizing maximum flow rates significantly higher than those used for IV infusions (p<0.0001) as 
compared by Wilcoxon test stratified by subject (van Elteren’s test) (van Elteren, 1960). In 
extension study 160902, subjects continued on TAK-771 treatment for a median of 669 days 
(mean 565.9 days). A decline in the rate of related AEs, both local and systemic was observed 
during long-term treatment with TAK-771.
The rate of adverse drug reactions (ADRs) per infusion obtained for TAK-771 compares 
favorably with published data on SCIG (Ochs et al., 2006). A lower rate of systemic ADRs was 
reported for TAK-771 than IVIG treatment; this is in line with numerous studies comparing 
SCIG with IVIG (Berger, 2004, Gardulf and Hammarström, 1996, Moore and Quinn, 2008). 
While in Study 160603 local ADRs during TAK-771 treatment, which were mostly mild and 
moderate in severity, were reported at a rate of 0.203 AEs per infusion, the frequency of local 
ADRs per infusion was as low as 0.103 during long-term treatment with TAK-771 in extension 
Study 160902.
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TAK-771 (10%IGI with rHuPH20)
Clinical Study Protocol: TAK-771-3004
19 May 2022
The nature of ADRs was similar for 10% IGI administered SC in Studies 160601 and 160603, 
and for TAK-771 treatment in Studies 160603, 160902, and 161101; the most commonly 
reported reactions were infusion site reactions. Infusion site reactions are expected in most 
patients during SCIG therapy, but they are not reported to be troublesome in the majority of 
patients (Gardulf et al., 1995, Misbah et al., 2009, Moore and Quinn, 2008).
Across 7 completed clinical studies, 2 serious adverse events (SAEs) were reported that were 
considered to be related to TAK-771. These events were cases of hemolytic anemia in healthy 
volunteers. They were conservatively assessed by the investigator as possibly being related to 
TAK-771, with an alternative etiology of viral infection (H1N1 Influenza A California) which 
affected 10 of the 12 subjects who participated in this study and was documented by 
seroconversion.
There have been no serious hypersensitivity reactions, including anaphylactic reactions, 
attributed to rHuPH20 in the studies with TAK-771. The current clinical and safety data for 
TAK-771 demonstrate that exposure is safe and well-tolerated, and there has been no evidence of 
a lack of treatment effect when rHuPH20-reactive binding antibodies have been detected. Based 
upon data available to date, the incidence of the formation of anti-rHuPH20 antibodies is low, no 
neutralizing antibodies have been observed, no clinical signs or symptoms have been associated 
with positive anti-rHuPH20 antibody titers.
Based on all the above, it was considered that the benefits of TAK-771 for treatment of patients 
with PID outweigh the risks.
Always refer to the latest version of the TAK-771 investigator’s brochure (IB) for the overall 
benefit/risk assessment and the most accurate and current information regarding drug 
metabolism, PK, efficacy, and safety of TAK-771.
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 (ICH GCP, 1996; ICH E6 R2, 2016), 
and applicable national and local regulatory requirements.
The responsibilities of the study sponsor and investigator(s) are described fully in Appendix 1.
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Clinical Study Protocol: TAK-771-3004
19 May 2022
3. OBJECTIVES AND ENDPOINTS
3.1 Study Objectives
3.1.1 Primary Objective
The primary objective of the study is to assess serum trough levels of total IgG when using
TAK-771 as maintenance therapy in Japanese subjects with PID.
3.1.2 Secondary Objectives
The secondary objectives of this study are listed below:

To characterize the PK profiles of TAK-771 in Japanese subjects with PID following
TAK-771 administration.

To evaluate the safety and tolerability of TAK-771 in Japanese subjects with PID.

To evaluate the efficacy of TAK-771 in Japanese subjects with PID.

To assess disease activity and HRQoL in Japanese subjects with PID following TAK-771
administration.
3.2 Study Endpoints
3.2.1 Primary Endpoint
The primary endpoint for the study is the serum trough levels of total IgG (total serum trough 
IgG antibodies) measured during the trough evaluation period of Epoch 2 (administration of 
TAK-771).
For a detailed description of endpoints and the planned statistical analysis, refer to Section 9.
3.2.2 Secondary Endpoints
Endpoints cover PK, safety and tolerability, efficacy, and disease activity and HRQoL.
Pharmacokinetic endpoints and parameters:

PK parameters for total serum levels of IgG and for IgG subclasses in PK assessment
period in Epoch 2 (in a subset of 5 to 7 subjects aged 12 years and older), which may
include but not limited to the following: maximum concentration (Cmax), time to maximum
concentration (Tmax), AUC, half-life, apparent total clearance (CL/F), apparent volume of
distribution (Vz/F), minimum concentration (Cmin)

Serum trough levels of IgG subclasses in the trough evaluation period of Epoch 2

Trough levels of specific antibodies to clinically relevant pathogens (Clostridium tetani
toxoid, Haemophilus influenzae [HIB], Hepatitis B virus [HBV]) in Epoch 1 and 2
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TAK-771 (10%IGI with rHuPH20)
Clinical Study Protocol: TAK-771-3004
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Safety and tolerability endpoints: 
Safety endpoints/outcome measures:

Occurrence of treatment-emergent adverse events (TEAEs) in Epoch 1 and 2, including but
not limited to: TAK-771-related and non-related, serious, non-serious, severe, local and
systemic TEAEs, as well as TEAEs leading to premature discontinuation from study, and
infusion-associated TEAEs

Changes in clinical laboratory parameters in Epoch 1 and 2

Changes in vital signs and body weight in Epoch 1 and 2
Change from baseline in vital signs and body weight, and change from pre-infusion to
post-infusion in vital signs

Development of positive titer (≥ 1:160) binding antibodies, and development of
neutralizing antibodies, to rHuPH20 in Epoch 2
Number and percentage of subjects who develop anti-rHuPH20 binding antibody titers of
≥1:160
Number and percentage of subjects who develop neutralizing antibodies to rHuPH20
Tolerability endpoints/outcome measures:

Occurrence of tolerability events related to the infusion of TAK-771 in Epoch 1 and 2.
A tolerability event is considered to have occurred if an infusion was not tolerable, which
is defined as any changes in dosing of TAK-771 such as reduction of infusion rate,
interruption or discontinuation of TAK-771 due to TEAEs related to TAK-771. Number
and percentage of subjects who experienced tolerability events will be measured.

Number of weeks to reach final dose interval (3 weeks or 4 weeks) in Epoch 1

Percentage of subjects who achieve a treatment interval of 3 or 4 weeks in Epoch 2

Percentage of subjects who maintain a treatment interval of 3 or 4 weeks in Epoch 2
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TAK-771 (10%IGI with rHuPH20)
Clinical Study Protocol: TAK-771-3004
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Efficacy endpoints:

Annual rate of validated acute serious bacterial infections (ASBIs) per subject in Epoch 1
and 2

Annual rate of all infections per subject in Epoch 1 and 2

Healthcare Resource Utilization in Epoch 1 and 2:
-
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

Infusion parameters in Epoch 2, including but not limited to: number of infusions per
month, number of infusion sites per infusion, number of infusion sites per month, duration
of individual infusions, maximum infusion rate/site, and infusion volume/site
Disease activity and health-related quality of life endpoints:

QoL: PEDS-QL (Varni et al., 1999), SF-36 v2 (Ware and Sherbourne, 1992), EQ-5D-3L
Health Questionnaire (Shaw et al., 2005) in Epoch 1 and 2

Treatment Satisfaction (TSQM-9) (Daly et al., 1991) in Epoch 1 and 2

Treatment Preference at End-of-study (EOS)/Early termination
Endpoint details will be provided in the study Statistical Analysis Plan (SAP).
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Table 5. Objectives and Endpoints
Objectives
Endpoints
Primary

To assess serum trough levels of total IgG
when using TAK-771 as maintenance
therapy in Japanese subjects with PID.

The serum trough levels of total IgG (total serum trough
IgG antibodies) measured during the trough evaluation
period of Epoch 2 (administration of TAK-771).
Secondary

To characterize the PK profiles of TAK-771
in Japanese subjects with PID following
TAK-771 administration.

PK parameters for total serum levels of IgG and for IgG
subclasses in PK assessment period in Epoch 2(in a subset
of 5 to 7 subjects aged 12 years and older), which may
include but not limited to the following: Cmax, Tmax, AUC,
half-life, CL/F, Vz/F, Cmin

Serum trough levels of IgG subclasses in the trough
evaluation period of Epoch 2

Trough levels of specific antibodies to clinically relevant
pathogens (Clostridium tetani toxoid, HIB, HBV) in the
trough evaluation period of Epoch 1 and 2

To evaluate the safety and tolerability of
TAK-771 in Japanese subjects with PID.

Occurrence of TEAEs in Epoch 1 and 2, including but not
limited to: TAK-771-related and non-related, serious, non-
serious, severe, local and systemic TEAEs, as well as
TEAEs leading to premature discontinuation from study,
and infusion-associated TEAEs

Changes in clinical laboratory parameters in Epoch 1 and 2

Changes in vital signs and body weight in Epoch 1 and 2
Change from baseline in vital signs and body weight, and
change from pre-infusion to post-infusion in vital signs

Development of positive titer (≥ 1:160) binding antibodies,
and development of neutralizing antibodies, to rHuPH20 in
Epoch 2

Occurrence of tolerability events related to the infusion of
TAK-771 in Epoch 1 and 2

Number of weeks to reach final dose interval (3 weeks or
4 weeks) in Epoch 1

Percentage of subjects who achieve a treatment interval of
3 or 4 weeks in Epoch 2

Percentage of subjects who maintain a treatment interval of
3 or 4 weeks in Epoch 2
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Table 5. Objectives and Endpoints
Objectives
Endpoints

To evaluate the efficacy of TAK-771 in
Japanese subjects with PID.

Annual rate of validated ASBIs per subject in Epoch 1 and 2

Annual rate of all infections per subject in Epoch 1 and 2

Health Resource Utilization: in Epoch 1 and 2
-
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

Infusion parameters in Epoch 2, including but not limited
to: number of infusions per month, number of infusion sites
per month, duration of individual infusions, maximum
infusion rate/site, and infusion volume/site

To assess disease activity and HRQoL in
Japanese subjects with PID following
TAK-771 administration.

QoL: PEDS-QL, SF-36 v2, EQ-5D-3L Health
Questionnaire in Epoch 1 and 2

Treatment Satisfaction (TSQM-9) in Epoch 1 and 2

Treatment Preference at EOS/Early termination
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4. STUDY DESIGN
4.1 Overall Design
This is a phase 3, open-label, non-controlled, multi-dose, multicenter study to evaluate serum
trough levels of IgG, PK, efficacy, safety and tolerability of TAK-771 in Japanese subjects with
PID, as well as to assess disease activity and HRQoL. A total of 15 subjects aged 2 years or older
will be enrolled, of whom 12 subjects are expected to complete the study. Approximately 10 to
15 study sites are planned, located in Japan.
This study will enroll patients with a confirmed diagnosis of PID, who have been receiving a 
consistent dose of IVIG, SCIG or TAK-664*NOTE 1 at least 3 months prior to screening. The 
diagnosis must be confirmed by the Medical Director prior to TAK-771 treatment.
The study consists of signing informed (e)Consent, screening, treatment period (Epoch 1: dose 
ramp-up period, Epoch 2: dose adjustment period and trough evaluation period), and EOS/Early 
termination visit.
After informed consent has been obtained, subjects will undergo screening to determine the 
eligibility.
Screening
Subjects who are switching from IVIG or cSCIG will enter screening period for up to 13 weeks 
to undergo procedures for the determination of eligibility and will continue to receive their own 
immunoglobulin treatment at the same dose and dosing frequency as prescribed prior to their 
entry into this study. During the screening period, subjects will have 2 visits to have IgG trough 
levels measured at least 2 timepoints, which needs to be at least 3 weeks apart. After confirming 
the eligibility, subjects will enter the Epoch 1 and receive the initial dosing of TAK-771 SC 
1 week after the last IVIG or cSCIG administration.
Subjects who have been receiving TAK-664 and are switching from Study TAK-664-3001 or 
TAK-664-3002 (TAK-664 studies, hereafter) will directly move on to the treatment period 
without entering the screening period. To determine the eligibility, the data including the latest 
laboratory data and IgG trough levels collected in the TAK-664 studies will be used. After 
confirming the eligibility, subjects will enter the Epoch 1 and receive the initial dosing of 
TAK-771 SC 1 week (for subjects switching from TAK-664 weekly dosing) or 2 weeks (for 
subjects switching from TAK-664 bi-weekly dosing) after the last TAK-664 administration.
Epoch 1
For all subjects, TAK-771 will be started with the ramp-up infusion (3 to 6 weeks) 
(Section 6.3.3.1).
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4.2 Scientific Rationale for Study Design
This is a phase 3, open-label, non-controlled study enrolling patients who have been treated with 
IVIG, SCIG, or TAK-664. As IgG replacement therapy has been recognized as an important 
treatment for patients with PID; and as the number of eligible subjects is small because of 
prevalence, an open-label non-controlled single-arm design was chosen and the PID patients who 
complete an ongoing clinical trial (TAK-664 studies) of TAK-664 (20% SCIG) are allowed to 
enroll this study.
4.3 Justification for Dose
The IgG dosing regimen for TAK-771 will be the same as the subject’s previous monthly 
equivalent IVIG dose or SCIG when administered at a dosing frequency of every 3 or 4 weeks.
In the pivotal PID Phase 3 study (Study 160603), the geometric mean (GM) area under the curve 
over a dosing interval (AUC0-τ) ratio (SC/IV) for IgG was found to be 93.3%, with a 90% 
confidence interval (CI) of 91.4% to 95.2%. The median AUC0-τ (normalized to a 1-week dosing 
interval) was similar after SC vs IV administration (90.5 vs 93.9 gx days/L). As expected with 
SC administration, the median Cmax was lower after SC than after IV infusion (15.5 g/L vs 
21.9 g/L) while the median time to reach Cmax was longer (Tmax: 5.0 vs 0.1 days). Clearance (or 
apparent clearance for SC administration) and trough concentration (Cmin) after SC infusion were 
similar to the values calculated after IV infusion. The median ratio of IgG trough levels for 
TAK-771 was 98.5% (95% CI: 93.4%; 102.5%).
Dose conversion factor will not be applied since comparable exposure has been demonstrated 
between TAK-771 and IVIG at similar dose levels in previous studies; that is, subjects who has 
been receiving IVIG and entering the study will receive the same IgG monthly equivalent dose 
as their own pre-study IVIG treatment regimen that was effective in maintaining the subject’s 
PID conditions.
4.4 Duration of Subject Participation and Study Completion Definition
The subject’s maximum duration of participation is expected to be approximately 43 weeks. 
The study will be completed in approximately 2 years.
The study completion date is defined as the date on which the last subject in the study completes 
the final protocol-defined assessment(s). 
All AEs/SAEs which had been reported until EOS/Early termination visit will be followed until 
resolution, medically stabilized, or 30 days after EOS/Early termination visit, whichever comes 
first
4.5 Sites and Regions
The study will be conducted at approximately 10 to 15 sites in Japan.
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5. STUDY POPULATION
Each subject must participate in the informed consent process and provide written and/or
electronic informed consent/assent before any procedures specified in the protocol are
performed.
5.1 Inclusion Criteria
The subject will not be considered eligible for the study without meeting all of the criteria below.
1.
Be a Japanese person.
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 IUIS Committee 2017 (Picard et al., 2018).
The diagnosis must be confirmed by the Medical Director prior to TAK-771 treatment.
3.
Subject is 2 years or older at the time of screening/enrollment.
4.
Written and/or electronic 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. If a subject is <18 years of age, written and/or electronic informed
consent should also be obtained from the subject's legally authorized representative in
addition to written informed assent by a subject if appropriate.
5.
Subject has been receiving a stable clinical dose of IVIG or cSCIG, which is equivalent to
approximately 200 to 600 mg/kg body weight per 3 to 4 week period for IVIG and
approximately 50 to 200 mg/kg body weight per week for cSCIG based on the description
in the package insert, consistently over a period of at least 3 months prior to screening, or
Subject has been receiving of TAK-664 with fixed dose and dosing frequency at least
3 months prior to enrollment. That is, subject is about to complete Study TAK-664-3001 or
participating in Study TAK-664-3002.
6.
Subject who has been receiving IVIG or cSCIG had all serum trough levels of IgG ≥5 g/L
within 1 month prior to the screening/enrollment.
7.
Serum trough levels at screening/enrollment meet one of the following:
a.
IVIG-treated or cSCIG-treated subjects
Subject who had serum trough levels of IgG ≥5 g/L at the last 2 points in screening
procedure before the first administration of TAK-771.
b.
TAK-664-treated subjects
Subject who had serum trough levels of IgG ≥5 g/L at the last 2 points in TAK-664
studies before the first administration of TAK-771.
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8.
Subject is willing and able to comply with the requirements of the protocol.
9.
Subject is willing and able to comply with use of digital tools and applications.
5.2 Exclusion Criteria
The subject will be excluded from the study if any of the following exclusion criteria are met. 
1.
Subject has a known history of or is positive at screening/enrollment 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
For subjects who are switching from TAK-664 studies, the eligibility will be reconfirmed
after result of the specialty test conducted at Week 1 become available.
2.
Abnormal laboratory values at screening/enrollment 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 aminotransferase (AST)
>2.5 times the upper limit of normal (ULN) for the testing laboratory*NOTE 2
b.
Persistent severe neutropenia (defined as an absolute neutrophil count [ANC]
≤500/mm3) *NOTE 2
3.
Subject has presence of renal function impairment defined by eGFR
<60 mL/min/1.73m2.*NOTE 2
4.
Subject has been diagnosed with, or had 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/enrollment 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 IVIG, SCIG, and/or
Immune Serum Globulin infusions
9.
Subject has immunoglobulin A (IgA) deficiency (serum IgA less than 0.07 g/L) and history
of hypersensitivity, or history of confirmed anti-IgA antibodies, or both.
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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/enrollment*NOTE 3.
11. Subject has active infection and is receiving antibiotic therapy for the treatment of
infection at the time of screening/enrollment*NOTE 3 or had a serious bacterial infection
within the 3 months prior to screening/enrollment
12. Subject has a bleeding disorder, or a platelet count less than 20,000/μL*NOTE 2, or in the
opinion of the investigator, would be at significant risk of increased bleeding or bruising as
a result of SC therapy.
13. Subject has total protein >9 g/dL*NOTE 2 or myeloma, or macroglobulinemia (IgM) or
paraproteinemia.
14. Subject has a known allergy to hyaluronidase
15. Women of childbearing potential who meet 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. See Section 5.4.1 and
Appendix 4 for adequate birth-control measures.
16. Subject has participated in another clinical study and has been exposed to an
investigational product or device within 30 days prior to study enrollment, (exception:
TAK-664 studies).
17. Subject is scheduled to participate in another non-observational (interventional) clinical
study involving an investigational product or device during the course of the study.
18. Subjects who experiences clinically significant AEs in TAK-664 studies and it may worsen
by participating in this study
19. Subject has severe dermatitis that would preclude adequate sites for safe product
administration
*NOTE 2: For subjects who are switching from TAK-664 studies, the latest laboratory data obtained in the
TAK-664 studies will be used to determine the eligibility.
*NOTE 3:The exceptional use of antibiotics is allowed. See Section 6.8.4 for the details.
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5.3 Restrictions 
Not applicable
5.4 Reproductive Potential
There are limited data available on the use of TAK-771 during pregnancy. Study 161301 
(pregnancy registry) reported that TAK-771 given during pregnancy was not associated with 
labor and delivery complications. Two minor birth defects (cleft lip without cleft palate and 
talipes calcaneovalgus) were reported in 2 infants in the TAK-771 Arm and assessed as unrelated 
with treatment. Please see the IB addendum for the detailed information.
There are limited safety data available on the use of TAK-771 in breast-feeding women.
The effects of TAK-771 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 investigational product. 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 investigational product.
Female subjects should be either:

Premenarchal and either Tanner stage 1 or less than age 9 years,

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

Females of childbearing potential with a negative urine beta-human chorionic
gonadotropin (β-hCG) pregnancy test conducted at screening for subjects switching from
IVIG or cSCIG treatment, and at pre-infusion at Week 1 for subjects switching from
TAK-664 studies. If subjects switching from TAK-664 studies have a result of pregnancy
test conducted at EOS/Early termination visit, it can be used to determine the pregnancy.
Females of childbearing potential must agree to abstain from sexual activity that could
result in pregnancy or agree to use acceptable methods of contraception.
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Acceptable methods of contraception include the following:

Intrauterine devices plus condoms

Double-barrier methods (eg, condoms and diaphragms with spermicidal gel or foam)

Hormonal contraceptives (oral, depot, patch, injectable, or vaginal ring), stabilized for at
least 30 days prior to the Week 1, plus condoms. Note: If subject becomes sexually active
during the study, they should use one of the other acceptable methods noted above in
addition to the hormonal contraceptive until it has been stabilized for 30 days. See
Appendix 4 for contraceptive guidance.
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6. STUDY INTERVENTION
6.1 Investigational Product
6.1.1 Identity of Investigational Product
The investigational product is TAK-771 (10% IGI with rHuPH20).
Immune Globulin Infusion 10% (Human) - 10% IGI
The 10% IGI component of TAK-771 manufactured from human plasma by employing a 
modified Cohn-Oncley cold alcohol fractionation process, as well as cation and anion exchange 
chromatography. Screening against potentially infectious agents (such as HIV, hepatitis A virus 
[HAV], HBV, HCV, hepatitis E virus [HEV], and Parvovirus B19 [B19V]) begins with the 
donor selection process and continues throughout plasma collection and preparation. To further 
improve the margin of safety, three validated, dedicated, independent, and effective virus 
inactivation/removal steps have been integrated into the manufacturing and formulation 
processes, namely solvent/detergent treatment, nanofiltration, and incubation at a low pH and 
elevated temperature in the final formulation.
The finished medicinal product, 10% IGI, is a purified, functionally intact IgG solution 
formulated with 0.25 M glycine (for a stabilizing effect) at 10% w/v protein concentration and a 
pH of 4.6 to 5.1.
The preparation is an isotonic solution containing approximately 100 mg of protein per mL, of 
which at least 98% is IgG with an IgG subclass distribution representative of native human 
plasma. The product contains no preservatives.
Recombinant Human Hyaluronidase - rHuPH20
rHuPH20 drug product is supplied as a sterile, clear, colorless, ready-for-use solution in the label 
strength of 160 U/mL, containing the additional excipients sodium chloride, sodium phosphate, 
human albumin, ethylenediaminetetraacetic acid disodium, calcium chloride, and sodium 
hydroxide and/or hydrochloric acid added for pH adjustment. rHuPH20 solution contains 0.1% 
human albumin with an approximate pH of 7.4 and osmolality of 290 to 350 mOsm. rHuPH20 
solution is preservative-free. rHuPH20 solution provides for high margins of safety with respect 
to viruses, due to comprehensive virus testing at the Master Cell Bank, Working Cell Bank and 
bulk harvest stage, effective virus reduction during the purification process, and the use of 
pharmaceutical grade human albumin as an excipient with no other materials of human or animal 
origin involved in the manufacturing process.
Additional information is provided in the current IB.
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6.2 Non-investigational Product
For subjects switching from IVIG or cSCIG treatment, the IVIG or cSCIG product administered 
during screening period is an approved IG product procured locally, which is administered as per 
local product label. Additional information is provided in the appropriate product package label. 
The IVIG or cSCIG will not be managed by interactive response technology (IRT) and will not 
be provided by the sponsor as investigational product.
The IVIG or cSCIG used in screening period will be the same IG preparation being administered 
to the patient prior to enrollment in the study and will be sourced by the sites. The lot number of 
IVIG or cSCIG used for the study should be recorded in electronic case report form (eCRF) by 
clinical site personnel.
6.3 Administration of Investigational Product
6.3.1 Interactive Response Technology for Investigational Product Management
This is an open-label, non-controlled study where all subjects will be enrolled to receive 
TAK-771. Individual subject numbers are automatically assigned to all subjects via the IRT as 
they consent to take part in the study. Within each study site (numbered uniquely within a 
protocol), the subject number is assigned according to the sequence of subject presentation for 
study participation.
Interactive response technology will be used for study drug supply management, inventory 
management, supply ordering, study drug expiration tracking, temperature excursion reporting, 
and return of study drug.
Details for the handling of study drug will be described in the pharmacy manual.
6.3.2 Allocation of Subjects to Treatment 
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.
Individual subject treatment is automatically assigned by the IRT. Subjects will be assigned to 
receive the next available medication ID number allocated to each study site. The medication ID 
number will be entered onto the eCRF.
6.3.3 Dosing
Subcutaneous infusion of rHuPH20 solution will be administered first, followed by SC infusion 
of 10% IGI within 10 minutes of completion of the infusion of rHuPH20 solution at the same 
location. The recommended site(s) for SC infusion are the middle to upper abdomen and thighs. 
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If more than one site are used, the infusion sites should be rotated by choosing opposite sides of 
the body. Avoid bony prominences, or scarred areas. The product should not be infused at or 
around an infected or acutely inflamed area due to the potential risk of spreading a localized 
infection.
rHuPH20 and 10% IGI solutions for administration must be prepared according to separate 
written procedures which will be provided in infusion manuals.
6.3.3.1 Dosing in Epoch 1 (Ramp-up Period)
This study employs a dose ramp-up schedule until the subject’s full-dose is reached in order to 
increase the SC infusion volume gradually. Dosing during ramp-up period for tolerated doses are 
shown in Table 6 for 4-week dosing interval regimen and Table 7 for 3-week dosing interval 
regimen.
Table 6 Subjects with 4-week Dosing Interval Regimen with TAK-771
Week
Infusion Number
Dose of 10% IGI
Week 1
1st. infusion
1/4 of full dose
Week 2
2nd. infusion
1/2 of full dose
Week 4
3rd. infusion
3/4 of full dose
Week 7 and the following 4-week intervals
4th. infusion and the following infusions
full dose
Table 7 Subjects with 3-week Dosing Interval Regimen with TAK-771
Week
Infusion Number
Dose of 10% IGI
Week 1
1st. infusion
1/3 of full dose
Week 2
2nd. infusion
2/3 of full dose
Week 4 and the following 3-week intervals
3rd. infusion and the following infusions
full dose
Subjects who are switching from IVIG treatment (every 3 or 4 weeks):
The first administration of investigational product will take place 1 week after the last IVIG 
administration at screening. If the first administration of investigational product is tolerated, 
each week interval will be increased by 1 week until the planned dosing intervals (every 3 or 
4 weeks).
Investigational product should be administered with the same dose of IgG and frequency (every 
3 or 4 weeks) as previous IVIG treatment, after the initial ramp-up.
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Subjects who are switching from cSCIG treatment (Weekly):
The first administration of investigational product will take place 1 week after the last cSCIG 
administration at screening. If the first administration of investigational product is tolerated, 
each week interval will be increased by 1 week until the planned dosing intervals (every 3 or 
4 weeks).
The dosing interval (every 3 or 4 weeks) can be chosen by investigator considering subject 
preference and tolerability. The IG dose should be calculated on the basis of weekly equivalents 
from cSCIG treatment, that is to say the 3- or 4-weeks investigational product dose is calculated 
by multiplying cSCIG weekly dose by 3 or 4.
Subjects who are switching from TAK-664 studies (weekly or bi-weekly): 
The first administration of investigational product will take place 1 week (for subjects switching 
from TAK-664 weekly dosing) or 2 weeks (for subjects switching from TAK-664 bi-weekly 
dosing) after the last TAK-664 administration in the TAK-664 studies, the first interval should 
be the same as the TAK-664 treatment. If the first administration of investigational product is 
tolerated, each week interval will be increased by 1 week until the planned dosing intervals 
(every 3 or 4 weeks). The dosing interval (every 3 or 4 weeks) can be chosen by investigator 
considering subject preference and tolerability. The IG dose should be calculated on the basis of 
weekly equivalents from TAK-664 treatment, that is to say the 3- or 4-weeks investigational 
product dose is calculated by multiplying TAK-664 weekly dose by 3 or 4. 
6.3.3.2 Dosing in Epoch 2
6.3.3.2.1 rHuPH20
Dose: 80 U/g IgG (rHuPH20 drug product: 160 U/mL)
Dosing Frequency: Same as 10% IGI
Mode of Administration: For the initial 2 administrations in the study, infuse rHuPH20 solution 
at 60 to 120 mL/h/site as tolerated (or a total of 120 to 240 mL/h at 2 infusion sites or 180 to 
360 mL/h at 3 infusion sites). For subsequent administrations, rHuPH20 solution infusion rate 
may be increased as tolerated by the subject and at the discretion of the investigator, but not to 
exceed 300 mL/h/site (or not to exceed a total of 600 mL/h at 2 infusion sites or 900 mL/h at 
3 infusion sites).
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6.3.3.2.2 10% IGI
Dose: The total amount of IgG administered per month will be maintained as equivalent to that 
of previous IG treatment. The dose will be adjusted, if needed, to maintain an IgG trough level 
≥5 g/L.
Dosing Frequency: Every 3 or 4 weeks after the initial ramp-up. It should be the same as the 
previous IVIG treatment for subjects switching from IVIG treatment and can be chosen by the 
investigator considering subject preference and tolerability.
Mode of Administration: SC infusion, to be administered via an infusion pump (Sapphire™ 
Multi-Therapy, See Section 6.9) at 1, 2, or 3 infusion sites per infusion day. 
Maximum Infusion Rate
For the initial 2 infusions in the study, the maximum infusion rate should be 80 mL/h and 
240 mL/h per site, for subjects <40 kg and ≥40 kg body weight, respectively. 
Step-wise increases are suggested in subsequent infusions with rate increases of up to 300 mL/h 
per infusion site (or up to a total of 600 mL/h over 2 sites if bifurcated needle set is used, or up to 
a total of 900 mL/h if trifurcated needle set is used) for subjects weighing ≥40 kg. For subjects 
weighing <40 kg, infusion rates of up to 160 mL/h per infusion site (or up to a total of 320 mL/h 
and 480 mL/h over 2 and 3 sites if bifurcated and trifurcated needle set is used, respectively). 
Table 8. 10% IGI Infusion Rates
First 2 Infusions
Subsequent 2 or 3 Infusions
subjects <40 kg
subjects ≥40 kg
subjects <40 kg
subjects ≥40 kg
Intervals
Rate per site
Rate per site
Rate per site
Rate per site
5 to 15 minutes
5 mL/h
10 mL/h
10 mL/h
10 mL/h
5 to 15 minutes
10 mL/h
30 mL/h
20 mL/h
30 mL/h
5 to 15 minutes
20 mL/h
60 mL/h
40 mL/h
120 mL/h
5 to 15 minutes
40 mL/h
120 mL/h
80 mL/h
240 mL/h
Remainder of infusion
80 mL/h
240 mL/h
160 mL/h
300 mL/h
Volume of Infusion Per Site
10% IGI solution may be administered at a volume of up to 600 mL per infusion site for subjects
≥40 kg or up to 300 mL per infusion site for subjects <40 kg, as tolerated. On a given infusion 
day, the maximum infusion volume should not exceed 1200 mL for subjects weighing ≥40 kg or 
600 mL for subjects weighing <40 kg.
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If a subject’s total IgG dose on a given day exceeds 1200 mL for subjects weighing ≥40 kg or 
600 mL for subjects weighing <40 kg, or exceeds the SC maximum infusion volume the subject 
can tolerate, the TAK-771 dose may be administered over multiple days as divided doses with 
48 to 72 hours between doses (eg, Day 1 and Day 3 of a given infusion cycle) to allow 
absorption of infusion fluid at infusion site(s).
6.3.3.2.3 Location of the Infusion Procedures
Initial SC infusions (during the ramp-up period and, at a minimum, the first full-dose infusion) 
will be administered at the study site, and to provide training to the subject (and/or, as applicable, 
a caregiver who may assist the subject with self-administration) on self-infusion procedures. At 
the investigator’s discretion, the remainder of the SC infusions may take place at the study site or 
other suitable location. Self-administration of SC infusions at home may be allowed at the 
discretion of investigator after the training, evaluation and verification of subject’s (and/or 
caregiver’s) proficiency in self-infusion procedures are completed.
6.3.3.2.4 Monitoring Subject Treatment Compliance
Subcutaneous infusions will be administered by an appropriately trained healthcare professional 
(eg, infusion nurse) or, if applicable, can be administered by the subject and/or a caregiver. 
Training, evaluation, and verification of the subject’s (and/or caregiver’s) proficiency in 
performing self-infusion procedures by the investigator/designee, must be documented as a 
prerequisite before the subject (and/or caregiver) will be allowed to begin self-administration of 
SC infusions at sites, home or other suitable locations. A healthcare professional (eg, infusion 
nurse) may be present to observe the subject’s self-administration. A proficiency checklist will 
be completed by the investigator/designee once training begins and until the subject’s (and/or 
caregiver’s) proficiency is demonstrated. The proficiency check will not be required when the 
subject has self-administration of SC infusions at home.
6.3.4 Dose Modification
The dose (in milligrams IgG per kg body weight) should remain stable throughout the study. In 
order to maintain the same dose in mg/kg when there has been an increase in body weight (kg), it 
will be necessary to increase the absolute dose (in g or mg) administered.
The dose of TAK-771 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% compared to that the current dose 
of TAK-771 was determined based on, 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 dose of 
TAK-771 should not be changed.
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Serum trough levels of IgG ≥ 5 g/L are targeted to be maintained throughout the study. If levels 
fall below 5 g/L, the subject’s dose must be adjusted to maintain minimum trough levels of 
5 g/L. If the dose is adjusted because IgG levels are below 5 g/L, a trough level should be 
reevaluated at the next infusion and the dose should be readjusted if necessary. 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 eCRFs.
6.4 Labeling, Packaging, Storage, and Handling of Investigational Product
6.4.1 Labeling
The product will be labeled according to the regulatory requirements for clinical studies.
6.4.2 Packaging
rHuPH20 drug product (160 U/mL) will be supplied as a clear, colorless, ready-for-use sterile 
liquid preparation in single-use glass vials. The product should be inspected visually for 
particulate matter and discoloration. The product should not be used if particulate matter and/or 
discoloration is observed.
10% IGI will be supplied as a ready-for-use sterile liquid preparation in single-use glass vials. 
10% IGI is a clear or slightly opalescent and colorless or pale yellow solution. The product 
should be inspected visually for particulate matter and discoloration. The product should not be 
used if particulate matter and/or discoloration is observed.
Changes to sponsor-supplied packaging prior to dosing may not occur without full agreement in 
advance by the sponsor.
6.4.3 Storage
TAK-771 must be stored under refrigerated conditions (2° to 8°C). Do not freeze the product. 
Do not use if expiration date is exceeded.
The investigator has overall responsibility for ensuring that investigational product 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. Investigational products are 
distributed by the pharmacy. The pharmacist will enter the unique subject identifier on the 
investigational product vial/carton labels as they are distributed.
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Investigational product must be stored in accordance with labeled storage conditions. 
Temperature monitoring is required at the storage location to ensure that the investigational 
product is maintained within an established temperature range. The investigator is responsible 
for ensuring that the temperature is monitored throughout the duration of the study and that
records are maintained; the temperature should be monitored continuously by using either an 
in-house system, a mechanical recording device such as a calibrated chart recorder, or by 
manual means, such that both minimum and maximum thermometric values over a specific 
time period can be recorded and retrieved as required. Such a device (ie, certified min/max 
thermometer) would require manual resetting upon each recording. The sponsor must be 
notified immediately upon discovery of any excursion from the established range. 
Temperature excursions will require site investigation as to cause and remediation. 
The sponsor will determine the ultimate impact of excursions on the investigational product and 
will provide supportive documentation as necessary. Under no circumstances should the product 
be dispensed to subjects until the impact has been determined and the product is deemed 
appropriate for use by the sponsor.
The sponsor should be notified immediately if there are any changes to the storage area of the 
investigational product that could affect the integrity of the product(s), eg, fumigation of a 
storage room.
6.5 Drug Accountability
Investigators will be provided with sufficient amounts of the investigational product to carry out 
this protocol for the agreed number of subjects. The investigator or designee will acknowledge 
receipt of the investigational product, documenting shipment content and condition. Accurate 
records of all investigational product dispensed, used, returned, and/or destroyed must be 
maintained as detailed further in this section.
The investigator has overall responsibility for administering/dispensing investigational product. 
Where permissible, tasks may be delegated to a qualified designee (eg, a pharmacist) who is 
adequately trained in the protocol. This delegation must be documented in the applicable study 
delegation of authority form.
The site may use an alternative method for dispensing. If permitted by country or local 
regulations and ethics committees (ECs), the investigational product can be shipped from the site 
directly to the subject’s home address via courier. Subjects must be provided with instructions on 
how to receive, store, and ultimately return investigational/sponsor-supplied treatments.
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The investigator or his/her designee (as documented by the investigator in the applicable study 
delegation of authority form) will administer/dispense the investigational product only to 
subjects included in this study following the procedures set out in the study protocol. Each 
subject will be given only the investigational product carrying his/her treatment assignment. 
All administered/dispensed medication will be documented in the subject’s source and/or other 
investigational product record. The investigator is responsible for ensuring the retrieval of all 
study supplies from subjects. Due to the health/safety concerns with returning the investigational 
product container, the investigator must request that subjects keep the empty investigational 
product packaging after use and return it for drug accountability purposes.
No investigational product stock or returned inventory from a 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 
investigational product, and empty/used investigational product packaging are to be sent to a 
nominated contractor on behalf of the sponsor. Investigational product being returned to the 
sponsor’s designated contractors must be counted and verified by clinical site personnel and the 
sponsor (or designated contract research organization [CRO]). For unused supplies where the 
original supplied tamper-evident feature is verified as intact, the tamper-evident feature must not 
be broken and the labeled amount is to be documented in lieu of counting. Shipment return 
forms, when used, must be signed prior to shipment from the site. Validated electronic return 
systems (ie, IRT) do not require a shipment form. Returned investigational product must be 
packed in a tamper-evident manner to ensure product integrity. Contact the sponsor for 
authorization to return any investigational product prior to shipment. Shipment of all returned 
investigational product must comply with local, state, and national laws.
Based on entries in the site drug accountability forms, it must be possible to reconcile 
investigational products delivered with those used and returned. All investigational products 
must be accounted for and all discrepancies investigated and documented to the sponsor’s 
satisfaction.
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6.6 Training
The study monitor will ensure that the investigator and study site personnel understand all 
requirements of the protocol, the investigational status of the investigational product, and his/her 
regulatory responsibilities as an investigator. Training may be provided at an investigator’s 
meeting, at the study site, and/or by instruction manuals. In addition, the study monitor will be 
available for consultation with the investigator and will serve as the liaison between the study 
site and the sponsor.
6.7 Subject Compliance
For study procedures that are to be performed under the direct supervision of the 
investigator/healthcare professional (eg, infusion nurse) at the study site or infusion center, no 
separate procedures will be used to monitor subject compliance.
The procedure to monitor treatment compliance is provided in Section 6.3.3.2.4.
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 signing of informed (e)Consent (or pharmacokinetic equivalent of 
5 half-lives, whichever is longer) and through the final study contact must be recorded in the 
subject’s source document and appropriate eCRF.
6.8.1 Prior Treatment
Prior treatment includes all treatment taken within 30 days (or pharmacokinetic equivalent of 
5 half-lives, whichever is longer) of the date of signing of informed (e)Consent until the date of 
the first dose of investigational product. For subjects switching from TAK-664 studies, the 
records of all treatment (including investigational product the subject received) that were 
collected during the TAK-664 studies will be used in this study. Prior treatment information 
must be recorded in the subject’s source document and appropriate eCRF.
6.8.2 Concomitant Treatment 
Concomitant treatment refers to all treatment taken between the dates of the first dose of 
investigational product and study completion/termination, inclusive. Concomitant treatment 
information must be recorded in the subject’s source document and appropriate eCRF.
6.8.3 Permitted Treatment
Treatments not listed in Section 6.8.4 are considered allowable.
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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, with
3 exceptions shown in below.
-
Use of antibiotics for a period of up to 72 hours if required due to trauma or a
scheduled procedure
-
Use of anti-viral/fungal/protozoal drug for infections which are not treated by IG
(e.g trimethoprim/sulfamethoxazole twice a week)
-
Low-dose continuous administration of macrolides which are used for anti-
inflammatory effects (e.g. For adults (≥15 years old): erythromycin 400 mg/day;
clarithromycin 200 mg/day, For children (<15 years old): erythromycin 10 mg/kg/day;
clarithromycin 5 mg/kg/day)
-
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 IG 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

For subjects who are switching from IVIG treatment:
Subjects who are prone to AEs occurring in conjunction with infusions of IVIG 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 IVIG 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.
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
For subjects who are switching from cSCIG treatment or TAK-664 studies:
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.
6.9 Devices Used in Clinical Trial
In this study, ʻDevice Used in Clinical Trialʼ is defined as below:
Device name 
SapphireTM Multi-Therapy
Type
Infusion pump
Manufacturer
Q Core Medical Ltd.
6.9.1 Marketing approval
Sapphire Multi-Therapy has not yet been approved for marketing in Japan.
Administration of TAK-771 using Sapphire Multi-Therapy has already been evaluated for the 
compatibility with the drug and the mechanical suitability by Sponsor in Europe and the US 
where TAK-771 had been approved and marketed.
6.9.2 Indications for Use
Sapphire Multi-Therapy will be used for administration  of TAK-771 and to adjust the 
administration rate and volume of TAK-771 for SC infusion.
6.9.3 Usage Instructions and Warnings
For the usage instructions and warnings of Sapphire Multi-Therapy, see the User Manual 
(Q Core Medical, 2021) that will be provided to investigators.
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7. DISCONTINUATION OF STUDY INTERVENTION AND SUBJECT
DISCONTINUATION/WITHDRAWAL
7.1 Discontinuation of Study Treatment
If investigational product is discontinued, regardless of the reason, the evaluation listed for 
EOS/Early termination visit will be performed as completely as possible. Comments 
(spontaneous or elicited) or complaints made by the subject must be recorded in the source 
documents. The reason for discontinuation, date of discontinuation of the investigational product, 
and the total amount of investigational product administered must be recorded in the source 
documents.
Subjects who prematurely discontinue the study will not be replaced.
7.2 Reasons for Discontinuation
The reason for discontinuation must be determined by the investigator and recorded in the 
subject’s source document. If a subject is discontinued for more than 1 reason, each reason 
should be documented in the source and the most clinically relevant reason should be indicated. 
Reasons for discontinuation include, but are not limited to: 

Adverse event

Protocol deviation

Withdrawal by subject

Lost to follow-up

Lack of efficacy

Other
7.3 Withdrawal from the Study
A subject may withdraw from the study at any time and for any reason without prejudice to 
his/her future medical care by the physician or at the institution, or may be withdrawn at any 
time at the discretion of the investigator or sponsor (eg, in the interest of subject safety). The 
investigator is encouraged to discuss withdrawal of a subject with the medical monitor when 
possible.
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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 (in person or by phone or video). 
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 be assessed for final safety evaluations and return any unused 
investigational product.
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8. STUDY ASSESSMENTS AND PROCEDURES
8.1 Study Periods
The study consists of signing informed (e)Consent, screening period (up to 13 weeks), treatment
period (Epoch 1: 3 to 6 weeks of dose ramp-up period, Epoch 2: 12 weeks of dose adjustment
period and 12 weeks of trough evaluation period), and EOS/Early termination visit. Tabulated
schedules of study procedures are provided for 4-week dosing interval regimen in Table 1 (for
subjects switching from IVIG or cSCIG) and Table 2 (for subjects switching from TAK-664),
and for 3-week dosing interval regimen in Table 3 (for subjects switching from IVIG or cSCIG)
and Table 4 (for subjects switching from TAK-664). Study assessments are detailed in
Section 8.2.
8.1.1 Screening 
Any subject who provides informed (e)Consent /assent (i.e., signs and dates the informed 
consent form [ICF]/assent) is considered a subject in the study. If a subject is <18 years of age, 
the informed (e)Consent should also be signed and dated by the subject's legally authorized 
representative in addition to written and/or electronic informed assent by a subject if appropriate.
The written and/or electronic 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.
Subjects who are switching from IVIG or cSCIG treatment:
Subjects will be screened up to 13 weeks prior to the initial dose of investigational product. 
Subjects will continue to receive their own IG treatment at the same dose and dosing frequency 
as prescribed prior to their entry into this study.
The following procedures and assessments will be performed during the screening period:

Availability of signed informed (e)Consent

Assessment of eligibility

Demographic information

Body height and weight

Medical and Medication history

Physical examination

Vital signs (see Section 8.2.4.4)
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
Clinical laboratory assessments (see Table 9  for 4-week dosing interval regimen and
Table 11 for 3-week dosing interval regimen)

Serum IgG
Immunoglobulin G trough levels will be measured at least 2 points. The time interval
between measurement of IgG trough levels should be at least 3 weeks. The last 2 values
measured in the screening period, which become available before the initial administration
of investigational product, will be used to assess the eligibility.

Specialty tests

Concomitant medication and non-drug therapies

Adverse events

Pregnancy test
Subjects who are switching from TAK-664 studies:
Subjects who are switching from TAK-664 studies will directly move on to the treatment period 
without entering the screening period. The eligibility will be determined based on the data 
including the latest laboratory data and IgG trough levels collected in the TAK-664 studies. For 
IgG trough levels, the latest 2 values measured in the TAK-664 studies and available at the 
enrollment will be used to assess the eligibility.
Screen failure
A screen failure is a subject who has given informed (e)Consent and failed to meet the inclusion 
and/or met at least 1 of the exclusion criteria and has not been administered investigational 
product(s). 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 
subject identification code at re-screening.
8.1.2 Treatment Period
Eligible subjects will move on to the treatment period and receive investigational product.
8.1.2.1 Epoch 1 (Ramp-up Period)
Investigational product administration will be started with the ramp-up infusion.
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The following procedures and assessments will be performed at the study site before the 
investigational product is administered.

Physical examination

Body weight

Vital signs (see Section 8.2.4.4)

Clinical laboratory assessments (Week 1 only, see Table 9 and Table 10 for 4-week dosing
interval regimen and Table 11 and Table 12 for 3-week dosing interval regimen)

Serum IgG (Week 1 only)

Anti-rHuPH20 antibody (Week 1 only)

Retention samples (Week 1 only)

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)

Healthcare Resource Utilization (see Section 8.2.5.4)

Investigational product treatment
Collection of Infusion related data e.g.: lot number, start and stop time, infusion site,
maximum infusion rate achieved (mL/h) and changed rate if there is, total infusion volume
(mL), infusion completion, and the reason if infusion is not completed as planned.
For subjects who are switching from TAK-664 studies, the following procedures and
assessments will also be performed at Week 1 prior to the initial dose of investigational product. 
The assessments for the Week 1 can be combined with the EOS/Early termination visit 
assessments in TAK-664 studies, and data collected in the TAK-664 studies can be used if 
available:

Availability of signed informed (e)Consent

Assessment of eligibility

Demographic information

Body height

Medical and Medication history

Specialty tests (the eligibility will be reconfirmed after the result become available)

Pregnancy test
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8.1.2.2 Epoch 2 (24-week Treatment Period)
Investigational product will be administered subcutaneously at 3- or 4-week intervals after the 
ramp-up. The number of study site visits during the treatment period will vary across subjects, 
depending on their dosing intervals of investigational product
The following procedures and assessments will be performed at the study site (detailed 
scheduled provided in Table 1 and Table 2 for 4-week dosing interval regimen and in Table 3
and Table 4 for 3-week dosing interval regimen):

Physical examination

Body weight

Vital signs (see Section 8.2.4.4)

Clinical laboratory assessments (see Table 9 and Table 10 for 4-week dosing interval
regimen and Table 11 and Table 12 for 3-week dosing interval regimen)

Serum IgG

Anti-rHuPH20 antibody (only at Week 19 for 4-week dosing interval regimen and Week
16 for 3-week dosing interval regimen)

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)

Healthcare Resource Utilization (see Section 8.2.5.4)

Investigational product treatment
Collection of Infusion related data e.g.: lot number, start and stop time, infusion site,
maximum infusion rate achieved (mL/h) and changed rate if there is, total infusion volume
(mL), infusion completion, and the reason if infusion is not completed as planned.

Self-administration proficiency (See Section 6.3.3.2.4)
8.1.3 End-of-Study/Early Termination Visit
All subjects completing or exiting the study should complete the EOS/Early termination 
procedures. The visit will be 21 days after the last dose for 3-week dosing intervals and 28 days 
after the last dose for 4-week dosing intervals.
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The following procedures and assessments will be performed at the study site (see Table 1 and 
Table 2 for 4-week dosing interval regimen and Table 3 and Table 4 for 3-week dosing interval 
regimen):

Physical examination

Body weight

Vital signs (see Section 8.2.4.4)

Clinical laboratory assessments (see Table 9 and Table 10 for 4-week dosing interval
regimen and Table 11 and Table 12 for 3-week dosing interval regimen)

Serum IgG

Anti-rHuPH20 antibody (Testing is not required if the subject enroll the extension study)

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)

Healthcare Resource Utilization (see Section 8.2.5.4)
8.1.4 Follow-up Period
There is no follow-up period.
8.1.5 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 the treatment period can be enrolled in the 
extension study.
8.2 Study Assessments
8.2.1 Demographic and Other Baseline Characteristics
8.2.1.1 Demographics
Subject demographic information including gender, age, and race will be collected prior to the 
subject receiving the first dose of investigational product.
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8.2.1.2 Medical and Medication History
Medical and medication history will be collected and recorded in the subject’s source documents 
and appropriate eCRF.
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 (or pharmacokinetic 
equivalent of 5 half-lives, whichever is longer) prior to signing of informed (e)Consent until 
study completion/termination will be recorded on the concomitant medications and non-drug 
therapies case report forms (CRFs). For subjects switching from TAK-664 studies, the records of 
all treatment (including investigational product the subjects received) that were collected during 
the TAK-664 studies will be used as prior treatment in this study.
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 Table 9 through Table 12 in 
Appendix 2 by using standard assay methods for the determination of total IgG concentration 
and IgG subclasses.
The blood drawing for the IgG trough level 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 in a subset of 5 to 7 subjects aged 12 years and older. 
The parameters to be assessed may include but not limited to: Cmax, Tmax, AUC, half-life, CL/F, 
Vz/F, and Cmin.
For a schedule of PK testing, see Table 13 and Table 14 in Appendix 2 for 4-week and 3-week 
dosing interval regimen, respectively. Subjects who divided the dosing in multiple days will not 
be eligible for PK profile sampling.
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8.2.2.3 Specific Antibodies
Specific antibody tests (quantitative method) to Clostridium tetani toxoid, HIB and HBV will be 
performed at Week 1, PK troughs (just before infusion), and the EOS/Early termination visit. 
The test at PK troughs (just before infusion) is not required for subjects who are not included in 
the PK profile assessment.
For a schedule of specific antibody testing, see Table 9 through Table 12 in 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. 
Acute serious bacterial infections will include bacteremia/sepsis, bacterial meningitis, 
osteomyelitis/septic arthritis, bacterial pneumonia, and visceral abscess that are caused by a 
recognized bacterial pathogen. The diagnostic criteria for ASBIs are included in Appendix 5.
The ASBI rate will be calculated as the mean number of ASBIs per subject per year. 
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 eCRFs.
3.
Days on antibiotics
Days on antibiotics will be collected using diaries or other source data options throughout
the study and will be transcribed to eCRFs.
4.
Number of hospitalizations due to illness/infection and length of stay (in days)
Admissions to a hospital as an inpatient and the number of days in hospital will be
collected using diaries or other source data options throughout the study and will be
transcribed to eCRFs.
5.
Number of acute (urgent or unscheduled) physician visits due to illness/infection
Acute (urgent or unscheduled) physician visits due to illness/infection, will be collected
using diaries or other source data options throughout the study and will be transcribed to
eCRFs.
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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 visits, 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 pre-existing 
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 Body Height and Weight
Body height will be measured at screening and recorded in the subject’s source documents and 
appropriate eCRF.
Body weight will be measured at each screening and study visits including the EOS/Early 
termination visit, and recorded in the subject’s source documents and the appropriate eCRF.
8.2.4.3 Adverse Events
At each screening and study visit, subjects will be questioned in a general way to ascertain if 
AEs have occurred since the previous visit (eg, “Have you had any health problems since your 
last visit?”). Adverse events are collected from the time informed (e)Consent is signed. Refer to  
Appendix 3 for AE definitions, assessment, collection time frame, and reporting procedures.
8.2.4.4 Vital Signs
Vital signs include body temperature (°C), 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 at each screening and study visits including the EOS/Early 
termination visit. For the initial 3 SC infusions, vital signs are to be monitored and recorded 
at any time prior to infusion, in the event of occurrence of AE(s), and within 60 minutes 
of completion of an infusion. During subsequent infusion visits, vital signs will be taken 
once per administration, but will be recorded multiple times if an AE occurs. When 
subjects have self-infusion at home and an AE occurs, subjects (and/or caregivers) should 
measure vital signs by themselves and record the values on the subject diary. 
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Guidance for self-measurement and documentation of vital signs will be given to subjects 
(and/or caregiver) by the investigator/designee.
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 (baseline is defined as the last value 
before the initial dose) in vital signs may be deemed clinically significant and whether the 
change should be considered and recorded as an AE.
8.2.4.5 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.
8.2.4.5.1 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 {WBC} count]) 
with differential (i.e., basophils, eosinophils, lymphocytes, monocytes, neutrophils) and platelet 
counts. In addition, 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.
Blood will be obtained for assessment of hematology and clinical chemistry including IgG and 
IgG subclasses at baseline, distinct study visits, and at EOS/Early termination visit. IgG and IgG 
subclasses will also be measured for PK purposes. This will only be performed in subjects aged 
12 years and older. For a schedule of laboratory test blood drawings, see Appendix 2. 
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These assessments will be performed on EDTA-anticoagulated whole blood and serum, 
respectively, processed through a central laboratory. 
8.2.4.5.2 Anti-rHuPH20 Antibodies
Blood samples for the detection of anti-rHuPH20 binding and neutralizing antibodies will be 
collected at baseline, in the mid of the study and, if subject is not enrolling the extension study, 
at EOS/Early termination visit. For a schedule of blood sample drawings, see Appendix 2. Blood 
samples for the detection of anti-rHuPH20 binding and neutralizing antibodies will be collected 
and processed according to directions provided in the laboratory manual. At each collection 
timepoint, plasma samples will be collected into separate tubes labeled for binding antibodies 
and neutralizing antibodies. All subjects will be monitored for the formation of anti-rHuPH20 
antibodies using validated anti-rHuPH20 antibody detection assay (also known as the Screening 
and Confirmatory Binding Assay). Samples with binding antibody titers ≥1:160 will be analyzed 
for the presence of neutralizing antibodies using a validated assay based on neutralization of 
rHuPH20 activity at the central laboratory.
The test results (titers, and binding or neutralizing) will be assessed for clinical significance by 
the investigator in the Electronic Data Capture (EDC) database but are not to be reported as AEs. 
8.2.4.5.3 Immunogenicity Panel
At Week 1 predose, samples will be collected for the following tests to be conducted: 50% 
hemolytic complement activity of serum (CH50), serum complement component 3 (C3), serum 
complement component 4 (C4), Complement 1q (C1q) binding assay, and circulating immune 
complex (CIC) Raji cell assay.
All subjects will have anti-rHuPH20 antibody testing in pre-identified central laboratories for 
anti-rHuPH20 binding antibodies, and neutralizing antibodies will also be measured for subjects 
with an anti-rHuPH20 binding antibody titer ≥160 (Section 8.2.4.5.2). If a subject has a positive 
titer ≥10,000 at any time during the study, characterization of antibodies may be performed 
(include antibodies cross reacting with Hyal 1, 2, and 4). When there is more than one samples 
from a same subject has a positive titer ≥10,000, the cross-reactivity analyses for each subject at 
the peak titer sample will be analyzed, not more than a one-time point from the same subject in a 
given study. If the cross-reactivity data is going to be included in any interim Safety Data 
Analysis deliverable/milestone, the highest titer sample of the subject observed by the time of 
data cut-off for interim analysis will be used for analysis. At any time during the course of the 
study, subjects who have (a) two consecutive anti-rHuPH20 binding antibody titers of ≥1:160 
which are elevated from the subject’s baseline titers, and (b) a moderate or severe AE which 
may be a result of immune-mediated response to either immunoglobulin or rHuPH20 will be 
asked to return to the study site as soon as possible to undergo an additional panel of testing. 
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That panel assesses CH50, serum C3, serum C4, C1q binding assay and CIC Raji cell assay.
For a schedule of laboratory test blood drawings, see Appendix 2.
8.2.4.5.4 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 Sections 5.4 and Section 8.2.4.6). 
8.2.4.5.5 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, or B19V (see also 
Section 8.2.4.5.7.2).
8.2.4.5.6 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 antiglobulin test (Coombs-test or AGT)

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 antiglobulin test (Coombs-test or AGT)

urine hemosiderin

hemoglobin
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
lactate dehydrogenase

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.
8.2.4.5.7 Assessment of Laboratory Values
8.2.4.5.7.1 Toxicity Grading Scale
The investigator will be asked to assess each abnormal laboratory value as described in 
Section 8.2.4.5.7.2. 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). 
8.2.4.5.7.2 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 CRF. If the abnormal value was not deemed an AE because it was due to a 
lab error, was due to a pre-existing disease (described in Appendix 3.1), was not clinically 
significant, was a symptom of a new/worsened condition already recorded as an AE, or was due 
to another issue that will be specified, the investigator will record the justification on the 
laboratory form. Additional tests and other evaluations required to establish the significance or 
etiology of an abnormal result or to monitor the course of an AE should be obtained when 
clinically indicated. Any abnormal value that persists should be followed at the discretion of the 
investigator. Any positive seroconversion result for HIV, HAV, HBV, HCV, HEV, or B19V 
shall be re-tested and confirmed.
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8.2.4.6 Pregnancy Test
A urine pregnancy test will be performed on all females of childbearing potential at screening  
for subjects switching from IVIG or cSCIG treatment, and at pre-infusion at Week 1 for subjects 
switching from TAK-664 studies; if pregnancy is suspected; or on withdrawal of the subject 
from the study. If subjects switching from TAK-664 studies have a result of pregnancy test 
conducted at EOS/Early termination visit in the TAK-664 studies, it can be used to determine the 
pregnancy; no need to repeat the test in this study.
All pregnancies are reported from the time informed (e)Consent is signed until EOS/Early 
termination visit. See Appendix 3.8 for the pregnancy reporting.
8.2.5 Other
8.2.5.1 Pharmacodynamics 
Not applicable
8.2.5.2 Genetics
Not applicable
8.2.5.3 Disease Activity and Health-related Quality of Life 
Paper questionnaire or electronic collection device will be used to capture the QoL/treatment 
satisfaction data.
8.2.5.3.1 Quality of Life 
A QoL assessment will be performed at Week 1, 12 weeks after the ramp-up in treatment period 
(Week 19 for 4-week dosing interval regimen and Week 16 for 3-week dosing interval regimen), 
and at the EOS/Early termination visit.
Quality of life will be analyzed separately for the age groups of 2 to 7 years (PEDS-QL, 
observer: parent), 8 to 13 years (PEDS-QL, observer: subject), and 14 years and older (SF-36, 
observer: subject). Additionally, all subjects will complete the EQ-5D-3L Health Questionnaire, 
analyzed separately for the age groups: 2 to 11 years EQ-5D-3L (observer: parent) and 12 years 
and older EQ-5D-3L (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.
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8.2.5.3.2 Treatment Satisfaction
Treatment Satisfaction Questionnaire for Medication (TSQM-9) will be assessed at Week 1, 
12 weeks after the ramp-up in treatment period (Week 19 for 4-week dosing interval regimen 
and Week 16 for 3-week dosing interval regimen), and at the EOS/Early termination visit.
Data will be analyzed separately for the age groups of 2 to 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.
8.2.5.3.3 Treatment Preference
Treatment preference will be assessed at the EOS/Early termination visit.
Treatment preference will be analyzed separately for the age groups of 2 to 13 years (observer: 
parent) and 14 years and older (observer: subject). Age will be defined as the age at screening.
8.2.5.4 Healthcare Resource Utilization 
Days not able to attend school/work or to perform normal daily activities due to illness/infection, 
days on antibiotics, number of hospitalizations due to illness/infection and length of stay (in 
days) and number of acute (urgent or unscheduled) physician visits due to illness/infection will 
be collected as described in Section 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 prior to the first infusion at Week 1. 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 throughout the study period:

Occurrence of AEs (including infections). The investigator will provide guidance for the
subject/caregiver regarding identification and documentation of AEs
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
Concomitant medication use

Days not able to attend school/work or to perform normal daily activities due to
illness/infection

Number of hospitalizations, indication for the hospitalization (infection or non-infection)
and days hospitalized

Number of acute physician visits (office and emergency room) due to infection or other
illnesses
TAK-771 infusion related data should be recorded in the subject diary when subjects have self-
administration of SC infusions at home. Vital signs self-measured should also be recorded in the 
subject diary when subjects have self-infusion at home and an AE occurs. The investigator will 
provide guidance for the subject/caregiver regarding self-measurement and documentation of 
vital signs. The subject diary will serve as a source record and remain at the study site. The 
investigator will review the diary for completeness and request missing information periodically 
and in a timely manner. Untoward events recorded in the diary will be reported as AEs according 
to the investigator’s discretion and clinical judgment. 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.
8.2.9 Product Administration
TAK-771 infusion related data will be collected and recorded in the eCRF. The data to be 
collected includes but not limited to: lot number, start and stop time, infusion site, maximum 
infusion rate achieved (mL/h) and changed rate if there is, total infusion volume (mL), infusion 
completion, and the reason if infusion is not completed as planned.
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9. STATISTICAL CONSIDERATIONS
9.1 Statistical Analysis Process
The study will be analyzed by the sponsor or its agent.
The SAP will provide the statistical methods and definitions for the analysis of the PK, efficacy 
and safety data, as well as describe the approaches to be taken for summarizing other study 
information such as subject disposition, demographics and baseline characteristics, 
investigational product exposure, and prior and concomitant medications. The SAP will also 
include a description of how missing, unused and spurious data will be addressed.
To preserve the integrity of the statistical analysis and study conclusions, the SAP will be 
finalized prior to database lock. Specifications for the corresponding tables, figures, and listings 
(TFLs) will be provided separately, in the study TFL shells document.
All statistical analyses will be performed using SAS® (SAS Institute, Cary, NC 27513) version 
9.4 or higher
9.2 Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee
No interim analysis, adaptive design, or data monitoring committee is planned for this study.
9.3 Sample Size and Power Considerations
The planned total sample size for this study is 15 subjects (enrolled). 
Of the 15 subjects to be enrolled, 12 subjects are expected to complete treatment period of the 
study, assuming a dropout rate of 20%. Subjects who prematurely discontinue the study will not 
be replaced. The number of subjects expected to complete treatment period (12 subjects) is 
considered adequate for the evaluation of serum trough IgG levels, safety and tolerability, and 
efficacy of TAK-771, 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 to 3,500. Of the number of PID patients (2,900 to 3,500), an 
estimated 1,450 to 1,750 would be potential targets for IG replacement therapy. In clinical 
practice, most patients requiring a switch to SCIG (as is required by the study design) are 
already being treated with the approved SCIG product (Hizentra®). In the Hizentra® New 
Drug Application review report, the estimated number of patients who could receive IG 
replacement therapy was 1,155, which is lower than the estimated 1,450 to 1,750 patients. 
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Even if both patients who are treated with IVIG or Hizentra® can participate in this study, the 
number of potentially eligible patients for the planned study is extremely limited, making it 
infeasible to enroll a large sample size. Therefore, the applicant made the study design that PID 
patients who complete ongoing clinical trials (TAK-664 studies) of TAK-664 (20% SCIG) are 
able to enroll in this study.
Based on feasibility and the sponsor’s clinical experience with IgG products, a total sample size 
of 15 subjects (12 completers) is considered suitable for providing adequate estimates of trough 
levels (study primary objective), as well as adequate 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 enrolled subjects who have signed informed (e)Consent and are assigned
to subject identification codes.
Baseline summaries (e.g., subject disposition) will be based on the Enrolled Set.

Full Analysis Set (FAS): All enrolled subjects who received investigational drug at least
once.
Analysis of efficacy, disease activity and HRQoL will be based on the FAS.

Safety Analysis Set (SAS): All enrolled subjects who received investigational drug at least
once.
Analysis of safety, tolerability and product administration will be based on the SAS.

Pharmacokinetic Analysis Set (PKAS): All enrolled subjects who received investigational
drug at least once, have had at least 1 evaluable serum IgG concentration, and no major
protocol deviations or events that would affect the serum IgG concentration analysis
results.
Analysis of serum IgG trough concentrations will be based on the PKAS and analysis of
PK profiles will be based on the subset of 5 to 7 subjects aged 12 years and older in the
PKAS.
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9.5 Pharmacokinetic Analyses
The primary PK endpoint is the serum trough levels of total IgG (total serum trough IgG 
antibodies) measured during the trough evaluation period of Epoch 2 (administration of 
TAK-771).
The secondary PK endpoints are:

PK parameters for total serum levels of IgG and for IgG subclasses in the PK assessment
period of Epoch 2 (in a subset of 5 to 7 subjects aged 12 years and older)

Serum trough levels of IgG subclasses in the trough evaluation period of Epoch 2

Trough levels of specific antibodies to Clostridium tetani toxoid, HIB, and HBV in
Epoch 1 and 2.
All PK data will be summarized using the following descriptive statistics: number of subjects 
(n), mean, median, standard deviation (SD), minimum value, maximum value. For serum IgG, 
IgG subclasses and specific antibodies trough levels, descriptive statistics will also include GM 
and the corresponding 2-sided 95% CI. No formal statistical comparison (hypothesis testing) of 
treatments will be performed. CIs are for descriptive purposes only and caution should be 
exhibited in their interpretation as this study is not designed for hypothesis testing.
9.6 Efficacy Analysis
Assessment of efficacy is a secondary objective of the study. Efficacy endpoint data (defined 
below) will be analyzed using descriptive statistics: number of subjects (n), mean, median, SD, 
minimum value, maximum value, 1st quartile (Q1) and 3rd quartile (Q3). It will be summarized 
by Epoch and overall treatment period.

Annual rate of validated ASBIs per subject

Annual rate of all infections per subject

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)
-
Number of acute (urgent or unscheduled) physician visits due to illness/infection
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9.7 Safety Analyses
Assessment of safety and tolerability is a secondary objective of this study. Safety and 
tolerability endpoints (defined below) will be summarized using descriptive statistics (n, mean, 
median, SD, minimum value, maximum value, Q1, and Q3) for continuous endpoints/outcome 
measures, and by Epoch and overall treatment period where applicable. Categorical 
endpoints/outcome measures of safety and tolerability will be summarized in terms of number 
and percent of subjects and number of occurrences in each category.

Occurrence of TEAEs, including but not limited to: TAK-771-related and non-related,
serious, non-serious, severe, local and systemic TEAEs, as well as TEAEs leading to
premature discontinuation from study, and infusion-associated TEAEs

Occurrence of tolerability events related to the infusion of TAK-771
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 TAK-771 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.

Changes in clinical laboratory parameters

Changes in vital signs and body weight.
Change from baseline in vital signs and body weight, and change from pre-infusion to
post-infusion in vital signs

Development of positive titer (≥ 1:160) binding antibodies, and development of
neutralizing antibodies, to rHuPH20
Number and percentage of subjects who develop anti-rHuPH20 binding antibody titers of
≥1:160
Number and percentage of subjects who develop neutralizing antibodies to rHuPH20
Baseline is defined as the last non-missing value before the initial dose of investigational drug.
9.7.1 Analysis of Adverse Events
9.7.1.1 Definitions
Treatment-emergent adverse events, defined as AEs with onset after date-time of first dose of 
investigational drug, or medical conditions present prior to the start of investigational drug but 
increased in severity or relationship after date-time of first dose of investigational drug.
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Non-TEAEs, defined as AEs with onset before date-time of first dose of investigational drug, or 
medical conditions present prior to the start of investigational drug but did not increase in 
severity or relationship after date-time of first dose of investigational drug.
Related TEAEs, defined as TEAEs causally related to investigational product.
9.7.1.2 Handling of Recurrent Adverse Events and Other Adverse Event 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 investigational drug), the 
AE with the maximum severity (AE that is severe) will be used in analysis.
Related AEs: An AE that follows a reasonable temporal sequence from administration of a drug 
(including the course after withdrawal of the drug), or for which possible involvement of the 
drug cannot be ruled out, although factors other than the drug, such as underlying diseases, 
complications, concomitant medications and concurrent treatments, may also be responsible. 
Relationship (causality) to study procedures should also be determined for all AEs. The 
relationship should be assessed as “Related” if the investigator considers that there is reasonable 
possibility that an event is due to a study procedure. Otherwise, the relationship should be 
assessed as “Not Related”.
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 investigational drug. 
For example, if a subject experienced a mild headache not related to the investigational drug, and 
a moderate headache related to investigational drug, then the subject will be counted once for 
headache using the moderate headache related to investigational drug.
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 24.0 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. 
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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, and any TEAE leading to death.

Summaries by SOC and PT: In the summaries, SOC will be sorted alphabetically, and PT
will be sorted within each SOC in descending frequency 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 investigational drug. For example, if a
subject experienced a mild headache not related to the investigational drug, and a moderate
headache related to investigational drug, then the subject will be counted once for
headache using the moderate headache related to investigational drug.

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 SY, by SOC and PT
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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 SY is number of events divided by 
total number of days of exposure, converted into years.
AEs per SY summary adjusts for differences in subjects’ durations in the study. 
For number of AEs, multiple occurrences of the same AE in the same subject will be counted 
multiple times.
Number of AEs and AEs per 1000 SYs will be provided for all AEs (if analyzable), by primary 
SOC and PT.
The following calculations apply, where applicable:

AEs per infusion = number of AEs / total number of infusions administered to subjects in
the analysis set

AEs per subject = number of AEs / total number of subjects in the analysis set

AEs per SY = 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 x (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 investigational drug + 1) 
/ 365.25. If the subject’s last date is missing, then the date of last dose of investigational drug 
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
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
Number of weeks to reach final dose interval (3 weeks or 4 weeks) in Epoch 1

Percentage of subjects who achieve a treatment interval of 3 or 4 weeks in Epoch 2

Percentage of subjects who maintain a treatment interval of 3 or 4 weeks in Epoch 2
9.7.2 Clinical Laboratory Data
Baseline is defined as the last non-missing value before initial dose of study drug.
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 
reference range), normal (within the reference range), high (above the upper limit of the 
reference range), and missing. Missing data will not be imputed. In addition, shift-from-baseline 
summaries will be produced by toxicity grade.
9.7.3 Vital Signs and Body Weight
Raw (actual) vital signs and body weight, and changes in raw values from baseline at each post-
baseline assessment time point will be summarized as appropriate. For vital signs, change from 
pre-infusion to post-infusion will also be summarized as appropriate.
9.7.4 Antibodies
Number and percentage of subjects who develop anti-rHuPH20 binding antibody titers of ≥1:160 
in Epoch 2 will be summarized. Samples with anti-rHuPH20 binding antibody titers ≥1:160 will 
be analyzed for the presence of neutralizing antibodies, and the number and percentage of 
subjects who develop neutralizing antibodies to rHuPH20 in Epoch 2 will be summarized.
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9.8 Other Analyses
9.8.1 Disease Activity and Health-related Quality of Life Analyses
All disease activity and HRQoL data (defined below) will be listed in the subject data listing(s). 
For the endpoint of Treatment Preference at EOS/Early Termination, number and percentage of 
subjects in each category will be summarized. For other endpoints shown below, raw (actual) 
and change from baseline values will be summarized descriptively, and summaries will be 
provided.

QoL: PEDS-QL (Varni et al., 1999), SF-36 v2 (Ware and Sherbourne, 1992), EQ-5D-3L
Health Questionnaire (Shaw et al., 2005) in Epoch 1 and 2

Treatment Satisfaction (TSQM-9) (Daly et al., 1991) in Epoch 1 and 2
9.8.2 Product Administration
Infusion parameters in Epoch 2 will be summarized descriptively. The parameters may include 
but not limited to the following:

Number of infusions per month

Number of infusion sites per infusion

Number of infusion sites per month

Duration of individual infusion

Maximum infusion rate/site

Infusion volume/site
Endpoint details will be provided in the study SAP.
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APPENDIX 9  PROTOCOL HISTORY 
Document
Date
Global/Country/Site Specific
Amendment 1
19 May 2022
Japan
Original Protocol
13 July 2021
Japan
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SAP_001.pdf: 
Statistical Analysis Plan 
NCT Number: NCT05150340 
Title: A Phase 3, Open-label, Non-controlled Study to Evaluate the Pharmacokinetics, 
Safety and Tolerability, and Efficacy of TAK-771 in Japanese Subjects with Primary 
Immunodeficiency Diseases (PID) 
Study Number: TAK-771-3004 
Document Version and Date: Version 2.0 / 21-Sep-2023 
Certain information within this document has been redacted (ie, specific content is 
masked irreversibly from view) to protect either personally identifiable information or 
company confidential information. 


STATISTICAL ANALYSIS PLAN
Study Number: TAK-771-3004
Study Title: A Phase 3, Open-label, Non-controlled Study to Evaluate the Pharmacokinetics, 
Safety and Tolerability, and Efficacy of TAK-771 in Japanese Subjects with Primary 
Immunodeficiency Diseases (PID)
Phase: Phase 3
Version: Final 2.0
Date: 21-Sep-2023
Prepared by: 
Based on:
Protocol Version: Protocol Version 2.0
Protocol Date: 17-May-2022
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REVISION HISTORY
Version 
Approval Date
Primary Rationale for Revision
1.0
29Oct2021
Not Applicable
2.0
21Sep2023
Updated protocol version.
Deleted clinically significant changes in laboratory 
evaluations, vital signs and weight throughout SAP since 
these are no longer endpoints in Protocol Ver 2.0.
Section 5.0: Added Epoch 2 Safety Analysis Set and 
Epoch 2 Full Analysis Set and added a description about 
PK Analysis Set.
Section 6.3.1: Primary Immunodeficiency Diagnosis was 
added and revised the Analysis Set. 
Section 6.4: Updated the term “therapy” to “surgery”, as 
was done in Protocol 2.0.
Section 6.4.2: Revised the definition of concomitant 
according to Protocol 2.0.
Section 6.6.1, Section 6.6.2: Clarification of analysis 
content.
Section 6.6.3: 
-
Deleted number of subjects with
hospitalizations and length of stay per stay.
-
Added derivation for the number of acute
physician visits / emergency room visits.
Section 6.6.4: Added derivations for maximum infusion 
rate/site and infusion volume/site.
Section 6.7.1.1: Added the types of tables to be analyzed 
and revised the derivations of local/systemic TEAE.
Section 6.7.3: Description has changed to the following, 
and also mentioned in Section 8.0.
“For vital signs, change from pre infusion to post-infusion 
will also be summarized by Epoch and overall treatment 
period”→“For vital signs, change from pre infusion to 
post-infusion will also be summarized for Epoch 1”.
Section 6.7.4.1: Revised the description according to 
Protocol 2.0 and added the logic for anti-rHuPH20 titer 
that is abnormal or rises above baseline.
Removed the section for Life Quality Index, since it was 
removed from the Protocol.
Section 6.8: 
-
Added a derivation for the number of weeks
to reach final dose interval (3 weeks or
4 weeks) in Epoch 1 and percentage of
subjects who achieve a treatment interval of
3 or 4 weeks in Epoch 2 and reasons for
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dose adjustment for the number (percentage) 
of subjects for whom the infusion rate was 
reduced/interrupted/stopped for tolerability 
concerns or for AEs. 
-
For the number (percentage) of subjects for
whom the infusion rate was
reduced/interrupted/stopped for tolerability
concerns or for AEs, derivation was revised.
-
Reference page in eCRF has changed from
“Dosing Injection rHuPH20” to “Dosing
Injection 10%IGI”.
Section 6.9: Changed the end of exposure as the end of 
treatment instead of the end of Epoch or study and deleted 
Total dose received. Added Number of infusions.
Section 6.10.1.2: Changed the description to calculate
SF-36 using special software.
Section 6.10.3: Revised to calculate number and 
percentage of subjects in each category, instead of 
descriptive statistics.
Section 9.2.6: Added the logic of the end of Epoch 1 for 
subjects who completed Epoch 1 and continued to 
Epoch 2.
Section 9.2.7: Added the visit windows for home records 
of vital sign.
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TABLE OF CONTENTS
REVISION HISTORY.....................................................................................................................2
TABLE OF CONTENTS.................................................................................................................4
LIST OF IN-TEXT TABLES ..........................................................................................................7
LIST OF IN-TEXT FIGURES.........................................................................................................7
ABBREVIATIONS .........................................................................................................................8
1.0
OBJECTIVES, ENDPOINTS AND ESTIMANDS ..........................................................10
1.1
Objectives ....................................................................................................................10
1.1.1
Primary Objective................................................................................................10
1.1.2
Secondary Objectives ..........................................................................................10
1.2
Endpoints .....................................................................................................................10
1.2.1
Primary Endpoint.................................................................................................10
1.2.2
Secondary Endpoints...........................................................................................10
1.2.2.1
Pharmacokinetic Endpoints.........................................................................10
1.2.2.2
Safety and Tolerability Endpoints...............................................................11
1.2.2.3
Efficacy Endpoints......................................................................................11
1.2.2.4
Disease Activity and Health-Related Quality of Life Endpoints................12
1.3
Estimand ......................................................................................................................12
2.0
STUDY DESIGN...............................................................................................................12
3.0
STATISTICAL HYPOTHESES AND DECISION RULES.............................................14
3.1
Statistical Hypotheses ..................................................................................................14
3.2
Statistical Decision Rules ............................................................................................14
3.3
Multiplicity Adjustment...............................................................................................14
4.0
SAMPLE-SIZE DETERMINATION................................................................................15
5.0
ANALYSIS SETS .............................................................................................................15
5.1
Enrolled Set..................................................................................................................15
5.2
Safety Analysis Set ......................................................................................................15
5.3
Full Analysis Set..........................................................................................................16
5.4
Pharmacokinetic Analysis Set......................................................................................16
6.0
STATISTICAL ANALYSIS .............................................................................................16
6.1
General Considerations................................................................................................16
6.2
Disposition of Subjects ................................................................................................17
6.2.1
Protocol Deviations .............................................................................................17
6.2.2
COVID-19 ...........................................................................................................17
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6.3
Demographic and Other Baseline Characteristics .......................................................17
6.3.1
Demographics......................................................................................................17
6.3.2
Medical History and Concurrent Medical Conditions.........................................18
6.4
Medication History and Concomitant Medications/Procedures/Surgeries..................19
6.4.1
Prior Medications/Procedures/Surgeries .............................................................19
6.4.2
Concomitant Medications/Procedures/Surgeries.................................................19
6.5
Pharmacokinetic Analysis............................................................................................19
6.5.1
Primary and Secondary Pharmacokinetics Endpoints Analysis..........................19
6.6
Efficacy Analysis.........................................................................................................20
6.6.1
Annual Rate of Validated Acute Serious Bacterial Infections ............................20
6.6.2
Annual Rate of All Infections..............................................................................21
6.6.3
Healthcare Resource Utilization..........................................................................21
6.6.3.1
Days Not Able to Attend School/Work or to Perform Normal Daily 
Activities Due to Illness/Infection ..............................................................21
6.6.3.2
Days on Antibiotics.....................................................................................22
6.6.3.3
Number of Hospitalizations Due to Illness/Infection and Length of Stay..22
6.6.3.4
Number of Acute (Urgent of Unscheduled) Physician Visits Due to 
Illness/Infection...........................................................................................23
6.6.4
Infusion Parameters in Epoch 2...........................................................................23
6.7
Safety Analysis ............................................................................................................24
6.7.1
Adverse Events....................................................................................................24
6.7.1.1
Summaries of Treatment-Emergent Adverse Events..................................25
6.7.1.2
Adverse Events per Infusion, per Subject, per Subject Year......................26
6.7.1.3
Subgroup Analysis for Treatment-Emergent Adverse Events....................27
6.7.2
Clinical Laboratory Outcomes ............................................................................27
6.7.3
Vital Signs ...........................................................................................................28
6.7.4
Anti-rHuPH20 Antibodies...................................................................................29
6.8
Tolerability Analysis....................................................................................................29
6.9
Extent of Exposure and Infusion Compliance .............................................................31
6.10
Disease Activity and Health-related Quality of Life ...................................................31
6.10.1
Quality of Life .....................................................................................................31
6.10.1.1
PEDS-QL ....................................................................................................32
6.10.1.2
SF-36...........................................................................................................32
6.10.1.3
EQ-5D-3L Health Questionnaire ................................................................33
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6.10.2
Treatment Satisfaction.........................................................................................34
6.10.2.1
Treatment Satisfaction Questionnaire for Medication-9.............................34
6.10.3
Treatment Preference...........................................................................................35
6.11
Other Safety Analysis ..................................................................................................35
6.11.1
Physical Examination..........................................................................................35
6.11.2
Pregnancy Test ....................................................................................................35
6.12
Interim Analyses ..........................................................................................................35
7.0
REFERENCES ..................................................................................................................36
8.0
CHANGES TO PROTOCOL PLANNED ANALYSES...................................................37
9.0
APPENDIX........................................................................................................................38
9.1
Changes from the Previous Version of the SAP..........................................................38
9.2
Data Handling Conventions.........................................................................................38
9.2.1
General Data Reporting Conventions..................................................................38
9.2.1.1
Dates & Times.............................................................................................38
9.2.1.2
Spelling format............................................................................................38
9.2.1.3
Paper Size, Orientation, and Margins .........................................................38
9.2.1.4
Fonts............................................................................................................38
9.2.1.5
Descriptive Statistics...................................................................................38
9.2.1.6
Percentages..................................................................................................38
9.2.1.7
Listings........................................................................................................39
9.2.2
Definition of Baseline..........................................................................................39
9.2.3
Handling of Missing, Unused, and Spurious Data ..............................................39
9.2.3.1
Missing medication dates............................................................................39
9.2.3.2
Missing Adverse Event Dates.....................................................................40
9.2.3.3
Missing Relationship to Study Drug for Adverse Events...........................41
9.2.3.4
Missing Severity for Adverse Events..........................................................41
9.2.3.5
Character Values of Clinical Laboratory Variables....................................41
9.2.4
Reference Start Date and Study Day...................................................................41
9.2.5
Multicenter Study................................................................................................42
9.2.6
Date of Start/End of Epoch..................................................................................42
9.2.7
Definition of Visit Windows ...............................................................................42
9.3
Analysis Software........................................................................................................46
9.4
Programming Notes for Lab Toxicity Grading............................................................47
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LIST OF IN-TEXT TABLES
Table 1
Japanese Value Set for EQ-5D-3L Health State Index Score................................33
Table 2
Convention for Converting Non-Standard Laboratory Results .............................41
Table 3
Visit Windows for 4-week Dosing Interval, IVIG and cSCIG Subjects ...............43
Table 4
Visit Windows for 4-week Dosing Interval, TAK-664 Subjects...........................44
Table 5
Visit Windows for 3-week Dosing Interval, IVIG and cSCIG Subjects ...............45
Table 6
Visit Windows for 3-week Dosing Interval, TAK-664 Subjects...........................46
LIST OF IN-TEXT FIGURES
Figure 1
Schematic of Study Design....................................................................................14
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ABBREVIATIONS
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ASBI
acute serious bacterial infection
AST
aspartate aminotransferase
ATC
Anatomical Therapeutic Chemical
AUC
area under the curve
B19V
Parvovirus B19
BP
bodily pain
BUN
blood urea nitrogen
CL/F
apparent total clearance
Cmax
maximum concentration
Cmin
minimum concentration
COVID-19
coronavirus 2019
CPK
creatinine phosphokinase
cSCIG
conventional subcutaneous immunoglobulin
CTMS
clinical trial management system
eCRF
electronic case report form
EOS
end of study
FAS
full analysis set
GH
general health
HAV
hepatitis A virus
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HEV
hepatitis E virus
HIB
hepatitis B virus
HIV
human immunodeficiency virus
HRQoL
health-related quality of life
IG
immunoglobulin
IgG
immunoglobulin G
IGI
immune globulin infusion
IVIG
intravenous immunoglobulin
LDH
lactate dehydrogenase
MCS
mental component summary
MedDRA
Medical Dictionary for Regulatory Activities
MH
mental health
n
number of subjects
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PCR
polymerase chain reaction
PCS
physical component summary
PF
physical functioning
PID
primary immunodeficiency diseases
PK
pharmacokinetic
PKAS
pharmacokinetic analysis set
PT
Preferred Term
RCS
role/social component summary
RE
role emotional
RP
role physical
SAS
safety analysis set
SC
subcutaneous
SCIG
subcutaneous immunoglobulin
SD
standard deviation
SF
social functioning
SI units
International System of Units
SOC
System Organ Class
SY
subject-year
TEAE 
treatment-emergent adverse event
Tmax
time to maximum concentration
TSQM
Treatment Satisfaction Questionnaire for Medication
VAS
visual analogue scale
VT
vitality
Vz/F
apparent volume of distribution
WBC
white blood cell
WHO-DD
World Health Organization Drug Dictionary
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1.0
OBJECTIVES, ENDPOINTS AND ESTIMANDS
1.1
Objectives
1.1.1
Primary Objective
The primary objective of the study is to assess serum trough levels of total immunoglobulin G 
(IgG) when using TAK-771 as maintenance therapy in Japanese subjects with Primary 
Immunodeficiency Diseases (PID). 
1.1.2
Secondary Objectives
The secondary objectives of this study are listed below:

To characterize the pharmacokinetic (PK) profiles of TAK-771 in Japanese subjects with PID
following TAK-771 administration.

To evaluate the safety and tolerability of TAK-771 in Japanese subjects with PID.

To evaluate the efficacy of TAK-771 in Japanese subjects with PID.

To assess disease activity and health-related quality of life (HRQoL) in Japanese subjects
with PID following TAK-771 administration.
1.2
Endpoints
1.2.1
Primary Endpoint
The primary endpoint for the study is the serum trough levels of total IgG (total serum trough 
IgG antibodies) measured during the trough evaluation period of Epoch 2 (administration of 
TAK-771).
1.2.2
Secondary Endpoints
Secondary endpoints cover PK, safety and tolerability, efficacy, and disease activity and 
HRQoL.
1.2.2.1
Pharmacokinetic Endpoints
Pharmacokinetic endpoints and parameters:

PK parameters for total serum levels of IgG and for IgG subclasses in PK assessment period
in Epoch 2 (in a subset of 5 to 7 subjects aged 12 years and older), which may include but not
limited to the following: maximum concentration (Cmax), time to maximum concentration
(Tmax), area under the curve (AUC), half-life, apparent total clearance (CL/F), apparent
volume of distribution (Vz/F), minimum concentration (Cmin).

Serum trough levels of IgG subclasses in the trough evaluation period of Epoch 2.
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
Trough levels of specific antibodies to clinically relevant pathogens (Clostridium tetani
toxoid, Haemophilus influenzae [HIB], Hepatitis B virus [HBV]) in Epoch 1 and 2.
1.2.2.2
Safety and Tolerability Endpoints
Safety endpoints/outcome measures:

Occurrence of treatment-emergent adverse events (TEAEs) in Epoch 1 and 2, including but
not limited to: TAK-771-related and non-related, serious, non-serious, severe, local and
systemic TEAEs, as well as TEAEs leading to premature discontinuation from study, and
infusion-associated TEAEs.

Changes in clinical laboratory parameters in Epoch 1 and 2.

Changes in vital signs and body weight in Epoch 1 and Epoch 2. Change from baseline in
vital signs and body weight, and change from pre-infusion to post-infusion in vital signs.

Development of positive titer (≥1:160) binding antibodies, and development of neutralizing
antibodies, to Recombinant Human Hyaluronidase (rHuPH20) in Epoch 2.
Number and percentage of subjects who develop anti-rHuPH20 binding antibody titers of
≥1:160.
Number and percentage of subjects who develop neutralizing antibodies to rHuPH20.
Tolerability endpoints/outcome measures:

Occurrence of tolerability events related to the infusion of TAK-771 in Epoch 1 and 2.
A tolerability event is considered to have occurred if an infusion was not tolerable, which is
defined as any changes in dosing of TAK-771 such as reduction of infusion rate, interruption
or discontinuation of TAK-771 due to TEAEs related to TAK-771. Number and percentage
of subjects who experienced tolerability events will be measured.

Number of weeks to reach final dose interval (3 weeks or 4 weeks) in Epoch 1.

Percentage of subjects who achieve a treatment interval of 3 or 4 weeks in Epoch 2.

Percentage of subjects who maintain a treatment interval of 3 or 4 weeks in Epoch 2.
1.2.2.3
Efficacy Endpoints
Efficacy endpoints/outcome measures:

Annual rate of validated acute serious bacterial infections (ASBIs) per subject in Epoch 1 and
2.

Annual rate of all infections per subject in Epoch 1 and 2.

Healthcare Resource Utilization in Epoch 1 and 2:
–
Days not able to attend school/work or to perform normal daily activities due to
illness/infection.
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After informed consent has been obtained, subjects will undergo screening to determine the 
eligibility.
Screening
Subjects who are switching from IVIG or conventional subcutaneous immunoglobulin (cSCIG) 
will enter screening period for up to 13 weeks to undergo procedures for the determination of 
eligibility and will continue to receive their own immunoglobulin treatment at the same dose and 
dosing frequency as prescribed prior to their entry into this study. During the screening period, 
subjects will have IgG trough levels measured at least 2 timepoints. After confirming the 
eligibility, subjects will enter the Epoch 1 and receive the initial dosing of TAK-771 
subcutaneous (SC) 1 week after the last IVIG or cSCIG administration.
Subjects who have been receiving TAK-664 and are switching from Study TAK-664-3001 or 
TAK-664-3002 (TAK-664 studies, hereafter) will directly move on to the treatment period 
without entering the screening period. To determine the eligibility, the data including the latest 
laboratory data and IgG trough levels collected in the TAK-664 studies will be used. After 
confirming the eligibility, subjects will enter the Epoch 1 and receive the initial dosing of 
TAK-771 SC 1 week (for subjects switching from TAK-664 weekly dosing) or 2 weeks (for 
subjects switching from TAK-664 bi-weekly dosing) after the last TAK-664 administration.
Epoch 1
For all subjects, TAK-771 will be started with the ramp-up infusion (3 to 6 weeks), see 
Section 6.3.3.1 of clinical study protocol for details.
Epoch 2
TAK-771 will be administered subcutaneously at 3- or 4-weeks dosing intervals after the 
ramp-up. Subjects will remain on this dosing interval until the end of 24-week treatment period.
PK assessment will be performed in 5 to 7 subjects aged 12 years and older. PK assessment will 
be started just before the last SC infusion (Week 27 [Visit 6] for 4-week dosing interval, and 
Week 25 [Visit 8] for 3-week dosing interval, depending on the subject’s treatment schedule, see 
Figure 2 in clinical study protocol for details) and serum samples will be collected at 7 time 
points in total until the EOS visit. Alternatively, PK assessment can be started at 1 visit earlier (at 
Week 23 [Visit 5] for 4-week dosing interval, and Week 22 [Visit 7] for 3-week dosing interval, 
depending on the subject’s treatment schedule) and completed just before the last SC infusion at 
the discretion of investigator. A schedule of PK assessment is provided in Appendix 2 of clinical 
study protocol.
All study subjects completing or exiting the study should complete the EOS/Early termination 
procedures. The visit will be 21 days after the last dose for 3-week dosing intervals and 28 days 
after the last dose for 4-week dosing intervals. This will mark the subjects’ completion of the 
study. The recovering/resolving AEs will be followed until resolution, medically stabilized, or 
30 days after the study completion/termination visit, whichever comes first.
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*NOTE 1: TAK-664 (20% immune globulin infusion [IGI]) is another immune globulin (IG) preparation for SC use that is
currently under development. In Japan, there are 2 ongoing clinical studies in patients with PID; pivotal study (Study 
TAK-664-3001) and the extension study (Study TAK-664-3002).
A schematic of the study design is shown in Figure 1. A schedule of assessments is listed in 
Section 1.3 of clinical study protocol.
Primary analysis will be performed, at database release after Last Participant Last Visit, at 
100% primary endpoint data availability.
No interim analysis, adaptive design, or data monitoring committee are planned for this study.
Figure 1
Schematic of Study Design
IVIG: intravenous immunoglobulin; SC: subcutaneous; SCIG: subcutaneous immunoglobulin; cSCIG: conventional 
subcutaneous immunoglobulin; IgG: immunoglobulin G
3.0
STATISTICAL HYPOTHESES AND DECISION RULES
No statistical hypothesis testing will be performed.
3.1
Statistical Hypotheses
Not applicable.
3.2
Statistical Decision Rules
Not applicable.
3.3
Multiplicity Adjustment
Not applicable.
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4.0
SAMPLE-SIZE DETERMINATION
The planned total sample size for this study is 15 subjects (enrolled subjects).
Of the 15 subjects to be enrolled, 12 subjects are expected to complete treatment period of the 
study, assuming a dropout rate of 20%. Subjects who prematurely discontinue the study will not 
be replaced. The number of subjects expected to complete treatment period (12 subjects) is 
considered adequate for the evaluation of serum trough IgG levels, safety and tolerability, and 
efficacy of TAK-771, 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 to 3,500. Of the number of PID patients (2,900 to 3,500), an 
estimated 1,450 to 1,750 would be potential targets for IG replacement therapy. In clinical 
practice, most patients requiring a switch to SCIG (as is required by the study design) are 
already being treated with the approved SCIG product (Hizentra®). In the Hizentra® New 
Drug Application review report, the estimated number of patients who could receive IG 
replacement therapy was 1,155, which is lower than the estimated 1,450 to 1,750 patients. Even 
if all patients who are treated with IVIG or Hizentra® can participate in this study, the number of 
potentially eligible patients for the planned study is extremely limited, making it infeasible to 
enroll a large sample size. Therefore, the applicant made the study design that PID patients who 
complete ongoing clinical trials (TAK-664 studies) of TAK-664 (20% SCIG) are able to enroll in 
this study.
Based on feasibility and the sponsor’s clinical experience with IgG products, a total sample size 
of 15 subjects (12 completers) is considered suitable for providing adequate estimates of trough 
levels (study primary objective), as well as adequate estimates of safety and tolerability, efficacy, 
disease activity and HRQoL (secondary objectives).
5.0
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).
5.1
Enrolled Set
The Enrolled Set will contain all enrolled subjects who have signed informed (e)Consent and are 
assigned to subject identification codes.
Baseline summaries (e.g., subject disposition) will be based on the Enrolled Set.
5.2
Safety Analysis Set
The Safety Analysis Set (SAS) will contain all enrolled subjects who received investigational 
drug at least once.
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Analysis of safety, tolerability and product administration will be based on the SAS.
Moreover, Epoch 2 Safety Analysis Set contains subjects that meet the above criteria for Safety 
Analysis Set in Epoch 2.
5.3
Full Analysis Set
The Full Analysis Set (FAS) will contain all enrolled subjects who received investigational drug 
at least once.
Analysis of efficacy, disease activity and HRQoL will be based on the FAS.
Moreover, Epoch 2 Full Analysis Set contains subjects that meet the above criteria for Full 
Analysis Set in Epoch 2.
5.4
Pharmacokinetic Analysis Set 
The Pharmacokinetic Analysis Set (PKAS) will contain all enrolled subjects who received 
investigational drug at least once, have had at least 1 evaluable serum IgG concentration, and no 
major protocol deviations or events that would affect the serum IgG concentration analysis 
results.
Analysis of serum IgG trough concentrations will be based on the PKAS and analysis of PK 
profiles will be based on the subset of 5 to 7 subjects aged 12 years and older in the PKAS.
For more information on PKAS, see Clinical Pharmacology Analysis Plan version 2.0. (Also see 
there for details on PKAS1 and PKAS2.)
6.0
STATISTICAL ANALYSIS
6.1
General Considerations
Efficacy, safety and tolerability endpoints will be analyzed using descriptive statistics for 
continuous endpoints/outcome measures (e.g., change from baseline): number of subjects (n), 
mean, median, standard deviation (SD), minimum value, maximum value, 1st quartile (Q1) and 
3rd quartile (Q3). Minimum and maximum values will be presented with the same number of 
decimal places as the recorded data. Means, medians, Q1 and Q3 will be presented to 1 more 
decimal place than the recorded data. The SDs will be presented to 2 more decimal places than 
the recorded data. Descriptive statistics will be summarized by Epoch and overall treatment 
period. Summaries will also be provided, by treatment period, visit/timepoint, and overall 
treatment period, where applicable.
For the categorical endpoints/outcome measures of safety and tolerability assessments, the 
numbers and percentages of each possible value will be tabulated by Epoch and overall treatment 
period. The denominator for the percentage will be based on the number of subjects who 
provided non-missing responses to the categorical variable.
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6.2
Disposition of Subjects
The number of subjects screened, the number and percentage of subjects with screen failure and 
reason for screen failure will be presented for all subjects who signed the Informed Consent 
Form. 
The number and percentage of subjects eligible for Epoch 1, treated, ongoing on treatment (only 
to be provided at dry run), who completed/discontinued early from treatment (including reason 
for withdrawal), ongoing in study by Epoch (only to be provided at dry run), and who 
completed/discontinued early from the study (including reason for withdrawal) will be provided 
by Epoch and overall treatment period based on the Enrolled Set.
Similarly, the number of subjects included and excluded from each analysis set (including reason 
for exclusion) will be summarized based on the Enrolled set. A listing showing inclusion and 
exclusion of each subject from each analysis set, including reason for exclusion, will be 
provided.
6.2.1
Protocol Deviations
Protocol deviations as obtained from a clinical trial management system (CTMS) will be 
assessed throughout the study. All identified deviations will be reported in the CTMS. Protocol 
deviations from the CTMS will be coded to severity categories (“major” and “minor”) and 
provided as part of the CTMS transfer to Biostatistics. 
Protocol deviations will be summarized by deviation type and severity for the SAS. All protocol 
deviations will be presented in a listing. In particular, protocol deviations identified as exclusion 
from the PKAS will be flagged in the listings.
6.2.2
COVID-19
A separate table and listing of protocol deviations related to the Coronavirus disease 2019 
(COVID-19) pandemic will be presented for each epoch. Missing data due to the COVID-19 
pandemic will not be handled any differently than missing data for other reasons.
6.3
Demographic and Other Baseline Characteristics
6.3.1
Demographics
The following subject demographic and baseline characteristics will be presented for the SAS
and PKAS1:

Age at informed consent (years)

Sex

Ethnicity

Race
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
Weight at baseline (kg)

Height at baseline (cm)

BMI at baseline (kg/m2)

Dosing frequency per interval – 4-week dosing interval or 3-week dosing interval

Prior treatment at consent –IVIG, cSCIG or TAK-664

Primary Immunodeficiency Diagnosis (see all the categories below)
–
Congenital Agamma - XLA 21
–
Agammaglobulinemia – AR
–
X-Linked Hyper IgM (XHIM)
–
Hyper-IgM – AR
–
Severe Combined Immune Deficiency
–
Common Variable Deficiency
–
Wiskott Aldrich Syndrome
–
Specific Antibody Deficiency,
–
Specific Antibody Deficiency with IgG Subclass Deficiency
–
Specific Antibody Deficiency with Low IgG
–
Ataxia Telangiectasia
–
Muccocutaneous Candidiasis
–
Complete DiGeorge Syndrome
–
Other
Continuous measurements will be summarized using descriptive statistics, and categorical data 
will be presented by number and percentage of subjects in each category.
6.3.2
Medical History and Concurrent Medical Conditions
Medical history will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
version 24.0 or higher and will be summarized by System Organ Class (SOC) and Preferred 
Term (PT) based on the SAS. A subject having more than one medical/surgical event within the 
same SOC/PT will be counted only once for that SOC or PT.
All medical history will be listed. Medical histories that started before first dose of 
investigational drug AND were on going at the time of the first dose of investigational drug or 
ended on the first dose of investigational drug will be flagged as “ongoing” in the listing. 
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6.4
Medication History and Concomitant Medications/Procedures/Surgeries
6.4.1
Prior Medications/Procedures/Surgeries
Prior medications will be coded using the World Health Organization Drug Dictionary 
(WHO-DD) dated 01 Mar 2021 or newer. Prior surgeries and procedures will be coded using 
MedDRA version 24.0 or higher.
Prior medications/procedures/surgeries are defined as any medication/procedure/ surgery that 
started and stopped prior to the first dose of investigational drug.
Partial date imputation for medications is described in Section 9.2.3.1.
The prior medications/procedures/surgeries will be summarized by the number and percentage of 
subjects within each Preferred Term of a medical product, procedure/surgery name for the SAS. 
Multiple medication usage by a subject in the same category (i.e., Preferred Term of a medical 
product name) will be counted only once. 
All prior surgeries, procedures and medications will be listed for the SAS.
6.4.2
Concomitant Medications/Procedures/Surgeries
Concomitant medications will be coded using the WHO-DD dated 01 Mar 2021 or newer. 
Concomitant surgeries and procedures will be coded using MedDRA version 24.0 or higher.
Concomitant medications/procedures/surgeries refer to all treatment taken between the dates of 
the first dose of investigational product and study completion/termination, inclusive.
Partial date imputation for medications is described in Section 9.2.3.1. 
Concomitant medications/procedures/surgeries will be summarized by the number and 
percentage of subjects within each medical product/procedure/surgery name for the SAS. 
Multiple medication usage by a subject in the same category (i.e., medical product name) will be 
counted only once.
All concomitant surgeries, procedures and medications will be listed for the SAS.
6.5
Pharmacokinetic Analysis
6.5.1
Primary and Secondary Pharmacokinetics Endpoints Analysis
The analyses of primary and secondary PK endpoints will be described in the Clinical 
Pharmacology Analysis Plan, which will be produced by 
 Clinical 
Pharmacology team. 
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6.6
Efficacy Analysis
All efficacy analyses will be based on the FAS. Efficacy data, including derived efficacy 
parameters defined in the subsections below, will be presented in listings. 
6.6.1
Annual Rate of Validated Acute Serious Bacterial Infections
Acute Serious Bacterial Infections will include bacteremia/sepsis, bacterial meningitis, 
osteomyelitis/septic arthritis, bacterial pneumonia, and visceral abscess that are caused by a 
recognized bacterial pathogen. The diagnostic criteria for ASBIs are included in Appendix 5 of 
clinical study protocol.
The annual rate of validated ASBIs will be calculated as the mean number of ASBIs per subject 
per year and be summarized using descriptive statistics for Epoch 1 and overall treatment period 
based on the FAS. 
Number of ASBIs per subject per year will be calculated as below: 

For Epoch 1: number of ASBIs / duration of in Epoch 1 * 365.25 days per year, where
duration of Epoch 1 is calculated as the end date of Epoch 1 – the start date of Epoch 1 + 1
(See Section 9.2.6 for the definition of start date/end date of an Epoch).

For overall treatment period: number of ASBIs / duration of study * 365.25 days per year,
where duration in study is calculated as the date of EOS/Early termination visit – the date of
first dose of investigational drug + 1.
Additionally, the generalized linear model procedure for Poisson regression with log link will be 
used via the SAS procedure PROC GENMOD to estimate ASBI rate per person per year and its 
one-sided 99% upper confidence bound (or equivalently, the upper bound of the two-sided 98%
confidence interval). Subject-year will be calculated for each subject as (duration of study in 
days/365.25), and the natural log-transformed subject-year will be used in the generalized linear 
model as an offset variable. To handle over-dispersion, the exponential distribution dispersion 
parameter will be assumed to be given by the deviance divided by the degrees of freedom and all 
statistics will be adjusted accordingly. No covariates other than the intercept term will be 
included in the model. The estimated intercept term and the upper bound of its two-sided 98% CI 
will be transformed by using the natural exponential function, to provide the point estimate of the 
ASBI rate per person per year and its one-sided 99% upper confidence bound.
The number and percentage of subjects with bacteremia/sepsis, bacterial meningitis, 
osteomyelitis/septic arthritis, bacterial pneumonia, and visceral abscess will be summarized.
The diagnosis of ASBIs will be presented in listings.
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6.6.2
Annual Rate of All Infections
All infections will be reported as AEs and are defined as all PTs under the “Infections and 
infestations” SOC of MedDRA version 24.0 or higher. 
The annual rate of all infections will be calculated as the mean number of all infections per 
subject per year and be summarized using descriptive statistics for Epoch 1 and overall treatment 
period based on the FAS. Point-estimate and 95% CI of the annual rate of all infections 
calculated using a Poisson model with subject-year in study as the offset variable will be 
provided for Epoch 1 and overall treatment period based on FAS.
Number of infections per subject per year will be calculated as below: 

For Epoch 1: number of infections / duration of in Epoch 1 * 365.25 days per year, where
duration of Epoch 1 is calculated as the end date of Epoch 1 – the start date of Epoch 1 + 1
(See Section 9.2.6 for the definition of start date/end date of an Epoch).

For overall treatment period: number of infections / duration of study * 365.25 days per year,
where duration in study is calculated as the date of EOS/Early termination visit - the date of
first dose of investigational drug + 1.
The number and percentage of subjects with any infections will be summarized.
6.6.3
Healthcare Resource Utilization
6.6.3.1
Days Not Able to Attend School/Work or to Perform Normal Daily Activities Due to 
Illness/Infection
Number of days not able to attend school/work or 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 electronic case report form (eCRF) and calculated as below: 

By Epoch: sum of days not able to attend school/work or perform normal daily activities due
to illness/infection per subject / duration of each Epoch * 365.25 days per year, where
duration of each Epoch is calculated as the end date of the Epoch – the start date of the
Epoch + 1 (See Section 9.2.6 for the definition of start date/end date of an Epoch).

For overall treatment period: sum of days not able to attend school/work or perform normal
daily activities due to illness/infection per subject / duration of study * 365.25 days per year,
where duration in study is calculated as the date of EOS/Early termination visit - the date of
first dose of investigational drug + 1.
The mean days not able to attend school/work or perform normal daily activities due to 
illness/infection per year will be summarized using descriptive statistics by Epoch and overall
treatment period based on the FAS. 
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6.6.3.2
Days on Antibiotics
Number of days on antibiotics will be collected in the “Concomitant Medications” eCRF page. 
Antibiotics are defined as any medication coded under ATC Level 2 therapeutic class
“Antibacterial for Systematic Use”. 
Number of days on antibiotics is defined as the number of days that antibiotics were taken as 
concomitant medications and will be calculated as below:

By Epoch: sum of the actual number of distinct days that antibiotics were taken per subject /
duration of each Epoch * 365.25 days per year, where duration of each Epoch is calculated as
the end date of the Epoch – the start date of the Epoch + 1 (See Section 9.2.6 for the
definition of start date/end date of an Epoch).

For overall treatment period: sum of the actual number of distinct days that antibiotics were
taken per subject / duration of study * 365.25 days per year, where duration in study is
calculated as the date of EOS/Early termination visit - the date of first dose of investigational
drug + 1.
If a subject took multiple antibiotics on a single day, that day will be counted for only once.
Partial date imputation for medications is described in Section 9.2.3.1.
The mean days on antibiotics per year will be summarized using descriptive statistics by Epoch 
and overall treatment period based on the FAS.
6.6.3.3
Number of Hospitalizations Due to Illness/Infection and Length of Stay
Admissions to a hospital as an inpatient and the number of days in hospital will be collected 
using diaries or other source data options throughout the study and will be transcribed to eCRFs.
Number of hospitalizations and total length of stay per subject will be summarized using 
descriptive statistics by Epoch and overall treatment period based on the FAS. 
Number of hospitalizations and total length of stay per subject will be calculated as below:

By Epoch: number of hospitalizations OR number of days of total length of stay per subject /
duration of each Epoch * 365.25 days per year, where duration of each Epoch is calculated as
the end date of the Epoch – the start date of the Epoch + 1 (See Section 9.2.6 for the
definition of start date/end date of an Epoch).

For overall treatment period: number of hospitalizations OR number of days of total length of
stay per subject / duration of study * 365.25 days per year, where duration in study is
calculated as the date of EOS/Early termination visit - the date of first dose of investigational
drug + 1.
A hospitalization will be counted for a specific Epoch only if that hospitalization started during 
that Epoch.
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6.6.3.4
Number of Acute (Urgent of Unscheduled) Physician Visits Due to Illness/Infection
Acute (urgent or unscheduled) physician visits due to illness/infection, will be collected using 
diaries or other source data options throughout the study and will be transcribed to eCRFs.
Number of acute physician visits due to illness/infection will be summarized using descriptive 
statistics by Epoch and overall treatment period based on the FAS.
Number of acute physician visits / emergency room visits per subject will also be standardized 
toper year (365.25 days) as below:

By Epoch: Number of acute physician visits OR emergency room visits per subject / duration
of each epoch * 365.25 days per year, where duration of each epoch is calculated as the start
date of the epoch – the end date of the epoch + 1 (See Section 9.2.6 for the definition of
start/end of epoch).

For overall treatment period: Number of acute physician visits OR emergency room visits per
subject / duration of study * 365.25 days per year, where duration in study is calculated as
the number of days from the first dose of study drug to the date of EOS/Early Termination
Visit.
6.6.4
Infusion Parameters in Epoch 2
Infusion parameters in Epoch 2 will be summarized descriptively based on FAS. The parameters 
may include but not limited to the following:

Number of infusions per month

Total number of infusions administered in Epoch 2 / (duration of Epoch 2 / 30.4375), where
duration of Epoch 2 is calculated as the end date of the Epoch 2 – the start date of the
Epoch 2 + 1 (See Section 9.2.6 for the definition of start date/end date of an Epoch).

Number of infusion sites per infusion

Total number of infusion sites injected in Epoch 2 / Total number of infusions administered
in Epoch 2.

Number of infusion sites per month

Total number of infusion sites injected in Epoch 2 / (duration of Epoch 2 / 30.4375), where
duration of Epoch 2 is calculated as the end date of the Epoch 2 – the start date of the
Epoch 2 + 1 (See Section 9.2.6 for the definition of start date/end date of an Epoch).

Duration of infusion

End date and time of infusion in Epoch 2 – Start date and time of infusion in Epoch 2, for
each infusion per subject. .

Maximum infusion rate/site

Maximum Infusion Rate results from CRF / number of infusion sites/body.
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
Infusion volume/site

Scheduled Dose results from CRF / number of infusion sites/body.
6.7
Safety Analysis
All safety summaries will be based on the SAS. All safety data, including derived data, will be 
presented in listings. However partial or missing date will appear as partial or missing in the 
listings.
6.7.1
Adverse Events
All AEs will be coded using the MedDRA version 24.0 or higher and then reported by MedDRA 
SOC and PT, and overall. Only TEAEs will be analyzed. Non-TEAEs will be listed only.
Treatment-emergent adverse events, defined as AEs with onset after date-time of first dose of 
investigational drug but before EOS/Early termination visit, or medical conditions present prior 
to the start of investigational drug but increased in severity or relationship after date-time of first 
dose of investigational drug.
Non-TEAEs, defined as AEs with onset before date-time of first dose of investigational drug, or 
medical conditions present prior to the start of investigational drug but did not increase in 
severity or relationship after date-time of first dose of investigational drug.
Related TEAEs, defined as TEAEs causally related to investigational product.
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 investigational drug), the AE 
with the maximum severity (AE that is severe) will be used in analysis.
Related AEs: An AE that follows a reasonable temporal sequence from administration of a drug 
(including the course after withdrawal of the drug), or for which possible involvement of the 
drug cannot be ruled out, although factors other than the drug, such as underlying diseases, 
complications, concomitant medications and concurrent treatments, may also be responsible. 
Relationship (causality) to study procedures should also be determined for all AEs. The 
relationship should be assessed as “Related” if the investigator considers that there is reasonable 
possibility that an event is due to a study procedure. Otherwise, the relationship should be 
assessed as “Not Related”.
Recurrent AEs: If more than 1 AE 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 investigational drug. For example, if a 
subject experienced a mild headache not related to the investigational drug, and a moderate 
headache related to investigational drug, then the subject will be counted once for headache 
using the moderate headache related to investigational drug.
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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.
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. 
6.7.1.1
Summaries of Treatment-Emergent Adverse Events
A TEAE will be counted for a specific Epoch, only if that TEAE started during that Epoch. For 
AE summaries by Epoch, the number of subjects reaching that Epoch will be presented and will 
be used as denominator for percentage calculation.
An overall summary of the number and percentage of subjects with any TEAE, any local TEAE,
any local TEAE related to IP, any systemic TEAE, any systemic TEAE related to IP, any 
related/non-related TEAE, any severe TEAE, any severe related TEAE, any serious TEAE, any 
serious related TEAE, any infusion-associated TEAE, any TEAE leading to study 
discontinuation, and any TEAE leading to death, as well as the total number of events for each 
category will be provided for each Epoch, and overall treatment period.
Derivation of Local TEAEs and systemic TEAEs are as follows: 
–
Local TEAEs: Injection Site Reaction Flag is checked as “Yes” from “Adverse Events”
page in eCRF.
–
Systemic TEAEs: Injection Site Reaction Flag is not checked as “Yes” from “Adverse
Events” page in eCRF.
Infusion-associated TEAEs are captured in the “Adverse Events” eCRF page as ‘Infusion-
Related Reaction Flag’ checked as “Yes”.
The number and percentage of subjects with any TEAE, as well as the number of TEAEs, will be 
summarized by SOC, PT, Epoch and overall treatment period for IP related TEAEs. The 
summary by SOC, PT and overall treatment period will be repeated for IP-related serious TEAEs 
and IP-related local/systemic TEAEs.
Additionally, the number and percentage of subjects with any TEAE, as well as the number of 
TEAEs, will be summarized by relationship to IP, SOC, PT, Epoch and overall treatment period. 
The same summary will be repeated for serious TEAEs, non-serious TEAEs, TEAEs leading to 
study discontinuation, TEAEs leading to death (overall treatment period only), TEAEs related to 
study procedure, Infusion associated TEAEs, local TEAEs and Systemic TEAEs.
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The number and percentage of subjects with any TEAE, as well as the number of TEAEs, will be 
summarized by Severity, SOC, PT, Epoch and overall treatment period. Similarly, the same 
summary by Severity, SOC, PT and overall treatment period is repeated for related/non-related 
TEAEs.
6.7.1.2
Adverse Events per Infusion, per Subject, per Subject Year
The following summaries will be provided for overall treatment period: 

Number of TEAEs per infusion, by SOC and PT

TEAEs per infusion = number of TEAEs / total number of infusions administered to subjects
in the analysis set, SAS

Number of TEAEs per subject, by SOC and PT

TEAEs per subject = number of TEAEs / total number of subjects in the analysis set, SAS

Number of TEAEs per Subject-Year (SY), by SOC and PT

TEAEs per SY = number of TEAEs / total number of days of exposure, i.e., the sum of
duration of treatment for all subjects in the analysis set, SAS, converted into years

Where duration of treatment is calculated as the number of days from the first dose of
investigational drug to the end date of the Epoch with last treatment. (See Section 9.2.6 for
the definition of start date/end date of an Epoch).

Number of TEAEs per 1000 SYs will be provided for all TEAEs (if analyzable), by primary
SOC and PT

TEAEs per 1000 SYs = 1000 × (Total Number of TEAEs in the study for all subjects / Total
SYs in the study)

Where Total SYs will be calculated by summing subjects’ durations in the study. Each
subject’s duration will be calculated as the number of days from the first dose of
investigational drug to the date of EOS/Early termination visit. If the subject’s last date is
missing, then the date of last dose of investigational drug will be used if available.
The above-mentioned summaries will be repeated for TEAEs, local/systemic TEAEs, related 
TEAEs, local/systemic related TEAEs, serious TEAEs, serious related TEAEs, infusion-
associated TEAEs, serious infusion-associated TEAEs, severe infusion-associated TEAEs, 
related infusion-associated TEAEs, related severe infusion-associated TEAEs, related serious 
infusion-associated TEAEs.
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6.7.1.3
Subgroup Analysis for Treatment-Emergent Adverse Events
The TEAE summaries in Section 6.7.1.1 are provided for the following subgroups.
Subgroup:
Age group [<18, ≥18 years old]
Summary:
An overall summary, summary of TEAEs by SOC and PT, summary of 
related TEAEs by SOC and PT and summary of TEAEs by relationship to 
IP, SOC and PT
6.7.2
Clinical Laboratory Outcomes
Laboratory evaluations that are performed at study site visits will be collected and processed via 
a central laboratory and presented in International System of Units (SI Units). 
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 {WBC} count]) 
with differential (i.e., basophils, eosinophils, lymphocytes, monocytes, neutrophils) and platelet 
counts. In addition, absolute neutrophil count (ANCs) will be determined by laboratory 
calculation.
The clinical chemistry panel will consist of sodium, potassium, chloride, bicarbonate, protein, 
albumin, alanine aminotransferase (ALT), serum total bilirubin, aspartate aminotransferase 
(AST), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), blood urea nitrogen (BUN), 
serum creatinine, creatinine phosphokinase (CPK), glucose, haptoglobin, lipase.
Urinalysis includes: color, specific gravity, pH, protein, glucose, ketones, bilirubin, urobilinogen, 
blood, nitrite, leukocyte esterase, and microscopic examination. 
Specialty tests include: hepatitis B surface antigen (HBsAg), polymerase chain reaction (PCR)
for hepatitis C virus (HCV) and PCR for human immunodeficiency virus (HIV)-1/2. For a 
schedule of laboratory test blood drawings, see Appendix 2 of clinical study protocol. These 
assessments will be performed at the central laboratory.
Additional specialty tests may be performed if required to establish the etiology of an AE or of 
abnormal laboratory results, such as tests for HIV, hepatitis A virus (HAV), hepatitis B virus 
(HBV), HCV, hepatitis E virus (HEV), or Parvovirus B19 (B19V).
Tests for hemolysis:
Scheduled tests will only be performed in subjects aged 12 years and older.

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 antiglobulin test (Coombs-test or AGT)
–
urine hemosiderin
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
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 antiglobulin test (Coombs-test or AGT)
–
urine hemosiderin
–
hemoglobin
–
lactate dehydrogenase
–
serum haptoglobin
Hematology, clinical chemistry, urinalysis and hemolysis results will be summarized by Epoch 
and overall treatment period as described below. Specialty test results will be listed only.
Raw (actual) clinical laboratory values (SI units) and changes in raw values from baseline at 
each post-baseline assessment time point will be summarized as continuous variables. See 
Section 9.2.2 for definition of baseline. If more than one laboratory result is reported per study 
visit per parameter, the last non-missing result will be selected for analysis.
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 
reference range), normal (within the reference range), high (above the upper limit of the 
reference range), and missing. Missing data will not be imputed. In addition, shift-from-baseline 
summaries will be produced by toxicity grade.
Clinical laboratory values for abnormalities for the following parameters will be classified 
according to a 5-point (Grades 0-4) toxicity grading scale provided in Appendix 6 of clinical 
study protocol, and programming instruction can be found in Appendix 9.4: ALP, ALT, AST, 
BUN, hemoglobin, lymphocytes, neutrophils, platelet count, potassium, serum creatinine, 
sodium, serum total bilirubin, WBC. The classification of abnormalities will be performed by the 
central laboratory and the toxicity grades will be provided in the raw datasets.
If the reported value of a clinical laboratory parameter cannot be used in a statistical analysis due 
to, for example, that a character string is reported for a numerical variable (e.g., “<X”), a coded 
value will be used in the analysis instead as specified in Section 9.2.3.5. However, the actual 
values as reported in the database will be presented in listings.
All clinical laboratory test results will be presented in listings. 
6.7.3
Vital Signs
Vital signs include body temperature (°C), 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 sign values are to be recorded on the appropriate eCRF. 
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Raw (actual) vital signs and body weight, and changes in raw values from baseline at each 
post-baseline assessment time point will be summarized by Epoch and overall treatment period. 
For vital signs, change from pre-infusion to post-infusion will also be summarized for Epoch 1.
If more than one vital sign result is reported per time point per parameter, the last non-missing 
result will be selected for analysis.
6.7.4
Anti-rHuPH20 Antibodies
All subjects will be monitored for the formation of anti-rHuPH20 antibodies using validated 
anti-rHuPH20 antibody detection assay (also known as the Screening and Confirmatory Binding 
Assay). Samples with binding antibody titers ≥1:160 will be analyzed for the presence of 
neutralizing antibodies using a validated assay based on neutralization of rHuPH20 activity at the 
central laboratory.
Number and percentage of subjects who develop anti-rHuPH20 binding antibody titers of ≥1:160 
in Epoch 2 will be summarized. Samples with anti-rHuPH20 binding antibody titers ≥1:160 will 
be analyzed for the presence of neutralizing antibodies, and the number and percentage of 
subjects who develop neutralizing antibodies to rHuPH20 in Epoch 2 will be summarized. The 
number and percentage of subject with any interpretation of hyaluronidase antibody test results 
will also be presented by categories of interpretation.
6.8
Tolerability Analysis
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 TAK-771 infusion. A tolerability event is 
considered to have occurred if an infusion was not tolerable. Tolerability events will be 
measured in terms of the number and percentage of subjects for which the infusion was not 
tolerable.
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The following summaries will be provided:

Number (percentage) of subjects for whom the infusion rate was reduced for tolerability
concerns or for AEs and reasons for dose adjustment.

Infusion rates reduced are collected as “Dose Reduced” or “Dose Rate Reduced” under the
item of “Action Taken with Study Treatment”, as well as the “Reason for Dose Adjustment”
is “Adverse Event” or “Intolerability” in either the “Dosing Injection 10%IGI” or 10%IGI
part of “Dosing Injection” eCRF page. This summary will be provided by Epoch and overall
treatment duration.

Number (percentage) of subjects for whom the infusion was interrupted for tolerability
concerns or for AEs

Infusion rates interrupted are collected as “Drug Interrupted” under the item of “Action
Taken With Study Treatment”, as well as the “Reason for Dose Adjustment” is “Adverse
Event” or “Intolerability” in either the “Dosing Injection 10%IGI” or 10%IGI part of
“Dosing Injection” eCRF page. This summary will be provided by Epoch and overall
treatment duration.

Number (percentage) of subjects for whom the infusion was stopped for tolerability concerns
or for AEs

Infusion rates stopped are collected as “Drug Withdrawn” under the item of “Action Taken
With Study Treatment”, as well as the “Reason for Dose Adjustment” is “Adverse Event” or
“Intolerability” in either the “Dosing Injection 10%IGI” or 10%IGI part of “Dosing
Injection” eCRF page. This summary will be provided by Epoch and overall treatment
duration.

Number (percentage) of subjects for whom the infusion rate was reduced or interrupted or
stopped for tolerability concerns or for AEs

This summary will be provided by Epoch and overall treatment duration.

Number of weeks to reach final dose interval (3 weeks or 4 weeks) in Epoch 1

For subjects with E2 dosing start date, the number of weeks to reach final dose interval is
defined as treatment duration of Epoch 1 /7

Percentage of subjects who achieve a treatment interval of 3 or 4 weeks in Epoch 2

Subjects who achieve a treatment interval of 3 or 4 weeks are the number of subjects with
Epoch 2 dosing start date.

Percentage of subjects who maintain a treatment interval of 3 or 4 weeks in Epoch 2

Subjects who maintain a treatment interval are subjects whose regimen in Epoch 2 are
retained the same as determined at the end of Epoch 1.
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6.9
Extent of Exposure and Infusion Compliance
Extent of exposure will be summarized by Epoch and overall treatment period in terms of days 
of exposure and number of infusions for the SAS.
Days of exposure will be calculated as below:

By Epoch: number of days from the date of the first dose of investigational drug in each
Epoch to the date of the end of treatment in each Epoch (See Section 9.2.6 for the definition
of start date/end date of an Epoch).

For overall treatment period: number of number of days from the first dose of investigational
drug to the date of the end of treatment.
Infusion compliance will be summarized by Epoch and overall treatment period for the SAS.
Infusion compliance is calculated as the total number of applied infusions including completed, 
interrupted, and stopped infusions, divided by the number of expected infusions, multiplied by 
100. The number of expected infusions for each Epoch is based on the number of infusions per 
dosing interval regimen if each Epoch is completed.
Extent of exposure and infusion compliance will be presented in listings. For 10% IGI, the 
details of overdose for the overall treatment period will also be presented in the listing.
6.10 
Disease Activity and Health-related Quality of Life
All disease activity and HRQoL summaries will be based on the FAS, and all data will be 
provided in listings.
6.10.1 
Quality of Life
Quality of life will be analyzed separately for the age groups of 2 to 7 years (PEDS-QL, 
observer: parent), 8 to13 years (PEDS-QL, observer: subject), and 14 years and older (SF-36, 
observer: subject). Additionally, all subjects will complete the EQ-5D-3L Health Questionnaire, 
analyzed separately for the age groups: 2 to11 years EQ-5D-3L (observer: parent) and 12 years 
and older EQ-5D-3L (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.
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6.10.1.1
PEDS-QL
The PEDS-QL Inventory is a 23-item, brief measure of health-related quality of life in children 
and young people. The measure can be completed by parents as well as children and young 
people. 
The 23 items in the PEDS-QL comprise 4 Generic Core Scales:

Physical Functioning (8 items)

Emotional Functioning (5 items)

Social Functioning (5 items)

School Functioning (5 items)
Items on the PEDS-QL will be reverse scored and transformed to a 0-100 scale using the 
following rules: 0 (Never) = 100; 1 (Almost Never) = 75; 2 (Sometimes) = 50; 3 (Often) = 25; 
4 (Almost Always) = 0.
Scale scores will be calculated as the sum of the items over the number of items answered (to 
account for missing data). If more than 50% of items are missing, the scale score will not be 
computed.
Total scale score will be calculated as the mean of all items.
Descriptive statistics of total scale score of PEDS-QL and change from baseline (if both scores 
are available) will be presented by treatment interval, visit, and age groups (2-7 years; 
8-13 years).
6.10.1.2 
SF-36
SF-36 is a 36-item, patient-reported survey of patient health.
SF-36 measures eight scales: physical functioning (PF), role physical (RP), bodily pain (BP), 
general health (GH), vitality (VT), social functioning (SF), role emotional (RE), and mental 
health (MH). 
Two sets of scores will be derived from the SF-36: eight scale scores, and three summary scores: 
physical component summary (PCS) score, mental component summary (MCS) scores and 
role/social component summary (RCS).
PCS score, MCS score and RCS score can be calculated using Web Tool mentioned in
Section 9.3. Use the latest PCS score, MCS score and RCS score (use “3PCS”, “3MCS” AND 
“3RCS” variables in the software output results file). Descriptive statistics of the PCS score, 
MCS score and RCS score, and the corresponding changes from baseline will be presented by 
treatment interval, visit for subjects with age of 14 years and older at screening.
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6.10.1.3
EQ-5D-3L Health Questionnaire
EQ-5D-3L Health Questionnaire consists of 2 parts: the EQ-5D descriptive system and the EQ 
visual analogue scale (VAS).
EQ-5D-3L descriptive system comprises the following five dimensions: mobility, self-care, usual 
activities, pain/discomfort and anxiety/depression. Each dimension has 3 levels: no problems
(Level 1), some problems (Level 2), and extreme problems (Level 3). This part of the EQ-5D-3L 
provides a descriptive profile that can be used to generate a health state profile. Each health state 
profile can be assigned a health state index score based on societal preference weights for the 
health state. Health state index scores generally range from less than 0 (where 0 is a health state 
equivalent to death; negative values are valued as worse than death) to 1 (perfect health), with 
higher scores indicating higher health utility. The health state index score will be calculated from 
individual health profiles using Japanese value set as listed in Table 1. 
The health state index score ℎwill be calculated using the following formula:
ℎ= 1 −(	 + )
where  represents ten dummy variables that indicate the presence of either a Level 2 or a 
Level 3 in a given dimension of the evaluated state. In other words,  stands for the dimensions: 
M for mobility, SC for self-care, UA for usual activities, PD for pain or discomfort, AD for 
anxiety or depression; and  stands for either Level 2 or Level 3. 	 is constant term representing 
any move away from perfect health. 
For example, assuming there is a subject with health state profile = 11223. The health state index 
for this subject is calculated as: 1 – 0.152 – 0.044 – 0.080 – 0.112 = 0.612. 
Table 1
Japanese Value Set for EQ-5D-3L Health State Index Score
Coefficient
Value
	
0.152


0.075
0.418


0.054
0.102


0.044
0.133


0.080
0.194


0.063
0.112
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EQ VAS is a 0-100 scale where the subjects are asked to self-rate health. The VAS can be used 
as a quantitative measure of health outcome that reflects the patient’s own judgement.
Descriptive statistics of the health state index score of ED-5D and ED VAS score and change 
from baseline (if both scores are available) will be presented by treatment interval, visit, and age 
groups (2-11 years; 12 years and older).
6.10.2
Treatment Satisfaction
Treatment Satisfaction Questionnaire for Medication (TSQM-9) will be assessed at Week 1, 
12 weeks after the ramp-up in treatment period (Week 19 for 4-week dosing interval regimen 
and Week 16 for 3-week dosing interval regimen), and at the EOS/Early termination visit.
Data will be analyzed separately for the age groups of 2 to 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.
6.10.2.1
Treatment Satisfaction Questionnaire for Medication-9
Treatment Satisfaction Questionnaire for Medication-9 is a self-administered, 9-item, validated 
measure that assesses treatment satisfaction in the following 3 domains: effectiveness (items 
1-3), convenience (items 4-6), and global satisfaction (items 7-9).
Items 1-6 and Item 9 will be coded on a scale of 1-7. Items 7 and 8 will be coded on a scale of 
1 to 5. The scores of TSQM-9 domains are calculated by summing up item values within each 
domain and transforming them into scores ranging from 0 to 100 using the following formula:

Effectiveness
–
If all items are completed: = [(item1 + item2 + item3) - 3]/18*100
–
If one item is missing: = [sum of completed items - 2]/12*100

Convenience
–
If all items are completed: = [(item4 + item5 + item6) - 3]/18*100
–
If one item is missing: = [sum of completed items - 2]/12*100

Global satisfaction
–
If all items are completed = [(item7 + item8 + item9) - 3]/14*100
–
If either Item 7 or 8 is missing: = [sum of completed items - 2]/10*100
–
If item 9 is missing: = [(item 7 + item 8) -2]/8*100
The TSQM-9 domain scores range from 0 to 100, where higher scores represent better 
satisfaction on that domain. A score can be computed for a domain only if no more than one item is 
missing from that domain. 
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Descriptive statistics of TSQM-9 domain scores and change from baseline will be presented by 
treatment interval, Epoch, visit, and age groups (2-12 years; 13 years and older).
6.10.3 
Treatment Preference
Treatment preference will be analyzed separately for the age groups of 2 to 13 years (observer: 
parent) and 14 years and older (observer: subject). Age will be defined as the age at screening.
Number and percentage of subjects per answer to each question of treatment preference will be 
presented by age groups (2-13 years; 14 years and older) at EOS/Early termination visit.
6.11 
Other Safety Analysis
6.11.1 
Physical Examination
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.
All physical examination will be listed only.
6.11.2 
Pregnancy Test
A urine pregnancy test will be performed on all females of childbearing potential at screening for 
subjects switching from IVIG or cSCIG treatment, and at pre-infusion at Week 1 for subjects 
switching from TAK-664 studies. All pregnancies are reported from the time informed 
(e)Consent is signed until EOS/Early termination visit.
All pregnancy test will be listed only.
6.12 
Interim Analyses
No interim analysis, adaptive design, or data monitoring committee is planned for this study.
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7.0
REFERENCES
Daly, P. B., Evans, J. H., Kobayashi, R. H., Kobayashi, A. L., Ochs, H. D., Fischer, S. H., et al. 
1991. Home-based immunoglobulin infusion therapy: quality of life and patient health 
perceptions. Ann Allergy, 67(5), 504-10.
Shaw, J. W., Johnson, J. A. and Coons, S. J. 2005. US valuation of the EQ-5D health states: 
development and testing of the D1 valuation model. Med Care, 43(3), 203-20.
Varni, J. W., Seid, M. and Rode, C. A. 1999. The PedsQL: measurement model for the pediatric 
quality of life inventory. Med Care, 37(2), 126-39.
Ware, J. E., Jr. and Sherbourne, C. D. 1992. The MOS 36-item short-form health survey (SF-36). 
I. Conceptual framework and item selection. Med Care, 30(6), 473-83.
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8.0
CHANGES TO PROTOCOL PLANNED ANALYSES

Description has changed to the following on Section 6.7.3.
“For vital signs, change from pre infusion to post-infusion will also be summarized by Epoch 
and overall treatment period” →“For vital signs, change from pre infusion to post-infusion will
also be summarized for Epoch 1”

Added the logic of the end of Epoch 1 on Section 9.2.6 for subjects who completed Epoch 1
and continued to Epoch 2.
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9.0
APPENDIX 
9.1
Changes from the Previous Version of the SAP
See REVISION HISTORY.
9.2
Data Handling Conventions 
9.2.1
General Data Reporting Conventions 
9.2.1.1
Dates & Times
Depending on data available, dates and times will take the form yyyy-mm-dd hh:mm:ss.
9.2.1.2
Spelling format 
English US. 
9.2.1.3
Paper Size, Orientation, and Margins
The size of paper will be letter and the page orientation will be landscape. Margins will provide 
at least 1 inch (2.54 centimeters) of white space all around the page.
9.2.1.4
Fonts
The font type ‘Courier New’ will be used, with a font size of 8. The font color will be black with 
no bolding, underlining, italics or subscripting.
9.2.1.5
Descriptive Statistics
If the original data has N decimal places, then the summary statistics will have the following 
decimal places:

Minimum and maximum: N;

Mean and median: N + 1;

SD: N + 2
9.2.1.6
Percentages
Percentages will be reported to one decimal place. Rounding will be applied, except for 
percentages <0.1 but >0.0 which will be presented as ‘<0.1’ and percentages <100.0 
but >99.9 which will be presented as ‘>99.9’.
Where counts are zero, no percentages will appear in the output.
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9.2.1.7
Listings
All listings will be ordered by the following (unless otherwise indicated in the output template):

Allocated treatment group;

Subject ID;

Parameter, when applicable;

Date/Time, when applicable.

Timepoint, when applicable
9.2.2
Definition of Baseline 
Unless otherwise specified, baseline is defined as the last non-missing value (including 
unscheduled assessments) before the start of initial dose of investigational drug. In the case 
where the timing of last non-missing value coincidence with the date of initial dose of 
investigational drug, the last non-missing value will be considered as pre-baseline. 
9.2.3
Handling of Missing, Unused, and Spurious Data 
No imputation for missing data will be applied except for the partial dates for prior/concomitant 
medications and AEs, the missing severity for AEs and the missing relationship to 
investigational drug for AEs.
Imputed data will not be presented in the listings. The original missing or partial data will be
presented in the listings. 
9.2.3.1
Missing medication dates
Partial or completely missing medication dates will be handled as described below to determine 
if the medications are prior or concomitant. Imputed medication dates will not be presented in 
the listings.
9.2.3.1.1
Incomplete Start Date

If a medication start date is completely missing, then the medication will be considered
concomitant.

Missing day and month:
–
If the year of the incomplete start date is the same as the year of the date of the first dose
of investigational drug, then the day and month of the date of the first dose of
investigational drug will be assigned to the missing fields.
–
If the year of the incomplete start date is before the year of the date of the first dose of
investigational drug, then December 31 will be assigned to the missing fields.
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–
If the year of the incomplete start date is after the year of the date of the first dose of
investigational drug, then 01 January will be assigned to the missing fields.

Missing month only:
–
The day will be treated as missing and both month and day will be replaced according to
the above procedure.

Missing day only:
–
If the month and year of the incomplete start date are the same as the month and year of
the date of the first dose of investigational drug, then the day of the date of the first dose
of investigational drug will be assigned to the missing day.
–
If either the year is before the year of the date of the first dose of investigational drug or
if both years are the same but the month is before the month of the date of the first dose
of investigational drug, then the last day of the month will be assigned to the missing day.
–
If either the year is after the year of the date of the first dose of investigational drug or if
both years are the same but the month is after the month of the date of the first dose of
investigational drug, then the first day of the month will be assigned to the missing day.
9.2.3.1.2
Incomplete Stop Date 
The following rules will be applied to impute the missing numerical fields. If the imputed stop 
date is before the start date (imputed or non-imputed start date), then the imputed stop date will 
be equal to the start date. 

Missing Day and Month

31 December will be assigned to the missing fields.

Missing Month only
–
The day will be treated as missing and both month and day will be replaced according to
the above procedure.

Missing Day only
–
The last day of the month will be assigned to the missing day.
9.2.3.2
Missing Adverse Event Dates
The following approaches will be applied for missing AE dates: 

To facilitate categorization of AEs as treatment emergent, imputation of dates will be used.

If an AE start date is completely missing, then the AE will be considered treatment-emergent
in Epoch 1.
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
For AEs with partial start dates, non-missing date parts will be used to determine if the AE is
treatment-emergent or not. If a determination cannot be made using the non-missing date
parts as to when the AE occurred relative to investigational drug administration in Epoch 1 or
Epoch 2 (e.g., AE start year and month are the same as the year and month of the first dose of
investigational drug), then the AE will be classified as treatment-emergent.

To facilitate categorization of AEs as treatment-emergent, the same imputation of start date
used for medication dates will be used of AE start date. See Section 9.2.3.1 for details.
9.2.3.3
Missing Relationship to Study Drug for Adverse Events 
If the relationship to investigational drug is missing for an AE starting on or after the date of the 
first dose of investigational drug, a causality of “Related” will be assigned. The imputed values 
for relationship to investigational drug will be used for incidence summaries, while the actual 
values will be presented in listings.
9.2.3.4
Missing Severity for Adverse Events 
If severity is missing for an AE starting prior to the date of the first dose of investigational drug, 
then no imputation will be applied. If the severity is missing for an AE starting on or after the 
date and time of the first dose of investigational drug, then the worst severity will be assigned, 
i.e., “Severe”. The imputed values for severity assessment will be used for incidence summaries,
while the actual values will be used in listings.
9.2.3.5
Character Values of Clinical Laboratory Variables
Any non-standard laboratory results will be converted to numeric values using the example rules 
shown in Table 2.
Table 2
Convention for Converting Non-Standard Laboratory Results
Non-Standard Lab Values
Standardized Numeric Values
<0.2
Deduct 0.01 from the reference value. i.e., 0.19
<0.1
Deduct 0.01 from the reference value. i.e., 0.09
>1.045
Add 0.001 to the reference value. i.e., 1.046
9.2.4
Reference Start Date and Study Day
Reference start date is defined as the day of the first dose of investigational drug, TAK-771. 
Study day will be calculated from the reference start date and will be used to show start/stop day 
of assessments and events. 
If the date of the event is on or after the reference start date, then: 

Study Day = (date of event – reference start date) + 1
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If the date of the event is prior to the reference start date, then: 

Study Day = (date of event – reference start date)
In the situation where the event date is partial or missing, the date will appear partial or missing 
in the listings, and Study Day, and any corresponding durations will be presented based on the 
imputations specified in Section 9.2.3.
9.2.5
Multicenter Study
This study will be conducted by multiple investigators at multiple centers. Data from all centers 
will be pooled together in the analyses and there are no plans to perform an analysis of 
homogeneity of the results across centers.
9.2.6
Date of Start/End of Epoch 
The start date of an Epoch is defined as the date of first investigational drug administration in the 
corresponding Epoch. 
The end date of an Epoch is defined as follow:

For subjects who completed Epoch 1 but did not continue to Epoch 2, end date is defined as,

The date of last investigational drug administration +
(13 days if subjects are on the 3-week dosing regimen; or
20 days if subjects are on the 4-week dosing regimen)

For subjects who completed Epoch 1 and continued to Epoch 2, end date is defined as
the date of first investigational drug administration in Epoch 2 - 1. 

For subjects who completed Epoch 2, end date is defined as,
The date of last investigational drug administration +
(20 days if subjects are on the 3-week dosing regimen; or
27 days if subjects are on the 4-week dosing regimen
For subjects who discontinued the study during the corresponding Epoch, the early 
discontinuation date will be set as the end date of the corresponding Epoch.
9.2.7
Definition of Visit Windows 
In general, there are no visit windowing is defined for this study.
However, for home treatment records of vital signs, derive the visit as in the following (for 
Baseline visit, please refer to Section 9.2.2):
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9.4
Programming Notes for Lab Toxicity Grading
The following table represents the protocol-specified grading criteria after the updates have been 
made to support good programming practice. It is planned to use these final updated criteria for 
the lab toxicity grading.
Protocol-Specified Toxicity Grading Scale for Laboratory Values – Version for programming
Analyte
Direction WNL is 
Grade 0
No
Grade 
1
Units
Grade 0a
Grade 1a
Grade 2a
Grade 3a
Grade 4a
Low
High
Low
High
Low
High
Low
High
Low
High
ALP
Increase
YES
NO
ULN
.
.
.
<=2.5
>2.5
<=5.0 >5.0
<=20 >20.0
.
ALT
Increase
YES
NO
ULN
.
.
.
<=2.5
>2.5
<=5.0 >5.0
<=20 >20.0
.
AST
Increase
YES
NO
ULN
.
.
.
<=2.5
>2.5
<=5.0 >5.0
<=20 >20.0
.
LDH
Increase
YES
NO
ULN
.
.
.
<=2.5
>2.5
<=5.0 >5.0
<=20 >20.0
.
BUN
Increase
NO
NO
ULN
0.0
<=1.5
>1.5
<=2.5
>2.5
<=5.0 >5.0
<=10
>10.0
.
Hemoglobin
Decrease
YES
NO
g/dL
.
.
>=10.0
>=8.0 <10.0 >=6.5
<8.0 >=0.0
<6.5
Lymphocytes
Decrease
NO
NO
x10^3/uL >=2.0
.
>=1.5
<2.0
>=1.0
<1.5 >=0.5
<1.0 >=0.0
<0.5
Neutrophils
Decrease
NO
NO
x10^3/uL >=2.0
.
>=1.5
<2.0
>=1.0
<1.5 >=0.5
<1.0 >=0.0
<0.5
Platelet 
Count
Decrease
YES
NO
x10^3/uL
.
.
.>=75
>=50.0 <75.0 >=25
<50.0 >=0.0 <25.0
Potassium
Decrease
NO
NO
mmol/L
>=3.5
.
>=3.0
<3.5
>=2.5
<3.0 >=2.0
<2.5
>=0.0
<2.0
Potassium
Increase
NO
NO
mmol/L
0.0
<=5.5
>5.5
<=6.0
>6.0
<=6.5 >6.5
<=7.0
>7.0
.
Serum 
Creatinine
Increase
YES
NO
ULN
.
.
.
<=1.5
>1.5
<=3.0 >3.0
<=6.0
>6.0
.
Sodium
Decrease
NO
NO
mmol/L >=136
.
>=130 <136 >=123 <130 >=116 <123 >=0.0 <116
Sodium
Increase
NO
NO
mmol/L
0.0
<=145 >145 <=150 >150 <=157 >157 <=165 >165
.
Serum 
Total Bilirubin
Increase
YES
YES
ULN
.
.
.
.
.
<=1.5 >1.5
<=3.0
>3.0
.
WBC
Decrease
NO
NO
x10^3/uL >=4.0
.
>=3.0
<4.0 >=2.0
<3.0 >=1.0
<2.0 >=0.0
<1.0
ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, BUN=blood urea nitrogen, 
WBC=white blood cell, WNL=within normal limits, ULN=upper limit of normal, ECOG=Eastern Cooperative Oncology Group, 
WHO=World Health Organization
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