Conditions: Healthy Volunteers
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 51
Healthy volunteers: yes

Brief summary:
The purpose of the study is to assess the tolerability, safety, and pharmacokinetics of HYQVIA with ramp-up and no ramp-up dosing in healthy adult participants.

Detailed description:
This study will comprise of Part 1 and Part 2. Each study part will consist of three treatment arms (Part 1 \[approximately 24 participants\]: Treatment Arms 1-3 and Part 2 \[approximately 24 participants\]: Treatment Arms 4-6). Treatment arms will be initiated in parallel within each study part. Each participant will participate in only one treatment arm. After participants in Treatment Arms 1-3 (Study Part 1) will complete Week 9, the tolerability and, safety data through Week 9 will be reviewed by a safety review team. (Participants in arms 1-3 will continue in the study as the safety review is being completed.) Once the safety review for Arms 1-3 (Study part 1) will be completed and approved, Treatment Arms 4-6 (Study Part 2) will begin.

Arms:
arm 1: Participants received a subcutaneous (SC) infusion of HYQVIA 0.1 g/kg (1/4 of TDL) on Day 1 and 8, 0.2 g/kg (1/2 of TDL) on Day 15, 0.3 g/kg (3/4 of TDL) on Day 29 followed by 0.4 g/kg (full TDL) on Day 50 in Ramp-Up dosing manner. arm 2: Participants received a SC infusion of HYQVIA 0.25 g/kg (1/4 of TDL) on Day 1 and 8, 0.5 g/kg (1/2 of TDL) on Day 15, 0.75 g/kg (3/4 of TDL) on Day 29 followed by 1.0 g/kg (full TDL) on Day 50 in Ramp-Up dosing manner. arm 3: Participants received a SC infusion of HYQVIA 0.2 g/kg (1/2 of TDL) on Day 1 and 15, followed by 0.4 g/kg (full TDL) on Day 29 and 57 in Ramp-Up dosing manner. arm 4: Participants received a SC infusion of HYQVIA 0.5 g/kg (1/2 of TDL) on Day 1 and 15, followed by 1.0 g/kg (full TDL) on Day 29 and 57 in Ramp-Up dosing manner. arm 5: Participants received a SC infusion of HYQVIA 0.4 g/kg (full TDL) SC infusion on Day 1, 29 and 57 without Ramp-Up dosing manner. arm 6: Participants received a SC infusion of HYQVIA 1.0 g/kg (full TDL) SC infusion on Day 1, 29 and 57 without Ramp-Up dosing manner.

Interventions: intervention 1: HYQVIA intervention 2: HYQVIA intervention 3: HYQVIA intervention 4: HYQVIA intervention 5: HYQVIA intervention 6: HYQVIA
Intervention descriptions: intervention 1: Participants received a SC infusion of HYQVIA 0.1 g/kg (1/4 of TDL) on Day 1 and 8, 0.2 g/kg (1/2 of TDL) on Day 15, 0.3 g/kg (3/4 of TDL) on Day 29 followed by 0.4 g/kg (full TDL) on Day 50 in Ramp-Up dosing manner. intervention 2: Participants received a SC infusion of HYQVIA 0.25 g/kg (1/4 of TDL) on Day 1 and 8, 0.5 g/kg (1/2 of TDL) on Day 15, 0.75 g/kg (3/4 of TDL) on Day 29 followed by 1.0 g/kg (full TDL) on Day 50 in Ramp-Up dosing manner. intervention 3: Participants received a SC infusion of HYQVIA 0.2 g/kg (1/2 of TDL) on Day 1 and 15, followed by 0.4 g/kg (full TDL) on Day 29 and 57 in Ramp-Up dosing manner. intervention 4: Participants received a SC infusion of HYQVIA 0.5 g/kg (1/2 of TDL) on Day 1 and 15, followed by 1.0 g/kg (full TDL) on Day 29 and 57 in Ramp-Up dosing manner. intervention 5: Participants received a SC infusion of HYQVIA 0.4 g/kg (full TDL) SC infusion on Day 1, 29 and 57 without Ramp-Up dosing manner. intervention 6: Participants received a SC infusion of HYQVIA 1.0 g/kg (full TDL) SC infusion on Day 1, 29 and 57 without Ramp-Up dosing manner.

Protocol document:
Prot_000.pdf: 
NCT Number: NCT04578535
Title: A Phase 1, Open-Label, Randomized Study to Assess the Tolerability, Safety, 
and Pharmacokinetics of Subcutaneous Immune Globulin Infusion 10% (Human) 
with Recombinant Human Hyaluronidase (HYQVIA/HyQvia) with Ramp-Up and 
No Ramp-Up Dosing in Healthy Adult Subjects
Study Number: TAK-771-1001
Document Version and Date: Protocol Amendment #1, 30-JUN-2020
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. 
Clinical Study Protocol


 
PROTOCOL: TAK-771-1001 
Title: 
A Phase 1, Open-Label, Randomized Study to Assess the Tolerability, 
Safety, and Pharmacokinetics of Subcutaneous Immune Globulin 
Infusion 10% (Human) with Recombinant Human Hyaluronidase 
(HYQVIA/HyQvia) with Ramp-Up and No Ramp-Up Dosing in 
Healthy Adult Subjects 
Drug: 
HYQVIA/HyQvia 
IND: 
014381 
EUDRACT No.: 
Non-EUDRACT 
Sponsor:  
Baxalta US Inc.* 
300 Shire Way, Lexington, MA 02421  
AND 
Baxalta Innovations GmbH* 
Industriestrasse 67, A-1221 Vienna  
*Baxalta is now part of Shire 
Principal/ 
Coordinating 
Investigator: 
, MD, JD, CPI, FCLM 
 
 
Protocol History: 
Amendment 1.0: 30 JUN 2020 
Replaces: Original Protocol: 04 FEB 2020 
Confidentiality Statement 
This document contains confidential and proprietary information of Shire and is disclosed pursuant to 
confidentiality and non-disclosure obligations. This information should be used solely for the purposes for which it 
was provided and should not be copied, shared with, or disclosed to any third party without the express written 
consent of Shire. 
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Clinical Study Protocol: TAK-771-1001 
 
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Investigator’s Acknowledgement 
I have read this protocol for Study TAK-771-1001. 
Title: A Phase 1, Open-Label, Randomized Study to Assess the Tolerability, Safety, and 
Pharmacokinetics of Subcutaneous Immune Globulin Infusion 10% (Human) with Recombinant 
Human Hyaluronidase (HYQVIA/HyQvia) with Ramp-Up and No Ramp-Up Dosing in Healthy 
Adult Subjects. 
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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EMERGENCY CONTACT INFORMATION 
In the event of an SAE, the investigator must fax or e-mail the "Shire Clinical Study Adverse 
Event Form for Serious Adverse Events (SAEs) and Non-serious AEs as Required by the 
Protocol" within 24 hours to the Shire Global Drug Safety Department (Fax: +1-484-595-8155; 
E-mail: drugsafety@shire.com). The fax number and e-mail address are also provided on the 
form (sent under separate cover). A copy of this form must also be sent to the contract research 
organization (CRO)/Shire Medical Monitor using the details below. 
For protocol- or safety-related questions or concerns during or outside normal business 
hours, the investigator must contact the Medical Monitor: 
, MD 
, Clinical Medicine 
Global R&D, Plasma Derived Therapies 
Takeda Pharmaceutical Company Limited 
Mobile: 
 
E-mail: 
 
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ADDITIONAL CONTACT INFORMATION  
In case of any other issues, including non-safety-related issues or if the medical monitor is 
unable to be reached, the investigator must contact the Shire Study Manager. 
, RN  
E-mail: 
 
Mobile: 
 
If unavailable, please contact: 
 
E-mail: 
 
Mobile: 
 
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PRODUCT QUALITY COMPLAINTS 
Investigators are required to report investigational product quality complaints or non-medical 
complaints to Shire within 24 hours. If requested, defective product(s) will be returned to the 
sponsor for inspection and analysis. 
A product quality complaint includes any instances where there is an allegation or report relating 
to Shire licensed or investigational products, received in writing, electronically, or orally, which 
indicates an impact to a product’s strength, identity, safety, purity, or quality, or which suggests 
that the product did not meet the criteria defined in the regulatory applications, licenses, or 
marketing authorizations for the product. Examples of investigational product quality complaints 
include, but are not limited to, the following: 
Unit issues 
• Bottle/vial fill shortage or overage 
• Syringe/vial cracked/broken 
• Syringe leakage 
• Missing components 
• Product discoloration 
• Device malfunction 
Labeling 
• Label missing 
• Leaflet or Instructions For Use 
(IFU) missing  
• Label illegible 
• Incomplete, inaccurate, or misleading 
labeling 
• Lot number or serial number missing 
Packaging 
• Damaged packaging (e.g., 
secondary, primary, bag/pouch) 
• Tampered seals 
• Inadequate or faulty closure 
• Missing components within package 
Foreign 
material 
• Contaminated product 
• Particulate in bottles/vials 
• Particulate in packaging 
 
 
Please report the product quality complaint using the “Product Quality Complaint Data 
Collection Form” via the email address: 
PQC@shire.com 
Telephone number (provided for reference if needed): 
Shire, Lexington, MA (USA) 
1-800-828-2088 
For instructions on reporting AEs related to product complaints, see Section 9.5.2. 
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TABLE OF CONTENTS 
PROTOCOL SIGNATURE PAGE ............................................................................................. 2 
Sponsor’s (Shire) Approval...................................................................................................... 2 
Investigator’s Acknowledgement ............................................................................................ 3 
SUMMARY OF CHANGES FROM PREVIOUS PROTOCOL VERSION .......................... 4 
EMERGENCY CONTACT INFORMATION .......................................................................... 5 
ADDITIONAL CONTACT INFORMATION ........................................................................... 6 
PRODUCT QUALITY COMPLAINTS ..................................................................................... 7 
TABLE OF CONTENTS ............................................................................................................. 8 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ......................................... 13 
1. PROTOCOL SUMMARY ..................................................................................................... 16 
1.1 Study Synopsis................................................................................................................... 16 
1.2 Study Schematic ................................................................................................................ 23 
1.3 Study Schedules................................................................................................................. 24 
1.3.1 Schedule of Study Procedures: Treatment Arms 1 and 4 ...................................... 24 
1.3.2 Schedule of Study Procedures: Treatment Arms 2 and 5 ...................................... 27 
1.3.3 Schedule of Study Procedures: Treatment Arms 3 and 6 ...................................... 30 
2. BACKGROUND INFORMATION ...................................................................................... 33 
2.1 Indications for HYQVIA/HyQvia ................................................................................... 34 
2.2 Product Background......................................................................................................... 34 
2.2.1 Preclinical Information ............................................................................................. 34 
2.2.2 Clinical Information .................................................................................................. 34 
2.3 Risk/Benefit and Ethical Assessment .............................................................................. 37 
2.4 Compliance Statement ...................................................................................................... 37 
3. STUDY RATIONALE, OBJECTIVES AND ENDPOINTS .............................................. 38 
3.1 Rationale for the Study ..................................................................................................... 38 
3.2 Study Objectives ............................................................................................................... 38 
3.2.1 Primary Objectives .................................................................................................... 38 
3.2.2 Secondary Objectives ................................................................................................ 38 
3.3 Study Endpoints ................................................................................................................ 38 
3.3.1 Primary Endpoints .................................................................................................... 38 
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3.3.2 Secondary Endpoints ................................................................................................. 39 
3.3.2.1 Safety and Immunogenicity Endpoints ............................................................. 39 
3.3.2.2 PK Endpoints ...................................................................................................... 39 
4. STUDY DESIGN ..................................................................................................................... 40 
4.1 Study Design ...................................................................................................................... 40 
4.2 Duration and Study Completion Definition ................................................................... 42 
4.3 Study Continuation from Study Part 1 to Study Part 2 ................................................ 42 
5. STUDY POPULATION ......................................................................................................... 44 
5.1 Inclusion Criteria .............................................................................................................. 44 
5.2 Exclusion Criteria ............................................................................................................. 44 
5.3 Reproductive Potential ..................................................................................................... 46 
5.3.1 Female Contraception ............................................................................................... 47 
5.3.2 Male Contraception ................................................................................................... 48 
5.4 Discontinuation of Study and Subjects ........................................................................... 48 
5.4.1 Stopping Criteria for Individual Subjects ............................................................... 48 
5.4.2 Subject Withdrawal Criteria .................................................................................... 48 
5.4.3 Criteria for Premature Termination or Suspension of the Study ......................... 50 
6. PRIOR AND CONCOMITANT TREATMENT ................................................................. 51 
6.1 Prior Treatment ................................................................................................................ 51 
6.2 Concomitant Treatment ................................................................................................... 51 
6.2.1 Permitted Treatment ................................................................................................. 51 
6.2.2 Prohibited Treatment ................................................................................................ 51 
7. INVESTIGATIONAL PRODUCT........................................................................................ 52 
7.1 Identity of Investigational Product ................................................................................. 52 
7.1.1 Blinding the Treatment Assignment ........................................................................ 52 
7.2 Administration of Investigational Product(s) ................................................................. 52 
7.2.1 Allocation of Subjects to Treatment ........................................................................ 53 
7.2.2 Dosing .......................................................................................................................... 53 
7.3 Labeling, Packaging, Storage, and Handling ................................................................. 54 
7.3.1 Labeling ...................................................................................................................... 54 
7.3.2 Packaging .................................................................................................................... 54 
7.3.3 Storage ........................................................................................................................ 55 
7.4 Drug Accountability ......................................................................................................... 55 
7.5 Subject Compliance .......................................................................................................... 56 
8. STUDY PROCEDURES ........................................................................................................ 57 
8.1 Study Schedule .................................................................................................................. 57 
8.1.1 Screening Period ........................................................................................................ 57 
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8.1.1.1 Screening Failure ................................................................................................ 57 
8.1.1.2 Rescreening of Subjects ...................................................................................... 57 
8.1.2 Randomization ........................................................................................................... 58 
8.1.3 Day Prior Treatment (D-1)/Treatment Period ........................................................ 59 
8.1.3.1 Day -1 (For all Treatment Arms) ...................................................................... 59 
8.1.3.2 Week 1 (For all Treatment Arms) ..................................................................... 59 
8.1.3.3 Weeks 2-9 ............................................................................................................. 59 
8.1.4 Week 24/25 Follow-up Period (EOS/ET Visit) ........................................................ 59 
8.2 Study Evaluations and Procedures ................................................................................. 59 
8.2.1 Informed Consent Procedure ................................................................................... 60 
8.2.2 Demographic and Other Baseline Characteristics ................................................. 60 
8.2.3 Safety ........................................................................................................................... 60 
8.2.3.1 Physical Examinations ....................................................................................... 60 
8.2.3.2 Vital Signs ............................................................................................................ 61 
8.2.3.3 Electrocardiogram .............................................................................................. 61 
8.2.3.4 Clinical Laboratory Tests .................................................................................. 61 
8.2.3.5 Pregnancy Screen ............................................................................................... 65 
8.2.3.6 Drug and Alcohol Screen ................................................................................... 65 
8.2.3.7 Virology Screen ................................................................................................... 65 
8.2.4 Pharmacokinetic and Immunogenicity Sample Collection and Handling 
Procedures .................................................................................................................. 66 
8.2.4.1 Blood Sample Collection and Handling Procedures ....................................... 66 
8.2.4.2 Immunogenicity Panel ........................................................................................ 67 
8.2.5 Volume of Blood to be Drawn from Each Subject .................................................. 69 
8.3 Backup Samples and Biobanking .................................................................................... 69 
9. SAFETY ASSESSMENT ....................................................................................................... 70 
9.1 Adverse Events .................................................................................................................. 70 
9.1.1 Definitions ................................................................................................................... 70 
9.1.1.1 Serious Adverse Event ........................................................................................ 70 
9.1.1.2 Suspected Unexpected Serious Adverse Reaction (SUSAR) ........................... 71 
9.1.1.3 Nonserious Adverse Event ................................................................................. 71 
9.1.1.4 Unexpected Adverse Events ............................................................................... 72 
9.1.1.5 Adverse Reactions Plus Suspected Adverse Reactions.................................... 72 
9.1.1.6 Preexisting Diseases ............................................................................................ 72 
9.1.2 Assessment of Adverse Events .................................................................................. 72 
9.1.2.1 Severity ................................................................................................................ 73 
9.1.2.2 Causality .............................................................................................................. 74 
9.2 Outcome Categorization ................................................................................................... 75 
9.3 Urgent Safety Measures ................................................................................................... 76 
9.4 Untoward Medical Occurrences ...................................................................................... 77 
9.5 Reporting Procedures ....................................................................................................... 77 
9.5.1 Reporting AEs ............................................................................................................ 77 
9.5.2 Reporting SAEs .......................................................................................................... 78 
9.5.3 SAE Follow-Up ........................................................................................................... 79 
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9.5.4 Assessment of Laboratory Values ............................................................................ 79 
9.5.4.1 Toxicity Grading Scale ....................................................................................... 79 
9.6 Precautions and Warnings ............................................................................................... 81 
9.7 Management of Infusion-Related AEs ............................................................................ 81 
9.8 Non-Medical Complaints ................................................................................................. 81 
9.9 Medical, Medication, and Non-Drug Therapy History ................................................. 82 
9.10 Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting ........................................................................................................................... 82 
10. DATA MANAGEMENT AND STATISTICAL METHODS ........................................... 83 
10.1 Data Collection ................................................................................................................ 83 
10.1.1 CRFs (Electronic and Paper) .................................................................................. 83 
10.2 Clinical Data Management ............................................................................................ 84 
10.3 Data Handling ................................................................................................................. 84 
10.4 Statistical Analysis Process ............................................................................................ 84 
10.5 Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee ....... 85 
10.6 Sample Size Calculation and Power Considerations ................................................... 85 
10.7 Study Population ............................................................................................................. 85 
10.8 Pharmacokinetic and Pharmacodynamic Analyses..................................................... 86 
10.8.1 Pharmacokinetic Analysis ....................................................................................... 86 
10.8.2 Pharmacodynamic Analysis .................................................................................... 87 
10.9 Safety and Immunogenicity Analyses ........................................................................... 87 
10.10 Additional Analysis of AEs .......................................................................................... 89 
10.11 Other Analyses .............................................................................................................. 90 
10.11.1 Analysis of Demography and Other Baseline Characteristics .......................... 90 
11. ETHICS ................................................................................................................................. 91 
11.1 Informed Consent ........................................................................................................... 91 
11.2 Institutional Review Board or Ethics Committee ........................................................ 92 
11.3 Good Clinical Practice Compliance .............................................................................. 94 
12. DATA HANDLING AND RECORD KEEPING ............................................................... 95 
12.1 Privacy and Confidentiality ........................................................................................... 95 
12.2 Study Documentation and Case Report Forms ........................................................... 96 
12.3 Document and Data Retention....................................................................................... 97 
13. QUALITY CONTROL AND QUALITY ASSURANCE .................................................. 98 
13.1 Investigator’s Responsibility .......................................................................................... 98 
13.1.1 Final Clinical Study Report .................................................................................... 98 
13.2 Training ........................................................................................................................... 98 
13.3 Monitoring ....................................................................................................................... 98 
13.4 Auditing ........................................................................................................................... 98 
13.5 Non-Compliance with the Protocol ............................................................................... 99 
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14. FINANCING AND INSURANCE ....................................................................................... 99 
15. PUBLICATION POLICY .................................................................................................... 99 
16. REFERENCES .................................................................................................................... 100 
APPENDIX 1  PROTOCOL HISTORY................................................................................. 101 
 
Tables 
Table 1. Planned Dose Levels ....................................................................................................... 41 
Table 2: Subcutaneous Infusion Rates for IGI, 10% .................................................................... 54 
Table 3. Chemistry Panel .............................................................................................................. 62 
Table 4. Hematology Panel ........................................................................................................... 63 
Table 5. Urinalysis Panel .............................................................................................................. 64 
Table 6: Coagulation Panel ........................................................................................................... 64 
Table 7. Primary Specimen Collections........................................................................................ 66 
Table 8. List of Conditions/Symptoms That May be a Result of Immune-Mediated Response to 
Either Immunoglobulin, rHuPH20, or Other Factors ........................................................... 68 
Table 9. Immunogenicity Panel .................................................................................................... 68 
Table 10. Estimated Volume of Blood to be Drawn from Each Subject ...................................... 69 
Table 11. Grading of Laboratory Parameters ............................................................................... 80 
Table 12. PK Parameters............................................................................................................... 86 
Table 13. Summary of Ramp-Up and No Ramp-Up Dosing Groups ........................................... 88 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
ADA 
Anti-drug antibody 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
aPTT 
Activated partial thromboplastin time 
AR 
Adverse reaction 
AST 
Aspartate aminotransferase 
AUClast 
The area under the concentration-time curve, from time 0 to the last quantifiable 
concentration, as calculated by the linear-log trapezoidal method. 
BMI 
Body mass index 
BP 
Blood pressure 
BUN 
blood urea nitrogen 
CBC 
Complete blood count 
CFR 
Code of Federal Regulations 
CIDP 
Chronic inflammatory demyelinating polyradiculoneuropathy 
CL/F 
Apparent total plasma clearance after extravascular administration 
Cmax 
Maximum observed concentration  
CRF 
Case report form 
CRO 
Contract research organization 
CRU 
Clinical Research Unit 
CTA 
Clinical Trial Agreement 
D 
Day 
DL 
Dose level 
DNA 
Deoxyribonucleic acid  
EC 
Ethics committee 
ECG 
Electrocardiogram 
EOS 
End of study 
ET 
Early termination 
EU 
European Union 
FSH 
Follicle stimulating hormone 
g 
Gram 
GCP 
Good Clinical Practice 
h 
Hour(s) 
Hb 
Hemoglobin 
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Abbreviation 
Definition 
Hct 
Hematocrit 
HbsAG 
Hepatitis B surface antigen 
HbsAb 
Hepatitis B surface Antibody 
HbcAb 
Hepatitis B core Antibody 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus  
HIV 
Human immunodeficiency virus 
HR 
Heart rate 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IgA 
Immunoglobulin A 
IGI 
Immune Globulin Infusion 
IgG 
Immunoglobulin G 
IgM 
Immunoglobulin M  
INR 
International normalized ratio 
IRB 
Institutional Review Board 
IP 
Investigational product 
Kg 
Kilogram 
LDH 
lactate dehydrogenase 
M 
Molar 
m2 
Meters squared 
MCH 
Mean Corpuscular Hemoglobin 
MCHC 
Mean Corpuscular Hemoglobin Concentration 
MCV 
Mean Corpuscular Volume 
MedDRA® 
Medical Dictionary for Regulatory Activities® 
mg 
Milligram 
Min 
Minute 
mL 
Milliliter 
mmHg 
Millimeter of mercury 
mOsmol 
Milliosmolar 
msec 
Millisecond 
nADA 
Neutralizing anti-drug antibody 
NCA 
Noncompartmental analysis 
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Abbreviation 
Definition 
PE 
Full physical examination 
PID 
Primary immune deficiency 
P-gp 
P-glycoprotein 
PGx 
Pharmacogenomics 
PI 
Principal investigator 
PK 
Pharmacokinetic(s) 
PT 
Prothrombin time 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
RBC 
Red blood cells  
RDW 
Red Cell Distribution Width 
RNA 
Ribonucleic acid 
rHuPH20 
Recombinant human hyaluronidase PH20  
RR 
Respiratory rate 
Sch 
Schedule 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous 
SD 
Standard deviation 
SIC 
Subject identification code 
t½ 
Terminal disposition phase half-life 
TDL 
Target (full) dose level 
TEAE 
Treatment-emergent adverse event 
ULN 
Upper limit of normal 
UPCR 
urine protein to creatinine ratio 
US 
United States 
USA 
United States of America 
Vz/F 
Volume of distribution during the terminal disposition phase after extravascular administration 
W 
Week 
WBC 
White blood cells 
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1. PROTOCOL SUMMARY 
1.1 Study Synopsis 
Protocol number: TAK-771-1001 
Drug: Subcutaneous Immune Globulin Infusion 10% (Human, 
abbreviated as IGI, 10%) with Recombinant Human Hyaluronidase 
(abbreviated as rHuPH20) (referred to as HYQVIA or HyQvia) 
Title of the study: A Phase 1, Open-Label, Randomized Study to Assess the Tolerability, Safety, and 
Pharmacokinetics of Subcutaneous Immune Globulin Infusion 10% (Human) with Recombinant Human 
Hyaluronidase (HYQVIA/HyQvia) with Ramp-Up and No Ramp-Up Dosing in Healthy Adult Subjects 
Number of subjects (total and for each treatment arm): 
The planned total sample size for this study is 48 randomized subjects with 8 subjects enrolled in each of the 
6 treatment arms. 
Site(s) and Region(s):  
Single site, USA 
Study period (planned): 
Initiation: approximately Q3 2020 
Completion: approximately Q3 2021 
Clinical phase: 
1 
Study Subject Population: Healthy male and female subjects aged 19 – 50 years inclusive, at screening and 
Body Mass Index (BMI) between 18 and 30 kg/m2, inclusive at screening. This study plans to enroll 8 subjects in 
each of the 6 treatment arms, and a minimum of 3 subjects in each of the 2 BMI groups (18 to <25 kg/m2, ≥25 to 
30 kg/m2) in each treatment arm, achievable using stratified randomization (BMI as the stratification factor). 
Objectives: 
Primary: 
To assess the tolerability of HYQVIA with and without ramp-up dosing in healthy adult subjects. 
Secondary: 
• 
To assess the safety and immunogenicity of HYQVIA with and without ramp-up dosing in healthy adult 
subjects. 
• 
To characterize the pharmacokinetics (PK) of total IgG and IgG subclasses after subcutaneous 
administration of HYQVIA in healthy adult subjects.  
Rationale: 
Dose ramp up has been considered necessary for HYQVIA in the Phase 3 Study (Study 161403) because the 
majority of CIDP patient population are naïve to subcutaneous (SC) infusions, or inexperienced with SC 
infusions at large volumes (>60 mL per infusion site; infusion volume maximum per day: up to 600 mL (1 site) 
or 1200 mL (2 sites)).  As a result, a dose ramp-up schedule has been included in Study 161403, which involves 
stepwise gradual increase until the subject’s full dose is reached to improve tolerability. Dose ramp up is 
currently in the approved prescribing information for primary immune deficiency. Despite the current use of 
ramp up dosing in PID and CIDP patients, the tolerability and safety of HYQVIA without ramp-up has not been 
evaluated in clinical studies. This Phase 1 study is planned to assess the tolerability, safety and immunogenicity 
profiles of HYQVIA with and without ramp-up dosing and to characterize the PK of total IgG and IgG subclasses 
after Sc administration of HYQVIA in healthy adult subjects. 
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Investigational product, dose, and mode of administration:  
Subcutaneous Immune Globulin Infusion 10% (Human, abbreviated as IGI, 10%) with Recombinant Human 
Hyaluronidase (abbreviated as rHuPH20) (referred to as HYQVIA or HyQvia). 
The target dose level (TDL) for IGI, 10% will be 0.4 g/kg (Part 1) and 1.0 g/kg (Part 2). 
Dose Level 1 (DL1) =1/4 of TDL;  
Dose Level 2 (DL2) =1/2 of TDL;  
Dose Level 3 (DL3) =3/4 of TDL; 
Dose Level 4 (DL4) =TDL. 
The dose for rHuPH20 is 80 U/g IgG. 
Methodology: 
This study is a phase 1, open-label, randomized, single-center study to evaluate the tolerability, safety and 
immunogenicity of HYQVIA with and without ramp-up dosing and to characterize the PK of total IgG and 
IgG subclasses after SC administration of HYQVIA in healthy adult subjects.   
Study Parts: 
This study is comprised of two parts, Study Parts 1 & 2.  The target dose level (TDL) of either 0.4g/kg (Part 1) or 
1.0 g/kg (Part 2) will be achieved through dose ramp-up or no ramp up (i.e. direct administration of the TDL). 
Each study part consists of three Treatment Arms (Part 1: Treatment Arms 1-3 and Part 2: Treatment Arms 4-6):  
• 
Treatment Arms 1 and 4 will follow ramp up Schedule-A (Sch-A), in which subjects will receive 
HYQVIA from ¼ of the TDL at Week 1 to the full TDL at Week 8. 
• 
Treatments Arms 2 and 5 will follow ramp up Schedule-B (Sch-B), in which subjects will receive 
HYQVIA from ½ of the TDL at Week 1 to the full TDL at Week 5. 
• 
Treatment Arms 3 and 6 will follow ramp up Schedule-C (Sch-C), in which subjects will directly receive 
the full TDL at Week 1 without ramp-up dosing.  
 
A total of 48 subjects are planned and will be randomized to 6 parallel treatment arms (8 subjects per treatment 
arm, equal randomization ratio): 24 subjects in total to Part 1 and 24 subjects in total to Part 2. Treatment arms 
will be initiated in parallel within each study part.  Each subject will participate in only one treatment arm. 
After subjects in Treatment Arms 1-3 have completed Week 9 treatment in Study Part 1, and the tolerability, 
safety and immunogenicity data through Week 9 for the subjects has been reviewed by a safety review team 
consisting of the Investigator, the Sponsor's Medical Monitor, and the Sponsor’s Global Drug Safety Physician, 
Treatment Arms 4-6 in Study Part 2 will begin.  
Study Periods 
The study consists of 3 periods: 
• 
Screening period: up to 21 days prior to first dosing.  
• 
Study treatment period: 8 weeks for Treatment Arms 1 and 4; 9 weeks for Treatment Arms 2, 3, 5, and 6. 
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• 
Follow up period: 16 (± 1) weeks after receiving the last infusion of HYQVIA with the end of study 
(EOS) being in Weeks 24 (± 1) (Treatment Arms 1 and 4) or 25 (± 1) (Treatment Arms 2, 3, 5, and 6). 
All subjects who received at least one dose of HYQVIA (including subjects who terminate the study 
early) will return to the Clinical Research Unit (CRU) 16 (± 1) weeks after the last infusion of HYQVIA 
for follow-up procedures. 
 
Tolerability, safety and immunogenicity will be assessed throughout the treatment period for all treatment arms.  
The PK of immunoglobin G (IgG) and IgG subclasses will be characterized based on their serum concentration-
time profiles post the first infusion.  
All subjects will be monitored for the formation of binding anti-rHuPH20 antibodies (binding ADA). Samples 
with antibody titers ≥1:160 (ADA positive) will be analyzed for the presence of neutralizing antibodies. At any 
time over the course of the study, subjects who have (a) 2 consecutive anti-rHuPH20 antibody titers of ≥1:160 
that are elevated from the subject’s baseline titers, and (b) a moderate or severe AE that may be a result of 
immune-mediated response to either immunoglobulin, rHuPH20, or other concomitant medications will be asked 
to return to the CRU as soon as possible to undergo an additional panel of immunogenicity testing. 
After the EOS visit has been completed, no further visits are planned, unless determined necessary by the 
investigator. Positive binding antibody titers associated with serious or severe AEs may require additional  
follow-up assessments. 
Eligibility criteria: 
The subject will not be considered eligible for the study without meeting all the criteria below. Subjects cannot be 
randomized or enrolled before all inclusion and exclusion criteria (including laboratory test results) are within 
acceptable ranges as per protocol. 
Inclusion Criteria: 
1. 
An understanding, ability, and willingness to fully comply with study procedures and restrictions. 
2. 
Ability to voluntarily provide written, signed, and dated (personally or via a legally authorized 
representative) informed consent as applicable to participate in the study. 
3. 
Age 19-50 years inclusive at the time of consent. The date of signature of the informed consent is defined 
as the beginning of the screening period. This inclusion criterion will only be assessed at the first 
screening visit. 
4. 
Male, or non-pregnant, non-breastfeeding female who agrees to comply with any applicable contraceptive 
requirements of the protocol, or females of non-childbearing potential. 
5. 
Must be considered “healthy”. Healthy as determined by the investigator on the basis of screening 
evaluations and healthy status is defined by absence of evidence of any active or chronic disease 
following a detailed medical and surgical history, a complete physical examination including vital signs, 
12-lead ECG, hematology, blood chemistry, and urinalysis. 
6. 
Body mass index (BMI) between 18.0 and 30.0 kg/m² inclusive. 
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Exclusion Criteria: 
1. 
Any current or relevant history of medical (e.g. any hematological, hepatic, respiratory, cardiovascular, 
renal or neurological) or psychiatric conditions, which by judgment of the investigator might compromise 
the safety of the subject or integrity of the study, interfere with the subject’s participations in the trial and 
compromise the trial objectives or any condition that presents undue risk from the investigational product 
or procedures. 
Note: Subjects on stable dose of hormone replacements (i.e. thyroid hormone replacement) or oral 
contraceptives are permitted. 
2. 
Clinically significant cardiac conditions including but not limited to uncontrolled hypertension, 
myocardial infarction, unstable coronary artery disease and clinically significant arrythmias and 
conduction disorders. 
3. 
Known or suspected intolerance or hypersensitivity to the investigational product(s), closely related 
compounds, or any of the stated ingredients (e.g. human IG, hyaluronidase, albumin). 
4. 
Known history of hypersensitivity or severe allergic reactions (e.g. urticaria, breathing difficulty, severe 
hypotension, or anaphylaxis) following administration of blood or blood components. 
5. 
Significant illness, as judged by the investigator, within 30 days of the first dose of investigational 
product. 
6. 
Known history of alcohol or other substance abuse within the last year. 
7. 
Donation of blood within 60 days, or blood products (e.g., plasma or platelets) within 2 weeks prior 
receiving the first dose of investigational product.  
8. 
Subjects will be excluded if any of the following laboratory parameters meet the criteria below: 
• 
Hemoglobin < 11 g/dL 
• 
Absolute neutrophil count ≤1500/mm and platelet count ≤100,000/mm3 
• 
Liver function: alanine aminotransferase (ALT) ≥2.5 × upper limit normal (ULN), aspartate 
aminotransferase (AST) ≥2.5 × upper limit normal (ULN), alkaline phosphatase ≥1.5 × ULN or 
total bilirubin ≥1.5 mg/dL 
• 
Renal function: creatinine clearance ≤60 mL/min based on Cockcroft-Gault equation 
• 
Coagulation tests: aPTT >1.2 X ULN; INR >1.2  
Subjects will be excluded if any other laboratory values are outside the reference range and are clinically 
significant per investigator’s judgment.   
9. 
Within 30 days prior to the first dose of investigational product: 
• 
Has participated in another clinical study involving immunoglobulin products within 12 months of 
screening. 
• 
Have used an investigational product (or 5 half-lives, whichever is longer). 
• 
Have been enrolled in a clinical study (including vaccine studies or has been vaccinated with 
approved product) that, in the investigator’s opinion, may impact this study.  Subjects who have 
received any vaccine (including live attenuated vaccines) during the last 30 days before dosing will 
be excluded. No live attenuated virus vaccines are allowed during the study until the end of the 
follow up period. 
• 
Have had any substantial changes in eating habits, as assessed by the investigator. 
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10. Confirmed systolic blood pressure >139 mmHg or <89 mmHg and diastolic blood pressure >89 mmHg or 
<49 mmHg. 
11. A positive screen for alcohol or drugs of abuse at screening or D-1. 
12. A positive HIV, HCV, or ongoing/active hepatitis B infection at screening. Subjects with immunity to 
hepatitis B from either active vaccination or from previous natural infection are eligible to participate in 
the study. 
13. Smoking more than 5 cigarettes or equivalent per day, unable to stop smoking during confinement in the 
CRU. 
14. Severe dermatitis or anatomical abnormality that would interfere with HYQVIA administration or 
endpoint assessments. Note: the skin at the administration site should not be covered by tattoos. 
15. Current use of any herbal, or homeopathic preparations are not permitted.   
16. Unable or unwilling to discontinue antihistamines or medications with antihistamine properties, sedatives, 
anxiolytics, systemic steroids, or topical steroids or antibiotics on any area below the chest for a minimum 
of 48 hours prior to each infusion visit and through 72 hours post last infusion. 
17. Current or relevant history of hypercoagulable conditions (e.g. Protein C, Protein S, and antithrombin III 
deficiency), thrombotic/thromboembolic events or venous thrombosis. 
Maximum duration of subject involvement in the study: 
Planned Study Duration: Up to 28 weeks from screening to EOS 
Duration of Treatment: Up to 9 weeks 
Endpoints and statistical analysis: 
Primary Endpoints:  
The primary endpoint corresponding to the primary objective of the study is the occurrence of tolerability 
events related to the infusion of HYQVIA.  
Definition: An infusion is considered tolerable if the infusion rate was not reduced or the infusion was not 
interrupted or stopped, due to HYQVIA infusion. 
A tolerability event is considered to have occurred if an infusion was tolerable. Tolerability events will be 
measured in terms of the number and percentage of subjects for which the infusion was tolerable.  
Secondary Endpoints:  
Safety and Immunogenicity endpoints:  
• 
Occurrence of TEAEs, including but not limited to: HYQVIA-related and non-related *, serious, 
nonserious, severe, local and systemic TEAEs, TEAEs leading to premature discontinuation from study, 
and infusion-associated TEAEs, as well as number and percentage of subjects and infusions with 
suspected adverse reactions plus adverse reactions of interest (additional information is provided in 
Section 10.10). 
* Any TEAE that is recorded by the investigator as “possibly related” or “probably related” to HYQVIA 
will be considered HYQVIA-related AE, and any AE recorded as “unlikely related” or “not related” 
will be considered unrelated AE. 
• 
Clinical laboratory parameters  
• 
Vital signs  
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• 
Immunogenicity: occurrence of binding and neutralizing antibodies to rHuPH20  
Note that clinically significant treatment-emergent changes in clinical laboratory measurements and vital signs 
will be recorded in the study database as TEAEs. 
PK endpoints: 
• 
PK parameters for serum total IgG and IgG subclasses after a single dose of HYQVIA (i.e. after Week 1 
dosing), including but are not limited to Cmax, Tmax, AUClast, t1/2, CL/F and Vz/F. 
Statistical Considerations: 
No interim analysis is planned for this study. 
No statistical hypothesis testing will be performed.  
Tolerability, safety and immunogenicity endpoint data will be analyzed using descriptive statistics. Continuous 
endpoints (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. Baseline is defined as the 
last non-missing value before the initial dose of HYQVIA. Categorical endpoints (e.g., occurrence of adverse 
events) will be summarized in terms of number and percent of subjects and number of occurrences in each 
category, as appropriate.  
Summaries of AEs, labs, vital signs, and immunogenicity will be presented, as appropriate, by dosing group 
(Ramp-Up, No Ramp-Up) and treatment arms within dosing schedule, as displayed with the planned total sample 
size and sample size for each treatment arm:  
Ramp-Up  
(N=32) 
No Ramp-Up  
(N=16) 
Schedule A 
Schedule B 
 
Total 
Schedule C 
 
Total 
Low 
High 
Low 
High 
Low 
High 
Treatment 1 
(n=8) 
Treatment 4 
(n=8) 
Treatment 2 
(n=8) 
Treatment 5 
(n=8) 
All 
(n=32) 
Treatment 3 
(n=8) 
Treatment 6 
(n=8) 
All 
(n=16) 
Low=0.4 g/kg, High=1.0 g/kg. 
 
Additional summaries will be presented by visit/time point (e.g., laboratory parameters).  
The overall summary, based on descriptive statistics, is the summary of the overall 
tolerability/safety/immunogenicity profile in the Ramp-Up dosing group (all treatments pooled) versus the overall 
profile in the No Ramp-Up group (all treatments pooled).  
Claim of tolerability/safety/immunogenicity of HYQVIA will be based on clinical judgment on the totality of 
evidence, to be derived from the overall summary, with no predefined tolerability/safety/immunogenicity 
statistical margin or criteria. 
Note: AEs below refer to TEAEs. 
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The following will be displayed in statistical outputs, including but not limited to: 
• 
Number (percentage) of subjects with HYQVIA-related AEs (causally related AEs), and HYQVIA-related 
SAEs, and number of such events 
 
AEs recorded in the study database as “possibly related” or “probably related” to HYQVIA will be 
considered HYQVIA-related AEs 
• 
Number (percentage) of subjects with HYQVIA-related AEs that were mild, moderate, or severe in 
severity, and number of events in each category 
• 
Number (percentage) of subjects with any AEs, any serious and/or nonserious AEs, and any local and 
systemic AEs/SAEs, regardless of causality  
• 
Number (percentage) of infusions for which the infusion rate was reduced, and/or the infusion was 
interrupted or stopped due to intolerability and/or AEs. 
• 
Number (percentage) subjects who completed infusions without requiring any adjustment due to 
intolerability and/AEs 
• 
Number (percentage) of subjects who prematurely discontinued study due to AEs  
• 
Rate of AEs, expressed as number of events per infusion, per subject, and per subject-year 
• 
Raw (actual) values and change from baseline in clinical laboratory parameters 
• 
Raw (actual) values and change from baseline in vital signs 
• 
Number (percentage) of subjects who have developed binding and neutralizing antibodies to rHuPH20. 
Subject-level tolerability and safety data, including derived data, will be presented in subject data listings. 
The PK parameters including but not limited to the following, will be calculated for total IgG and IgG subclasses 
in serum, as appropriate, using noncompartmental analysis (NCA):  
• 
AUClast, Cmax, tmax, t½, CL/F, and Vz/F. 
 
Sample Size Justification:  
Assessment of tolerability to HYQVIA SC administration is the primary objective of this study.  
This study is not designed for statistical hypothesis testing, and therefore the sample size was not based on 
statistical considerations. The planned total sample size for this study is 48 randomized subjects (8 subjects per 
treatment arm and 6 treatment arms, equal randomization ratio). 
Of the 48 subjects to be randomized, a minimum of 36 subjects are expected to complete the study, assuming a 
conservative overall dropout rate of 25% in this healthy subject study (overall dropout rates assumed for 
HYQVIA patient studies are generally 10%-15%). The number of subjects expected to complete the study (36) is 
considered adequate for providing statistically reliable assessment of tolerability, safety, immunogenicity, and 
PK. 
 
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1.2 Study Schematic 
 
 
 
 
 
 
 
After all subjects in Study Part 1 
complete Week 9, a safety data review 
of the data collected through Week 9 
will be conducted before the first 
dosing is initiated in Study Part 2. 
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1.3 Study Schedules 
1.3.1 Schedule of Study Procedures: Treatment Arms 1 and 4 
Visit/Assessment 
Screening Period 
Treatment Period 
Follow-up Period 
(EOS/ET) 
Study Week/Day 
Within 21 Days 
prior to dosing 
D-1 
W1 
W2 
W3 
W5 
W8 
W24  
(+/- 1 week) 
D1 
D2 
D4 
D6 
D8 
D15 ±2 D29 ±2 D50 ±3 
Informed Consent1 
X 
 
 
 
 
 
 
 
 
 
 
Demographics2 
X 
 
 
 
 
 
 
 
 
 
 
Visit at Clinical Site  
X 
X6 
X6 
X 
X 
X 
X6 
X6 
X6 
X6 
X 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
Medical History3 
X 
X 
 
 
 
 
 
 
 
 
 
Concomitant Medications 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
Physical Examination 4 
X 
X 
 
 
 
 
X 
X 
X 
X 
X 
Height &BMI calculation (screening only), 
Weight Measurements5 
X 
X 
 
 
 
 
X 
X 
X 
X 
X 
Study Treatment Administration 7 
 
 
DL1 
 
 
 
DL1 
DL2 
DL3 
DL4 
 
Drugs of Abuse/Alcohol Screen8 
X 
X 
 
 
 
 
 
 
 
 
 
Infusion Site Evaluation9 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
HIV, HBV, HCV10 
X 
 
 
 
 
 
 
 
 
 
X 
Pregnancy (all females) & FSH 
(postmenopausal females only)11 
X 
X 
 
 
 
 
X 
X 
X 
X 
X 
Adverse Events/Serious Adverse Events 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 12 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-Lead ECG13 
X 
 
 
 
 
 
 
 
 
 
X 
Serum Chemistry, Hematology, and Urinalysis 14 
X 
X 
 
 
 
 
 
X 
X 
X 
X 
Hemolytic Panel15 
 
X 
X (as applicable) 
Coagulation Tests16 
X 
 
 
 
 
 
 
 
 
 
X 
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Visit/Assessment 
Screening Period 
Treatment Period 
Follow-up Period 
(EOS/ET) 
Study Week/Day 
Within 21 Days 
prior to dosing 
D-1 
W1 
W2 
W3 
W5 
W8 
W24  
(+/- 1 week) 
D1 
D2 
D4 
D6 
D8 
D15 ±2 D29 ±2 D50 ±3 
rHuPH20 Immunogenicity: ADA and nADA 
Blood Collection  
 
 
X 
 
 
 
 
 
X 
X 
X 
PK Blood Sample Collection17 
 
 
X 
X 
X 
X 
X 
 
 
 
 
Immunogenicity Panel18 
 
 
X 
X (as applicable) 
Abbreviations: ADA=anti-drug antibody; BMI=body mass index; BP= blood pressure; BUN= blood urea nitrogen; CBC= complete blood count;  
CRU= Clinical Research Unit; D=Day; DL=dose level; ECG=electrocardiogram; EOS=end of study; ET=early termination; FSH=follicle stimulating hormone; 
Hb=Hemoglobin, Hct=Hematocrit; HBsAG=hepatitis B surface antigen; HBsAb= Hepatitis B surface Antibody; HBcAb= hepatitis B core Antibody;   
HBV= hepatitis B virus; HCV=hepatitis C virus; HIV=human immunodeficiency virus; HR= heart rate; LDH= lactate dehydrogenase; MCH= Mean Corpuscular 
Hemoglobin; MCHC= Mean Corpuscular Hemoglobin Concentration; MCV= Mean Corpuscular Volume; nADA=neutralizing anti-drug antibody; PI= Principal 
Investigator; PK=pharmacokinetic; RBC= red blood cell; RDW= Red Cell Distribution Width; RR= respiratory rate; TDL= Target dose level; UPCR= urine 
protein to creatinine ratio; W=week; WBC= white blood cells. 
1. 
Written consent must be obtained prior to performing any protocol specific procedure. 
2. 
Age, gender, ethnicity, and race. 
3. 
Medical History: includes any significant or relevant diseases, surgeries, or other medical events and medication/treatment history if applicable. 
4. 
Physical Examination: Full physical examination will be performed at screening and EOS/ET visit, and partial physical examination can be done at the rest 
of the visits to assess any new abnormalities or changes from baseline. 
Full physical examination will include general appearance, head and neck, eyes and ears, nose and throat, chest, lungs, heart, abdomen, extremities and 
joints, lymph nodes, skin, and neurological.  
Partial physical examination will include: general appearance, head and neck, assessment of injection sites, and skin. Other organ systems will be 
assessed per PI’s judgment (Section 8.2.3.1). 
5. 
Height and BMI will be assessed at the first physical examination only.  
Weight: Body weight will be measured on the day of each dosing specified in Section 1.3.1. The dose should be recalculated if the body weight differs 
more than 10% from the previous dosing day body weight.  
6. 
Overnight stay at the CRU. Subjects will check in on D -1 and will stay for 2 overnights for the first visit (D-1 and D1). For rest of the visits subjects will 
be confined to the CRU for 24 hours from the start of the infusion.  During confinement period, standard meals and snacks will be provided at appropriate 
times. Subjects must be well hydrated prior to drug administration. 
7. 
The TDL is 0.4 and 1.0 g/kg with rHuPH20 80U/g IgG for Study Parts 1 and 2, respectively. Each DL is calculated as the following: DL1=1/4 of TDL; 
DL2=1/2 of TDL; DL3 =3/4 of TDL; and DL4=TDL. See also footnote 5. 
8. 
Drug screen will include: opiates (includes morphine, heroin (diacetylmorphine), codeine, 6-acetylmorphine, dihydrocodeine, hydrocodone, thebaine, and, 
hydromorphone), amphetamines, barbiturates, benzodiazepines, cocaine, cannabinoids, phencyclidine. See Section 8.2.3.6.  
Continued on next page 
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Continued 
9. 
Infusion sites will be evaluated for any potential local or systemic effects such as infusion site (local) events (e.g. erythema, pain, oedema and leaking).  
Subjects will also be evaluated/observed for acute or delayed allergic reactions, change in vital signs, pyrexia, upper abdominal pain, nausea, vomiting, 
diarrhea, and/ or pain in extremities. Please refer also to Section 9.7 and Table 8 in Section 8.2.4.2 for more information about infusion related AEs. 
10. Testing will be performed by the local laboratory at Screening, during the follow up period and at EOS/ET. Include HCV antibody, HBsAg, HBsAb, 
HBcAb and HIV 1/2 antibodies. Subjects who are HIV, HBsAg or HCV antibody positive at screening will not be enrolled.  
11. Pregnancy test will be done only in women of childbearing potential. Serum pregnancy test will be obtained at screening and subjects must have a negative 
serum pregnancy test (within 7 days prior to inclusion). For subsequent dosing days, a urine pregnancy test prior to dosing will be acceptable. Follicle 
stimulating hormone (FSH) levels may be done once at screening on menopausal or peri-menopausal women, or as judged by investigator 
12. Vital signs, RR, HR, BP and body temperature will be measured at screening. Only BP, HR and RR will be measured every 30 minutes from starting the 
infusion until the end of infusion, and every 1-2 hours after the infusion for 8 hours, at discharge and as needed per investigator’s judgment until 
discharged.  
13. ECGs (12-lead) will be collected at prespecified time points in the Section 1.3.1 and as clinically indicated. 
14. Hematology includes CBC (Hct, Hg, RBC, RDW, MCV, MCH, MCHC, platelets, WBC with absolute differential counts of neutrophils, lymphocytes, 
monocytes, eosinophils, and basophils). See Section 8.2.3.4.2. 
Serum Chemistry ALT, AST, ALP, K+, Na+, Cl-, Ca2+Mg2+, Bilirubin (total and direct), LDH, BUN, creatinine, uric acid, glucose , albumin, lipid 
profile. See Section 8.2.3.4.1.  
Urine Test. Urinalysis will include color, specific gravity, pH, protein, glucose, ketones, bilirubin, urobilinogen, blood, nitrite, leukocyte esterase. 
Dipstick urine test is acceptable. Microscopic analyses will be done if clinically indicated. If ≥ 2+ protein on urine dipstick, then collect spot urine sample 
to calculate UPCR or collect 24h urine. Tests will be performed at prespecified time points in the Section 1.3.1 and as clinically indicated. No need to 
repeat before first dose if screening test is done within 7 days. See Section 8.2.3.4.4.  
15. The hemolytic anemia panel will consist of Hgb, LDH, serum haptoglobin, plasma-free (unbound) Hgb, serum direct anti-globulin (direct Coombs) test 
(antibody elution to be performed if direct Coombs test is positive), reticulocyte count, as well as urine hemosiderin. The lab results obtained from the  
D-1 and will serve as the baseline values. In case of absence of D-1 result for any reason screening Hgb result serve as the baseline Hgb value. Hgb and 
LDH values can be taken from the hematology and clinical chemistry panels, if conducted on the same day as the hemolytic panel. For subsequent tests, if 
there is a reduction in Hgb of 1 g/dL or more compared to baseline Hgb, every effort is to be made to perform a hemolytic panel within 72 h; if it is not 
feasible to do so, the hemolytic panel must be performed as soon as possible, but at the next scheduled visit, at the latest. At any time during the study, an 
unscheduled hemolytic panel may be performed in the event of suspected hemolytic anemia. Any LDH test result of 2× ULN or greater will trigger analysis 
of the sample for LDH isoenzymes (see Section 8.2.3.4.3). 
16. aPTT and INR: assessments will be performed at specified time points in the Section 1.3.1 and as clinically indicated. See Section 8.2.3.4.5. 
17. PK samples will be obtained at specified time points in the Section 1.3.1 and on the subsequent days approximately the same time as the start of Day 1 
dosing. 
18. The immunogenicity panel outlined in Section 8.2.4.2 will be collected at baseline (D1) and any time deemed necessary during the course of the study. 
Subjects, who have (a) two consecutive anti-rHuPH20 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, rHuPH20 (see Table 8), or other concomitant medications , will 
be asked to return to the CRU as soon as possible to undergo an additional panel of immunogenicity testing outlined in Table 9.  
Note: Multiple activities scheduled on the same day or at the same time will be conducted in the following order, when applicable: ECG, vital signs, 
blood sampling and study drug administration. 
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1.3.2 Schedule of Study Procedures: Treatment Arms 2 and 5  
Visit/Assessment 
Screening Period 
Treatment Period 
Follow-up Period 
(EOS/ET) 
Study Week/Day 
Within 21 Days 
prior to dosing D-1 
W1 
W2 
W3 
W5 
W9 
W25  
(+/- 1 week) 6 
D1 
D2 
D4 
D6 
D8 
D15 ±2 D29 ±2 
D57 ±3 
Informed Consent1 
X 
 
 
 
 
 
 
 
 
 
 
Demographics2 
X 
 
 
 
 
 
 
 
 
 
 
Visit at Clinical Site  
X 
X6 
X6 
X 
X 
X 
X 
X6 
X6 
X6 
X 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
Medical History3 
X 
X 
 
 
 
 
 
 
 
 
 
Concomitant Medications 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
Physical Examination 4 
X 
X 
 
 
 
 
 
X 
X 
X 
X 
Height &BMI Calculation (screening only) & 
Weight Measurements5 
X 
X 
 
 
 
 
 
X 
X 
X 
X 
Study Treatment Administration 7 
 
 
DL2 
 
 
 
 
DL2 
DL4 
DL4 
 
Drugs of Abuse/Alcohol Screen8 
X 
X 
 
 
 
 
 
 
 
 
 
Infusion Site Evaluation 9 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
HIV, HBV, HCV10 
X 
 
 
 
 
 
 
 
 
 
X 
Pregnancy (all females) & FSH 
(postmenopausal females only)11 
X 
X 
 
 
 
 
 
X 
X 
X 
X 
Adverse Events/Serious Adverse Events 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 12 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-Lead ECG13 
X 
 
 
 
 
 
 
 
 
 
X 
Serum Chemistry, Hematology, and Urinalysis 14 
X 
X 
 
 
 
 
 
X 
X 
X 
X 
Hemolytic Panel15 
 
X 
X (as applicable) 
Coagulation Tests16 
X 
 
 
 
 
 
 
 
 
 
X 
rHuPH20 Immunogenicity: ADA and nADA 
Blood Collection  
 
 
X 
 
 
 
 
 
X 
X 
X 
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Visit/Assessment 
Screening Period 
Treatment Period 
Follow-up Period 
(EOS/ET) 
Study Week/Day 
Within 21 Days 
prior to dosing D-1 
W1 
W2 
W3 
W5 
W9 
W25  
(+/- 1 week) 6 
D1 
D2 
D4 
D6 
D8 
D15 ±2 D29 ±2 
D57 ±3 
PK Blood Sample Collection17 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
Immunogenicity Panel18 
 
 
X 
X (as applicable) 
Abbreviations: ADA=anti-drug antibody; BMI=body mass index; BP= blood pressure; BUN= blood urea nitrogen; CBC= complete blood count;  
CRU= Clinical Research Unit; D=Day; DL=dose level; ECG=electrocardiogram; EOS=end of study; ET=early termination; FSH=follicle stimulating hormone; 
Hb=Hemoglobin, Hct=Hematocrit; HBsAG=hepatitis B surface antigen; HBsAb= Hepatitis B surface Antibody;  HBcAb= hepatitis B core Antibody;   
HBV= hepatitis B virus; HCV=hepatitis C virus; HIV=human immunodeficiency virus; HR= heart rate; LDH= lactate dehydrogenase; MCH= Mean 
Corpuscular Hemoglobin; MCHC= Mean Corpuscular Hemoglobin Concentration; MCV= Mean Corpuscular Volume; nADA=neutralizing anti-drug antibody; 
PI= Principal Investigator;  PK=pharmacokinetic; RBC= red blood cell; RDW= Red Cell Distribution Width; RR= respiratory rate; TDL= Target dose level; 
UPCR= urine protein to creatinine ratio; W=week; WBC= white blood cells. 
1. 
Written consent must be obtained prior to performing any protocol specific procedure. 
2. 
Age, gender, ethnicity, and race. 
3. 
Medical History: includes any significant or relevant diseases, surgeries, or other medical events and medication/treatment history if applicable. 
4. 
Physical Examination: Full physical examination will be performed at screening and EOS/ET visit, and partial physical examination can be done at the 
rest of the visits to assess any new abnormalities or changes from baseline. 
Full physical examination will include general appearance, head and neck, eyes and ears, nose and throat, chest, lungs, heart, abdomen, extremities and 
joints, lymph nodes, skin, and neurological.  
Partial physical examination will include: general appearance, head and neck, assessment of injection sites, skin. Other organ systems will be assessed 
per PI’s judgment (Section 8.2.3.1). 
5. 
Height and BMI will be assessed at the first physical examination only.  
Weight: Body weight will be measured on the day of each dosing specified in Section 1.3.2. The dose should be recalculated if the body weight differs 
more than 10% from the previous dosing day body weight.  
6. 
Overnight stay at the CRU. Subjects will check in on D -1 and will stay for 2 overnights for the first visit (D-1 and D1). For rest of the visits subjects will 
be confined to the CRU for 24 hours from the start of the infusion. During confinement period, standard meals and snacks will be provided at appropriate 
times. Subjects must be well hydrated prior to drug administration.  
7. 
The TDL is 0.4 and 1.0 g/kg with rHuPH20 80U/g IgG for Study Parts 1 and 2, respectively. Each DL is calculated as the following: DL1=1/4 of TDL; 
DL2=1/2 of TDL; DL3 =3/4 of TDL; and DL4=TDL. See also footnote 5. 
8. 
Drug screen will include: opiates (includes morphine, heroin (diacetylmorphine), codeine, 6-acetylmorphine, dihydrocodeine, hydrocodone, thebaine, and, 
hydromorphone), amphetamines, barbiturates, benzodiazepines, cocaine, cannabinoids, phencyclidine. See Section 8.2.3.6.  
9. Infusion sites will be evaluated for any potential local or systemic effects such as infusion site (local) events (e.g. erythema, pain, oedema and leaking).  
Subjects will also be evaluated/observed for acute or delayed allergic reactions, change in vital signs, pyrexia, upper abdominal pain, nausea, vomiting, 
diarrhea, and/ or pain in extremities.  Please refer also to Section 9.7 and Table 8 in Section 8.2.4.2 for more information about infusion related AEs. 
Continued on next page 
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Clinical Study Protocol: TAK-771-1001 
 
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Continued 
10. Testing will be performed by the local laboratory at Screening, during the follow up period and at EOS/ET. Include HCV antibody, HBsAg, HBsAb, 
HBcAb and HIV 1/2 antibodies. Subjects who are HIV, HBsAg or HCV antibody positive at screening will not be enrolled.  
11. Pregnancy test will be done only in women of childbearing potential. Serum pregnancy test will be obtained at screening and subjects must have a 
negative serum pregnancy test (within 7 days prior to inclusion). For subsequent dosing days, a urine pregnancy test prior to dosing will be acceptable. 
Follicle stimulating hormone (FSH) levels may be done once at screening on menopausal or peri-menopausal women, or as judged by investigator 
12. Vital signs, RR, HR, BP and body temperature will be measured at screening. Only BP, HR and RR will be measured every 30 minutes from starting the 
infusion until the end of infusion, and every 1-2 hours after the infusion for 8 hours, at discharge and as needed per investigator’s judgment until 
discharged.  
13. ECGs (12-lead) will be collected at prespecified time points in the Section 1.3.2 and as clinically indicated. 
14. Hematology includes CBC (Hct, Hg, RBC, RDW, MCV, MCH, MCHC, platelets, WBC with absolute differential counts of neutrophils, lymphocytes, 
monocytes, eosinophils, and basophils). See Section 8.2.3.4.2. 
Serum Chemistry ALT, AST, ALP, K+, Na+, Cl-, Ca2+Mg2+, Bilirubin (total and direct)LDH, BUN, creatinine, uric acid, glucose, albumin, lipid profile. 
See Section 8.2.3.4.1. 
Urine Test. Urinalysis will include color, specific gravity, pH, protein, glucose, ketones, bilirubin, urobilinogen, blood, nitrite, leukocyte esterase. 
Dipstick urine test is acceptable. Microscopic analyses will be done if clinically indicated. If ≥ 2+ protein on urine dipstick, then collect spot urine 
sample to calculate UPCR or collect 24h urine. Tests will be performed at prespecified time points in the Section 1.3.2 and as clinically indicated. No 
need to repeat before first dose if screening test is done within 7 days. See Section 8.2.3.4.4.  
15. The hemolytic anemia panel will consist of Hgb, LDH, serum haptoglobin, plasma-free (unbound) Hgb, serum direct anti-globulin (direct Coombs) test 
(antibody elution to be performed if direct Coombs test is positive), reticulocyte count, as well as urine hemosiderin. The lab results obtained from the  
D-1 and will serve as the baseline values. In case of absence of D-1 result for any reason screening Hgb result serve as the baseline Hgb value. Hgb and 
LDH values can be taken from the hematology and clinical chemistry panels, if conducted on the same day as the hemolytic panel. For subsequent tests, if 
there is a reduction in Hgb of 1 g/dL or more compared to baseline Hgb, every effort is to be made to perform a hemolytic panel within 72 h; if it is not 
feasible to do so, the hemolytic panel must be performed as soon as possible, but at the next scheduled visit, at the latest. At any time during the study, an 
unscheduled hemolytic panel may be performed in the event of suspected hemolytic anemia Any LDH test result of 2× ULN or greater will trigger 
analysis of the sample for LDH isoenzymes (see Section 8.2.3.4.3).   
16. aPTT and INR: assessments will be performed at specified time points in the Section 1.3.2 and as clinically indicated. See Section 8.2.3.4.5. 
17. PK samples will be obtained at specified time points in the Section 1.3.2 and on the subsequent days approximately the same time as the start of Day 1 
dosing.  
18. The immunogenicity panel outlined in Section 8.2.4.2 will be collected at baseline (D1) and any time deemed necessary during the course of the study. 
Subjects who have (a) two consecutive anti-rHuPH20 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, rHuPH20 (see Table 8), or other concomitant medications, will 
be asked to return to the CRU as soon as possible to undergo an additional panel of immunogenicity testing outlined in Table 9. 
Note: Multiple activities scheduled on the same day or at the same time will be conducted in the following order, when applicable: ECG, vital signs, 
blood sampling and study drug administration. 
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1.3.3 Schedule of Study Procedures: Treatment Arms 3 and 6  
Visit/Assessment 
Screening Period 
Treatment Period 
Follow-up Period 
(EOS/ET) 
Study Week/Day 
Within 21 D 
prior to dosing D-1 
W1 
W2 
W3 
W5 
W9 
W25  
(+/- 1 week)6 
D1 
D2 
D4 
D6 
D8 
D15 ±2 D29 ±2 D57 ±3 
Informed Consent1 
X 
 
 
 
 
 
 
 
 
 
 
Demographics2 
X 
 
 
 
 
 
 
 
 
 
 
Visit at Clinical Site  
X 
X6 
X6 
X 
X 
X 
X 
X 
X6 
X6 
X 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
Medical History3 
X 
X 
 
 
 
 
 
 
 
 
 
Concomitant Medications 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
Physical Examination 4 
X 
X 
 
 
 
 
 
 
X 
X 
X 
Height & BMI Calculation (screening only), 
Weight Measurements5   
X 
X 
 
 
 
 
 
 
X 
X 
X 
Study Treatment Administration 7 
 
 
DL4 
 
 
 
 
 
DL4 
DL4 
 
Drugs of Abuse/Alcohol Screen8 
X 
X 
 
 
 
 
 
 
 
 
 
Infusion Site Evaluation 9 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
HIV, HBV, HCV10 
X 
 
 
 
 
 
 
 
 
 
X 
Pregnancy (all females) & FSH (postmenopausal 
females only)11 
X 
X 
 
 
 
 
 
 
X 
X 
X 
Adverse Events/Serious Adverse Events 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 12 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-Lead ECG13 
X 
 
 
 
 
 
 
 
 
 
X 
Serum Chemistry, Hematology, and Urinalysis 14 
X 
X 
 
 
 
 
 
X 
X 
X 
X 
Hemolytic Panel15 
 
X 
X (as applicable) 
Coagulation Tests16 
X 
 
 
 
 
 
 
 
 
 
X 
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Clinical Study Protocol: TAK-771-1001 
 
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Visit/Assessment 
Screening Period 
Treatment Period 
Follow-up Period 
(EOS/ET) 
Study Week/Day 
Within 21 D 
prior to dosing D-1 
W1 
W2 
W3 
W5 
W9 
W25  
(+/- 1 week)6 
D1 
D2 
D4 
D6 
D8 
D15 ±2 D29 ±2 D57 ±3 
rHuPH20 Immunogenicity: ADA and nADA 
Blood Collection  
 
 
X 
 
 
 
 
 
X 
X 
X 
PK Blood Sample Collection17 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Immunogenicity Panel18 
 
 
X 
X (as applicable) 
Abbreviations: ADA=anti-drug antibody; BMI=body mass index; BP= blood pressure; BUN= blood urea nitrogen; CBC= complete blood count;  
CRU= Clinical Research Unit; D=Day; DL=dose level; ECG=electrocardiogram; EOS=end of study; ET=early termination; FSH=follicle stimulating hormone; 
Hb=Hemoglobin, Hct=Hematocrit; HBsAG=hepatitis B surface antigen; HBsAb= Hepatitis B surface Antibody;  HBcAb= hepatitis B core Antibody;  
HBV= hepatitis B virus; HCV=hepatitis C virus; HIV=human immunodeficiency virus; HR= heart rate; LDH= lactate dehydrogenase; MCH= Mean 
Corpuscular Hemoglobin; MCHC= Mean Corpuscular Hemoglobin Concentration; MCV= Mean Corpuscular Volume; nADA=neutralizing anti-drug antibody; 
PI= Principal Investigator; PK=pharmacokinetic; RBC= red blood cell; RDW= Red Cell Distribution Width; RR= respiratory rate; TDL= Target dose level; 
UPCR= urine protein to creatinine ratio; W=week; WBC= white blood cells. 
1. 
Written consent must be obtained prior to performing any protocol specific procedure. 
2. 
Age, gender, ethnicity, and race. 
3. 
Medical History: includes any significant or relevant diseases, surgeries, or other medical events and medication/treatment history if applicable. 
4. 
Physical Examination: Full physical examination will be performed at screening and EOS/ET visit, and partial physical examination can be done at the 
rest of the visits to assess any new abnormalities or changes from baseline. 
Full physical examination will include general appearance, head and neck, eyes and ears, nose and throat, chest, lungs, heart, abdomen, extremities and 
joints, lymph nodes, skin, and neurological.  
Partial physical examination will include: general appearance, head and neck, assessment of injection sites, skin. Other organ systems will be assessed 
per PI’s judgment (Section 8.2.3.1). 
5. 
Height and BMI will be assessed at the first physical examination only.  
Weight: Body weight will be measured on the day of each dosing specified in Section 1.3.3.  The dose should be recalculated if the body weight differs 
more than 10% from the previous dosing day body weight.  
6. 
Overnight stay at the CRU. Subjects will check in on D -1 and will stay for 2 overnights for the first visit (D-1 and D1). For rest of the visits subjects will 
be confined to the CRU for 24 hours from the start of the infusion. During confinement period, standard meals and snacks will be provided at appropriate 
times. Subjects must be well hydrated prior to drug administration. 
7. 
The TDL is 0.4 and 1.0 g/kg with rHuPH20 80U/g IgG for Study Parts 1 and 2, respectively. Each DL is calculated as the following: DL1=1/4 of TDL; 
DL2=1/2 of TDL; DL3 =3/4 of TDL; and DL4=TDL. See also footnote 5. 
8. 
Drug screen will include: opiates (includes morphine, heroin (diacetylmorphine), codeine, 6-acetylmorphine, dihydrocodeine, hydrocodone, thebaine, and, 
hydromorphone), amphetamines, barbiturates, benzodiazepines, cocaine, cannabinoids, phencyclidine. See Section 8.2.3.6.  
Continued on next page 
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Clinical Study Protocol: TAK-771-1001 
 
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Continued 
9. 
Infusion sites will be evaluated for any potential local or systemic effects such as infusion site (local) events (e.g. erythema, pain, oedema and leaking). 
Subjects will also be evaluated/observed for acute or delayed allergic reactions, change in vital signs, pyrexia, upper abdominal pain, nausea, vomiting, 
diarrhea, and/ or pain in extremities. Please refer also to Section 9.7 and Table 8 in Section 8.2.4.2 for more information about infusion related AEs. 
10. Testing will be performed by the local laboratory at Screening, during the follow up period and at EOS/ET. Include HCV antibody, HBsAg, HBsAb, 
HBcAb and HIV 1/2 antibodies. Subjects who are HIV, HBsAg or HCV antibody positive at screening will not be enrolled.  
11. Pregnancy test will be done only in women of childbearing potential. Serum pregnancy test will be obtained at screening and subjects must have a 
negative serum pregnancy test (within 7 days prior to inclusion). For subsequent dosing days, a urine pregnancy test prior to dosing will be acceptable. 
Follicle stimulating hormone (FSH) levels may be done once at screening on menopausal or peri-menopausal women, or as judged by investigator 
12. Vital signs, RR, HR, BP and body temperature will be measured at screening. Only BP, HR and RR will be measured every 30 minutes from starting the 
infusion until the end of infusion, and every 1-2 hours after the infusion for 8 hours, at discharge and as needed per investigator’s judgment until 
discharged.  
13. ECGs (12-lead) will be collected at prespecified time points in the Section 1.3.3 and as clinically indicated. 
14. Hematology includes CBC (Hct, Hg, RBC, RDW, MCV, MCH, MCHC, platelets, WBC with absolute differential counts of neutrophils, lymphocytes, 
monocytes, eosinophils, and basophils). See Section 8.2.3.4.2. 
Serum Chemistry ALT, AST, ALP, K+, Na+, Cl-, Ca2+Mg2+, Bilirubin (total and direct), LDH, BUN, creatinine, uric acid, glucose, albumin, lipid 
profile. See Section 8.2.3.4.1. 
Urine Test. Urinalysis will include color, specific gravity, pH, protein, glucose, ketones, bilirubin, urobilinogen, blood, nitrite, leukocyte esterase. 
Dipstick urine test is acceptable. Microscopic analyses will be done if clinically indicated. If ≥ 2+ protein on urine dipstick, then collect spot urine 
sample to calculate UPCR or collect 24h urine. Tests will be performed at prespecified time points in the Section 1.3.3 and as clinically indicated. No 
need to repeat before first dose if screening test is done within 7 days. See Section 8.2.3.4.4.  
15. The hemolytic anemia panel will consist of Hgb, LDH, serum haptoglobin, plasma-free (unbound) Hgb, serum direct anti-globulin (direct Coombs) test 
(antibody elution to be performed if direct Coombs test is positive), reticulocyte count, as well as urine hemosiderin. The lab results obtained from the  
D-1 and will serve as the baseline values. In case of absence of D-1 result for any reason screening Hgb result serve as the baseline Hgb value. Hgb and 
LDH values can be taken from the hematology and clinical chemistry panels, if conducted on the same day as the hemolytic panel. For subsequent tests, if 
there is a reduction in Hgb of 1 g/dL or more compared to baseline Hgb, every effort is to be made to perform a hemolytic panel within 72 h; if it is not 
feasible to do so, the hemolytic panel must be performed as soon as possible, but at the next scheduled visit, at the latest. At any time during the study, an 
unscheduled hemolytic panel may be performed in the event of suspected hemolytic anemia. Any LDH test result of 2× ULN or greater will trigger 
analysis of the sample for LDH isoenzymes (see Section 8.2.3.4.3). 
16. aPTT and INR: assessments will be performed at specified time points in the Section 1.3.3 and as clinically indicated. See Section 8.2.3.4.5. 
17. PK samples will be obtained at specified time points in the Section 1.3.3 and on the subsequent days approximately the same time as the start of Day 1 
dosing.  
18. The immunogenicity panel outlined in Section 8.2.4.2 will be collected at baseline (D1) and any time deemed necessary during the course of the study. 
Subjects who have (a) two consecutive anti-rHuPH20 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, rHuPH20 (see Table 8), or other concomitant medications will 
be asked to return to the CRU as soon as possible to undergo an additional panel of immunogenicity testing outlined in Table 9). 
Note: Multiple activities scheduled on the same day or at the same time will be conducted in the following order, when applicable: ECG, vital signs, 
blood sampling and study drug administration. 
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2. BACKGROUND INFORMATION 
HYQVIA (also known as TAK-771) is an immune globulin infusion (IGI) (Human) 10% with a 
recombinant human hyaluronidase (rHuPH20) indicated for the treatment of Primary 
Immunodeficiency in adults. This includes, but is not limited to, common variable 
immunodeficiency, X-linked agammaglobulinemia, congenital agammaglobulinemia,  
Wiskott-Aldrich syndrome, and severe combined immunodeficiencies (Baxalta US Inc., 2019). 
HYQVIA is administered subcutaneously and has 2 components, Human IGI, 10% which 
provides the therapeutic effect, and rHuPH20 which enhances the absorption and dispersion of 
the volume when using a subcutaneous administration. 
The IGI, 10% (Human) of HYQVIA supplies a broad spectrum of opsonizing and neutralizing 
IgG antibodies against a wide variety of bacterial and viral agents. The IGI, 10% (Human) also 
contains a spectrum of antibodies capable of interacting with and altering the activity of cells of 
the immune system as well as antibodies capable of reacting with cells such as erythrocytes. The 
role of these antibodies and the mechanisms of action of IgG in the IGI, 10% (Human) of 
HYQVIA have not been fully elucidated (Baxalta US Inc., 2019). 
Hyaluronan is a polysaccharide found in the extracellular matrix of the connective tissue.  
It is depolymerized by naturally occurring enzymes in the hyaluronidase family. Unlike the 
stable structural components of the interstitial matrix, hyaluronan has a very fast turnover with 
a half-life of approximately 0.5 days. The rHuPH20 component of HYQVIA increases 
permeability of the subcutaneous tissue by temporarily depolymerizing hyaluronan.  
In the doses administered, rHuPH20 of HYQVIA acts locally. The effects of the hyaluronidase 
are reversible and permeability of the subcutaneous tissue is restored within 24 to 48 hours 
(Baxalta US Inc., 2019). 
HYQVIA has been approved for primary immune deficiency and is being studied in Study 
161403, a Phase 3 double blind randomized placebo-controlled study to evaluate the efficacy, 
and safety and tolerability of HYQVIA as a maintenance therapy for chronic inflammatory 
demyelinating polyradiculoneuropathy (CIDP). Majority of CIDP patient population are naïve to 
subcutaneous infusions, or inexperienced with subcutaneous infusions of large volumes (>60 mL 
per infusion site). There have been concerns for potential dropout in the Phase 3 study of CIDP 
due to intolerability of HYQVIA, and measures have been taken to improve tolerability and 
mitigate dropout, including infusing over multiple concurrent infusion sites (1-2) to allow 
smaller volume at each site, splitting the dose into divided doses to be given over more than 
1 day, and utilizing a dose ramp-up schedule which involves stepwise gradual increase until the 
subject’s full dose is reached, as well as an infusion rate ramp-up regimen that is in place and 
will not exceed 300 mL/hr/site. However, the safety and tolerability of HYQVIA without 
utilizing dose or infusion rate ramp-up has not been evaluated. 
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2.1 Indications for HYQVIA/HyQvia  
IGI, 10% with rHuPH20 is licensed as HyQvia® in the EU (as of May 2013) and as HYQVIA® 
in the US (as of Sep 2014). Licensed indications vary by country/region. Indications may include 
replacement therapy in adults for primary immunodeficiency disease (PIDD) (in EU and US) and 
replacement therapy in patients with multiple myeloma, chronic lymphocytic leukaemia with 
severe secondary hypogammaglobulinaemia and recurrent infections, and 
hypogammaglobulinaemia in patients pre- or post-allogenic hematopoietic stem cell 
transplantation (HSCT) (in EU). 
2.2 Product Background 
2.2.1 Preclinical Information 
Findings from nonclinical studies for HYQVIA are detailed in the investigator’s brochure (IB) 
for IGI, 10% with rHuPH20. 
Development and reproductive toxicology studies have been conducted with recombinant human 
hyaluronidase in mice and rabbits. No adverse effects on pregnancy were associated with anti-
rHuPH20 antibodies (Baxalta US Inc., 2019). 
An in vitro mutagenicity test was performed for IGI, 10% (Human) and there was no 
evidence of mutagenicity observed. No long-term carcinogenicity tests were performed  
(Baxalta US Inc., 2019). 
2.2.2 Clinical Information 
The clinical development program for HYQVIA/HyQvia has demonstrated that IGI, 10% 
administered via SC treatment with rHuPH20 is safe in healthy subjects and patient populations, 
which are detailed in the IB for IGI, 10% with rHuPH20. 
Common adverse reactions observed in clinical trials in >5% of subjects were: local infusion site 
reactions, headache, antibody formation against rHuPH20, fatigue, nausea, pyrexia, and vomiting 
(Baxalta US Inc., 2019). 
Study 160603 compared the efficacy, PK, safety and tolerability of IGIV, 10% and IGI, 10% 
administered subcutaneously following rHuPH20 solution. Study 160902, an extension to 
study 160603, assessed the long-term tolerability and safety of IGI, 10% following 
administration of rHuPH20 solution. Eighteen percent (15 of 83) of subjects of patients with 
PID receiving IGI, 10% with rHuPH20 in Baxter Study 160603 and Study 160902 developed 
non-neutralizing antibodies to rHuPH20. The clinical significance of these antibodies is not 
known. The clinical data from Study 160603 and Study 160902 have shown no temporal 
association between ARs and the presence of anti-rHuPH20 antibodies, and there was no 
increase in incidence or severity of ARs in subjects who developed anti-rHuPH20 antibodies.  
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In all subjects, antibody titers decreased despite continued treatment. There is a theoretical 
potential risk for such antibodies to cross-react with human hyaluronidase which is known to be 
expressed in the adult male testes, epididymis, and sperm. It is unknown whether these 
antibodies may interfere with fertilization and fetal development in humans. Treatment-emergent 
antibodies against rHuPH20 (binding and neutralizing antibodies) will be monitored during this 
clinical study (See Section 8.2.4.2 for details). 
No clinical studies have been conducted with HYQVIA in pregnant women. HYQVIA should 
not be used by women who are pregnant or are planning to become pregnant and an alternate 
treatment should be considered. It is recommended that women of childbearing potential take 
appropriate measures to prevent pregnancy during HYQVIA treatment (see Section 5.3.1 for a 
list of highly effective contraceptive measures). If a woman becomes pregnant, treatment with 
HYQVIA should be stopped. 
IGI, 10%, the therapeutically active component of HYQVIA/HyQvia, is identical to that in 
GAMMAGARD LIQUID/KIOVIG. IGI, 10% administered via IV treatment (GAMMAGARD 
LIQUID/KIOVIG) is efficacious and safe in the particular fields of therapeutic use and approved 
indications, i.e., PID, ITP and MMN, as demonstrated in the clinical development program for 
GAMMAGARD LIQUID/KIOVIG. Please see the IB for Immune Globulin Infusion (Human), 
10% Solution (IGI, 10%) for further information, as well as the Prescribing Information for 
GAMMAGARD LIQUID and the SmPC for KIOVIG. 
Serious ARs (defined as SAEs occurring during or within 72 hours (h) of infusion or any 
casually related SAE occurring within the study period) which occurred in the clinical trials of 
GAMMAGARD LIQUID/KIOVIG were aseptic meningitis, pulmonary embolism, and blurred 
vision. The most common ARs observed in ≥5% of patients were: 
• 
PID, IV administration: headache, fatigue, pyrexia, nausea, chills, rigors, pain in extremity, 
diarrhea, migraine, dizziness, vomiting, cough, urticaria, asthma, laryngeal pain, rash, 
arthralgia, myalgia, oedema peripheral, pruritus, and cardiac murmur. 
• 
PID, SC administration: infusion site (local) event, headache, fatigue, heart rate increased, 
pyrexia, abdominal pain upper, nausea, vomiting, asthma, blood pressure systolic 
increased, diarrhea, ear pain, aphthous stomatitis, migraine, oropharyngeal pain, and pain 
in extremity. 
• 
MMN, IV administration: headache, chest discomfort, muscle spasms, muscular weakness, 
nausea, oropharyngeal pain, and pain in extremity. 
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Rare but serious events may occur with IGI products, including hypersensitivity, thrombosis, 
renal dysfunction/failure, hyperproteinemia, increased serum viscosity, and hyponatremia 
hemolysis, hemolysis, transfusion related acute lung injury (TRALI), and aseptic meningitis 
syndrome. 
Thrombosis may occur following treatment with immune globulin products, including HYQVIA. 
Risk factors may include advanced age, prolonged immobilization, hypercoagulable conditions, 
history of venous or arterial thrombosis, use of estrogens, indwelling central vascular catheters, 
hyperviscosity, and cardiovascular risk factors. Thrombosis may occur in the absence of known 
risk factors (Baxalta US Inc., 2019). 
IgG products, including HYQVIA, contain blood group antibodies which may act as hemolysins 
and induce in vivo coating of red blood cells (RBC) with IgG. These antibodies may cause a 
positive direct antiglobulin reaction and hemolysis. Acute intravascular hemolysis has been 
reported following intravenously administered IgG, including IGI, 10% (Human), and delayed 
hemolytic anemia can develop due to enhanced RBC sequestration (Baxalta US Inc., 2019). 
In patients who are at risk of developing renal dysfunction because of pre-existing renal 
insufficiency or predisposition to acute renal failure (such as diabetes mellitus, age greater 
than 65, volume depletion, sepsis, paraproteinemia, or patients receiving known nephrotoxic 
drugs), renal function should be monitored and lower, more frequent dosing can be considered 
(Baxalta US Inc., 2019). 
Periodic monitoring of renal function and urine output is particularly important in patients 
judged to be at increased risk for developing acute renal failure. Assess renal function, including 
measurement of blood urea nitrogen and serum creatinine, before the initial infusion of HYQVIA 
and again at appropriate intervals thereafter. If renal function deteriorates, consider 
discontinuation of HYQVIA (Baxalta US Inc., 2019). 
Always refer to the latest version of the IB for HYQVIA for the overall risk/benefit assessment 
and the most accurate and current information regarding the metabolism, pharmacokinetics, 
efficacy, and safety of HYQVIA. 
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2.3 Risk/Benefit and Ethical Assessment 
There will be no direct health benefit for healthy participants in this study from receipt of 
HYQVIA. An indirect health benefit to the subjects enrolled in this study is the free medical tests 
received at screening and during the study. 
The risks associated with dosing HYQVIA are anticipated to be similar to those previously 
documented in the product label for HYQVIA, please refer to the safety information in 
Section 2.2.2 as the dose provided in the study are within the dosing recommendation of the 
product label (Baxalta US Inc., 2019). The risk of HYQVIA in healthy subjects in this study is 
anticipated to be similar to those previously reported studies found in the HYQVIA IB 
(IB 2019). 
The inclusion and exclusion criteria, screening, and safety monitoring practices employed in this 
protocol (i.e., 12-lead ECG, vital signs, clinical laboratory tests, AE monitoring, and physical 
examination) are adequate to protect the subject’s safety. 
2.4 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), 
Title 21 of the US Code of Federal Regulations (US CFR), the EU Directives (2001/20/EC; 
2005/28/EC), and applicable national and local regulatory requirements. 
The responsibilities of the study sponsor and investigator(s) are described fully in Section 11 and 
Section 13. 
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3. STUDY RATIONALE, OBJECTIVES AND ENDPOINTS 
3.1 Rationale for the Study 
Dose ramp up has been considered necessary for HYQVIA in the Phase 3 Study (Study 161403) 
because the majority of CIDP patient population are naïve to subcutaneous (SC) infusions, or 
inexperienced with SC infusions at large volumes (>60 mL per infusion site; infusion volume 
maximum per day: up to 600 mL (1 site) or 1200 mL (2 sites)). As a result, a dose ramp-up 
schedule was included in Study 161403 which involves a stepwise gradual increase until the 
subject’s full dose is reached to improve tolerability. Dose ramp-up is currently in the approved 
prescribing information for primary immune deficiency. Despite the current use of ramp up 
dosing in PID and CIDP patients, the tolerability and safety of HYQVIA without ramp-up has 
not been evaluated in clinical settings. This Phase 1 study is planned to assess the tolerability, 
safety and immunogenicity profile of HYQVIA with and without ramp-up dosing in healthy 
adult subjects and to characterize the PK of total IgG and IgG subclasses in serum after SC 
administration of HYQVIA in healthy adult subjects. 
3.2 Study Objectives 
3.2.1 Primary Objectives 
To assess the tolerability of HYQVIA with and without ramp-up dosing in healthy adult subjects. 
3.2.2 Secondary Objectives 
• 
To assess the safety and immunogenicity of HYQVIA with and without ramp-up dosing in 
healthy adult subject 
• 
To characterize the pharmacokinetics (PK) of total IgG and IgG subclasses in serum after 
subcutaneous administration of HYQVIA in healthy adult subjects.  
 
3.3 Study Endpoints 
3.3.1 Primary Endpoints 
The primary endpoint corresponding to the primary objective of the study is the occurrence of 
tolerability events related to the infusion of HYQVIA. 
Definition: An infusion is considered tolerable if the infusion rate was not reduced, or the 
infusion was not interrupted or stopped, due to HYQVIA infusion. 
A tolerability event is considered to have occurred if an infusion was tolerable. Tolerability 
events will be measured in terms of the number and percentage of subjects for which the infusion 
was tolerable). 
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3.3.2 Secondary Endpoints  
3.3.2.1 Safety and Immunogenicity Endpoints  
• 
Occurrence of TEAEs, including but not limited to: HYQVIA-related and non-related *, 
serious, nonserious, severe, local and systemic TEAEs, TEAEs leading to premature 
discontinuation from study, and infusion-associated TEAEs, as well as number and 
percentage of subjects and infusions with suspected adverse reactions plus adverse 
reactions of interest (additional information is provided in Section 10.10). 
*Any TEAE that is recorded by the investigator as “possibly related” or “probably related” 
to HYQVIA will be considered HYQVIA-related AE, and any AE recorded as “unlikely 
related” or “not related” (defined in Section 9.1.2.2) will be considered unrelated AE. 
• 
Clinical laboratory parameters  
• 
Vital signs  
• 
Immunogenicity: occurrence of binding and neutralizing antibodies to rHuPH20  
Note that clinically significant treatment-emergent changes in clinical laboratory measurements 
and vital signs will be recorded in the study database as TEAEs. 
3.3.2.2 PK Endpoints 
• 
PK parameters for serum total IgG and IgG subclasses after a single dose of HYQVIA 
(i.e. after Week 1 dosing), including but are not limited to Cmax, Tmax, AUClast, t1/2, CL/F 
and Vz/F. 
 
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4. STUDY DESIGN 
4.1 Study Design  
This study is a Phase 1, open-label, randomized, single-center study to evaluate the tolerability, 
safety and immunogenicity of HYQVIA with and without ramp-up dosing and to characterize 
the PK of total IgG and IgG subclasses in serum after SC administration of HYQVIA in healthy 
adult subjects. 
Section 1.2 provides a schematic of the study design. 
Study Parts: 
This study is comprised of two parts, Study Parts 1 & 2.  The target dose level (TDL) of either 
0.4g/kg (Part 1) or 1.0 g/kg (Part 2) will be achieved through dose ramp-up or no ramp up 
(i.e. direct administration of the TDL).  Each study part consists of three Treatment Arms  
(Part 1: Treatment Arms 1-3 and Part 2: Treatment Arms 4-6): 
• 
Treatment Arms 1 and 4 will follow ramp up Schedule-A (Sch-A), in which subjects will 
receive HYQVIA from ¼ of the TDL at Week 1 to the full TDL at Week 8.  
• 
Treatments Arms 2 and 5 will follow ramp up Schedule-B (Sch-B), in which subjects will 
receive HYQVIA from ½ of the TDL at Week 1 to the full TDL at Week 5. 
• 
Treatment Arms 3 and 6 will follow ramp up Schedule-C (Sch-C), in which subjects will 
directly receive the full TDL at Week 1 without ramp-up dosing.  
 
Each subject meeting all eligibility criteria will be randomized to 1 of the 3 treatment arms in 
each Study Part. Additional information regarding randomization is provided in Section 8.1.2. 
Subjects meeting all eligibility criteria will be assigned to the 3 treatment arms in each Study 
Part at a randomization ratio of 1:1:1, and a minimum of 3 subjects in each of the 2 BMI groups 
(18 to <25 kg/m2,  >25 to 30 kg/m2) in each treatment arm, achievable using stratified 
randomization (BMI as the stratification factor). 
After all subjects in Treatment Arms 1-3 have completed Week 9 treatment in Study Part 1, and 
their tolerability, safety and immunogenicity data through Week 9 have been reviewed by a 
safety review team consisting of the Investigator, the Sponsor’s Medical Monitor, and the 
Sponsor’s Global Drug Safety Physician.  Proceeding to Study Part 2 dosing may only occur 
following this review. 
Treatment arms will be initiated in parallel in each study part. Each subject will participate in 
only one treatment arm. 
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The planned dose levels including ramp-up dose levels of IGI, 10% to be evaluated are outlined 
in Table 1. 
Table 1. Planned Dose Levels 
DL 
Fraction of TDL 
Part 1 (g/kg) 
Part 2 (g/kg) 
DL1 
1/4 of TDL 
0.1 
0.25 
DL2 
1/2 of TDL 
0.2 
0.5 
DL3 
3/4 of TDL 
0.3 
0.75 
DL4 
TDL 
0.4 
1.0 
 
Study Periods 
The study consists of 3 periods: 
• 
Screening period: up to 21 days prior to first dosing. 
• 
Study treatment period: 8 weeks for Treatment Arms 1 and 4; 9 weeks for Treatment 
Arms 2, 3, 5, and 6. 
• 
Follow up period: 16 (± 1) weeks after receiving the last infusion of HYQVIA with 
the end of study (EOS/ET) being in Weeks 24 (± 1) (Treatment arms 1 and 4) or 
25 (± 1) (Treatment arms 2, 3, 5, and 6). 
 
All subjects who received at least one dose of HYQVIA (including subjects who terminate the 
study early) will return to the Clinical Research Unit (CRU) 16 (± 1) weeks after the last infusion 
of HYQVIA for follow-up procedures. 
Tolerability, safety and immunogenicity will be assessed throughout the study treatment period 
for all treatment arms. 
The PK of total IgG and IgG subclasses in serum will be characterized based on their serum 
concentration-time profiles post the first infusion (i.e. Week 1 dosing). 
All subjects will be monitored for the formation of binding anti-rHuPH20 antibodies (binding 
ADA). Samples with antibody titers ≥1:160 (ADA positive) will be analyzed for the presence 
of neutralizing antibodies. At any time during the course, subjects who have (a) 2 consecutive 
anti-rHuPH20 antibody titers of ≥1:160 that are elevated from the subject’s baseline titers, and 
(b) a moderate or severe AE that may be a result of immune-mediated response to either 
immunoglobulin, rHuPH20, or other concomitant medications will be asked to return to the 
CRU as soon as possible to undergo an additional panel of immunogenicity testing. 
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After the EOS visit has been completed, no further visits are planned, unless determined 
necessary by the investigator. Positive binding antibody titers associated with serious or severe 
AEs may require additional follow-up assessments. 
4.2 Duration and Study Completion Definition 
The approximate overall duration of the study is 27 to 28 weeks from screening to EOS. 
The study completion date is defined as the date on which the last subject in the study completes 
the final protocol-defined assessment(s). Please note that this includes the follow-up visit or 
contact, whichever is later (refer to Section 8.1.4 for the defined follow-up period for this 
protocol). 
4.3 Study Continuation from Study Part 1 to Study Part 2  
After all study subjects in Study Part 1 complete the treatment period (Week 9), a safety data 
review of the data collected through Week 9 for all subjects in Study Part 1 (including but not 
limited to AEs, vital signs, clinical laboratory data) will be conducted. This safety data review 
will be conducted by a safety review team consisting of the Investigator, the Sponsor's Medical 
Monitor, and the Sponsor’s Global Drug Safety Physician before the first dosing in Study Part 2 
is initiated. Ad hoc study team members may be included in the safety data review as needed. 
This safety data review will be based on unmonitored and unverified data at the time that the 
review takes place. 
Safety data listing (including AEs, vital signs, and clinical laboratory data) from Study Part 1 
will be prepared by the designated CRO. Proceeding to Study Part 2 may only occur following a 
review of the safety data. The safety review team consisting of the investigator, the Sponsor’s 
Medical Monitor and the Sponsor’s Global Drug Safety Physician may consider potential 
changes in Study Part 2 based on the overall tolerability and safety data from Study Part 1. 
The changes to Study Part 2 may include, but are not limited to:  
• 
Administration of an intermediate dose between the current dose for Study Part 1 and the 
planned dose for Study Part 2. 
• 
Not proceeding to Study Part 2 and terminating the study. 
 
All data provided for the safety review meeting will be based on unmonitored/unverified data. 
The decision from the safety review meeting will be documented to include, at a minimum: 
• 
A list of meeting participants 
• 
A summary of the data considered during the meeting 
• 
A summary of the decision, including any concerns which were raised 
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• 
The final decision, stating that the decision is agreed by the Investigator, the Sponsor’s 
Medical Monitor(s) and the Sponsor’s Global Drug Safety Physician. 
 
The final decision to proceed to Study Part 2 must be confirmed in writing (scanned copy or fax 
is acceptable) by the Sponsor’s Medical Monitor prior to dosing any subjects in Study Part 2. 
In the absence of the Investigator, the decision to proceed to Study Part 2 may be delegated in 
writing to a medically qualified Sub-investigator, on the provision that this delegation is in 
agreement with the Sponsor. 
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5. STUDY POPULATION 
The subject will not be considered eligible for the study without meeting all of the criteria below. 
Subjects cannot be randomized or enrolled before all inclusion and exclusion criteria (including 
laboratory test results) are within acceptable ranges as per protocol. 
5.1 Inclusion Criteria 
1. An understanding, ability, and willingness to fully comply with study procedures and 
restrictions. 
2. Ability to voluntarily provide written, signed, and dated (personally or via a legally 
authorized representative) informed consent to participate in the study. 
3. Age 19-50 years inclusive at the time of consent. The date of signature of the informed 
consent is defined as the beginning of the screening period. This inclusion criterion will 
only be assessed at the first screening visit. 
4. Male, or non-pregnant, non-breastfeeding female who agrees to comply with any 
applicable contraceptive requirements of the protocol, or females of non-childbearing 
potential. 
5. Must be considered “healthy”. Healthy as determined by the investigator on the basis of 
screening evaluations and healthy status is defined by absence of evidence of any active or 
chronic disease following a detailed medical and surgical history, a complete physical 
examination including vital signs, 12-lead ECG, hematology, blood chemistry, and 
urinalysis. 
6. Body mass index (BMI) between 18.0 and 30.0 kg/m² inclusive. 
 
5.2 Exclusion Criteria 
1. Any current or relevant history of medical (e.g. any hematological, hepatic, respiratory, 
cardiovascular, renal or neurological) or psychiatric conditions, which by judgment of the 
investigator might compromise the safety of the subject or integrity of the study, interfere 
with the subject’s participations in the trial and compromise the trial objectives or any 
condition that presents undue risk from the investigational product or procedures. 
Note: Subjects on stable dose of hormone replacements (i.e. thyroid hormone replacement) 
or oral contraceptives are permitted. 
2. Clinically significant cardiac conditions including but not limited to uncontrolled 
hypertension, myocardial infarction, unstable coronary artery disease and clinically 
significant arrythmias and conduction disorders. 
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3. Known or suspected intolerance or hypersensitivity to the investigational product(s), 
closely related compounds, or any of the stated ingredients (e.g. human IG, hyaluronidase, 
albumin). 
4. Known history of hypersensitivity or severe allergic reactions (e.g. urticaria, breathing 
difficulty, severe hypotension, or anaphylaxis) following administration of blood or blood 
components. 
5. Significant illness, as judged by the investigator, within 30 days of the first dose of 
investigational product. 
6. Known history of alcohol or other substance abuse within the last year. 
7. Donation of blood within 60 days, or blood products (e.g., plasma or platelets) within 
2 weeks prior receiving the first dose of investigational product. 
8. Subjects will be excluded if any of the following laboratory parameters meet the criteria 
below: 
• 
Hemoglobin < 11 g/dL 
• 
Absolute neutrophil count ≤1500/mm3 and platelet count ≤100,000/mm3 
• 
Liver function: alanine aminotransferase (ALT) ≥2.5 × upper limit normal (ULN), 
aspartate aminotransferase (AST) ≥2.5 × upper limit normal (ULN), alkaline 
phosphatase ≥1.5 × ULN or total bilirubin ≥1.5 mg/dL 
• 
Renal function: creatinine clearance ≤60 mL/min based on Cockcroft-Gault equation 
• 
Coagulation tests: aPTT >1.2 X ULN; INR >1.2 
Subjects will be excluded if any other laboratory values are outside the reference range 
and are clinically significant per investigator’s judgment. 
9. Within 30 days prior to the first dose of investigational product: 
• 
Has participated in another clinical study involving immunoglobulin products within 
12 months of screening. 
• 
Have used an investigational product (or 5 half-lives, whichever is longer). 
• 
Have been enrolled in a clinical study (including vaccine studies or has been 
vaccinated with approved product) that, in the investigator’s opinion, may impact this 
study. Subjects who received any vaccine (including live attenuated vaccines) in the 
30 days before dosing will be excluded. No live attenuated virus vaccines are allowed 
during in the study until the end of the follow up period. 
• 
Have had any substantial changes in eating habits, as assessed by the investigator. 
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10. Confirmed systolic blood pressure >139 mmHg or <89 mmHg and diastolic blood pressure 
>89 mmHg or <49 mmHg. 
11. A positive screen for alcohol or drugs of abuse at screening. 
12. A positive HIV HCV, or ongoing/active hepatitis B infection at screening. Subjects with 
immunity to hepatitis B from either active vaccination or from previous natural infection 
are eligible to participate in the study. 
13. Smoking more than 5 cigarettes or equivalent per day, unable to stop smoking during 
confinement in the CRU. 
14. Severe dermatitis or anatomical abnormality that would interfere with HYQVIA 
administration or endpoint assessments. Note: the skin at the administration site should not 
be covered by tattoos. 
15. Current use of any herbal, or homeopathic preparations are not permitted.   
16. Unable or unwilling to discontinue antihistamines or medications with antihistamine 
properties, sedatives, anxiolytics, systemic steroids, or topical steroids or antibiotics on any 
area below the chest for a minimum of 48 hours prior to each infusion visit and through 
72 hours post last infusion. 
17. Current or relevant history of hypercoagulable conditions (e.g. Protein C, Protein S, and 
antithrombin III deficiency), thrombotic/thromboembolic events or venous thrombosis. 
 
5.3 Reproductive Potential 
No clinical studies have been conducted with GAMMAGARD LIQUID/KIOVIG or HYQVIA in 
pregnant women. 
Animal reproduction studies have not been conducted with GAMMAGARD LIQUID/KIOVIG 
(IGI, 10%) and IGI, 10% component of HYQVIA. It is also not known whether IGI, 10% can 
cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. 
However, clinical experience with immunoglobulins suggests that no harmful effects of 
IGI, 10% on fertility are to be expected. 
Development and reproductive toxicology studies have been conducted with recombinant human 
hyaluronidase in mice and rabbits. No adverse effects on pregnancy were associated with anti-
rHuPH20 antibodies. In these studies, maternal antibodies to recombinant human hyaluronidase 
were transferred to offspring in utero. The effects of antibodies to the rHuPH20 component of 
HYQVIA on the human embryo or on human fetal development are unknown. 
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5.3.1 Female Contraception 
Sexually active females of child-bearing potential should be using an acceptable form of 
contraception. Females of child-bearing potential must be advised to use acceptable 
contraceptives throughout the study period and for 90 days following the last dose of IP. If 
hormonal contraceptives are used, they should be administered according to the package insert. 
Females of child-bearing potential who are not currently sexually active must agree to use 
acceptable contraception, as defined below, if they become sexually active during the period of 
the study and 90 days following the last dose of IP. 
Female subjects should be either: 
1. Postmenopausal (12 consecutive months of spontaneous amenorrhea and ≥age 51 years) 
2. 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 
3. Of child-bearing potential with a negative urine and/or serum β-hCG pregnancy test at 
screening and prior to randomization. Females of child-bearing potential must agree to 
abstain from sexual activity that could result in pregnancy or agree to use acceptable 
methods of contraception listed below: 
i. 
Combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation: 
• 
oral 
• 
intravaginal 
• 
transdermal 
ii. 
Progestogen-only hormonal contraception associated with inhibition of ovulation: 
• 
oral 
• 
injectable 
• 
implantable* 
iii. 
Intrauterine device (IUD)* 
• 
Intrauterine hormone-releasing system (IUS) * 
• 
Bilateral tubal occlusion* 
• 
Vasectomised partner(s) * 
• 
Sexual abstinence during the entire study period 
* Contraception methods that are considered to have low user dependency. 
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Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus 
interruptus), spermicides only, and lactational amenorrhoea method (LAM) are not acceptable 
methods of contraception. Female condom and male condom should not be used together. 
5.3.2 Male Contraception 
From signing of informed consent, throughout the duration of the study, and for 90 days after last 
dose of HYQVIA, nonsterilized male subjects who are sexually active with a female partner of 
childbearing potential must use barrier contraception (e.g., condom with or without spermicidal 
cream or jelly). In addition, they must be advised not to donate sperm during this period. 
5.4 Discontinuation of Study and Subjects 
5.4.1 Stopping Criteria for Individual Subjects  
Individual subjects may be discontinued from study if any of the following criteria are met: 
• 
Subject experiences: 
 thrombotic/thromboembolic event 
 acute intravascular hemolysis 
 anaphylactic / anaphylactoid reaction 
 acute renal failure 
 aseptic meningitis or  
 any HYQVIA-related toxicity deemed to pose an unacceptable risk to the subject, as 
determined by the study investigator. 
• 
If there is a persistent HYQVIA-related AE that does not recover to baseline within 
30 days, unless otherwise agreed by medical monitor and the study investigator, based on 
the type and severity of AE. 
• 
Any other AE, laboratory abnormality, or intercurrent illness, which in the opinion of the 
study investigator presents a substantial clinical risk to the subject, with continued dosing 
with the investigational drug (IP). 
 
5.4.2 Subject Withdrawal Criteria 
The participation in this trial is completely voluntary. Subjects are free to withdraw anytime 
from the study by informing the investigator. If a subject, for whatever reason is no longer 
appropriate to continue receiving study drug, they will be notified and withdrawn from the study. 
Prior to removal from the study all efforts must be made to have all subjects’ complete safety 
assessment as completely as possible, as defined in Section 1.3 for early termination. 
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The reason for discontinuation, date of discontinuation of the IP, and the total amount of IP 
administered must be recorded in the source documents and the case report form (CRF). 
Comments (spontaneous or elicited) or complaints made by the subject must be recorded in the 
source documents.  If a subject discontinued for more than 1 reason, each reason should be 
documented in the source document and the most clinically relevant reason should be indicated. 
Reasons for discontinuation include but are not limited to: 
• 
Completion of the protocol 
• 
Protocol violation 
• 
Voluntary withdrawal: the subject wishes to withdraw from the study.  
Note: All attempts should be made to determine the underlying reason for the withdrawal 
 
and, where possible, the primary underlying reason should be recorded (i.e., 
 
withdrawal due to an AE should not be recorded in the “voluntary withdrawal” 
 
category). 
• 
Study termination: the sponsor, IRB, IEC, or regulatory agency terminates the study. 
• 
Screen failure 
• 
investigator’s discretion  
• 
Lost to follow-up. 
• 
A positive pregnancy test for females. 
• 
Adverse event 
• 
Other 
 
Subjects who withdraw or are discontinued early may be replaced at the discretion of the 
Sponsor. Replacement of discontinued or withdrawn subjects due to any reason will be assessed 
on a case by case basis. 
For subjects “Lost to Follow-up” Prior to Last Scheduled Visit, a minimum of 3 documented 
attempts must be made to contact any subject lost to follow-up at any time point prior to the last 
scheduled contact (office visit or telephone contact). At least 1 of these documented attempts 
must include a written communication sent to the subject’s last known address via courier or 
mail (with an acknowledgement of receipt request) asking that they return to the site for final 
safety evaluations. 
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5.4.3 Criteria for Premature Termination or Suspension of the Study 
The sponsor reserves the right to terminate this study at any time. The study will be completed as 
planned unless one or more of the following criteria are satisfied that require temporary 
suspension or early termination of the study: 
• 
The safety data review team (the Investigator, the Sponsor’s Medical Monitor, and the 
Sponsor’s Global Drug Safety Physician) recommends discontinuation of the study based 
on review of the data as described in Section 4.3. 
• 
New information or other evaluation regarding the safety or efficacy of the IP that 
indicates a change in the known risk/benefit profile of this product and the risk is no longer 
acceptable for subjects participating in the study. 
• 
Significant violation of Good Clinical Practice (GCP) that compromises the ability to 
achieve the primary study objectives or compromises subject's safety. 
 
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6. PRIOR AND CONCOMITANT TREATMENT 
6.1 Prior Treatment 
Prior treatment includes all treatment (including but not limited to herbal treatments) received 
within 60 days from the date of first dose of IP. Prior treatment information must be recorded on 
the appropriate CRF page. 
6.2 Concomitant Treatment  
Concomitant treatment refers to all treatment taken between the dates of the first dose of IP and 
the end of the follow-up period, inclusive. Concomitant treatment information must be recorded 
on the appropriate CRF page. 
6.2.1 Permitted Treatment 
Subjects should refrain from taking any medications (excluding those medications listed below) 
during the course of the study. Any medication which is considered necessary for the subject’s 
safety and well-being may be given at the discretion of the investigator. The administration of all 
medications (including IPs) must be listed on the appropriate CRF page. 
Medications permitted during the study are listed below: 
• 
Hormonal contraceptives for females of childbearing potential administered according to 
the package insert. 
• 
Hormone replacement therapy 
• 
Over the counter (OTC) medications (e.g. NSAIDs, Tylenol, vitamins) if needed per 
discretion of investigator. 
 
6.2.2 Prohibited Treatment 
No concomitant medications or treatments allowed except those mentioned in Section 6.2.1 or 
necessary for SAE or AE treatments as SOC. 
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7. INVESTIGATIONAL PRODUCT 
7.1 Identity of Investigational Product 
Subcutaneous Immune Globulin Infusion 10% (Human) (IGI, 10%) with Recombinant Human 
Hyaluronidase (rHuPH20) (also referred to as IGI, 10% with rHuPH20, or HYQVIA). IGI, 10% 
(Human) will be supplied in 5 g/50 mL and 20 g/200mL vials with rHuPH20 160U/mL supplied 
separately in 15 mL vials. 
The IGI, 10% (Human) is a ready-for-use, sterile, liquid preparation of highly purified and 
concentrated IgG antibodies. The distribution of the IgG subclasses is similar to that of normal 
plasma. The fragment crystallizable region (Fc) and the antigen-binding fragment (Fab) 
functions are maintained in the primary component. Pre-kallikrein activator activity is not 
detectable. The IGI, 10% (Human) contains 100 mg/mL protein. At least 98% of the protein is 
IgG, average immunoglobulin A (IgA) concentration is low (not more than 140 ug/mL), and 
immunoglobulin M (IgM) is present in trace amounts. The IGI, 10% (Human) contains a broad 
spectrum of IgG antibodies against bacterial and viral agents. Glycine (0.25 M) serves as a 
stabilizing and buffering agent. There is no added sugar, sodium, or preservatives. The pH is 
4.6 to 5.1. The osmolality is 240 to 300 mOsmol/kg. The IGI, 10% (Human) is manufactured 
from large pools of human plasma. IgG preparations are purified from plasma pools using a 
modified Cohn Oncley cold ethanol fractionation process, as well as cation and anion exchange 
chromatography. 
7.1.1 Blinding the Treatment Assignment 
Not applicable. 
7.2 Administration of Investigational Product(s) 
Prior to receiving the first dose of HYQVIA, subjects are to be randomized to a treatment arm as 
shown in Section 1.3 and Section 1.2. 
Subjects will receive IGI, 10% either from a partial TDL dose to a full TDL dose with a ramp-up 
dosing scheme or directly at the full TDL dose without ramp-up. The TDLs are 0.4 g/kg and 
1.0 g/kg for Study Part 1 and Study Part 2, respectively.  Each study part consists of three 
treatment arms with different ramp up schedules. 
rHuPH20 is administered prior to the infusion of IGI, 10%.  The dose for rHuPH20 is 80 U/g IG. 
Please refer to the infusion manual/pharmacy manual for detailed instructions on the 
administration of the investigational product.  
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7.2.1 Allocation of Subjects to Treatment 
Subjects who complete the study screening assessments and meet all the eligibility criteria will 
be assigned a unique randomization identification number at the time of the first dosing, different 
from the screening number, and will receive the corresponding HYQVIA dose, according to a 
randomization scheme.  
Each subject will participate in only one Study part and will receive only one of the three 
treatment arms: Treatment Arms 1, 2, or 3 (Part 1) or Treatment Arms 4, 5, or 6 (Part 2). 
If replacement subjects are used, the replacement subject number will be 100 more than the 
original (e.g., Subject No. 101 will replace Subject No. 1). 
7.2.2 Dosing 
Infusion sites: 
Please refer to the infusion manual/Pharmacy manual for complete dosing instruction of the 
investigational product.  
One (1) or 2 infusion sites per infusion day will be used. If two sites are to be used, they must be 
on the opposite sides of the body.  Infusion sites will be rotated if the infusion occurs on 
consecutive days due to dose is greater than 120 grams per day. The infusion site will be either: 
• 
Right upper quadrant (RUQ) or left upper quadrant (LUQ) (please avoid 2 inches away 
from the umbilicus) and/or 
• 
Upper 2/3rds of the medial or lateral thigh. 
Infusion volume maximum per day: 
• 
Up to 600 mL (1 site) or 1200 mL (2 sites).  For infusions greater than 600 mL, 
a bifurcated needle will be used.  Volumes will be evenly infused over two sites 
(e.g. 1000mLs will be infused in 2 sites at 500 mL each.) [rHuPH20 volume is not counted 
in the total dose of 600 mL/site] 
Infusion rate: 
• 
rHuPH20: Infuse the two components (rHuPH20 and IGI, 10%) sequentially, beginning 
with rHuPH20 solution administered subcutaneously, at a dose of 80 U/g IgG, to be 
followed by subcutaneous infusion of IGI, 10% solution within 10 minutes of completion 
of the infusion of rHuPH20 solution. The rHuPH20 should be administered at an initial rate 
per site of approximately 1 to 2 mL per minute (60 to 120 mL/h/site), or a total of 120 to 
240 mL/h, over 2 sites), or as tolerated. For subsequent administrations, rHuPH20 solution 
infusion rate may be increased as tolerated by the subject and at the discretion of the 
investigator, but is not to exceed 300 mL/h/site or not to exceed a total of 600 mL/h over 
2 sites. 
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• 
IGI, 10%: The maximum infusion rate should be 240 mL/h/site for the first infusion and 
then maximum infusion rate of up to 300 mL/h/site. Stepwise increase in subcutaneous 
infusion rate will be used according to Table 2. 
Sequential administration: 
• 
rHuPH20 will be infused first by the pump; within 10 minutes, IGI, 10% will be 
administered using the same infusion site(s). 
 
Table 2: Subcutaneous Infusion Rates for IGI, 10%   
 
Infusion Rate Per Infusion Site (mL/h) 
1st infusion 
Remaining infusions 
First 15 min 
10 
10 
Next 15 min 
30 
30 
Next 15 min 
60 
120 
Next 15 min 
120 
240 
Remainder of infusion 
240 
300 
 
7.3 Labeling, Packaging, Storage, and Handling 
7.3.1 Labeling 
Study drug containers will be affixed with a clinical label in accordance with local regulatory 
requirements. 
The pharmacy at the CRU will provide each dose of the IGI, (Human) 10% in a pooling bag and 
a bag tag label for each subject based on the randomized ramp up schedules.  The pharmacy will 
prepare and dispense the rHuPH20 to be administered prior to IGI, (Human) 10% per the 
instructions in the Pharmacy Manual. 
7.3.2 Packaging 
Each labeled carton of IGI, 10% (Human) will contain either one labeled vial of IGI, 10% 
(Human) 5 gram, 5g/50 mL or one labeled vial of 20 gram, 20g/200mL. 
Each labeled carton of rHuPH20 will contain one labeled 15 mL vial of rHuPH20 160U/mL. 
Changes to sponsor-supplied packaging prior to dosing may not occur without full agreement in 
advance by the sponsor. 
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7.3.3 Storage 
The Sponsor will supply sufficient quantities of HYQVIA products to allow completion of this 
study.  
The lot numbers and expiration dates of HYQVIA supplied will be recorded in the final report. 
HYQVIA will be stored according to the product labels provided with the product. 
Records will be made of the receipt, preparation, dispensing, and final disposition of HYQVIA 
supplied. 
7.4 Drug Accountability 
The investigator will be provided with sufficient amounts of IGI, 10% (Human) and rHuPH20 to 
carry out this protocol for the agreed-upon number of subjects. The investigator or designee will 
acknowledge receipt of the products, documenting shipment content (quantities, lot numbers and 
condition. Accurate records of all IP dispensed, used, returned, and/or destroyed must be 
maintained as detailed further in this section. 
The investigator has overall responsibility for dispensing and administering IP. Where 
permissible, tasks may be delegated to a qualified designee (e.g., a pharmacist) who is 
adequately trained in the protocol and who works under the direct supervision of the investigator. 
This delegation must be documented in the applicable study delegation of authority form. 
The investigator or his/her designee (as documented by the investigator in the applicable study 
delegation of authority form) will dispense and administer IGI, 10% and rHuPH20 only to 
subjects included in this study following the procedures set out in the study protocol. Each 
subject will be given only IGI, 10% and rHuPH20 for his/her treatment assignment. All 
dispensed and administered medication will be documented on the CRFs and/or other IP records 
(including all lot numbers and expiration dates). The pharmacy will retain all empty, partially 
used and unused vials of IGI 10% and rHUPH20 for drug accountability. Due to health and 
safety concerns, the IP pooling bags, needle sets and other disposable ancillary supplies used for 
infusion will be disposed of as per protocol and local health waste regulations.  
No IP, stock or returned inventory from a Shire-sponsored study may be removed from the site 
where originally shipped without prior knowledge and consent by the sponsor. If such transfer is 
authorized by the sponsor, all applicable local, state, and national laws must be adhered to for the 
transfer. 
The sponsor or its representatives must be permitted access to review the supplies storage and 
distribution procedures and records. 
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At the end of the study, or as instructed by the sponsor, all unused stock, empty/partially used 
cartons and vials of IGI, 10% and rHuPH20 will be destroyed  by the site according to their 
procedures and/or SOPs. There will be a well-documented site procedure and/or SOP for 
destruction of the study drug. Prior to the destruction of IGI 10% and rHuPH20 vials, drug 
accountability must be performed. Vials will be counted and verified by clinical site personnel 
and the sponsor (or designated CRO). For unused supplies where the original supplied 
tamper-evident feature is verified as intact, the tamper-evident feature must not be broken and 
the labeled amount is to be documented in lieu of counting. The following information will be 
documented on the destruction certificate or documented in conjunction with the destruction 
certificate and verified  at time of destruction: date of destruction, method of destruction, number 
of units destroyed, including lot numbers, and, if applicable,  the name of the company 
contracted by the pharmacy who performed the destruction (if not directly performed by the 
pharmacy). Destruction of all IGI, 10% and rHuPH20 must comply with the site SOPs, and local, 
state, and national laws. 
Please refer to the current version of the pharmacy manual that has been provided for any 
other instructions or updates to this procedure.  
Based on entries in the site drug accountability forms, it must be possible to reconcile IGI, 10% 
and rHuPH20 delivered with those used and returned. All IGI, 10% and rHuPH20 must be 
accounted for and all discrepancies investigated and documented to the sponsor’s satisfaction. 
7.5 Subject Compliance 
Compliance must be assessed by observation of dosing by the investigator or designee. The 
investigator/nominated person will record details on the drug accountability log(s) and/or source 
documents. In addition, details of the dosing time (time, date, dose level) will be captured in the 
appropriate CRF. 
Drug accountability must be assessed at the container/packaging level for unused IP that is 
contained within the original tamper-evident sealed container (e.g., bottles, trays, vials) or at the 
individual count level for opened containers/packaging. The pharmacist/nominated person will 
record details on the drug accountability form. 
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8. STUDY PROCEDURES 
8.1 Study Schedule 
See Section 1.3 for study procedures.  
8.1.1 Screening Period  
Screening procedures must be completed within 21 days prior to receiving the first dose of IP. 
The CRU is responsible for maintaining an enrollment/screening log that includes all subjects 
who provided informed consent. The log will also serve to document the reason for screening 
failure. All screening data for enrolled/randomized subjects will be collected and reported in 
CRFs. Screen failures will be reviewed according to the monitoring plan, but will not be entered 
in the EDC. All screening assessments and procedures are to be performed by the principal 
investigator or a qualified designee. See Section 1.3 for a complete list of screening procedures 
to be performed. 
Written, signed, and dated informed consent prior to the performance of any study-related 
procedures must be obtained by the principal investigator or a designee. A copy of the signed 
informed consent must be given to the subject or legally-authorized representative for their 
records. 
8.1.1.1 Screening Failure 
A screen failure is a subject who has given informed consent and fail to meet all 
inclusion/exclusion criteria and has not been administered IP. 
For purposes of data collection, all subjects who give consent to the study but are not dosed will 
be reported as screen failures even if they were otherwise fully eligible for the study (for 
example, alternates/reserve subjects). 
8.1.1.2 Rescreening of Subjects 
Subjects who fail to meet all inclusion/exclusion criteria will not be permitted to be rescreened 
for the study at any point. 
Eligible subjects who meet all inclusion/exclusion criteria but are unable to participate in the 
study due to scheduling conflicts/timing may be rescreened based on investigator’s discretion 
and sponsor’s approval. In these cases, a new screening number must be assigned for each 
subject who is rescreened and a new informed consent form must be signed. 
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8.1.2 Randomization 
Prior to receiving the first infusion of HYQVIA, screened subjects who are qualified to enroll in 
this study are to be randomized to a treatment arm as depicted in the Study Schematic 
(Section 1.2). 
This study comprises of two parts, Study Parts 1 & 2. Each study part consists of 3 Treatment 
Arms, and each subject will participate in only one Treatment Arm:  
• 
Part 1 (TDL 0.4 g/kg): Treatment Arms 1-3 
• 
Part 2 (TDL 1.0 g/kg): Treatment Arms 4-6 
 
A total of 48 subjects will be randomized to 6 parallel treatment arms (8 subjects per treatment 
arm, equal randomization ratio): 24 subjects in total to Part 1 and 24 subjects in total to Part 2. 
Randomization will be stratified by BMI group (18 to <25 kg/m2 and >25 to 30 kg/m2) in order 
to ensure a minimum of 3 subjects are randomized to each of the 2 BMI groups in each treatment 
arm in each part (BMI as the stratification factor). 
Example 
It is worthwhile to provide an example to illustrate the planned stratified randomization, using 
dummy (not real) data. The example below shows a balance between the treatment arms in each 
Part (8 subjects in total per Treatment Arm) while ensuring that each Treatment Arm has a 
minimum of 3 subjects in each stratum (BMI group). Note that the stratified randomization is not 
to ensure an equal number of subjects for each stratum, but instead it is to ensure a minimum of 
3 subjects are randomized to each Treatment Arm in each Study Part, as displayed in the 
example. 
BMI group 
(kg/m2) 
Study Part 1 
Study Part 2 
Total 
Treatment 1 Treatment 2 Treatment 3 Treatment 4 Treatment 5 
Treatment 6 
18 to <25  
3 
4 
3 
5 
4 
4 
23 
>25 to <30  
5 
4 
5 
3 
4 
4 
25 
Total 
8 
8 
8 
8 
8 
8 
48 
 
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8.1.3 Day Prior Treatment (D-1)/Treatment Period 
8.1.3.1 Day -1 (For all Treatment Arms) 
Subjects will check into the CRU and undergo the assessments as described in Schedule of Study 
Procedures (Section 1.3).  
NOTE: When confined, standard meals and snacks will be provided at appropriate times. 
Subjects must be well hydrated prior to drug administration. 
8.1.3.2 Week 1 (For all Treatment Arms) 
Study drug will be administered on Day 1 at the clinical research center and assessments 
specified in Schedule of Study Procedures (Section 1.3) will be completed. 
8.1.3.3 Weeks 2-9 
All subjects in Treatment Arms 1 and 4 will be dosed on D8, D15, D29 and D50. 
All subjects in Treatment Arms 2 and 5 will be dosed on D15, D29 and D57.  
All subjects in Treatment Arms 3 and 6 will be dosed on D29 and D57. 
Procedures and laboratory test performed are assessed as described in Schedule of Study 
Procedures (Section 1.3). 
8.1.4 Week 24/25 Follow-up Period (EOS/ET Visit)  
The follow-up period for this study is 16 (± 1) weeks after receiving the last infusion of 
HYQVIA with the end of study being in Weeks 24 (Treatments 1 and 4) or 25 (Treatments 2, 3, 
5, and 6). 
At the end of the study follow up period visit (EOS/ET), final inquiries for SAEs, AEs, and 
concomitant treatments will be made. 
Procedures and laboratory tests performed are assessed as described in Schedule of Study 
Procedures (Section 1.3). 
8.2 Study Evaluations and Procedures 
The Schedule of Study Procedures (Section 1.3) summarizes the clinical procedures to be 
performed at each visit. Individual clinical procedures are described in detail below. Additional 
evaluations/testing may be deemed necessary by the investigator or designee and/or the Sponsor 
for reasons related to subject safety. 
Any nonscheduled procedures required for urgent evaluation of safety concerns take precedence 
over all routine scheduled procedures. 
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8.2.1 Informed Consent Procedure 
The purpose of the study, the procedures to be carried out and the potential hazards will be 
described to the subjects in non-technical terms. Subjects will be required to read, sign, and date 
an ICF summarizing the discussion prior to screening, and will be assured that they may 
withdraw from the study at any time without jeopardizing their medical care. 
Subjects will be given a copy of their signed ICF. 
8.2.2 Demographic and Other Baseline Characteristics 
Baseline is defined as the last non-missing value before the initial dose of HYQVIA. 
Demographic data, including patient number, gender, age, race and ethnicity will be recorded. 
Body height (cm) and weight (kg) will be measured and reported as outlined in the Schedule of 
Study Procedures (Section 1.3). 
BMI will be calculated based on the height and weight measured at screening. The weight should 
be measured on the same scale throughout the course of the study. If applicable, BMI will be 
recalculated with the subsequent measures of weight from screening. 
Abnormalities identified at the screening visit will be documented in the subject’s source 
documents and on the medical history CRF. Changes after the screening visit will be captured as 
AEs on the AE CRF page, as deemed by the investigator. 
8.2.3 Safety 
8.2.3.1 Physical Examinations 
At screening and subsequent study visits (as described in Section 1.3) a complete physical 
examination will be performed on the following body systems: general appearance, head and 
neck, eyes and ears, nose and throat, chest, lungs, heart, abdomen, extremities and joints, lymph 
nodes, skin, and neurological. At screening, if an abnormal condition is detected, the condition 
will be described on the medical history CRF. At study visits, if a new abnormal or worsened 
abnormal pre-existing condition is detected, the condition will be described on the AE CRF. If 
the abnormal value was not deemed an AE because it was due to error, due to a preexisting not 
clinically significant disease, 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. 
A partial physical exam will be done at the times specified in Section 1.3. A partial physical 
exam will include: general appearance, head and neck, assessment of injection sites, and skin. 
Other organ systems will be assessed per the PI's judgement. 
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8.2.3.2 Vital Signs 
Single measurements of body temperature, respiratory rate, blood pressure, and heart rate, will 
be measured as outlined in the Schedule of Study Procedures (Section 1.3). Additional vital signs 
may be taken at any other times, if deemed necessary. 
Blood pressure and heart rate measurements will be performed with subjects in a seated position, 
except when they are supine or semi-reclined because of study procedures and/or AEs 
(e.g., nausea, dizziness) or if deemed necessary by the investigator or designee. 
At the predose time points, blood pressure and heart rate will be performed within 2 hours prior 
to dosing. When scheduled postdose, vital signs will be performed within approximately 
15 minutes of the scheduled time point. 
Only BP, HR and RR will be measured every 30 minutes from starting the infusion until the end 
of infusion, and every 1-2 hours after the infusion for 8 hours, at discharge and as needed per 
investigator’s judgement until discharged. 
8.2.3.3 Electrocardiogram  
A 12-lead electrocardiogram (ECG) will be performed at screening for the determination of 
eligibility (e.g., exclusion of clinically significant cardiac abnormalities, such as unstable cardiac 
arrhythmias, and detection of other clinically significant cardiac abnormalities that may indicate 
an underlying condition that may impede the subject’s participation in the study, pose increased 
risk to the subject, or confound the results of the study). ECG will be reviewed by the 
investigator or a designee. ECG will be performed at EOS/ET. 
8.2.3.4 Clinical Laboratory Tests 
All clinical laboratory tests will be performed according to the laboratory’s standard procedures. 
Reference ranges will be supplied by the laboratory and used to assess the results for clinical 
significance and out-of-range changes which may be associated with, or constitute, an AE. 
The investigator should assess out-of-range clinical laboratory values for clinical significance, 
indicating if the value(s) is/are not clinically significant or clinically significant. Abnormal 
clinical laboratory values, which are unexpected or not explained by the subject’s clinical 
condition, may, at the discretion of the investigator or sponsor, be repeated as soon as possible 
until confirmed, explained, or resolved. 
All tests listed below will be performed as outlined in the Schedule of Study Procedures 
(Section 1.3). In addition, laboratory safety tests may be performed at various unscheduled time 
points, if deemed necessary by the investigator or designee. 
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Samples for hematology and clinical chemistry assessments will be collected in the appropriate 
matrix as specified in the laboratory manual. With the exception of screening and early 
termination visits, samples for hematology and clinical chemistry collected during the treatment 
period must be collected prior to IP administration. At any time during the study, unscheduled 
hematology and/or clinical chemistry test(s) may be performed as part of AE/safety investigation 
or may be repeated once in the event of abnormalities in test results due to errors. 
Hematology and clinical chemistry assessments will be performed at the local laboratory 
following standardized assay procedures. 
Some of the parameters will be evaluated according toxicity grading scale provided in 
Section 9.5.4.1.  
8.2.3.4.1 Biochemistry 
Blood samples for serum biochemistry will be collected according to the timepoints provided in 
Section 1.3. Sample collection details are provided in the Laboratory Manuals. 
Serum chemistry tests will be performed after at least an 8-hour fast (on the screening day only); 
however, in case of dropouts or rechecks, subjects may not have fasted for 8 hours prior to the 
serum chemistry sample being taken. 
Chemistry evaluations will consist of the following standard chemistry panel (Table 3): 
Table 3. Chemistry Panel 
Blood Urea Nitrogen 
Albumin 
Bilirubin (total and direct) 
Sodium 
ALP 
Potassium 
AST 
Chloride 
Triglycerides 
Glucose 
Cholesterol 
Creatinine * 
ALT 
Low-density lipoprotein 
LDH 
High-density lipoprotein 
Uric acid 
Magnesium 
 
Calcium 
* At screening, creatinine clearance will be calculated using the Cockcroft-Gault formula. 
 
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8.2.3.4.2 Hematology 
Blood samples for hematology will be collected according to the timepoints provided in 
Section 1.3. Sample collection details are provided in the Laboratory Manuals. The following 
parameters will be assessed: 
Hematology will consist of the following tests (Table 4): 
Table 4. Hematology Panel 
Hemoglobin 
Red blood cell count 
Red Cell Distribution Width (RDW) 
Platelet count 
Mean Corpuscular Volume (MCV) 
 
Mean Corpuscular Hemoglobin (MCH) 
 
Mean Corpuscular Hemoglobin Concentration (MCHC) 
 
Hematocrit  
White blood cells (WBC) with absolute differential counts of 
neutrophils, lymphocytes, monocytes, eosinophils, and basophils 
 
 
8.2.3.4.3 Hemolytic Panel  
The first hemolytic panel will be measured at D-1. The Hgb result obtained from the D-1 will 
serve as the baseline Hgb value for the duration of the study. In case of absence of D-1 results for 
any reason, screening Hgb result serve as the baseline Hgb value. Hemoglobin and LDH values 
can be taken from the hematology and clinical chemistry panels, if conducted on the same day as 
the hemolytic panel. For subsequent tests, if there is a reduction in Hgb of ≥1 g/dL compared to 
baseline Hgb, every effort is to be made to perform a hemolytic panel within 72 hours. If it is not 
feasible to do so, the hemolytic panel must be performed as soon as possible but at the next 
scheduled visit, at latest. At any time during the study, an unscheduled hemolytic panel may be 
performed in the event of suspected hemolytic anemia. Any LDH test result of 2 x ULN or 
greater will trigger analysis of the sample for LDH isoenzymes. 
It is not necessary to repeat the hemolytic panel if the drop of ≥ 1 g/dL Hgb remains constant 
72 hours after the first full dose of the IP or after an unscheduled visit blood draw, unless it drops 
further. It is recommended that the investigator uses good medical judgement in assessing 
subjects with an unexplained decrease in serum Hgb as other medical conditions beside 
hemolysis can cause this, and therefore may require additional investigations.  
The hemolytic anemia panel will consist of Hgb, LDH, serum haptoglobin, plasma-free 
(unbound) Hgb, serum direct anti-globulin (direct Coombs) test (antibody elution to be 
performed if direct Coombs test is positive), reticulocyte count, as well as urine hemosiderin. 
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Hemolytic tests will be performed at the local laboratory or other laboratories as appropriate 
(e.g., antibody elution in the event of positive direct Coombs test). Complete hematology and 
clinical chemistry assessments may be performed in order to obtain laboratory results required 
for a hemolytic panel. 
8.2.3.4.4 Urinalysis 
A urine sample for urinalysis will be collected according to the timepoints provided in 
Section 1.3. Sample collection details are provided in the Laboratory Manuals.  
Urinalysis will consist of the following tests (Table 5). 
Table 5. Urinalysis Panel 
pH 
Bilirubin 
Specific gravity 
Blood * 
Protein * 
Nitrite * 
Glucose 
Urobilinogen 
Ketones 
Leukocyte esterase * 
Color 
 
* If urinalysis is positive for protein, blood, nitrite and/or leukocyte esterase, a microscopic examination (for red 
blood cells, white blood cells, bacteria, casts, and epithelial cells) will be performed. 
 
Microscopic examination will be conducted if protein and/or blood is/are detected during 
urinalysis. At a minimum the microscopic examination will consist of red blood cells, white 
blood cells, casts, and bacteria.  
8.2.3.4.5 Coagulation  
Samples will be collected according to the timepoints provided in Section 1.3. Sample collection 
details are provided in the Laboratory Manual.  
Coagulation will consist of the following tests (Table 6). 
Table 6: Coagulation Panel 
aPTT 
INR 
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8.2.3.5 Pregnancy Screen 
Subjects must have a negative serum pregnancy test at screening and a negative serum pregnancy 
test within 7 days before the first IP administration If the serum pregnancy test at screening is 
older than 7 days., a serum pregnancy test is required on D-1. For the rest of the visits, a urine 
pregnancy test prior to dosing will be acceptable. Pregnancy tests are to be performed on all 
females of child-bearing potential at the screening visit, D-1, or if pregnancy is suspected, prior 
to each dosing and at EOS/ET visits.  
Follicle stimulating hormone (FSH) levels may be done once at screening on menopausal or peri-
menopausal women, or as judged by investigator. 
8.2.3.6 Drug and Alcohol Screen  
A urine screen for drugs of abuse and alcohol will be performed at the time points described in 
Section 1.3. Additional drug and alcohol screens may be performed at the investigator’s 
discretion. 
Urine samples are to be tested for amphetamines, barbiturates, benzodiazepines, cannabinoids, 
cocaine, methadone, opiates (includes morphine, heroin (diacetylmorphine), codeine,  
6-acetylmorphine, dihydrocodeine, hydrocodone, thebaine, and, hydromorphone), and 
phencyclidine. Results of urine drug and alcohol screens will be reviewed and verified by the 
study monitor but will not be collected in the CRF database. 
Any positive result for drugs of abuse or alcohol at screening or on Day -1 will exclude the 
subject from further participation in the study. 
8.2.3.7 Virology Screen  
Blood samples will be drawn at timepoints listed in Section 1.3. Sample collection details are 
provided in the Laboratory Manual.   The following parameters will be drawn for the virology 
screen: HIV 1/2  antibodies, HBsAg, HBsAb, HBcAb and HCV antibody. 
The test results must be confirmed negative prior to enrollment in the study. If a test result is 
positive, the subject will be excluded from entering the study. Results of the virology screen will 
be reviewed and verified by the study monitor but will not be collected in the CRF database. 
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8.2.4 Pharmacokinetic and Immunogenicity Sample Collection and Handling Procedures 
8.2.4.1 Blood Sample Collection and Handling Procedures 
Blood samples will be collected at the time specified in Section 1.3 to measure serum 
concentrations of total IgG and IgG subclasses, and anti-rHuPH20 antibodies (ADA and nADA). 
Blood samples will be drawn according to the time points specified in Section 1.3 and processed 
as described in the Laboratory Manual. The actual time that the sample was obtained will be 
recorded in the subject’s source document and on the appropriate CRF page. In instances where 
more than 1 blood collection tube is used, the time of the initial blood draw will be recorded for 
all tubes collected at that time point on the appropriate CRF page. After applying a tourniquet, 
venous blood will be drawn with a disposable needle. If a catheter is used, the first milliliter of 
blood on each sampling occasion will be discarded. Saline can be used to keep catheters patent. 
Serum or plasma sample tubes for bioanalysis must be freezer-safe and identified with freezer-
safe labels provided by the specialty laboratory. The labels will contain the following 
information: 
• 
Study number 
• 
Subject identifier  
• 
Treatment  
• 
Period 
• 
Nominal day 
• 
Nominal time 
• 
Matrix identifier (plasma) 
• 
Split (primary or backup) 
 
Primary specimen collection parameters are provided in Table 7. 
Table 7. Primary Specimen Collections 
Specimen Name 
Primary Specimen 
Description of Intended Use 
Sample Collection 
Serum sample for PK 
Serum 
Serum sample for PK analysis 
Mandatory 
rHuPH20 Immunogenicity 
ADA and nADA sample 
Plasma  
Plasma sample for 
Immunogenicity analyses 
Mandatory 
ADA=anti-drug antibody; nADA=neutralizing anti-drug antibody 
 
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Serum PK samples and plasma ADA and nADA samples will be collected and processed 
according to the instructions provided in the Laboratory Manual. 
All subjects will be monitored for the formation of anti-rHuPH20 antibodies using validated anti-
rHuPH20 antibody detection assay (ADA) (also known as the Screening and Confirmatory 
Binding Assay). Samples with antibody titers ≥1:160 will be analyzed for the presence of 
neutralizing antibodies (nADA) using a validated assay based on neutralization of rHuPH20 
activity.  
8.2.4.2 Immunogenicity Panel  
At baseline (D1 predose), samples are to 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), C1q binding assay, and circulating immune complex 
(CIC) Raji cell assay. 
At any time during the course, subjects who have (a) 2 consecutive anti-rHuPH20 antibody titers 
of ≥1:160 that are elevated from the subject’s baseline titers, and (b) a moderate or severe AE 
that may be a result of immune-mediated response to either immunoglobulin, rHuPH20, or other 
concomitant medications (Table 8) will be asked to return to the CRU as soon as possible to 
undergo an additional panel of testing outlined in Table 9. 
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Table 8. List of Conditions/Symptoms That May be a Result of Immune-Mediated 
Response to Either Immunoglobulin, rHuPH20, or Other Factors 
Allergic reactions 
 Urticaria 
 New-onset bronchospasm 
 Oedema of tongue, lips, face (angioedema) 
 Anaphylaxis 
 Stevens-Johnson syndrome 
 Erythema multiforme 
 Toxic epidermal necrolysis 
Immune complex mediated reactions – Local 
 Induration/nodule at the site of administration that persists for more than 48 hours 
 Excessive inflammation at the site of administration - severe redness, heat, swelling, and/or pain 
 Tissue necrosis/ulceration at the site of administration 
 Dystrophic or fibrotic changes at the site of administration  
 Pigmented skin changes at the site of drug administration 
Immune complex mediated reactions – Systemic 
 Arthritis 
 Vasculitis (purpuric rash) 
 Glomerulonephritis - hematuria, red cell casts in urine, progressive renal dysfunction 
 
Table 9. Immunogenicity Panel 
1. Repeat test for anti-rHuPH20 binding antibody titers >1:160 
2. Hematology panel with manual differential  
3. Clinical chemistry panel 
4. CH50 
5. Serum C3 
6. Serum C4 
7. C1q binding assay 
8. CIC Raji cell assay 
9. Blood draw for additional testing as necessary 
 
Blood samples are to be collected and processed according to the directions provided in the 
laboratory manual. The tests should be performed at the central laboratory and/or specialty 
laboratories as appropriate. 
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8.2.5 Volume of Blood to be Drawn from Each Subject 
Table 10. Estimated Volume of Blood to be Drawn from Each Subject 
Assessment 
Sample Volume (mL) 
Number of Samples 
Total Volume (mL) 
PK Samples 
15 
5 (Treatment Arms 1 and 4) 
6 (Treatment Arms 2 and 5) 
7 (Treatment Arms 3 and 6) 
Up to 105 mL 
ADA and nADA samples 
10 
4 
40mL 
Hemolytic Anemia Panel 
17 
1 
17 
Serology test 
5 
2 
10 
Serum chemistry (male and female 
subjects) and β-hCG (female 
subjects only per Section 1.3) 
5 
6 
30 
Hematology 
4 
6 
24 
Total 
Up to 226 mL 
 
Note: The amount of blood to be drawn for each assessment is an estimate. The amount of blood 
to be drawn may vary according to the instructions provided by the manufacturer or 
laboratory for an individual assessment; however, the total volume drawn over the course of 
the study should be approximately 226 mL. When more than 1 blood assessment is to be 
done at the same time point/period and if they require the same type of tube, the assessments 
may be combined. Additional samples may be collected as required per protocol. 
8.3 Backup Samples and Biobanking 
Backup samples from PK and immunogenicity testing should be taken and stored appropriately 
for repeat or additional analysis, if necessary. These samples may also be used short-term for 
further evaluation of an AE, or follow-up of other test results. The following back up samples are 
planned: 
• 
Serum IgG samples (back-up aliquots) 
• 
Anti-rHuPH20 binding antibody samples (back-up aliquots) 
• 
Anti-rHuPH20 neutralizing antibody samples (back-up aliquots) 
 
By signing the informed consent form (ICF), subjects agree to the possible future analysis of 
these samples. At any time, the subjects can contact the CRU staff to request destruction of the 
residual samples once PK and immunogenicity assessments required to meet the secondary 
objective of the study are completed. Any additional research on these samples unspecified by 
this protocol and ICF will require approval from the subjects. 
Samples will be stored in a coded form for no more than 2 years after the final study report has 
been completed and then the samples will subsequently be destroyed.  
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9. SAFETY ASSESSMENT 
9.1 Adverse Events 
9.1.1 Definitions 
An AE is defined as any untoward medical occurrence in a subject administered an IP that does 
not necessarily have a causal relationship with the treatment. An AE can therefore be any 
unfavorable and unintended sign (e.g., an abnormal laboratory finding), symptom (e.g., rash, 
pain, discomfort, fever, dizziness, etc.), disease (e.g., peritonitis, bacteremia, etc.), or outcome of 
death temporally associated with the use of an IP, whether or not considered causally related to 
the IP.  
A treatment-emergent adverse event (TEAE) is defined as any event not present prior to the 
initiation of the treatments or any event already present that worsens in either intensity or 
frequency following exposure to the treatments. 
9.1.1.1 Serious Adverse Event  
A serious adverse event (SAE) is defined as an untoward medical occurrence that at any dose 
meets one or more of the following criteria: 
1. Outcome is fatal/results in death (including fetal death) 
2. Is life-threatening – defined as an event in which the subject was, in the judgment of the 
investigator, at risk of death at the time of the event; it does not refer to an event that 
hypothetically might have caused death had it been more severe. 
3. Requires inpatient hospitalization or results in prolongation of an existing hospitalization – 
inpatient hospitalization refers to any inpatient admission, regardless of length of stay. 
4. Results in persistent or significant disability/incapacity (i.e., a substantial disruption of a 
person’s ability to conduct normal life functions) 
5. Is a congenital anomaly/birth defect 
6. Is a medically important event – a medical event that may not be immediately life-
threatening or result in death or require hospitalization but may jeopardize the subject or 
may require medical or surgical intervention to prevent one of the other outcomes listed in 
the definitions above. Examples of such events are:  
• 
Intensive treatment in an emergency room or at home for allergic bronchospasm, 
blood dyscrasias, or convulsions that do not result in hospitalization, or development 
of drug dependence or drug abuse 
• 
Reviewed and confirmed seroconversion for HIV, HAV, HBV, HCV, HEV, or B19V 
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• 
Thromboembolic events (e.g., deep vein thrombosis, pulmonary embolism, myocardial 
infarction, cerebrovascular events [e.g., stroke, transient ischemic attack]) 
• 
Hemolytic anemia 
 
Uncomplicated pregnancies, following maternal exposure to IP are not considered as an (S)AE. 
Any pregnancy that occurs after maternal administration of medicinal product will be reported 
on a Pregnancy Report Form and 1 year postdelivery, if feasible. Any pregnancy complication or 
pregnancy termination by therapeutic, elective, or spontaneous abortion shall be considered an 
SAE. 
9.1.1.2 Suspected Unexpected Serious Adverse Reaction (SUSAR) 
Any suspected adverse reaction to study treatment (i.e., including active comparators) that is 
both serious and unexpected. 
The event(s) must meet all of the following: 
• 
Suspected adverse reaction 
• 
Serious 
• 
Unexpected 
• 
Assessed as related to study treatment 
 
Once determined to meet the criteria for a SUSAR, a SAE should be submitted to regulatory 
agencies expeditiously.  
The sponsor will ensure that all relevant information about suspected unexpected serious adverse 
reactions (SUSARs) that are fatal or life-threatening, as well as all other serious unexpected ARs, 
are reported to regulatory authorities within the timeframes mandated by the applicable 
regulations (e.g. ICH Guideline E2A and the European Clinical Trial Directive (2001/20/EC). 
The sponsor will comply with applicable laws/requirements for reporting SUSARs and all other 
SAEs to the ECs and investigators. 
9.1.1.3 Nonserious Adverse Event 
A nonserious AE is an AE that does not meet the criteria of an SAE.  
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9.1.1.4 Unexpected Adverse Events 
An unexpected adverse event is an AE whose nature, severity, specificity, or outcome is not 
consistent with the term, representation, or description used in the Reference Safety Information 
(RSI). “Unexpected” also refers to the AEs that are mentioned in the IB and/or prescribing 
information as occurring with a class of drugs or as anticipated from the pharmacological 
properties of the product but are not specifically mentioned as occurring with the particular 
product under investigation. The expectedness of AEs will be determined by the sponsor using 
the IB and prescribing information as the RSI. This determination will include considerations 
such as the number of AEs previously observed, but not on the basis of what might be 
anticipated from the pharmacological properties of a product. 
9.1.1.5 Adverse Reactions Plus Suspected Adverse Reactions 
An AR plus suspected AR is any AE that meets any of the following criteria: 
• 
An AE considered by either the investigator and/or the sponsor to be possibly or probably 
related to IP administration, or  
• 
An AE that begins during infusion of IP or within 72 h following the end of IP infusion, or 
• 
An AE for which causality assessment is missing or indeterminate. 
 
9.1.1.6 Preexisting Diseases 
Preexisting diseases that are present before entry into the study are described in the medical 
history, and those that manifest with the same severity, frequency, or duration after IP exposure, 
will not be recorded as AEs. However, when there is an increase in the severity, duration, or 
frequency of a preexisting disease, the event must be described on the AE CRF. 
9.1.2 Assessment of Adverse Events 
All other AE from the first IP exposure until study completion/discontinuation date will be 
described on the AE CRF using the medical diagnosis (preferred), or, if no diagnosis could be 
established at the time of reporting the AE, a symptom or sign, in standard medical terminology 
in order to avoid the use of vague, ambiguous, or colloquial expressions (see definition in 
Section 9.1). Each AE will be evaluated by the investigator for: 
1. Seriousness as defined in Section 9.1.1.1 
2. Severity as defined in Section 9.1.2.1. 
3. Causal relationship to IP exposure or study procedure as defined in Section 9.1.2.2. 
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For each AE, the outcome (i.e., recovering/resolving, recovered/resolved, recovered/resolved 
with sequelae, not recovered/not resolved, fatal, unknown) and if applicable action taken 
(i.e., dose increased, dose not changed, dose reduced, drug interrupted, drug withdrawn, not 
applicable, or unknown) will also be recorded on the AE CRF. Recovering/resolving AEs will be 
followed until resolution, medically stabilized, or 30 days after the study completion/termination 
visit, whichever comes first. Follow-up information will be recorded in the appropriate CRF(s) 
as applicable, unless the database has already locked. If the severity rating for an ongoing AE 
changes before the event resolves, the original AE report will be revised (i.e., the event will not 
be reported as separate AE). During the course of any AE, the highest severity rating will be 
reported. 
Deviations from the protocol-specified dosage (including overdosing, underdosing, and 
withdrawal) that result in adverse events meeting criteria for SAEs, treatment errors 
(including incorrect route of administration, use of an incorrect product, and deviations from the 
protocol-defined dosing schedule), failures of expected pharmacological actions, and unexpected 
therapeutic or clinical benefits will be followed with regard to occurrence of AEs, and/or other 
observations because these events may be reportable to regulatory authorities. 
Any pregnancy that occurs after maternal administration of IP will be reported on a Pregnancy 
Report Form and followed-up at estimated date of delivery and 1 year postdelivery, if feasible. 
Any pregnancy complication or pregnancy termination by therapeutic, elective, or spontaneous 
abortion shall be considered an SAE.  
If an investigator becomes aware of an SAE occurring in a subject within 30 days after 
study completion, the SAE must be reported on the provided SAE Report Form within 
24 h after awareness; no additional reporting on CRFs is necessary. Thereafter, AEs of any 
nature are to be reported using standard forms such as the Council for International 
Organizations of Medical Sciences (CIOMS) form or MedWatch form, etc. 
9.1.2.1 Severity 
The severity of AEs must be recorded during the course of the event including the start and stop 
dates for each change in severity. An event that changes in severity is captured as a new event. 
Worsening medical conditions, signs or symptoms present prior to initiation of IP, must be 
recorded as new AEs. 
For example, if a subject reports mild intermittent dyspepsia prior to initiation of dosing with the 
IP, and the dyspepsia becomes severe and more frequent after first dose of a new AE of severe 
dyspepsia (with the appropriate date of onset) should be documented in the source. 
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The investigator will assess the severity of each AE using his/her clinical expertise and judgment 
based on the most appropriate description below: 
1. Mild 
• 
The AE is a transient discomfort and does not interfere in a significant manner with 
the subject’s normal functioning level. 
• 
The AE resolves spontaneously or may require minimal therapeutic intervention. 
2. Moderate 
• 
The AE produces limited impairment of function and may require therapeutic 
intervention. 
• 
The AE produces no sequela/sequelae. 
3. Severe 
• 
The AE results in a marked impairment of function and may lead to temporary 
inability to resume usual life pattern. 
• 
The AE produces sequela/sequelae, which require (prolonged) therapeutic 
intervention. 
 
These severity definitions will also be used to assess the severity of an AE with a study-related 
procedure(s), if necessary. 
9.1.2.2 Causality 
Causality is a determination of whether there is a reasonable possibility that the IP is 
etiologically related to/associated with the AE. Causality assessment includes, e.g., assessment of 
temporal relationships, dechallenge/rechallenge information, association (or lack of association) 
with underlying disease, presence (or absence) of a more likely cause, and physiological 
plausibility. For each AE, the investigator will assess the causal relationship between the IP and 
the AE using his/her clinical expertise and judgment according to the following most appropriate 
algorithm for the circumstances of the AE: 
1. Not related (both circumstances must be met) 
• 
Is due to underlying or concurrent illness, complications, concurrent treatments, or 
effects of concurrent drugs 
• 
Is not associated with the IP (i.e., does not follow a reasonable temporal relationship to 
the administration of IP or has a much more likely alternative etiology).  
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2. Unlikely related (either 1 or both circumstances are met) 
• 
Has little or no temporal relationship to the IP  
• 
A more likely alternative etiology exists 
3. Possibly related (both circumstances must be met) 
• 
Follows a reasonable temporal relationship to the administration of IP 
• 
An alternative etiology is equally or less likely compared to the potential relationship 
to the IP 
4. Probably related (both circumstances must be met) 
• 
Follows a strong temporal relationship to the administration of IP, which may include 
but is not limited to the following:  
 Reappearance of a similar reaction upon re-administration (positive rechallenge) 
 Positive results in a drug sensitivity test (skin test, etc.) 
 Toxic level of the IP as evidenced by measurement of the IP concentrations in the 
blood or other bodily fluid 
• Another etiology is unlikely or significantly less likely 
 
For events assessed as not related or unlikely related and occurring within 72 h after completion 
of IP administration, the investigator shall provide the alternative etiology. These causality 
definitions will also be used to assess the relationship of an AE with a study-related procedure(s), 
if necessary. 
Note: all local infusion site adverse events will be considered adverse reactions irrespective 
of investigator/sponsor opinions of causality. 
9.2 Outcome Categorization 
The outcome of AEs must be recorded in the source during the course of the study. Outcomes are 
as follows: 
• 
Recovered/resolved – subject returned to first assessment status with respect to the AE. 
• 
Recovering/resolving – the intensity is lowered by one or more stages: the diagnosis has or 
signs/symptoms have almost disappeared; the abnormal laboratory value improved, but has 
not returned to the normal range or to the baseline value; the subject died from a cause 
other than the particular AE with the condition remaining “recovering/resolving.” 
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• 
Not recovered/not resolved – there is no change in the diagnosis, signs or symptoms; the 
intensity of the diagnosis, signs/symptoms or laboratory value on the last day of the 
observed study period has become worse than when it started; is an irreversible congenital 
anomaly; the subject died from another cause with the particular AE state remaining “Not 
recovered/not resolved.” 
• 
Recovered/ Resolved with sequelae – the subject recovered from an acute AE but was left 
with permanent/significant impairment (e.g., recovered from a cardiovascular accident but 
with some persisting paresis). 
• 
Fatal – an AE that is considered as the cause of death. 
• 
Unknown – the course of the AE cannot be followed up due to hospital change or 
residence change at the end of the subject’s participation in the study. 
 
If applicable, action taken (i.e., dose increased, dose not changed, dose reduced, drug interrupted, 
drug withdrawn, not applicable, or unknown) will also be recorded on the AE CRF.  
9.3 Urgent Safety Measures 
An urgent safety measure is an immediate action taken, which is not defined by the protocol, in 
order to protect subjects participating in a clinical trial from immediate harm. Urgent safety 
measures may be taken by the sponsor or clinical investigator, and may include any of the 
following: 
1. Immediate change in study design or study procedures 
2. Temporary or permanent halt of a given clinical trial or trials 
3. Any other immediate action taken in order to protect clinical trial participants from 
immediate hazard to their health and safety 
The investigator may take appropriate urgent safety measures in order to protect subjects against 
any immediate hazard to their health or safety. The measures should be taken immediately and 
may be taken without prior authorization from the sponsor. In the event(s) of an apparent 
immediate hazard to the subject, the investigator will notify the sponsor immediately by phone 
and confirm notification to the sponsor in writing as soon as possible, but within 1 calendar day 
after the change is implemented. The sponsor will also ensure the responsible ethics committees 
and relevant competent authorities are notified of the urgent safety measures taken in such cases 
according to local regulations. 
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9.4 Untoward Medical Occurrences 
Untoward medical occurrences occurring before the first exposure to IP are not considered AEs 
(according to the definition of AE, see Section 9.1). However, each serious untoward medical 
occurrence experienced before the first IP exposure (i.e., from the time of signed informed 
consent up to but not including the first IP exposure) will be described on the AE CRF and on 
the SAE Report Form. These events will not be considered as SAEs and will not be included in 
the analysis of SAEs.  
For the purposes of this study, each nonserious untoward medical occurrence experienced by a 
subject undergoing study-related procedure(s) before the first IP exposure will be recorded on 
the AE CRF; these events will not be considered as AEs and will not be included in the analysis 
of AEs.  
9.5 Reporting Procedures 
9.5.1 Reporting AEs 
At each study visit, the investigator will assess whether any subjective AEs have occurred. A 
neutral question, such as “How have you been feeling since your last visit?” may be asked. 
Subjects may report AEs occurring at any other time during the study. Subjects experiencing an 
SAE prior to the first exposure to IP must be monitored until the symptoms subside and any 
clinically relevant changes in laboratory values have returned to Baseline or there is a 
satisfactory explanation for the change. Nonserious AEs that begin prior to the first exposure to 
IP, related or unrelated to the study procedure, need not be followed-up for the purposes of the 
protocol. 
All subjects experiencing AEs, whether considered associated with the use of the study 
medication or not, must be monitored until the symptoms subside and any clinically relevant 
changes in laboratory values have returned to Baseline or until there is a satisfactory explanation 
for the changes observed. All AEs will be documented in the AE page of the eCRF, whether or 
not the investigator concludes that the event is related to the drug treatment. The following 
information will be documented for each event (systemic/local): 
• 
Event term. 
• 
Start and end date and time. 
• 
Pattern of AE (frequency). 
• 
Severity/Intensity. 
• 
Causality (investigator’s opinion of the causal relationship between the event and 
administration of HYQVIA). 
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• 
Action taken with HYQVIA. 
• 
Outcome of event. 
• 
Seriousness. 
 
9.5.2 Reporting SAEs 
All initial and follow-up SAE reports must be reported by the investigator to the Shire Global 
Drug Safety Department and the CRO/Shire Medical Monitor within 24 hours of becoming 
aware of the event.  Note: The 24-hour reporting requirement for SAEs does not apply to reports 
of abuse, misuse, overdose, or medication errors unless they result in an SAE. 
The investigator must complete, sign, and date the Shire “Clinical Study Serious Adverse Event 
for Serious Adverse Events (SAEs) and Non-serious AEs as Required by Protocol” Form and 
verify the accuracy of the information recorded on the form with the corresponding source 
documents (Note:  Source documents are not to be sent unless requested), and fax or e-mail the 
form to the Shire Global Drug Safety Department. 
Fax: +1-484-595-8155 
E-mail: drugsafety@shire.com 
A copy of the Shire Clinical Study Serious Adverse Event Form for Serious Adverse Events 
(SAEs) and Non-serious AEs as Required by Protocol (and any applicable follow-up reports) 
must also be sent to the CRO/Shire Medical Monitor using the details specified in the emergency 
contact information section of the protocol. 
A Takeda SAE form must be completed, in English and signed by the investigator immediately 
or within 24 hours of first onset or notification of the event. The information should be 
completed as fully as possible but contain, at a minimum: 
• 
A short description of the event and the reason why the event is categorized as serious. 
• 
Subject identification number. 
• 
Investigator’s name. 
• 
Name of the study medication(s). 
• 
Causality assessment. 
 
Any SAE spontaneously reported to the investigator following the AE collection period should 
be reported to the Sponsor if considered related to study participation. 
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Reporting of SAEs that begin before first administration of IP will follow the same procedure for 
SAEs occurring on treatment. 
9.5.3 SAE Follow-Up 
If information is not available at the time of the first report becomes available at a later date, the 
investigator should complete a follow-up SAE form or provide other written documentation and 
fax it immediately within 24 hours of receipt. Copies of any relevant data from the hospital notes 
(e.g., ECGs, laboratory tests, discharge summary, postmortem results) should be sent to the 
addressee, if requested. 
All SAEs should be followed up until resolution or permanent outcome of the event. The 
timelines and procedure for follow-up reports are the same as those for the initial report. 
Serious Adverse Event Collection Time Frame 
All SAEs (regardless of relationship to IP) are collected from the time the subject signs the 
informed consent until the defined follow-up period stated in Section 8.1.4, and must be 
reported to the Shire Global Drug Safety Department and the CRO/Shire Medical Monitor 
within 24 hours of the first awareness of the event. 
In addition, any SAE(s) considered “related” to the IP and discovered by the investigator at any 
interval after the study has completed must be reported to the Shire Global Drug Safety 
Department within 24 hours of the first becoming aware of the event. 
9.5.4 Assessment of Laboratory Values 
9.5.4.1 Toxicity Grading Scale 
The Common Toxicity Criteria of the Eastern Cooperative Oncology Group, 2006, published by 
Oken et al., 1982, will be used to grade the following laboratory values: 
• 
ALP, ALT, AST, BUN, Hgb, lymphocytes, neutrophils, platelet count, serum creatinine, 
serum total bilirubin, and WBC.  
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 World Health 
Organization (WHO) toxicity grading system (World Health Organization, 2003). 
The laboratory parameters and the corresponding grading scale are provided below. 
The toxicity scale is defined as: 0 = none, 1 = mild, 2 = moderate, 3 = severe, 4 = life-threatening 
(Food and Drug Administration, 2008). 
Laboratory parameters not listed Table 11 will not be graded. However, clinical significance of 
those abnormal laboratory values will be assessed as described in Section 9.1.2. 
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Table 11. Grading of Laboratory Parameters 
Analyte 
Direction 
WNL is Grade 0 
No 
Grade 1 
Units 
Grade 0a 
Grade 1a 
Grade 2a 
Grade 3a 
Grade 4a 
Source 
Low High Low High Low High Low High Low High 
ALP 
Increase 
YES 
NO 
ULN 
. 
. 
. 
2.5 
2.6 
5.0 
5.1 
20 
20.1 
. 
ECOG 
ALT 
Increase 
YES 
NO 
ULN 
. 
. 
. 
2.5 
2.6 
5.0 
5.1 
20 
20.1 
. 
ECOG 
AST 
Increase 
YES 
NO 
ULN 
. 
. 
. 
2.5 
2.6 
5.0 
5.1 
20 
20.1 
. 
ECOG 
LDH 
Increase 
YES 
NO 
ULN 
. 
. 
. 
2.5 
2.6 
5.0 
5.1 
20 
20.1 
. 
N/A 
BUN 
Increase 
NO 
NO 
ULN 
0.0 
1.4 
1.5 
2.5 
2.6 
5.0 
5.1 
10 
10.1 
. 
ECOG 
Hemoglobin 
Decrease 
YES 
NO 
g/dL 
. 
. 
. 
10.0 
8.0 
9.9 
6.5 
7.9 
0.0 
6.4 
ECOG 
Lymphocytes 
Decrease 
NO 
NO 
x10^3/uL 
2.0 
. 
1.5 
1.9 
1.0 
1.4 
0.5 
0.9 
0.0 
0.4 
ECOG 
Neutrophils 
Decrease 
NO 
NO 
x10^3/uL 
2.0 
. 
1.5 
1.9 
1.0 
1.4 
0.5 
0.9 
0.0 
0.4 
ECOG 
Platelet Count 
Decrease 
YES 
NO 
x10^3/uL 
. 
. 
. 
75.0 
50.0 
74.9 
25 
49.9 
0.0 
24.9 
ECOG 
Potassium 
Decrease 
NO 
NO 
mmol/L 
3.5 
. 
3.0 
3.4 
2.5 
2.9 
2.0 
2.4 
0.0 
1.9 
WHO 
Potassium 
Increase 
NO 
NO 
mmol/L 
0.0 
5.5 
5.6 
6.0 
6.1 
6.5 
6.6 
7.0 
7.1 
. 
WHO 
Serum Creatinine 
Increase 
YES 
NO 
ULN 
. 
. 
. 
1.4 
1.5 
3.0 
3.1 
6.0 
6.1 
. 
ECOG 
Sodium 
Decrease 
NO 
NO 
mmol/L 
136 
. 
130 
135 
123 
129 
116 
122 
0.0 
115 
WHO 
Sodium 
Increase 
NO 
NO 
mmol/L 
0.0 
145 
146 
150 
151 
157 
158 
165 
166 
. 
WHO 
Serum  
Total Bilirubin 
Increase 
YES 
YES 
ULN 
. 
. 
. 
. 
. 
1.4 
1.5 
3.0 
3.1 
. 
ECOG 
WBC 
Decrease 
NO 
NO 
x10^3/uL 
4.0 
. 
3.0 
3.9 
2.0 
2.9 
1.0 
1.9 
0.0 
0.9 
ECOG 
Abbreviations:  ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase;  
LDH = lactate dehydrogenase; BUN = blood urea nitrogen; ULN = upper limit of normal; ECOG = Eastern Cooperative Oncology Group;  
WHO = World Health Organization; WNL = within normal limits. 
a  
The toxicity scale is defined as: 0 = none, 1 = mild, 2 = moderate, 3 = severe, 4 = life-threatening (Food and Drug Administration, 2008).  
Grading scale criteria taken from ECOG (Eastern Cooperative Oncology Group, 2006) and WHO (World Health Organization, 2003) guidelines, with the 
exception of LDH that use the same thresholds as defined for ALT and AST. 
 
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9.6 Precautions and Warnings 
Please see Section 2.2.2 for clinical information. 
9.7 Management of Infusion-Related AEs 
It is the investigator’s responsibility to monitor the safety and well-being of the subject and to 
assure that all post-randomization infusions are conducted in the prescribed and timely manner 
throughout the study, regardless of the location of administration. Subjects will be provided with 
information about the typical signs and symptoms of possible AEs, and when the subject should 
immediately call the investigator or go to the emergency room/department for immediate 
treatment.  
The occurrence of certain AEs, such as headache, chills, or body aches, may be reduced by 
slowing the infusion rate.  
Any suspicion of allergic, hypersensitivity, or anaphylactic reaction(s) requires immediate 
discontinuation of the infusion and administration of appropriate medical treatment in 
accordance with the local standard of care. 
Any rate reductions, interruptions or discontinuation of an infusion and, if applicable, any 
medications and/or non-drug therapies used to treat AE(s), must be recorded in the appropriate 
CRF(s). The use of any pre-medication(s) must be recorded in the appropriate CRF(s). 
9.8 Non-Medical Complaints 
A non-medical complaint (NMC) is any alleged product deficiency that relates to identity, 
quality, durability, reliability, safety and performance of the product but did not result in an 
AE. NMCs include but are not limited to the following: 
1. A failure of a product to exhibit its expected pharmacological activity and/or design 
function, e.g. reconstitution difficulty 
2. Missing components 
3. Damage to the product or unit carton 
4. A mislabeled product (e.g., potential counterfeiting/tampering) 
5. A bacteriological, chemical, or physical change or deterioration of the product causing it to 
malfunction or to present a hazard or fail to meet label claims 
 
Any NMCs of the product will be documented on an NMC form and reported to the sponsor 
within 1 business day. If requested, defective product(s) will be returned to the sponsor for 
inspection and analysis according to procedures. 
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9.9 Medical, Medication, and Non-Drug Therapy History 
At screening, the subject’s medical history will be described for the following body systems 
including severity (defined in Section 9.1.2.1.) 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 other medications taken and non-drug therapies received from enrollment until 
completion/termination will be recorded on the concomitant medications and non-drug therapies 
CRFs. 
9.10 Regulatory Agency, Institutional Review Board, Ethics Committee, and Site Reporting 
The investigator is responsible for notifying the local IRB/EC of SAEs or significant safety 
findings, or the relevant local regulatory authority of all SAEs that occur at his or her site as 
required by IRB/EC procedures. 
The Sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
(SUSARs) and any other applicable SAEs to regulatory authorities, investigators and IRBs or 
IECs, as applicable, in accordance with national regulations in the countries where the study is 
conducted. Relative to the first awareness of the event by/or further provision to the Sponsor or 
Sponsor’s designee, SUSARs will be submitted within 7 days for fatal and life-threatening 
events and 15 days for other serious events, unless otherwise required by national regulations. 
The Sponsor will also prepare an expedited report for other safety issues where these might 
materially alter the current benefit-risk assessment of an investigational medicinal product or that 
would be sufficient to consider changes in the investigational medicinal products administration 
or in the overall conduct of the Study. The investigational site also will forward a copy of all 
expedited reports to his or her IRB or IEC in accordance with national regulations. 
In addition, the sponsor is responsible for notifying active sites of all related, unexpected SAEs 
occurring during all interventional studies across the TAK-771 program. 
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10. DATA MANAGEMENT AND STATISTICAL METHODS 
10.1 Data Collection 
The investigators’ authorized site personnel must enter the information required by the study 
CRF Completion Guidelines or similar for all data requiring transcription of the source. A study 
monitor will visit each site in accordance with the monitoring plan and review the CRF data 
against the source data for completeness and accuracy. Discrepancies between source data and 
data entered on the CRF will be addressed by qualified site personnel. When a data discrepancy 
warrants correction, the correction will be made by authorized site personnel. Data collection 
procedures will be discussed with the site at the site initiation visit and/or at the investigator’s 
meeting. Once a subject is randomized, it is expected that site personnel will complete the CRF 
entry within approximately 3 business days of the subject’s visit. 
10.1.1 CRFs (Electronic and Paper) 
Completed CRFs are required for each subject who signs an informed consent. 
The Sponsor or its designee will supply investigative site with access to CRFs. The Sponsor will 
make arrangements to train appropriate site staff in the use of the CRF. These forms are used to 
transmit the information collected in the performance of this study to the Sponsor and regulatory 
authorities. eCRFs must be completed in English. Data are transcribed directly onto CRFs. 
After completion of the entry process, computer logic checks will be run to identify items, such 
as inconsistent dates, missing data, and questionable values. Queries may be issued by Takeda 
personnel (or designees) and will be answered by the site. 
Corrections are recorded in an audit trail that captures the old information, the new information, 
identification of the person making the correction, the date the correction was made, and the 
reason for change. Reasons for significant corrections should additionally be included. 
The principal investigator must review the CRFs for completeness and accuracy and must sign 
and date the appropriate CRFs as indicated. Furthermore, the investigator must retain full 
responsibility for the accuracy and authenticity of all data entered on the CRFs. 
After the lock of the clinical study database, any change of, modification of, or addition to the 
data on the CRFs should be made by the investigator with use of change and modification 
records of the CRFs. The principal investigator must review the data change for completeness 
and accuracy and must sign and date.  
CRFs will be reviewed for completeness and acceptability at the CRU during periodic visits 
by study monitors. The Sponsor or its designee will be permitted to review the subject’s 
medical and hospital records pertinent to the study to ensure accuracy of the CRFs.  
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The completed CRFs are the sole property of the Sponsor and should not be made available in 
any form to third parties, except for authorized representatives of appropriate governmental 
health or regulatory authorities, without written permission of the Sponsor. 
10.2 Clinical Data Management 
Data are to be entered into a clinical database as specified in the data management plan. Quality 
control and data validation procedures are applied to ensure the validity and accuracy of the 
clinical database. 
Data are to be reviewed and checked for omissions, errors, and values requiring further 
clarification using computerized and manual procedures. Data queries requiring clarification are 
to be communicated to the site for resolution. Only authorized personnel will make corrections to 
the clinical database, and all corrections are documented in an auditable manner. 
10.3 Data Handling 
The full details of procedures for data handling will be documented in the Data Management 
Plan. AEs, medical history, and concurrent conditions will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA). Drugs will be coded using the World Health 
Organization Drug Dictionary. 
10.4 Statistical Analysis Process 
The study will be analyzed by the sponsor or its agent. 
The study SAP will provide the statistical methods and definitions for the analysis of the study 
data, as well as describe the approaches to be taken for summarizing other study information 
such as subject disposition, demographics and baseline characteristics, IP 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 scientific integrity and regulatory utility of the statistical analysis and study 
conclusions, the SAP will be finalized prior to the study database lock. 
All statistical analyses will be performed externally by the sponsor-designated contract research 
organization (CRO), using SAS® (SAS Institute, Cary, NC 27513), Version 9.4 or higher. 
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10.5 Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee 
There is no planned interim analysis or adaptive design in this study. There is no DMC planned 
for this study. 
The tolerability and safety date up to Week 9 in Study Part 1 will be reviewed by a safety review 
team consisting of the Investigator, the Sponsor's Medical Monitor, and the Sponsor’s Global 
Drug Safety Physician before the first dosing in Study Part 2 is initiated (Section 4.1). 
10.6 Sample Size Calculation and Power Considerations 
Assessment of tolerability is the primary objective of this study. 
This study is not designed for statistical hypothesis testing, and therefore the sample size was not 
based on statistical considerations. 
The planned total sample size for this study is 48 randomized subjects (8 subjects per treatment 
arm and 6 treatments arms, equal randomization ratio). 
Of the 48 subjects to be randomized and enrolled, a minimum of 36 subjects are expected to 
complete the study, assuming a conservative dropout rate of 25% in this healthy subject study 
(overall dropout rates assumed for HYQVIA patient studies are generally 10%-15%). The 
number of subjects expected complete the study (36) is considered also adequate for providing 
reliable estimates of tolerability, safety, and PK for those using ramp up and no ramp up dosing. 
10.7 Study Population 
Analysis of tolerability, safety, immunogenicity and PK data will be based on the following 
analysis sets (analysis populations): 
Enrolled Set: 
All screened subjects for whom a randomization number has been assigned. Background 
summaries (e.g., subject disposition) will be based on the Enrolled Set. 
Safety Set: 
All enrolled subjects who received at least one dose of HYQVIA will be included in the safety 
evaluations. Analysis of tolerability, safety, and immunogenicity data will be based on the Safety 
Set. 
PK Set: 
All enrolled subjects who received at least one dose of HYQVIA and have at least one evaluable 
post-dose serum concentration for total IgG or IgG subclasses. Analysis of PK data will be based 
on the PK Set. 
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10.8 Pharmacokinetic and Pharmacodynamic Analyses 
10.8.1 Pharmacokinetic Analysis 
Serum levels of total IgG and IgG subclasses with and without baseline corrections will be 
summarized. Serum concentrations of total IgG and IgG subclasses at each nominal sampling 
time will also be summarized by dosing group and visit/timepoint using descriptive statistics. 
Individual PK parameters derived using NCA based on baseline-corrected total serum IgG or 
IgG subclasses levels will also be summarized. Summary statistics (number of subjects in the 
dosing group, number of subjects in the dosing group with evaluable PK parameter values, 
arithmetic mean, and SD, coefficient of variation, median, maximum, minimum, and geometric 
mean) will be provided for all PK parameters. In addition, 95% confidence intervals for 
geometric mean for the PK parameters will be provided for descriptive purposes only. 
Figures of individual and mean (± SD) concentration-time profiles will be produced. No 
statistical hypothesis testing will be performed. Tabular and graphical summaries will be 
presented, as appropriate, by Treatments (or Schedules), visit and timepoint.  
PK parameters that may be calculated from concentration-time profiles of total serum IgG and 
IgG subclasses using non-compartmental analysis (NCA), may include and not be limited to the 
following. 
Table 12. PK Parameters 
Pharmacokinetic Parameter 
Definition 
Cmax  
Maximum concentration occurring at tmax 
tmax  
Time of maximum observed concentration sampled during a dosing interval 
AUClast  
Area under the curve from the time of dosing to the last time point with 
measurable concentration 
t½  
Terminal half-life 
CL/F  
Apparent total clearance after extravascular administration 
Vz/F 
Apparent volume of distribution associated with the terminal slope following 
extravascular administration  
 
No value for Vz/F, or t½ will be reported for cases that do not exhibit a terminal log linear phase 
in the concentration time profile. 
No PK parameters will be calculated for subjects with 2 or fewer consecutive time points with 
detectable concentrations. 
Individual and mean serum concentration time curves (both linear and log linear) will be 
included in the final report. 
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10.8.2 Pharmacodynamic Analysis 
Not applicable. 
10.9 Safety and Immunogenicity Analyses 
The study will assess the tolerability, safety, and immunogenicity of HYQVIA in terms of 
the occurrence of HYQVIA-related AEs (primary endpoint), the occurrence of other AEs,  
anti-rHuPH20 antibody formation during treatment with HYQVIA (immunogenicity), as well 
as changes in clinical laboratory parameters and vital signs. 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Number and percentage of subjects with TEAEs, number of TEAEs, and other 
outcomes will be calculated overall, by SOC and by preferred term. TEAEs will be further 
summarized by severity and relationship to IP. TEAEs related to IP, TEAEs leading to 
withdrawal, SAEs, and deaths will be similarly summarized. 
Tolerability, safety and immunogenicity endpoint data will be analyzed using descriptive 
statistics. Continuous endpoints (e.g., change from baseline) will be summarized using the 
following descriptive statistics: number of subjects (n), mean, median, SD, minimum value, 
maximum value. Baseline is defined as the last non-missing value before the initial dose of 
HYQVIA. Categorical endpoints (e.g., occurrence of adverse events) will be summarized in 
terms of number and percent of subjects and number of occurrences in each category, as 
appropriate. 
Summaries of AEs, clinical laboratory parameters, vital signs, and immunogenicity will be 
presented, as appropriate, by dosing group (Ramp-Up, No Ramp Up) and treatment arms within 
dosing schedule, as displayed in the table below with the planned total sample size and sample 
size for each treatment arm. In addition, labs, vital signs, and immunogenicity data will be 
summarized by dosing group and visit. Potentially clinically important findings will also be 
summarized. ECGs data will be provided in the subject data listing(s) only. No statistical 
summary is planned. 
Note that in the display above, Ramp-Up dosing group (32 subjects in total) resulted from 
pooling of Treatment Arms 1, 2, 4, and 5, with 8 subjects each, and No Ramp-Up (16 subjects in 
total) resulted from pooling Treatment Arms 3 and 6, with 8 subjects each. 
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Table 13. Summary of Ramp-Up and No Ramp-Up Dosing Groups 
Ramp-Up 
(N=32) 
No Ramp-Up 
(N=16) 
Schedule A 
Schedule B 
 
Total 
Schedule C 
 
Total 
Low 
High 
Low 
High 
Low 
High 
Treatment 1 
(n=8) 
Treatment 4 
(n=8) 
Treatment 2 
(n=8) 
Treatment 5 
(n=8) 
All 
(n=32) 
Treatment 3 
(n=8) 
Treatment 6 
(n=8) 
All 
(n=16) 
Low = 0.4 g/kg, High = 1.0 g/kg. 
 
The overall summary, based on descriptive statistics, is the summary of the overall 
tolerability/safety/immunogenicity profile in the Ramp-Up dosing group (all treatments pooled) 
versus the overall profile in the No Ramp-Up group (all treatments pooled). 
Claim of tolerability/safety/immunogenicity of HYQVIA will be based on clinical judgment on 
the totality of evidence, to be derived from the overall summary, with no predefined 
tolerability/safety/immunogenicity statistical margin or criteria. 
Note: AEs below refer to TEAEs. 
The following will be displayed in statistical outputs, including but not limited to: 
• 
Number (percentage) of subjects with HYQVIA-related AEs (causally related AEs), and 
HYQVIA-related SAEs, and number of such events 
 AEs recorded in the study database as “possibly related” or “probably related” to 
HYQVIA will be considered HYQVIA-related AEs 
• 
Number (percentage) of subjects with HYQVIA-related AEs that were mild, moderate, or 
severe in severity, and number of events in each category 
• 
Number (percentage) of subjects with any AEs, any serious and/or nonserious AEs, and 
any local and systemic AEs/SAEs, regardless of causality  
• 
Number (percentage) of infusions for which the infusion rate was reduced, and/or the 
infusion was interrupted or stopped due to intolerability and/or AEs. 
• 
Number (percentage) subjects who completed infusions without requiring any adjustment 
due to intolerability and/AEs 
• 
Number (percentage) of subjects who prematurely discontinued study due to AEs  
• 
Rate of AEs, expressed as number of events per infusion, per subject, and per subject-year 
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• 
Raw (actual) values and change from baseline in clinical laboratory parameters 
• 
Raw (actual) values and change from baseline in vital signs 
• 
Number (percentage) of subjects who have developed binding and neutralizing antibodies 
to rHuPH20. 
 
Subject-level tolerability and safety data, including derived data, will be presented in subject data 
listings. 
Refer to Section 9.1 for AE definitions and details of procedures for recording, evaluating, and 
Reporting of AEs. 
10.10 Additional Analysis of AEs 
Specified in Section 3.3 is the safety endpoint, the number (percentage) of subjects and infusions 
with adverse reactions (AR) plus suspected AR of interest. This additional safety endpoint will 
be analyzed using descriptive statistics. 
Separate AE summaries will be produced for each criterion listed below. 
Definition: An AR plus suspected AR of interest is defined all AEs that meet one or more of the 
following criteria: 
a. 
The AE is a local infusion site AE. 
Note: All local infusion site AEs will be considered AR irrespective of 
 
investigator/sponsor opinions of causality. 
b. The AE began during infusion of HYQVIA or within 72 hours of the last infusion. 
c. 
The AE was considered at least possibly related to HYQVIA infusion by the investigator 
and/or the sponsor. 
d. The AE’s causality assessment was missing or indeterminate. 
e. 
The incidence of the AE preferred term among subjects in the combined high target level 
dose (1.0 g/kg) groups exceeded that among subjects in the combined low target level dose 
(0.4 g/kg) groups by 5% (absolute) or more. 
 
The summary is planned to display only AEs with Overall absolute difference of ≥5%, as 
illustrated below in an example, using dummy (not real) data; “XX” represents data. 
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AE 
Preferred 
Term 
Ramp-Up 
No Ramp-Up 
Overall 
High Dose 
(N=16) 
Low Dose 
(N=16) 
Difference 
(absolute) 
High Dose 
(N=8) 
Low Dose 
(N=8) 
Difference 
(absolute) 
High Dose 
(N=24) 
Low Dose 
(N=24) 
Difference 
(absolute) 
Term 1 
XX 
XX 
XX 
XX 
XX 
XX 
20% 
15% 
5% 
Term 2 
XX 
XX 
XX 
XX 
XX 
XX 
12% 
6% 
6% 
Term 3 
XX 
XX 
XX 
XX 
XX 
XX 
3% 
11% 
8% 
 
10.11 Other Analyses 
10.11.1 Analysis of Demography and Other Baseline Characteristics 
Demographic and other baseline characteristics data (including but not limited to baseline age, 
gender, weight, height, and BMI) will be summarized. Continuous data (e.g., age) and 
categorical data (e.g., gender) will be summarized using descriptive statistics. 
All subject-level data, including derived data, will be displayed in subject data listings. 
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11. ETHICS 
11.1 Informed Consent 
Investigators will choose patients for enrollment considering the study eligibility criteria. The 
investigator will exercise no selectivity so that no bias is introduced from this source. 
All patients must sign an informed consent form before entering into the study according to 
applicable national and local regulatory requirements and ICH GCP. Before use, the informed 
consent form will be reviewed by the sponsor and approved by the IRB and regulatory 
authority(ies), where applicable, (see Section 11.2). The informed consent form will include a 
comprehensive explanation of the proposed treatment without any exculpatory statements, in 
accordance with the elements required by ICH GCP and applicable national and local regulatory 
requirements. Patients will be allowed sufficient time to consider participation in the study. By 
signing the informed consent form, patients agree that they will complete all evaluations required 
by the study, unless they withdraw voluntarily or are terminated from the study for any reason. 
The sponsor will provide to the investigator in written form any new information 
that significantly bears on the subjects’ risks associated with IP exposure. The informed consent 
will be updated, if necessary. This new information and/or revised informed consent form, that 
have been approved by the applicable IRB and regulatory authorities, where applicable, will be 
provided by the investigator to the subjects who consented to participate in the study. 
The subject, or the subject’s legally acceptable representative, must be given ample opportunity 
to: (1) inquire about details of the study, and (2) decide whether or not to participate in the study. 
If the subject, or the subject’s legally acceptable representative, determines he or she will 
participate in the study, then the informed consent form and subject authorization form (if 
applicable) must be signed and dated by the subject, or the subject’s legally acceptable 
representative, at the time of consent and prior to the subject entering into the study. The subject 
or the subject’s legally acceptable representative should be instructed to sign using their legal 
names, not nicknames, using blue or black ballpoint ink. The investigator must also sign and date 
the informed consent form and subject authorization (if applicable) at the time of consent and 
prior to subject entering into the study; however, the Sponsor may allow a designee of the 
investigator to sign to the extent permitted by applicable law. 
Once signed, the original informed consent form, subject authorization form (if applicable), and 
subject information sheet (if applicable) will be stored in the investigator’s site file. The 
investigator must document the date the subject signs the informed consent in the subject’s 
medical record. Copies of the signed informed consent form, the signed subject authorization 
form (if applicable), and subject information sheet (if applicable) shall be given to the subject. 
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All revised informed consent forms must be reviewed and signed by relevant subjects or the 
relevant subject’s legally acceptable representative in the same manner as the original informed 
consent. The date the revised consent was obtained should be recorded in the subject’s medical 
record, and the subject should receive a copy of the revised informed consent form. 
It is the responsibility of the investigator to obtain written informed consent from all study 
subjects prior to any study-related procedures including screening assessments. All consent 
documentation must be in accordance with applicable regulations and GCP. Each subject or the 
subject’s legally-authorized representative, as applicable, is requested to sign and date the subject 
informed consent form or a certified translation if applicable, after the subject has received and 
read (or been read) the written subject information and received an explanation of what the study 
involves, including but not limited to: the objectives, potential benefits and risk, inconveniences, 
and the subject’s rights and responsibilities. A copy of the informed consent documentation 
(i.e., a complete set of subject information sheets and fully executed signature pages) must be 
given to the subject or the subject’s legally authorized representative, as applicable. This 
document may require translation into the local language. Signed consent forms must remain 
in each subject’s study file and must be available for verification at any time. 
The principal investigator provides the sponsor with a copy of the consent form which was 
reviewed by the IRB/EC and which received their favorable opinion/approval. A copy of the 
IRB/EC’s written favorable opinion/approval of these documents must be provided to the 
sponsor, prior to the start of the study unless it is agreed to and documented (abiding by 
regulatory guidelines and national provisions) prior to study start that another party (i.e., sponsor 
or coordinating principal investigator) is responsible for this action.  Additionally, if the IRB/EC 
requires modification of the sample subject information and consent document provided by the 
sponsor, the documentation supporting this requirement must be provided to the sponsor. 
11.2 Institutional Review Board or Ethics Committee 
IRBs and IECs must be constituted according to the applicable state and federal/local 
requirements of each participating region. The Sponsor or designee will require documentation 
noting all names and titles of members who make up the respective IRB or IEC. If any member 
of the IRB or IEC has direct participation in this study, written notification regarding his or her 
abstinence from voting must also be obtained. Those American sites unwilling to provide names 
and titles of all members due to privacy and conflict of interest concerns should instead provide a 
Federal Wide Assurance Number or comparable number assigned by the Department of Health 
and Human Services. 
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The Sponsor or designee will supply relevant documents for submission to the respective IRB or 
IEC for the protocol’s review and approval. This protocol, the Investigator’s Brochure, a copy of 
the informed consent form, and, if applicable, subject recruitment materials and/or 
advertisements and other documents required by all applicable laws and regulations, must be 
submitted to a central or local IRB or IEC for approval. The IRB’s or IEC’s written approval of 
the protocol and subject informed consent must be obtained and submitted to the Sponsor or 
designee before commencement of the study (i.e., before shipment of the Sponsor-supplied drug 
or study specific screening activity). The IRB or IEC approval must refer to the study by exact 
protocol title, number, and version date; identify versions of other documents (e.g., informed 
consent form) reviewed; and state the approval date. The Sponsor will ship drug/notify site once 
the Sponsor has confirmed the adequacy of site regulatory documentation and, when applicable, 
the Sponsor has received permission from competent authority to begin the Study. Until the site 
receives drug/notification no protocol activities, including screening, may occur. 
Sites must adhere to all requirements stipulated by their respective IRB or IEC. This may include 
notification to the IRB or IEC regarding protocol amendments, updates to the informed consent 
form, recruitment materials intended for viewing by subjects, local safety reporting requirements, 
reports and updates regarding the ongoing review of the study at intervals specified by the 
respective IRB or IEC, and submission of the investigator’s final status report to IRB or IEC. All 
IRB and IEC approvals and relevant documentation for these items must be provided to the 
Sponsor or its designee. 
Subject incentives should not exert undue influence for participation. Payments to subjects must 
be approved by the IRB or IEC and Sponsor. 
Responsibility for coordinating with IRBs/ECs is defined in the clinical trial agreement. 
IP supplied will not be released until the sponsor has received written IRB/EC approval. 
Prior to implementing changes in the study, the sponsor and the IRB/EC must approve any 
revisions of all informed consent documents and amendments to the protocol unless there is a 
subject safety issue. If required by local law, substantial amendments to the protocol must also 
be approved by the appropriate regulatory agency prior to implementation. 
For sites outside the EU, the investigator is responsible for keeping the IRB/EC appraised of the 
progress of the study and of any changes made to the protocol, at least annually or more 
frequently in accordance with the requirements, policies, and procedures established by the 
IRB/EC. This can be the responsibility of the sponsor or investigator for sites within the EU; or 
for multicenter studies, the coordinating principal investigator, according to national provisions.  
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The investigator must also keep the local IRB/EC informed of any serious and significant AEs as 
required by IRB/EC procedures. 
11.3 Good Clinical Practice Compliance 
The investigator must undertake to perform the study in accordance with ICH GCP Guideline E6 
(1996) and E6 R2 (2017), EU Directive 2001/20/EC, and applicable regulatory requirements and 
guidelines. 
It is the investigator’s responsibility to ensure that adequate time and appropriately trained 
resources are available at the site prior to commitment to participate in this study.  The 
investigator should also be able to estimate or demonstrate a potential for recruiting the required 
number of suitable subjects within the agreed recruitment period. 
The investigator will maintain a list of appropriately qualified persons to whom the investigator 
has delegated significant study-related tasks, and shall, upon request of the sponsor, provide 
documented evidence of any licenses and certifications necessary to demonstrate such 
qualification. Curriculum vitae for investigators and sub-investigators are provided to the study 
sponsor (or designee) before starting the study. 
If a potential research subject has a primary care physician, the investigator should, with the 
subject’s consent, inform them of the subject’s participation in the study. 
Agreement with the final clinical study report is documented by the signed and dated signature 
of the principal investigator, in compliance with Directive 2001/83/EC as amended by Directive 
2003/63/EC and ICH Guidance E3 (1995). 
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12. DATA HANDLING AND RECORD KEEPING 
12.1 Privacy and Confidentiality 
The Sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this study, a subject’s source data will only be linked to 
the Sponsor’s clinical study database or documentation via a unique identification number. As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, age, or 
date of birth, and subject initials may be used to verify the subject and accuracy of the subject’s 
unique identification number. 
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the 
Sponsor requires the investigator to permit its monitor or designee’s monitor, representatives 
from any regulatory authority (e.g., FDA, Medicines and Healthcare products Regulatory 
Agency, Pharmaceuticals and Medical Devices Agency), the Sponsor’s designated auditors, and 
the appropriate IRBs and IECs to review the subject’s original medical records (source data or 
documents), including, but not limited to, laboratory test result reports, ECG reports, admission 
and discharge summaries for hospital admissions occurring during a subject’s study 
participation, and autopsy reports. Access to a subject’s original medical records requires the 
specific authorization of the subject as part of the informed consent process (see Section 11.1). 
Copies of any subject source documents that are provided to the Sponsor must have certain 
personally identifiable information removed (i.e., subject name, address, and other identifier 
fields not collected on the subject’s CRF). 
All US-based sites and laboratories or entities providing support for this study, must, where 
applicable, comply with the HIPAA of 1996.  A site that is not a covered entity as defined by 
HIPAA must provide documentation of this fact to the sponsor. 
The confidentiality of records that may be able to identify subjects will be protected in 
accordance with applicable laws, regulations, and guidelines. 
After subjects have consented to take part in the study, the sponsor and/or its representatives’ 
reviews their medical records and data collected during the study. These records and data may, in 
addition, be reviewed by others including the following: independent auditors who validate the 
data on behalf of the sponsor; third parties with whom the sponsor may develop, register, or 
market Subcutaneous Immune Globulin Infusion 10% (Human)( HYQVIA/HyQvia) with 
Recombinant Human Hyaluronidase (rHuPH20); national or local regulatory authorities; and 
the IRB(s)/EC(s) which gave approval for the study to proceed. The sponsor and/or its 
representatives accessing the records and data will take all reasonable precautions in accordance 
with applicable laws, regulations, and guidelines to maintain the confidentiality of subjects’ 
identities. 
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Subjects are assigned a unique identifying number; however, their initials and date of birth may 
also be collected, if permitted under local laws governing privacy. 
The results of studies containing subjects’ unique identifying number, relevant medical records, 
and possibly initials and dates of birth, where allowed per local law, may be transferred to, and 
used in, other countries which may not afford the same level of protection that applies within the 
countries where this study is conducted. The purpose of any such transfer would include: to 
support regulatory submissions, to conduct new data analyses to publish or present the study 
results, or to answer questions asked by regulatory or health authorities. 
12.2 Study Documentation and Case Report Forms 
The investigator will maintain complete and accurate paper format study documentation in a 
separate file. Study documentation may include information defined as “source data”, records 
detailing the progress of the study for each subject, signed informed consent forms, 
correspondence with the IRB and the study monitor/sponsor, enrollment and screening 
information, CRFs, SAE reports (SAERs), laboratory reports (if applicable), and data 
clarifications requested by the sponsor.  
The investigator will comply with the procedures for data recording and reporting. Any 
corrections to paper study documentation must be performed as follows: 1) the first entry will be 
crossed out entirely, remaining legible; and 2) each correction must be dated and initialed by the 
person correcting the entry; the use of correction fluid and erasing are prohibited. 
The investigator is responsible for the procurement of data and for the quality of data recorded 
on the CRFs. CRFs will be provided in electronic form.  
If electronic format CRFs are provided by the sponsor, only authorized CRU personnel will 
record or change data on the CRFs. If data is not entered on the CRFs during the study visit, the 
data will be recorded on paper, and this documentation will be considered source documentation. 
Changes to a CRF will require documentation of the reason for each change. An identical 
(electronic/paper) version of the complete set of CRFs for each subject will remain in the 
investigator file at the CRU in accordance with the data retention policy (see Section 12.2). 
The handling of data by the sponsor, including data quality assurance, will comply with 
regulatory guidelines (e.g., ICH GCP) and the standard operating procedures of the sponsor. 
Data management and control processes specific to the study will be described in the data 
management plan. 
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12.3 Document and Data Retention  
The investigator will retain study documentation and data (paper and electronic forms) in 
accordance with applicable regulatory requirements and the document and data retention policy, 
as described in the CTA. 
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13. QUALITY CONTROL AND QUALITY ASSURANCE 
13.1 Investigator’s Responsibility 
The investigator will comply with the protocol (which has been approved/given favorable 
opinion by the IRB), ICH GCP, and applicable national and local regulatory requirements as 
described in the CTA. The investigator is ultimately responsible for the conduct of all aspects of 
the study at the CRU and verifies by signature the integrity of all data transmitted to the sponsor. 
The term “investigator” as used in this protocol as well as in other study documents, refers to the 
investigator or authorized study personnel that the investigator has designated to perform certain 
duties. Subinvestigators or other authorized study personnel are eligible to sign for the 
investigator, except where the investigator’s signature is specifically required. 
13.1.1 Final Clinical Study Report 
The investigator, or coordinating investigator(s) for multicenter studies, will sign the clinical 
study report. The coordinating investigator will be selected before study start. 
13.2 Training 
The study monitor will ensure that the investigator and CRU personnel understand all 
requirements of the protocol, the investigational status of the IP, and his/her regulatory 
responsibilities as an investigator. Training may be provided at an investigator’s meeting, at the 
CRU, 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 CRU and the sponsor. 
13.3 Monitoring 
The study monitor is responsible for ensuring and verifying that each CRU conducts the study 
according to the protocol, standard operating procedures, other written instructions/agreements, 
ICH GCP, and applicable national and local regulatory guidelines/requirements. The investigator 
will permit the study monitor to visit the CRU at appropriate intervals, as described in the CTA. 
Monitoring processes specific to the study will be described in the clinical monitoring plan. 
13.4 Auditing 
To ensure compliance with relevant regulations, data generated by this study must be available 
for inspection upon request by representatives of, for example, the US FDA (as well as other US 
national and local regulatory authorities), the EMA, the Medicines and Healthcare products 
Regulatory Agency, other regulatory authorities, the sponsor or its representatives, and the 
IRB/EC for each site. 
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The sponsor and/or sponsor’s representatives may conduct audits to evaluate study conduct and 
compliance with the protocol, standard operating procedures, other written 
instructions/agreements, ICH GCP, and applicable national and local regulatory 
guidelines/requirements. The investigator will permit auditors to visit the CRU, as described in 
the CTA. Auditing processes specific to the study will be described in the audit plan. 
13.5 Non-Compliance with the Protocol 
The investigator may deviate from the protocol only to eliminate an apparent immediate hazard 
to the subject. In the event(s) of an apparent immediate hazard to the subject, the investigator 
will notify the sponsor immediately by phone and confirm notification to the sponsor in writing 
as soon as possible, but within 1 calendar day after the change is implemented. The sponsor 
(Baxalta) will also ensure the responsible EC/IRB and relevant competent authority is notified of 
the urgent measures taken in such cases according to local regulations. 
If monitoring and/or auditing identify serious and/or persistent non-compliance with the 
protocol, the sponsor may terminate the investigator’s participation. The sponsor will notify the 
EC/IRB and applicable regulatory authorities of any investigator termination. 
14. FINANCING AND INSURANCE 
The investigator will comply with investigator financing, investigator/sponsor insurance, and 
subject compensation policies, if applicable, as described in the CTA. 
15. PUBLICATION POLICY 
The investigator will comply with the publication policy as described in the CTA. 
 
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16. REFERENCES 
Baxalta US Inc. 2019. HYQVIA [Immune Globulin Infusion 10% (Human) with Recombinant 
Human Hyaluronidase] - Prescribing Information.Web Link: 
https://www.shirecontent.com/PI/PDFs/HYQVIA_USA_ENG.pdf 
Eastern Cooperative Oncology Group 2006. Common toxicity criteria of the Eastern Cooperative 
Oncology Group.Web Link: http://www.ecog.org/general/ctc.pdf 
Food and Drug Administration 2008. U.S.Department of Health and Human Services, Center for 
Biologics Evaluation and Research, Guidance for industry: Safety, efficacy, and 
pharmacokinetic studies to support marketing of immune globulin intravenous (human) 
as replacement therapy for primary humoral immunodeficiency.Web Link: 
https://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulator
yInformation/Guidances/Blood/ucm078526.pdf 
Oken, M. M., Creech, R. H., Tormey, D. C., Horton, J., Davis, T. E., McFadden, E. T. & 
Carbone, P. P. 1982. Toxicity and response criteria of the Eastern Cooperative Oncology 
Group. Am J Clin Oncol, 5, 649-655. 
World Health Organization 2003. Toxicity grading scale for determining the severity of adverse 
events.Web Link: 
http://www.icssc.org/Documents/Resources/AEManual2003AppendicesFebruary_06_20
03%20final.pdf 
Investigator’s Brochure, IGI, 10% with rHuPH20, Immune Globulin Infusion 10% (Human) with 
Recombinant Human Hyaluronidase. Edition 6.0: Approval Date: 05 Mar 2019 
 
For non-commercial use only


For non-commercial use only

SAP_001.pdf: 
NCT Number: NCT04578535
Title: A Phase 1, Open-Label, Randomized Study to Assess the Tolerability, Safety, 
and Pharmacokinetics of Subcutaneous Immune Globulin Infusion 10% (Human) 
with Recombinant Human Hyaluronidase (HYQVIA/HyQvia) with Ramp-Up and 
No Ramp-Up Dosing in Healthy Adult Subjects
Study Number: TAK-771-1001
Document Version and Date: Statistical Analysis Plan Version 2.0, 22-APR-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. 
Statistical Analysis Plan


Shire        
 CONFIDENTIAL 
Page 1 of 45 
Statistical Analysis Plan v2.0 
Protocol Number: TAK-771-1001 
22 April 2022 
STATISTICAL ANALYSIS PLAN 
HYQVIA/HyQvia 
PHASE 1 
A Phase 1, Open-Label, Randomized Study to Assess the Tolerability, Safety, and 
Pharmacokinetics of Subcutaneous Immune Globulin Infusion 10% (Human) with Recombinant 
Human Hyaluronidase (HYQVIA/HyQvia) with Ramp-Up and No Ramp-Up Dosing in Healthy 
Adult Subjects 
PROTOCOL IDENTIFIER: TAK-771-1001 
Study Sponsor(s): 
Baxalta US Inc.* 
300 Shire Way, Lexington, MA 02421 
AND 
Baxalta Innovations GmbH* 
Industriestrasse 67, A-1221 Vienna 
*Baxalta is now part of Shire
Author: 
, PPD statistician 
, PPD pharmacokineticist 
Protocol: 
Amendment 1.0: 30 Jun 2020 
SAP Version #: 
V2.0 
SAP Date: 
22APR2022 
Status: 
Final 
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Statistical Analysis Plan v2.0 
Protocol Number: TAK-771-1001 
22 April 2022 
 
 
 
 
REVISION HISTORY 
Version  
Issue Date 
Summary of Changes 
1.0 
Original Version  
2.0 
22APR2022 
• 
Section 7: Tolerability Analysis 
Definitions of tolerability analysis clarified. 
• 
Section 8.1 Adverse Events:  
Text added to define local versus systemic 
adverse events; 
definition of subject-years updated. 
• 
Section 9: Pharmacokinetic Analysis 
Clarification on required tables and figures; 
clarification of handling of baseline-corrected 
concentrations <0; another PK parameter 
(AUC0-D8) added. 
 
 
 
 
 
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Statistical Analysis Plan v2.0 
Protocol Number: TAK-771-1001 
22 April 2022 
 
 
 
 
TABLE OF CONTENTS 
REVISION HISTORY ............................................................................................... 2 
TABLE OF CONTENTS............................................................................................ 3 
ABBREVIATIONS..................................................................................................... 6 
1. 
INTRODUCTION ........................................................................................... 8 
2. 
OBJECTIVES AND ENDPOINTS ................................................................. 8 
2.1 
Objectives .................................................................................................... 8 
2.1.1 Primary Objective .................................................................................. 8 
2.1.2 Secondary Objectives ............................................................................. 8 
2.2 
Endpoints ..................................................................................................... 9 
2.2.1 Primary Endpoints ................................................................................. 9 
2.2.2 Safety and Immunogenicity Endpoints .................................................... 9 
2.2.3 PK Endpoints......................................................................................... 9 
3. 
STUDY DESIGN ............................................................................................. 9 
3.1 
General Description ...................................................................................... 9 
3.2 
Randomization ........................................................................................... 13 
3.3 
Blinding ..................................................................................................... 13 
3.4 
Sample Size and Power Considerations ....................................................... 13 
4. 
STATISTICAL ANALYSIS SETS................................................................ 14 
4.1 
Enrolled Set................................................................................................ 14 
4.2 
Safety Set ................................................................................................... 14 
4.3 
Pharmacokinetic Set ................................................................................... 14 
5. 
STUDY SUBJECTS ...................................................................................... 14 
5.1 
Disposition of Subjects ............................................................................... 14 
5.2 
Demographic and Other Baseline Characteristics ......................................... 15 
5.3 
Medical History .......................................................................................... 16 
5.4 
Prior Therapies, Procedures, and Medication ............................................... 16 
5.5 
Concomitant Therapies, Procedures, and Medications .................................. 17 
5.6 
Exposure to Investigational Product............................................................. 17 
5.7 
Measurements of Treatment Compliance ..................................................... 17 
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5.8 
Protocol Deviations .................................................................................... 18 
6. 
EFFICACY ANALYSES............................................................................... 18 
7. 
TOLERABILITY ANALYSIS ...................................................................... 18 
7.1 
Definitions.................................................................................................. 18 
7.2 
Summaries of Infusion Tolerability ............................................................. 19 
8. 
SAFETY ANALYSIS .................................................................................... 20 
8.1 
Adverse Events........................................................................................... 20 
8.1.1 Definitions ........................................................................................... 20 
8.1.2 AE Data Summaries ............................................................................. 21 
8.2 
Clinical Laboratory Data ............................................................................. 23 
8.3 
Vital Signs.................................................................................................. 25 
8.4 
Electrocardiogram ...................................................................................... 26 
8.5 
Other Safety Data ....................................................................................... 26 
8.5.1 Immunogenicity Testing for Anti-Drug Antibodies ............................... 26 
8.5.2 COVID-19 ........................................................................................... 26 
8.5.3 Physical Examination ........................................................................... 26 
8.5.4 Pregnancy ............................................................................................ 26 
9. 
PHARMACOKINETIC ANALYSIS ............................................................ 26 
9.1 
Drug Concentration .................................................................................... 26 
9.2 
Handling Below Limit of Quantitation Values ............................................. 27 
9.3 
Pharmacokinetic Parameters........................................................................ 28 
9.4 
Statistical Analysis of Pharmacokinetic Data ............................................... 28 
10. 
PHARMACODYNAMIC ANALYSIS .......................................................... 29 
11. 
OTHER ANALYSES .................................................................................... 29 
12. 
INTERIM ANALYSIS/ DATA MONITORING (REVIEW) COMMITTEE29 
13. 
DATA HANDLING CONVENTIONS .......................................................... 29 
13.1 
General Data Reporting Conventions........................................................... 29 
13.2 
Repeated or Unscheduled Assessments of Safety Parameters........................ 30 
13.3 
Handling of Missing, Unused, and Spurious Data ........................................ 30 
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13.3.1 Missing Date Information for Prior or Concomitant Medications 
(Therapies/Procedures)......................................................................... 30 
13.3.1.1 Incomplete Start Date ............................................................. 30 
13.3.1.2 Incomplete Stop Date ............................................................. 31 
13.3.2 Missing Date Information for Adverse Events ....................................... 31 
13.3.2.1 Incomplete Start Date ............................................................. 32 
13.3.2.2 Incomplete Stop Date ............................................................. 32 
13.3.3 Missing Severity Assessment for Adverse Events.................................. 32 
13.3.4 Missing Relationship to IP for Adverse Events...................................... 32 
13.3.5 Character Values of Clinical Laboratory Variables ................................ 32 
14. 
ANALYSIS SOFTWARE.............................................................................. 32 
15. 
CHANGES TO ANALYSIS SPECIFIED IN PROTOCOL.......................... 33 
16. 
REFERENCES.............................................................................................. 34 
17. 
APPENDICES ............................................................................................... 35 
17.1 
Schedule of Activities ................................................................................. 35 
17.2 
Grading of Laboratory Parameters ............................................................... 45 
 
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Statistical Analysis Plan v2.0 
Protocol Number: TAK-771-1001 
22 April 2022 
 
 
 
 
ABBREVIATIONS 
λz 
terminal disposition elimination rate constant  
ADA 
anti-drug antibody 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
aPTT 
activated partial thromboplastin time  
AR 
adverse reaction 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
AUC0-D8 
area under the concentration-time curve from time zero to Day 8 
AUC0-last 
area under the concentration-time curve from time zero to the last 
quantifiable concentration 
AUC0-∞ 
area under the concentration-time curve from time zero extrapolated to 
infinity  
BMI 
body mass index 
BUN 
blood urea nitrogen 
CBC 
complete blood count; 
CIDP 
chronic inflammatory demyelinating polyradiculoneuropathy 
Cmax 
maximum observed concentration 
CL/F 
apparent total clearance after extravascular administration 
CRU 
clinical research unit 
DL 
dose level 
DMC 
Data monitoring committee 
eCRF 
electronic case report form 
ECG 
electrocardiogram 
EOS 
end of study 
ET 
early termination 
FSH 
follicle stimulating hormone 
Hb 
hemoglobin 
Hct 
hematocrit 
HBsAG 
hepatitis B surface antigen 
HBsAb 
hepatitis B surface Antibody 
HBcAb 
hepatitis B core Antibody 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
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Statistical Analysis Plan v2.0 
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HIV 
human immunodeficiency virus 
HR 
heart rate 
IgG 
Immunoglobulin G 
IGI 
Immune Globulin Infusion 
INR 
International normalized ratio 
IP 
investigational product 
LDH 
lactate dehydrogenase 
LLOQ 
lower limit of quantification 
MCH 
Mean Corpuscular Hemoglobin 
MCHC 
Mean Corpuscular Hemoglobin Concentration 
MCV 
Mean Corpuscular Volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
N 
number of subjects 
nADA 
neutralizing anti-drug antibody 
PCI 
potentially clinically important 
PK 
pharmacokinetic(s) 
p.p 
percentage points 
PT 
preferred term 
RBC 
red blood cells 
RDW 
Red Cell Distribution Width 
rHuPH20 
recombinant human hyaluronidase PH20 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis System 
SD 
standard deviation 
SOC 
system organ class 
TEAE   
treatment-emergent adverse event 
t½ 
terminal disposition phase half-life 
TDL 
target (full) dose level 
TEAE 
treatment-emergent adverse event 
tmax 
time of maximum observed concentration 
ULN 
upper limit of normal 
UPCR 
urine protein to creatinine ratio 
Vz/F 
apparent volume of distribution during the terminal disposition phase 
after extravascular administration 
WBC 
white blood cells 
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Statistical Analysis Plan v2.0 
Protocol Number: TAK-771-1001 
22 April 2022 
 
 
 
 
1. 
INTRODUCTION  
Dose ramp up has been considered necessary for HYQVIA in the Phase 3 Study (Study 161403) 
because the majority of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) 
patient population are naïve to subcutaneous (SC) infusions, or inexperienced with SC infusions 
at large volumes (>60 mL per infusion site; infusion volume maximum per day: up to 600 mL (1 
site) or 1200 mL (2 sites)). As a result, a dose ramp-up schedule was included in Study 161403 
which involves a stepwise gradual increase until the subject’s full dose is reached to improve 
tolerability. Dose ramp-up is currently in the approved prescribing information for primary 
immune deficiency. Despite the current use of ramp up dosing in primary immunodeficiency 
disease and CIDP patients, the tolerability and safety of HYQVIA without ramp-up has not been 
evaluated in clinical settings. This Phase 1 study is planned to assess the tolerability, safety and 
immunogenicity profile of HYQVIA with and without ramp-up dosing in healthy adult subjects 
and to characterize the pharmacokinetics (PK) of total Immunoglobulin G (IgG) and IgG 
subclasses in serum after SC administration of HYQVIA in healthy adult subjects. 
This statistical analysis plan (SAP) provides a technical and detailed elaboration of the statistical 
analyses of safety and tolerability data as well as PK analyses, as described in the amended 
protocol (amendment 1) dated 30 Jun 2020. Specifications for tables, figures, and listings are 
contained in a separate document.  
2. 
OBJECTIVES AND ENDPOINTS 
2.1 
Objectives 
2.1.1 
Primary Objective 
To assess the tolerability of HYQVIA with and without ramp-up dosing in healthy adult subjects. 
2.1.2 
Secondary Objectives 
• To assess the safety and immunogenicity of HYQVIA with and without ramp-up dosing 
in healthy adult subjects. 
• To characterize the PK of total IgG and IgG subclasses in serum after SC administration 
of HYQVIA in healthy adult subjects. 
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Statistical Analysis Plan v2.0 
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2.2 
Endpoints 
2.2.1 
Primary Endpoints 
The primary endpoint corresponding to the primary objective of the study is the occurrence of 
tolerability events related to the infusion of HYQVIA. 
Note: For definitions related to tolerability of infusions refer to section 7.1. 
2.2.2 
Safety and Immunogenicity Endpoints 
• Occurrence of treatment-emergent adverse events (TEAEs), including but not limited to: 
HYQVIA-related and non-related, serious, nonserious, severe, local and systemic TEAEs, 
TEAEs leading to premature discontinuation from study, and infusion-associated TEAEs, 
as well as number and percentage of subjects and infusions with suspected adverse 
reactions (AR) plus AR of interest. 
• Clinical laboratory parameters 
• Vital signs 
• Immunogenicity: occurrence of binding and neutralizing antibodies (anti-drug antibodies 
[ADA]) to recombinant human hyaluronidase PH20 (rHuPH20) 
 
Note that clinically significant treatment-emergent changes in clinical laboratory measurements 
and vital signs will be recorded in the study database as TEAEs. 
2.2.3 
PK Endpoints 
PK parameters for serum total IgG and IgG subclasses after a single dose of HYQVIA (i.e. after 
Week 1 dosing), including but not limited to maximum observed concentration (Cmax), time of 
maximum observed concentration (tmax), the area under the concentration-time curve, from time 
zero to the last quantifiable concentration, as calculated by the linear-log trapezoidal method 
(AUClast), area under the concentration-time curve from time zero extrapolated to infinity 
(AUC0­∞), terminal disposition phase half-life (t1/2), apparent total clearance after extravascular 
administration (CL/F, only for total IgG) and apparent volume of distribution during the terminal 
disposition phase after extravascular administration (Vz/F, only for total IgG).  
3. 
STUDY DESIGN 
3.1 
General Description 
This study is a Phase 1, open-label, randomized, single-center study to evaluate the tolerability, 
safety and immunogenicity of HYQVIA with and without ramp-up dosing and to characterize the 
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Statistical Analysis Plan v2.0 
Protocol Number: TAK-771-1001 
22 April 2022 
 
 
 
 
PK of total IgG and IgG subclasses in serum after SC administration of HYQVIA in healthy 
adult subjects. 
The investigational product is subcutaneous Immune Globulin Infusion 10% (Human) (IGI 10%) 
with Recombinant Human Hyaluronidase (rHuPH20) (also referred to as IGI 10% with 
rHuPH20, or HYQVIA); infusion of IGI 10% will be followed by an infusion of rHuPH20. 
This study is comprised of two parts, Study Parts 1 & 2. The IGI 10% target dose level (TDL) of 
either 0.4 g/kg (Part 1) or 1.0 g/kg (Part 2) will be achieved through dose ramp-up or no ramp up 
(i.e., immediate administration of the TDL). Each study part consists of three Treatment Arms 
(Part 1: Treatment Arms 1-3 and Part 2: Treatment Arms 4-6): 
• Treatment Arms 1 and 4 will follow ramp up Schedule-A (Sch-A), in which subjects will 
receive HYQVIA from ¼ of the TDL at Week 1 to the full TDL at Week 8. 
• Treatments Arms 2 and 5 will follow ramp up Schedule-B (Sch-B), in which subjects will 
receive HYQVIA from ½ of the TDL at Week 1 to the full TDL at Week 5. 
• Treatment Arms 3 and 6 will follow ramp up Schedule-C (Sch-C), in which subjects will 
directly receive the full TDL at Week 1 without ramp-up dosing. 
 
Treatment arms will be initiated in parallel in each study part. Each subject will participate in 
only one treatment arm. 
Subjects meeting all eligibility criteria will be assigned to one of the 3 treatment arms in a Study 
Part at a randomization ratio of 1:1:1, and a minimum of 3 subjects in each of the body mass 
index (BMI) groups (18 to <25 kg/m2, ≥25 to 30 kg/m2) in each treatment arm, achievable using 
stratified randomization (BMI as the stratification factor). 
After all subjects in Treatment Arms 1-3 have completed Week 9 treatment in Study Part 1, their 
tolerability, safety and immunogenicity data through Week 9 will be reviewed by a safety review 
team consisting of the Investigator, the Sponsor’s Medical Monitor, and the Sponsor’s Global 
Drug Safety Physician. Proceeding to Study Part 2 dosing may only occur following this review. 
The planned dose levels including ramp-up dose levels of IGI 10% to be evaluated are outlined 
in Table 1. 
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Statistical Analysis Plan v2.0 
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Table 1 Planned Dose Levels IGI 10% 
DL 
Fraction of TDL 
Part 1 (g/kg) 
Part 2 (g/kg) 
DL1 
1/4 of TDL 
0.1 
0.25 
DL2 
1/2 of TDL 
0.2 
0.50 
DL3 
3/4 of TDL 
0.3 
0.75 
DL4 
TDL 
0.4 
1.0 
 
 
Each study part consists of 3 periods: 
 
• Screening period: up to 21 days prior to first dosing. 
• Study treatment period: 8 weeks for Treatment Arms 1 and 4; 9 weeks for Treatment 
Arms 2, 3, 5, and 6. 
• Follow up period: 16 (± 1) weeks after receiving the last infusion of HYQVIA with the 
end of study or early termination (EOS/ET) being in Weeks 24 (± 1) (Treatment arms 1 
and 4) or 25 (± 1) (Treatment arms 2, 3, 5, and 6). 
 
All subjects who received at least one dose of HYQVIA (including subjects who terminate the 
study early) will return to the Clinical Research Unit (CRU) 16 (± 1) weeks after the last infusion 
of HYQVIA for follow-up procedures. 
 
 
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Statistical Analysis Plan v2.0 
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Figure 1: Study Schematic 
 
 
 
 
 
After all subjects in Study Part 1 
complete Week 9, a safety data review of 
the data collected through Week 9 will 
be conducted before the first dosing is 
initiated in Study Part 2 
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3.2 
Randomization 
Prior to receiving the first infusion of HYQVIA, screened subjects who are qualified to enroll in 
this study are to be randomized to a treatment arm as depicted in the Study Schematic. 
This study comprises of two parts, Study Parts 1 & 2. Each study part consists of 3 treatment 
arms, and each subject will participate in only one treatment arm: 
• Part 1 (TDL 0.4 g/kg): Treatment Arms 1-3 
• Part 2 (TDL 1.0 g/kg): Treatment Arms 4-6 
A total of 48 subjects will be randomized to 6 parallel treatment arms (8 subjects per treatment 
arm, equal randomization ratio): 24 subjects in total to Part 1 and 24 subjects in total to Part 2. 
Randomization will be stratified by BMI group (18 to <25 kg/m2 and ≥25 to 30 kg/m2) in order 
to ensure a minimum of 3 subjects are randomized to each of the 2 BMI groups in each treatment 
arm in each part (BMI as the stratification factor). 
3.3 
Blinding  
Blinding is not applicable for this open-label study. 
3.4 
Sample Size and Power Considerations 
Assessment of tolerability is the primary objective of this study. This study was not designed for 
statistical hypothesis testing, and therefore the sample size was not based on statistical 
considerations. 
The planned total sample size for this study is 48 randomized subjects (8 subjects per treatment 
arm and 6 treatments arms, equal randomization ratio). 
Of the 48 subjects to be randomized and enrolled, a minimum of 36 subjects are expected to 
complete the study, assuming a conservative dropout rate of 25% in this healthy subject study 
(overall dropout rates assumed for HYQVIA patient studies are generally 10%-15%). The 
number of subjects expected complete the study (36) is considered also adequate for providing 
reliable estimates of tolerability, safety, and PK for those using ramp up and no ramp up dosing. 
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4. 
STATISTICAL ANALYSIS SETS 
4.1 
Enrolled Set  
All screened subjects for whom a randomization number has been assigned. Background 
summaries (e.g., subject disposition) will be based on the Enrolled Set, unless otherwise 
specified in this SAP. 
4.2 
Safety Set   
All enrolled subjects who received at least one dose of HYQVIA will be included in the safety 
evaluations. Analysis of tolerability, safety, and immunogenicity data will be based on the Safety 
Set. 
4.3 
Pharmacokinetic Set  
All enrolled subjects who received at least one dose of HYQVIA and have at least one evaluable 
post-dose serum concentration for total IgG or IgG subclasses. Analysis of PK data will be based 
on the PK Set.  
The protocol deviation log will be reviewed on a case-by-case basis. Exclusion of any subject 
from the PK Set will be determined at the discretion of the Sponsor’s Pharmacokineticist.  
5. 
STUDY SUBJECTS 
5.1 
Disposition of Subjects 
Subject disposition summaries and listings will be based on the Enrolled Set, and the summaries 
will be presented by dosing group (Ramp-Up , No Ramp-Up, and Overall) and treatment arms 
within dosing group, following the format in Table 2 below. 
Table 2 General Display of Subject Disposition and Subject Characteristics Summary Data 
Ramp-Up 
No Ramp-Up 
(N=16) 
Overall 
Total  
(n=48) 
(N=32) 
Schedule A 
Schedule B 
Total 
Schedule C 
Total 
Low TDL 
High TDL 
Low TDL 
High TDL 
Low TDL 
High TDL 
Treatment 1 Treatment 4 
Treatment 2 
Treatment 5 
All 
Treatment 3 
Treatment 6 
All 
(n=8) 
(n=8) 
(n=8) 
(n=8) 
(n=32) 
(n=8) 
(n=8) 
(n=16) 
Low=0.4 g/kg, High=1.0 g/kg. 
Note: Sample sizes (n) shows planned sample size; n for Ramp-Up Total (n=32) results from pooling of Treatment 
Arms 1, 2, 4, and 5, with 8 subjects each; n for No Ramp-Up Total (n=16) results from pooling Treatment Arms 3 
and 6, with 8 subjects each; n for Overall Total (n=48) results from pooling across Ramp-Up and No Ramp-Up. 
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Subject disposition will be summarized once for the whole population and additionally once by 
BMI group. 
The number and percentage of subjects included in each analysis set (Enrolled, Safety and PK) 
will be summarized. The reasons for exclusion from the PK set will be included in the same 
summary. 
The number and percentage of subjects who completed the study or prematurely discontinued 
will be presented, along with primary reasons for discontinuation, as recorded on the study 
completion page of the eCRF.  
All enrolled subjects who prematurely discontinued the study will be listed in the subject 
disposition listing along with reasons for discontinuation. 
5.2 
Demographic and Other Baseline Characteristics 
The following demographic characteristics will be summarized in the following order in the 
tables: age (years), sex, ethnicity, race. Other baseline characteristics include weight (kg), height 
(cm), BMI (kg/m2), and BMI group (18 to <25 kg/m2 and ≥25 to 30 kg/m2). 
Age will be calculated as the integer part of (date of informed consent is signed – date of birth + 
1)/365.25. BMI from the screening visit eCRF will be used; if BMI from screening visit is 
missing, height and weight from the screening visit will be used to calculate BMI as: weight (kg) 
/ (height [m])2. 
Continuous variables, such as age, weight, height, and BMI will be summarized using descriptive 
statistics including n, mean, standard deviation (SD), median, minimum, and maximum. 
Categorical variables such as sex, ethnicity, and race will be summarized by reporting the 
number and percentage of subjects in each category.  
All demographic and other baseline characteristics variables that will be summarized will be 
taken from the Screening Visit (or the last value measured prior to the first administration of 
investigational product). Summaries will be based on the Safety Set and PK Set, as appropriate. 
Demographics and other baseline characteristics data will be listed, and the listing will be based 
on the Enrolled Set.  
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5.3 
Medical History 
At screening, the subject’s medical history will be described for the following body systems 
including severity 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 other medications taken and non-drug therapies received from enrollment until 
completion/termination will be recorded on the concomitant medications and non-drug therapies 
CRFs  
Medical history will be coded using Medical Dictionary for Regulatory Activities (MedDRA) 
version 24.0.  
Medical history will be listed and summarized by system organ class (SOC) and preferred term 
(PT) for each dosing group (Ramp-Up, No Ramp-Up) and treatment arms within dosing group 
for the Safety Set. The summary will include number and percentage of subjects who 
experienced the event, and number of events experienced. System organ class will be sorted 
alphabetically, and PT will be sorted within each SOC in descending overall frequency of no-
ramp-up group.  
5.4 
Prior Therapies, Procedures, and Medication  
Prior treatments, medications, or procedures are defined as any treatment, medication, or 
procedure received within 60 days prior to the date of first dose of HYQVIA.  
Prior medications will be coded using the World Health Organization (WHO) Drug Dictionary 
version Global B3 March 2020. Prior therapies and procedures will not be coded. 
The number and proportion of subjects receiving each prior medication will be summarized by 
therapeutic class and preferred name for each dosing group (Ramp-Up, No Ramp-Up) and 
treatment arms within dosing schedule for the Safety Set. Therapeutic class will be sorted 
alphabetically, and preferred name within each therapeutic class will be sorted in descending 
overall frequency of the no-ramp up group. Multiple medication usage by a subject in the same 
category will be counted only once. 
No summaries will be provided for prior therapies and prior procedures. 
All prior therapies, procedures, and medications will be listed. 
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5.5 
Concomitant Therapies, Procedures, and Medications  
Concomitant therapies, medications, or procedures are defined as any therapy, medication, or 
procedure with start date on or after first date of HYQVIA administration, or with start date prior 
to HYQVIA administration but continuing at or after HYQVIA administration. Any therapy, 
medication, or procedure with a start date after the end of the follow-up period (Weeks 24 (± 1) 
(Treatment Arms 1 and 4) or 25 (± 1) (Treatment Arms 2, 3, 5, and 6)) will be considered post-
treatment and not concomitant.  
Concomitant medications will be coded using the WHO Drug Dictionary version Global B3 
March 2020. Concomitant therapies and procedures will not be coded. 
The number and proportion of subjects receiving each concomitant medication will be 
summarized by therapeutic class and preferred name for each dosing group (Ramp-Up, No 
Ramp-Up) and treatment arms within dosing schedule for the Safety Set. Therapeutic class will 
be sorted alphabetically, preferred name within each therapeutic class will be sorted by 
descending overall frequency of the no ramp-up group. Multiple medication usage by a subject in 
the same category will be counted only once. 
No summaries will be provided for concomitant therapies and concomitant procedures. 
All concomitant therapies, procedures, and medication will be listed. 
5.6 
Exposure to Investigational Product 
An exposure data listing, based on the Safety Set, will be provided and include start and end date 
and time of dose administration, and other exposure data, e.g. planned dose/volume. 
5.7 
Measurements of Treatment Compliance  
Treatment compliance will be summarized by means of number of infusions completed, number 
of infusions with change of infusion rate (flow), number of infusions interrupted, number of 
infusions stopped (discontinued), and the percentage of total volume administrated relative to the 
planned volume; all based on the number of initiated infusions. All compliance-related data will 
be included in the exposure data listing.  
To determine whether the infusion rate is changed, the Study Drug Administration CRF form 
will be used. If “Was the infusion rate reduced?” = “Yes” or “Infusion Rate Changed” is 
checked, then the infusion rate will be considered to have been changed. 
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5.8 
Protocol Deviations 
Protocol deviations will be recorded separately from the clinical database using a Protocol 
Deviation tracker. Protocol deviations will be classified as major or minor per the agreed 
protocol deviation management plan and will be documented in the Protocol Deviation tracker. 
The Sponsor study team will review the protocol deviations and their classification throughout 
the study and before database lock. 
Protocol deviations will be summarized by category (major/minor) for each dosing group (Ramp-
Up, No Ramp-Up) and treatment arms within dosing group, based on the Safety Set. All protocol 
deviations will be listed based on the Safety Set.  
6. 
EFFICACY ANALYSES 
There is no efficacy endpoint in this study; therefore, no efficacy analyses are planned for this 
study. 
7. 
TOLERABILITY ANALYSIS 
For the purpose of the tolerability analysis, the term “tolerability” refers to tolerability of the 
infusion (“infusion tolerability”). An infusion is considered tolerable if the infusion rate was not 
reduced and the infusion was neither interrupted nor stopped due to a HYQVIA-related AE with 
onset during the infusion. This definition is an interpretation/clarification of the original 
definition written in the protocol.  
7.1 
Definitions 
An infusion is considered not tolerated (intolerable), if the infusion rate was reduced or the 
infusion was interrupted or stopped, due to a HYQVIA-related AE with onset during the 
infusion. Otherwise, the infusion is considered tolerable. 
The complete HYQVIA infusion will be considered not tolerated (intolerable) if either of the 
component infusions (rHuPH20 or IGI 10%) was not tolerated.  
A component infusion (rHuPH20 or IGI 10%) will be considered not tolerated (intolerable) if 
both of the following are true: 
1. The infusion rate was reduced, the infusion was interrupted, or the infusion was stopped 
prior to completion. 
2. The reason for the rate reduction, interruption, or stoppage was a HYQVIA-related AE with 
onset during the infusion.  
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The following algorithm will be used to connect the above logic to the eCRF and thus determine 
if a component infusion was not tolerated. 
1. Did a HYQVIA-related AE occur during the infusion?  
a. “HYQVIA related” means that at least one of the following two items is true 
i. On the AE form: “Relationship to investigational product” = “Possibly 
related” or “Probably related” 
ii. On the AE form: “Relationship to IP administration process” = “Possibly 
related” or “Probably related” 
b. “occur during infusion” means that start time of the AE (from the AE form) was 
between start and end time of the infusion (from the infusion form). 
c. If the answer to this question is no, stop here: the infusion will be considered 
tolerated. 
d. If the answer to this question is yes, proceed to the next question. 
2. Are any of the following true? If yes, the infusion was not tolerated; otherwise, it was 
tolerated. 
a. Dose was reduced and interrupted, which is determined by either of the following: 
i. On the AE form, “Action taken with study procedure” = “Procedure 
interrupted” or “Procedure stopped” 
ii. On the AE form, “Action taken with study drug” = “Dose reduced” or “Drug 
interrupted” or “Drug withdrawn” 
iii. On the infusion form, “Was the infusion rate reduced” = “Yes” 
b. Dose was not completed, which is determined by either of the following: 
i. On the infusion form, “Was the drug administration complete” = “No” 
ii. On the infusion form, “Total Volume Administered” < “Planned Volume” 
 
7.2 
Summaries of Infusion Tolerability 
All tolerability summaries will be presented by dosing group (Ramp-Up, No Ramp-Up),  
treatment arm within dosing group, and stratified by BMI group. For subjects who dropped out 
early (before the last infusion as per protocol), planned infusions for the treatment arm that were 
not initiated for the subject are not considered for those summaries. 
All tolerability summaries will also be performed for the complete HYQVIA infusion, and 
broken down by the two component infusions, rHuPH20 and IGI 10%.  
The number and percentage of subjects who tolerated all actual, defined as infusions that were 
initiated, infusions will be summarized for the complete HYQVIA infusion, and broken down by 
the two component infusions, rHuPH20 and IGI 10%. A similar summary will be provided for 
the IGI 10% infusions broken down by dose level (¼ TDL, ½ TDL, 3/4TDL, TDL, as 
applicable). 
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Further summary tables (for HYQVIA overall and for each component rHuPH20 and IGI 10%) 
will be done showing the number of planned infusions for each subject and descriptive statistics 
(n, mean, standard deviation (SD), median, minimum, and maximum) for the number actual 
(initiated) infusions, the number of tolerated infusions and the percentage of tolerated infusions 
(relative to the number of initiated infusions). 
Finally, the number and percentage of tolerated infusions (HYQVIA overall, rHuPH20, IGI 10%) 
across all subjects within a treatment arm will be summarized. The percentage will be calculated 
as total number of tolerated infusions of all subjects within the treatment arm divided by total 
number of infusions initiated for all subjects within the treatment arm. 
Infusion tolerability data, including the percentage of tolerated infusions for each subject, will be 
presented in a data listing. 
8. 
SAFETY ANALYSIS  
The safety analysis will be performed using the Safety Set. Details for reporting AEs are described 
in section 8.1; details reporting of laboratory data and vital signs are described in section 8.2 and 
8.3, respectively; ECG data will be provided in the subject data listing(s) only (see section 8.4); 
for details on reporting immunogenicity refer to section 8.5.1. 
For each safety variable, unless otherwise specified, the last non-missing value before the 
administration of IP will be used as baseline for all analyses of that safety endpoint. 
All safety data, including derived data, will be presented in subject data listings, and all listings 
will include subject’s sex, age, and race. Immunogenicity data will be listed accordingly. 
8.1 
Adverse Events  
Adverse events will be coded using MedDRA version 24.0. 
8.1.1 
Definitions 
Treatment-emergent AEs (TEAEs) are defined as any events not present prior to the initiation 
of the treatments or any event already present that worsens in either intensity or frequency 
following exposure to the treatments. 
HYQVIA-related AEs: 
To determine whether an AE is related to HYQVIA, two items on the AE CRF form will be 
used: “Relationship to investigational product” and “Relationship to IP administration process”. 
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If either of these items is marked as “Possibly related” or “Probably related”, then the AE is 
related to HYQVIA. Otherwise, the AE is not related. 
Local vs systemic TEAEs will be classified using the AE term. If the reported term includes 
“infusion site” or “injection site”, it will be classified as a local AE; all other AEs will be 
classified as a systemic TEAE. In the case of the following terms: “EDEMA”, “PRURITUS”, 
“ERYTHEMA” without also including “at infusion/injection site”, these will be queried to 
determine local or systemic TEAE. In addition, prior to final analysis the medical director will 
review all AEs reported terms to verify if local or systemic TEAE. Following all queries and 
medical director review, the reported terms will be updated as appropriate to include “infusion 
site” or “injection site”. 
Infusion-associated TEAEs will be defined as any TEAE that begins during the infusion or 
within 24 hours following.  
Temporally-associated TEAEs will be defined as TAEs which begin during the infusion or 
within 72 hours following the end of IP infusion.  
Adverse reaction (AR) plus suspected adverse reaction is any AE that meets any of the 
following criteria: 
• the AE is considered a local (infusion site) AE; 
• the AE is considered by either the investigator and/or the sponsor to be HYQVIA related; 
• the AE is a temporally associated TEAE; 
• the AE’s causality assessment is missing or indeterminate. 
 
8.1.2 
AE Data Summaries 
All TEAE summaries will be provided by dosing group (Ramp-Up, No Ramp Up, and Overall) 
and treatment arms within dosing schedule, similarly as shown in Table 2 in section 5.1. 
An overall TEAE summary will be presented, showing the number and percent of subjects (and 
number of events) with/of any TEAEs, severe TEAEs, serious and nonserious TEAEs, 
HYQVIA-related and non-related TEAEs, HYQVIA-related SAEs, local and systemic TEAEs, 
TEAEs leading to premature discontinuation from the study, infusion-associated TEAEs, 
temporally associated TEAEs, and AR plus suspected AR of interest. 
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Further summaries will be provided for  
• Number and percentage of subjects with TEAEs, as well as the number of TEAEs, 
summarized by SOC and PT  
• Number and percentage of subjects with TEAEs, as well as the number of TEAEs, 
summarized by PT (descending frequency in no-ramp up group) 
• TEAE rates (per infusion, per subject, annual rate) by SOC and PT 
• Number and percentage of subjects with TEAEs (and number of TEAEs) by PT and 
severity 
• Percent of subjects with AR and suspected AR of interest by dosing schedule (ramp-up, 
no ramp-up, overall) and dose level (high vs low dose, and difference high-dose) by PT; 
see further details below 
• Number and percentage of subjects with TEAEs, as well as the number of TEAEs, 
leading to discontinuation summarized by SOC and PT  
• Number and percentage of subjects with serious TEAEs, as well as the number of TEAEs, 
leading to discontinuation summarized by SOC and PT 
• Number and percentage of subjects with HYQVIA-related TEAEs, as well as the number 
of TEAEs, summarized by SOC and PT  
• Number and percentage of subjects with HYQVIA-related TEAEs (and number of 
TEAEs) by PT and severity 
• Number and percentage of subjects with serious HYQVIA-related TEAEs, as well as the 
number of TEAEs, leading to discontinuation summarized by SOC and PT 
• Number and percentage of subjects (and number of events) of local versus systemic AEs 
by PT and relationship 
• Number and percentage of subjects with TEAEs, as well as the number of TEAEs, 
leading to death summarized by SOC and PT  
For the above summaries the following rules shall be applied. If more than 1 AE occurs with 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 
HYQVIA. For example, if a subject experienced a mild headache not related to HYQVIA, and a 
moderate headache related to HYQVIA, then the subject will be counted once for headache using 
the moderate headache related to HYQVIA. Presentation by SOC and PT will present SOC 
sorted alphabetically and PT within SOC sorted by descending overall frequency of no ramp-up 
group. The TEAEs, and TEAEs related to HYQVIA, will be summarized by PT, sorted by 
descending frequency of no-ramp up group. 
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For the summary of subjects with AR and suspected AR of interest it is planned to display only 
AEs with an absolute difference of ≥ 5 percentage points (p.p.) in the incidence rate between the 
high and low dose arm overall, as illustrated below in an example, using dummy (not real) data; 
“XX” represents data. 
 
AE 
Ramp -Up 
No Ramp-Up 
Overall 
Preferred 
Low Dose High Dose Difference Low Dose High Dose Difference Low Dose High Dose Difference 
Term 
(N=16) 
(N=16) 
(absolute) 
(N=8) 
(N=8) 
(absolute) 
(N=24) 
(N=24) 
(absolute) 
Term 1 
XX (xx%) 
XX (xx%) 
xx p.p. 
XX (xx%) 
XX (xx%) 
xx p.p. 
xx (20%) 
xx (15%) 
5 p p. 
Term 2 
XX (xx%) 
XX (xx%) 
xx p.p. 
XX (xx%) 
XX (xx%) 
xx p.p. 
xx (12%) 
xx (6%) 
6 p p. 
Term 3 
XX (xx%) 
XX (xx%) 
xx p.p. 
XX (xx%) 
XX (xx%) 
xx p.p. 
xx (3%) 
xx (11%) 
8 p p. 
 
The rate of each TEAE, HYQVIA-related and HYQVIA-unrelated TEAEs, local/systemic 
TEAEs, expressed as number of events per infusion, per subject, and per subject-year will be 
derived as described below: 
• The number of events per infusion will be calculated as total number of AEs divided by 
total number of infusion performed for each treatment arm. 
• The number of events per subject will be calculated as total number of AEs divided by 
total number of subjects for each treatment arm. 
• The number of events per subject-year will be calculated as total number of AEs divided 
by total subject-year by treatment arm. Total subject-years for a treatment arm will be 
calculated as the sum of the individual subject-years, which will be calculated as the time 
(in years) from first treatment initiation until 72 hours after the last treatment, and will be 
calculated as following: 
𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆−𝑌𝑌𝑌𝑌𝑌𝑌𝑌𝑌𝑌𝑌= (𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷 𝑜𝑜𝑜𝑜 𝐿𝐿𝐿𝐿𝐿𝐿𝐿𝐿 𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚+ 72) −(𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷 𝑜𝑜𝑜𝑜 𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹 𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇) + 1
365.25
 
All AEs (TEAEs and non-TEAEs) will be provided in the AE subject listings.  
8.2 
Clinical Laboratory Data 
Descriptive statistics for clinical laboratory values and changes from baseline at each assessment 
time point as well shift tables from baseline to each visit for quantitative variables (based on the 
respective normal ranges) will be presented by dosing group (Ramp-Up, No Ramp-Up) and 
treatment arms within dosing schedule, for the following clinical laboratory variables: 
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Biochemistry 
Blood urea nitrogen (BUN), bilirubin (total and direct), ALP, AST, 
triglycerides, cholesterol, ALT, lactate dehydrogenase (LDH), urine acid, 
albumin, sodium, potassium, chloride, glucose, creatinine (At screening, 
creatinine clearance will be calculated using the Cockcroft-Gault formula), 
low­density lipoprotein, high-density lipoprotein, magnesium, calcium 
Hematology 
Hemoglobin, red cell distribution width (RDW), mean corpuscular volume 
(MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin 
concentration (MCHC), hematocrit, white blood cells (WBC) with absolute 
differential counts of neutrophils, lymphocytes, monocytes, eosinophils, and 
basophils, red blood cell count, platelet count 
Hemolytic Panel Hgb, LDH, serum haptoglobin, plasma-free (unbound) Hgb, serum direct 
anti­globulin (direct Coombs) test (antibody elution to be performed if direct 
Coombs test is positive), reticulocyte count, urine hemosiderin. 
Urinalysis 
pH, specific gravity, protein, glucose, ketones, color, bilirubin, blood, nitrites, 
urobilinogen, leukocyte esterase. If urinalysis is positive for protein, blood, 
nitrite and/or leukocyte esterase, a microscopic examination (for red blood 
cells, white blood cells, bacteria, casts, and epithelial cells) will be performed. 
Coagulation 
Activated partial thromboplastin time (aPTT), and international normalized 
ratio (INR). 
Clinical significance of abnormal laboratory values was to be assessed by the investigator; this 
assessment of clinical significance is not captured in the study database. Clinically significant 
laboratory values were to be reported as AE and therefore are summarized in context with the AE 
data summaries described in section AE Data Summaries. 
Selected clinical laboratory parameters will be graded as the toxicity grading criteria listed in 
Appendix 17.2, Table 7. When the units in this table are specified as “ULN”, the grades will be 
derived by using the ULN values given in each grade column, i.e. for ALP, Grade 1 = ULN to 
2.5*ULN. Else, they will be derived by comparing the laboratory values to the ones in the tables. 
If a lab parameter doesn’t show a value for a particular grade, that grade won’t be assessed. For 
example, Bilirubin will not have a grade 1; consequently, bilirubin will have a Grade 0 and 
Grade 2 will be calculated as ULN – ULN*1.4. 
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For each parameter for that toxicity grading is applied, the number and percentage of subjects by 
toxicity grade will be summarized for baseline and for the maximum post-baseline toxicity grade 
(by dosing schedule and treatment arm). The percentages will be calculated relative to the 
number of subjects with available baseline values and at least 1 post-baseline assessment. The 
numerator is the total number of subjects with at least 1 post-baseline grade value.  
All laboratory data will be listed, all abnormal laboratory data will be identified. 
8.3 
Vital Signs 
Descriptive statistics for vital signs (e.g. weight, heart rate, respiratory rate, systolic and diastolic 
blood pressure) and their changes from baseline at each post-baseline visit will be presented by 
dosing group (Ramp-Up, No Ramp-Up) and treatment arms within dosing schedule. 
Vital sign values will be considered potentially clinically important (PCI) if they meet both the 
observed value criteria and the change from baseline criteria listed in Table 3 below.  
The number and percentage of subjects with PCI post-baseline values will be tabulated by 
treatment arm. The percentages will be calculated relative to the number of subjects with baseline 
and at least 1 post-baseline assessment. The numerator is the total number of subjects with at 
least 1 PCI post­baseline vital sign value. A supportive listing of subjects with post-baseline PCI 
values will be provided including the subject number, baseline, and post-baseline PCI values.  
Table 3 Criteria for Potentially Clinically Important (PCI) Vital Signs 
Parameter 
Classification 
Criteria 
Systolic blood 
pressure (mm Hg) 
HIGH and INCREASE 
≥ 140 and increase of ≥ 20 from baseline value 
LOW and DECREASE 
≤ 90 and decrease of ≥ 20 from baseline value 
Diastolic blood 
pressure (mm Hg) 
HIGH and INCREASE 
≥ 90 and increase of ≥ 15 from baseline value 
LOW and DECREASE 
≤ 50 and decrease of ≥ 15 from baseline value 
Heart rate (bpm) 
HIGH and INCREASE 
≥ 100 and increase of > 15 from baseline value 
LOW and DECREASE 
≤ 45 and decrease of > 15 from baseline value 
Weight 
HIGH 
Increase of ≥ 5% from baseline value 
LOW 
Decrease of ≥ 5% from baseline value 
 
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All vital signs data (including height and weight) will be listed. 
8.4 
Electrocardiogram 
Electrocardiogram (ECG) data will be provided in the subject data listing(s) only. 
8.5 
Other Safety Data 
8.5.1 
Immunogenicity Testing for Anti-Drug Antibodies 
The number and percentage of subjects who have developed binding and neutralizing antibodies 
to rHuPH20, along with the number and percentage of subjects who have binding titers ≥ 160, 
will be summarized by visit/time and by treatment arm.. The ADA results will also be included 
in a listing.  
8.5.2 
COVID-19 
All COVID-19 data collected in the eCRF will be presented in a data listing. 
8.5.3 
Physical Examination 
All physical examination data will be presented in a data listing. 
8.5.4 
Pregnancy 
All pregnancy data will be presented in a data listing.  
9. 
PHARMACOKINETIC ANALYSIS  
All summaries and analyses of the PK data will be based on the PK Set defined in Section 4.3. 
9.1 
Drug Concentration 
Blood samples will be drawn from each subject during this study for the determination of serum 
concentrations of total IgG and IgG subclasses (IgG1, IgG2, IgG3, and IgG4). Serial blood 
samples will be collected on Day 1 (pre-dose), and Days 2, 4, 6, 8, (all Treatment Arms 1 to 6), 
15 (Treatment Arms 2, 3, 5, and 6 only), and 29 (Treatment Arms 3 and 6 only) after 
administration of the investigational product. The Day 1 pre-dose concentration will be 
considered as baseline. Serum concentrations of total IgG and IgG subclasses will be measured 
using validated analytical methods. 
Individual total IgG and IgG subclasses serum concentrations (uncorrected and baseline-
corrected) will be listed by treatment arm, subject, and time (showing scheduled and actual time).  
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Individual total IgG and IgG subclasses serum concentrations (uncorrected and baseline-
corrected) will be summarized by treatment arm and scheduled time by means of descriptive 
statistics (including number of subjects (N), number of observations (n), arithmetic mean, SD, 
percent coefficient of variation (%CV), median, minimum, maximum, and geometric mean, 
geometric mean %CV and 95% confidence interval of geometric mean).  
Individual and mean total IgG and IgG subclasses serum concentrations (uncorrected and 
baseline-corrected) will be presented in figures listed below on both linear and semi-logarithmic 
scales: 
• Individual uncorrected concentration-time profiles by treatment arm  
(all subjects of a treatment arm within 1 figure, using actual time) 
• Individual baseline-corrected concentration-time profiles by treatment arm 
(all subjects of a treatment arm within 1 figure, using actual time) 
• 
Mean uncorrected concentration -time profile 
(all treatment arms within 1 figure, using scheduled time) 
• Mean baseline-corrected concentration -time profile 
(all treatment arms within 1 figure, using scheduled time) 
 
9.2 
Handling Below Limit of Quantitation Values 
The following procedures will be used for total IgG and IgG subclasses serum PK concentrations 
below the lower limit of quantification (LLOQ): 
• Samples that are below limit of quantification (BLQ) will be reported as <LLOQ in the 
data listings, where LLOQ is replaced by the actual value for LLOQ for the specific PK 
assay. Baseline-corrected concentrations < 0, will be reported as 0 (in listings those 
values will be specially marked as set to 0). 
• Samples that are BLQ are treated as zero in the calculation of summary statistics (e.g. 
mean, SD, etc.) for the serum PK concentrations at individual time points; similarly, 
baseline-corrected concentrations < 0 will be set to zero for calculation of the summary 
statistics. Geometric mean will be set to missing where zero values exist. 
• Mean concentrations (uncorrected and baseline-corrected) are reported as zero if all 
values are BLQ or zero, and no other descriptive statistics are reported. If the calculated 
mean (±SD) concentration is less than the LLOQ, the value will be reported as calculated. 
The mean values derived using these concentrations will be used to create the mean 
serum concentration versus time plots. 
• For calculation of area under the serum concentration curve (AUC), BLQ values are set 
equal to zero in the dataset loaded into Phoenix® WinNonlin® (Certara USA, Inc, 
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Princeton, NJ) for PK analysis. WinNonlin® uses the zero values that occur before the 
first time point with a concentration greater than LLOQ. Values that are BLQ after the 
first measurable concentration will be set to “missing” in the dataset loaded into 
WinNonlin®. 
• Missing values will not be imputed.   
9.3 
Pharmacokinetic Parameters 
The PK analysis will be conducted using Phoenix® WinNonlin® (Certara USA, Inc, Princeton, 
NJ) Version 8.0 or higher. Pharmacokinetic parameters will be determined from the IgG (total 
and subclasses) uncorrected and baseline-corrected serum concentration-time data using non-
compartmental analysis based on actual sampling times. No PK parameters will be calculated for 
subjects with 2 or fewer consecutive time points with measurable concentrations. 
The PK parameters for IgG (total and subclasses) will include, but may not be limited to: 
Cmax 
Maximum observed concentration 
tmax 
Time of maximum observed concentration 
AUClast 
Area under the concentration-time curve from time zero to the last quantifiable 
concentration, calculated using the linear-up/log-down trapezoidal rule. 
In this method, the linear trapezoidal method of calculation is used for each 
incremental trapezoid and the log trapezoidal rule for each decremental 
trapezoid 
AUC0-∞ 
Area under the concentration-time curve from time zero extrapolated to infinity 
AUC0-D8 
Area under the concentration-time curve from time zero (Day 1) to Day 8. 
λz 
Terminal disposition elimination rate constant 
t½ 
Terminal disposition phase half-life 
CL/F 
Apparent total clearance after extravascular administration (only for total IgG) 
Vz/F 
Apparent volume of distribution during the terminal disposition phase after 
extravascular administration (only for total IgG) 
9.4 
Statistical Analysis of Pharmacokinetic Data 
Descriptive statistical analysis of PK parameters will be based on the PK Set. The uncorrected 
and baseline-corrected serum PK parameters of total IgG and IgG subclasses (listed in section 
9.3) will be summarized by treatment arm. Summaries will include; N, n, arithmetic mean, SD, 
%CV, median, minimum, maximum, geometric mean, %CV of geometric mean and 95% 
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confidence intervals (CIs) for geometric mean. For tmax summaries will include only N, n, 
median, minimum, and maximum.  
Uncorrected and baseline-corrected serum PK parameters AUClast, AUC0-∞, AUC0-D8 and Cmax of 
total IgG and IgG subclasses will be illustrated graphically (by treatment arm) as listed below 
• Scatter plot of individual with mean uncorrected PK parameter 
• Scatter plot of Individual with mean baseline-corrected PK parameter 
• Boxplot of uncorrected PK parameters 
• Boxplot of baseline-corrected PK parameters 
Individual uncorrected and baseline-corrected serum PK parameters of total IgG and IgG 
subclasses will be listed. 
10. 
PHARMACODYNAMIC ANALYSIS 
Not applicable.   
11. 
OTHER ANALYSES 
Not applicable.   
12. 
INTERIM ANALYSIS/ DATA MONITORING (REVIEW) COMMITTEE  
No planned interim analysis, or data monitoring committee are planned for this study. 
13. 
DATA HANDLING CONVENTIONS  
13.1 
General Data Reporting Conventions  
Continuous variables will be summarized using the following descriptive statistics:  number of 
subjects (n), mean, median, SD, minimum, maximum.  Unless specified otherwise, summary 
statistics will be presented to 1 more significant digit than the raw data. The minimum and 
maximum values will be presented to the same number of decimal places as the raw data; the 
mean and median will be presented to 1 more decimal place than the raw data; and the SD and 
standard error will be presented to 2 more decimal places than the raw data. BMI, averaged 
laboratory results e.g. diastolic/systolic blood pressure and pulse (when taken in triplicate), and 
derived questionnaire scores will be rounded to 1 decimal place for reporting. 
Categorical and count variables will be summarized by the number of subjects and the percent of 
subjects in each category, as appropriate.  Percentages will be presented as whole numbers. 
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13.2 
Repeated or Unscheduled Assessments of Safety Parameters  
If a subject has repeated or unscheduled assessments before the start of IP, then the results from 
the most recent assessment made prior to the start of IP will be used as baseline. 
 If post-baseline assessments are repeated, these will be captured as unscheduled visits, and the 
value recorded at the scheduled visit will be used for generating descriptive statistics. 
All assessments, including unscheduled and repeated assessments, will be presented in the data 
listings. 
13.3 
Handling of Missing, Unused, and Spurious Data  
13.3.1 Missing Date Information for Prior or Concomitant Medications 
(Therapies/Procedures) 
For prior or concomitant medications, incomplete (i.e., partially missing) start date and/or stop 
date will be imputed.  When the start date and the stop date are both incomplete for a subject, 
impute the start date first. 
13.3.1.1 
Incomplete Start Date  
The following rules will be applied to impute the missing start dates.  If the stop date is complete 
and the imputed start date is after the stop date, then the start date will be imputed using the stop 
date. 
13.3.1.1.1 Missing Day and Month 
• 
If the year of the incomplete start date is the same as the year of the dose date of IP, then the 
day and month of the dose date of IP will be assigned to the missing fields 
• 
If the year of the incomplete start date is before the year of the dose date of IP, then December 
31 will be assigned to the missing fields 
• 
If the year of the incomplete start date is after the year of the dose date of IP, then 01 January 
will be assigned to the missing fields. 
13.3.1.1.2 Missing Month Only 
• 
The day will be treated as missing and both month and day will be replaced according to the 
above procedure. 
13.3.1.1.3 Missing Day Only 
• 
If the month and year of the incomplete start date are the same as the month and year of the 
dose date of IP, then the day of the dose date of IP will be assigned to the missing day 
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• 
If either the year is before the year of the dose date of IP or if both years are the same, but 
the month is before the month of the dose date of IP, then the last day of the month will be 
assigned to the missing day 
• 
If either the year is after the year of the dose date of IP or if both years are the same, but the 
month is after the month of the dose date of IP, then the first day of the month will be 
assigned to the missing day. 
13.3.1.2 
Incomplete Stop Date  
The following rules will be applied to impute the missing stop dates.  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. 
13.3.1.2.1 Missing Day and Month 
• 
If the year of the incomplete stop date is the same as the year as of the date of the last dose 
of IP, then the day and month of the date of the last dose of IP will be assigned to the missing 
fields 
• 
If the year of the incomplete stop date is before the year of the dose date of IP, then 31 
December will be assigned to the missing fields 
• 
If the year of the incomplete stop date is after the year of the dose date of IP, then 01 January 
will be assigned to the missing fields. 
13.3.1.2.2 Missing Month Only 
• 
The day will be treated as missing and both month and day will be replaced according to the 
above procedure. 
13.3.1.2.3 Missing Day Only 
• 
If the month and year of the incomplete stop date are the same as the month and year of the 
dose date of IP, then the day of the dose date of IP will be assigned to the missing day 
• 
If either the year is before the year of the dose date of IP or if both years are the same, but 
the month is before the month of the dose date of IP, then the last day of the month will be 
assigned to the missing day 
• 
If either the year is after the year of the dose date of IP or if both years are the same, but the 
month is after the month of the dose date of IP, then the first day of the month will be 
assigned to the missing day. 
13.3.2 Missing Date Information for Adverse Events  
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 study drug administration, e.g. AE start year and month 
are the same as the year and month of the dose date of IP, then the AE will be classified as 
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treatment-emergent. 
 
To facilitate categorization of AEs as treatment emergent, imputation of dates can be used.  For 
AEs, incomplete (i.e., partially missing) start dates start dates will be imputed and will follow the 
same rules as in Section 13.3.1.1. Incomplete stop dates will not be imputed.   
13.3.2.1 
Incomplete Start Date  
Follow the same rules as in Section 13.3.1.1. 
13.3.2.2 
Incomplete Stop Date  
Incomplete stop dates will not be imputed. 
13.3.3 Missing Severity Assessment for Adverse Events  
If severity is missing for an AE starting prior to the dose date of IP, then a severity of “Mild” will 
be assigned.  If the severity is missing for an AE starting on or after the dose date of IP, then a 
severity of “Severe” will be assigned.  The imputed values for severity assessment will be used 
for incidence summaries, while both the actual and the imputed values will be used in data 
listings. 
13.3.4 Missing Relationship to IP for Adverse Events  
If the relationship to IP is missing for an AE starting on or after the dose date of IP, a causality of 
“Related” will be assigned.  The imputed values for relationship to double-blind IP will be used 
for incidence summaries, while both the actual and the imputed values will be presented in data 
listings. 
13.3.5 Character Values of Clinical Laboratory Variables 
The actual values of clinical laboratory variables as reported in the database will be presented in 
data listings. No coded values (e.g., when a character string is reported for a numerical variable) 
are necessary. 
14. 
ANALYSIS SOFTWARE  
Statistical analyses will be performed using Version 9.4 (or newer) of SAS on a suitably 
qualified environment.   
PK analyses will be performed using Phoenix WinNonlin (Certara USA, Inc., Princeton, NJ) 
Version 8.0 or higher. 
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15. 
 CHANGES TO ANALYSIS SPECIFIED IN PROTOCOL 
Not applicable. 
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16. 
REFERENCES 
Eastern Cooperative Oncology Group 2006. Common toxicity criteria of the Eastern 
Cooperative Oncology Group.Web Link: http://www.ecog.org/general/ctc.pdf 
Food and Drug Administration 2008. U.S.Department of Health and Human Services, Center 
for Biologics Evaluation and Research, Guidance for industry: Safety, efficacy, and 
pharmacokinetic studies to support marketing of immune globulin intravenous (human) 
as replacement therapy for primary humoral immunodeficiency.Web Link: 
https://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegula
tor yInformation/Guidances/Blood/ucm078526.pdf 
World Health Organization 2003. Toxicity grading scale for determining the severity of 
adverse events.Web Link: 
http://www.icssc.org/Documents/Resources/AEManual2003AppendicesFebruary_06_
2003%20final.pdf 
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Takeda                                                                                                          CONFIDENTIAL 
 
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17. 
APPENDICES  
17.1 
Schedule of Activities 
The below tables are from the amended protocol (amendment 1) dated 30 Jun 2020. Sections referenced in the footnotes are 
protocol sections. 
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Table 4 Schedule of Study Procedures: Treatment Arms 1 and 4 
 
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Takeda                                                                                                          CONFIDENTIAL 
 
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Takeda                                                                                                          CONFIDENTIAL 
 
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Takeda                                                                                                          CONFIDENTIAL 
 
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Table 5 Schedule of Study Procedures: Treatment Arms 2 and 5 
 
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Takeda                                                                                                          CONFIDENTIAL 
 
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Takeda                                                                                                          CONFIDENTIAL 
 
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Takeda                                                                                                          CONFIDENTIAL 
 
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Table 6 Schedule of Study Procedures: Treatment Arms 3 and 6 
 
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Takeda                                                                                                          CONFIDENTIAL 
 
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Takeda                                                                                                          CONFIDENTIAL 
 
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Takeda                                                                                                          CONFIDENTIAL 
 
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17.2 
Grading of Laboratory Parameters 
Table 7 Grading of Laboratory Parameters 
 
Analyte 
Direction 
 
WNL is 
Grade 0 
No 
Grade 1 
 
Units 
Grade 0a 
Grade 1 a 
Grade 2 a 
Grade 3 a 
Grade 4 a 
Source 
Low 
High Low High 
Low High 
Low High Low High 
ALP 
Increase 
YES 
NO 
ULN 
. 
. 
. 
2.5 
2.6 
5.0 
5.1 
20 
20.1 
. 
ECOG 
ALT 
Increase 
YES 
NO 
ULN 
. 
. 
. 
2.5 
2.6 
5.0 
5.1 
20 
20.1 
. 
ECOG 
AST 
Increase 
YES 
NO 
ULN 
. 
. 
. 
2.5 
2.6 
5.0 
5.1 
20 
20.1 
. 
ECOG 
LDH 
Increase 
YES 
NO 
ULN 
. 
. 
. 
2.5 
2.6 
5.0 
5.1 
20 
20.1 
. 
N/A 
BUN 
Increase 
NO 
NO 
ULN 
0.0 
1.4 
1.5 
2.5 
2.6 
5.0 
5.1 
10 
10.1 
. 
ECOG 
Hemoglobin 
Decrease 
YES 
NO 
g/dL 
. 
. 
. 
10.0 
8.0 
9.9 
6.5 
7.9 
0.0 
6.4 
ECOG 
Lymphocytes 
Decrease 
NO 
NO 
x10^3/uL 
2.0 
. 
1.5 
1.9 
1.0 
1.4 
0.5 
0.9 
0.0 
0.4 
ECOG 
Neutrophils 
Decrease 
NO 
NO 
x10^3/uL 
2.0 
. 
1.5 
1.9 
1.0 
1.4 
0.5 
0.9 
0.0 
0.4 
ECOG 
Platelet Count 
Decrease 
YES 
NO 
x10^3/uL 
. 
. 
. 
75.0 
50.0 
74.9 
25 
49.9 
0.0 
24.9 
ECOG 
Potassium 
Decrease 
NO 
NO 
mmol/L 
3.5 
. 
3.0 
3.4 
2.5 
2.9 
2.0 
2.4 
0.0 
1.9 
WHO 
Potassium 
Increase 
NO 
NO 
mmol/L 
0.0 
5.5 
5.6 
6.0 
6.1 
6.5 
6.6 
7.0 
7.1 
. 
WHO 
Serum Creatinine 
Increase 
YES 
NO 
ULN 
. 
. 
. 
1.4 
1.5 
3.0 
3.1 
6.0 
6.1 
. 
ECOG 
Sodium 
Decrease 
NO 
NO 
mmol/L 
136 
. 
130 
135 
123 
129 
116 
122 
0.0 
115 
WHO 
Sodium 
Increase 
NO 
NO 
mmol/L 
0.0 
145 
146 
150 
151 
157 
158 
165 
166 
. 
WHO 
Serum Total Bilirubin 
Increase 
YES 
YES 
ULN 
. 
. 
. 
. 
. 
1.4 
1.5 
3.0 
3.1 
. 
ECOG 
WBC 
Decrease 
NO 
NO 
x10^3/uL 
4.0 
. 
3.0 
3.9 
2.0 
2.9 
1.0 
1.9 
0.0 
0.9 
ECOG 
Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; LDH = lactate dehydrogenase; BUN = 
blood urea nitrogen; ULN = upper limit of normal; ECOG = Eastern Cooperative Oncology Group; WHO = World Health Organization; WNL = within 
normal limits. 
a      The toxicity scale is defined as: 0 = none, 1 = mild, 2 = moderate, 3 = severe, 4 = life-threatening (Food and Drug Administration, 2008). 
Grading scale criteria taken from ECOG (Eastern Cooperative Oncology Group, 2006) and WHO (World Health Organization, 2003) guidelines, 
with the exception of LDH that use the same thresholds as defined for ALT and AST. 
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