Post-Authorization Safety, Tolerability and Immunogenicity Evaluation of HyQvia in Pediatric Subjects With Primary Immunodeficiency Diseases
Phase: PHASE4
Conditions: Primary Immunodeficiency Diseases (PID)
Sponsor: Baxalta now part of Shire

CLINICAL STUDY PROTOCOL 
NCT Number: 
NCT03116347 
Study Title: 
Post-Authorization Safety, Tolerability and Immunogenicity 
Evaluation of HyQvia in Pediatric Subjects with Primary 
Immunodeficiency Diseases 
Study Number: 
161504 
Protocol Version and Date: 
Original Protocol: 16-MAR-2016 
Protocol Amendment 1: 07-OCT-2016 
Protocol Amendment 2: 04-DEC-2019 

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CLINICAL STUDY PROTOCOL
PRODUCT: HyQvia
STUDY TITLE: Post-Authorization Safety, Tolerability and Immunogenicity 
Evaluation of HyQvia in Pediatric Subjects with Primary Immunodeficiency Diseases
STUDY SHORT TITLE: Post-Authorization Safety, Tolerability and Immunogenicity 
Evaluation of HyQvia in Pediatric PIDD subjects
PROTOCOL IDENTIFIER: 161504
CLINICAL TRIAL PHASE 4
ORIGINAL: 2016 MAR 16
OTHER ID(s)
NCT Number: Not Yet Available 
EudraCT Number: Not Yet Available
IND NUMBER: Not Applicable
Study Sponsor(s):
Baxalta US Inc.
One Baxter Way
Westlake Village, CA  91362, 
UNITED STATES
Baxalta Innovations GmbH
Industriestrasse 67
A-1221 Vienna,
AUSTRIA
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2. SERIOUS ADVERSE EVENT REPORTING
The investigator will comply with applicable laws/requirements for reporting serious 
adverse events (SAEs) to the ECs.
ALL SAEs ARE TO BE REPORTED ON THE 
SERIOUS ADVERSE EVENT REPORT (SAER) FORM AND TRANSMITTED 
TO THE SPONSOR WITHIN 24 HOURS AFTER BECOMING AWARE OF THE 
EVENT.
See SAE Protocol Sections for further information and SAER form for contact 
information.
Further details are also available in the study team roster.
For definitions and information on the assessment of these events, refer to the following:

AE, Section 12.1

SAE, Section 12.1.1.1

Assessment of AEs, Section 12.1.2
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3. SYNOPSIS 
INVESTIGATIONAL PRODUCT
Name of Investigational 
Product (IP)
1. HyQvia
2. KIOVIG 100 mg/ml solution for infusion
3. SUBCUVIA 160 g/l solution for infusion
(For better readability the names KIOVIG and SUBCUVIA will be used 
throughout the document.)
Name(s) of Active 
Ingredient(s)
Human Normal Immunoglobulin
CLINICAL CONDITION(S)/INDICATION(S)

Primary Immunodeficiency Diseases (PIDD)
PROTOCOL ID
161504
PROTOCOL TITLE
Post-Authorization Safety, Tolerability and Immunogenicity Evaluation 
of HyQvia in Pediatric Subjects with Primary Immunodeficiency Diseases
Short Title
Post-Authorization Safety, Tolerability and Immunogenicity Evaluation 
of HyQvia in Pediatric PIDD subjects
STUDY PHASE
Ph4 (post-authorization)
PLANNED STUDY PERIOD
Initiation
2016
Primary Completion
2021
Study Completion
2021
Duration
Approximately five years
STUDY OBJECTIVES AND PURPOSE
Study Purpose
The purpose of the study is to acquire additional data on safety, tolerability and immunogenicity of 
HyQvia in pediatric (age <18 years) subjects with Primary Immunodeficiency Diseases (PIDD).
Primary Objective
Safety of HyQvia treatment in pediatric subjects with PIDD who have received prior 
immunoglobulin therapy before enrollment into the study.
Secondary Objective(s)
Further safety assessments (e.g. immunogenicity), tolerability, characteristic of product 
administration and efficacy (immunoglobulin G [IgG] trough levels)
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STUDY DESIGN
Study Type/ Classification/ 
Discipline
Safety, Immunogenicity
Control Type
No control
Study Indication Type
Treatment
Intervention Model
Single-group
Blinding/Masking
Open-label
Study Design
This study is a Phase 4, post-authorization, prospective, non-controlled, 
multicenter study to evaluate the safety, tolerability, and other 
parameters of subcutaneous (SC) treatment using HyQvia in 
approximately 40 pediatric subjects with PIDD who have received 
immunoglobulin therapy before enrollment into this study. Subjects will 
have regular anti-recombinant human hyaluronidase PH20 (rHuPH20) 
antibody testing (binding and neutralizing anti-rHuPH20 antibody) 
throughout the study (approximately every three months).
Epoch 1: Pediatric patients with PIDD who are on non-HyQvia 
intravenous (IV) or SC treatment with immunoglobulin (IV-pretreated, 
SC pretreated) will be enrolled and treated with HyQvia subcutaneously 
with a dose or interval ramp-up period of up to six weeks. Subjects 
already treated with HyQvia (HyQvia pretreated) will be enrolled 
directly into Epoch 2. Epoch 1 infusions will be administered at the 
study site. 
Epoch 2: The ramp-up (Epoch 1) is followed by Epoch 2 with HyQvia 
treatment at the following intervals. For IV-pretreated subjects: every 
three or four weeks, depending on the subject’s previous IV dosing 
schedule. For SC-pretreated subjects: every three or four weeks, at the 
discretion of investigator and subject. For HyQvia pretreated subjects: 
No change in frequency of administration. After one year in Epoch 2, 
the anti-rHuPH20 binding antibody assay results during that year will be 
used to decide the next steps in the study (see Figure 1: Study Flow 
Chart in Supplements). Subjects with anti-rHuPH20 antibody titer < 160 
at all time-points during the study will complete the study 
termination/completion visit at the next possible occasion. Subjects with 
anti-rHuPH20 antibody titer ≥ 160 during the study and/or at the last 
measurement will continue in Epoch 2 for an additional two years of 
HyQvia treatment and observation. 
The first two or three infusion(s) during Epoch 2 will be administered 
at the study site. It is preferable that subsequent infusions be 
performed at home (or equivalent site) by the subject or caregiver, if in 
the opinion of the investigator, such treatment is safe and appropriate. 
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In that case, the investigator/designee must have trained the subject or 
caregiver and must be satisfied that the subject or caregiver is capable of 
self-administration of SC infusions at home before the subject or 
caregiver will be permitted to conduct the SC infusion at home.
Epoch 3: Epoch 3 is up to one year safety follow-up for subjects whose 
anti-rHuPH20 antibody titer was ≥ 160 during Epoch 1 or Epoch 2 and 
who experience either a related Serious Adverse Event (SAE) or a 
related severe Adverse Event (AE).
Subjects in Epoch 3 will be treated with KIOVIG intravenously or 
SUBCUVIA subcutaneously, at the discretion of the investigator and the 
subject. 
In the event that a subject in Epoch 1 or in Epoch 2 experiences a related 
SAE or severe AE without anti-rHuPH20 antibody titer ≥ 160, the 
subject can (at the discretion of the investigator and subject) either be 1)
terminated from the study or 2) change directly to Epoch 3 or
3) continue in Epoch 1 or 2 with appropriate medical intervention such 
as decreasing the HyQvia infusion rate and/or premedication.
Subjects with antibody titer of ≥ 160 when entering Epoch 3 continue 
regular anti-rHuPH20 antibody testing (approximately every three
months) for approximately one year or until anti-rHuPH20 antibody titer 
declines to < 2560 for at least two consecutive measurements, whichever 
comes first. These subjects complete the study termination or 
completion visit when the AE or SAE resolves and the anti-rHuPH20 
titer is <2560.
Infusions in Study Epoch 3 will be administered at home or at the study 
site.
The study termination/completion visit will be conducted at the study 
site.
Planned Duration of Subject 
Participation
Study Epoch 1 (Ramp-up): Up to six weeks for HyQvia-naïve subjects 
Study Epoch 2 (Final dosing): Up to three years
Study Epoch 3 (Safety Follow-up): Up to one year
The maximum subject participation period is approximately four years.
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Primary Outcome Measure 
1.
Number and rate per infusion (excluding infections) of all severe related AEs
2.
Number and rate per infusion (excluding infections) of related SAEs
Secondary Outcome Measure(s) 
Efficacy
1.
Trough levels of IgG (for Study Epoch 1 and 2)
Safety 
1.
Proportion of subjects who achieve a treatment interval of three or four weeks in Epoch 2 
2.
Proportion of subjects who maintain a treatment interval of three or four weeks in Epoch 2 for 12 
months
3.
Number and rate per infusion (excluding infections) of local AEs and Adverse Reactions (ARs)
4.
Number and rate per infusion (excluding infections) of systemic AEs and ARs
5.
Number and rate per infusion (excluding infections) of all AEs and all ARs
6.
Number and rate per infusion (excluding infections) of all temporally associated AEs 
7.
Number and rate per infusion (excluding infections) of all causally related and/or temporally 
associated AEs
8.
Number and rate per infusion (excluding infections) of all SAEs 
9.
Number/proportion of subjects who develop positive titer (≥160) of binding or neutralizing 
antibodies to rHuPH20
Mode of Product Administration (For Study Epoch 1 and 2)
1.
Infusions
a.
Number of infusions per month
b.
Number of infusion sites (needle sticks) per infusion/month
c.
Duration of infusion
d.
Maximum infusion rate/site
e.
Infusion volume/site
f.
Number/proportion of infusions that are discontinued, slowed, or interrupted due to an AE
2.
Number of weeks to reach final dose interval (three weeks or four weeks)
3.
Assessment of Treatment Preference Questionnaire
4.
Assessment of Treatment Satisfaction with Medication Questionnaire:  TSQM-9
5.
Assessment of Health-related Quality of Life Questionnaires:  Peds-QL, EQ-5D
Tertiary Outcome Measure(s) 
1.
Number of acute serious bacterial infections
2.
Number of all infections
3.
Days not able to go to school/work or to perform normal daily activities
4.
Days on antibiotics
5.
Number of hospitalizations, indication for the hospitalization (infection or non-infection) and days 
hospitalized
6.
Number of acute physician visits (office and emergency room) due to infection or other illnesses
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INVESTIGATIONAL PRODUCT(S), DOSE AND MODE OF ADMINISTRATION
Active Product
1. HyQvia Immune Globulin Infusion 10% (Human) with Recombinant Human 
Hyaluronidase
Subjects will be treated with HyQvia in Study Epoch 1 and Study Epoch 2.
Dosage Form: injectable
Mode of Administration: SC
Dosage Frequency:
Study Epoch 1 (Ramp-up): 
One treatment interval of one week, then one treatment interval of two weeks, 
then one treatment interval of three weeks (for subjects who are planned to be 
treated every four weeks)
Study Epoch 2 (Final dosing):
HyQvia dose once every three or four weeks:

For IV-pretreated subjects: every three or four weeks, depending on the 
subject’s previous IV dosing schedule. 

For SC-pretreated subjects: every three or four weeks, at the discretion of 
investigator and subject
Dose: HyQvia weekly dose will be equivalent to 100% (±5%) of pre-study 
treatment
Example for IgG dosing:
Pre-Study
Epoch 1 
(Ramp-Up)
Epoch 2 
(Final Dose)
Admin. 
Route
Dose
First 
Infusion at 
Baseline: 
1-Week Dose
Second 
Infusion at 
Week 1: 
2-Week Dose
Third 
Infusion at 
Week 3: 
3-Week Dose
IV
0.6 g/kg 
every 3 weeks
0.2 g/kg
0.4 g/kg
-
0.6 g/kg 
every 3 weeks
IV
0.6 g/kg 
every 4 weeks
0.15 g/kg
0.3 g/kg
0.45 g/kg
0.6 g/kg 
every 4 weeks
SC
0.1 g/kg 
every week
0.1 g/kg
0.2 g/kg
-
0.3 g/kg 
every 3 weeks
SC
0.1 g/kg 
every week
0.1 g/kg
0.2 g/kg
0.3 g/kg
0.4 g/kg 
every 4 weeks
Infusion Rate:
Study Epoch 1 (Ramp-up): 

For subjects with a body weight (BW) of < 40 kg: 5 ml/h/site (at start) to 
80 ml/h/site (maximum, if tolerated)

For subjects with a BW of ≥ 40 kg: 10 ml/h/site (at start) to 240 ml/h/site 
(maximum, if tolerated)
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Study Epoch 2 (Final dosing):

For subjects with a BW of < 40 kg: 10 ml/h/site (at start) to 160 ml/h/site 
(maximum, if tolerated)

For subjects with a BW of ≥ 40 kg: 10 ml/h/site (at start) to 300 ml/h/site 
(maximum, if tolerated)
If infusions have been tolerated after the subject has received two HyQvia 
infusions at the dose for the final infusion interval (three or four week dose), then 
investigators may choose an infusion rate schedule at their own discretion.
2. KIOVIG
Subjects may be treated with KIOVIG in Study Epoch 3 (Safety Follow-up).
Dosage form: injectable
Mode of Administration: intravenous
The infusion rate and infusion volume per site will follow the suggestions of the 
KIOVIG product information. 
Dosage frequency: Once every three or four weeks 
Dose: The weekly dose will be equivalent to 100% (±5%) of the dose in the 
previous study epoch
3.
SUBCUVIA
Subjects may be treated with SUBCUVIA in Study Epoch 3 (Safety Follow-up).
Dosage form: injectable
Mode of Administration: subcutaneous
The infusion rate and infusion volume per site will follow the suggestions of the 
SUBCUVIA product information. 
Dosage frequency: Once every week or biweekly
Dose: The weekly dose will be equivalent to 100% (±5%) of the dose in the 
previous study epoch.
SUBJECT SELECTION
Targeted Accrual
Sample size: Approximately 40 pediatric subjects already on IgG treatment pre-study 
will be enrolled. The study will enroll approximately six subjects two to less than 
six years of age, 12 subjects six to <12 years of age, 22 subjects 12 to <18 years of 
age. The study will be conducted in the European Economic Area.
Study sites: Approximately 20
Number of 
Groups/
Arms/Cohorts
1
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Inclusion Criteria
1. Subject must have a documented diagnosis of a form of primary humoral immunodeficiency involving 
a defect in antibody formation and requiring gammaglobulin replacement, as defined according to the 
International Union of Immunological Societies (IUIS) Scientific Committee 2015 1 and by diagnostic 
criteria according to Conley et al.2 prior to enrollment. The diagnosis must be confirmed by the 
sponsor Medical Director prior to first treatment with investigational product (IP) in the study.
2. Subject is at least two and below 18 years of age at the time of screening.
3. Subject has been receiving a consistent dose of IgG, administered in compliance with the respective 
product information for a period of at least three months prior to screening. The average minimum 
pre-study dose over that interval was equivalent to 300 mg/kg BW/4 weeks and a maximum dose 
equivalent to 1000 mg/kg BW/4 weeks.
4. Subject has a serum trough level of IgG >5 g/L at screening.
5. If female of childbearing potential, subject presents with a negative pregnancy test and agrees to 
employ adequate birth control measures for the duration of the study. 
Subject/legally authorized representative is willing and able to comply with the requirements of the 
protocol.
Exclusion Criteria
1. Subject has a known history of or is positive at screening for one or more of the following: hepatitis B 
surface antigen (HBsAg), polymerase chain reaction (PCR) for hepatitis C virus (HCV), PCR for 
human immunodeficiency virus (HIV) Type 1/2. 
2. Abnormal laboratory values at screening meeting any one of the following criteria (abnormal tests 
may be repeated once to determine if they are persistent):
a.
Persistent alanine aminotransferase (ALT) and aspartate amino transferase (AST) >2.5 times 
the upper limit of normal (ULN) for the testing laboratory
b.
Persistent severe neutropenia (defined as an absolute neutrophil count [ANC] 500/mm3)
3. Subject has anemia that would preclude phlebotomy for laboratory studies, according to standard 
practice at the site.
4. Subject has an ongoing history of hypersensitivity or persistent reactions (urticaria, breathing 
difficulty, severe hypotension, or anaphylaxis) following IV immunoglobulin, SC immunoglobulin, 
and/or Immune Serum Globulin (ISG) infusions.
5. Subject has severe immunoglobulin A (IgA) deficiency (less than 7.0 mg/dL) with known anti-IgA 
antibodies and a history of hypersensitivity.
6. Subject has a known allergy to hyaluronidase.
7. Subject has active infection and is receiving antibiotic therapy for the treatment of infection at the 
time of screening.
8. Subject has a bleeding disorder or a platelet count less than 20,000/µL, or who, in the opinion of the 
investigator, would be at significant risk of increased bleeding or bruising as a result of SC therapy. 
9. Subject has severe dermatitis that would preclude adequate sites for safe product administration.
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10. Subject has participated in another clinical study involving an IP or investigational device within 
30 days prior to enrollment or is scheduled to participate in another clinical study involving an IP or 
investigational device during the course of this study.
11. Subject is a family member or employee of the investigator.
12. If female, subject is pregnant or lactating at the time of enrollment.
STATISTICAL ANALYSIS
Sample Size Calculation
The planned sample size for the study is approximately 40 pediatric subjects.
Planned Statistical Analysis
Statistical analyses and data displays will be mainly descriptive. Data from all enrolled subjects will be 
included in the analysis. All SAEs and non-serious AEs will be categorized according to Medical 
Dictionary for Regulatory Activities (MedDRA) system organ class and preferred term. All analyses will 
be performed using SAS® version 9.2 or higher (SAS Institute, Cary, NC, USA).
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4. TABLE OF CONTENTS
1. STUDY PERSONNEL.................................................................................................. 2
1.1 Authorized Representative (Signatory) / Responsible Party .............................. 2
1.2 Study Organization................................................................................................. 2
2. SERIOUS ADVERSE EVENT REPORTING........................................................... 3
3. SYNOPSIS..................................................................................................................... 4
4. TABLE OF CONTENTS ........................................................................................... 12
5. LIST OF ABBREVIATIONS .................................................................................... 18
6. BACKGROUND INFORMATION .......................................................................... 21
6.1 Description of Investigational Product ............................................................... 21
6.1.1 HyQvia............................................................................................................ 21
6.1.2 KIOVIG 100 mg/ml solution for infusion and SUBCUVIA 160 g/l solution 
for injection.................................................................................................... 22
6.1.3 Immunoglobulin Treatment.......................................................................... 23
6.1.4 Immunoglobulin and Hyaluronidase Treatment........................................ 25
6.2 Clinical Condition/Indication .............................................................................. 26
6.3 Findings from Nonclinical and Clinical Studies................................................. 27
6.3.1 Clinical Study 160602.................................................................................... 27
6.3.2 Clinical Study 160603.................................................................................... 28
6.3.2.1 Pharmacokinetic Properties .................................................................. 30
6.3.3 Clinical Study 160902.................................................................................... 31
6.3.3.1 Disposition of Subjects ........................................................................... 32
6.3.3.2 Extent of Exposure ................................................................................. 32
6.3.3.3 Efficacy .................................................................................................... 32
6.3.3.4 Safety........................................................................................................ 33
6.3.4 Clinical Study 161101.................................................................................... 35
6.3.5 HyQvia Pregnancy Registry 161301 ............................................................ 37
6.3.6 HyQvia PASS 161302 .................................................................................... 38
6.3.7 HyQvia Study 161406.................................................................................... 39
6.4 Evaluation of Anticipated Risks and Benefits of the Investigational Product(s) 
to Human Subjects................................................................................................ 40
6.4.1 HyQvia............................................................................................................ 40
6.4.1.1 Pregnancy, Breast Feeding, Fertility .................................................... 41
6.4.2 KIOVIG.......................................................................................................... 41
6.4.3 SUBCUVIA..................................................................................................... 43
6.5 Compliance Statement.......................................................................................... 43
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7. STUDY PURPOSE AND OBJECTIVES ................................................................. 43
7.1 Study Purpose ....................................................................................................... 43
7.2 Primary Objective................................................................................................. 43
7.3 Secondary Objectives ........................................................................................... 43
7.4 Tertiary Objectives............................................................................................... 43
8. STUDY DESIGN......................................................................................................... 44
8.1 Brief Summary...................................................................................................... 44
8.2 Overall Study Design............................................................................................ 44
8.2.1 Epoch 1............................................................................................................ 44
8.2.2 Epoch 2............................................................................................................ 44
8.2.3 Epoch 3............................................................................................................ 45
8.3 Duration of Study Period(s) and Subject Participation .................................... 46
8.4 Outcome Measures ............................................................................................... 46
8.4.1 Primary Outcome Measure........................................................................... 46
8.4.2 Secondary Outcome Measures ..................................................................... 46
8.4.2.1 Efficacy .................................................................................................... 46
8.4.2.2 Safety/Tolerability .................................................................................. 46
8.4.2.3 Mode of Product Administration .......................................................... 47
8.4.3 Tertiary Outcome Measures......................................................................... 47
8.4.4 Exploratory Outcomes Measure................................................................... 47
8.5 Randomization and Blinding............................................................................... 48
8.6 Study Stopping Rules............................................................................................ 48
8.7 Investigational Product(s) .................................................................................... 48
8.7.1 Packaging, Labeling, and Storage................................................................ 48
8.7.1.1 rHuPH20.................................................................................................. 48
8.7.1.2 IGI, 10%.................................................................................................. 48
8.7.1.3 KIOVIG................................................................................................... 49
8.7.1.4 SUBCUVIA ............................................................................................. 49
8.7.2 Administration ............................................................................................... 50
8.7.3 Description of Treatment.............................................................................. 50
8.7.3.1 HyQvia..................................................................................................... 50
8.7.3.2 KIOVIG................................................................................................... 52
8.7.3.3 SUBCUVIA 160 g/l ................................................................................. 52
8.7.4 Investigational Product Accountability ....................................................... 52
8.8 Source Data ........................................................................................................... 53
9. SUBJECT SELECTION, WITHDRAWAL, AND DISCONTINUATION .......... 54
9.1 Inclusion Criteria.................................................................................................. 54
9.2 Exclusion Criteria................................................................................................. 54
9.3 Withdrawal and Discontinuation ........................................................................ 55
10. STUDY PROCEDURES .......................................................................................... 57
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10.1 Informed Consent ............................................................................................... 57
10.2 Subject Identification Code................................................................................ 57
10.3 Screening and Study Visits................................................................................. 57
10.4 Medications and Non-Drug Therapies.............................................................. 58
10.5 Subject Diary....................................................................................................... 59
10.6 Subject Completion/Discontinuation ................................................................ 60
10.7 Procedures for Monitoring Subject Compliance ............................................. 61
11. ASSESSMENT OF EFFICACY.............................................................................. 62
11.1 IgG Trough Levels.............................................................................................. 62
11.2 Treatment Preference Questionnaire................................................................ 62
11.3 Treatment Satisfaction Questionnaire for Medication.................................... 62
11.4 HRQoL Questionnaire ....................................................................................... 63
11.4.1 PedsQL.......................................................................................................... 63
11.4.2 EQ-5D ........................................................................................................... 63
12. ASSESSMENT OF SAFETY................................................................................... 64
12.1 Adverse Events.................................................................................................... 64
12.1.1 Definitions..................................................................................................... 64
12.1.1.1 Serious Adverse Event.......................................................................... 64
12.1.1.2 Non-Serious Adverse Event ................................................................. 65
12.1.1.3 Unexpected Adverse Events................................................................. 65
12.1.1.4 Preexisting Diseases.............................................................................. 65
12.1.2 Assessment of Adverse Events.................................................................... 66
12.1.2.1 Severity .................................................................................................. 67
12.1.2.2 Causality................................................................................................ 67
12.1.2.3 Safety Reporting ................................................................................... 68
12.2 Urgent Safety Measures ..................................................................................... 69
12.3 Untoward Medical Occurrences........................................................................ 70
12.4 Non-Medical Complaints ................................................................................... 70
12.5 Medical, Medication, and Non-Drug Therapy History................................... 71
12.6 Physical Examinations........................................................................................ 71
12.7 Clinical Laboratory Parameters........................................................................ 71
12.7.1 Hematology and Clinical Chemistry.......................................................... 71
12.7.2 Urine Tests.................................................................................................... 72
12.7.3 Pregnancy Test............................................................................................. 72
12.7.4 Hemolysis Test.............................................................................................. 72
12.7.5 IgG Trough Levels and IgG Subclasses and Specific Antibody Tests .... 72
12.7.6 Anti-rHuPH20 Antibodies .......................................................................... 73
12.7.7 Viral Pathogen Serology.............................................................................. 73
12.7.8 Assessment of Laboratory Values .............................................................. 73
12.7.8.1 Toxicity Grading Scale......................................................................... 73
12.7.8.2 Assessment of Abnormal Laboratory Values..................................... 74
12.7.9 Backup Samples and Biobanking............................................................... 74
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12.8 Vital Signs............................................................................................................ 74
12.8.1 Screening....................................................................................................... 75
12.8.2 Infusion at Study Site .................................................................................. 75
12.8.3 Infusion at Home.......................................................................................... 75
12.8.4 End-of-Study ................................................................................................ 75
12.9 Acute Serious Bacterial Infections .................................................................... 75
12.9.1 Infection: Bacteremia/Sepsis(a).................................................................... 76
12.9.2 Infection: Bacterial Meningitis................................................................... 76
12.9.3 Infection: Osteomyelitis/Septic Arthritis................................................... 77
12.9.4 Infections: Bacterial Pneumonia(d)............................................................. 77
12.9.5 Infection: Visceral Abscess ......................................................................... 78
13. STATISTICS............................................................................................................. 79
13.1 Sample Size and Power Calculations ................................................................ 79
13.2 Analysis Sets ........................................................................................................ 79
13.2.1 Full Analysis Set........................................................................................... 79
13.2.2 Per-Protocol Analysis Set............................................................................ 79
13.2.3 Safety Analysis Set....................................................................................... 79
13.3 Handling of Missing, Unused, and Spurious Data........................................... 79
13.4 Methods of Analysis............................................................................................ 79
13.4.1 Primary Outcome Measure......................................................................... 80
13.4.2 Secondary Outcome Measures ................................................................... 80
13.4.2.1 Efficacy .................................................................................................. 80
13.4.2.2 Safety...................................................................................................... 80
13.4.2.3 Mode of Product Administration (For Study Epoch 1 and 2).......... 81
13.4.2.4 HRQoL................................................................................................... 81
13.4.3 Tertiary Outcome Measures....................................................................... 81
13.4.3.1 Infections ............................................................................................... 81
13.4.3.2 Healthcare Resource Utilization Endpoints....................................... 82
13.5 Planned Interim Analysis of the Study ............................................................. 82
14. DIRECT ACCESS TO SOURCE DATA/DOCUMENTS .................................... 82
15. QUALITY CONTROL AND QUALITY ASSURANCE...................................... 83
15.1 Investigator’s Responsibility.............................................................................. 83
15.1.1 Final Clinical Study Report ........................................................................ 83
15.2 Training ............................................................................................................... 83
15.3 Monitoring........................................................................................................... 83
15.4 Safety Monitoring ............................................................................................... 83
15.5 Auditing ............................................................................................................... 84
15.6 Non-Compliance with the Protocol ................................................................... 84
15.7 Laboratory and Reader Standardization ......................................................... 84
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16. ETHICS ..................................................................................................................... 85
16.1 Subject Privacy ................................................................................................... 85
16.2 Ethics Committee and Regulatory Authorities................................................ 85
16.3 Informed Consent ............................................................................................... 85
17. DATA HANDLING AND RECORD KEEPING................................................... 87
17.1 Confidentiality Policy ......................................................................................... 87
17.2 Study Documentation and Case Report Forms ............................................... 87
17.3 Document and Data Retention........................................................................... 87
18. FINANCING AND INSURANCE........................................................................... 88
19. PUBLICATION POLICY........................................................................................ 88
20. SUPPLEMENTS....................................................................................................... 89
20.1 Study Flow Chart................................................................................................ 89
20.2 Schedule of Study Procedures and Assessments.............................................. 90
20.3 Clinical Laboratory Assessments ...................................................................... 94
20.4 Toxicity Grading Scale for Laboratory Values................................................ 98
21. REFERENCES.......................................................................................................... 99
INVESTIGATOR ACKNOWLEDGEMENT............................................................ 105
Tables
Table 1 Pharmacokinetic Parameters of HyQvia Compared to  Intravenous 
Administration of IGI 10%....................................................................................... 30
Table 2  Example for IgG dosing...................................................................................... 51
Table 3 STUDY EPOCH 1 – Ramp Up  Schedule of Study Procedures and Assessments
................................................................................................................................... 90
Table 4 STUDY EPOCH 2 – Year 1  Schedule of Study Procedures and Assessments. 91
Table 5 STUDY EPOCH 2 – Year 2 and Year 3 Schedule of Study Procedures and 
Assessments .............................................................................................................. 92
Table 6 STUDY EPOCH 3  Schedule of Study Procedures and Assessments................ 93
Table 7 STUDY EPOCH 1 – Ramp Up  Clinical Laboratory Assessments.................... 94
Table 8 STUDY EPOCH 2 – Year 1  Clinical Laboratory Assessments ........................ 95
Table 9 STUDY EPOCH 2 – Year 2 and Year 3 Clinical Laboratory Assessments....... 96
Table 10 STUDY EPOCH 3 Clinical Laboratory Assessments ...................................... 97
Table 11 Grading of Laboratory Parameters ................................................................... 98
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Figures
Figure 1 Study Design for Clinical Study 161504........................................................... 89
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5. LIST OF ABBREVIATIONS
Abbreviation
Definition
ADR
Adverse drug reaction (i.e., related AE) 
AE
Adverse event
AR
Adverse reaction
AIDS
Acquired immune deficiency syndrome
ALP
Alkaline phosphatase
ALT 
Alanine amino transferase (SGPT)
ANC
Absolute neutrophil count
AST 
Aspartate amino transferase (SGOT)
AUC
Area under the curve
B19V
Parvovirus B19
BUN
Blood urea nitrogen
BW
Body weight
CHMP
Committee for Medicinal Products for Human Use
CLL
Chronic lymphocytic leukemia
CI
Confidence interval
Cmax
Maximum concentration
Cmin
Minimum concentration
CRF
Case report form
CSF
Cerebrospinal fluid
CT
Computed tomography
CXR
Chest x-ray
EC
Ethics committee
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic case report form
EDC
Electronic data capture
EPR
Electronic Patient Reported 
EU
European Union
Fc
Crystallizable region of antibody
FDA
Food and Drug Administration
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Abbreviation
Definition
GCP
Good Clinical Practice
h, hr
Hour(s)
HAV
Hepatitis A virus
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HEV
Hepatitis E virus
Hgb
Hemoglobin
HIV 
Human immunodeficiency virus 
HRQoL
Health related quality of life
ICH
International Council for Harmonization
IgA
Immunoglobulin A
IGIV, 10%
Immune Globulin Intravenous (Human) GAMMAGARD 
LIQUID/KIOVIG
IgG
Immunoglobulin G
IGI
Immunoglobulin
IGIV
Immune globulin intravenous (human)
IGSC
Immune globulin subcutaneous (human)
IP
Investigational Product
ISG
Immune serum globulin
ISRB
Internal safety review board
ITP
Idiopathic thrombocytopenic purpura 
IV
Intravenous
LDH
Lactate dehydrogenase 
MedDRA
Medical Dictionary for Regulatory Activities
min
Minute(s)
mL
Milliliter(s)
MM
Multiple myeloma
MMN
Multi-focal motor neuropathy
MRI
Magnetic resonance imaging
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Abbreviation
Definition
NMC
Non-medical complaint
PaCO2
Partial pressure (tension) of carbon dioxide
PASS
Post-authorization safety study
PCR
Polymerase chain reaction
PIDD
Primary immunodeficiency disease
PK
Pharmacokinetic(s)
RBC
Red blood cell (count)
rHuPH20
Recombinant human hyaluronidase PH20 
(active ingredient in the U.S. marketed product HYLENEX)
SAP
Statistical analysis plan
S/D
Solvent/detergent
SAE
Serious adverse event
SAER
Serious adverse event report
SC
Subcutaneous
SCIG
Subcutaneous immunoglobulin G
SIC
Subject identification code
SmPC
Summary of product characteristics
Tmax
Time to maximum concentration
TRALI
Transfusion related acute lung injury
ULN
Upper limit of normal
VASBI
Validated acute serious bacterial infection
WBC
White blood cell (count)
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6. BACKGROUND INFORMATION
Purified human immunoglobulin G (IgG) preparations were first used in 1952 for the 
treatment of patients with primary immunodeficiency diseases (PIDD), a class of 
disorders that result in increased susceptibility to infection, including both recurrent 
pyogenic infections secondary to defects of humoral immunity and opportunistic 
infections resulting from defects in cell-mediated immunity.3;4 Individuals with these 
disorders require replacement therapy with immunoglobulin products to prevent or 
reduce the severity of infections. In addition to PIDD syndromes, immunoglobulin 
preparations have been indicated for secondary immunodeficiencies, such as B-cell 
chronic lymphocytic leukemia (CLL), acquired immunodeficiency syndrome (AIDS), 
and immunodeficiency after bone marrow transplantation.5;6;7;8 Immunoglobulins are also 
effective in the management of autoimmune disorders, such as idiopathic 
thrombocytopenic purpura (ITP) 9;10;11, Kawasaki syndrome 12;13, and multi-focal motor 
neuropathy (MMN).14
6.1 Description of Investigational Product
6.1.1 HyQvia
HyQvia 100 mg/ml solution for infusion for subcutaneous (SC) use is a dual vial unit 
consisting of one vial of human normal immunoglobulin (Immune Globulin 10% or 
IG 10%) and one vial of recombinant human hyaluronidase (rHuPH20). 
The IG 10% component provides the therapeutic effect of this medicinal product. 
The rHuPH20 facilitates the dispersion and absorption of IG 10%.
Human normal immunoglobulin contains mainly IgG with a broad spectrum of 
opsonizing and neutralizing antibodies against infectious agents.
Human normal immunoglobulin contains the IgG antibodies present in the normal 
population. It is usually prepared from pooled human plasma from not fewer than 
1,000 donations. It has a distribution of IgG subclasses closely proportional to that in 
native human plasma. Adequate doses of human normal immunoglobulin may restore 
abnormally low IgG levels to the normal range.
rHuPH20 is a soluble recombinant form of human hyaluronidase that modifies the 
permeability of connective tissue through the hydrolysis of hyaluronan. Hyaluronan 
is a polysaccharide found in the intercellular matrix of connective tissue and of 
certain specialized tissues. It is degraded by naturally occurring hyaluronidase 
and has a very fast natural turnover in SC tissue. 
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As a permeation enhancer, rHuPH20 temporarily accelerates the break-down of 
hyaluronan, resulting in a temporary increase in the permeability of the interstitial matrix 
that facilitates more rapid dispersion and absorption and improved bioavailability of the 
IG 10%.
HyQvia therapeutic indications include:
Replacement therapy in adults (≥18 years) with primary immunodeficiency 
syndromes such as:
a.
congenital agammaglobulinaemia and hypogammaglobulinaemia
b. common variable immunodeficiency
c.
severe combined immunodeficiency
d. IgG subclass deficiencies with recurrent infections
Replacement therapy in adults (≥18 years) with myeloma or CLL with severe 
secondary hypogammaglobulinaemia and recurrent infections
6.1.2 KIOVIG 100 mg/ml solution for infusion and SUBCUVIA 160 g/l solution for 
injection
KIOVIG is a liquid unmodified IgG preparation with an osmolality that is similar to 
physiologic osmolality and contains no added sugars, sodium, or preservatives. The 
manufacturing process includes three independent, validated viral inactivation or removal 
steps: solvent/detergent (S/D) treatment, nanofiltration and incubation at a low pH and 
elevated temperature. The product contains immunoglobulins with intact Fc regions
(crystallizable region of the antibody) in isotonic solution including glycine for 
stabilization. KIOVIG is a ready-to-use 10% liquid preparation. 
A detailed description of KIOVIG is provided in the Summary of Product Characteristics 
(SmPC) and the Investigator’s Brochure for Immune Globulin Infusion (Human), 10% 
(IGI 10%) for intravenous (IV) and SC administration.
SUBCUVIA is a 16% ready to use solution of polyvalent human normal immunoglobulin 
for SC infusion in patients with primary and secondary immune deficiency syndromes.
Further information is provided in the respective SmPC.
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6.1.3 Immunoglobulin Treatment
Defective antibody formation, with or without decreased levels of serum 
immunoglobulins, is the most common abnormality in the majority of PIDD. It leads to 
increased susceptibility to viral and bacterial infections, especially of the sinopulmonary 
and gastrointestinal tracts. Decreased immunoglobulin levels are found not only in the 
group made up predominantly of antibody defects (e.g., X-linked agammaglobulinemia, 
selective IgG subclass deficiency, common variable immunodeficiency, or X-linked 
hyperimmunoglobulin M syndrome), but also in the group of combined 
immunodeficiencies (e.g., severe combined immunodeficiency, Wiskott-Aldrich 
Syndrome) that have defects in both T- and B-cells.1
Immunoglobulin treatment to prevent infections is also performed in Secondary 
Immunodeficiencies, such as CLL or multiple myeloma (MM). CLL is the most frequent 
form of leukemia in Western countries. It is characterized by the clonal proliferation and 
accumulation of neoplastic B lymphocytes in the blood, bone marrow, lymph nodes, and 
spleen.15 MM is a plasma-cell neoplasm that is characterized by skeletal destruction, 
renal failure, anemia, hypercalcemia but also recurrent infections.16
Individuals with PIDD require lifelong replacement therapy with immunoglobulin 
products to prevent or reduce severity of infections. Initially, immunoglobulin
replacement therapy was given by the intramuscular route, however, since the early 
1980s in the US, the overwhelming majority of patients have been treated by the IV 
route. In the past several years SC administration has gained popularity. Currently, the 
majority of immunoglobulin products in the US are licensed for IV administration; 
though, in December 2005, the first SC preparation was licensed by ZLB-Behring.17,18
SC administration of immunoglobulin preparations for PIDD patients has been accepted 
in many countries worldwide and is the predominant mode in the Scandinavian countries, 
particularly in Sweden. The first attempts, in the late 1970s, used intramuscular 
preparations administered at slow infusion rates, but in later years rapid infusion rates 
have been used more successfully.19,20,21,22,23
All of the gammaglobulin preparations licensed for SC use are formulated at 10-20%. 
Commonly they are formulated at 16% and are similar to Cohn Fraction II, therefore, 
they cannot be infused intravenously. The higher concentration, relative to IV 
preparations that are formulated at 5% to 12%, allows for a smaller infusion volume. 
This method of immunoglobulin replacement therapy is considered to be effective, safe 
and also highly appreciated by patients, as it has a low risk of systemic adverse reactions
(ARs). When given weekly or every other week, SC IgG leads to higher trough serum 
IgG concentrations than monthly IV infusions (at the same monthly dose).24,25  
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After adequate training by healthcare professionals, SC infusions of immunoglobulin can 
easily be performed by many patients at home, thus increasing patient comfort and 
independence and reducing cost.26
Immunoglobulin administered intravenously is immediately available in the blood, 
and slowly equilibrates to the extra-vascular compartment over three to five days.27
Subcutaneously administered immunoglobulin is slowly absorbed from the SC space 
into the blood and at the same time equilibrates with the extra-vascular compartment. 
Consequently, there is no high spike in the IgG concentration as is seen following IV 
infusion. A study in 1972 by Smith, et al., used pharmacokinetic (PK) modeling and 
determined that the bioavailability of SC and IM was 100% when compared to IV.28
More recent studies mandated by the Food and Drug Administration (FDA) showed that 
the bioavailability (measured as the area under the curve (AUC) of immune globulin 
concentration over time) of SC immunoglobulin is lower than that of IV 
immunoglobulin.18,29 Accordingly, it is recommended that the dose of SC
immunoglobulin be adjusted to 137-153% of the IV dose to provide a comparable IgG 
exposure.18;30 Despite the technical difficulties of comparing AUC for two different 
routes and frequencies of administration, studies of intradermally administered 
immunoglobulin in ratsi suggest that there is decreased bioavailability through the SC 
route. This may be due to the mode of absorption of large protein molecules, which 
cannot readily diffuse through the capillary walls and must be absorbed via the 
lymphatics.31
The primary practical disadvantage of SC administration of immunoglobulin is that only 
small volumes can be infused at each site, necessitating the use of multiple sites on a 
weekly or biweekly (every-other-week) basis. Generally, using a 16% solution, 
approximately 20 mL can be infused per site; an adult patient receiving 400 mg/kg body 
weight (BW) thus would require at least three sites per week or 12 sites per month. Even 
though weekly or biweekly administration has the benefit of maintaining better IgG 
trough levels than monthly IV infusions, the requirement for multiple needle insertions 
may deter many patients.
                                                
i
Halozyme Report Number R1005-0551.
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6.1.4 Immunoglobulin and Hyaluronidase Treatment
The SC space is formed by a collagen and elastin network filled with a gel-like substance, 
hyaluronan or hyaluronic acid. It is largely responsible for the resistance to fluid flow 
through this tissue. Hyaluronidase derived from sheep or cows has been used for the last 
sixty years to temporarily depolymerize the hyaluronan and facilitate SC infusions of 
fluids for re-hydration.32 rHuPH20 is a 63 kd protein genetically engineered from the 
sequence of the naturally occurring human protein. It temporarily depolymerizes the 
hyaluronan, decreasing the resistance to fluid flow and thus facilitating infusions into the 
SC space. The high molecular weight hyaluronan has a rapid turnover and is restored 
within 24 to 48 h, leaving no observable changesii. Weekly infusions into cynomolgus 
monkeys in doses up to two mg/kg (> 1,000 fold higher than the HyQvia dose in humans)
did not lead to adverse reactions during a follow-up of 39 weeksiii. Infusion of rHuPH20 
improved absorption and bioavailability of intradermally injected IgG in rabbits, 
pegylated interferon and infliximab in rats, and increased the rate of infusion and comfort 
of infusions of lactated Ringer’s solution in the arms of adult human volunteers three- to 
four-fold.33 Studies investigating the effects of rHuPH20 on SC infusions of large 
quantities of IgG in dogs and rabbits have been difficult to interpret due to the rapid 
absorption of IgG alone in this model. However, at higher doses of rHuPH20, 
bioavailability seemed to increase. The human SC compartment is much tighter than that 
of these animals and thus, human studies were required. rHuPH20 can facilitate 
absorption of small molecules such as insulin and morphine in humans; in phase 1 trials 
rHuPH20 improved bioavailability of proteins such as infliximabiv and enabled drug 
dispensation and absorption at the administration site of rituximab and trastuzumab.34  
In a phase 1/2 clinical study of HyQvia (Study 160602) the average bioavailability of the 
IgG in seven subjects was 92%, suggesting a significant improvement compared to SC 
administration in the absence of rHuPH20.
The immunogenicity of rHuPH20 has been monitored in a number of clinical trialsv. No 
positive skin reactions were observed when rHuPH20 was administered to 100 healthy 
volunteers in a skin allergy clinical trial.35  In Study 160603, a total of 13 subjects had at 
least one plasma sample that tested positive for rHuPH20-binding antibodies (positivity 
defined as a sample with a titer of ≥160) following HyQvia treatment. The peak of the 
observed positive titers ranged from 160 up to 81,920 and have declined during the 
long-term extension study despite continued exposure to rHuPH20.  
                                                
ii
Halozyme Report R08014.
iii
Halozyme Report R09050.
iv
Halozyme Report R05109.
v
Halozyme Report Number 10059.
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None of these samples contained neutralizing antibodies. No local or systemic reactions 
were attributed to the presence of rHuPH20 antibodies. Based upon data available to date, 
including data from long-term exposure in Study 160902 (63 subjects received HyQvia 
for a total number of 187.7 subject-years), the incidence of the formation of anti-
rHuPH20 binding antibodies is 18%, no neutralizing antibodies have been observed, no 
clinical signs or symptoms have been associated with positive anti-rHuPH20 binding 
antibody titers. In addition, there was no evidence of a lack of treatment effect when 
rHuPH20-binding antibodies were detected.
Antibodies reactive to rHuPH20 have also been identified in the normal population with a 
prevalence between 3 and 12%.36 No signal of associated infertility or 
autoimmune/inflammatory condition could be identified.
Non-clinical data for rHuPH20 or antibodies to rHuPH20 reveal no special hazard for 
humans based on conventional studies of safety pharmacology, repeated dose toxicity and 
developmental toxicity. Reversible effects on fertility have been reported in male and 
female guinea pigs immunized to produce antibodies to hyaluronidase. However, 
antibodies to hyaluronidase did not influence reproduction in mouse, rabbit, sheep, or 
cynomolgus monkey. 
6.2 Clinical Condition/Indication 
Primary antibody deficiencies are characterized by decreased serum levels of 
immunoglobulin isotypes and increased susceptibility to infection by various 
microorganisms, including encapsulated bacteria. Treatment with immunoglobulins is 
indicated whenever there is a defect in antibody production, regardless of the actual level 
of IgG. Studies have clearly demonstrated that antibody replacement reduces the number 
and severity of patients’ symptoms and infections as immunoglobulins are able to 
neutralize infectious agents, enhance phagocytosis, and modulate the immune response. 
Antibody replacement can be accomplished either intravenously or subcutaneously.
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6.3 Findings from Nonclinical and Clinical Studies
6.3.1 Clinical Study 160602
Phase I/II Determination of the Dose of Recombinant Human Hyaluronidase 
Required Enabling up to 600 mg/kg Body Weight of Immune Globin Intravenous 
(Human) 10% to be Administered Subcutaneously in a Single Infusion Site in 
Subjects with Primary Immunodeficiency Disease
This study was a prospective, open-label, non-controlled, two-arm, multicenter study 
with the aim of determining the dose of rHuPH20 necessary to infuse a full four-week 
dose of IGIV 10% in a single SC site with good tolerability.37 An infusion was defined as 
having been tolerated if it caused no more than mild local adverse drug reactions (ADRs) 
(e.g., minimal swelling, redness, or pain) that the investigator did not assess as 
unacceptable for other medical reasons. All infusions were administered at the study site. 
A total of 11 adult subjects (four male, seven female) participated in the study. In Study 
Arm 1, four adult/adolescent subjects received only SC infusions of IGIV 10% to 
determine tolerability. After this initial assessment of tolerability, seven subjects (five 
female and two male) were enrolled in Study Arm 2 for determination of tolerability of 
SC infusions as described for Study Arm 1 and comparison of PKparameters obtained 
after IV and SC administration of IGIV 10% in the initial phase of Study Arm 2. 
The only severe and potentially life-threatening adverse event (AE) that occurred in the 
study was an anaphylactic reaction that was attributed to an antibiotic drug taken 
immediately prior to onset of the symptoms. This serious adverse event (SAE) occurred 
more than 24 hours after an infusion and was not considered related to use of the study 
drugs by the investigator. The subject continued in the study without further reactions. 
All other AEs, which occurred in four subjects in Study Arm 1 and six of seven subjects 
in Study Arm 2, were non-serious local AEs, of which the majority were mild and none 
were severe. Local AEs included infusion site erythema, infusion site pain, infusion site 
edema, infusion site warmth, injection site pruritus, infusion site swelling, and symptoms 
categorized as infusion site reactions. 
The primary safety endpoint was the proportion of SC infusions, which were not 
interrupted or stopped due to AEs. Two SC infusions, one in each study arm, had to be 
interrupted due to mild infusion site pain and mild chest pain, respectively. In one subject 
in Study Arm 2, the infusion rate had to be decreased due to a mild infusion site reaction. 
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In conclusion, this study of SC use of IGIV 10% facilitated by prior injection of 
rHuPH20 yielded initial favorable results in terms of tolerability of a full four-week dose 
of IGIV 10% administered by SC infusion in a single infusion site and in terms of
bioavailability of IgG after SC administration.
6.3.2 Clinical Study 160603
Efficacy, Tolerability and Pharmacokinetic Comparison of Immune Globulin 
Intravenous (Human) 10% (GAMMAGARD LIQUID, KIOVIG) Administered 
Intravenously or Subcutaneously Following Administration of Recombinant Human 
Hyaluronidase (rHuPH20) in Subjects with Primary Immunodeficiency Diseases
Study 160603 was a prospective, open-label, non-controlled, multi-center, Phase III 
study.38 The purpose of the study was to develop a SC treatment option for subjects with 
PIDD that allows SC administration of GAMMAGARD LIQUID/KIOVIG at the same 
frequency as IV administration. The study consisted of two study parts:
Study Epoch 1: IV treatment with GAMMAGARD LIQUID/KIOVIG
Study Epoch 2: SC treatment with GAMMAGARD LIQUID/KIOVIG after 
administration of 75 U/g IgG rHuPH20 at three- or four-week treatment intervals
Study Arm 1 was comprised of subjects who previously participated in Study 160601 and 
wished to also participate in this follow-up study; these subjects only completed Study 
Epoch 2. Study Arm 2 comprised all other subjects; these subjects completed Study 
Epoch 1 and Study Epoch 2.
Eighty-nine subjects were enrolled in the study, of which 87 were treated via both IV and 
SC routes. Eighty-four subjects completed Study Epoch 1 and 68 subjects completed 
Study Epoch 2. Sixteen subjects withdrew or were discontinued from the study, including 
three subjects who withdrew during the ramp-up period at the beginning of HyQvia
treatment. Four adults withdrew due to local pain and swelling; in two of these subjects, 
the swelling extended from the abdominal site to the genitalia, causing transient 
discomfort. In one of the subjects, the swelling was accompanied by erythema. One 
other subject withdrew due to a perceived increase in infections. 
Of the 1,359 SC infusions with rHuPH20 during the ramp-upvi period and Epoch 2, 
90.1% were administered in the abdomen and 8.6% in the thighs. 
                                                
vi
The treatment intervals and doses used for the initial infusions were gradually increased during the first 
weeks of treatment (referred to as the ramp-up), in order to allow the subjects to adjust to increasing 
volumes administered SC.
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The median duration of individual infusions was similar or lower when GAMMAGARD 
LIQUID/KIOVIG was administered SC with rHuPH20 than for IV administration. The 
percentage of subjects who had no infusions that required a reduction in flow rate, 
interruption, or had to be stopped due to tolerability concerns or AEs was similar between
SC infusions with rHuPH20 (84.0%) and IV administration (88.5%).
The rate of infusions temporally associated with systemic AEs was lower for SC 
administration with rHuPH20 compared to IV administration, whereas the rate of 
infusions temporally associated with local AEs was higher for SC administration with 
rHuPH20. The trend toward less frequent systemic AEs and more frequent local AEs 
during SC administration with rHuPH20 compared to IV treatment was also evident in 
the nature of AEs reported in Medical Dictionary for Regulatory Activities (MedDRA)
Preferred Terms. Of the AEs in Epoch 1 that were considered by the investigator to be 
possibly or probably related to GAMMAGARD LIQUID/KIOVIG, the most common 
were headache, chills, nausea, fatigue, pyrexia, and vomiting. The most common AEs 
possibly or probably related to both GAMMAGARD LIQUID/KIOVIG and rHuPH20 in 
Epoch 2 (excluding the ramp-up) were infusion site pain, infusion site erythema, infusion 
site discomfort, headache, infusion site pruritus, infusion site edema, and infusion site 
swelling. No severe headache was related to SC infusions with rHuPH20. AEs possibly 
or probably related to rHuPH20 but not GAMMAGARD LIQUID/KIOVIG in Epoch 2 
(excluding the ramp-up) included infusion site pain and infusion site pruritus. The 
majority of AEs were mild; very few severe AEs occurred. All SAEs were assessed as 
unrelated to the study drugs. A comparison of data from the present study and Study 
160601 demonstrated no appreciable differences in the median rates of AEs temporally 
associated with or related to either or both study drugs. 
GAMMAGARD LIQUID/KIOVIG administered SC with rHuPH20 at 108% of the 
IV dose was effective in preventing bacterial infections in pediatric and adult subjects 
with PIDD. Analysis of the secondary endpoints demonstrated that GAMMAGARD 
LIQUID/KIOVIG given SC with rHuPH20 had higher bioavailability as determined by 
AUC per dose/kg than when infused SC without rHuPH20. Compared to IV infusion, 
SC administration with rHuPH20 was administered at the same dosing interval and 
resulted in similar IgG trough levels while eliciting fewer systemic ARs. Furthermore, 
SC infusion with rHuPH20 was the subjects’ preferred mode of treatment with 
GAMMAGARD LIQUID/KIOVIG.
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6.3.2.1 Pharmacokinetic Properties
With administration of HyQvia, peak serum IgG levels are achieved in the recipient’s 
circulation after a delay of approximately three to five days.
Data from the clinical trial of HyQvia show that serum IgG trough levels can be 
maintained by dosing regimens of 320 to 1,000 mg/kg BW/four weeks given at intervals 
of three or four-weeks.
The PKs of HyQvia was evaluated in this Phase 3 efficacy and safety study in 60 patients 
with PIDD aged 12 years and older. The pharmacokinetic results are presented in the 
table below, as compared to data for IV administration of IGI 10% obtained in the same 
study.
Table 1
Pharmacokinetic Parameters of HyQvia Compared to 
Intravenous Administration of IGI 10%
Parameter
HyQvia
Median (95% Cle)
N=60
IGIV, 10%
Median (95% Cl)
N=68
Cmax
a[g/l]
15.5 (14.5; 17.1)
21.9 (20.7; 23.9)
Cmin
b [g/l]
10.4 (9.4 to 11.2)
10.1 (9.5 to 10.9)
AUCc per week [g*days/l]
90.52 (83.8 to 98.4)
93.9 (89.1 to 102.1)
Tmax
d [days]
5.0 (3.3 to 5.1)
0.1 (0.1 to 0.1)
Apparent clearance or clearance [ml/kg/day]
1.6 (1.4 to 1.79)
1.4 (1.2 to 1.4)
Terminal half-life [days]
45.3 (41.0 to 60.2)
35.7 (32.4 to 40.4)
a
Concentration maximum.
b
Concentration minimum.
c
Area under the curve.
d
Time to maximum concentration.
e
Confidence interval.
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6.3.3 Clinical Study 160902
Long-Term Tolerability and Safety of Immune Globulin Subcutaneous (IGSC) 
Solution Administered Subcutaneously Following Administration of Recombinant 
Human Hyaluronidase (rHuPH20) in Subjects with Primary Immunodeficiency 
Diseases
The purpose of the study was to assess the long-term safety, tolerability, and 
practicability of the SC treatment with IGI, 10% facilitated with rHuPH20 in subjects 
with PIDD who have completed Baxter Clinical Study Protocol 160603. The primary 
objective of this study was to evaluate the long-term tolerability and safety of IGI, 10%
given SC after an SC administration of rHuPH20 in subjects with PIDD. The secondary 
objectives included: monitoring the long-term efficacy of IG, 10% given SC after an 
administration of rHuPH20 in subjects with PIDD, evaluating the effect of varying the 
dose frequency of IG, 10% rHuPH20 on IgG trough levels and assessing the 
practicability of treating PIDD with IGI, 10% given SC after an administration of 
rHuPH20 when treatment occurs in a home treatment environment.
In Study 160902, subjects began on the same doses of IGI, 10% and rHuPH20 that were 
used for the last infusions in Study Epoch 2 of Study 160603.  In order to pursue the 
secondary objective “effect of varying the dose frequency of IGI, 10%/rHuPH20 on IgG 
trough levels”, subjects were requested to change their drug administration interval to a 
two-week drug interval (receiving a two-week dose) from a three- or four-week drug 
administration interval, provided both the subject and the investigator agreed that the 
change was appropriate. This new treatment interval started after three infusions on the 
three or four-week interval and was maintained for a minimum of four months.  It was
intended to allow for evaluation of whether a more frequent administration of IGI, 10%
leads to improved IgG trough levels. After the four-month trial period, subjects could
revert to their previous dose interval or continue on the two-week interval, depending on 
the subject’s preference.
On 01 August of 2012, the FDA requested administration of rHuPH20 drug product in all 
ongoing HyQvia clinical studies in the US to be suspended and patients were switched to 
treatment with KIOVIG/GAMMAGARD LIQUID only (Protocol Amendment 5).  
Subjects were treated with conventional IGIV or IGSC for 24 weeks, or, for those who 
had anti-rHuPH20 antibody titers ≥160 at the time rHuPH20 was discontinued, for 
48 weeks.
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6.3.3.1 Disposition of Subjects
Sixty-six subjects were screened for eligibility to participate in this study. Out of the 
66 patients who rolled over from Study 160603 into 160902, 63 subjects were treated 
with IGSC, 10% with rHuPH20; three subjects received IGIV, 10%. Of the 63 subjects 
under IGSC, 10% with rHuPH20 treatment, 15 withdrew or were discontinued from the 
study; 48 switched to the Safety Follow-up when Protocol Amendment 5 went into effect. 
Of the 15 subjects discontinued from IGSC, 10% with rHuPH20, four withdrew, one
subject died, one subject had bone marrow transplant, six subjects had their clinical site 
closed out by sponsor, and three had their site elected to exit study. Of the 48 subjects 
switched to the Safety Follow-up period, one subject withdrew after experiencing an AE. 
In total, 50 subjects completed the study: 47 subjects from the Safety Follow-up and three
subjects who received IGI, 10% IV or SC without rHuPH20 throughout the study. The 
majority of enrolled subjects were in the age range category of 16 to <65 years (47 out of 
66), followed by 65 years and older (eight subjects), seven subjects in the range of 12 to 
<16 years and four subjects in the range of two to <12 years. The median age was 
43.0 years. Of the 66 subjects who met all inclusion/exclusion criteria, 50 (75.8%) 
completed the study.
6.3.3.2 Extent of Exposure
IGSC, 10% with rHuPH20 was administered to 63 subjects prior to the Safety Follow-up 
period for a median treatment duration of 669 days (range: 60-729 days) and a mean 
(± SD) of 565.9 ± 211.8 days. The mean (± SD) dose received per week, per body mass, 
was 0.156 ± 0.051 g/kg/week. Across all age groups, the median initial rate of 
IGSC, 10% infusion with rHuPH20 was 10 mL/hr (range: 5-300) and the median 
maximum rate of infusion achieved was 300 mL/hr (range: 10-350). Across all age 
groups and infusion intervals, a median number of 1.09 infusions/month (range: 0.3-2.1) 
was administered. IGSC, 10% with rHuPH20 treatment required a median number of 
1.58 infusion sites/month (range 0.3-4.2) across all age groups and infusion intervals. For 
the majority of subjects in this study (41/66; 62.1%), the four-week infusion interval was 
the most frequently followed infusion interval. The two-week infusion interval was the 
most frequent interval for 15/66 (22.7%) subjects and 7/66 (10.6%) subjects most 
frequently followed a three-week infusion interval.
6.3.3.3 Efficacy
Analysis of the efficacy results in this study indicates that rHuPH20-facilitated SC 
treatment with IGI, 10% is efficacious in the treatment of adult and pediatric subjects 
with PIDD, in terms of IgG trough levels, infection rates, and patient-related outcomes.
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Two validated acute serious bacterial infections (VASBIs) occurred in 66 subjects under 
IGSC, 10% treatment with rHuPH20. The annual rate of VASBIs was statistically 
significantly lower than the threshold specified as providing substantial evidence of 
efficacy. 
The point estimate for the annualized rate of all infections was 2.86 (95% Confidence 
Interval [CI]: 2.36-3.43) during IGSC, 10% with rHuPH20 treatment.
IgG trough levels maintained under IGSC, 10% with rHuPH20 treatment did not 
substantially vary with infusion interval changes and were lower with the longest 
(four-week) infusion interval (median steady-state trough level: 10.90 g/L (two-week 
interval), 12.30 g/L (three-week interval), 9.76 g/L (four-week interval). 
Percent change of steady-state trough levels was 105.90% (mean and median) for 
subjects who switched from a three-week to a two-week infusion interval and a mean of 
113.23% (median 112.44%) for subjects who switched from a four-week to a two-week 
infusion interval.
The point estimate for the annualized rate of days off school/work was less than 
eight days per year. The rate of days on antibiotics was less than 65 days per year. The 
rate of hospitalizations was less than one per year and the rate of days hospitalized, less 
than one day per year. The rate of acute physician visits due to infection or other illness 
was less than five visits per year.
6.3.3.4 Safety
rHuPH20-facilitated SC treatment with IGI, 10% was safe and well tolerated by adult and 
pediatric subjects with PIDD.
No SAEs occurred that were considered by the investigator to be related to either of the 
study drugs. In total, 11 subjects experienced SAEs during the study. One subject 
experienced an SAE after study completion.
Throughout the study, the proportion of infusions requiring adjustment for tolerability 
concerns or for AEs was low (0.1% of infusions stopped, 0.6% of infusions interrupted; 
1% infusion rate reduced). 
The most common related AEs under IGSC, 10% treatment facilitated by rHuPH20 were 
infusion site pain, infusion site pruritus, nausea, myalgia, infusion site erythema, 
headache, fatigue, asthenia, chills, infusion site discomfort, and pain. 
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The rate of all AEs related to IGI, 10%, by infusion, was 0.13 during rHuPH20-facilitated 
IGSC, 10% treatment administration, and 0.22 during the Safety Follow-up period. 
During rHuPH20-facilitated IGSC, 10% treatment, the rate of all AEs related to 
rHuPH20, by infusion, was 0.01 and the rate of all AEs related to both IGI, 10% and 
rHuPH20 by infusion, was 0.06.
The rate of all causally related AEs by infusion was 0.20 during rHuPH20-facilitated 
IGSC, 10% treatment administration. The rate of all causally-related local AEs, by 
infusion, was 0.10 during rHuPH20-facilitated IGSC, 10% treatment administration. 
During rHuPH20-facilitated IGSC, 10% treatment, the rate of related systemic AEs by 
infusion, including or excluding infections was 0.1.
The rate of all temporally-associated AEs by infusion was 0.28 during 
rHuPH20-facilitated IGSC, 10% treatment. The rate of all temporally-associated local 
AEs by infusion was 0.10 during rHuPH20-facilitated IGSC, 10% treatment. During 
rHuPH20-facilitated IGSC, 10% treatment, the rate of temporally-associated systemic 
AEs by infusion including infections was 0.18 and excluding infections was 0.16. 
Throughout the study, 7.4 % of infusions were associated with one or more local AEs.
No subjects developed neutralizing antibodies in the entire duration of the follow-up 
including data obtained in Study 160603 starting with first exposure to IGSC, 10% 
facilitated by rHuPH20 and in Study 160902. 
A total of 13/66 subjects had anti-rHuPH20 antibody titers ≥160 in Study 160902. 
Eleven subjects had developed anti-rHuPH20 antibody titers ≥160 in Study 160603. Two 
subjects each newly developed one anti-rHuPH20 antibody titer of 160 in Study 160902. 
In the majority of subjects with anti-rHuPH20 antibody titers ≥160, the titers declined 
over time during IGSC, 10% with rHuPH20 treatment.
Assessment of hematology parameters, clinical chemistry parameters, urinalysis and 
specific antibody tests and viral pathogen serology did not raise any safety concerns with 
respect to the SC administration of IGI, 10% with rHuPH20.
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6.3.4 Clinical Study 161101 
Tolerability, Safety and Administration Mode Evaluation of rHuPH20 Facilitated 
Subcutaneous Treatment with Immune Globulin Infusion (Human), 10% in 
Subjects with Primary Immunodeficiency Diseases
This US study was a Phase 2/3, prospective, non-controlled, multicenter study to evaluate 
tolerability and safety and other parameters of SC treatment using Immune Globulin 
Infusion (Human), 10% (IGI, 10%. IGI, 10% is the same product as IGIV 10% licensed 
in the EU as KIOVIG) with rHuPH20 in a total of approximately 60 PIDD subjects 
already pre-treated with immunoglobulin products (Gamunex administered IV, Hizentra 
or Privigen). 
PIDD patients already on IV or SC treatment were enrolled and treated with IGI, 10% 
and rHuPH20 subcutaneously with a dose/interval ramp-up of three weeks. The ramp-up 
period was Epoch 1.
The ramp-up was followed by Epoch 2, a six month period of IGSC, 10% with rHuPH20 
treatment:
For IV-pretreated subjects: every three weeks or four weeks, depending on the 
subject’s previous IV dosing schedule
For SC-pretreated subjects: every three weeks or four weeks, at the discretion of 
investigator and subject
The rHuPH20 administration was discontinued as of 01 August 2012 at the request of the 
FDA. Those subjects who did not withdraw from the study completed the planned 
infusions using conventional IGIV or IGSC. The last subject completed the study on 
04 January 2013. 
A total of 37 subjects started the treatment. All but one of the subjects reached Epoch 2. 
During Epoch 2, nine subjects withdrew. At the time when rHuPH20 administration was 
stopped, one subject had completed Epoch 2. The remaining 26 were switched to 
Epoch 3. During Epoch 3, two subjects withdrew, 24 completed Epoch 3. Thus, 
25 subjects including the one subject who completed Epoch 2 without ever reaching 
Epoch 3 completed the study. 
Analysis of the efficacy results in this study indicate that rHuPH20-facilitated SC 
treatment with IGI, 10% was efficacious in the treatment of adults and pediatric subjects 
with PIDD, in terms of IgG trough levels, infection-rates, and subject related outcomes.
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Trough levels of total IgG at the end of Epoch 2 (geometric mean: 9.21 g/L [95% CI: 
8.28-10.25]) were comparable to the levels measured at screening (geometric mean:
10.53 g/L [95% CI: 9.46-11.73]). 
No serious bacterial infections were reported in any subject throughout the study. The 
point estimate for the rate of all infections per year was 2.45 for Epoch 1 and Epoch 2 
combined.
The point estimate for the rate per month of days off either from work, school, or daily 
activity was less than one day/month. The rate of days on antibiotics was less than three
days/month. No subjects were hospitalized during the study period and the rate of acute 
physician visit due to infection or other illness was less than one visit/month.
Analysis of the mode of infusion was inconclusive due to the premature stop of subject 
enrollment and early termination of Epoch 2, however the following results were 
observed.
Median number of infusions per month: 2.90 in Epoch 1; 1.09 in Epoch 2. Median 
number of infusion sites (needle sticks) per infusion/month: 2.90 in Epoch 1; 1.12 in 
Epoch 2. Median duration of infusion: less than two hours. Median maximum infusion 
rate: 240mL/h in Epoch 1; 300mL/h in Epoch 2. 
Treatment with IGI, 10% when administrated either SC with rHuPH20 (Epochs 1 and 2) 
or SC without rHuPH20 or IV (Epoch 3) was safe and well tolerated. No SAEs occurred 
that were considered by the investigator to be related to either of the study drugs.
During Epoch 1 and Epoch 2 combined, 59 related systemic AEs occurred. The rate of 
related systemic AEs/infusion, excluding infections (primary outcome) was 0.326 
(95% CI: 0.186-0.522) and the rate per number of subjects was 37.8% (14/37), for 
Epochs 1 and 2 combined. The rate per infusion of local AEs (including infections) 
related to IGI, 10% was 0.066 in Epoch 1, 0.028 in Epoch 2 and 0.006 in Epoch 3. 
The rate of local AEs related to rHuPH20 per infusion was 0.039 in Epoch 1 and 0.038 in 
Epoch 2. The rate of local AEs related to both rHuPH20 and IGI, 10% per infusion was 
0.776 in Epoch 1 and 0.745 in Epoch 2.
According to MedDRA preferred term classification, the most common AEs related to 
IGI, 10% with rHuPH20 in both Epoch 1 and Epoch 2 were “infusion site pain”, 
“infusion site erythema”, and “infusion site swelling”.
No patient developed neutralizing anti-rHuPH20 antibodies in the course of the study. 
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Assessment of hematology parameters, clinical chemistry parameters, and urinalysis did 
not raise any safety concerns with respect to the SC administration of IGI, 10% with 
rHuPH20.
6.3.5 HyQvia Pregnancy Registry 161301
Pregnancy Registry to collect Long-Term Safety Data from Women treated with 
HyQvia (Immune Globulin (Human) 10% with rHuPH20
This study is an ongoing non-interventional, prospective, uncontrolled, two-arm, open-
label, multicenter post-authorization pregnancy registry. Subjects who prior to the study 
received HyQvia and at enrollment receive a licensed human normal immunoglobulin 
other than HyQvia or an alternative treatment during the study are assigned to Study 
Arm 1 (Alternative Product Arm); subjects in countries where HyQvia treatment during 
pregnancy is not indicated are enrolled in this arm. Subjects who continue treatment with 
HyQvia during pregnancy are followed in Study Arm 2 (HyQvia Arm).
The study is conducted in the European Economic Area, North America, and other 
countries where the product is licensed, as needed. This pregnancy registry with regular 
assessment of antibodies against rHuPH20 was a commitment to the Committee for 
Medicinal Products for Human Use (CHMP) and the FDA in the course of the HyQvia
Marketing Authorization Procedure. Further data shall be collected to evaluate safety of 
women who become pregnant during or after treatment with HyQvia as well as the 
physical and neurological development of the infant during the first two years of life.
The primary objective is to collect and assess clinical safety data regarding the possible 
effects of HyQvia on the course and outcome of the pregnancy, and on the growth and 
development of the fetus/infant. The secondary objectives are to collect any laboratory 
safety data and additional safety assessments obtained during the clinical management of 
the pregnancy or in the evaluation of the fetus in utero and the infant post-partum.
In this registry pregnant women ever treated with HyQvia will be enrolled. In the 
European Union (EU) the therapeutic indications for HyQvia are PIDD, CLL, and 
myeloma. In the USA, HyQvia is licensed for the treatment of PIDD. Although the target 
population consists mainly of women treated for the approved indications in the 
respective country, any woman who becomes pregnant after being exposed to HyQvia
will be encouraged to participate in the registry.
Visits to the investigator (for example immunologist) and all other medical care will 
be performed as is standard for the site and for the subject’s healthcare. 
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However, the pregnant subject will be invited to return approximately every three months 
to the site for blood samples to be taken to assess antibodies against rHuPH20, as 
requested by the CHMP and the FDA.
As soon as the patient becomes aware of the pregnancy, she should inform the treating 
physician. According to her treatment, the subject enters the study in one of the following 
two Study Arms.
Study Arm 1 (Alternative Product Arm): Subjects who stop treatment with HyQvia will 
be followed in Study Arm 1. The treating physician of the pregnant woman prescribes a 
licensed human normal immunoglobulin other than HyQvia for IV or SC infusion or an 
alternative treatment, at his/her discretion. 
Study Arm 2 (HyQvia Arm): Subjects who continue treatment with HyQvia according to 
their treatment regimen will be followed in Study Arm 2.
The overall duration of the study is approximately six years from study initiation 
(Registry ready to enroll) to study completion (i.e., end data collection). The enrollment 
period is expected to be three years. The participation period for the pregnant woman is 
from enrollment to study completion/termination visit after the delivery/end of 
pregnancy. The participation period for the infant is from enrollment until the age of 
two years to assess the development, unless prematurely discontinued.
6.3.6 HyQvia PASS 161302
Non-Interventional Post-Authorization Safety Study on the Long-Term Safety of 
HyQvia in Subjects treated with HyQvia
This is a non-interventional, prospective, uncontrolled, multi-center, open-label, 
post-authorization safety study (PASS) in the European Economic Area. The Post-
Authorization Safety Surveillance was a commitment to the CHMP in the course of the 
HyQvia Marketing Authorization Procedure. 
The purpose of the study is to acquire additional data (including the assessment of anti-
rHuPH20 antibodies) on the long-term safety of HyQvia and to assess the prescribed 
treatment regimens and treatment administration in routine clinical practice.
The primary objective is to collect and assess safety data, in particular the occurrence of 
long-term changes in incidence and severity of related AEs in patients treated with 
HyQvia. 
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Secondary objectives are to collect data on the prescribed treatment regimen, 
anti-rHuPH20 antibodies and, as available, other laboratory safety assessments, total IgG, 
further safety assessments that are obtained during the routine clinical management of the 
subjects, treatment administration, and health-related quality of life (HRQoL) and health 
resource use assessments (optional).
Adult patients (≥ 18 years) who have been prescribed treatment with HyQvia are
enrolled. Treatment regimens are prescribed at the discretion of the attending physician in 
accordance with routine clinical practice. Visits to the investigator and all other medical 
care are performed as is standard for the site and for the subject´s healthcare. In addition, 
however, the subject is requested to have additional blood samples drawn at the time of 
routine laboratory assessments approximately every three months, but no more often than 
four times a year, for the measurement of antibodies against rHuPH20.
The overall duration of the study is approximately six years from study initiation (i.e., 
first subject enrolled) to study completion (i.e., last subject last visit). The recruitment 
period is expected to be approximately three years. Enrollment started in Q3 2014. The 
subject participation period is approximately three to six years from enrollment to subject 
completion (i.e., study termination/completion visit), depending on the time point of 
enrollment, unless prematurely discontinued. It is anticipated that approximately 80 to 
120 subjects will be eligible for enrollment in this study.
6.3.7 HyQvia Study 161406
Non-Interventional Post-Marketing Safety Study on the Long-Term Safety of 
HyQvia (Global)
This prospective, uncontrolled, multi-center, open-label, post- HyQvia marketing 
authorization surveillance study with assessment of anti-rHuPH20 antibodies was agreed 
upon with the FDA in the course of the HyQvia Biologic License review and approval 
process.
The purpose of the study is to acquire additional data (including the assessment of 
anti-rHuPH20 antibodies) on the long-term safety of HyQvia and to assess the prescribed 
treatment regimens and treatment administration in a total of 250 adult evaluable subjects 
with PIDD under routine clinical conditions. Further data shall be collected in subjects 
with an anti-rHuPH20 antibody titer ≥ 160.
The primary objective is to collect and assess safety data, in particular the occurrence of 
long-term changes in incidence and severity of related AEs in patients treated with 
HyQvia.
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Secondary objectives are to collect data on anti-rHuPH20 antibodies and, as available, 
other laboratory safety assessments, total IgG, further safety assessments that are 
obtained during the routine clinical management of the subjects, the prescribed treatment 
regimen, treatment administration, HRQoL and health resource use assessments.
6.4 Evaluation of Anticipated Risks and Benefits of the Investigational Product(s) to 
Human Subjects
6.4.1 HyQvia
The clinical development program for HyQvia has demonstrated that IGI, 10% 
administered via SC treatment with rHuPH20 is efficacious and safe in persons with 
PIDD. The safety, tolerability, efficacy and bioavailability of HyQvia were investigated 
in one pivotal Phase III study (160603), an extension study (160902) in patients with 
PIDD. One supportive clinical study (160602) in patients with PIDD using Gammagard 
Liquid administered subcutaneously was also conducted. Further information is provided 
in the IB for Immune Globulin Infusion 10% (Human) with Recombinant Human 
Hyaluronidase (IGI, 10% with rHuPH20) as well as Prescribing Information for HyQvia
and SmPC for HyQvia.
The most common ARs observed in PIDD clinical trials in >5% of subjects were: local 
reactions, headache, antibody formation against rHuPH20, fatigue, nausea, pyrexia, and 
vomiting.
The safety and efficacy of chronic use of the rHuPH20 solution in HyQvia has not been 
established in conditions other than PIDD. Study 160603 compared the efficacy, PKs, 
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 PIDD receiving 
IGI, 10% with rHuPH20 in 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. 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.
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6.4.1.1 Pregnancy, Breast Feeding, Fertility
Subcutaneous immunoglobulin G (SCIG) products have been shown to cross the 
placenta, increasingly during the third trimester. Clinical experience with 
immunoglobulins suggests that no harmful effects on the course of pregnancy, or on the 
fetus and the neonate are to be expected. Development and reproductive toxicology 
studies have been conducted with rHuPH20in mice and rabbits. No adverse effects on 
pregnancy and fetal development were associated with anti-rHuPH20 antibodies. In these 
studies, maternal antibodies to rHuPH20were transferred to offspring in utero. The effects 
of antibodies to the rHuPH20component of HyQvia on the human embryo or on human 
fetal development are currently unknown. Immunoglobulins are excreted into the milk 
and may contribute to protecting the neonate from pathogens which have a mucosal 
portal of entry.
The safety of HyQvia for use in human pregnancy has not been established in controlled 
clinical trials and therefore should only be given with caution to pregnant or 
breastfeeding women.
There are currently no clinical safety data for HyQvia on fertility available. Clinical 
experience with immunoglobulins suggests that no harmful effects of IG 10% on fertility 
are to be expected. Animal studies do not indicate direct or indirect harmful effects of 
rHuPH20 with respect to reproductive potential at the doses used for facilitating 
administration of IG 10%.
Subjects who become pregnant during the study should be withdrawn from the study and 
recommended to participate in the HyQvia Pregnancy Registry (Study 161301), if 
available in the respective country.
See Section 6.4.2 for the known risks associated with IGI, 10%.
6.4.2 KIOVIG
IGI, 10% administered via IV treatment (KIOVIG) is efficacious and safe in the 
particular fields of therapeutic use and approved indications, i.e., PIDD, ITP and MMN, 
as demonstrated in the clinical development program for KIOVIG. Please see the 
investigator’s brochure for Immune Globulin Infusion (Human), 10% Solution 
(IGI, 10%) for further information, as well as SmPC for KIOVIG.
Serious ARs (defined as SAEs occurring during or within 72 hours of infusion or any 
casually related SAE occurring within the study period) which occurred in the clinical 
trials of KIOVIG were aseptic meningitis, pulmonary embolism, and blurred vision.
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The most common ARs observed in ≥5% of patients were:
PIDD, IV administration: headache, fatigue, pyrexia, nausea, chills, rigors, pain in 
extremity, diarrhea, migraine, dizziness, vomiting, cough, urticaria, asthma, 
pharyngolaryngeal pain, rash, arthralgia, myalgia, edema peripheral, pruritus, and 
cardiac murmur.
PIDD, 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.
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 with immune globulin products, including IGI, 10%. Risk factors 
may include advanced age, prolonged immobilization, hypercoagulable conditions, 
history of venous or arterial thrombosis, use of estrogens, indwelling vascular catheters, 
hyperviscosity, and cardiovascular risk factors.
Renal dysfunction, acute renal failure, osmotic nephrosis, and death may occur in 
predisposed patients receiving immune globulin intravenous (IGIV) products including 
IGI, 10%. Renal dysfunction and acute failure occur more commonly with IGIV products 
containing sucrose. IGI, 10% does not contain sucrose.
IGI, 10% contains blood group antibodies (isoagglutinins) that may cause hemolysis. 
Delayed hemolytic anemia can develop subsequent to IGI, 10% therapy due to enhanced 
red blood cell (RBC) sequestration. Acute hemolysis, consistent with intravascular 
hemolysis, has been reported. The following risk factors may be related to the 
development of hemolysis: high doses (e.g., ≥2 g/kg, single administration or divided 
over several days) and non-O blood group. Underlying inflammatory state in an 
individual patient may increase the risk of hemolysis but its role is uncertain.
Contraindications to IGI treatment include anaphylactic or severe systemic 
hypersensitivity reactions to IG and IgA deficient patients with antibodies against IgA 
and a history of hypersensitivity. 
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IGI, 10% has a high margin of safety. Screening against potentially infectious agents 
begins with the donor selection process and continues throughout plasma collection and 
preparation. Three validated, dedicated, independent, and effective virus 
inactivation/removal steps have been integrated into the manufacturing and formulation 
processes, further increasing the margin of safety. In addition, careful screening and 
monitoring of subjects in this study will be utilized to minimize the above and other 
known risks associated with IG therapy (e.g., exclusion criteria, blood group typing at 
baseline, and laboratory monitoring for hemolysis). 
Further information is provided in the SmPC for KIOVIG, and the IB for Immune 
Globulin Infusion (Human), 10% Solution (IGI, 10%).
6.4.3 SUBCUVIA
Information about SUBCUVIA is provided in the SmPC.
6.5 Compliance Statement
This study will be conducted in accordance with this protocol, the International Council 
for Harmonisation Guideline for Good Clinical Practice E6 (ICH GCP, April 1996), 
Title 21 of the US Code of Federal Regulations (US CFR), the EU Directives 2001/20/EC 
and 2005/28/EC, and applicable national and local regulatory requirements.
7. STUDY PURPOSE AND OBJECTIVES
7.1 Study Purpose
The purpose of the study is to acquire additional data on safety, tolerability and 
immunogenicity of HyQvia in pediatric (age <18 years) subjects with PIDD.
7.2 Primary Objective
The primary objective of the study is to assess the safety of HyQvia treatment in pediatric 
subjects with PIDD who received immunoglobulin therapy prior to study enrollment.
7.3 Secondary Objectives
Secondary objectives of the study are further assessments (e.g. immunogenicity), 
tolerability, characteristic of product administration and efficacy (IgG trough levels).
7.4 Tertiary Objectives
Tertiary objectives are further safety and efficacy assessments. The study objectives are 
described in more detail in Section 11, Section 12, Supplement 20.2 and Figure 1.
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8. STUDY DESIGN
8.1 Brief Summary
This study is a Phase 4, post-authorization, prospective, non-controlled, multicenter study 
to evaluate safety, tolerability, and other parameters of SC treatment using HyQvia in 
approximately 40 pediatric subjects with PIDD who received immunoglobulin therapy 
prior to study enrollment.
The purpose of the study is to acquire additional data on safety, tolerability and 
immunogenicity of HyQvia in pediatric subjects.
8.2 Overall Study Design
The overall study design is illustrated in Figure 1. Details on the procedures to be 
performed at each study visit can be found in Supplement 20.2 Schedule of Study 
Procedures and Supplement 20.3 Clinical Laboratory Assessments. In this study 
approximately 40 pediatric subjects with PIDD will be enrolled, who have received prior 
immunoglobulin therapy. The study will enroll approximately six subjects aged 2 to 
<6 years, 12 subjects 6 to <12 years, and 22 subjects 12 to <18 years of age. The study 
will be conducted in the European Economic Area.
All subjects will have regular anti-rHuPH20 antibody testing (binding and neutralizing 
anti-rHuPH20 antibody) throughout the study (approximately every three months). 
8.2.1 Epoch 1
Pediatric patients with PIDD who are on non-HyQvia IV or SC treatment with 
immunoglobulin (IV-pretreated, SC-pretreated) will be enrolled and treated with HyQvia 
subcutaneously with a dose or interval ramp-up period of up to six weeks. Subjects 
already treated with HyQvia (HyQvia-pretreated) will be enrolled directly into Epoch 2. 
Epoch 1 infusions will be administered at the study site. 
8.2.2 Epoch 2
The ramp-up (Epoch 1) is followed by Epoch 2 with HyQvia treatment at the following 
intervals:
For IV-pretreated subjects: every three or four weeks, depending on the subject’s 
previous IV dosing schedule.
For SC-pretreated subjects: every three or four weeks, at the discretion of 
investigator and subject.
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For HyQvia pre-treated subjects: No change in frequency of administration.
After one year in Epoch 2, the anti-rHuPH20 binding antibody assay results during that 
year will be used to decide the next steps in the study (see Figure 1 Study Flow Chart in
Supplements):
Subjects with anti-rHuPH20 antibody titer < 160 at all time-points during the study 
will complete the study termination/completion visit at the next possible occasion. 
Subjects with anti-rHuPH20 antibody titer ≥ 160 during the study and/or at the last 
measurement will continue in Epoch 2 for an additional two years of HyQvia 
treatment and observation. 
The first two to three infusions during Epoch 2 will be administered at the study site. It is 
preferable that subsequent infusions be performed at home (or equivalent site), by the 
subject/caregiver, if in the opinion of the investigator, such treatment is safe and 
appropriate. In that case, the investigator/designee must have trained the subject or 
caregiver and must be satisfied that the subject or caregiver is capable of 
self-administration of SC infusions at home before the subject or caregiver will be 
permitted to conduct the SC infusion at home.
8.2.3 Epoch 3
Epoch 3 is up to one year safety follow-up for subjects whose anti-rHuPH20 antibody 
titer was ≥ 160 during Epoch 1 or Epoch 2 and who experience either a related SAE or a 
related severe AE.
In the event that a subject in Epoch 1 or in Epoch 2 experiences a related SAE or severe 
AE without anti-rHuPH20 antibody titer ≥ 160, the subject can (at the discretion of the 
investigator and subject) either be 1) terminated from the study or 2) change directly to 
Epoch 3 or 3) continue in Epoch 1 or 2 with appropriate medical intervention such as 
decreasing the HyQvia infusion rate and/or premedication.
Subjects with antibody titer of ≥ 160 when entering Epoch 3 continue regular 
anti-rHuPH20 antibody testing (approximately every three months) for approximately 
one year or until anti-rHuPH20 antibody titer declines to < 2560 for at least two 
consecutive measurements, whichever comes first. These subjects complete the study 
termination/completion visit when the AE/SAE resolves and the anti-rHuPH20 titer is 
< 2560.
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Subjects in Epoch 3 will be treated with KIOVIG (IGI, 10%) intravenously or 
SUBCUVIA subcutaneously, at the discretion of the investigator and the subject.
Infusions in Study Epoch 3 will be administered at home or at the study site.
The study termination/completion visit will be conducted at the study site.
8.3 Duration of Study Period(s) and Subject Participation
The overall duration of the study is approximately five years from study initiation (i.e., 
first subject enrolled) to study completion (i.e., last subject last visit). The recruitment 
period is expected to be one year. 
The maximum subject participation period is approximately four years from enrollment 
to subject completion (i.e., study termination/completion visit), unless prematurely 
discontinued.
8.4 Outcome Measures
8.4.1 Primary Outcome Measure
1. Number and rate per infusion (excluding infections) of all severe related AEs
2. Number and rate per infusion (excluding infections) of related SAEs
8.4.2 Secondary Outcome Measures
8.4.2.1 Efficacy 
1. Trough levels of IgG (for Study Epoch 1 and 2)
8.4.2.2 Safety/Tolerability
1. Proportion of subjects who achieve a treatment interval of three or four weeks in 
Epoch 2 
2. Proportion of subjects who maintain a treatment interval of three or four weeks in 
Epoch 2 for 12 months
3. Number and rate per infusion (excluding infections) of local AEs and ARs
4. Number and rate per infusion (excluding infections) of systemic AEs and ARs
5. Number and rate per infusion (excluding infections) of all AEs and all ARs
6. Number and rate per infusion (excluding infections) of all temporally associated 
AEs 
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7. Number and rate per infusion (excluding infections) of all causally related and/or 
temporally associated AEs
8. Number and rate per infusion (excluding infections) of all SAEs 
9. Number/proportion of subjects who develop positive titer (≥160) of binding or 
neutralizing antibodies to rHuPH20
8.4.2.3 Mode of Product Administration
For Study Epoch 1 and 2
1. Infusions
a. Number of infusions per month
b. Number of infusion sites (needle sticks) per infusion/month
c. Duration of infusion
d. Maximum infusion rate/site
e. Infusion volume/site
f. Number/proportion of infusions that are discontinued, slowed, or interrupted 
due to an AE
2. Number of weeks to reach final dose interval (3 weeks or 4 weeks)
3. Assessment of Treatment Preference Questionnaire
4. Assessment of HRQoL Questionnaire: Peds-QL, EQ-5D
8.4.3 Tertiary Outcome Measures
1. Number of acute serious bacterial infections
2. Number of all infections
3. Days not able to go to school or work or to perform normal daily activities
4. Days on antibiotics
5. Number of hospitalizations, indication for the hospitalization (infection or non-
infection) and days hospitalized
6. Number of acute physician visits (office and emergency room) due to infection or 
other illnesses.
8.4.4 Exploratory Outcomes Measure
Not applicable.
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8.5 Randomization and Blinding
This is a nonrandomized, open-label, active treatment clinical study.
8.6 Study Stopping Rules 
Stopping rules will not be established for this study as the pediatric subjects will be 
treated with a licensed human normal immunoglobulin, according to the routine standard 
at the study site, for the duration of the study. 
8.7 Investigational Product(s)
8.7.1 Packaging, Labeling, and Storage
8.7.1.1 rHuPH20
Dosage Form: Injection, solution
Packaging: rHuPH20 drug product (160 U/mL) will be supplied as a clear, colorless, 
ready-for-use sterile liquid preparation in single-use glass vials. The product should be 
inspected visually for particulate matter and discoloration. The product should not be 
used if particulate matter and/or discoloration is observed.
Labeling: The product will be labeled according to the regulatory requirements for 
clinical studies.
Storage: rHuPH20 drug product must be stored under refrigerated conditions (2° to 8°C 
or 36° to 46°F). Do not freeze the product. Do not use if expiration date is exceeded.
8.7.1.2 IGI, 10%
Dosage Form: Injection, solution.
Packaging: IGI, 10% will be supplied as a ready-for-use sterile liquid preparation in 
single-use glass vials. IGI, 10% is a clear or slightly opalescent and colorless or pale 
yellow solution. The product should be inspected visually for particulate matter and 
discoloration. The product should not be used if particulate matter and/or discoloration is 
observed.
Labeling: IGI, 10% will be labeled according to regulatory requirements for clinical 
studies.
Storage: IGI, 10% must be stored under refrigerated conditions (2°C to 8°C or 36°F to 
46°F). Do not freeze the product. Do not use if expiration date is exceeded.
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Prior to use, the vials must be removed from refrigeration and placed at room temperature 
for a minimum of 90 minutes to a maximum of 24 hours to equilibrate and should be kept 
at room temperature during administration. 
If IGI, 10% is pooled in a bag, it must be used as soon as possible, but no longer than 
three hours from the time of pooling. 
8.7.1.3 KIOVIG
Dosage Form: Injection, solution
Packaging: IGIV, 10% will be supplied as a ready-for-use sterile liquid preparation in 
single-use glass vials of 5 g (50 mL) and 10 g (100 mL).
Labeling: The study product will be labeled according to the valid regulatory 
requirements for clinical studies.
Storage: Refrigeration. IGIV, 10% must be stored under refrigerated conditions (2° to 
8°C or 36° to 46°F). Do not freeze the product. Do not use if expiration date is exceeded.
Prior to use, the unopened vials must be removed from refrigeration and placed at room 
temperature for a minimum of 90 minutes to a maximum of 24 hours to equilibrate and 
should be kept at room temperature during administration.
8.7.1.4 SUBCUVIA
Dosage form: Injection, solution
Packaging:
5 mL of solution in a vial (Type I glass) with a stopper (halogenobutyl rubber) 
10 mL of solution in a vial (Type I glass) with a stopper (halogenobutyl rubber) 
Labeling: The study product will be labeled according to the valid regulatory 
requirements for clinical studies.
Storage and Shelf Life: Store in a refrigerator (2ºC - 8ºC). Do not freeze. Shelf Life: 
30 months. Do not use if expiration date is exceeded. Keep the container in the outer 
carton in order to protect from light. Once opened: use immediately.
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8.7.2 Administration
rHuPH20 will be administered at a dose ratio of 80 U/g IgG before the infusion of IGI, 
10%. The full vial of rHuPH20 associated with each vial of IGI, 10% should be used.
rHuPH20 should be injected at a rate of approximately1-2 mL/min, or faster if tolerated, 
through the same SC needle that will be used to infuse the IGI, 10%.  As soon as the 
rHuPH20 infusion is completed, but no longer than ten minutes after it is completed, the 
administration tubing to deliver IGI, 10% should be connected to the same SC needle set 
used to administer rHuPH20 in order to flush the remaining rHuPH20 into the SC tissue 
and start the infusion of immunoglobulin.
8.7.3 Description of Treatment
8.7.3.1 HyQvia 
Subjects will be treated with HyQvia in Study Epoch 1 and Study Epoch 2.
Dosage Form: Injection
Mode of Administration: subcutaneous
Dosage Frequency:
Study Epoch 1 (Ramp-up):
One treatment interval of one week, then one treatment interval of two weeks, then one 
treatment interval of three weeks (for subjects in whom treatment is expected to be every 
four weeks).
Study Epoch 2 (Final dosing): 
Once every three or four weeks:
For IV-pretreated subjects: every three or four weeks, depending on the subject’s 
previous IV dosing schedule
For SC-pretreated subjects: every three or four weeks, at the discretion of investigator 
and subject
Dose: HyQvia weekly dose will be equivalent to 100% (±5%) of pre-study treatment
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Table 2
Example for IgG dosing
Pre-Study
Epoch 1 
(Ramp-Up)
Epoch 2 
(Final Dose)
Admin. 
Route
Dose
First Infusion 
at Baseline: 
1-Week Dose
Second Infusion 
at Week 1: 
2-Week Dose
Third Infusion 
at Week 3: 
3-Week Dose
IV
0.6 g/kg 
every 3 weeks
0.2 g/kg
0.4 g/kg
-
0.6 g/kg 
every 3 weeks
IV
0.6 g/kg 
every 4 weeks
0.15 g/kg
0.3 g/kg
0.45 g/kg
0.6 g/kg 
every 4 weeks
SC
0.1 g/kg 
every week
0.1 g/kg
0.2 g/kg
-
0.3 g/kg 
every 3 weeks
SC
0.1 g/kg 
every week
0.1 g/kg
0.2 g/kg
0.3 g/kg
0.4 g/kg 
every 4 weeks
Infusion Rate:
Study Epoch 1 (Ramp-up): 
For subjects with a BW of < 40 kg: 5 ml/h/site (at start) to 80 ml/h/site (maximum, 
if tolerated)
For subjects with a BW of ≥ 40 kg: 10 ml/h/site (at start) to 240 ml/h/site 
(maximum, if tolerated)
Study Epoch 2 (Final dosing):
For subjects with a BW of < 40 kg: 10 ml/h/site (at start) to 160 ml/h/site 
(maximum, if tolerated)
For subjects with a BW of ≥ 40 kg: 10 ml/h/site (at start) to 300 ml/h/site 
(maximum, if tolerated)
If infusions have been tolerated after the subject has received two HyQvia infusions at the 
dose for the final infusion interval (three or four week dose), then the investigator may 
choose an infusion rate schedule at his/her own discretion.
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8.7.3.2 KIOVIG
Subjects may be treated with KIOVIG in Study Epoch 3 (Safety Follow-up).
Dosage form: injectable
Mode of Administration: intravenous
The infusion rate and infusion volume per site will follow the suggestions of the KIOVIG
product information. 
Dosage frequency: Once every three or four weeks 
Dose: The weekly dose will be equivalent to 100% (±5%) of the dose in the previous 
study Epoch.
8.7.3.3 SUBCUVIA 160 g/l
Subjects may be treated with SUBCUVIA in Study Epoch 3 (Safety Follow-up).
Dosage form: injectable
Mode of Administration: subcutaneous
The infusion rate and infusion volume per site will follow the suggestions of the 
SUBCUVIA product information. 
Dosage frequency: Once every week or biweekly
Dose: The weekly dose will be equivalent to 100% (±5%) of the dose in the previous 
study epoch.
8.7.4 Investigational Product Accountability
The investigator will ensure that the investigational product(s) (IP[s]) are stored as 
specified in the protocol and that the storage area is secured, with access limited to 
authorized study personnel. The investigator will maintain records that the IP(s) was 
received, including the date received, drug identity code, date of manufacture or 
expiration date, amount received and disposition. IP(s) must be dispensed only at the 
study site or other suitable location (e.g. infusion center; home, as applicable per study 
design). Records will be maintained that includes the subject identification code (SIC), 
dispensation date, and amount dispensed. All remaining partially used and/or unused 
IP(s) will be returned to the sponsor or sponsor’s representative after study 
completion/termination, or destroyed with the permission of the sponsor in accordance 
with applicable laws and study site procedures. If IP(s) is to be destroyed, the investigator 
will provide documentation in accordance with sponsor’s specifications.
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8.8 Source Data
Per International Council for Harmonization (ICH) Good Clinical Practice (GCP), source 
data are defined as all information in original records and certified copies of original 
records of clinical findings, observations, or other activities in a clinical trial that are 
necessary for the reconstruction and evaluation of the trial. Source data are contained in 
source documents (original records or certified copies), which may be in paper and/or 
electronic format. Source data for this study comprise the following: hospital records, 
medical records, clinical and office charts, laboratory notes, memoranda, subjects' diaries 
or evaluation checklists, outcomes reported by subjects, pharmacy dispensing records, 
recorded data from automated instruments, copies or transcriptions certified after 
verification as being accurate copies, microfiches, photographic negatives, microfilm or 
magnetic media, x-rays, subject files, and records kept at the pharmacy, at the 
laboratories and at medico-technical departments involved in the clinical study.
No data will be entered directly into the electronic case report form (eCRF). 
For additional information on study documentation and eCRFs, see Section 17.2. The use 
of subject diaries is described in Section 10.
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9. SUBJECT SELECTION, WITHDRAWAL, AND DISCONTINUATION
9.1 Inclusion Criteria
Subjects who meet ALL of the following criteria are eligible for this study:
1. Subject must have a documented diagnosis of a form of primary humoral 
immunodeficiency involving a defect in antibody formation and requiring 
gammaglobulin replacement, as defined according to the IUIS (International 
Union of Immunological Societies) Scientific Committee 2015 1 and by 
diagnostic criteria according to Conley et al.2 prior to enrollment. The diagnosis 
must be confirmed by the sponsor Medical Director prior to first treatment with IP 
in the study.
2.
Subject is at least two and below 18 years of age at the time of screening.
3.
Subject has been receiving a consistent dose of IgG, administered in compliance 
with the respective product information for a period of at least three months prior 
to screening. The average minimum pre-study dose over that interval was 
equivalent to 300 mg/kg BW/four weeks and a maximum dose equivalent to 
1000 mg/kg BW/4 weeks.
4.
Subject has a serum trough level of IgG > 5 g/L at screening.
5.
If female of childbearing potential, subject presents with a negative pregnancy test 
and agrees to employ adequate birth control measures for the duration of the 
study. 
6.
Subject/legally authorized representative is willing and able to comply with the 
requirements of the protocol.
9.2 Exclusion Criteria
Subjects who meet ANY of the following criteria are not eligible for this study:
1.
Subject has a known history of or is positive at screening for one or more of the 
following: hepatitis B surface antigen (HBsAg), polymerase chain reaction (PCR) 
for hepatitis C virus (HCV), PCR for human immunodeficiency virus (HIV) 
Type 1/2. 
2.
Abnormal laboratory values at screening meeting any one of the following criteria 
(abnormal tests may be repeated once to determine if they are persistent):
a. Persistent alanine aminotransferase (ALT) and aspartate amino transferase 
(AST) >2.5 times the upper limit of normal (ULN) for the testing laboratory
b. Persistent severe neutropenia (defined as an absolute neutrophil count [ANC] 
≤500/mm3)
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3.
Subject has anemia that would preclude phlebotomy for laboratory studies, 
according to standard practice at the site.
4.
Subject has an ongoing history of hypersensitivity or persistent reactions 
(urticaria, breathing difficulty, severe hypotension, or anaphylaxis) following IV 
immunoglobulin, SC immunoglobulin, and/or Immune Serum Globulin (ISG) 
infusions.
5.
Subject has severe immunoglobulin A (IgA) deficiency (less than 7.0 mg/dL) with 
known anti-IgA antibodies and a history of hypersensitivity. . 
6.
Subject has a known allergy to hyaluronidase.
7.
Subject has active infection and is receiving antibiotic therapy for the treatment of 
infection at the time of screening.
8.
Subject has a bleeding disorder or a platelet count less than 20,000/µL, or who, in 
the opinion of the investigator, would be at significant risk of increased bleeding 
or bruising as a result of SC therapy. 
9.
Subject has severe dermatitis that would preclude adequate sites for safe product 
administration.
10. Subject has participated in another clinical study involving an IP or 
investigational device within 30 days prior to enrollment or is scheduled to 
participate in another clinical study involving an IP or investigational device 
during the course of this study.
11. Subject is a family member or employee of the investigator.
12. If female, subject is pregnant or lactating at the time of enrollment.
9.3 Withdrawal and Discontinuation
Any subject may voluntarily withdraw (i.e., reduce the degree of participation in the 
study) consent for continued participation and data collection. The reason for withdrawal 
will be recorded on the End of Study eCRF. Assessments to be performed at the
termination visit (including in cases of withdraw or discontinuation) are described in 
Section 10.6 and Supplement 20.2.
Discontinuation (i.e., complete withdrawal from study participation) may be due to 
dropout (i.e., active discontinuation by subject) or loss to follow-up (i.e., discontinuation 
by subject without notice or action). Additionally, the investigator and sponsor have the 
discretion to discontinue any subject from the study if, in their judgment, continued 
participation would pose an unacceptable risk for the subject. 
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Subjects also will be withdrawn from treatment or discontinued from further study 
participation for the following reasons:
The subject becomes pregnant. IP exposure will be discontinued. If the subject has 
been exposed to rHuPH20, she will be encouraged to participate in the HyQvia 
Pregnancy Registry (Study 161301), if available in the respective country. If the 
subject declines to enroll in the registry, attempts will be made to follow the subject
through completion of the pregnancy and up to 1 year post-delivery, if feasible. The 
investigator will record a narrative description of the course of the pregnancy and 
its outcome.
The subject begins lactating. IP exposure will be discontinued. The investigator will 
record a narrative description of the course of the baby’s development.
The subject twice consecutively misses administration of IP. 
The subject does not comply with the protocol (per the investigator’s discretion).
The subject develops severe hypersensitivity reactions related to IP administration.
The subject uses prohibited medications (see Section 10.4) during the course of this 
study.
The subject participates in another clinical study involving an IP or device during 
the course of this study.
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10. STUDY PROCEDURES
10.1 Informed Consent
Any patient who provides informed consent (i.e., signs and dates the informed consent 
form and assent form, if applicable) and meets all inclusion and none of the exclusion 
criteria, is considered a subject in the study.
10.2 Subject Identification Code
The following series of numbers will comprise the SIC: protocol identifier (e.g., 090701) 
to be provided by the sponsor, three-digit number study site number (e.g., 02) to be 
provided by the sponsor, and three-digit subject number (e.g., 0003) reflecting the order 
of providing informed consent. For example, the third subject who signed an informed 
consent form at study site 02 will be identified as Subject 090701-020003. All study 
documents (e.g., case report forms [CRFs], clinical documentation, sample containers, 
drug accountability logs, etc.) will be identified with the SIC. Additionally, a uniquely 
coded SIC(s) is permitted as long as it does not contain a combination of information that 
allows identification of a subject (e.g., collection of a subject’s initials and birth date
would not be permitted), in compliance with laws governing data privacy.
10.3 Screening and Study Visits
The study site is responsible for maintaining a screening log that includes all subjects 
who provided informed consent. The log also will serve to document the reason for 
screening failure. All screening data will be collected and reported in eCRFs, regardless 
of screening outcome. If a subject is re-screened, the End of Study eCRF for the prior 
screening should be completed, and a new ICF, new SIC and new eCRF are required for 
that subject.
The overall study design is illustrated in the Figure 1. Details on the procedures to be 
performed at each study visit, including screening, can be found in Supplement 20.2
Schedule of Study Procedures and Assessments and Supplement 20.3 Clinical Laboratory 
Assessments. 
Details on the treatment regimen including dose (total dose in mg/kg BW/week) and the 
infusion interval will be collected. Changes to the treatment regimen, including the 
reason for the change, will also be collected.
In addition, details on product administration such as infusion date and start/stop time, lot 
number, actual volume infused, maximum infusion rate achieved, number and location of 
infusion sites (needle sticks) per infusion, will be collected.
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Details of the treatment regimen and product administration, if performed at the site, 
should be recorded on the CRF. Administration details for home treatment should be 
recorded by the subject/subject´s legally authorized representative in the subject diary.
10.4 Medications and Non-Drug Therapies 
The use of all antibiotic therapy must be associated with a corresponding AE, and 
documented accordingly.
The following medications and non-drug therapies are not permitted during the course of 
the study:
Prophylactic treatment with systemic antibacterial antibiotics is not allowed during 
the study. The use of systemic prophylactic antibacterial antibiotics by a subject 
will be considered a protocol deviation. However prophylaxis for viral infections, 
fungi and parasites (including pneumocystis pneumonia) which are not treated by 
immunoglobulin, can be used and should be recorded as concomitant medication. 
Use of Trimethaprim-Sulfamethoxazole for pneumocystis prophylaxis is acceptable 
in doses typical for pneumocystis pneumonia, but not low dose daily therapy that 
can also be used for antibacterial prophylaxis. Brief (less than 72 hours), 
prophylaxis for surgery (including dental procedures) or injury is permitted but 
treatment and indication must be recorded.
Other IGIV or IGSC products
Pre-medication on the day of product administration:
In this study, subjects should not receive pre-medication for SC infusions unless an 
AR of at least moderate severity, not resolving with a reduction in the infusion rate, 
occurs during or after at least two infusions. Should this occur, subjects may be 
pretreated with antipyretics, corticosteroids or antihistamines at the discretion of the 
investigator. Topical anesthetics (e.g., EMLA) may be used if the needle insertion 
was intolerable in prior infusions. Subjects who have a history of using topical 
anesthetics (e.g., EMLA) may use these topical anesthetics for SC infusions. The 
use of such pre-medications should be recorded on the concomitant medication 
record.
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10.5 Subject Diary
An electronic subject diary will be provided to each subject/caregiver at enrollment to 
record the following information:
Occurrence of AEs (including infections). The investigator will provide guidance 
for the subject/caregiver regarding identification and documentation of AEs 
Concomitant medication use 
Details of the product administration as specified in Section 10.3
Days not able to attend school/work or to perform normal daily activities due to 
illness/infection
Non-study-required out-patient visits (including urgent care visits to see healthcare 
providers) and hospitalizations
Subjects and/or their legally authorized representatives will be trained on use of the diary. 
The diary will be provided in electronic format and remain with the subject for the 
duration of the study. The investigator will review the diary for completeness and request 
missing information periodically and in a timely manner. Untoward events recorded in 
the diary will be reported as AEs according to the investigator’s discretion and clinical 
judgment.
Subject entries in the diary will serve as source records. During study participation the 
investigator has access to the database holding the subject diary data. After study closure, 
the investigator will receive the diary records for their subjects, including audit trail 
records, in PDF format. The data will be transmitted to the CRF by a validated transfer.
Electronic Patient Reported (EPR) modules will be used to enable deployment of 
required subject diaries to subjects based on protocol requirements. EPRs can be 
programmed to allow a certain level of data validation at the time of data entry by the 
subject; this allows cleaning of subject reported data at the time of data collection. 
Additionally EPR compliance reports enable monitoring of patient compliance, and 
proactive follow up if required. EPRs can be deployed in local languages as needed. 
Automated reminder e-mails are sent to subjects who do not complete required EPRs. 
Following a certain number of reminder e-mails, the link to that particular EPR is 
disabled; this ensures that EPRs are collected in a timely manner during the study.
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10.6 Subject Completion/Discontinuation
A subject is considered to have completed the study when he/she ceases active 
participation in the study because the subject has, or is presumed to have, completed all
study procedures according to the protocol (with or without protocol deviations).
Reasons for completion/discontinuation will be reported on the 
Completion/Discontinuation eCRF, including: completed, screen failure, AE (e.g., death), 
discontinuation by subject (e.g., lost to follow-up [defined as three documented 
unsuccessful attempts to contact the subject], dropout), physician decision (e.g., 
pregnancy, progressive disease, non-compliance with IP/protocol violation(s), recovery), 
study terminated by sponsor, or other (reason to be specified by the investigator, e.g., 
technical problems). Regardless of the reason, all data available for the subject up to the 
time of completion/discontinuation should be recorded on the appropriate eCRF. 
Every effort will be made to have discontinued subjects complete the study 
completion/termination visit. If the completion/termination visit is done as an additional, 
unscheduled visit, the assessment results shall be recorded with the 
completion/termination visit. If a subject terminates participation in the study and does 
not return for the completion/termination visit, their last recorded assessments shall 
remain recorded with their last visit. The reason for discontinuation will be recorded, and 
the data collected up to the time of discontinuation will be used in the analysis and 
included in the clinical study report. If additional assessments are required, the 
assessments shall be recorded separately. Assessments to be performed at the termination 
visit (including in cases of withdraw or discontinuation) can be found in Supplement 20.2
Schedule of Study Procedures and Assessments and Supplement 20.3 Clinical Laboratory 
Assessments.
In the event of subject discontinuation due to an AE, clinical and/or laboratory 
investigations that are beyond the scope of the required study observations/assessments 
may be performed as part of the evaluation of the event. These investigations will take 
place under the direction of the investigator in consultation with the sponsor, and the 
details of the outcome may be reported to the appropriate regulatory authorities by the 
sponsor. 
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10.7 Procedures for Monitoring Subject Compliance
For study procedures that are to be performed under the direct supervision of the 
investigator/healthcare professional (e.g., infusion nurse) at the study site or infusion 
center, no separate procedures will be used to monitor subject compliance.
Training, evaluation, and verification of the subject’s (and/or caregiver’s) proficiency in 
performing self-infusion procedures by the investigator/designee, must be documented as 
a prerequisite before the subject (and/or caregiver) will be allowed to begin 
self-administration of SC infusions. A healthcare professional (e.g., infusion nurse) may 
be present to observe the subject’s self-administration. The subject (and/or caregiver) 
may be asked to return to the study site during the study so that the investigator/designee 
can further assess and document that the subject (and/or caregiver) is capable of 
continuing to independently performing self-infusion procedures.
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11. ASSESSMENT OF EFFICACY
11.1 IgG Trough Levels
IgG trough levels will be determined at several time points (see Supplement 20.3 Clinical 
Laboratory Assessments). Standard assay methods will be used for the determination of 
IgG and IgG subclasses. The measurement will be performed at the central laboratory. 
11.2 Treatment Preference Questionnaire
The treatment preference questionnaire, internally developed at Baxalta, is a self-
administered, non-validated scale assessing patient preference for various attributes of 
IgG therapy, such as ease of administration, frequency and duration of administration, 
and convenience.
The treatment preference questionnaire will be administered at the study site using a 
translated version, as applicable. It is recommended that the subject complete the 
assessment using the same translated version throughout the course of the study. For 
subjects aged 13 to <18 years, the subject should complete the questionnaire themselves
(observer: subject). For subjects under the age of 13, the parent should complete the 
questionnaire on behalf of their child (observer: parent).  The same observer should be 
employed for the duration of subject participation. 
For detailed administration time points, see Supplement 20.2 Schedule of Study 
Procedures and Assessments.
11.3 Treatment Satisfaction Questionnaire for Medication
The Abbreviated Treatment Satisfaction Questionnaire for Medication (TSQM-9) is a 
9-item, validated, self-administered instrument to assess patients’ satisfaction with 
medication. The 3 domains assessed are effectiveness, convenience, and global 
satisfaction.
The TSQM-9 will be administered at the study site using a validated translated version, as 
applicable. It is recommended that the subject complete the assessment using the same 
translated version throughout the course of the study. For subjects aged 13 to <18 years, 
the subject should complete the questionnaire themselves (observer:  subject). For 
subjects under the age of 13, the parent should complete the questionnaire on behalf of 
their child (observer: parent).  The same observer should be employed for the duration of 
subject participation. 
For detailed administration time points, see Supplement 20.2 Schedule of Study 
Procedures and Assessments.
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11.4 HRQoL Questionnaire
11.4.1 PedsQL
The PedsQL is a validated questionnaire designed to measure generic HRQoL among a 
pediatric population.  Both patient and proxy versions of the questionnaire are available.  
This questionnaire measures four domains, including; Physical functioning, Emotional 
functioning, Social functioning and school functioning.  A total score and domain scores 
can be calculated.  Higher scores indicate better health status.39
Quality of life (QoL) will be assessed separately for the age groups two to four years, and 
five to seven years, eight to 12 years (PEDS-QL, observer: parent), and 13 to <18 years 
(PEDS-QL, observer: subject) . The same observer should be employed for the duration 
of subject participation. 
Age will be defined as the age at screening, in order to determine which age-specific 
assessment is to be used. The same age-specific assessment is to be used for the duration 
of the study. In the event that the language or age group is not available, the assessment 
in the closest age group will be used. In the event that the appropriate language is not 
available, the questionnaire will not be administered for that subject. For detailed 
administration time points, see Supplement 20.2 Schedule of Study Procedures and 
Assessments.
11.4.2 EQ-5D
The EQ-5D is a validated, self-administered assessment of overall health designed by the 
EuroQol Group.40 It is a descriptive system of HRQoL states consisting of 5 dimensions 
(mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). Subjects 
are asked to describe their health state that day by choosing 1 of 3 responses that reflect 
the levels of severity for each of the 5 dimensions: no problems, some or moderate 
problems, or extreme problems. The EQ-5D also includes a standard vertical 20-cm 
visual analogue scale (similar to a thermometer) for recording a subject’s rating of their 
current HRQoL state.
The EQ-5D will be administered at the study site using a validated translated version, as 
applicable. It is recommended that the subject complete the assessment using the same 
translated version throughout the course of the study. For subjects aged 13 to <18 years, 
the subject should complete the questionnaire themselves (observer:  subject). For 
subjects under the age of 13, the parent should complete the questionnaire on behalf of 
their child (observer: parent).  In the event that the appropriate language is not available, 
the questionnaire will not be administered for that subject. For detailed administration 
time points, see Supplement 20.2 Schedule of Study Procedures and Assessments.
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12. ASSESSMENT OF SAFETY
12.1 Adverse Events
12.1.1 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.
Temporally associated AEs are all AEs which occur during the infusion or within 
72 hours of completion of infusion.
12.1.1.1 Serious Adverse Event
A SAE is defined as an untoward medical occurrence that at any dose meets one or more 
of the following criteria:
Outcome is fatal/results in death (including fetal death)
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.
Requires inpatient hospitalization or results in prolongation of an existing 
hospitalization – inpatient hospitalization refers to any inpatient admission, 
regardless of length of stay.
Results in persistent or significant disability/incapacity (i.e., a substantial disruption 
of a person’s ability to conduct normal life functions)
Is a congenital anomaly/birth defect
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
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Reviewed and confirmed seroconversion for HIV, hepatitis A virus (HAV), 
hepatitis B virus (HBV), HCV, hepatitis E virus (HEV), or parvovirus B19 
(B19V)
Thromboembolic events (e.g., deep vein thrombosis, pulmonary embolism, 
myocardial infarction, cerebrovascular accidents [e.g., stroke, transient 
ischemic event])
Hemolytic anemia
Uncomplicated pregnancies, following maternal or paternal exposure to IP are not 
considered an (S)AE; however, any pregnancy complication or pregnancy termination by 
therapeutic, elective, or spontaneous abortion shall be considered an SAE.
12.1.1.2 Non-Serious Adverse Event
A non-serious AE is an AE that does not meet the criteria of an SAE.
12.1.1.3 Unexpected Adverse Events
An unexpected AE is an AE whose nature, severity, specificity, or outcome is not 
consistent with the term, representation, or description used in the Reference Safety 
Information. “Unexpected” also refers to the AEs that are mentioned in the investigator’s 
brochure 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 investigator’s brochure and/or 
prescribing information as the Reference Safety Information. This determination will 
include considerations such as the number of AEs previously observed, but not on the 
basis of what might be anticipated form the pharmacological properties of a product.
12.1.1.4 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.
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12.1.2 Assessment of Adverse Events
Each AE from signing informed consent 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 12.1). Each AE will be evaluated by the 
investigator for:
Seriousness as defined in Section 12.1.1.1
Severity as defined in Section 12.1.2.1
Causal relationship to IP exposure or study procedure as defined in Section 12.1.2.2
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 
Report Form. 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 or underdosing by 
more than 20%, abuse, and withdrawal), 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, lack of 
efficacy, and/or other observations because these events may be reportable to regulatory 
authorities.
Any pregnancy that occurs after administration of IP will be reported on a Pregnancy 
Report Form and followed-up at estimated date of delivery and one year post-delivery, if 
feasible. The investigator will record a narrative description of the course of the 
pregnancy and its outcome. Subjects who prematurely withdraw from the study because 
of pregnancy should be encouraged to participate in the pregnancy registry 
(Study 161301): Pregnancy Registry to collect Long-Term Safety Data from Women 
treated with HyQvia, if locally available.
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If an investigator becomes aware of an SAE occurring in a subject after study completion, 
the SAE must be reported on the provided SAE Report Form within 24 hours after 
awareness.
12.1.2.1 Severity
The investigator will assess the severity of each AE using his/her clinical expertise and 
judgment based on the most appropriate description below:
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.
Moderate

The AE produces limited impairment of function and may require therapeutic 
intervention.

The AE produces no sequela/sequelae.
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.
12.1.2.2 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 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:
Not related (both circumstances must be met)
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
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). 
Unlikely related (either one or both circumstances are met)

Has little or no temporal relationship to the IP 

A more likely alternative etiology exists
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
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: 
o
Reappearance of a similar reaction upon re-administration (positive 
rechallenge)
o
Positive results in a drug sensitivity test (skin test, etc.)
o
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 hours 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.
12.1.2.3 Safety Reporting
AEs/SAEs will be assessed at all study visits as outlined in the Schedule of Study 
Procedures and Assessments (see Table 5) and Section 12.1.2.
AEs/SAEs are to be recorded on the AE page of the eCRF or the SAE Report Form.  
Each event should be recorded separately.
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Any SAE, including death due to any cause, which occurs during this study, whether or 
not related to the investigational product, must be reported immediately (within 24 hours 
of the study center’s first knowledge of the event).  All SAEs must be reported using the 
paper SAE Report Form to meet the 24 hour timeline requirement (contacts and 
instructions to be provided in separate documentation). 
The initial SAE information reported on the applicable SAE Report Formmust at least 
include the following:
Protocol Number
Subject identification number and demographics (gender, age at onset of event 
and/or date of birth)
Investigational product exposure (i.e., date, start-time, stop-time, 
infusion/infiltration rate, product identification)
Medical Term for Event (Diagnosis preferably) 
Description of the (S)AE, including:

Date of onset

(S)AE treatment (drug, dose, route of administration)

Causal relationship by the Investigator

Measures taken (i.e., action taken regarding investigational product in direct 
relationship to the AE)
Seriousness criteria (i.e., death, life-threatening, or other criterion)
Cause of death
Autopsy findings (if available)
Name, address, fax number, email, and telephone number of the reporting investigator 
(SAE Report Forms).
12.2 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: 
Immediate change in study design or study procedures
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Temporary or permanent halt of a given clinical trial or trials
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 one calendar day after the change is implemented. The sponsor 
will also ensure the responsible ethics committee(s) (ECs) and relevant competent 
authority(s) are notified of the urgent safety measures taken in such cases according to 
local regulations.
12.3 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 12.1). 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 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 non-serious 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. 
12.4 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:
A failure of a product to exhibit its expected pharmacological activity and/or design 
function, e.g., reconstitution difficulty
Missing components
Damage to the product or unit carton
A mislabeled product (e.g., potential counterfeiting/tampering)
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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 one business day. If requested, defective product(s) will be returned to the 
sponsor for inspection and analysis according to procedures.
12.5 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 12.1.2.1) 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 medications taken and non-drug therapies received from providing informed consent
until completion/termination will be recorded on the concomitant medications and 
non-drug therapies CRFs.
12.6 Physical Examinations
At screening and subsequent study visits (as described in Supplement 20.2), a 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 an error, due to a preexisting disease (described in Section 12.1.1.4), not 
clinically significant, a symptom of a new/worsened condition already recorded as an AE, 
or due to another issue that will be specified, the investigator will record the justification 
on the source record.
12.7 Clinical Laboratory Parameters
For detailed sampling time points see Supplement 20.3 Clinical Laboratory Assessments.
12.7.1 Hematology and Clinical Chemistry
The hematology panel will consist of complete blood count (hemoglobin [Hgb], 
hematocrit, erythrocytes [i.e., RBC], and leukocytes [i.e., white blood cell count [WBC])
with differential (i.e., basophils, eosinophils, lymphocytes, monocytes, neutrophils) and 
platelet counts. 
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The clinical chemistry panel will consist of sodium, potassium, chloride, bicarbonate, 
protein, albumin, ALT, bilirubin, alkaline phosphatase (ALP), blood urea nitrogen
(BUN), creatinine, and glucose.
Hematology and clinical chemistry assessments will be performed on 
EDTA-anticoagulated whole blood and serum, respectively, at the central laboratory. 
12.7.2 Urine Tests
Urinalysis will include color, specific gravity, pH, protein, glucose, ketones, bilirubin, 
urobilinogen, blood, nitrite, leukocyte esterase, and microscopic examination. Urinalysis 
tests will be conducted at the central laboratory.
12.7.3 Pregnancy Test
For female subjects of childbearing potential, urine pregnancy test will be performed at a 
central laboratory, unless a serum pregnancy test is mandatory as specified by local 
regulatory/institutional requirements.
12.7.4 Hemolysis Test
Hemolysis test will consist of Hgb, lactate dehydrogenase (LDH), serum haptoglobin, 
plasma-free (unbound) Hgb, serum direct anti-globulin (direct Coomb’s) test (antibody 
elution to be performed if direct Coomb’s test is positive), reticulocyte count, as well as 
urine hemosiderin. If there is a reduction in Hgb of two g/dL or more compared to 
baseline Hgb, every effort is to be made to perform a repeat test consisting of the 
hemolysis tests described above within 72 hours; if it is not feasible to do so, the 
hemolytic panel must be performed as soon as possible. At any time during the study, an 
unscheduled hemolytic panel may be performed in the event of suspected hemolytic 
anemia.
Hemolysis test will be performed at the central laboratory or other laboratories as 
appropriate (e.g., antibody elution in the event of positive direct Coomb’s test). Complete 
hematology and clinical chemistry assessments may be performed in order to obtain 
laboratory results required for a hemolytic panel.
12.7.5 IgG Trough Levels and IgG Subclasses and Specific Antibody Tests
IgG total and IgG subclass trough levels and levels of specific antibodies will be 
determined on all subjects by using standard assay methods (to be performed at the 
central laboratory).
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At infusion visits where blood is drawn for trough levels, the blood drawing for the IgG 
determination will always take place before the infusion is administered.
12.7.6 Anti-rHuPH20 Antibodies
All subjects will have regular anti-rHuPH20 antibody testing in pre-identified central 
laboratories (binding and neutralizing anti-rHuPH20 antibody) throughout the study 
(approximately every three months, see Supplement 20.3). At any time during the course 
of study, subjects who have 1) two consecutive anti-rHuPH20 antibody titers of ≥1:160 
that are elevated from the subject’s baseline titers, and 2) a moderate or severe AE that
may be a result of immune-mediated response to either immunoglobulin or rHuPH20 will 
be asked to return to the study site as soon as possible to undergo an additional panel of 
testing:
50% hemolytic complement activity of serum, 
serum complement component 3, 
serum complement component 4, 
C1q binding assay, and 
circulating immune complex Raji cell assay.
12.7.7 Viral Pathogen Serology
Tests for viral pathogen serology include: HBsAg by enzyme-linked immunosorbent 
assay (ELISA), PCR for HCV and PCR for HIV-1/2. These assessments will be 
performed at the central laboratory at the timepoints specified in Supplement 20.3.
12.7.8 Assessment of Laboratory Values
12.7.8.1 Toxicity Grading Scale
The following laboratory values will be evaluated by the sponsor/sponsor’s representative
according to the Common Toxicity Criteria of the Eastern Cooperative Oncology Group 
(ECOG), published by Oken et al.41:
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 toxicity grading system.42 The laboratory parameters and the 
corresponding grading scale are provided in Section 12.7. 
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The toxicity scale is defined as: zero = none, one = mild, two = moderate, 
three = severe, four = life-threatening. Laboratory parameters not listed in Table 11
will not be graded. However, clinical significance of those abnormal laboratory 
values will be assessed as described in Section 12.7.8.2.
12.7.8.2 Assessment of Abnormal Laboratory Values 
The investigator’s assessment of each laboratory value will be recorded on the 
eCRF laboratory form. For each abnormal laboratory value, the investigator will 
determine whether the value is considered clinically significant or not. 
For clinically significant values, the investigator will indicate if the value constitutes an 
new AE (see definition in Section 12.1, and record the sign, symptom, or medical 
diagnosis on the AE CRF), is a symptom or related to a previously recorded AE, is due to 
a pre-existing disease (described in Section 12.1.1.4), or is due to another issue that will 
be specified. If the abnormal value was not clinically significant, the investigator will 
indicate the reason, i.e., because it is due to a preexisting disease, due to a lab error, or 
due to another issue that will be specified. Additional tests and other evaluations required 
to establish the significance or etiology of an abnormal value, or to monitor the course of 
an AE should be obtained when clinically indicated. Any abnormal value that persists 
should be followed at the discretion of the investigator.
Any seroconversion result for HIV, HAV, HBV, HCV, HEV, or B19V shall be re-tested.
12.7.9 Backup Samples and Biobanking
Backup samples taken and stored short-term may be used, for example, for re-testing, 
follow-up of an AE(s) or other test results, and/or assay development. After study testing 
is completed, the remaining samples may be stored in a coded form for no more than two
years after the final study report has been completed and then the samples will 
subsequently be destroyed.
For this study, no samples will be taken or stored long-term in a biobank for future 
analyses.
12.8 Vital Signs
Vital signs will include body temperature (°C or °F), respiratory rate (breaths/min), pulse 
rate (beats/min), and systolic and diastolic blood pressure (mmHg). Height (in or cm) and 
weight (lb or kg) will also be collected.
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Vital signs will be measured as described below:
12.8.1 Screening
All vital signs
12.8.2 Infusion at Study Site
1. Within 30 min prior to infusion:

All vital signs. Height and weight can be taken at any time at this visit. 
2. 30 (± 5) min after initiation of infusion:

All vital signs except height and weight
3. During the infusion if a systemic AE occurs, to be assessed as needed:

All vital signs except height and weight
4. Within 30 min of completion of the infusion:

All vital signs except height and weight
12.8.3 Infusion at Home
No assessment of vital signs
12.8.4 End-of-Study 
All vital signs
Vital sign values are to be recorded on the eCRF. For each abnormal vital sign value, the 
investigator will determine whether to report an AE (see definition in Section 12.1 and 
record the medical diagnosis [preferably], symptom, or sign on the AE CRF). Additional 
tests and other evaluations required to establish the significance or etiology of an 
abnormal value, or to monitor the course of an AE should be obtained when clinically 
indicated. Any abnormal value that persists should be followed at the discretion of the 
investigator.
12.9 Acute Serious Bacterial Infections
Acute serious bacterial infections will be defined as follows based on the US FDA 
Guidance for Industry to Support Marketing of Human IGIV as Replacement Therapy for 
Primary Humoral Immunodeficiency 43 and the EMA guideline on the clinical 
investigation of human normal immunoglobulin for SC and /or intramuscular 
administration.44
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12.9.1 Infection: Bacteremia/Sepsis(a)
1. Symptoms: chills, rigors
2. Physical findings- fever, hypothermia, tachycardia, tachypnea, hypocarbia,
hypotension (systolic blood pressure <90 mm Hg or a reduction of >40 mm Hg
from baseline in the absence of other causes of hypotension), altered mental
status, petechiae, purpura, oliguria, cutaneous vasodilation/vasoconstriction
3. Laboratory tests: positive blood culture(b), leukocytosis (WBC count
>12,000/mm3), differential WBC count demonstrating >10% immature (band)
neutrophils, leukopenia, thrombocytopenia, coagulopathy, lactic acidosis
(a) Two of the following should be present to make the diagnosis of sepsis in adults:
temperature >38°C oral/ > 39°C rectal or <36°C oral or < 37°C rectal; heart rate
>90 beats/min; respiratory rate >20 breaths/min, or partial pressure of carbon dioxide
(PaCO2) <32 mm Hg; WBC >12,000/mm3, <4,000/mm3, or >10% immature (band)
forms. For pediatric patients, we recommend you employ the definition of sepsis using
age-specific criteria as recommended by the International Consensus Conference on
Pediatric Sepsis.45
(b) Indwelling catheter- or vascular access device-related blood-borne infections are not
included because evidence is lacking that these are preventable with IGI replacement
therapy. For subjects without indwelling catheters or vascular access devices, a single
blood culture positive for a pathogenic organism will meet the diagnostic criteria for
bacteremia. Multiple blood cultures are typically obtained in cases of suspected
bacteremia/sepsis, as per standard medical practice, and the finding of a single positive
culture should prompt additional confirmatory cultures. Subjects meeting criteria for
positive blood culture but without two or more of the sepsis criteria listed above will be
classified as having bacteremia.
12.9.2 Infection: Bacterial Meningitis
1. Symptoms: headache, stiff neck, mental status changes, irritability, decreased
feeding (infants), photophobia, nausea/vomiting, rigors, seizures
2. Physical findings: Kernig’s sign, Brudzinski’s sign, meningococcal rash, fever of
>38 °C oral or >39°C rectal
3. Laboratory tests: positive cerebrospinal fluid (CSF) Gram stain and/or culture
and/or positive CSF bacterial antigen assay, positive blood culture(c), CSF
leukocytosis with neutrophil predominance, decrease in CSF glucose
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(c) A blood culture positive for growth of Streptococcus pneumoniae, Neisseria 
meningitides, or Haemophilus influenzae, in combination with CSF leukocytosis and/or 
decrease in CSF glucose, can serve to confirm the diagnosis of acute bacterial meningitis
12.9.3 Infection: Osteomyelitis/Septic Arthritis
1. Symptoms: pain, decreased range of motion, tenderness, edema, redness, 
warmth over the involved site (local inflammatory symptoms/signs may be 
lacking in adults)
2. Physical findings: evidence of soft tissue infection adjacent to the involved 
bone/joint; drainage from sinus tract from involved bone; fever of >38°C oral 
or >39°C rectal
3. Laboratory tests: positive blood culture, positive probe to bone, positive bone 
aspirate culture, positive bone biopsy culture, positive bone histopathology, 
positive joint fluid Gram stain and culture
4. Imaging studies: positive X-ray, nuclear medicine bone scan, magnetic 
resonance imaging (MRI) scan, or computed tomography (CT) scan showing 
bony destruction with radiolucent areas; for chronic osteomyelitis: sequestra, 
involucre
12.9.4 Infections: Bacterial Pneumonia(d)
1. Symptoms: productive cough/change in character of sputum, dyspnea or 
tachypnea, chills, chest pain, rigors, headache, fatigue, sweats, anorexia, 
myalgias
2. Physical findings: rales; pulmonary consolidation as reflected by: dullness on 
percussion, bronchial breath sounds, egophony; fever >38°C oral or > 39°C 
rectal, or <36°C, hypothermia (temperature < 36°C oral or < 37°C rectal)
3. Laboratory tests: leukocytosis; differential WBC count of >10% band 
neutrophils; leukopenia; hypoxemia (PaO2 < 60 mm Hg on room air); positive 
blood culture; Gram stain and culture of deep expectorated sputum(e), positive 
culture with or without positive Gram stain of transtracheal aspirate, pleural 
fluid culture, lung biopsy, bronchoscopy with BAL or protected brush sampling,
4. Imaging studies: Pulmonary infiltrate with consolidation on chest X-Ray 
([CXR]; new in comparison with baseline or previous CXR)
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(d) For the diagnosis of pneumonia in adults, commonly at least two of the listed 
symptoms and/or signs should be present in conjunction with at least one laboratory and 
one imaging studies diagnostic elementvii.  However, for the purposes of counting serious 
infection episodes in a clinical study of IGI, the finding of a new pulmonary infiltrate 
with consolidation on CXR is considered sufficient. To establish the diagnosis of 
bacterial pneumonia for pediatric patients, most of the same diagnostic criteria listed may 
be used, with the following exceptions: Because pediatric patients may not produce a 
sputum specimen for culture, blood cultures or serology may be substituted to identify the 
etiologic bacterial pathogen. In infants age three to 24 months, who tend to have a higher 
baseline temperature, fever is defined as a rectal temperature >38.3°C (101°F). In 
children >two years, fever is more commonly defined as a rectal temperature >38°C 
(100.4°F). In pediatric patients, elevations of WBC counts >15,000/mm3 are frequent but 
could be variable in patients with bacterial pneumonia, or leukopenia with WBC count 
<5000/mm3 may be observed, usually associated with severe infection
(e) We recommend a deep expectorated sputum Gram stain demonstrate the presence of 
microorganisms on examination of 10 to 20 oil immersion microscopic fields and <ten 
squamous epithelial cells and >25 polymorphonuclear leukocytes at tenX low power 
magnification to determine suitability of sputum culture.
12.9.5 Infection: Visceral Abscess
1. Symptoms: abdominal pain, anorexia, weight loss, cough/pleuritic chest pain 
(hepatic abscess), rigors (seldom present)
2. Physical findings: intermittent fevers (temperature >38°C oral or >39°C rectal); 
abdominal tenderness; palpable mass; hepatomegaly; jaundice
3. Laboratory tests: positive Gram stain and/or culture from the infected site, with 
isolation of an appropriate pathogen; positive blood culture; leukocytosis with 
accompanying left shift; differential WBC of >10% immature (band) 
neutrophils; elevated serum amylase concentration (pancreatic abscess); 
elevated alkaline phosphatase concentration (hepatic abscess) pyuria in renal 
abscess
4. Imaging studies: typical findings on ultrasound, CT scan, MRI scan, or 
radionuclide scan
                                                
vii Further evaluation, in particular laboratory evaluation (culture and white blood count with differential to 
evaluate for the presence of immature neutrophils) and chest x-rays, should be aggressively pursued 
whenever a bacterial pneumonia is suspected
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13. STATISTICS
13.1 Sample Size and Power Calculations
The sample size selected for the study is primarily determined by the objective to collect 
safety data in a sufficient number (about 40) of pediatric (age <18 years) subjects with 
PIDD who have received prior immunoglobulin therapy before enrollment into this study.
In addition, the guideline of the CHMP on the clinical investigation of human normal 
immunoglobulin for SC and/or intramuscular administration 44 indicates that at least 
40 patients should be included to evaluate replacement therapy in primary 
immunodeficiency syndromes.
13.2 Analysis Sets
13.2.1 Full Analysis Set
All patients who provide informed consent (i.e., sign and date the Informed Consent 
Form, if applicable), and meet enrollment eligibility (i.e., meets all inclusion criteria and 
do not meet any exclusion criteria) will be included in the full analysis set.
13.2.2 Per-Protocol Analysis Set
All patients in the full analysis set who have no major protocol deviations will be 
included in the per-protocol analysis set.
13.2.3 Safety Analysis Set
The safety analysis set will contain all subjects in the full analysis set who receive at least 
one dose of HyQvia.
13.3 Handling of Missing, Unused, and Spurious Data
The handling of missing, unused or spurious data will be described in the statistical 
analysis plan (SAP).
13.4 Methods of Analysis
In this study no hypothesis will be tested. Detailed statistical analysis methods will be 
described in the SAP. Statistical analyses and data displays will be mainly descriptive.
Data from all enrolled subjects will be included in the analysis. If groups of sufficient 
sample size (such as age groups or PIDD types) are available, CIs may accompany the 
point estimates. All SAEs and non-serious AEs will be categorized according to 
MedDRA system organ class and preferred term. Tables will be prepared to list for each 
SAE and non-serious AE the number of events and the number of subjects who 
experienced one or more event. All analyses will be performed using SAS® version 9.2 or 
higher (SAS Institute, Cary, NC, USA). 
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13.4.1 Primary Outcome Measure
Number and rate per infusion (excluding infections) of all severe related AEs
Number and rate per infusion (excluding infections) of related SAEs
For the endpoint of incidence of all severe related AEs and related SAEs, a point estimate 
and corresponding 95% CI (by the Wilson score method) for the proportion of subjects 
with one or more related SAEs will be provided. In addition, incidence of all severe 
related AEs and related SAEs will be calculated as rate per infusion and rate per 
subject-year, and will be analyzed for changes in frequency and for changes in severity 
over time. All SAEs will be listed. No statistical hypotheses will be tested.
13.4.2 Secondary Outcome Measures 
13.4.2.1 Efficacy 
Trough levels of IgG (for Study Epoch 1 and 2): Descriptive statistics will be provided 
for the trough level of IgG for study Epoch 1 and 2.  
13.4.2.2 Safety 
The following secondary safety endpoints will be analyzed:
Proportion of subjects who achieve a treatment interval of three or four weeks in 
Epoch 2 
Proportion of subjects who maintain a treatment interval of three or four weeks in 
Epoch 2 for 12 months
Number and rate per infusion (excluding infections) of local AEs and ARs
Number and rate per infusion (excluding infections) of systemic AEs and ARs 
Number and rate per infusion (excluding infections) of all AEs and all ARs
Number and rate per infusion (excluding infections) of all temporally associated 
AEs 
Number and rate per infusion (excluding infections) of all causally related and/or 
temporally associated AEs
Number and rate per infusion (excluding infections) of all SAEs 
Number/proportion of subjects who develop positive titer (≥160) of binding or 
neutralizing antibodies to rHuPH20
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Descriptive methods, mainly frequency tables, will be used for all secondary safety 
endpoints. In addition, incidence of all secondary safety endpoint will be calculates as 
rate per infusion and rate per subject-year.
13.4.2.3 Mode of Product Administration (For Study Epoch 1 and 2)
Number of Infusions
Number of infusions per month
Number of infusion sites (needle sticks) per infusion/month
Duration of infusion (defined as time from the start of rHuPH20 infusion until the 
stop time of immunoglobulin infusion)Maximum infusion rate/site
Infusion volume/site
Number/proportion of infusions that are discontinued, slowed, or interrupted due to 
an AE Number of weeks to reach final dose interval (defined as three or four weeks
infusion interval)
Nonparametric descriptive statistics (median, quartiles, and range) will be calculated and 
reported for the infusion administration variables. Frequency table will show the 
number/proportion of infusions discontinued, slowed or interrupted due to AE and total 
observation time in subject-years. 
13.4.2.4 HRQoL
Treatment Preference Questionnaire
Treatment Satisfaction Questionnaire for Medication (TSQM-9)
HRQoL Questionnaire: Peds-QL, EQ-5D
Total and domain scores on each of the HRQoL measures will be calculated for each 
subject, at each data assessment time point. Descriptive statistics will be shown for each 
of the scores, at each data assessment time point.
13.4.3 Tertiary Outcome Measures 
13.4.3.1 Infections
Number of acute serious bacterial infections
Number of all infections
Days on antibiotics
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For the endpoint of incidence of acute serious bacterial infection and all infections a point 
estimate and 95% CI (by the Wilson score method) for the proportion of subjects with 
one or more infection will be calculated.  In addition, incidence of all infection endpoints 
will be calculates as rate per infusion and rate per subject-year. Descriptive statistics will 
be performed and reported for the days on antibiotics. 
13.4.3.2 Healthcare Resource Utilization Endpoints
Days not able to go to school/work or to perform normal daily activities
Number of hospitalizations, indication for the hospitalization (infection or 
non-infection) and days hospitalized
Number of acute physician visits (office and emergency room) due to infection or 
other illnesses
Healthcare resource utilization endpoints, including hospitalization, acute physician visits 
and days missed for school/work or normal daily activities, will be summed and 
annualized for reporting purposes. Descriptive statistics will be performed and reported.
13.5 Planned Interim Analysis of the Study
Annual reports will be prepared. Details will be described in the SAP.
14. DIRECT ACCESS TO SOURCE DATA/DOCUMENTS
The investigator/study site will cooperate and provide direct access to study documents 
and data, including source documentation for monitoring by the study monitor, audits by 
the sponsor or sponsor’s representatives, review by the EC, and inspections by applicable 
regulatory authorities, as described in the Clinical Study Agreement. If contacted by an 
applicable regulatory authority, the investigator will notify the sponsor of contact, 
cooperate with the authority, provide the sponsor with copies of all documents received 
from the authority, and allow the sponsor to comment on any responses, as described in 
the Clinical Study Agreement.
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15. QUALITY CONTROL AND QUALITY ASSURANCE
15.1 Investigator’s Responsibility
The investigator will comply with the protocol (which has been approved/given favorable 
opinion by the EC), ICH GCP, and applicable regulatory requirements as described in the 
Clinical Study Agreement. The investigator is ultimately responsible for the conduct of 
all aspects of the study at the study site 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. Sub-investigators or other 
authorized study personnel are eligible to sign for the investigator, except where the 
investigator’s signature is specifically required.
15.1.1 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.
15.2 Training
The study monitor will ensure that the investigator and study site 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 study site, and/or by instruction manuals. In addition, the study monitor will be 
available for consultation with the investigator and will serve as the liaison between the 
study site and the sponsor.
15.3 Monitoring
The study monitor is responsible for ensuring and verifying that each study site conducts 
the study according to the protocol, standard operating procedures, other written 
instructions/agreements, ICH GCP, and applicable regulatory guidelines/requirements. 
The investigator will permit the study monitor to visit the study site at appropriate 
intervals, as described in the Clinical Study Agreement. Monitoring processes specific to 
the study will be described in the clinical monitoring plan.
15.4 Safety Monitoring
The safety of the subjects in this study shall be monitored by an internal safety review 
board (ISRB). 
The ISRB is a group of individuals with pertinent expertise within the sponsor that 
reviews on a regular basis accumulating data from an ongoing clinical study. 
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For this study, the ISRB will be composed of appropriate sponsor representatives from 
the relevant functions (e.g., Global Drug Safety, Clinical Research, Medical Affairs, 
Clinical Development) with expertise/specialization in PIDD clinical care and research. 
The ISRB can stop a trial if it finds toxicities or if treatment is proven to be not 
beneficial.
15.5 Auditing
The sponsor and/or sponsor’s representatives may conduct audits to evaluate study 
conduct and compliance with the protocol, standard operating procedures, other written 
instructions/agreements, ICH GCP, and applicable regulatory guidelines/requirements. 
The investigator will permit auditors to visit the study site, as described in the Clinical 
Study Agreement. Auditing processes specific to the study will be described in the audit 
plan.
15.6 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 one calendar day after the change is 
implemented. The sponsor will also ensure the responsible EC 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 and applicable regulatory authorities of any investigator termination.
15.7 Laboratory and Reader Standardization
Inter-laboratory standardization methods will be described in the data management plan
as needed. 
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16. ETHICS 
16.1 Subject Privacy
The investigator will comply with applicable subject privacy regulations/guidance as 
described in the Clinical Study Agreement.
16.2 Ethics Committee and Regulatory Authorities
Before patients participate in this study, the protocol, informed consent form, any 
promotional material/advertisements, and any other written information will be reviewed 
and approved/given favorable opinion by the EC and applicable regulatory authorities. 
The IB will be provided for review. The EC’s composition or a statement that the EC’s 
composition meets applicable regulatory criteria will be documented. The study will 
commence only upon the sponsor’s receipt of approval/favorable opinion from the EC 
and, if required, upon the sponsor’s notification of applicable regulatory authority(s) 
approval, as described in the Clinical Study Agreement. 
If the protocol or any other information given to the subject is amended, the revised 
documents will be reviewed and approved/given favorable opinion by the EC and 
applicable regulatory authorities, where applicable. The protocol amendment will only be 
implemented upon the sponsor’s receipt of approval and, if required, upon the sponsor’s 
notification of applicable regulatory authority(s) approval.
16.3 Informed Consent
Investigators will choose patients for participation considering the study eligibility 
criteria. The investigator will exercise no selectivity so that no bias is introduced from 
this source. 
All patients and/or their legally authorized representative must sign an informed consent 
form before entering into the study according to applicable regulatory requirements and 
ICH GCP. An assent form may be provided and should be signed by patients enrolled in 
the study. Before use, the informed consent form will be reviewed by the sponsor and 
approved by the EC and regulatory authority(s), where applicable, (see Section 16.2). 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 regulatory requirements. Patients or their legally authorized 
representative(s) will be allowed sufficient time to consider participation in the study. By 
signing the informed consent form, patients or their legally authorized representative(s) 
agree that they will complete all evaluations required by the study, unless they withdraw 
voluntarily or are terminated from the study for any reason.
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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 EC and regulatory authorities, 
where applicable, will be provided by the investigator to the subjects who consented to 
participate in the study.
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17. DATA HANDLING AND RECORD KEEPING
17.1 Confidentiality Policy
The investigator will comply with the confidentiality policy as described in the Clinical 
Study Agreement. 
17.2 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” 
(see Section 8.8), records detailing the progress of the study for each subject, signed 
informed consent forms, correspondence with the EC and the study monitor/sponsor, 
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 eCRFs are provided by the sponsor, only authorized study site 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 study site in accordance with the data 
retention policy (see Section 17.3).
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.
17.3 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 Clinical Study Agreement.
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18. FINANCING AND INSURANCE
The investigator will comply with investigator financing, investigator/sponsor insurance, 
and subject compensation policies, if applicable, as described in the Clinical Study 
Agreement.
19. PUBLICATION POLICY
The investigator will comply with the publication policy as described in the Clinical 
Study Agreement. 
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20. SUPPLEMENTS
20.1 Study Flow Chart
Figure 1
Study Design for Clinical Study 161504
Anti-rHuPH20 Ab titer 
< 160 (all assays)
Epoch 3
1 year Safety Follow-up 
(no HyQvia treatment)
Epoch 2
Year 2 and Year 3
HyQvia treatment
Anti-rHuPH20 Ab titer < 160 final assay, 
during the study ≥ 160
OR
Anti-rHuPH20 Ab titer 
≥ 160 final assay
Pre-study treatment:
IGIV, IGSC or HyQvia
Epoch 2
Year 1
HyQvia treatment
Anti-rHuPH20 Ab titer final assay of Year 1:
Enrollment
Epoch 1
Ramp Up (if necessary)
Subject has Anti-rHuPH20 
Ab titer ≥ 160 
AND
experiences related SAE 
or related severe AE
End of Study
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20.2 Schedule of Study Procedures and Assessments
Table 3
STUDY EPOCH 1 – Ramp Up 
Schedule of Study Procedures and Assessments
Procedures/Assessments Routinely 
Performed 
Pre-Infusion, Unless Stated 
Otherwise
Screening/
Enrollment
Treatment Visit in Study Epoch 1
First Infusion: 
Baseline
Second Infusion: Week 1 
(This Treatment is the End 
of Epoch 1 if Subject is 
Planning for 3-Week 
Treatment Intervals)
Third Infusion: Week 3 
(Only for Subjects Planning to 
Ramp Up to 4-Week 
Treatment Intervals)
Location
Site
Site
Site
Site
Informed Consenta
x
Eligibility Criteria
x
Infusion
x
x
x
Medical History
x
Concomitant Medications
x
x
x
x
Non-drug Therapies
x
x
x
x
Physical Exam
x
x
x
x
Adverse Events
x
x
x
Laboratories – see Lab Tableb
x
x
Vital Signs
x
x
x
x
HRQoL (PedsQL, EQ-5D)/
Treatment Preference questionnaire, 
TSQM-9 Assessment
x
a   Occurs prior to any study-specific procedure.
b    For laboratory assessments, see Supplement 20.3
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Table 4
STUDY EPOCH 2 – Year 1 
Schedule of Study Procedures and Assessments
Procedures/ Assessments 
Routinely Performed Pre-
Infusion, Unless Stated 
Otherwise
Visit in Study Epoch 2 (Visit +/- 2 weeks)
Month 0
Month 3
Month 6 
Month 9 
Month 12a
Study Completion/
Termination Visit 
(at Next Infusion), 
if Applicable
Location
Site
Site
Site
Site
Site
Site
Informed Consent
Infusiona
x
x
x
x
x
Concomitant Medications
x
x
x
x
x
x
Non-drug Therapies
x
x
x
x
x
x
Physical Exam
x
x
x
x
x
x
Adverse Events
x
x
x
x
x
x
Laboratories 
x
x
x
x
x
x
Vital Signs
x
x
x
x
x
x
HRQoL (PedsQL, EQ-5D), 
Treatment Preference
questionnaire, TSQM-9
Assessment
x
x
a    Further (additional) infusions may be administered after 12 months if rHuPH20-antibody results not available. AEs, concomitant medications, and 
non-drug therapies will continue to be recorded until EOS or continuation of Epoch 2 (dependent on antibody assay result).
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Table 5
STUDY EPOCH 2 – Year 2 and Year 3
Schedule of Study Procedures and Assessments
Procedures/ Assessments 
Routinely Performed Pre-
Infusion, Unless Stated 
Otherwise
Visit in Study Epoch 2 (Visit +/- 2 Weeks)
Month 15
Month 18
Month 21
Month 24
Month 27
Month 30
Month 33
Month 36/
Study Completion/
Termination Visit, 
if Applicablea
Location
Site
Site
Site
Site
Site
Site
Site
Site
Infusion
x
x
x
x
x
x
x
Concomitant Medications
x
x
x
x
x
x
x
x
Non-drug Therapies
x
x
x
x
x
x
x
x
Physical Exam
x
x
x
x
x
x
x
x
Adverse Events
x
x
x
x
x
x
x
x
Laboratories 
x
x
x
x
x
x
x
x
Vital Signs
x
x
x
x
x
x
x
x
HRQoL (PedsQL, EQ-5D)/
Rx-Preference, TSQM-9
Assessment
x
x
a
In case a subject has an anti-rHuPH20 antibody titer ≥ 160 and experiences a related serious or severe AE, the subject may go to Study Epoch 3 and 
will have the Study Completion/Termination Visit at the end of this Epoch
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Table 6
STUDY EPOCH 3 
Schedule of Study Procedures and Assessments 
Procedures/Assessments Routinely 
Performed Pre-Infusion, Unless 
Stated Otherwise
Visit in Study Epoch 3 (Visit +/- 2 Weeks)
Month 0 
Month 3
Month 6 
Months 9 
Month 12/
Study Completion/
Termination Visita
Location
Site
Site
Site
Site
Site
Infusion
x
x
x
x
Concomitant Medications
x
x
x
x
x
Non-drug Therapies
x
x
x
x
x
Physical Examb
x
x
x
x
x
Adverse Events
x
x
x
x
x
Laboratoriesc
x
x
x
x
x
Vital Signs
x
x
x
x
x
HRQoL (PedsQL, EQ-5D Treatment 
Preference questionnaire, TSQM-9
Assessment
x
x
a
Includes for cases of withdrawal or discontinuation.
b
Occurs prior to any study-specific procedure.
c
For laboratory assessments, see Supplement 20.3.
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20.3 Clinical Laboratory Assessments
Table 7
STUDY EPOCH 1 – Ramp Up 
Clinical Laboratory Assessments 
Assessments 
Routinely Performed Pre-Infusion, 
Unless Stated Otherwise
Screening/
Enrollment
Treatment Visit in Study Epoch 1
First Infusion: 
Baseline
Second Infusion: Week 1 
(This Treatment is the End 
of Epoch 1 if Subject is 
Planning for 3-Week 
Treatment Intervals)
Third Infusion: Week 3 
(Only for Subjects Planning to 
Ramp Up to 4-Week 
Treatment Intervals)
Location
Site
Site
Site
Site
Hematology
x
Clinical Chemistry
x
Urinalysis
x
Pregnancy Test in females of 
childbearing potential – Urine
x
Viral Pathogen Serology
x
Hemolysis Test
Specific Antibody Tests
x
IgG Trough Levels and IgG 
Subclasses
x
Antibodies to rHuPH20
x
Retention Samples
x
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Table 8
STUDY EPOCH 2 – Year 1 
Clinical Laboratory Assessments
Assessments 
Routinely Performed Pre-
Infusion, Unless Stated 
Otherwise
Visit in Study Epoch 2 (Visit +/- 2 Weeks)
Month 0
Month 3
Month 6 
Month 9 
Month 12 
Study Completion/
Termination Visit 
(at Next Infusion), 
if Applicable 
Location
Site
Site
Site
Site
Site
Site
Hematology
x
x
x
Clinical Chemistry
x
x
x
Urinalysis
x
x
x
Pregnancy Test in females of 
childbearing potential– Urine
x
Viral Pathogen Serology
x
Hemolysis Test
x
Specific Antibody Tests
x
IgG Trough Levels and IgG 
Subclasses
x
x
x
Antibodies to rHuPH20
x
x
x
x
x
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Table 9
STUDY EPOCH 2 – Year 2 and Year 3
Clinical Laboratory Assessments
Assessments 
Routinely Performed Pre-
Infusion, Unless Stated 
Otherwise
Visit in Study Epoch 2 (Visit +/- 2 Weeks)
Month 15
Month 18
Month 21
Month 24
Month 27
Month 30
Month 33
Month 36/
Study Completion/
Termination Visit, 
if Applicablea
Location
Site
Site
Site
Site
Site
Site
Site
Site
Hematology
x
x
x
x
Clinical Chemistry
x
x
x
x
Urinalysis
x
x
x
x
Pregnancy Test in females of 
childbearing potential – Urine
x
Viral Pathogen Serology
x
Hemolysis Test
xb
Specific Antibody Tests
x
IgG Trough Levels and IgG 
Subclasses
x
x
x
x
Antibodies to rHuPH20
x
x
x
x
x
x
x
x
a    In case a subject has an anti-rHuPH20 antibody titer ≥ 160 and experiences a related serious or severe AE, the subject may go to Study Epoch 3 and 
will have the Study Completion/Termination Visit at the end of this Epoch.
b   If there is a reduction in Hgb of two g/dL or more compared to baseline Hgb, every effort is to be made to perform a repeat test consisting of the 
hemolysis tests described above within 72 hours
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Table 10
STUDY EPOCH 3
Clinical Laboratory Assessments
Assessments Routinely 
Performed Pre-Infusion, 
Unless Stated Otherwise
Visit in Study Epoch 3 (Visit +/- 2 Weeks)
Month 0
Month 3
Month 6
Months 9
Month 12/
Study Completion/
Termination Visit
Location
Site
Site
Site
Site
Site
Hematology
x
x
x
Clinical Chemistry
x
x
x
Urinalysis
x
x
x
Pregnancy Test in females of 
childbearing potential – Urine
x
Viral Pathogen Serology
x
Hemolysis Test
x
Specific Antibody Tests
x
IgG Trough Levels and IgG 
Subclasses
x
x
x
Antibodies to rHuPH20
x
x
x
x
x
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20.4 Toxicity Grading Scale for Laboratory Values
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.
Normal
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
Normal
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; BUN=blood urea nitrogen; 
ECOG=Eastern Cooperative Oncology Group; LDH=lactate dehydrogenase; N/A=not applicable; ULN=upper limit of normal; 
WBC=white blood cell; WHO=World Health Organization; WNL=within normal limits.
a Grade refers to severity: 1=mild, 2=moderate, 3=severe, 4=life-threatening or disabling, 5 (not shown in the table)=death. Grading scale criteria 
taken from ECOG 41 and WHO 42 guidelines, with the exception of LDH that uses the same thresholds as defined for ALT and AST
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21. REFERENCES
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immunodeficiencies. Representing PAGID (Pan-American Group for 
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9. George JN, Raskob GE. Idiopathic thrombocytopenic purpura: diagnosis and 
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18. Ochs HD, Gupta S, Kiessling P et al. Safety and efficacy of self-administered 
subcutaneous immunoglobulin in patients with primary immunodeficiency diseases. 
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subcutaneous gammaglobulin infusions in patients with primary antibody 
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administration every second week results in high and stable serum immunoglobulin 
G levels in patients with primary antibody deficiencies. Clin.Exp.Immunol. 
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replacement in patients with primary antibody deficiencies: safety and costs. Lancet 
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25. Gardulf A, Hammarström L, Smith CI. Home treatment of 
hypogammaglobulinaemia with subcutaneous gammaglobulin by rapid infusion. 
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27. Schiff RI, Rudd C. Alterations in the half-life and clearance of IgG during therapy 
with intravenous gamma-globulin in 16 patients with severe primary humoral 
immunodeficiency. J.Clin.Immunol. 1986;6:256-264.
28. Smith GN, Griffiths B, Mollison D, Mollison PL. Uptake of IgG after intramuscular 
and subcutaneous injection. Lancet 1972;1:1208-1212.
29. ZLB Behring. Immune Globulin Subcutaneous (Human), Vivaglobin®. US Label.  
8. 2006. 
Link to Publisher´s Site: 
http://www.fda.gov/downloads/BiologicsBloodVaccines/BloodBloodProducts/Appr
ovedProducts/LicensedProductsBLAs/FractionatedPlasmaProducts/ucm070360.pdf
30. Wasserman RL, Melamed I, Nelson RP, Jr. et al. Pharmacokinetics of subcutaneous 
IgPro20 in patients with primary immunodeficiency. Clin.Pharmacokinet. 
2011;50:405-414.
31. Supersaxo A, Hein WR, Steffen H. Effect of molecular weight on the lymphatic 
absorption of water-soluble compounds following subcutaneous administration. 
Pharm.Res. 1990;7:167-169.
32. Olsson O, Löjgren O. Hyaluronidase as a factor hastening the spread and absorption 
of water-soluble radiopaque substances deposited intracutaneously, subcutaneously, 
or intramuscularly. Acta Radiol. 1949;31:250-256.
33. Thomas JR, Yocum RC, Haller MF, von Gunten CF. Assessing the role of human 
recombinant hyaluronidase in gravity-driven subcutaneous hydration: The INFUSE-
LR Study. J.Palliat.Med. 2007;10:1312-1320.
34. Shpilberg O, Jackisch C. Subcutaneous administration of rituximab (MabThera) and 
trastuzumab (Herceptin) using hyaluronidase. Br.J.Cancer 2013;109:1556-1561.
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35. Yocum RC, Kennard D, Heiner LS. Assessment and implication of the allergic 
sensitivity to a single dose of recombinant human hyaluronidase injection: a double-
blind, placebo-controlled clinical trial. J.Infus.Nurs. 2007;30:293-299.
36. Rosengren S, Dychter SS, Printz MA et al. Clinical immunogenicity of rHuPH20, a 
hyaluronidase enabling subcutaneous drug administration. AAPS J. 2015;17:1144-
1156.
37. Melamed IR, Stein MR, Wasserman RL et al. Recombinant human hyaluronidase 
facilitates dispersion of subcutaneously administered Gammagard Liquid and 
enables administration of a full monthly dose in a single site to patients with 
immunodeficiency diseases [abstract]. J.Allergy Clin.Immunol. 2008;121:S83.
38. Wasserman RL, Melamed I, Stein MR et al. Recombinant human hyaluronidase-
facilitated subcutaneous infusion of human immunoglobulins for primary 
immunodeficiency. J.Allergy Clin.Immunol. 2012;30:951-957.
39. Varni JW, Seid M, Rode CA. The PedsQL: measurement model for the pediatric 
quality of life inventory. Med.Care 1999;37:126-139.
40. Rabin R, de Charro F. EQ-5D: A measure of health status from the EuroQol Group. 
Ann.Med. 2001;33:337-343.
41. Oken MM, Creech RH, Tormey DC et al. Toxicity and response criteria of the 
Eastern Cooperative Oncology Group. Am.J.Clin.Oncol. 1982;5:649-655.
42. World Health Organization. Toxicity grading scale for determining the severity of 
adverse events.  96. 2-20-2003.  World Health Organization (WHO). 
Link to Publisher´s Site: 
http://www.icssc.org/Documents/Resources/AEManual2003AppendicesFebruary_0
6_2003%20final.pdf
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43. U.S.Department of Health and Human Services, Food and Drug Administration, 
and 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.  17. 2008.  U.S. Department of Health and Human Services, 
Food and Drug Administration (FDA). 
44. Committee for Medicinal Products for Human Use. Guideline on the clinical 
investigation of human normal immunoglobulin for subcutaneous and/or 
intramuscular administration (SCIg/IMIg). EMA/CHMP/BPWP/410415/2011 rev 1, 
10. 7-23-2015.  European Medicines Agency (EMEA). 
Link to Publisher´s Site: 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/201
5/07/WC500190211.pdf
45. Goldstein B, Giroir B, Randolph A. International pediatric sepsis consensus 
conference: definitions for sepsis and organ dysfunction in pediatrics. 
Pediatr.Crit.Care Med. 2005;6:2-8.
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INVESTIGATOR ACKNOWLEDGEMENT
PRODUCT: HyQvia
STUDY TITLE: Post-Authorization Safety, Tolerability and Immunogenicity 
Evaluation of HyQvia in Pediatric Subjects with Primary Immunodeficiency Diseases
PROTOCOL IDENTIFIER: 161504
CLINICAL TRIAL PHASE 4
ORIGINAL: 2016 MAR 16
OTHER ID(s)
NCT Number: Not Yet Available
EudraCT Number: Not Yet Available
IND NUMBER: Not Applicable
By signing below, the investigator acknowledges that he/she has read and understands 
this protocol, and will comply with the requirements for obtaining informed consent from 
all study subjects prior to initiating any protocol-specific procedures, obtaining written 
initial and ongoing EC(s) protocol review and approval, understands and abides by the 
requirements for maintenance of source documentation, and provides assurance that this 
study will be conducted according to all requirements as defined in this protocol, clinical 
study agreement, ICH GCP guidelines, and all applicable regulatory requirements.
Signature of Principal Investigator
Date
Print Name of Principal Investigator
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CLINICAL STUDY PROTOCOL
PRODUCT: HyQvia
STUDY TITLE: Post-Authorization Safety, Tolerability and Immunogenicity 
Evaluation of HyQvia in Pediatric Subjects with Primary Immunodeficiency Diseases
STUDY SHORT TITLE: Post-Authorization Safety, Tolerability and Immunogenicity 
Evaluation of HyQvia in Pediatric PIDD subjects
PROTOCOL IDENTIFIER: 161504
CLINICAL TRIAL PHASE 4
AMENDMENT 1: 2016 OCT 07
Replaces: ORIGINAL: 2016 MAR 16
ALL VERSIONS:
Amendment 1: 2016 OCT 07
Original: 2016 MAR 16
OTHER ID(s)
NCT Number: Not Yet Available 
EudraCT Number: 2016-003438-26
IND NUMBER: Not Applicable
Study Sponsor(s):
Baxalta US Inc.
One Baxter Way
Westlake Village, CA  91362, 
UNITED STATES
Baxalta Innovations GmbH
Industriestrasse 67
A-1221 Vienna,
AUSTRIA
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2. SERIOUS ADVERSE EVENT REPORTING
The investigator will comply with applicable laws/requirements for reporting serious 
adverse events (SAEs) to the ECs.
ALL SAEs, INCLUDING SUSARs, ARE TO BE REPORTED ON THE 
SERIOUS ADVERSE EVENT REPORT (SAER) FORM ANDTRANSMITTED TO 
THE SPONSOR WITHIN 24 HOURS AFTER BECOMING AWARE OF THE 
EVENT.
Drug Safety contact information: see SAE Report form.
Refer to SAE Protocol Sections and the study team roster for further information. 
For definitions and information on the assessment of these events, refer to the following:

AE, Section 12.1

SAE, Section 12.1.1.1

SUSARS, Section 12.1.1.2

Assessment of AEs, Section 12.1.2
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3. SYNOPSIS 
INVESTIGATIONAL PRODUCT
Name of Investigational 
Product (IP)
1. HyQvia, Immune Globulin Infusion 10% (Human) with Recombinant 
Human Hyaluronidase (IGI, 10% with rHuPH20).
2. KIOVIG 100 mg/ml solution for infusion
3. Cuvitru 200 mg/ml solution for subcutaneous injection
(For better readability the names HyQvia, KIOVIG and Cuvitru will be 
used throughout the document.)
Name(s) of Active 
Ingredient(s)
Human Normal Immunoglobulin
CLINICAL CONDITION(S)/INDICATION(S)

Primary Immunodeficiency Diseases (PIDD)
PROTOCOL ID
161504
PROTOCOL TITLE
Post-Authorization Safety, Tolerability and Immunogenicity Evaluation 
of HyQvia in Pediatric Subjects with Primary Immunodeficiency Diseases
Short Title
Post-Authorization Safety, Tolerability and Immunogenicity Evaluation 
of HyQvia in Pediatric PIDD subjects
STUDY PHASE
Ph4 (post-authorization)
PLANNED STUDY PERIOD
Initiation
2016
Primary Completion
2021
Study Completion
2021
Duration
Approximately five years
STUDY OBJECTIVES AND PURPOSE
Study Purpose
The purpose of the study is to acquire additional data on safety, tolerability and immunogenicity of 
HyQvia in pediatric (age two to <18 years) subjects with Primary Immunodeficiency Diseases
(PIDD).
Primary Objective
Safety of HyQvia treatment in pediatric subjects with PIDD who have received prior 
immunoglobulin therapy before enrollment into the study.
Secondary Objective(s)
Further safety assessments (e.g. immunogenicity), tolerability, characteristic of product 
administration and efficacy (immunoglobulin G [IgG] trough levels)
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STUDY DESIGN
Study Type/ Classification/ 
Discipline
Safety, Immunogenicity
Control Type
No control
Study Indication Type
Treatment
Intervention Model
Single-group
Blinding/Masking
Open-label
Study Design
This study is a Phase 4, post-authorization, prospective, non-controlled, 
multicenter study to evaluate the safety, tolerability, and other 
parameters of subcutaneous (SC) treatment using HyQvia in 
approximately 40 pediatric subjects with PIDD who have received 
immunoglobulin therapy before enrollment into this study. Subjects will 
have regular anti-recombinant human hyaluronidase PH20 (rHuPH20) 
antibody testing (binding and neutralizing anti-rHuPH20 antibody) 
throughout the study (approximately every three months).
Epoch 1: Pediatric patients with PIDD who are on non-HyQvia 
intravenous (IV) or SC treatment with immunoglobulin (IV-pretreated, 
SC pretreated) will be enrolled and treated with HyQvia subcutaneously 
with a dose or interval ramp-up period of up to six weeks. Subjects 
already treated with HyQvia (HyQvia pretreated) will be enrolled 
directly into Epoch 2. Epoch 1 infusions will be administered at the 
study site.
Epoch 2: The ramp-up (Epoch 1) is followed by Epoch 2 with HyQvia 
treatment at the following intervals. For IV-pretreated subjects: every 
three or four weeks, depending on the subject’s previous IV dosing 
schedule. For SC-pretreated subjects: every three or four weeks, at the 
discretion of investigator and subject. For HyQvia pretreated subjects: 
No change in frequency of administration. After one year in Epoch 2, 
the anti-rHuPH20 binding antibody assay results during that year will be 
used to decide the next steps in the study (see Figure 1: Study Flow 
Chart in Supplements). Subjects with anti-rHuPH20 antibody titer < 160 
at all time-points during the study will complete the study 
termination/completion visit at the next possible occasion. Subjects with 
anti-rHuPH20 antibody titer ≥ 160 during the study and/or at the last 
measurement will continue in Epoch 2 for an additional two years of 
HyQvia treatment and observation. 
The first two or three infusion(s) during Epoch 2 will be administered 
at the study site. It is preferable that subsequent infusions be 
performed at home (or equivalent site) by the subject or caregiver, if in 
the opinion of the investigator, such treatment is safe and appropriate. 
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In that case, the investigator/designee must have trained the subject or 
caregiver and must be satisfied that the subject or caregiver is capable of 
self-administration of SC infusions at home before the subject or 
caregiver will be permitted to conduct the SC infusion at home.
Epoch 3: Epoch 3 is up to one year safety follow-up for subjects whose 
anti-rHuPH20 antibody titer was ≥ 160 during Epoch 1 or Epoch 2 and 
who experience either a related Serious Adverse Event (SAE) or a 
related severe Adverse Event (AE).
Subjects in Epoch 3 will be treated with KIOVIG intravenously or 
Cuvitru subcutaneously, at the discretion of the investigator and the 
subject. 
In the event that a subject in Epoch 1 or in Epoch 2 experiences a related 
SAE or severe AE without anti-rHuPH20 antibody titer ≥ 160, the 
subject can (at the discretion of the investigator and subject) either be 1)
terminated from the study or 2) change directly to Epoch 3 or 
3) continue in Epoch 1 or 2 with appropriate medical intervention such 
as decreasing the HyQvia infusion rate and/or premedication.
Subjects with antibody titer of ≥ 160 when entering Epoch 3 continue 
regular anti-rHuPH20 antibody testing (approximately every three
months) for approximately one year or until anti-rHuPH20 antibody titer 
declines to < 2560 for at least two consecutive measurements, whichever 
comes first. These subjects complete the study termination or 
completion visit when the AE or SAE resolves or the anti-rHuPH20 titer 
is <2560.
Infusions in Study Epoch 3 will be administered at home or at the study 
site.
The study termination/completion visit will be conducted at the study 
site.
Planned Duration of Subject 
Participation
Study Epoch 1 (Ramp-up): Up to six weeks for HyQvia-naïve subjects 
Study Epoch 2 (Final dosing): Up to three years
Study Epoch 3 (Safety Follow-up): Up to one year
The maximum subject participation period is approximately four years.
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Primary Outcome Measure 
1.
Number and rate per infusion (excluding infections) of all severe related AEs
2.
Number and rate per infusion (excluding infections) of related SAEs
Secondary Outcome Measure(s) 
Efficacy
1.
Trough levels of IgG (for Study Epoch 1 and 2)
Safety 
1.
Proportion of subjects who achieve a treatment interval of three or four weeks in Epoch 2 
2.
Proportion of subjects who maintain a treatment interval of three or four weeks in Epoch 2 for 
12 months
3.
Number and rate per infusion (excluding infections) of local AEs and Adverse Reactions (ARs)
4.
Number and rate per infusion (excluding infections) of systemic AEs and ARs
5.
Number and rate per infusion (excluding infections) of all AEs and all ARs
6.
Number and rate per infusion (excluding infections) of all temporally associated AEs 
7.
Number and rate per infusion (excluding infections) of all causally related and/or temporally 
associated AEs
8.
Number and rate per infusion (excluding infections) of all SAEs 
9.
Number/proportion of subjects who develop positive titer (≥160) of binding or neutralizing 
antibodies to rHuPH20
Mode of Product Administration (For Study Epoch 1 and 2)
1.
Infusions
a.
Number of infusions per month
b.
Number of infusion sites (needle sticks) per infusion/month
c.
Duration of infusion
d.
Maximum infusion rate/site
e.
Infusion volume/site
f.
Number/proportion of infusions that are discontinued, slowed, or interrupted due to an AE
2.
Number of weeks to reach final dose interval (three weeks or four weeks)
3.
Assessment of Treatment Preference Questionnaire
4.
Assessment of Treatment Satisfaction with Medication Questionnaire:  TSQM-9
5.
Assessment of Health-related Quality of Life Questionnaires:  Peds-QL, EQ-5D
Tertiary Outcome Measure(s) 
1.
Number of acute serious bacterial infections
2.
Number of all infections
3.
Days not able to go to school/work or to perform normal daily activities
4.
Days on antibiotics
5.
Number of hospitalizations, indication for the hospitalization (infection or non-infection) and days 
hospitalized
6.
Number of acute physician visits (office and emergency room) due to infection or other illnesses
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INVESTIGATIONAL PRODUCT(S), DOSE AND MODE OF ADMINISTRATION
Active Product
1. HyQvia Immune Globulin Infusion 10% (Human) with Recombinant Human 
Hyaluronidase
Subjects will be treated with HyQvia in Study Epoch 1 and Study Epoch 2.
Dosage Form: injectable
Mode of Administration: SC
Dosage Frequency:
Study Epoch 1 (Ramp-up): 
One treatment interval of one week, then one treatment interval of two weeks, 
then one treatment interval of three weeks (for subjects who are planned to be 
treated every four weeks)
Study Epoch 2 (Final dosing):
HyQvia dose once every three or four weeks:

For IV-pretreated subjects: every three or four weeks, depending on the 
subject’s previous IV dosing schedule. 

For SC-pretreated subjects: every three or four weeks, at the discretion of 
investigator and subject
Dose: HyQvia weekly dose will be equivalent to 100% (±5%) of pre-study 
treatment
Example for IgG dosing:
Pre-Study
Epoch 1 
(Ramp-Up)
Epoch 2 
(Final Dose)
Admin. 
Route
Dose
First 
Infusion at 
Baseline: 
1-Week Dose
Second 
Infusion at 
Week 1: 
2-Week Dose
Third 
Infusion at 
Week 3: 
3-Week Dose
IV
0.6 g/kg 
every 3 weeks
0.2 g/kg
0.4 g/kg
-
0.6 g/kg 
every 3 weeks
IV
0.6 g/kg 
every 4 weeks
0.15 g/kg
0.3 g/kg
0.45 g/kg
0.6 g/kg 
every 4 weeks
SC
0.1 g/kg 
every week
0.1 g/kg
0.2 g/kg
-
0.3 g/kg 
every 3 weeks
SC
0.1 g/kg 
every week
0.1 g/kg
0.2 g/kg
0.3 g/kg
0.4 g/kg 
every 4 weeks
Infusion Rate:
Study Epoch 1 (Ramp-up): 

For subjects with a body weight (BW) of < 40 kg: 5 ml/h/site (at start) to 
80 ml/h/site (maximum, if tolerated)

For subjects with a BW of ≥ 40 kg: 10 ml/h/site (at start) to 240 ml/h/site 
(maximum, if tolerated)
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Study Epoch 2 (Final dosing):

For subjects with a BW of < 40 kg: 10 ml/h/site (at start) to 160 ml/h/site 
(maximum, if tolerated)

For subjects with a BW of ≥ 40 kg: 10 ml/h/site (at start) to 300 ml/h/site 
(maximum, if tolerated)
If infusions have been tolerated after the subject has received two HyQvia 
infusions at the dose for the final infusion interval (three or four week dose), then 
investigators may choose an infusion rate schedule at their own discretion.
2. KIOVIG
Subjects may be treated with KIOVIG in Study Epoch 3 (Safety Follow-up).
Dosage form: injectable
Mode of Administration: intravenous
The infusion rate and infusion volume per site will follow the suggestions of the 
KIOVIG SmPC. 
Dosage frequency: Once every three or four weeks 
Dose: The weekly dose will be equivalent to 100% (±5%) of the dose in the 
previous study epoch
3.
Cuvitru
Subjects may be treated with Cuvitru in Study Epoch 3 (Safety Follow-up).
Dosage form: Solution for injection
Mode of Administration: subcutaneous injection
The infusion rate and infusion volume per site will follow the suggestions of the 
Cuvitru SmPC. 
Dosage frequency: daily to once every two weeks, at the investigator´s discretion
Dose: The weekly dose will be equivalent to 100% (±5%) of the dose in the 
previous study epoch.
SUBJECT SELECTION
Targeted Accrual
Sample size: Approximately 40 pediatric subjects already on IgG treatment pre-
study will be enrolled. The study will enroll approximately six subjects two to less 
than six years of age, 12 subjects six to <12 years of age, 22 subjects 12 to <18 years 
of age. The study will be conducted in the European Economic Area.
Study sites: Approximately 20
Number of Groups/
Arms/Cohorts
1
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Inclusion Criteria
1. Subject must have a documented diagnosis of a form of primary humoral immunodeficiency involving 
a defect in antibody formation and requiring gammaglobulin replacement, as defined according to the 
International Union of Immunological Societies (IUIS) Scientific Committee 2015 1 prior to 
enrollment. The diagnosis must be confirmed by the sponsor´s Medical Director prior to first 
treatment with investigational product (IP) in the study.
2. Subject is at least two and below 18 years of age at the time of screening.
3. Subject has been receiving a consistent dose of IgG, administered in compliance with the respective 
product information for a period of at least three months prior to screening. The average minimum 
pre-study dose over that interval was equivalent to 300 mg/kg BW/4 weeks and a maximum dose 
equivalent to 1000 mg/kg BW/4 weeks.
4. Subject has a serum trough level of IgG >5 g/L at screening.
5. If female of childbearing potential, subject presents with a negative pregnancy test and agrees to 
employ adequate birth control measures for the duration of the study. 
6. Subject/legally authorized representative is willing and able to comply with the requirements of the 
protocol.
Exclusion Criteria
1. Subject has a known history of or is positive at screening for one or more of the following: hepatitis B 
surface antigen (HBsAg), polymerase chain reaction (PCR) for hepatitis C virus (HCV), PCR for 
human immunodeficiency virus (HIV) Type 1/2. 
2. Abnormal laboratory values at screening meeting any one of the following criteria (abnormal tests 
may be repeated once to determine if they are persistent):
a.
Persistent alanine aminotransferase (ALT) and aspartate amino transferase (AST) >2.5 times 
the upper limit of normal (ULN) for the testing laboratory
b.
Persistent severe neutropenia (defined as an absolute neutrophil count [ANC] 500/mm3)
3. Subject has anemia that would preclude phlebotomy for laboratory studies, according to standard 
practice at the site.
4. Subject has an ongoing history of hypersensitivity or persistent reactions (urticaria, breathing 
difficulty, severe hypotension, or anaphylaxis) following IV immunoglobulin, SC immunoglobulin, 
and/or Immune Serum Globulin (ISG) infusions.
5. Subject has severe immunoglobulin A (IgA) deficiency (less than 7.0 mg/dL) with known anti-IgA 
antibodies and a history of hypersensitivity.
6. Subject has a known allergy to hyaluronidase.
7. Subject has active infection and is receiving antibiotic therapy for the treatment of infection at the 
time of screening.
8. Subject has a bleeding disorder or a platelet count less than 20,000/µL, or who, in the opinion of the 
investigator, would be at significant risk of increased bleeding or bruising as a result of SC therapy. 
9. Subject has severe dermatitis that would preclude adequate sites for safe product administration in the 
opinion of the investigator.
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10. Subject has participated in another clinical study involving an IP or investigational device within 
30 days prior to enrollment or is scheduled to participate in another clinical study involving an IP or 
investigational device during the course of this study.
11. Subject is a family member or employee of the investigator.
12. If female, subject is pregnant or lactating at the time of enrollment.
STATISTICAL ANALYSIS
Sample Size Calculation
The planned sample size for the study is approximately 40 pediatric subjects.
Planned Statistical Analysis
Statistical analyses and data displays will be mainly descriptive. Data from all enrolled subjects will be 
included in the analysis. All SAEs and non-serious AEs will be categorized according to Medical 
Dictionary for Regulatory Activities (MedDRA) system organ class and preferred term. All analyses will 
be performed using SAS® version 9.2 or higher (SAS Institute, Cary, NC, USA).
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4. TABLE OF CONTENTS
1. STUDY PERSONNEL.................................................................................................. 2
1.1 Authorized Representative (Signatory) / Responsible Party .............................. 2
1.2 Study Organization................................................................................................. 2
2. SERIOUS ADVERSE EVENT REPORTING........................................................... 3
3. SYNOPSIS..................................................................................................................... 4
4. TABLE OF CONTENTS ........................................................................................... 12
5. LIST OF ABBREVIATIONS .................................................................................... 18
6. BACKGROUND INFORMATION .......................................................................... 21
6.1 Description of Investigational Product ............................................................... 21
HyQvia............................................................................................................ 21
6.1.1
KIOVIG 100 mg/ml solution for infusion and Cuvitru 200 mg/ml solution 
6.1.2
for subcutaneous injection............................................................................ 22
A detailed description of Cuvitru is provided in the SmPC. 
6.1.3
Immunoglobulin Treatment ......................................................................... 23
Immunoglobulin and Hyaluronidase Treatment........................................ 25
6.1.4
6.2 Clinical Condition/Indication .............................................................................. 26
6.3 Findings from Nonclinical and Clinical Studies................................................. 27
Clinical Study 160602.................................................................................... 27
6.3.1
Clinical Study 160603.................................................................................... 28
6.3.2
6.3.2.1 Pharmacokinetic Properties .................................................................. 30
Clinical Study 160902.................................................................................... 31
6.3.3
6.3.3.1 Disposition of Subjects ........................................................................... 32
6.3.3.2 Extent of Exposure ................................................................................. 32
6.3.3.3 Efficacy .................................................................................................... 32
6.3.3.4 Safety........................................................................................................ 33
Clinical Study 161101.................................................................................... 35
6.3.4
HyQvia Pregnancy Registry 161301 ............................................................ 37
6.3.5
HyQvia PASS 161302 .................................................................................... 38
6.3.6
HyQvia Study 161406.................................................................................... 39
6.3.7
6.4 Evaluation of Anticipated Risks and Benefits of the Investigational Product(s) 
to Human Subjects................................................................................................ 40
HyQvia............................................................................................................ 40
6.4.1
6.4.1.1 Pregnancy, Breast Feeding, Fertility .................................................... 41
KIOVIG.......................................................................................................... 41
6.4.2
Cuvitru............................................................................................................ 43
6.4.3
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6.5 Compliance Statement.......................................................................................... 43
7. STUDY PURPOSE AND OBJECTIVES ................................................................. 43
7.1 Study Purpose ....................................................................................................... 43
7.2 Primary Objective................................................................................................. 43
7.3 Secondary Objectives ........................................................................................... 43
7.4 Tertiary Objectives............................................................................................... 43
8. STUDY DESIGN......................................................................................................... 44
8.1 Brief Summary...................................................................................................... 44
8.2 Overall Study Design............................................................................................ 44
Epoch 1............................................................................................................ 44
8.2.1
Epoch 2............................................................................................................ 44
8.2.2
Epoch 3............................................................................................................ 45
8.2.3
8.3 Duration of Study Period(s) and Subject Participation .................................... 46
8.4 Outcome Measures ............................................................................................... 46
Primary Outcome Measure........................................................................... 46
8.4.1
Secondary Outcome Measures ..................................................................... 46
8.4.2
8.4.2.1 Efficacy .................................................................................................... 46
8.4.2.2 Safety/Tolerability .................................................................................. 46
8.4.2.3 Mode of Product Administration .......................................................... 47
Tertiary Outcome Measures......................................................................... 47
8.4.3
Exploratory Outcomes Measure................................................................... 47
8.4.4
8.5 Randomization and Blinding............................................................................... 48
8.6 Study Stopping Rules............................................................................................ 48
8.7 Investigational Product(s) .................................................................................... 48
Packaging, Labeling, and Storage................................................................ 48
8.7.1
8.7.1.1 rHuPH20.................................................................................................. 48
8.7.1.2 IGI, 10% .................................................................................................. 48
8.7.1.3 KIOVIG................................................................................................... 49
8.7.1.4 Cuvitru..................................................................................................... 49
Administration ............................................................................................... 50
8.7.2
Description of Treatment.............................................................................. 50
8.7.3
8.7.3.1 HyQvia..................................................................................................... 50
8.7.3.2 KIOVIG................................................................................................... 52
8.7.3.3 Cuvitru..................................................................................................... 52
Investigational Product Accountability ....................................................... 52
8.7.4
8.8 Source Data ........................................................................................................... 53
9. SUBJECT SELECTION, WITHDRAWAL, AND DISCONTINUATION .......... 54
9.1 Inclusion Criteria.................................................................................................. 54
9.2 Exclusion Criteria................................................................................................. 54
9.3 Withdrawal and Discontinuation ........................................................................ 55
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10. STUDY PROCEDURES .......................................................................................... 57
10.1 Informed Consent ............................................................................................... 57
10.2 Subject Identification Code................................................................................ 57
10.3 Screening and Study Visits................................................................................. 57
10.4 Medications and Non-Drug Therapies.............................................................. 58
10.5 Subject Diary....................................................................................................... 59
10.6 Subject Completion/Discontinuation ................................................................ 60
10.7 Procedures for Monitoring Subject Compliance ............................................. 61
11. ASSESSMENT OF EFFICACY.............................................................................. 62
11.1 IgG Trough Levels.............................................................................................. 62
11.2 Treatment Preference Questionnaire................................................................ 62
11.3 Treatment Satisfaction Questionnaire for Medication.................................... 62
11.4 HRQoL Questionnaire ....................................................................................... 63
PedsQL.......................................................................................................... 63
11.4.1
EQ-5D ........................................................................................................... 63
11.4.2
12. ASSESSMENT OF SAFETY................................................................................... 64
12.1 Adverse Events.................................................................................................... 64
Definitions..................................................................................................... 64
12.1.1
12.1.1.1 Serious Adverse Event.......................................................................... 64
12.1.1.2 Suspected Unexpected Serious Adverse Reaction (SUSAR)............. 65
12.1.1.3 Non-Serious Adverse Event ................................................................. 65
12.1.1.4 Unexpected Adverse Events................................................................. 65
12.1.1.5 Preexisting Diseases.............................................................................. 66
Assessment of Adverse Events.................................................................... 66
12.1.2
12.1.2.1 Severity .................................................................................................. 67
12.1.2.2 Causality................................................................................................ 68
12.2 Urgent Safety Measures ..................................................................................... 69
12.3 Untoward Medical Occurrences........................................................................ 69
12.4 Non-Medical Complaints ................................................................................... 70
12.5 Medical, Medication, and Non-Drug Therapy History................................... 70
12.6 Physical Examinations........................................................................................ 71
12.7 Clinical Laboratory Parameters........................................................................ 71
Hematology and Clinical Chemistry.......................................................... 71
12.7.1
Urine Tests.................................................................................................... 71
12.7.2
Pregnancy Test............................................................................................. 71
12.7.3
Hemolysis Test.............................................................................................. 72
12.7.4
IgG Trough Levels and IgG Subclasses and Specific Antibody Tests .... 72
12.7.5
Anti-rHuPH20 Antibodies .......................................................................... 72
12.7.6
Viral Pathogen Serology.............................................................................. 73
12.7.7
Assessment of Laboratory Values .............................................................. 73
12.7.8
12.7.8.1 Toxicity Grading Scale......................................................................... 73
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12.7.8.2 Assessment of Abnormal Laboratory Values..................................... 73
Backup Samples and Biobanking............................................................... 74
12.7.9
12.8 Vital Signs............................................................................................................ 74
Screening....................................................................................................... 74
12.8.1
Infusion at Study Site .................................................................................. 74
12.8.2
Infusion at Home.......................................................................................... 74
12.8.3
End-of-Study ................................................................................................ 75
12.8.4
12.9 Acute Serious Bacterial Infections .................................................................... 75
Infection: Bacteremia/Sepsis(a).................................................................... 75
12.9.1
Infection: Bacterial Meningitis................................................................... 76
12.9.2
Infection: Osteomyelitis/Septic Arthritis................................................... 76
12.9.3
Infections: Bacterial Pneumonia(d)............................................................. 77
12.9.4
Infection: Visceral Abscess ......................................................................... 78
12.9.5
13. STATISTICS............................................................................................................. 79
13.1 Sample Size and Power Calculations ................................................................ 79
13.2 Analysis Sets ........................................................................................................ 79
Full Analysis Set........................................................................................... 79
13.2.1
Per-Protocol Analysis Set............................................................................ 79
13.2.2
Safety Analysis Set....................................................................................... 79
13.2.3
13.3 Handling of Missing, Unused, and Spurious Data........................................... 79
13.4 Methods of Analysis............................................................................................ 79
Primary Outcome Measure......................................................................... 80
13.4.1
Secondary Outcome Measures ................................................................... 80
13.4.2
13.4.2.1 Efficacy .................................................................................................. 80
13.4.2.2 Safety...................................................................................................... 80
13.4.2.3 Mode of Product Administration (For Study Epoch 1 and 2).......... 81
13.4.2.4 HRQoL................................................................................................... 81
Tertiary Outcome Measures....................................................................... 81
13.4.3
13.4.3.1 Infections ............................................................................................... 81
13.4.3.2 Healthcare Resource Utilization Endpoints....................................... 82
13.5 Planned Interim Analysis of the Study ............................................................. 82
14. DIRECT ACCESS TO SOURCE DATA/DOCUMENTS .................................... 82
15. QUALITY CONTROL AND QUALITY ASSURANCE...................................... 83
15.1 Investigator’s Responsibility.............................................................................. 83
Final Clinical Study Report ........................................................................ 83
15.1.1
15.2 Training ............................................................................................................... 83
15.3 Monitoring........................................................................................................... 83
15.4 Safety Monitoring ............................................................................................... 83
15.5 Auditing ............................................................................................................... 84
15.6 Non-Compliance with the Protocol ................................................................... 84
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15.7 Laboratory and Reader Standardization ......................................................... 84
16. ETHICS ..................................................................................................................... 85
16.1 Subject Privacy ................................................................................................... 85
16.2 Ethics Committee and Regulatory Authorities................................................ 85
16.3 Informed Consent ............................................................................................... 85
17. DATA HANDLING AND RECORD KEEPING................................................... 87
17.1 Confidentiality Policy ......................................................................................... 87
17.2 Study Documentation and Case Report Forms ............................................... 87
17.3 Document and Data Retention........................................................................... 87
18. FINANCING AND INSURANCE........................................................................... 88
19. PUBLICATION POLICY........................................................................................ 88
20. SUPPLEMENTS....................................................................................................... 89
20.1 Study Flow Chart................................................................................................ 89
20.2 Schedule of Study Procedures and Assessments.............................................. 90
20.3 Clinical Laboratory Assessments ...................................................................... 94
20.4 Toxicity Grading Scale for Laboratory Values................................................ 98
21. REFERENCES.......................................................................................................... 99
22. SUMMARY OF CHANGES.................................................................................. 105
INVESTIGATOR ACKNOWLEDGEMENT............................................................ 111
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Tables
Table 1 Pharmacokinetic Parameters of HyQvia Compared to  Intravenous 
Administration of IGI 10%....................................................................................... 30
Table 2  Example for IgG dosing...................................................................................... 51
Table 3 STUDY EPOCH 1 – Ramp Up  Schedule of Study Procedures and Assessments
................................................................................................................................... 90
Table 4 STUDY EPOCH 2 – Year 1  Schedule of Study Procedures and Assessments. 91
Table 5 STUDY EPOCH 2 – Year 2 and Year 3 Schedule of Study Procedures and 
Assessments .............................................................................................................. 92
Table 6 STUDY EPOCH 3  Schedule of Study Procedures and Assessments................ 93
Table 7 STUDY EPOCH 1 – Ramp Up  Clinical Laboratory Assessments.................... 94
Table 8 STUDY EPOCH 2 – Year 1  Clinical Laboratory Assessments ........................ 95
Table 9 STUDY EPOCH 2 – Year 2 and Year 3 Clinical Laboratory Assessments....... 96
Table 10 STUDY EPOCH 3 Clinical Laboratory Assessments ...................................... 97
Table 11 Grading of Laboratory Parameters ................................................................... 98
Figures
Figure 1 Study Design for Clinical Study 161504........................................................... 89
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5. LIST OF ABBREVIATIONS
Abbreviation
Definition
ADR
Adverse drug reaction (i.e., related AE) 
AE
Adverse event
AR
Adverse reaction
AIDS
Acquired immune deficiency syndrome
ALP
Alkaline phosphatase
ALT 
Alanine amino transferase (SGPT)
ANC
Absolute neutrophil count
AST 
Aspartate amino transferase (SGOT)
AUC
Area under the curve
B19V
Parvovirus B19
BUN
Blood urea nitrogen
BW
Body weight
CHMP
Committee for Medicinal Products for Human Use
CLL
Chronic lymphocytic leukemia
CI
Confidence interval
Cmax
Maximum concentration
Cmin
Minimum concentration
CRF
Case report form
CSF
Cerebrospinal fluid
CT
Computed tomography
CXR
Chest x-ray
EC
Ethics committee
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic case report form
EDC
Electronic data capture
EPR
Electronic Patient Reported 
EU
European Union
Fc
Crystallizable region of antibody
FDA
Food and Drug Administration
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Abbreviation
Definition
GCP
Good Clinical Practice
h, hr
Hour(s)
HAV
Hepatitis A virus
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HEV
Hepatitis E virus
Hgb
Hemoglobin
HIV 
Human immunodeficiency virus 
HRQoL
Health related quality of life
ICH
International Council for Harmonization
IgA
Immunoglobulin A
IGIV, 10%
Immune Globulin Intravenous (Human) GAMMAGARD 
LIQUID/KIOVIG
IgG
Immunoglobulin G
IGI
Immunoglobulin
IGIV
Immune globulin intravenous (human)
IGSC
Immune globulin subcutaneous (human)
IP
Investigational Product
ISG
Immune serum globulin
ISRB
Internal safety review board
ITP
Idiopathic thrombocytopenic purpura 
IV
Intravenous
LDH
Lactate dehydrogenase 
MedDRA
Medical Dictionary for Regulatory Activities
min
Minute(s)
mL
Milliliter(s)
MM
Multiple myeloma
MMN
Multi-focal motor neuropathy
MRI
Magnetic resonance imaging
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Abbreviation
Definition
NMC
Non-medical complaint
PaCO2
Partial pressure (tension) of carbon dioxide
PASS
Post-authorization safety study
PCR
Polymerase chain reaction
PIDD
Primary immunodeficiency disease
PK
Pharmacokinetic(s)
RBC
Red blood cell (count)
rHuPH20
Recombinant human hyaluronidase PH20 
(active ingredient in the U.S. marketed product HYLENEX)
SAP
Statistical analysis plan
S/D
Solvent/detergent
SAE
Serious adverse event
SAER
Serious adverse event report
SC
Subcutaneous
SCIG
Subcutaneous immunoglobulin G
SIC
Subject identification code
SmPC
Summary of product characteristics
Tmax
Time to maximum concentration
TRALI
Transfusion related acute lung injury
ULN
Upper limit of normal
VASBI
Validated acute serious bacterial infection
WBC
White blood cell (count)
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6. BACKGROUND INFORMATION
Purified human immunoglobulin G (IgG) preparations were first used in 1952 for the 
treatment of patients with primary immunodeficiency diseases (PIDD), a class of 
disorders that result in increased susceptibility to infection, including both recurrent 
pyogenic infections secondary to defects of humoral immunity and opportunistic 
infections resulting from defects in cell-mediated immunity.3,4 Individuals with these 
disorders require replacement therapy with immunoglobulin products to prevent or 
reduce the severity of infections. In addition to PIDD syndromes, immunoglobulin 
preparations have been indicated for secondary immunodeficiencies, such as B-cell 
chronic lymphocytic leukemia (CLL), acquired immunodeficiency syndrome (AIDS), 
and immunodeficiency after bone marrow transplantation.5,6,7,8 Immunoglobulins are also 
effective in the management of autoimmune disorders, such as idiopathic 
thrombocytopenic purpura (ITP) 9,10,11, Kawasaki syndrome 12,13, and multi-focal motor 
neuropathy (MMN).14
6.1 Description of Investigational Product
HyQvia
6.1.1
HyQvia 100 mg/ml solution for infusion for subcutaneous (SC) use is a dual vial unit 
consisting of one vial of human normal immunoglobulin (Immune Globulin 10% or 
IG 10%) and one vial of recombinant human hyaluronidase (rHuPH20). 
The IG 10% component provides the therapeutic effect of this medicinal product. 
The rHuPH20 facilitates the dispersion and absorption of IG 10%.
Human normal immunoglobulin contains mainly IgG with a broad spectrum of 
opsonizing and neutralizing antibodies against infectious agents.
Human normal immunoglobulin contains the IgG antibodies present in the normal 
population. It is usually prepared from pooled human plasma from not fewer than 
1,000 donations. It has a distribution of IgG subclasses closely proportional to that in 
native human plasma. Adequate doses of human normal immunoglobulin may restore 
abnormally low IgG levels to the normal range.
rHuPH20 is a soluble recombinant form of human hyaluronidase that modifies the 
permeability of connective tissue through the hydrolysis of hyaluronan. Hyaluronan 
is a polysaccharide found in the intercellular matrix of connective tissue and of 
certain specialized tissues. It is degraded by naturally occurring hyaluronidase 
and has a very fast natural turnover in SC tissue. 
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As a permeation enhancer, rHuPH20 temporarily accelerates the break-down of 
hyaluronan, resulting in a temporary increase in the permeability of the interstitial matrix 
that facilitates more rapid dispersion and absorption and improved bioavailability of the 
IG 10%.
HyQvia therapeutic indications include:
Replacement therapy in adults (≥18 years) with primary immunodeficiency 
syndromes such as:
a.
congenital agammaglobulinaemia and hypogammaglobulinaemia
b. common variable immunodeficiency
c.
severe combined immunodeficiency
d. IgG subclass deficiencies with recurrent infections
Replacement therapy in adults (≥18 years) with myeloma or CLL with severe 
secondary hypogammaglobulinaemia and recurrent infections
KIOVIG 100 mg/ml solution for infusion and Cuvitru 200 mg/ml solution for 
6.1.2
subcutaneous injection
KIOVIG is a liquid unmodified IgG preparation with an osmolality that is similar to 
physiologic osmolality and contains no added sugars, sodium, or preservatives. The 
manufacturing process includes three independent, validated viral inactivation or removal 
steps: solvent/detergent (S/D) treatment, nanofiltration and incubation at a low pH and 
elevated temperature. The product contains immunoglobulins with intact Fc regions
(crystallizable region of the antibody) in isotonic solution including glycine for 
stabilization. KIOVIG is a ready-to-use 10% liquid preparation.
A detailed description of KIOVIG is provided in the Summary of Product Characteristics 
(SmPC).
Cuvitru 200 mg/ml solution for subcutaneous injection is a ready-for-use sterile, liquid 
preparation of highly purified, concentrated, functionally intact human IgG.
Therapeutic indications include replacement therapy in adults, and children and 
adolescents (0-18 years) with

primary immunodeficiency syndromes with impaired antibody production

hypogammaglobulinaemia and recurrent bacterial infections in patients with 
chronic lymphocytic leukaemia (CLL), in whom prophylactic antibiotics have 
failed or are contra-indicated
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
hypogammaglobulinaemia and recurrent bacterial infections in multiple 
myeloma (MM) patients

hypogammaglobulinaemia in patient’s pre- and post- allogeneic haematopoietic 
stem cell transplantation (HSCT).
A detailed description of Cuvitru is provided in the SmPC. Immunoglobulin 
6.1.3
Treatment
Defective antibody formation, with or without decreased levels of serum 
immunoglobulins, is the most common abnormality in the majority of PIDD. It leads to 
increased susceptibility to viral and bacterial infections, especially of the sinopulmonary 
and gastrointestinal tracts. Decreased immunoglobulin levels are found not only in the 
group made up predominantly of antibody defects (e.g., X-linked agammaglobulinemia, 
selective IgG subclass deficiency, common variable immunodeficiency, or X-linked 
hyperimmunoglobulin M syndrome), but also in the group of combined 
immunodeficiencies (e.g., severe combined immunodeficiency, Wiskott-Aldrich 
Syndrome) that have defects in both T- and B-cells.1
Immunoglobulin treatment to prevent infections is also performed in Secondary 
Immunodeficiencies, such as CLL or multiple myeloma (MM). CLL is the most frequent 
form of leukemia in Western countries. It is characterized by the clonal proliferation and 
accumulation of neoplastic B lymphocytes in the blood, bone marrow, lymph nodes, and 
spleen.15 MM is a plasma-cell neoplasm that is characterized by skeletal destruction, 
renal failure, anemia, hypercalcemia but also recurrent infections.16
Individuals with PIDD require lifelong replacement therapy with immunoglobulin 
products to prevent or reduce severity of infections. Initially, immunoglobulin
replacement therapy was given by the intramuscular route, however, since the early 
1980s in the US, the overwhelming majority of patients have been treated by the IV 
route. In the past several years SC administration has gained popularity. Currently, the 
majority of immunoglobulin products in the US are licensed for IV administration; 
though, in December 2005, the first SC preparation was licensed by ZLB-Behring.17,18
SC administration of immunoglobulin preparations for PIDD patients has been accepted 
in many countries worldwide and is the predominant mode in the Scandinavian countries, 
particularly in Sweden. The first attempts, in the late 1970s, used intramuscular 
preparations administered at slow infusion rates, but in later years rapid infusion rates 
have been used more successfully.19,20,21,22,23
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All of the gammaglobulin preparations licensed for SC use are formulated at 10-20%. 
Commonly they are formulated at 16% and are similar to Cohn Fraction II, therefore, 
they cannot be infused intravenously. The higher concentration, relative to IV 
preparations that are formulated at 5% to 12%, allows for a smaller infusion volume. 
This method of immunoglobulin replacement therapy is considered to be effective, safe 
and also highly appreciated by patients, as it has a low risk of systemic adverse reactions
(ARs). When given weekly or every other week, SC IgG leads to higher trough serum 
IgG concentrations than monthly IV infusions (at the same monthly dose).24,25  
After adequate training by healthcare professionals, SC infusions of immunoglobulin can 
easily be performed by many patients at home, thus increasing patient comfort and 
independence and reducing cost.26
Immunoglobulin administered intravenously is immediately available in the blood, 
and slowly equilibrates to the extra-vascular compartment over three to five days.27
Subcutaneously administered immunoglobulin is slowly absorbed from the SC space 
into the blood and at the same time equilibrates with the extra-vascular compartment. 
Consequently, there is no high spike in the IgG concentration as is seen following IV 
infusion. A study in 1972 by Smith, et al., used pharmacokinetic (PK) modeling and 
determined that the bioavailability of SC and IM was 100% when compared to IV.28
More recent studies mandated by the Food and Drug Administration (FDA) showed that 
the bioavailability (measured as the area under the curve (AUC) of immune globulin 
concentration over time) of SC immunoglobulin is lower than that of IV 
immunoglobulin.18,29 Accordingly, it is recommended that the dose of SC 
immunoglobulin be adjusted to 137-153% of the IV dose to provide a comparable IgG 
exposure.18,30 Despite the technical difficulties of comparing AUC for two different 
routes and frequencies of administration, studies of intradermally administered 
immunoglobulin in ratsi suggest that there is decreased bioavailability through the SC 
route. This may be due to the mode of absorption of large protein molecules, which 
cannot readily diffuse through the capillary walls and must be absorbed via the 
lymphatics.31
The primary practical disadvantage of SC administration of immunoglobulin is that only 
small volumes can be infused at each site, necessitating the use of multiple sites on a 
weekly or biweekly (every-other-week) basis. Generally, using a 16% solution, 
approximately 20 mL can be infused per site; an adult patient receiving 400 mg/kg body 
weight (BW) thus would require at least three sites per week or 12 sites per month. 
                                                
i
Halozyme Report Number R1005-0551.
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Even though weekly or biweekly administration has the benefit of maintaining better IgG 
trough levels than monthly IV infusions, the requirement for multiple needle insertions 
may deter many patients.
Immunoglobulin and Hyaluronidase Treatment
6.1.4
The SC space is formed by a collagen and elastin network filled with a gel-like substance, 
hyaluronan or hyaluronic acid. It is largely responsible for the resistance to fluid flow 
through this tissue. Hyaluronidase derived from sheep or cows has been used for the last 
sixty years to temporarily depolymerize the hyaluronan and facilitate SC infusions of 
fluids for re-hydration.32 rHuPH20 is a 63 kd protein genetically engineered from the 
sequence of the naturally occurring human protein. It temporarily depolymerizes the 
hyaluronan, decreasing the resistance to fluid flow and thus facilitating infusions into the 
SC space. The high molecular weight hyaluronan has a rapid turnover and is restored 
within 24 to 48 h, leaving no observable changesii. Weekly infusions into cynomolgus 
monkeys in doses up to two mg/kg (> 1,000 fold higher than the HyQvia dose in humans)
did not lead to adverse reactions during a follow-up of 39 weeksiii. Infusion of rHuPH20 
improved absorption and bioavailability of intradermally injected IgG in rabbits, 
pegylated interferon and infliximab in rats, and increased the rate of infusion and comfort 
of infusions of lactated Ringer’s solution in the arms of adult human volunteers three- to 
four-fold.33 Studies investigating the effects of rHuPH20 on SC infusions of large 
quantities of IgG in dogs and rabbits have been difficult to interpret due to the rapid 
absorption of IgG alone in this model. However, at higher doses of rHuPH20, 
bioavailability seemed to increase. The human SC compartment is much tighter than that 
of these animals and thus, human studies were required. rHuPH20 can facilitate 
absorption of small molecules such as insulin and morphine in humans; in phase 1 trials 
rHuPH20 improved bioavailability of proteins such as infliximabiv and enabled drug 
dispensation and absorption at the administration site of rituximab and trastuzumab.34  
In a phase 1/2 clinical study of HyQvia (Study 160602) the average bioavailability of the 
IgG in seven subjects was 92%, suggesting a significant improvement compared to SC 
administration in the absence of rHuPH20.
                                                
ii
Halozyme Report R08014.
iii
Halozyme Report R09050.
iv
Halozyme Report R05109.
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The immunogenicity of rHuPH20 has been monitored in a number of clinical trialsv. 
No positive skin reactions were observed when rHuPH20 was administered to 
100 healthy volunteers in a skin allergy clinical trial.35 In Study 160603, a total of 
13 subjects had at least one plasma sample that tested positive for rHuPH20-binding 
antibodies (positivity defined as a sample with a titer of ≥160) following HyQvia 
treatment. The peak of the observed positive titers ranged from 160 up to 81,920 and 
have declined during the long-term extension study despite continued exposure to 
rHuPH20.  None of these samples contained neutralizing antibodies. No local or systemic 
reactions were attributed to the presence of rHuPH20 antibodies. Based upon data 
available to date, including data from long-term exposure in Study 160902 (63 subjects 
received HyQvia for a total number of 187.7 subject-years), the incidence of the 
formation of anti-rHuPH20 binding antibodies is 18%, no neutralizing antibodies have 
been observed, no clinical signs or symptoms have been associated with positive anti-
rHuPH20 binding antibody titers. In addition, there was no evidence of a lack of 
treatment effect when rHuPH20-binding antibodies were detected.
Antibodies reactive to rHuPH20 have also been identified in the normal population with a 
prevalence between 3 and 12%.36 No signal of associated infertility or 
autoimmune/inflammatory condition could be identified.
Non-clinical data for rHuPH20 or antibodies to rHuPH20 reveal no special hazard for 
humans based on conventional studies of safety pharmacology, repeated dose toxicity and 
developmental toxicity. Reversible effects on fertility have been reported in male and 
female guinea pigs immunized to produce antibodies to hyaluronidase. However, 
antibodies to hyaluronidase did not influence reproduction in mouse, rabbit, sheep, or 
cynomolgus monkey. 
6.2 Clinical Condition/Indication 
Primary antibody deficiencies are characterized by decreased serum levels of 
immunoglobulin isotypes and increased susceptibility to infection by various 
microorganisms, including encapsulated bacteria. Treatment with immunoglobulins is 
indicated whenever there is a defect in antibody production, regardless of the actual level 
of IgG. Studies have clearly demonstrated that antibody replacement reduces the number 
and severity of patients’ symptoms and infections as immunoglobulins are able to 
neutralize infectious agents, enhance phagocytosis, and modulate the immune response. 
Antibody replacement can be accomplished either intravenously or subcutaneously.
                                                
v
Halozyme Report Number 10059.
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6.3 Findings from Nonclinical and Clinical Studies
Clinical Study 160602
6.3.1
Phase I/II Determination of the Dose of Recombinant Human Hyaluronidase 
Required Enabling up to 600 mg/kg Body Weight of Immune Globin Intravenous 
(Human) 10% to be Administered Subcutaneously in a Single Infusion Site in 
Subjects with Primary Immunodeficiency Disease
This study was a prospective, open-label, non-controlled, two-arm, multicenter study 
with the aim of determining the dose of rHuPH20 necessary to infuse a full four-week 
dose of IGIV 10% in a single SC site with good tolerability.37 An infusion was defined as 
having been tolerated if it caused no more than mild local adverse drug reactions (ADRs) 
(e.g., minimal swelling, redness, or pain) that the investigator did not assess as 
unacceptable for other medical reasons. All infusions were administered at the study site. 
A total of 11 adult subjects (four male, seven female) participated in the study. In Study 
Arm 1, four adult/adolescent subjects received only SC infusions of IGIV 10% to 
determine tolerability. After this initial assessment of tolerability, seven subjects (five 
female and two male) were enrolled in Study Arm 2 for determination of tolerability of 
SC infusions as described for Study Arm 1 and comparison of PK parameters obtained 
after IV and SC administration of IGIV 10% in the initial phase of Study Arm 2. 
The only severe and potentially life-threatening adverse event (AE) that occurred in the 
study was an anaphylactic reaction that was attributed to an antibiotic drug taken 
immediately prior to onset of the symptoms. This serious adverse event (SAE) occurred 
more than 24 hours after an infusion and was not considered related to use of the study 
drugs by the investigator. The subject continued in the study without further reactions. 
All other AEs, which occurred in four subjects in Study Arm 1 and six of seven subjects 
in Study Arm 2, were non-serious local AEs, of which the majority were mild and none 
were severe. Local AEs included infusion site erythema, infusion site pain, infusion site 
edema, infusion site warmth, injection site pruritus, infusion site swelling, and symptoms 
categorized as infusion site reactions. 
The primary safety endpoint was the proportion of SC infusions, which were not 
interrupted or stopped due to AEs. Two SC infusions, one in each study arm, had to be 
interrupted due to mild infusion site pain and mild chest pain, respectively. In one subject 
in Study Arm 2, the infusion rate had to be decreased due to a mild infusion site reaction. 
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In conclusion, this study of SC use of IGIV 10% facilitated by prior injection of 
rHuPH20 yielded initial favorable results in terms of tolerability of a full four-week dose 
of IGIV 10% administered by SC infusion in a single infusion site and in terms of 
bioavailability of IgG after SC administration.
Clinical Study 160603
6.3.2
Efficacy, Tolerability and Pharmacokinetic Comparison of Immune Globulin 
Intravenous (Human) 10% (GAMMAGARD LIQUID, KIOVIG) Administered 
Intravenously or Subcutaneously Following Administration of Recombinant Human 
Hyaluronidase (rHuPH20) in Subjects with Primary Immunodeficiency Diseases
Study 160603 was a prospective, open-label, non-controlled, multi-center, Phase III 
study.38 The purpose of the study was to develop a SC treatment option for subjects with 
PIDD that allows SC administration of GAMMAGARD LIQUID/KIOVIG at the same 
frequency as IV administration. The study consisted of two study parts:
Study Epoch 1: IV treatment with GAMMAGARD LIQUID/KIOVIG
Study Epoch 2: SC treatment with GAMMAGARD LIQUID/KIOVIG after 
administration of 75 U/g IgG rHuPH20 at three- or four-week treatment intervals
Study Arm 1 was comprised of subjects who previously participated in Study 160601 and 
wished to also participate in this follow-up study; these subjects only completed Study 
Epoch 2. Study Arm 2 comprised all other subjects; these subjects completed Study 
Epoch 1 and Study Epoch 2.
Eighty-nine subjects were enrolled in the study, of which 87 were treated via both IV and 
SC routes. Eighty-four subjects completed Study Epoch 1 and 68 subjects completed 
Study Epoch 2. Sixteen subjects withdrew or were discontinued from the study, including 
three subjects who withdrew during the ramp-up period at the beginning of HyQvia
treatment. Four adults withdrew due to local pain and swelling; in two of these subjects, 
the swelling extended from the abdominal site to the genitalia, causing transient 
discomfort. In one of the subjects, the swelling was accompanied by erythema. One 
other subject withdrew due to a perceived increase in infections. 
Of the 1,359 SC infusions with rHuPH20 during the ramp-upvi period and Epoch 2, 
90.1% were administered in the abdomen and 8.6% in the thighs. 
                                                
vi
The treatment intervals and doses used for the initial infusions were gradually increased during the first 
weeks of treatment (referred to as the ramp-up), in order to allow the subjects to adjust to increasing 
volumes administered SC.
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The median duration of individual infusions was similar or lower when GAMMAGARD 
LIQUID/KIOVIG was administered SC with rHuPH20 than for IV administration. The 
percentage of subjects who had no infusions that required a reduction in flow rate, 
interruption, or had to be stopped due to tolerability concerns or AEs was similar between 
SC infusions with rHuPH20 (84.0%) and IV administration (88.5%).
The rate of infusions temporally associated with systemic AEs was lower for SC 
administration with rHuPH20 compared to IV administration, whereas the rate of 
infusions temporally associated with local AEs was higher for SC administration with 
rHuPH20. The trend toward less frequent systemic AEs and more frequent local AEs 
during SC administration with rHuPH20 compared to IV treatment was also evident in 
the nature of AEs reported in Medical Dictionary for Regulatory Activities (MedDRA)
Preferred Terms. Of the AEs in Epoch 1 that were considered by the investigator to be 
possibly or probably related to GAMMAGARD LIQUID/KIOVIG, the most common 
were headache, chills, nausea, fatigue, pyrexia, and vomiting. The most common AEs 
possibly or probably related to both GAMMAGARD LIQUID/KIOVIG and rHuPH20 in 
Epoch 2 (excluding the ramp-up) were infusion site pain, infusion site erythema, infusion 
site discomfort, headache, infusion site pruritus, infusion site edema, and infusion site 
swelling. No severe headache was related to SC infusions with rHuPH20. AEs possibly 
or probably related to rHuPH20 but not GAMMAGARD LIQUID/KIOVIG in Epoch 2 
(excluding the ramp-up) included infusion site pain and infusion site pruritus. The 
majority of AEs were mild; very few severe AEs occurred. All SAEs were assessed as 
unrelated to the study drugs. A comparison of data from the present study and Study 
160601 demonstrated no appreciable differences in the median rates of AEs temporally 
associated with or related to either or both study drugs. 
GAMMAGARD LIQUID/KIOVIG administered SC with rHuPH20 at 108% of the 
IV dose was effective in preventing bacterial infections in pediatric and adult subjects 
with PIDD. Analysis of the secondary endpoints demonstrated that GAMMAGARD 
LIQUID/KIOVIG given SC with rHuPH20 had higher bioavailability as determined by 
AUC per dose/kg than when infused SC without rHuPH20. Compared to IV infusion, 
SC administration with rHuPH20 was administered at the same dosing interval and 
resulted in similar IgG trough levels while eliciting fewer systemic ARs. Furthermore, 
SC infusion with rHuPH20 was the subjects’ preferred mode of treatment with 
GAMMAGARD LIQUID/KIOVIG.
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6.3.2.1 Pharmacokinetic Properties
With administration of HyQvia, peak serum IgG levels are achieved in the recipient’s 
circulation after a delay of approximately three to five days.
Data from the clinical trial of HyQvia show that serum IgG trough levels can be 
maintained by dosing regimens of 320 to 1,000 mg/kg BW/four weeks given at intervals 
of three or four-weeks.
The PKs of HyQvia was evaluated in this Phase 3 efficacy and safety study in 60 patients 
with PIDD aged 12 years and older. The pharmacokinetic results are presented in the 
table below, as compared to data for IV administration of IGI 10% obtained in the same 
study.
Table 1
Pharmacokinetic Parameters of HyQvia Compared to 
Intravenous Administration of IGI 10%
Parameter
HyQvia
Median (95% Cle)
N=60
IGIV, 10%
Median (95% Cl)
N=68
Cmax
a[g/l]
15.5 (14.5; 17.1)
21.9 (20.7; 23.9)
Cmin
b [g/l]
10.4 (9.4 to 11.2)
10.1 (9.5 to 10.9)
AUCc per week [g*days/l]
90.52 (83.8 to 98.4)
93.9 (89.1 to 102.1)
Tmax
d [days]
5.0 (3.3 to 5.1)
0.1 (0.1 to 0.1)
Apparent clearance or clearance [ml/kg/day]
1.6 (1.4 to 1.79)
1.4 (1.2 to 1.4)
Terminal half-life [days]
45.3 (41.0 to 60.2)
35.7 (32.4 to 40.4)
a
Concentration maximum.
b
Concentration minimum.
c
Area under the curve.
d
Time to maximum concentration.
e
Confidence interval.
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Clinical Study 160902
6.3.3
Long-Term Tolerability and Safety of Immune Globulin Subcutaneous (IGSC) 
Solution Administered Subcutaneously Following Administration of Recombinant 
Human Hyaluronidase (rHuPH20) in Subjects with Primary Immunodeficiency 
Diseases
The purpose of the study was to assess the long-term safety, tolerability, and 
practicability of the SC treatment with IGI, 10% facilitated with rHuPH20 in subjects 
with PIDD who have completed Baxter Clinical Study Protocol 160603. The primary 
objective of this study was to evaluate the long-term tolerability and safety of IGI, 10%
given SC after an SC administration of rHuPH20 in subjects with PIDD. The secondary 
objectives included: monitoring the long-term efficacy of IG, 10% given SC after an 
administration of rHuPH20 in subjects with PIDD, evaluating the effect of varying the 
dose frequency of IG, 10% rHuPH20 on IgG trough levels and assessing the 
practicability of treating PIDD with IGI, 10% given SC after an administration of 
rHuPH20 when treatment occurs in a home treatment environment.
In Study 160902, subjects began on the same doses of IGI, 10% and rHuPH20 that were 
used for the last infusions in Study Epoch 2 of Study 160603.  In order to pursue the 
secondary objective “effect of varying the dose frequency of IGI, 10%/rHuPH20 on IgG 
trough levels”, subjects were requested to change their drug administration interval to a 
two-week drug interval (receiving a two-week dose) from a three- or four-week drug 
administration interval, provided both the subject and the investigator agreed that the 
change was appropriate. This new treatment interval started after three infusions on the 
three or four-week interval and was maintained for a minimum of four months.  It was
intended to allow for evaluation of whether a more frequent administration of IGI, 10%
leads to improved IgG trough levels. After the four-month trial period, subjects could
revert to their previous dose interval or continue on the two-week interval, depending on 
the subject’s preference.
On 01 August of 2012, the FDA requested administration of rHuPH20 drug product in all 
ongoing HyQvia clinical studies in the US to be suspended and patients were switched to 
treatment with KIOVIG/GAMMAGARD LIQUID only (Protocol Amendment 5).  
Subjects were treated with conventional IGIV or IGSC for 24 weeks, or, for those who 
had anti-rHuPH20 antibody titers ≥160 at the time rHuPH20 was discontinued, for 
48 weeks.
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6.3.3.1 Disposition of Subjects
Sixty-six subjects were screened for eligibility to participate in this study. Out of the 
66 patients who rolled over from Study 160603 into 160902, 63 subjects were treated 
with IGSC, 10% with rHuPH20; three subjects received IGIV, 10%. Of the 63 subjects 
under IGSC, 10% with rHuPH20 treatment, 15 withdrew or were discontinued from the 
study; 48 switched to the Safety Follow-up when Protocol Amendment 5 went into effect. 
Of the 15 subjects discontinued from IGSC, 10% with rHuPH20, four withdrew, one
subject died, one subject had bone marrow transplant, six subjects had their clinical site 
closed out by sponsor, and three had their site elected to exit study. Of the 48 subjects 
switched to the Safety Follow-up period, one subject withdrew after experiencing an AE. 
In total, 50 subjects completed the study: 47 subjects from the Safety Follow-up and three
subjects who received IGI, 10% IV or SC without rHuPH20 throughout the study. The 
majority of enrolled subjects were in the age range category of 16 to <65 years (47 out of 
66), followed by 65 years and older (eight subjects), seven subjects in the range of 12 to 
<16 years and four subjects in the range of two to <12 years. The median age was 
43.0 years. Of the 66 subjects who met all inclusion/exclusion criteria, 50 (75.8%) 
completed the study.
6.3.3.2 Extent of Exposure
IGSC, 10% with rHuPH20 was administered to 63 subjects prior to the Safety Follow-up 
period for a median treatment duration of 669 days (range: 60-729 days) and a mean 
(± SD) of 565.9 ± 211.8 days. The mean (± SD) dose received per week, per body mass, 
was 0.156 ± 0.051 g/kg/week. Across all age groups, the median initial rate of 
IGSC, 10% infusion with rHuPH20 was 10 mL/hr (range: 5-300) and the median 
maximum rate of infusion achieved was 300 mL/hr (range: 10-350). Across all age 
groups and infusion intervals, a median number of 1.09 infusions/month (range: 0.3-2.1) 
was administered. IGSC, 10% with rHuPH20 treatment required a median number of 
1.58 infusion sites/month (range 0.3-4.2) across all age groups and infusion intervals. For 
the majority of subjects in this study (41/66; 62.1%), the four-week infusion interval was 
the most frequently followed infusion interval. The two-week infusion interval was the 
most frequent interval for 15/66 (22.7%) subjects and 7/66 (10.6%) subjects most 
frequently followed a three-week infusion interval.
6.3.3.3 Efficacy
Analysis of the efficacy results in this study indicates that rHuPH20-facilitated SC 
treatment with IGI, 10% is efficacious in the treatment of adult and pediatric subjects 
with PIDD, in terms of IgG trough levels, infection rates, and patient-related outcomes.
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Two validated acute serious bacterial infections (VASBIs) occurred in 66 subjects under 
IGSC, 10% treatment with rHuPH20. The annual rate of VASBIs was statistically 
significantly lower than the threshold specified as providing substantial evidence of 
efficacy. 
The point estimate for the annualized rate of all infections was 2.86 (95% Confidence 
Interval [CI]: 2.36-3.43) during IGSC, 10% with rHuPH20 treatment.
IgG trough levels maintained under IGSC, 10% with rHuPH20 treatment did not 
substantially vary with infusion interval changes and were lower with the longest 
(four-week) infusion interval (median steady-state trough level: 10.90 g/L (two-week 
interval), 12.30 g/L (three-week interval), 9.76 g/L (four-week interval). 
Percent change of steady-state trough levels was 105.90% (mean and median) for 
subjects who switched from a three-week to a two-week infusion interval and a mean of 
113.23% (median 112.44%) for subjects who switched from a four-week to a two-week 
infusion interval.
The point estimate for the annualized rate of days off school/work was less than 
eight days per year. The rate of days on antibiotics was less than 65 days per year. The 
rate of hospitalizations was less than one per year and the rate of days hospitalized, less 
than one day per year. The rate of acute physician visits due to infection or other illness 
was less than five visits per year.
6.3.3.4 Safety
rHuPH20-facilitated SC treatment with IGI, 10% was safe and well tolerated by adult and 
pediatric subjects with PIDD.
No SAEs occurred that were considered by the investigator to be related to either of the 
study drugs. In total, 11 subjects experienced SAEs during the study. One subject 
experienced an SAE after study completion.
Throughout the study, the proportion of infusions requiring adjustment for tolerability 
concerns or for AEs was low (0.1% of infusions stopped, 0.6% of infusions interrupted; 
1% infusion rate reduced). 
The most common related AEs under IGSC, 10% treatment facilitated by rHuPH20 were 
infusion site pain, infusion site pruritus, nausea, myalgia, infusion site erythema, 
headache, fatigue, asthenia, chills, infusion site discomfort, and pain. 
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The rate of all AEs related to IGI, 10%, by infusion, was 0.13 during rHuPH20-facilitated 
IGSC, 10% treatment administration, and 0.22 during the Safety Follow-up period. 
During rHuPH20-facilitated IGSC, 10% treatment, the rate of all AEs related to 
rHuPH20, by infusion, was 0.01 and the rate of all AEs related to both IGI, 10% and 
rHuPH20 by infusion, was 0.06.
The rate of all causally related AEs by infusion was 0.20 during rHuPH20-facilitated 
IGSC, 10% treatment administration. The rate of all causally-related local AEs, by 
infusion, was 0.10 during rHuPH20-facilitated IGSC, 10% treatment administration. 
During rHuPH20-facilitated IGSC, 10% treatment, the rate of related systemic AEs by 
infusion, including or excluding infections was 0.1.
The rate of all temporally-associated AEs by infusion was 0.28 during 
rHuPH20-facilitated IGSC, 10% treatment. The rate of all temporally-associated local 
AEs by infusion was 0.10 during rHuPH20-facilitated IGSC, 10% treatment. During 
rHuPH20-facilitated IGSC, 10% treatment, the rate of temporally-associated systemic 
AEs by infusion including infections was 0.18 and excluding infections was 0.16. 
Throughout the study, 7.4 % of infusions were associated with one or more local AEs.
No subjects developed neutralizing antibodies in the entire duration of the follow-up 
including data obtained in Study 160603 starting with first exposure to IGSC, 10% 
facilitated by rHuPH20 and in Study 160902. 
A total of 13/66 subjects had anti-rHuPH20 antibody titers ≥160 in Study 160902. 
Eleven subjects had developed anti-rHuPH20 antibody titers ≥160 in Study 160603. Two 
subjects each newly developed one anti-rHuPH20 antibody titer of 160 in Study 160902. 
In the majority of subjects with anti-rHuPH20 antibody titers ≥160, the titers declined 
over time during IGSC, 10% with rHuPH20 treatment.
Assessment of hematology parameters, clinical chemistry parameters, urinalysis and 
specific antibody tests and viral pathogen serology did not raise any safety concerns with 
respect to the SC administration of IGI, 10% with rHuPH20.
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Clinical Study 161101 
6.3.4
Tolerability, Safety and Administration Mode Evaluation of rHuPH20 Facilitated 
Subcutaneous Treatment with Immune Globulin Infusion (Human), 10% in 
Subjects with Primary Immunodeficiency Diseases
This US study was a Phase 2/3, prospective, non-controlled, multicenter study to evaluate 
tolerability and safety and other parameters of SC treatment using Immune Globulin 
Infusion (Human), 10% (IGI, 10%. IGI, 10% is the same product as IGIV 10% licensed 
in the EU as KIOVIG) with rHuPH20 in a total of approximately 60 PIDD subjects 
already pre-treated with immunoglobulin products (Gamunex administered IV, Hizentra 
or Privigen). 
PIDD patients already on IV or SC treatment were enrolled and treated with IGI, 10% 
and rHuPH20 subcutaneously with a dose/interval ramp-up of three weeks. The ramp-up 
period was Epoch 1.
The ramp-up was followed by Epoch 2, a six month period of IGSC, 10% with rHuPH20 
treatment:
For IV-pretreated subjects: every three weeks or four weeks, depending on the 
subject’s previous IV dosing schedule
For SC-pretreated subjects: every three weeks or four weeks, at the discretion of 
investigator and subject
The rHuPH20 administration was discontinued as of 01 August 2012 at the request of the 
FDA. Those subjects who did not withdraw from the study completed the planned 
infusions using conventional IGIV or IGSC. The last subject completed the study on 
04 January 2013. 
A total of 37 subjects started the treatment. All but one of the subjects reached Epoch 2. 
During Epoch 2, nine subjects withdrew. At the time when rHuPH20 administration was 
stopped, one subject had completed Epoch 2. The remaining 26 were switched to 
Epoch 3. During Epoch 3, two subjects withdrew, 24 completed Epoch 3. Thus, 
25 subjects including the one subject who completed Epoch 2 without ever reaching 
Epoch 3 completed the study. 
Analysis of the efficacy results in this study indicate that rHuPH20-facilitated SC 
treatment with IGI, 10% was efficacious in the treatment of adults and pediatric subjects 
with PIDD, in terms of IgG trough levels, infection-rates, and subject related outcomes.
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Trough levels of total IgG at the end of Epoch 2 (geometric mean: 9.21 g/L [95% CI: 
8.28-10.25]) were comparable to the levels measured at screening (geometric mean:
10.53 g/L [95% CI: 9.46-11.73]). 
No serious bacterial infections were reported in any subject throughout the study. The 
point estimate for the rate of all infections per year was 2.45 for Epoch 1 and Epoch 2 
combined.
The point estimate for the rate per month of days off either from work, school, or daily 
activity was less than one day/month. The rate of days on antibiotics was less than three
days/month. No subjects were hospitalized during the study period and the rate of acute 
physician visit due to infection or other illness was less than one visit/month.
Analysis of the mode of infusion was inconclusive due to the premature stop of subject 
enrollment and early termination of Epoch 2, however the following results were 
observed.
Median number of infusions per month: 2.90 in Epoch 1; 1.09 in Epoch 2. Median 
number of infusion sites (needle sticks) per infusion/month: 2.90 in Epoch 1; 1.12 in 
Epoch 2. Median duration of infusion: less than two hours. Median maximum infusion 
rate: 240mL/h in Epoch 1; 300mL/h in Epoch 2. 
Treatment with IGI, 10% when administrated either SC with rHuPH20 (Epochs 1 and 2) 
or SC without rHuPH20 or IV (Epoch 3) was safe and well tolerated. No SAEs occurred 
that were considered by the investigator to be related to either of the study drugs.
During Epoch 1 and Epoch 2 combined, 59 related systemic AEs occurred. The rate of 
related systemic AEs/infusion, excluding infections (primary outcome) was 0.326 
(95% CI: 0.186-0.522) and the rate per number of subjects was 37.8% (14/37), for 
Epochs 1 and 2 combined. The rate per infusion of local AEs (including infections) 
related to IGI, 10% was 0.066 in Epoch 1, 0.028 in Epoch 2 and 0.006 in Epoch 3. 
The rate of local AEs related to rHuPH20 per infusion was 0.039 in Epoch 1 and 0.038 in 
Epoch 2. The rate of local AEs related to both rHuPH20 and IGI, 10% per infusion was 
0.776 in Epoch 1 and 0.745 in Epoch 2.
According to MedDRA preferred term classification, the most common AEs related to 
IGI, 10% with rHuPH20 in both Epoch 1 and Epoch 2 were “infusion site pain”, 
“infusion site erythema”, and “infusion site swelling”.
No patient developed neutralizing anti-rHuPH20 antibodies in the course of the study. 
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Assessment of hematology parameters, clinical chemistry parameters, and urinalysis did 
not raise any safety concerns with respect to the SC administration of IGI, 10% with 
rHuPH20.
HyQvia Pregnancy Registry 161301
6.3.5
Pregnancy Registry to collect Long-Term Safety Data from Women treated with 
HyQvia (Immune Globulin (Human) 10% with rHuPH20
This study is an ongoing non-interventional, prospective, uncontrolled, two-arm, open-
label, multicenter post-authorization pregnancy registry. Subjects who prior to the study 
received HyQvia and at enrollment receive a licensed human normal immunoglobulin 
other than HyQvia or an alternative treatment during the study are assigned to Study 
Arm 1 (Alternative Product Arm); subjects in countries where HyQvia treatment during 
pregnancy is not indicated are enrolled in this arm. Subjects who continue treatment with 
HyQvia during pregnancy are followed in Study Arm 2 (HyQvia Arm).
The study is conducted in the European Economic Area, North America, and other 
countries where the product is licensed, as needed. This pregnancy registry with regular 
assessment of antibodies against rHuPH20 was a commitment to the Committee for 
Medicinal Products for Human Use (CHMP) and the FDA in the course of the HyQvia
Marketing Authorization Procedure. Further data shall be collected to evaluate safety of 
women who become pregnant during or after treatment with HyQvia as well as the 
physical and neurological development of the infant during the first two years of life.
The primary objective is to collect and assess clinical safety data regarding the possible 
effects of HyQvia on the course and outcome of the pregnancy, and on the growth and 
development of the fetus/infant. The secondary objectives are to collect any laboratory 
safety data and additional safety assessments obtained during the clinical management of 
the pregnancy or in the evaluation of the fetus in utero and the infant post-partum.
In this registry pregnant women ever treated with HyQvia will be enrolled. In the 
European Union (EU) the therapeutic indications for HyQvia are PIDD, CLL, and 
myeloma. In the USA, HyQvia is licensed for the treatment of PIDD. Although the target 
population consists mainly of women treated for the approved indications in the 
respective country, any woman who becomes pregnant after being exposed to HyQvia
will be encouraged to participate in the registry.
Visits to the investigator (for example immunologist) and all other medical care will 
be performed as is standard for the site and for the subject’s healthcare. 
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However, the pregnant subject will be invited to return approximately every three months 
to the site for blood samples to be taken to assess antibodies against rHuPH20, as 
requested by the CHMP and the FDA.
As soon as the patient becomes aware of the pregnancy, she should inform the treating 
physician. According to her treatment, the subject enters the study in one of the following 
two Study Arms.
Study Arm 1 (Alternative Product Arm): Subjects who stop treatment with HyQvia will 
be followed in Study Arm 1. The treating physician of the pregnant woman prescribes a 
licensed human normal immunoglobulin other than HyQvia for IV or SC infusion or an 
alternative treatment, at his/her discretion. 
Study Arm 2 (HyQvia Arm): Subjects who continue treatment with HyQvia according to 
their treatment regimen will be followed in Study Arm 2.
The overall duration of the study is approximately six years from study initiation 
(Registry ready to enroll) to study completion (i.e., end data collection). The enrollment 
period is expected to be three years. The participation period for the pregnant woman is 
from enrollment to study completion/termination visit after the delivery/end of 
pregnancy. The participation period for the infant is from enrollment until the age of 
two years to assess the development, unless prematurely discontinued.
HyQvia PASS 161302
6.3.6
Non-Interventional Post-Authorization Safety Study on the Long-Term Safety of 
HyQvia in Subjects treated with HyQvia
This is a non-interventional, prospective, uncontrolled, multi-center, open-label, 
post-authorization safety study (PASS) in the European Economic Area. The Post-
Authorization Safety Surveillance was a commitment to the CHMP in the course of the 
HyQvia Marketing Authorization Procedure. 
The purpose of the study is to acquire additional data (including the assessment of anti-
rHuPH20 antibodies) on the long-term safety of HyQvia and to assess the prescribed 
treatment regimens and treatment administration in routine clinical practice.
The primary objective is to collect and assess safety data, in particular the occurrence of 
long-term changes in incidence and severity of related AEs in patients treated with 
HyQvia. 
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Secondary objectives are to collect data on the prescribed treatment regimen, 
anti-rHuPH20 antibodies and, as available, other laboratory safety assessments, total IgG, 
further safety assessments that are obtained during the routine clinical management of the 
subjects, treatment administration, and health-related quality of life (HRQoL) and health 
resource use assessments (optional).
Adult patients (≥ 18 years) who have been prescribed treatment with HyQvia are
enrolled. Treatment regimens are prescribed at the discretion of the attending physician in 
accordance with routine clinical practice. Visits to the investigator and all other medical 
care are performed as is standard for the site and for the subject´s healthcare. In addition, 
however, the subject is requested to have additional blood samples drawn at the time of 
routine laboratory assessments approximately every three months, but no more often than 
four times a year, for the measurement of antibodies against rHuPH20.
The overall duration of the study is approximately six years from study initiation (i.e., 
first subject enrolled) to study completion (i.e., last subject last visit). The recruitment 
period is expected to be approximately three years. Enrollment started in Q3 2014. The 
subject participation period is approximately three to six years from enrollment to subject 
completion (i.e., study termination/completion visit), depending on the time point of 
enrollment, unless prematurely discontinued. It is anticipated that approximately 80 to 
120 subjects will be eligible for enrollment in this study.
HyQvia Study 161406
6.3.7
Non-Interventional Post-Marketing Safety Study on the Long-Term Safety of 
HyQvia (Global)
This prospective, uncontrolled, multi-center, open-label, post- HyQvia marketing 
authorization surveillance study with assessment of anti-rHuPH20 antibodies was agreed 
upon with the FDA in the course of the HyQvia Biologic License review and approval 
process.
The purpose of the study is to acquire additional data (including the assessment of 
anti-rHuPH20 antibodies) on the long-term safety of HyQvia and to assess the prescribed 
treatment regimens and treatment administration in a total of 250 adult evaluable subjects 
with PIDD under routine clinical conditions. Further data shall be collected in subjects 
with an anti-rHuPH20 antibody titer ≥ 160.
The primary objective is to collect and assess safety data, in particular the occurrence of 
long-term changes in incidence and severity of related AEs in patients treated with 
HyQvia.
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Secondary objectives are to collect data on anti-rHuPH20 antibodies and, as available, 
other laboratory safety assessments, total IgG, further safety assessments that are 
obtained during the routine clinical management of the subjects, the prescribed treatment 
regimen, treatment administration, HRQoL and health resource use assessments.
6.4 Evaluation of Anticipated Risks and Benefits of the Investigational Product(s) to 
Human Subjects
HyQvia
6.4.1
The clinical development program for HyQvia has demonstrated that IGI, 10% 
administered via SC treatment with rHuPH20 is efficacious and safe in persons with 
PIDD. The safety, tolerability, efficacy and bioavailability of HyQvia were investigated 
in one pivotal Phase III study (160603), an extension study (160902) in patients with 
PIDD. One supportive clinical study (160602) in patients with PIDD using Gammagard 
Liquid administered subcutaneously was also conducted. Further information is provided 
in the SmPC for HyQvia.
The most common ARs observed in PIDD clinical trials in >5% of subjects were: local 
reactions, headache, antibody formation against rHuPH20, fatigue, nausea, pyrexia, and 
vomiting.
The safety and efficacy of chronic use of the rHuPH20 solution in HyQvia has not been 
established in conditions other than PIDD. Study 160603 compared the efficacy, PKs, 
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 PIDD receiving 
IGI, 10% with rHuPH20 in 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. 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.
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6.4.1.1 Pregnancy, Breast Feeding, Fertility
Subcutaneous immunoglobulin G (SCIG) products have been shown to cross the 
placenta, increasingly during the third trimester. Clinical experience with 
immunoglobulins suggests that no harmful effects on the course of pregnancy, or on the 
fetus and the neonate are to be expected. Development and reproductive toxicology 
studies have been conducted with rHuPH20in mice and rabbits. No adverse effects on 
pregnancy and fetal development were associated with anti-rHuPH20 antibodies. In these 
studies, maternal antibodies to rHuPH20were transferred to offspring in utero. The effects 
of antibodies to the rHuPH20component of HyQvia on the human embryo or on human 
fetal development are currently unknown. Immunoglobulins are excreted into the milk 
and may contribute to protecting the neonate from pathogens which have a mucosal 
portal of entry.
The safety of HyQvia for use in human pregnancy has not been established in controlled 
clinical trials and therefore should only be given with caution to pregnant or 
breastfeeding women.
There are currently no clinical safety data for HyQvia on fertility available. Clinical 
experience with immunoglobulins suggests that no harmful effects of IG 10% on fertility 
are to be expected. Animal studies do not indicate direct or indirect harmful effects of 
rHuPH20 with respect to reproductive potential at the doses used for facilitating 
administration of IG 10%.
Subjects who become pregnant during the study should be withdrawn from the study and 
recommended to participate in the HyQvia Pregnancy Registry (Study 161301), if 
available in the respective country.
See Section 6.4.2 for the known risks associated with IGI, 10%.
KIOVIG
6.4.2
IGI, 10% administered via IV treatment (KIOVIG) is efficacious and safe in the 
particular fields of therapeutic use and approved indications, i.e., PIDD, ITP and MMN, 
as demonstrated in the clinical development program for KIOVIG. Please see the SmPC
for KIOVIG.
Serious ARs (defined as SAEs occurring during or within 72 hours of infusion or any 
casually related SAE occurring within the study period) which occurred in the clinical 
trials of KIOVIG were aseptic meningitis, pulmonary embolism, and blurred vision.
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The most common ARs observed in ≥5% of patients were:
PIDD, IV administration: headache, fatigue, pyrexia, nausea, chills, rigors, pain in 
extremity, diarrhea, migraine, dizziness, vomiting, cough, urticaria, asthma, 
pharyngolaryngeal pain, rash, arthralgia, myalgia, edema peripheral, pruritus, and 
cardiac murmur.
PIDD, 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.
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 with immune globulin products, including IGI, 10%. Risk factors 
may include advanced age, prolonged immobilization, hypercoagulable conditions, 
history of venous or arterial thrombosis, use of estrogens, indwelling vascular catheters, 
hyperviscosity, and cardiovascular risk factors.
Renal dysfunction, acute renal failure, osmotic nephrosis, and death may occur in 
predisposed patients receiving immune globulin intravenous (IGIV) products including 
IGI, 10%. Renal dysfunction and acute failure occur more commonly with IGIV products 
containing sucrose. IGI, 10% does not contain sucrose.
IGI, 10% contains blood group antibodies (isoagglutinins) that may cause hemolysis. 
Delayed hemolytic anemia can develop subsequent to IGI, 10% therapy due to enhanced 
red blood cell (RBC) sequestration. Acute hemolysis, consistent with intravascular 
hemolysis, has been reported. The following risk factors may be related to the 
development of hemolysis: high doses (e.g., ≥2 g/kg, single administration or divided 
over several days) and non-O blood group. Underlying inflammatory state in an 
individual patient may increase the risk of hemolysis but its role is uncertain.
Contraindications to IGI treatment include anaphylactic or severe systemic 
hypersensitivity reactions to IG and IgA deficient patients with antibodies against IgA 
and a history of hypersensitivity. 
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IGI, 10% has a high margin of safety. Screening against potentially infectious agents 
begins with the donor selection process and continues throughout plasma collection and 
preparation. Three validated, dedicated, independent, and effective virus 
inactivation/removal steps have been integrated into the manufacturing and formulation 
processes, further increasing the margin of safety. In addition, careful screening and 
monitoring of subjects in this study will be utilized to minimize the above and other 
known risks associated with IG therapy (e.g., exclusion criteria, blood group typing at 
baseline, and laboratory monitoring for hemolysis). 
Further information is provided in the SmPC for KIOVIG.
Cuvitru
6.4.3
Information about Cuvitru is provided in the SmPC.
6.5 Compliance Statement
This study will be conducted in accordance with this protocol, the International Council 
for Harmonisation Guideline for Good Clinical Practice E6 (ICH GCP, April 1996), 
Title 21 of the US Code of Federal Regulations (US CFR), the EU Directives 2001/20/EC 
and 2005/28/EC, and applicable national and local regulatory requirements.
7. STUDY PURPOSE AND OBJECTIVES
7.1 Study Purpose
The purpose of the study is to acquire additional data on safety, tolerability and 
immunogenicity of HyQvia in pediatric (age two to <18 years) subjects with PIDD.
7.2 Primary Objective
The primary objective of the study is to assess the safety of HyQvia treatment in pediatric 
subjects with PIDD who received immunoglobulin therapy prior to study enrollment.
7.3 Secondary Objectives
Secondary objectives of the study are further assessments (e.g. immunogenicity), 
tolerability, characteristic of product administration and efficacy (IgG trough levels).
7.4 Tertiary Objectives
Tertiary objectives are further safety and efficacy assessments. The study objectives are 
described in more detail in Section 11, Section 12, Supplement 20.2 and Figure 1.
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8. STUDY DESIGN
8.1 Brief Summary
This study is a Phase 4, post-authorization, prospective, non-controlled, multicenter study 
to evaluate safety, tolerability, and other parameters of SC treatment using HyQvia in 
approximately 40 pediatric subjects with PIDD who received immunoglobulin therapy 
prior to study enrollment.
The purpose of the study is to acquire additional data on safety, tolerability and 
immunogenicity of HyQvia in pediatric subjects.
8.2 Overall Study Design
The overall study design is illustrated in Figure 1. Details on the procedures to be 
performed at each study visit can be found in Supplement 20.2 Schedule of Study 
Procedures and Supplement 20.3 Clinical Laboratory Assessments. In this study 
approximately 40 pediatric subjects with PIDD will be enrolled, who have received prior 
immunoglobulin therapy. The study will enroll approximately six subjects aged 2 to 
<6 years, 12 subjects 6 to <12 years, and 22 subjects 12 to <18 years of age. The study 
will be conducted in the European Economic Area.
All subjects will have regular anti-rHuPH20 antibody testing (binding and neutralizing 
anti-rHuPH20 antibody) throughout the study (approximately every three months).
Female subjects of childbearing potential should employ birth control measures as 
advised by the investigator or per the site´s standard recommendations for the duration of 
the study.
Epoch 1
8.2.1
Pediatric patients with PIDD who are on non-HyQvia IV or SC treatment with 
immunoglobulin (IV-pretreated, SC-pretreated) will be enrolled and treated with HyQvia 
subcutaneously with a dose or interval ramp-up period of up to six weeks. Subjects 
already treated with HyQvia (HyQvia-pretreated) will be enrolled directly into Epoch 2. 
Epoch 1 infusions will be administered at the study site.
Epoch 2
8.2.2
The ramp-up (Epoch 1) is followed by Epoch 2 with HyQvia treatment at the following 
intervals:
For IV-pretreated subjects: every three or four weeks, depending on the subject’s 
previous IV dosing schedule.
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For SC-pretreated subjects: every three or four weeks, at the discretion of 
investigator and subject.
For HyQvia pre-treated subjects: No change in frequency of administration.
After one year in Epoch 2, the anti-rHuPH20 binding antibody assay results during that 
year will be used to decide the next steps in the study (see Figure 1 Study Flow Chart in 
Supplements):
Subjects with anti-rHuPH20 antibody titer < 160 at all time-points during the study 
will complete the study termination/completion visit at the next possible occasion. 
Subjects with anti-rHuPH20 antibody titer ≥ 160 during the study and/or at the last 
measurement will continue in Epoch 2 for an additional two years of HyQvia 
treatment and observation. 
The first two to three infusions during Epoch 2 will be administered at the study site. It is 
preferable that subsequent infusions be performed at home (or equivalent site), by the 
subject/caregiver, if in the opinion of the investigator, such treatment is safe and 
appropriate. In that case, the investigator/designee must have trained the subject or 
caregiver and must be satisfied that the subject or caregiver is capable of 
self-administration of SC infusions at home before the subject or caregiver will be 
permitted to conduct the SC infusion at home.
Epoch 3
8.2.3
Epoch 3 is up to one year safety follow-up for subjects whose anti-rHuPH20 antibody 
titer was ≥ 160 during Epoch 1 or Epoch 2 and who experience either a related SAE or a 
related severe AE.
In the event that a subject in Epoch 1 or in Epoch 2 experiences a related SAE or severe 
AE without anti-rHuPH20 antibody titer ≥ 160, the subject can (at the discretion of the 
investigator and subject) either be 1) terminated from the study or 2) change directly to 
Epoch 3 or 3) continue in Epoch 1 or 2 with appropriate medical intervention such as 
decreasing the HyQvia infusion rate and/or premedication.
Subjects with antibody titer of ≥ 160 when entering Epoch 3 continue regular 
anti-rHuPH20 antibody testing (approximately every three months) for approximately 
one year or until anti-rHuPH20 antibody titer declines to < 2560 for at least two 
consecutive measurements, whichever comes first. These subjects complete the study 
termination/completion visit when the AE/SAE resolves or the anti-rHuPH20 titer is 
< 2560.
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Subjects in Epoch 3 will be treated with KIOVIG (IGI, 10%) intravenously or Cuvitru
subcutaneously, at the discretion of the investigator and the subject.
Infusions in Study Epoch 3 will be administered at home or at the study site.
The study termination/completion visit will be conducted at the study site.
8.3 Duration of Study Period(s) and Subject Participation
The overall duration of the study is approximately five years from study initiation (i.e., 
first subject enrolled) to study completion (i.e., last subject last visit). The recruitment 
period is expected to be one year. 
The maximum subject participation period is approximately four years from enrollment 
to subject completion (i.e., study termination/completion visit), unless prematurely 
discontinued.
8.4 Outcome Measures
Primary Outcome Measure
8.4.1
1. Number and rate per infusion (excluding infections) of all severe related AEs
2. Number and rate per infusion (excluding infections) of related SAEs
Secondary Outcome Measures
8.4.2
8.4.2.1 Efficacy 
1. Trough levels of IgG (for Study Epoch 1 and 2)
8.4.2.2 Safety/Tolerability
1. Proportion of subjects who achieve a treatment interval of three or four weeks in 
Epoch 2 
2. Proportion of subjects who maintain a treatment interval of three or four weeks in 
Epoch 2 for 12 months
3. Number and rate per infusion (excluding infections) of local AEs and ARs
4. Number and rate per infusion (excluding infections) of systemic AEs and ARs
5. Number and rate per infusion (excluding infections) of all AEs and all ARs
6. Number and rate per infusion (excluding infections) of all temporally associated 
AEs 
7. Number and rate per infusion (excluding infections) of all causally related and/or 
temporally associated AEs
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8. Number and rate per infusion (excluding infections) of all SAEs 
9. Number/proportion of subjects who develop positive titer (≥160) of binding or 
neutralizing antibodies to rHuPH20
8.4.2.3 Mode of Product Administration
For Study Epoch 1 and 2
1. Infusions
a. Number of infusions per month
b. Number of infusion sites (needle sticks) per infusion/month
c. Duration of infusion
d. Maximum infusion rate/site
e. Infusion volume/site
f. Number/proportion of infusions that are discontinued, slowed, or interrupted 
due to an AE
2. Number of weeks to reach final dose interval (3 weeks or 4 weeks)
3. Assessment of Treatment Preference Questionnaire
4. Assessment of HRQoL Questionnaire: Peds-QL, EQ-5D
Tertiary Outcome Measures
8.4.3
1. Number of acute serious bacterial infections
2. Number of all infections
3. Days not able to go to school or work or to perform normal daily activities
4. Days on antibiotics
5. Number of hospitalizations, indication for the hospitalization (infection or non-
infection) and days hospitalized
6. Number of acute physician visits (office and emergency room) due to infection or 
other illnesses.
Exploratory Outcomes Measure
8.4.4
Not applicable.
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8.5 Randomization and Blinding
This is a nonrandomized, open-label, active treatment clinical study.
8.6 Study Stopping Rules 
Stopping rules will not be established for this study as the pediatric subjects will be 
treated with a licensed human normal immunoglobulin, according to the routine standard 
at the study site, for the duration of the study. 
8.7 Investigational Product(s)
Packaging, Labeling, and Storage
8.7.1
8.7.1.1 rHuPH20
Dosage Form: Injection, solution
Packaging: rHuPH20 drug product (160 U/mL) will be supplied as a clear, colorless, 
ready-for-use sterile liquid preparation in single-use glass vials. The product should be 
inspected visually for particulate matter and discoloration. The product should not be 
used if particulate matter and/or discoloration is observed.
Labeling: The product will be labeled according to the regulatory requirements for 
clinical studies.
Storage: rHuPH20 drug product must be stored under refrigerated conditions (2° to 8°C 
or 36° to 46°F). Do not freeze the product. Do not use if expiration date is exceeded.
8.7.1.2 IGI, 10%
Dosage Form: Injection, solution.
Packaging: IGI, 10% will be supplied as a ready-for-use sterile liquid preparation in 
single-use glass vials. IGI, 10% is a clear or slightly opalescent and colorless or pale 
yellow solution. The product should be inspected visually for particulate matter and 
discoloration. The product should not be used if particulate matter and/or discoloration is 
observed.
Labeling: IGI, 10% will be labeled according to regulatory requirements for clinical 
studies.
Storage: IGI, 10% must be stored under refrigerated conditions (2°C to 8°C or 36°F to 
46°F). Do not freeze the product. Do not use if expiration date is exceeded.
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Prior to use, the vials must be removed from refrigeration and placed at room temperature 
for a minimum of 90 minutes to a maximum of 24 hours to equilibrate and should be kept 
at room temperature during administration. 
If IGI, 10% is pooled in a bag, it must be used as soon as possible, but no longer than 
three hours from the time of pooling. 
8.7.1.3 KIOVIG
Dosage Form: Injection, solution
Packaging: IGIV, 10% will be supplied as a ready-for-use sterile liquid preparation in 
single-use glass vials of 5 g (50 mL) and 10 g (100 mL).
Labeling: The study product will be labeled according to the valid regulatory
requirements for clinical studies.
Storage: Refrigeration. IGIV, 10% must be stored under refrigerated conditions (2° to 
8°C or 36° to 46°F). Do not freeze the product. Do not use if expiration date is exceeded.
Prior to use, the unopened vials must be removed from refrigeration and placed at room 
temperature for a minimum of 90 minutes to a maximum of 24 hours to equilibrate and 
should be kept at room temperature during administration.
8.7.1.4 Cuvitru
Dosage form: Solution for injection
Packaging:
5, 10, 20 or 40 ml of solution in a vial (Type I glass) with a stopper (bromobutyl).
Pack size: 1 vial. Not all pack sizes may be available.
Labeling: The study product will be labeled according to the valid regulatory 
requirements for clinical studies.
Storage and Shelf Life: Do not store above 25°C. Do not freeze the product.
Shelf Life: 2 years. Do not use if expiration date is exceeded. Keep the container in the 
outer carton in order to protect from light. Once opened, use immediately.
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Administration
8.7.2
rHuPH20 will be administered at a dose ratio of 80 U/g IgG before the infusion of IGI, 
10%. The full vial of rHuPH20 associated with each vial of IGI, 10% should be used.
rHuPH20 should be injected at a rate of approximately1-2 mL/min, or faster if tolerated, 
through the same SC needle that will be used to infuse the IGI, 10%.  As soon as the 
rHuPH20 infusion is completed, but no longer than ten minutes after it is completed, the 
administration tubing to deliver IGI, 10% should be connected to the same SC needle set 
used to administer rHuPH20 in order to flush the remaining rHuPH20 into the SC tissue 
and start the infusion of immunoglobulin.
Description of Treatment
8.7.3
8.7.3.1 HyQvia 
Subjects will be treated with HyQvia in Study Epoch 1 and Study Epoch 2.
Dosage Form: Injection
Mode of Administration: subcutaneous
Dosage Frequency:
Study Epoch 1 (Ramp-up):
One treatment interval of one week, then one treatment interval of two weeks, then one 
treatment interval of three weeks (for subjects in whom treatment is expected to be every 
four weeks).
Study Epoch 2 (Final dosing): 
Once every three or four weeks:
For IV-pretreated subjects: every three or four weeks, depending on the subject’s 
previous IV dosing schedule
For SC-pretreated subjects: every three or four weeks, at the discretion of investigator 
and subject
Dose: HyQvia weekly dose will be equivalent to 100% (±5%) of pre-study treatment
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Table 2
Example for IgG dosing
Pre-Study
Epoch 1 
(Ramp-Up)
Epoch 2 
(Final Dose)
Admin. 
Route
Dose
First Infusion 
at Baseline: 
1-Week Dose
Second Infusion 
at Week 1: 
2-Week Dose
Third Infusion 
at Week 3: 
3-Week Dose
IV
0.6 g/kg 
every 3 weeks
0.2 g/kg
0.4 g/kg
-
0.6 g/kg 
every 3 weeks
IV
0.6 g/kg 
every 4 weeks
0.15 g/kg
0.3 g/kg
0.45 g/kg
0.6 g/kg 
every 4 weeks
SC
0.1 g/kg 
every week
0.1 g/kg
0.2 g/kg
-
0.3 g/kg 
every 3 weeks
SC
0.1 g/kg 
every week
0.1 g/kg
0.2 g/kg
0.3 g/kg
0.4 g/kg 
every 4 weeks
Infusion Rate:
Study Epoch 1 (Ramp-up): 
For subjects with a BW of < 40 kg: 5 ml/h/site (at start) to 80 ml/h/site (maximum, 
if tolerated)
For subjects with a BW of ≥ 40 kg: 10 ml/h/site (at start) to 240 ml/h/site 
(maximum, if tolerated)
Study Epoch 2 (Final dosing):
For subjects with a BW of < 40 kg: 10 ml/h/site (at start) to 160 ml/h/site 
(maximum, if tolerated)
For subjects with a BW of ≥ 40 kg: 10 ml/h/site (at start) to 300 ml/h/site 
(maximum, if tolerated)
If infusions have been tolerated after the subject has received two HyQvia infusions at the 
dose for the final infusion interval (three or four week dose), then the investigator may 
choose an infusion rate schedule at his/her own discretion.
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8.7.3.2 KIOVIG
Subjects may be treated with KIOVIG in Study Epoch 3 (Safety Follow-up).
Dosage form: injectable
Mode of Administration: intravenous
The infusion rate and infusion volume per site will follow the suggestions of the KIOVIG
SmPC. 
Dosage frequency: Once every three or four weeks 
Dose: The weekly dose will be equivalent to 100% (±5%) of the dose in the previous 
study Epoch.
8.7.3.3 Cuvitru
Subjects may be treated with Cuvitru in Study Epoch 3 (Safety Follow-up).
Dosage form: injectable
Mode of Administration: subcutaneous
The infusion rate and infusion volume per site will follow the suggestions of the Cuvitru
SmPC. 
Dosage frequency: daily to once every two weeks, at the investigator´s discretion
Dose: The weekly dose will be equivalent to 100% (±5%) of the dose in the previous 
study epoch.
Investigational Product Accountability
8.7.4
The investigator will ensure that the investigational product(s) (IP[s]) are stored as 
specified in the protocol and that the storage area is secured, with access limited to 
authorized study personnel. The investigator will maintain records that the IP(s) was 
received, including the date received, drug identity code, date of manufacture or 
expiration date, amount received and disposition. IP(s) must be dispensed only at the 
study site or other suitable location (e.g. infusion center; home, as applicable per study 
design). Records will be maintained that includes the subject identification code (SIC), 
dispensation date, and amount dispensed. All remaining partially used and/or unused 
IP(s) will be returned to the sponsor or sponsor’s representative after study 
completion/termination, or destroyed with the permission of the sponsor in accordance 
with applicable laws and study site procedures. If IP(s) is to be destroyed, the investigator 
will provide documentation in accordance with sponsor’s specifications.
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8.8 Source Data
Per International Council for Harmonization (ICH) Good Clinical Practice (GCP), source 
data are defined as all information in original records and certified copies of original 
records of clinical findings, observations, or other activities in a clinical trial that are 
necessary for the reconstruction and evaluation of the trial. Source data are contained in 
source documents (original records or certified copies), which may be in paper and/or 
electronic format. Source data for this study comprise, but are not limited to, the 
following: hospital records, medical records, clinical and office charts, laboratory notes, 
memoranda, subjects' diaries or evaluation checklists, outcomes reported by subjects, 
pharmacy dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate copies, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, subject files, and records 
kept at the pharmacy, at the laboratories and at medico-technical departments involved in 
the clinical study.
No data will be entered directly into the electronic case report form (eCRF). 
For additional information on study documentation and eCRFs, see Section 17.2. The use 
of subject diaries is described in Section 10.
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9. SUBJECT SELECTION, WITHDRAWAL, AND DISCONTINUATION
9.1 Inclusion Criteria
Subjects who meet ALL of the following criteria are eligible for this study:
1. Subject must have a documented diagnosis of a form of primary humoral 
immunodeficiency involving a defect in antibody formation and requiring 
gammaglobulin replacement, as defined according to the IUIS (International 
Union of Immunological Societies) Scientific Committee 2015 1 prior to 
enrollment. The diagnosis must be confirmed by the sponsor´s Medical Director 
prior to first treatment with IP in the study.
2.
Subject is at least two and below 18 years of age at the time of screening.
3.
Subject has been receiving a consistent dose of IgG, administered in compliance 
with the respective product information for a period of at least three months prior 
to screening. The average minimum pre-study dose over that interval was 
equivalent to 300 mg/kg BW/four weeks and a maximum dose equivalent to 
1000 mg/kg BW/4 weeks.
4.
Subject has a serum trough level of IgG > 5 g/L at screening.
5.
If female of childbearing potential, subject presents with a negative pregnancy test 
and agrees to employ adequate birth control measures for the duration of the 
study. 
6.
Subject/legally authorized representative is willing and able to comply with the 
requirements of the protocol.
9.2 Exclusion Criteria
Subjects who meet ANY of the following criteria are not eligible for this study:
1.
Subject has a known history of or is positive at screening for one or more of the 
following: hepatitis B surface antigen (HBsAg), polymerase chain reaction (PCR) 
for hepatitis C virus (HCV), PCR for human immunodeficiency virus (HIV) 
Type 1/2. 
2.
Abnormal laboratory values at screening meeting any one of the following criteria 
(abnormal tests may be repeated once to determine if they are persistent):
a. Persistent alanine aminotransferase (ALT) and aspartate amino transferase 
(AST) >2.5 times the upper limit of normal (ULN) for the testing laboratory
b. Persistent severe neutropenia (defined as an absolute neutrophil count [ANC] 
≤500/mm3)
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3.
Subject has anemia that would preclude phlebotomy for laboratory studies, 
according to standard practice at the site.
4.
Subject has an ongoing history of hypersensitivity or persistent reactions 
(urticaria, breathing difficulty, severe hypotension, or anaphylaxis) following IV 
immunoglobulin, SC immunoglobulin, and/or Immune Serum Globulin (ISG) 
infusions.
5.
Subject has severe immunoglobulin A (IgA) deficiency (less than 7.0 mg/dL) with 
known anti-IgA antibodies and a history of hypersensitivity. . 
6.
Subject has a known allergy to hyaluronidase.
7.
Subject has active infection and is receiving antibiotic therapy for the treatment of 
infection at the time of screening.
8.
Subject has a bleeding disorder or a platelet count less than 20,000/µL, or who, in 
the opinion of the investigator, would be at significant risk of increased bleeding
or bruising as a result of SC therapy. 
9.
Subject has severe dermatitis that would preclude adequate sites for safe product 
administration in the opinion of the investigator.
10. Subject has participated in another clinical study involving an IP or 
investigational device within 30 days prior to enrollment or is scheduled to 
participate in another clinical study involving an IP or investigational device 
during the course of this study.
11. Subject is a family member or employee of the investigator.
12. If female, subject is pregnant or lactating at the time of enrollment.
9.3 Withdrawal and Discontinuation
Any subject may voluntarily withdraw (i.e., reduce the degree of participation in the 
study) consent for continued participation and data collection. The reason for withdrawal 
will be recorded on the End of Study eCRF. Assessments to be performed at the
termination visit (including in cases of withdraw or discontinuation) are described in 
Section 10.6 and Supplement 20.2.
Discontinuation (i.e., complete withdrawal from study participation) may be due to 
dropout (i.e., active discontinuation by subject) or loss to follow-up (i.e., discontinuation 
by subject without notice or action). Additionally, the investigator and sponsor have the 
discretion to discontinue any subject from the study if, in their judgment, continued 
participation would pose an unacceptable risk for the subject.
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Subjects also will be withdrawn from treatment or discontinued from further study 
participation for the following reasons:
The subject becomes pregnant. IP exposure will be discontinued. If the subject has 
been exposed to rHuPH20, she will be encouraged to participate in the HyQvia 
Pregnancy Registry (Study 161301), if available in the respective country. If the 
subject declines to enroll in the registry, attempts will be made to follow the subject
through completion of the pregnancy and up to 1 year post-delivery, if feasible. The 
investigator will record a narrative description of the course of the pregnancy and 
its outcome.
The subject begins lactating. IP exposure will be discontinued. The investigator will 
record a narrative description of the course of the baby’s development.
The subject twice consecutively misses administration of IP. 
The subject does not comply with the protocol (per the investigator’s discretion).
The subject develops severe hypersensitivity reactions related to IP administration.
The subject uses prohibited medications (see Section 10.4) during the course of this 
study.
The subject participates in another clinical study involving an IP or device during 
the course of this study.
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10. STUDY PROCEDURES
10.1 Informed Consent
Any patient who provides informed consent (i.e., signs and dates the informed consent 
form and assent form, if applicable. See also Section 16.3) and meets all inclusion and 
none of the exclusion criteria, is considered enrolled in the study and thus becomes a 
subject in the study.
10.2 Subject Identification Code
The following series of numbers will comprise the SIC: protocol identifier (e.g., 090701) 
to be provided by the sponsor, three-digit number study site number (e.g., 002) to be 
provided by the sponsor, and three-digit subject number (e.g., 0003) reflecting the order 
of providing informed consent. For example, the third subject who signed an informed 
consent form at study site 02 will be identified as Subject 090701-020003. All study 
documents (e.g., case report forms [CRFs], clinical documentation, sample containers, 
drug accountability logs, etc.) will be identified with the SIC. Additionally, a uniquely 
coded SIC(s) is permitted as long as it does not contain a combination of information that 
allows identification of a subject (e.g., collection of a subject’s initials and birth date
would not be permitted), in compliance with laws governing data privacy.
10.3 Screening and Study Visits
Screening will comprise all procedures to confirm subject eligibility. The investigator is 
responsible for maintaining a patient identification list that includes all enrolled subjects
which includes the following information: subject´s full name, subject number, and site 
number. The log also will serve to document the reason for screening failure. All 
screening data will be collected and reported in eCRFs, regardless of screening outcome.
If a subject is re-screened, the End of Study eCRF for the prior screening should be 
completed, and a new ICF, new SIC and new eCRF are required for that subject.
The overall study design is illustrated in the Figure 1. Details on the procedures to be 
performed at each study visit, including screening, can be found in Supplement 20.2
Schedule of Study Procedures and Assessments and Supplement 20.3 Clinical Laboratory 
Assessments.
All screening procedures must be completed up to 31 days prior to the first infusion. If a 
subject is scheduled to receive a dose of IgG before eligibility is fully confirmed (eg due 
to the unavailability of lab results), the subject may continue receiving the IgG product 
used prior to enrolment. Subjects may be re-screened once.
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Details on the treatment regimen including dose (total dose in mg/kg BW/week) and the 
infusion interval will be collected. Changes to the treatment regimen, including the 
reason for the change, will also be collected.
In addition, details on product administration such as infusion date and start/stop time, lot 
number, actual volume infused, maximum infusion rate achieved, number and location of 
infusion sites (needle sticks) per infusion, will be collected.
Details of the treatment regimen and product administration, if performed at the site, 
should be recorded on the CRF. Administration details for home treatment should be 
recorded by the subject/subject´s legally authorized representative in the subject diary.
10.4 Medications and Non-Drug Therapies 
The use of all antibiotic therapy must be associated with a corresponding AE, and 
documented accordingly.
The following medications and non-drug therapies are not permitted during the course of 
the study:
Prophylactic treatment with systemic antibacterial antibiotics is not allowed during 
the study. The use of systemic prophylactic antibacterial antibiotics by a subject 
will be considered a protocol deviation. However prophylaxis for viral infections, 
fungi and parasites (including pneumocystis pneumonia) which are not treated by 
immunoglobulin, can be used and should be recorded as concomitant medication. 
Use of Trimethaprim-Sulfamethoxazole for pneumocystis prophylaxis is acceptable 
in doses typical for pneumocystis pneumonia, but not low dose daily therapy that 
can also be used for antibacterial prophylaxis. Brief (less than 72 hours), 
prophylaxis for surgery (including dental procedures) or injury is permitted but 
treatment and indication must be recorded.
Other IGIV or IGSC products
Pre-medication on the day of product administration:
In this study, subjects should not receive pre-medication for SC infusions unless an 
AR of at least moderate severity, not resolving with a reduction in the infusion rate, 
occurs during or after at least two infusions. Should this occur, subjects may be 
pretreated with antipyretics, corticosteroids or antihistamines at the discretion of the 
investigator. Topical anesthetics (e.g., EMLA) may be used if the needle insertion 
was intolerable in prior infusions. Subjects who have a history of using topical 
anesthetics (e.g., EMLA) may use these topical anesthetics for SC infusions. 
The use of such pre-medications should be recorded on the concomitant medication 
record.
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10.5 Subject Diary
An electronic subject diary will be provided to each subject/caregiver at enrollment to 
record the following information:
Occurrence of AEs (including infections). The investigator will provide guidance 
for the subject/caregiver regarding identification and documentation of AEs 
Concomitant medication use 
Details of the product administration as specified in Section 10.3
Days not able to attend school/work or to perform normal daily activities due to 
illness/infection
Non-study-required out-patient visits (including urgent care visits to see healthcare 
providers) and hospitalizations
Subjects and/or their legally authorized representatives will be trained on use of the diary. 
The diary will be provided in electronic format and remain with the subject for the 
duration of the study. The investigator will review the diary for completeness and request 
missing information periodically and in a timely manner. Untoward events recorded in 
the diary will be reported as AEs according to the investigator’s discretion and clinical 
judgment.
Subject entries in the diary will serve as source records. During study participation the 
investigator has access to the database holding the subject diary data. After study closure, 
the investigator will receive the diary records for their subjects, including audit trail 
records, in PDF format. The data will be transmitted to the CRF by a validated transfer.
Electronic Patient Reported (EPR) modules will be used to enable deployment of 
required subject diaries to subjects based on protocol requirements. EPRs can be 
programmed to allow a certain level of data validation at the time of data entry by the 
subject; this allows cleaning of subject reported data at the time of data collection. 
Additionally EPR compliance reports enable monitoring of patient compliance, and 
proactive follow up if required. EPRs can be deployed in local languages as needed. 
Automated reminder e-mails are sent to subjects who do not complete required EPRs. 
Following a certain number of reminder e-mails, the link to that particular EPR is 
disabled; this ensures that EPRs are collected in a timely manner during the study.
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10.6 Subject Completion/Discontinuation
A subject is considered to have completed the study when he/she ceases active 
participation in the study because the subject has, or is presumed to have, completed all
study procedures according to the protocol (with or without protocol deviations).
Reasons for completion/discontinuation will be reported on the 
Completion/Discontinuation eCRF, including: completed, screen failure, AE (e.g., death), 
discontinuation by subject (e.g., lost to follow-up [defined as three documented 
unsuccessful attempts to contact the subject], dropout), physician decision (e.g., 
pregnancy, progressive disease, non-compliance with IP/protocol violation(s), recovery), 
study terminated by sponsor, or other (reason to be specified by the investigator, e.g., 
technical problems). Regardless of the reason, all data available for the subject up to the 
time of completion/discontinuation should be recorded on the appropriate eCRF. 
Every effort will be made to have discontinued subjects complete the study 
completion/termination visit. If the completion/termination visit is done as an additional, 
unscheduled visit, the assessment results shall be recorded with the 
completion/termination visit. If a subject terminates participation in the study and does 
not return for the completion/termination visit, their last recorded assessments shall 
remain recorded with their last visit. The reason for discontinuation will be recorded, and 
the data collected up to the time of discontinuation will be used in the analysis and 
included in the clinical study report. If additional assessments are required, the 
assessments shall be recorded separately. Assessments to be performed at the termination 
visit (including in cases of withdraw or discontinuation) can be found in Supplement 20.2
Schedule of Study Procedures and Assessments and Supplement 20.3 Clinical Laboratory 
Assessments.
In the event of subject discontinuation due to an AE, clinical and/or laboratory 
investigations that are beyond the scope of the required study observations/assessments 
may be performed as part of the evaluation of the event. These investigations will take 
place under the direction of the investigator in consultation with the sponsor, and the 
details of the outcome may be reported to the appropriate regulatory authorities by the 
sponsor. 
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10.7 Procedures for Monitoring Subject Compliance
For study procedures that are to be performed under the direct supervision of the 
investigator/healthcare professional (e.g., infusion nurse) at the study site or infusion 
center, no separate procedures will be used to monitor subject compliance.
Training, evaluation, and verification of the subject’s (and/or caregiver’s) proficiency in 
performing self-infusion procedures by the investigator/designee, must be documented as 
a prerequisite before the subject (and/or caregiver) will be allowed to begin 
self-administration of SC infusions. A healthcare professional (e.g., infusion nurse) may 
be present to observe the subject’s self-administration. The subject (and/or caregiver) 
may be asked to return to the study site during the study so that the investigator/designee 
can further assess and document that the subject (and/or caregiver) is capable of 
continuing to independently performing self-infusion procedures.
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11. ASSESSMENT OF EFFICACY
11.1 IgG Trough Levels
IgG trough levels will be determined at several time points (see Supplement 20.3 Clinical 
Laboratory Assessments). Standard assay methods will be used for the determination of 
IgG and IgG subclasses. The measurement will be performed at the central laboratory. 
11.2 Treatment Preference Questionnaire
The treatment preference questionnaire, internally developed at Baxalta, is a self-
administered, non-validated scale assessing patient preference for various attributes of 
IgG therapy, such as ease of administration, frequency and duration of administration, 
and convenience.
The treatment preference questionnaire will be administered at the study site using a 
translated version, as applicable. It is recommended that the subject complete the 
assessment using the same translated version throughout the course of the study. For 
subjects aged 13 to <18 years, the subject should complete the questionnaire themselves
(observer: subject). For subjects under the age of 13, the parent should complete the 
questionnaire on behalf of their child (observer: parent). The same observer should be 
employed for the duration of subject participation. 
For detailed administration time points, see Supplement 20.2 Schedule of Study 
Procedures and Assessments.
11.3 Treatment Satisfaction Questionnaire for Medication
The Abbreviated Treatment Satisfaction Questionnaire for Medication (TSQM-9) is a 
9-item, validated, self-administered instrument to assess patients’ satisfaction with 
medication. The 3 domains assessed are effectiveness, convenience, and global 
satisfaction.
The TSQM-9 will be administered at the study site using a validated translated version, as 
applicable. It is recommended that the subject complete the assessment using the same 
translated version throughout the course of the study. For subjects aged 13 to <18 years, 
the subject should complete the questionnaire themselves (observer:  subject). For 
subjects under the age of 13, the parent should complete the questionnaire on behalf of 
their child (observer: parent).  The same observer should be employed for the duration of 
subject participation. 
For detailed administration time points, see Supplement 20.2 Schedule of Study 
Procedures and Assessments.
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11.4 HRQoL Questionnaire
PedsQL
11.4.1
The PedsQL is a validated questionnaire designed to measure generic HRQoL among a 
pediatric population.  Both patient and proxy versions of the questionnaire are available.  
This questionnaire measures four domains, including; Physical functioning, Emotional 
functioning, Social functioning and school functioning.  A total score and domain scores 
can be calculated.  Higher scores indicate better health status.39
Quality of life (QoL) will be assessed separately for the age groups two to four years, and 
five to seven years, eight to 12 years (PEDS-QL, observer: parent), and 13 to <18 years 
(PEDS-QL, observer: subject) . The same observer should be employed for the duration 
of subject participation. 
Age will be defined as the age at screening, in order to determine which age-specific 
assessment is to be used. The same age-specific assessment is to be used for the duration 
of the study. In the event that the language or age group is not available, the assessment 
in the closest age group will be used. In the event that the appropriate language is not 
available, the questionnaire will not be administered for that subject. For detailed 
administration time points, see Supplement 20.2 Schedule of Study Procedures and 
Assessments.
EQ-5D
11.4.2
The EQ-5D is a validated, self-administered assessment of overall health designed by the 
EuroQol Group.40 It is a descriptive system of HRQoL states consisting of 5 dimensions 
(mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). Subjects 
are asked to describe their health state that day by choosing 1 of 3 responses that reflect 
the levels of severity for each of the 5 dimensions: no problems, some or moderate 
problems, or extreme problems. The EQ-5D also includes a standard vertical 20-cm 
visual analogue scale (similar to a thermometer) for recording a subject’s rating of their 
current HRQoL state.
The EQ-5D will be administered at the study site using a validated translated version, as 
applicable. It is recommended that the subject complete the assessment using the same 
translated version throughout the course of the study. For subjects aged 13 to <18 years, 
the subject should complete the questionnaire themselves (observer:  subject). For 
subjects under the age of 13, the parent should complete the questionnaire on behalf of 
their child (observer: parent).  In the event that the appropriate language is not available, 
the questionnaire will not be administered for that subject. For detailed administration 
time points, see Supplement 20.2 Schedule of Study Procedures and Assessments.
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12. ASSESSMENT OF SAFETY
12.1 Adverse Events
Definitions
12.1.1
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.
Temporally associated AEs are all AEs which occur during the infusion or within 
72 hours of completion of infusion.
12.1.1.1 Serious Adverse Event
A SAE is defined as an untoward medical occurrence that at any dose meets one or more 
of the following criteria:
Outcome is fatal/results in death (including fetal death)
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.
Requires inpatient hospitalization or results in prolongation of an existing 
hospitalization – inpatient hospitalization refers to any inpatient admission, 
regardless of length of stay.
Results in persistent or significant disability/incapacity (i.e., a substantial disruption 
of a person’s ability to conduct normal life functions)
Is a congenital anomaly/birth defect
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
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Reviewed and confirmed seroconversion for HIV, hepatitis A virus (HAV), 
hepatitis B virus (HBV), HCV, hepatitis E virus (HEV), or parvovirus B19 
(B19V)
Thromboembolic events (e.g., deep vein thrombosis, pulmonary embolism, 
myocardial infarction, cerebrovascular accidents [e.g., stroke, transient 
ischemic event])
Hemolytic anemia
Uncomplicated pregnancies, following maternal or paternal exposure to IP are not 
considered an (S)AE; however, any pregnancy complication or pregnancy termination by 
therapeutic, elective, or spontaneous abortion shall be considered an SAE.
12.1.1.2 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.
12.1.1.3 Non-Serious Adverse Event
A non-serious AE is an AE that does not meet the criteria of an SAE.
12.1.1.4 Unexpected Adverse Events
An unexpected AE is an AE whose nature, severity, specificity, or outcome is not 
consistent with the term, representation, or description used in the Reference Safety 
Information. “Unexpected” also refers to the AEs that are mentioned in the investigator’s 
brochure 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 investigator’s 
brochure and/or prescribing information as the Reference Safety Information. 
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This determination will include considerations such as the number of AEs previously 
observed, but not on the basis of what might be anticipated form the pharmacological 
properties of a product.
12.1.1.5 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.
Assessment of Adverse Events
12.1.2
Each AE from signing informed consent 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 12.1). Each AE will be evaluated by the 
investigator for:
Seriousness as defined in Section 12.1.1.1
Severity as defined in Section 12.1.2.1
Causal relationship to IP exposure or study procedure as defined in Section 12.1.2.2
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 
Report Form. 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.
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Deviations from the protocol-specified dosage (including overdosing or underdosing by 
more than 20%, abuse, and withdrawal), 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, lack of 
efficacy, and/or other observations because these events may be reportable to regulatory 
authorities.
Any pregnancy that occurs after administration of IP will be reported on a Pregnancy 
Report Form and followed-up at estimated date of delivery and one year post-delivery, if 
feasible. The investigator will record a narrative description of the course of the 
pregnancy and its outcome. Subjects who prematurely withdraw from the study because 
of pregnancy should be encouraged to participate in the pregnancy registry 
(Study 161301): Pregnancy Registry to collect Long-Term Safety Data from Women 
treated with HyQvia, if locally available.
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 hours after awareness.
12.1.2.1 Severity
The investigator will assess the severity of each AE using his/her clinical expertise and 
judgment based on the most appropriate description below:
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.
Moderate

The AE produces limited impairment of function and may require therapeutic 
intervention.

The AE produces no sequela/sequelae.
Severe

The AE results in a marked impairment of function and may lead to 
temporary inability to resume usual life pattern.
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
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.
12.1.2.2 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 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:
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). 
Unlikely related (either one or both circumstances are met)

Has little or no temporal relationship to the IP 

A more likely alternative etiology exists
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
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: 
o
Reappearance of a similar reaction upon re-administration (positive 
rechallenge)
o
Positive results in a drug sensitivity test (skin test, etc.)
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o
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 hours 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.
12.2 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: 
Immediate change in study design or study procedures
Temporary or permanent halt of a given clinical trial or trials
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 one calendar day after the change is implemented. The sponsor 
will also ensure the responsible ethics committee(s) (ECs) and relevant competent 
authority(s) are notified of the urgent safety measures taken in such cases according to 
local regulations.
12.3 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 12.1). 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. 
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For the purposes of this study, each non-serious 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. 
12.4 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:
A failure of a product to exhibit its expected pharmacological activity and/or design 
function, e.g., reconstitution difficulty
Missing components
Damage to the product or unit carton
A mislabeled product (e.g., potential counterfeiting/tampering)
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 one business day. If requested, defective product(s) will be returned to the 
sponsor for inspection and analysis according to procedures.
12.5 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 12.1.2.1) 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 medications taken and non-drug therapies received from providing informed consent
until completion/termination will be recorded on the concomitant medications and 
non-drug therapies CRFs.
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12.6 Physical Examinations
At screening and subsequent study visits (as described in Supplement 20.2), a 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 an error, due to a preexisting disease (described in Section 12.1.1.5), not 
clinically significant, a symptom of a new/worsened condition already recorded as an AE, 
or due to another issue that will be specified, the investigator will record the justification 
on the source record.
12.7 Clinical Laboratory Parameters
For detailed sampling time points see Supplement 20.3 Clinical Laboratory Assessments.
Blood drawing for trough levels will always take place before the infusion is 
administered.
Hematology and Clinical Chemistry
12.7.1
The hematology panel will consist of complete blood count (hemoglobin [Hgb], 
hematocrit, erythrocytes [i.e., RBC], and leukocytes [i.e., white blood cell count [WBC])
with differential (i.e., basophils, eosinophils, lymphocytes, monocytes, neutrophils) and 
platelet counts. 
The clinical chemistry panel will consist of sodium, potassium, chloride, bicarbonate, 
protein, albumin, ALT, bilirubin, alkaline phosphatase (ALP), blood urea nitrogen
(BUN), creatinine, and glucose.
Hematology and clinical chemistry assessments will be performed on 
EDTA-anticoagulated whole blood and serum, respectively, at the central laboratory. 
Urine Tests
12.7.2
Urinalysis will include color, specific gravity, pH, protein, glucose, ketones, bilirubin, 
urobilinogen, blood, nitrite, leukocyte esterase, and microscopic examination. Urinalysis 
tests will be conducted at the central laboratory.
Pregnancy Test
12.7.3
For female subjects of childbearing potential, urine pregnancy test will be performed at a 
central laboratory, unless a serum pregnancy test is mandatory as specified by local 
regulatory/institutional requirements.
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Hemolysis Test
12.7.4
Hemolysis test will consist of Hgb, lactate dehydrogenase (LDH), serum haptoglobin, 
plasma-free (unbound) Hgb, serum direct anti-globulin (direct Coomb’s) test (antibody 
elution to be performed if direct Coomb’s test is positive), reticulocyte count, as well as 
urine hemosiderin. If there is a reduction in Hgb of two g/dL or more compared to 
baseline Hgb, every effort is to be made to perform a repeat test consisting of the 
hemolysis tests described above within 72 hours; if it is not feasible to do so, the 
hemolytic panel must be performed as soon as possible. At any time during the study, an 
unscheduled hemolytic panel may be performed in the event of suspected hemolytic 
anemia.
Hemolysis test will be performed at the central laboratory or other laboratories as 
appropriate (e.g., antibody elution in the event of positive direct Coomb’s test). Complete 
hematology and clinical chemistry assessments may be performed in order to obtain 
laboratory results required for a hemolytic panel.
IgG Trough Levels and IgG Subclasses and Specific Antibody Tests
12.7.5
IgG total and IgG subclass trough levels and trough levels of specific antibodies against 
Clostridium tetani toxoid, Haemophilus influenzae, and HBV will be determined on all 
subjects. 
Testing will be performed at the central laboratory using standard assay methods.
Anti-rHuPH20 Antibodies
12.7.6
All subjects will have regular anti-rHuPH20 antibody testing in pre-identified central 
laboratories (binding and neutralizing anti-rHuPH20 antibody) throughout the study 
(approximately every three months, see Supplement 20.3). At any time during the course 
of the study, subjects who have 1) two consecutive anti-rHuPH20 antibody titers of 
≥1:160 that are elevated from the subject’s baseline titers, and 2) a moderate or severe 
AE that may be a result of immune-mediated response to either immunoglobulin or
rHuPH20 will be asked to return to the study site as soon as possible to undergo an 
additional panel of testing:
50% hemolytic complement activity of serum, 
serum complement component 3, 
serum complement component 4, 
C1q binding assay, and 
circulating immune complex Raji cell assay.
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Viral Pathogen Serology
12.7.7
Tests for viral pathogen serology include: HBsAg by enzyme-linked immunosorbent 
assay (ELISA), PCR for HCV and PCR for HIV-1/2. These assessments will be 
performed at the central laboratory at the time points specified in Supplement 20.3.
Assessment of Laboratory Values
12.7.8
12.7.8.1 Toxicity Grading Scale
The following laboratory values will be evaluated by the sponsor/sponsor’s representative
according to the Common Toxicity Criteria of the Eastern Cooperative Oncology Group 
(ECOG), published by Oken et al.41:
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 toxicity grading system.42 The laboratory parameters and the 
corresponding grading scale are provided in Section 12.7. 
The toxicity scale is defined as: zero = none, one = mild, two = moderate, 
three = severe, four = life-threatening. Laboratory parameters not listed in Table 11
will not be graded. However, clinical significance of those abnormal laboratory 
values will be assessed as described in Section 12.7.8.2.
12.7.8.2 Assessment of Abnormal Laboratory Values 
The investigator’s assessment of each laboratory value will be recorded on the 
eCRF laboratory form. For each abnormal laboratory value, the investigator will 
determine whether the value is considered clinically significant or not. 
For clinically significant values, the investigator will indicate if the value constitutes an 
new AE (see definition in Section 12.1, and record the sign, symptom, or medical 
diagnosis on the AE CRF), is a symptom or related to a previously recorded AE, is due to 
a pre-existing disease (described in Section 12.1.1.5), or is due to another issue that will 
be specified. If the abnormal value was not clinically significant, the investigator will 
indicate the reason, i.e., because it is due to a preexisting disease, due to a lab error, or 
due to another issue that will be specified. Additional tests and other evaluations required 
to establish the significance or etiology of an abnormal value, or to monitor the course of 
an AE should be obtained when clinically indicated. Any abnormal value that persists 
should be followed at the discretion of the investigator.
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Any seroconversion result for HIV, HAV, HBV, HCV, HEV, or B19V shall be re-tested.
Backup Samples and Biobanking
12.7.9
Backup samples taken and stored short-term may be used, for example, for re-testing, 
follow-up of an AE(s) or other test results, and/or assay development. After study testing 
is completed, the remaining samples may be stored in a coded form for no more than two
years after the final study report has been completed and then the samples will 
subsequently be destroyed.
For this study, no samples will be taken or stored long-term in a biobank for future 
analyses.
12.8 Vital Signs
Vital signs will include body temperature (°C or °F), respiratory rate (breaths/min), pulse 
rate (beats/min), and systolic and diastolic blood pressure (mmHg). Height (in or cm) and 
weight (lb or kg) will also be collected.
Vital signs will be measured as described below:
Screening
12.8.1
All vital signs
Infusion at Study Site
12.8.2
1. Within 30 min prior to infusion:

All vital signs. Height and weight can be taken at any time at this visit. 
2. 30 (± 5) min after initiation of infusion:

All vital signs except height and weight
3. During the infusion if a systemic AE occurs, to be assessed as needed:

All vital signs except height and weight
4. Within 30 min of completion of the infusion:

All vital signs except height and weight
Infusion at Home
12.8.3
No assessment of vital signs
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End-of-Study 
12.8.4
All vital signs
Vital sign values are to be recorded on the eCRF. For each abnormal vital sign value, the 
investigator will determine whether to report an AE (see definition in Section 12.1 and 
record the medical diagnosis [preferably], symptom, or sign on the AE CRF). Additional 
tests and other evaluations required to establish the significance or etiology of an 
abnormal value, or to monitor the course of an AE should be obtained when clinically 
indicated. Any abnormal value that persists should be followed at the discretion of the 
investigator.
12.9 Acute Serious Bacterial Infections
Acute serious bacterial infections will be defined as follows based on the US FDA 
Guidance for Industry to Support Marketing of Human IGIV as Replacement Therapy for 
Primary Humoral Immunodeficiency 43 and the EMA guideline on the clinical 
investigation of human normal immunoglobulin for SC and /or intramuscular 
administration.44
Infection: Bacteremia/Sepsis(a)
12.9.1
1. Symptoms: chills, rigors
2. Physical findings- fever, hypothermia, tachycardia, tachypnea, hypocarbia, 
hypotension (systolic blood pressure <90 mm Hg or a reduction of >40 mm Hg 
from baseline in the absence of other causes of hypotension), altered mental 
status, petechiae, purpura, oliguria, cutaneous vasodilation/vasoconstriction
3. Laboratory tests: positive blood culture(b), leukocytosis (WBC count 
>12,000/mm3), differential WBC count demonstrating >10% immature (band) 
neutrophils, leukopenia, thrombocytopenia, coagulopathy, lactic acidosis
(a) Two of the following should be present to make the diagnosis of sepsis in adults: 
temperature >38°C oral/ > 39°C rectal or <36°C oral or < 37°C rectal; heart rate 
>90 beats/min; respiratory rate >20 breaths/min, or partial pressure of carbon dioxide 
(PaCO2) <32 mm Hg; WBC >12,000/mm3, <4,000/mm3, or >10% immature (band) 
forms. For pediatric patients, we recommend you employ the definition of sepsis using 
age-specific criteria as recommended by the International Consensus Conference on 
Pediatric Sepsis.45
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(b) Indwelling catheter- or vascular access device-related blood-borne infections are not 
included because evidence is lacking that these are preventable with IGI replacement 
therapy. For subjects without indwelling catheters or vascular access devices, a single 
blood culture positive for a pathogenic organism will meet the diagnostic criteria for 
bacteremia. Multiple blood cultures are typically obtained in cases of suspected 
bacteremia/sepsis, as per standard medical practice, and the finding of a single positive 
culture should prompt additional confirmatory cultures. Subjects meeting criteria for 
positive blood culture but without two or more of the sepsis criteria listed above will be 
classified as having bacteremia.
Infection: Bacterial Meningitis
12.9.2
1. Symptoms: headache, stiff neck, mental status changes, irritability, decreased 
feeding (infants), photophobia, nausea/vomiting, rigors, seizures
2. Physical findings: Kernig’s sign, Brudzinski’s sign, meningococcal rash, fever of 
>38 °C oral or >39°C rectal
3. Laboratory tests: positive cerebrospinal fluid (CSF) Gram stain and/or culture 
and/or positive CSF bacterial antigen assay, positive blood culture(c), CSF 
leukocytosis with neutrophil predominance, decrease in CSF glucose
(c) A blood culture positive for growth of Streptococcus pneumoniae, Neisseria 
meningitides, or Haemophilus influenzae, in combination with CSF leukocytosis and/or 
decrease in CSF glucose, can serve to confirm the diagnosis of acute bacterial meningitis
Infection: Osteomyelitis/Septic Arthritis
12.9.3
1. Symptoms: pain, decreased range of motion, tenderness, edema, redness, 
warmth over the involved site (local inflammatory symptoms/signs may be 
lacking in adults)
2. Physical findings: evidence of soft tissue infection adjacent to the involved 
bone/joint; drainage from sinus tract from involved bone; fever of >38°C oral 
or >39°C rectal
3. Laboratory tests: positive blood culture, positive probe to bone, positive bone 
aspirate culture, positive bone biopsy culture, positive bone histopathology, 
positive joint fluid Gram stain and culture
4. Imaging studies: positive X-ray, nuclear medicine bone scan, magnetic 
resonance imaging (MRI) scan, or computed tomography (CT) scan showing 
bony destruction with radiolucent areas; for chronic osteomyelitis: sequestra, 
involucre
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Infections: Bacterial Pneumonia(d)
12.9.4
1. Symptoms: productive cough/change in character of sputum, dyspnea or 
tachypnea, chills, chest pain, rigors, headache, fatigue, sweats, anorexia, 
myalgias
2. Physical findings: rales; pulmonary consolidation as reflected by: dullness on 
percussion, bronchial breath sounds, egophony; fever >38°C oral or > 39°C 
rectal, or <36°C, hypothermia (temperature < 36°C oral or < 37°C rectal)
3. Laboratory tests: leukocytosis; differential WBC count of >10% band 
neutrophils; leukopenia; hypoxemia (PaO2 < 60 mm Hg on room air); positive 
blood culture; Gram stain and culture of deep expectorated sputum(e), positive 
culture with or without positive Gram stain of transtracheal aspirate, pleural 
fluid culture, lung biopsy, bronchoscopy with BAL or protected brush sampling,
4. Imaging studies: Pulmonary infiltrate with consolidation on chest X-Ray 
([CXR]; new in comparison with baseline or previous CXR)
(d) For the diagnosis of pneumonia in adults, commonly at least two of the listed 
symptoms and/or signs should be present in conjunction with at least one laboratory and 
one imaging studies diagnostic elementvii.  However, for the purposes of counting serious 
infection episodes in a clinical study of IGI, the finding of a new pulmonary infiltrate 
with consolidation on CXR is considered sufficient. To establish the diagnosis of 
bacterial pneumonia for pediatric patients, most of the same diagnostic criteria listed may 
be used, with the following exceptions: Because pediatric patients may not produce a 
sputum specimen for culture, blood cultures or serology may be substituted to identify the 
etiologic bacterial pathogen. In infants age three to 24 months, who tend to have a higher 
baseline temperature, fever is defined as a rectal temperature >38.3°C (101°F). In 
children >two years, fever is more commonly defined as a rectal temperature >38°C 
(100.4°F). In pediatric patients, elevations of WBC counts >15,000/mm3 are frequent but 
could be variable in patients with bacterial pneumonia, or leukopenia with WBC count 
<5000/mm3 may be observed, usually associated with severe infection
(e) We recommend a deep expectorated sputum Gram stain demonstrate the presence of 
microorganisms on examination of 10 to 20 oil immersion microscopic fields and <ten 
squamous epithelial cells and >25 polymorphonuclear leukocytes at tenX low power 
magnification to determine suitability of sputum culture.
                                                
vii Further evaluation, in particular laboratory evaluation (culture and white blood count with differential to 
evaluate for the presence of immature neutrophils) and chest x-rays, should be aggressively pursued 
whenever a bacterial pneumonia is suspected
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Infection: Visceral Abscess
12.9.5
1. Symptoms: abdominal pain, anorexia, weight loss, cough/pleuritic chest pain 
(hepatic abscess), rigors (seldom present)
2. Physical findings: intermittent fevers (temperature >38°C oral or >39°C rectal); 
abdominal tenderness; palpable mass; hepatomegaly; jaundice
3. Laboratory tests: positive Gram stain and/or culture from the infected site, with 
isolation of an appropriate pathogen; positive blood culture; leukocytosis with 
accompanying left shift; differential WBC of >10% immature (band) 
neutrophils; elevated serum amylase concentration (pancreatic abscess); 
elevated alkaline phosphatase concentration (hepatic abscess) pyuria in renal 
abscess
4. Imaging studies: typical findings on ultrasound, CT scan, MRI scan, or 
radionuclide scan
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13. STATISTICS
13.1 Sample Size and Power Calculations
The sample size selected for the study is primarily determined by the objective to collect 
safety data in a sufficient number (about 40) of pediatric (age two to <18 years) subjects
with PIDD who have received prior immunoglobulin therapy before enrollment into this 
study. In addition, the guideline of the CHMP on the clinical investigation of human 
normal immunoglobulin for SC and/or intramuscular administration 44 indicates that at 
least 40 patients should be included to evaluate replacement therapy in primary 
immunodeficiency syndromes.
13.2 Analysis Sets
Full Analysis Set
13.2.1
All patients who provide informed consent (i.e., sign and date the Informed Consent 
Form, if applicable), and meet enrollment eligibility (i.e., meets all inclusion criteria and 
do not meet any exclusion criteria) will be included in the full analysis set.
Per-Protocol Analysis Set
13.2.2
All patients in the full analysis set who have no major protocol deviations will be 
included in the per-protocol analysis set.
Safety Analysis Set
13.2.3
The safety analysis set will contain all subjects in the full analysis set who receive at least 
one dose of HyQvia.
13.3 Handling of Missing, Unused, and Spurious Data
The handling of missing, unused or spurious data will be described in the statistical 
analysis plan (SAP).
13.4 Methods of Analysis
In this study no hypothesis will be tested. Detailed statistical analysis methods will be 
described in the SAP. Statistical analyses and data displays will be mainly descriptive.
Data from all enrolled subjects will be included in the analysis. If groups of sufficient 
sample size (such as age groups or PIDD types) are available, CIs may accompany the 
point estimates. All SAEs and non-serious AEs will be categorized according to 
MedDRA system organ class and preferred term. Tables will be prepared to list for each 
SAE and non-serious AE the number of events and the number of subjects who 
experienced one or more event. All analyses will be performed using SAS® version 9.2 or 
higher (SAS Institute, Cary, NC, USA). 
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Primary Outcome Measure
13.4.1
Number and rate per infusion (excluding infections) of all severe related AEs
Number and rate per infusion (excluding infections) of related SAEs
For the endpoint of incidence of all severe related AEs and related SAEs, a point estimate 
and corresponding 95% CI (by the Wilson score method) for the proportion of subjects 
with one or more related SAEs will be provided. In addition, incidence of all severe 
related AEs and related SAEs will be calculated as rate per infusion and rate per 
subject-year, and will be analyzed for changes in frequency and for changes in severity 
over time. All SAEs will be listed. No statistical hypotheses will be tested.
Secondary Outcome Measures 
13.4.2
13.4.2.1 Efficacy 
Trough levels of IgG (for Study Epoch 1 and 2): Descriptive statistics will be provided 
for the trough level of IgG for study Epoch 1 and 2.  
13.4.2.2 Safety 
The following secondary safety endpoints will be analyzed:
Proportion of subjects who achieve a treatment interval of three or four weeks in 
Epoch 2 
Proportion of subjects who maintain a treatment interval of three or four weeks in 
Epoch 2 for 12 months
Number and rate per infusion (excluding infections) of local AEs and ARs
Number and rate per infusion (excluding infections) of systemic AEs and ARs 
Number and rate per infusion (excluding infections) of all AEs and all ARs
Number and rate per infusion (excluding infections) of all temporally associated 
AEs 
Number and rate per infusion (excluding infections) of all causally related and/or 
temporally associated AEs
Number and rate per infusion (excluding infections) of all SAEs 
Number/proportion of subjects who develop positive titer (≥160) of binding or 
neutralizing antibodies to rHuPH20
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Descriptive methods, mainly frequency tables, will be used for all secondary safety 
endpoints. In addition, incidence of all secondary safety endpoint will be calculates as 
rate per infusion and rate per subject-year.
13.4.2.3 Mode of Product Administration (For Study Epoch 1 and 2)
Number of Infusions
Number of infusions per month
Number of infusion sites (needle sticks) per infusion/month
Duration of infusion (defined as time from the start of rHuPH20 infusion until the 
stop time of immunoglobulin infusion)Maximum infusion rate/site
Infusion volume/site
Number/proportion of infusions that are discontinued, slowed, or interrupted due to 
an AE Number of weeks to reach final dose interval (defined as three or four weeks
infusion interval)
Nonparametric descriptive statistics (median, quartiles, and range) will be calculated and 
reported for the infusion administration variables. Frequency table will show the 
number/proportion of infusions discontinued, slowed or interrupted due to AE and total 
observation time in subject-years. 
13.4.2.4 HRQoL
Treatment Preference Questionnaire
Treatment Satisfaction Questionnaire for Medication (TSQM-9)
HRQoL Questionnaire: Peds-QL, EQ-5D
Total and domain scores on each of the HRQoL measures will be calculated for each 
subject, at each data assessment time point. Descriptive statistics will be shown for each 
of the scores, at each data assessment time point.
Tertiary Outcome Measures 
13.4.3
13.4.3.1 Infections
Number of acute serious bacterial infections
Number of all infections
Days on antibiotics
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For the endpoint of incidence of acute serious bacterial infection and all infections a point 
estimate and 95% CI (by the Wilson score method) for the proportion of subjects with 
one or more infection will be calculated.  In addition, incidence of all infection endpoints 
will be calculates as rate per infusion and rate per subject-year. Descriptive statistics will 
be performed and reported for the days on antibiotics. 
13.4.3.2 Healthcare Resource Utilization Endpoints
Days not able to go to school/work or to perform normal daily activities
Number of hospitalizations, indication for the hospitalization (infection or 
non-infection) and days hospitalized
Number of acute physician visits (office and emergency room) due to infection or 
other illnesses
Healthcare resource utilization endpoints, including hospitalization, acute physician visits 
and days missed for school/work or normal daily activities, will be summed and 
annualized for reporting purposes. Descriptive statistics will be performed and reported.
13.5 Planned Interim Analysis of the Study
Annual reports will be prepared. Details will be described in the SAP.
14. DIRECT ACCESS TO SOURCE DATA/DOCUMENTS
The investigator/study site will cooperate and provide direct access to study documents 
and data, including source documentation for monitoring by the study monitor, audits by 
the sponsor or sponsor’s representatives, review by the EC, and inspections by applicable 
regulatory authorities, as described in the Clinical Trial Agreement (CTA). If contacted 
by an applicable regulatory authority, the investigator will notify the sponsor of contact, 
cooperate with the authority, provide the sponsor with copies of all documents received 
from the authority, and allow the sponsor to comment on any responses, as described in 
the CTA.
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15. QUALITY CONTROL AND QUALITY ASSURANCE
15.1 Investigator’s Responsibility
The investigator will comply with the protocol (which has been approved/given favorable 
opinion by the EC), 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 study site 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. Sub-investigators or other 
authorized study personnel are eligible to sign for the investigator, except where the 
investigator’s signature is specifically required.
Final Clinical Study Report 
15.1.1
The investigator, or coordinating investigator(s) for multicenter studies, will sign the 
clinical study report. The coordinating investigator will be selected before study start.
15.2 Training
The study monitor will ensure that the investigator and study site 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 study site, and/or by instruction manuals. In addition, the study monitor will be 
available for consultation with the investigator and will serve as the liaison between the 
study site and the sponsor.
15.3 Monitoring
The study monitor is responsible for ensuring and verifying that each study site conducts 
the study according to the protocol, standard operating procedures, other written 
instructions/agreements, ICH GCP, and applicable national and local regulatory 
guidelines/requirements. The investigator will permit the study monitor to visit the study 
site at appropriate intervals, as described in the CTA. Monitoring processes specific to the 
study will be described in the clinical monitoring plan.
15.4 Safety Monitoring
The safety of the subjects in this study shall be monitored by an internal safety review 
board (ISRB). 
The ISRB is a group of individuals with pertinent expertise within the sponsor that 
reviews on a regular basis accumulating data from an ongoing clinical study. 
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For this study, the ISRB will be composed of appropriate sponsor representatives from 
the relevant functions (e.g., Global Drug Safety, Clinical Research, Medical Affairs, 
Clinical Development) with expertise/specialization in PIDD clinical care and research. 
The ISRB can stop a trial if it finds toxicities or if treatment is proven to be not 
beneficial.
15.5 Auditing
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 study site, as 
described in the CTA. Auditing processes specific to the study will be described in the 
audit plan.
15.6 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 one calendar day after the change is 
implemented. The sponsor will also ensure the responsible EC 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 and applicable regulatory authorities of any investigator termination.
15.7 Laboratory and Reader Standardization
Inter-laboratory standardization methods will be described in the data management plan
as needed. 
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16. ETHICS 
16.1 Subject Privacy
The study protocol, documentation, data and all other information generated will be held 
in strict confidence and in accordance with applicable laws, regulations, and guidelines. 
No information concerning the study or the data will be released to any unauthorized 
third party, without prior written approval of the Sponsor.
Country-specific data protection and privacy regulations will be observed in collecting, 
forwarding, processing, and storing data from study participants.
16.2 Ethics Committee and Regulatory Authorities
Before patients participate in this study, the protocol, informed consent form, any 
promotional material/advertisements, and any other written information will be reviewed 
and approved/given favorable opinion by the ethics committee (EC) and applicable 
regulatory authorities. The IB, if applicable, will be provided for review. The EC’s 
composition or a statement that the EC’s composition meets applicable regulatory criteria 
will be documented. The study will commence only upon the sponsor’s receipt of 
approval/favorable opinion from the EC and, if required, upon the sponsor’s notification 
of applicable regulatory authority(s) approval, as described in the CTA. 
If the protocol or any other information given to the subject is amended, the revised 
documents will be reviewed and approved/given favorable opinion by the EC and 
applicable regulatory authorities, where applicable. The protocol amendment will only be 
implemented upon the sponsor’s receipt of approval and, if required, upon the sponsor’s 
notification of applicable regulatory authority(s) approval.
16.3 Informed Consent
Investigators will choose patients for participation considering the study eligibility 
criteria. The investigator will exercise no selectivity so that no bias is introduced from 
this source. 
All patients and/or their legally authorized representative must sign an informed consent 
form before enrollment into the study according to applicable national and local 
regulatory requirements and ICH GCP. The case history for each individual shall 
document that informed consent was obtained prior to participation in the study.
An assent form may be provided and should be signed by patients enrolled in the study. 
Before use, the informed consent form will be reviewed by the sponsor and approved 
by the EC and regulatory authority(s), where applicable, (see Section 16.2). 
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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 or their 
legally authorized representative(s) will be allowed sufficient time to consider 
participation in the study. By signing the informed consent form, patients or their legally 
authorized representative(s) 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 EC and regulatory authorities, 
where applicable, will be provided by the investigator to the subjects who consented to 
participate in the study.
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17. DATA HANDLING AND RECORD KEEPING
17.1 Confidentiality Policy
The investigator will comply with the confidentiality policy as described in CTA. 
17.2 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” 
(see Section 8.8), records detailing the progress of the study for each subject, signed 
informed consent forms, correspondence with the EC and the study monitor/sponsor, 
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 eCRFs are provided by the sponsor, only authorized study site 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 study site in accordance with the data 
retention policy (see Section 17.3).
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.
17.3 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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18. FINANCING AND INSURANCE
The investigator will comply with investigator financing, investigator/sponsor insurance, 
and subject compensation policies, if applicable, as described in the CTA.
19. PUBLICATION POLICY
The investigator will comply with the publication policy as described in the CTA. 
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20. SUPPLEMENTS
20.1 Study Flow Chart
Figure 1
Study Design for Clinical Study 161504
Anti-rHuPH20 Ab titer 
< 160 (all assays)
Epoch 3
1 year Safety Follow-up 
(no HyQvia treatment)
Epoch 2
Year 2 and Year 3
HyQvia treatment
Anti-rHuPH20 Ab titer < 160 final assay, 
during the study ≥ 160
OR
Anti-rHuPH20 Ab titer 
≥ 160 final assay
Pre-study treatment:
IGIV, IGSC or HyQvia
Epoch 2
Year 1
HyQvia treatment
Anti-rHuPH20 Ab titer final assay of Year 1:
Enrollment
Epoch 1
Ramp Up (if necessary)
Subject has Anti-rHuPH20 
Ab titer ≥ 160 
AND
experiences related SAE or 
related severe AE
End of Study
Screening
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20.2 Schedule of Study Procedures and Assessments
Table 3
STUDY EPOCH 1 – Ramp Up 
Schedule of Study Procedures and Assessments
Procedures/Assessments Routinely 
Performed 
Pre-Infusion, Unless Stated 
Otherwise
Enrollment / 
Screening
Treatment Visit in Study Epoch 1
First Infusion: 
Baseline
Second Infusion: Week 1 
(This Treatment is the End 
of Epoch 1 if Subject is 
Planning for 3-Week 
Treatment Intervals)
Third Infusion: Week 3 
(Only for Subjects Planning to 
Ramp Up to 4-Week 
Treatment Intervals)
Location
Site
Site
Site
Site
Informed Consenta
x
Eligibility Criteria
x
Infusion
x
x
x
Medical History
x
Concomitant Medications
x
x
x
x
Non-drug Therapies
x
x
x
x
Physical Exam
x
x
x
x
Adverse Events
x
x
x
Laboratories – see Lab Tableb
x
x
Vital Signs
x
x
x
x
HRQoL (PedsQL, EQ-5D)/
Treatment Preference questionnaire, 
TSQM-9 Assessment
x
a   Occurs prior to any study-specific procedure.
b    For laboratory assessments, see Supplement 20.3
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Table 4
STUDY EPOCH 2 – Year 1 
Schedule of Study Procedures and Assessments
Procedures/ Assessments 
Routinely Performed Pre-
Infusion, Unless Stated 
Otherwise
Visit in Study Epoch 2 (Visit +/- 2 weeks)
Month 0
Month 3
Month 6 
Month 9 
Month 12a
Study Completion/
Termination Visit 
(at Next Infusion), 
if Applicable
Location
Site
Site
Site
Site
Site
Site
Informed Consent
Infusiona
x
x
x
x
x
Concomitant Medications
x
x
x
x
x
x
Non-drug Therapies
x
x
x
x
x
x
Physical Exam
x
x
x
x
x
x
Adverse Events
x
x
x
x
x
x
Laboratories 
x
x
x
x
x
x
Vital Signs
x
x
x
x
x
x
HRQoL (PedsQL, EQ-5D), 
Treatment Preference
questionnaire, TSQM-9
Assessment
x
x
a    Further (additional) infusions may be administered after 12 months if rHuPH20-antibody results not available. AEs, concomitant medications, and 
non-drug therapies will continue to be recorded until EOS or continuation of Epoch 2 (dependent on antibody assay result).
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Table 5
STUDY EPOCH 2 – Year 2 and Year 3
Schedule of Study Procedures and Assessments
Procedures/ Assessments 
Routinely Performed Pre-
Infusion, Unless Stated 
Otherwise
Visit in Study Epoch 2 (Visit +/- 2 Weeks)
Month 15
Month 18
Month 21
Month 24
Month 27
Month 30
Month 33
Month 36/
Study Completion/
Termination Visit, 
if Applicablea
Location
Site
Site
Site
Site
Site
Site
Site
Site
Infusion
x
x
x
x
x
x
x
Concomitant Medications
x
x
x
x
x
x
x
x
Non-drug Therapies
x
x
x
x
x
x
x
x
Physical Exam
x
x
x
x
x
x
x
x
Adverse Events
x
x
x
x
x
x
x
x
Laboratories 
x
x
x
x
x
x
x
x
Vital Signs
x
x
x
x
x
x
x
x
HRQoL (PedsQL, EQ-5D)/
Rx-Preference, TSQM-9
Assessment
x
x
a
In case a subject has an anti-rHuPH20 antibody titer ≥ 160 and experiences a related serious or severe AE, the subject may go to Study Epoch 3 and 
will have the Study Completion/Termination Visit at the end of this Epoch
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Table 6
STUDY EPOCH 3 
Schedule of Study Procedures and Assessments 
Procedures/Assessments Routinely 
Performed Pre-Infusion, Unless 
Stated Otherwise
Visit in Study Epoch 3 (Visit +/- 2 Weeks)
Month 0 
Month 3
Month 6 
Months 9 
Month 12/
Study Completion/
Termination Visita
Location
Site
Site
Site
Site
Site
Infusion
x
x
x
x
Concomitant Medications
x
x
x
x
x
Non-drug Therapies
x
x
x
x
x
Physical Examb
x
x
x
x
x
Adverse Events
x
x
x
x
x
Laboratoriesc
x
x
x
x
x
Vital Signs
x
x
x
x
x
HRQoL (PedsQL, EQ-5D Treatment 
Preference questionnaire, TSQM-9
Assessment
a
Includes for cases of withdrawal or discontinuation.
b
Occurs prior to any study-specific procedure.
c
For laboratory assessments, see Supplement 20.3.
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20.3 Clinical Laboratory Assessments
Table 7
STUDY EPOCH 1 – Ramp Up 
Clinical Laboratory Assessments 
Assessments 
Routinely Performed Pre-Infusion, 
Unless Stated Otherwise
Enrollment / 
Screening
Treatment Visit in Study Epoch 1
First Infusion: 
Baseline
Second Infusion: Week 1 
(This Treatment is the End 
of Epoch 1 if Subject is 
Planning for 3-Week 
Treatment Intervals)
Third Infusion: Week 3 
(Only for Subjects Planning to 
Ramp Up to 4-Week 
Treatment Intervals)
Location
Site
Site
Site
Site
Hematology
x
Clinical Chemistry
x
Urinalysis
x
Pregnancy Test in females of 
childbearing potential – Urine
x
Viral Pathogen Serology
x
Hemolysis Test
Specific Antibody Tests
x
IgG Trough Levels and IgG 
Subclasses
x
Antibodies to rHuPH20
x
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Table 8
STUDY EPOCH 2 – Year 1 
Clinical Laboratory Assessments
Assessments 
Routinely Performed Pre-
Infusion, Unless Stated 
Otherwise
Visit in Study Epoch 2 (Visit +/- 2 Weeks)
Month 0
Month 3
Month 6 
Month 9 
Month 12 
Study Completion/
Termination Visit 
(at Next Infusion), 
if Applicable 
Location
Site
Site
Site
Site
Site
Site
Hematology
x
x
x
Clinical Chemistry
x
x
x
Urinalysis
x
x
x
Pregnancy Test in females of 
childbearing potential– Urine
x
Viral Pathogen Serology
x
Hemolysis Test
xa
Specific Antibody Tests
IgG Trough Levels and IgG 
Subclasses
x
x
x
Antibodies to rHuPH20
x
x
x
x
x
a
If there is a reduction in Hgb of two g/dL or more compared to baseline Hgb, every effort is to be made to perform a repeat test consisting of the 
hemolysis tests described in section 12.7.4 within 72 hours in addition to the prescribed tests
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Table 9
STUDY EPOCH 2 – Year 2 and Year 3
Clinical Laboratory Assessments
Assessments 
Routinely Performed Pre-
Infusion, Unless Stated 
Otherwise
Visit in Study Epoch 2 (Visit +/- 2 Weeks)
Month 15
Month 18
Month 21
Month 24
Month 27
Month 30
Month 33
Month 36/
Study Completion/
Termination Visit, 
if Applicablea
Location
Site
Site
Site
Site
Site
Site
Site
Site
Hematology
x
x
x
x
Clinical Chemistry
x
x
x
x
Urinalysis
x
x
x
x
Pregnancy Test in females of 
childbearing potential – Urine
x
Viral Pathogen Serology
x
Hemolysis Testsb
x
Specific Antibody Tests
x
IgG Trough Levels and IgG 
Subclasses
x
x
x
x
Antibodies to rHuPH20
x
x
x
x
x
x
x
x
a    In case a subject has an anti-rHuPH20 antibody titer ≥ 160 and experiences a related serious or severe AE, the subject may go to Study Epoch 3 and 
will have the Study Completion/Termination Visit at the end of this Epoch.
b   If there is a reduction in Hgb of two g/dL or more compared to baseline Hgb, every effort is to be made to perform a repeat test consisting of the 
hemolysis tests described in section 12.7.4 within 72 hours
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Table 10
STUDY EPOCH 3
Clinical Laboratory Assessments
Assessments Routinely 
Performed Pre-Infusion, 
Unless Stated Otherwise
Visit in Study Epoch 3 (Visit +/- 2 Weeks)
Month 0
Month 3
Month 6
Months 9
Month 12/
Study Completion/
Termination Visit
Location
Site
Site
Site
Site
Site
Hematology
x
x
x
Clinical Chemistry
x
x
x
Urinalysis
x
x
x
Pregnancy Test in females of 
childbearing potential – Urine
x
Viral Pathogen Serology
x
Hemolysis Test
x
Specific Antibody Tests
x
IgG Trough Levels and IgG 
Subclasses
x
x
x
Antibodies to rHuPH20
x
x
x
x
x
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20.4 Toxicity Grading Scale for Laboratory Values
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.
Normal
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
Normal
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; BUN=blood urea nitrogen; 
ECOG=Eastern Cooperative Oncology Group; LDH=lactate dehydrogenase; N/A=not applicable; ULN=upper limit of normal; 
WBC=white blood cell; WHO=World Health Organization; WNL=within normal limits.
a Grade refers to severity: 1=mild, 2=moderate, 3=severe, 4=life-threatening or disabling, 5 (not shown in the table)=death. Grading scale criteria taken 
from ECOG 41 and WHO 42 guidelines, with the exception of LDH that uses the same thresholds as defined for ALT and AST
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21. REFERENCES
1. Picard C, Al-Herz W, Bousfiha A et al. Primary immunodeficiency diseases: An 
update on the classification from the International Union of Immunological 
Societies Expert Committee for Pri mary Immunodeficiency 2015. J.Clin.Immunol. 
2015;35:696-726.
3. Bruton OC. Agammaglobulinemia. Pediatrics. 1952;9:722-728.
4. Rosen FS, Cooper MD, Wedgwood RJ. The primary immunodeficiencies. 
N.Engl.J.Med. 1995;333:431-440.
5. Wolin MJ, Gale RP. IVIG in bone marrow transplantation. In: Lee ML, Strand V, 
eds. Intravenous Immunoglobulins in Clinical Practice. New York: Marcel Dekker, 
Inc.; 1997:113-118.
6. Griffiths H, Chapel H. Prevention of infections in B-cell lymphoproliferative 
diseeases. In: Lee ML, Strand V, eds. Intravenous Immunoglobulins in Clinical 
Practice. New York: Marcel Dekker; 1997:203-223.
7. Rechtman DJ. Use of intravenous immune globulin in adults with HIV disease. In: 
Lee ML, Strand V, eds. Intravenous Immunoglobulins in Clinical Practice. New 
York: Marcel Dekker, Inc.; 1997:167-174.
8. Abdel-Mageed A, Graham-Pole J, Del Rosario ML et al. Comparison of two doses 
of intravenous immunoglobulin after allogeneic bone marrow transplants. Bone 
Marrow Transplant. 1999;23:929-932.
9. George JN, Raskob GE. Idiopathic thrombocytopenic purpura: diagnosis and 
management. Am.J.Med.Sci. 1998;316:87-93.
10. Imbach P, Akatsuka J, Blanchette V et al. Immunthrombocytopenic purpura as a 
model for pathogenesis and treatment of autoimmunity. Eur.J.Pediatr. 
1995;154:S60-S64.
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11. McMillan R. The pathogenesis of chronic immune (idiopathic) thrombocytopenic 
purpura. Semin.Hematol. 2000;37:5-9.
12. Barron KS, Murphy DJ, Jr., Silverman ED et al. Treatment of Kawasaki syndrome: 
a comparison of two dosage regimens of intravenously administered immune 
globulin. J.Pediatr. 1990;117:638-644.
13. Rosenfeld EA, Shulman ST, Corydon KE et al. Comparative safety and efficacy of 
two immune globulin products in Kawasaki disease. J.Pediatr. 1995;126:1000-
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14. Hahn AF, Beydoun SR, Lawson V et al. A controlled trial of intravenous 
immunoglobulin in multifocal motor neuropathy. J.Peripher.Nerv.Syst. 
2013;18:321-330.
15. Rozman C, Montserrat E. Chronic lymphocytic leukemia. N.Engl.J.Med. 
1995;333:1052-1057.
16. Kyle RA, Rajkumar SV. Multiple myeloma. N.Engl.J.Med. 2004;351:1860-1873.
17. Gardulf A, Nicolay U, Asensio O et al. Rapid subcutaneous IgG replacement 
therapy is effective and safe in children and adults with primary 
immunodeficiencies - A prospective multi-national study. J.Clin.Immunol. 
2006;26:177-185.
18. Ochs HD, Gupta S, Kiessling P et al. Safety and efficacy of self-administered 
subcutaneous immunoglobulin in patients with primary immunodeficiency diseases. 
J.Clin.Immunol. 2006;26:265-273.
19. Berger M, Cupps TR, Fauci AS. Immunoglobulin replacement therapy by slow 
subcutaneous infusion. Ann.Intern.Med. 1980;93:55-56.
20. Welch MJ, Stiehm ER. Slow subcutaneous immunoglobulin therapy in a patient 
with reactions to intramuscular immunglobulin. J.Clin.Immunol. 1983;3:285-286.
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21. Roord JJ, van der Meer JW, Kuis W et al. Home treatment in patients with antibody 
deficiency by slow subcutaneous infusion of gammaglobulin. Lancet 1982;1:689-
690.
22. Gardulf A, Björvell H, Gustafson R, Hammarström L, Smith CI. Safety of rapid 
subcutaneous gammaglobulin infusions in patients with primary antibody 
deficiency. Immunodeficiency. 1993;4:81-84.
23. Gustafson R, Gardulf A, Hansen S et al. Rapid subcutaneous immunoglobulin 
administration every second week results in high and stable serum immunoglobulin 
G levels in patients with primary antibody deficiencies. Clin.Exp.Immunol. 
2008;152:274-279.
24. Gardulf A, Andersen V, Björkander J et al. Subcutaneous immunoglobulin 
replacement in patients with primary antibody deficiencies: safety and costs. Lancet 
1995;345:365-369.
25. Gardulf A, Hammarström L, Smith CI. Home treatment of 
hypogammaglobulinaemia with subcutaneous gammaglobulin by rapid infusion. 
Lancet 1991;338:162-166.
26. Gardulf A, Hammarström L. Subcutaneous administration of immunoglobulins.  
What are the advantages? Clin.Immunother. 1996;6:108-116.
27. Schiff RI, Rudd C. Alterations in the half-life and clearance of IgG during therapy 
with intravenous gamma-globulin in 16 patients with severe primary humoral 
immunodeficiency. J.Clin.Immunol. 1986;6:256-264.
28. Smith GN, Griffiths B, Mollison D, Mollison PL. Uptake of IgG after intramuscular 
and subcutaneous injection. Lancet 1972;1:1208-1212.
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29. ZLB Behring. Immune Globulin Subcutaneous (Human), Vivaglobin®. US Label.  
8. 2006. 
Link to Publisher´s Site: 
http://www.fda.gov/downloads/BiologicsBloodVaccines/BloodBloodProducts/Appr
ovedProducts/LicensedProductsBLAs/FractionatedPlasmaProducts/ucm070360.pdf
30. Wasserman RL, Melamed I, Nelson RP, Jr. et al. Pharmacokinetics of subcutaneous 
IgPro20 in patients with primary immunodeficiency. Clin.Pharmacokinet. 
2011;50:405-414.
31. Supersaxo A, Hein WR, Steffen H. Effect of molecular weight on the lymphatic 
absorption of water-soluble compounds following subcutaneous administration. 
Pharm.Res. 1990;7:167-169.
32. Olsson O, Löjgren O. Hyaluronidase as a factor hastening the spread and absorption 
of water-soluble radiopaque substances deposited intracutaneously, subcutaneously, 
or intramuscularly. Acta Radiol. 1949;31:250-256.
33. Thomas JR, Yocum RC, Haller MF, von Gunten CF. Assessing the role of human 
recombinant hyaluronidase in gravity-driven subcutaneous hydration: The INFUSE-
LR Study. J.Palliat.Med. 2007;10:1312-1320.
34. Shpilberg O, Jackisch C. Subcutaneous administration of rituximab (MabThera) and 
trastuzumab (Herceptin) using hyaluronidase. Br.J.Cancer 2013;109:1556-1561.
35. Yocum RC, Kennard D, Heiner LS. Assessment and implication of the allergic 
sensitivity to a single dose of recombinant human hyaluronidase injection: a double-
blind, placebo-controlled clinical trial. J.Infus.Nurs. 2007;30:293-299.
36. Rosengren S, Dychter SS, Printz MA et al. Clinical immunogenicity of rHuPH20, a 
hyaluronidase enabling subcutaneous drug administration. AAPS J. 2015;17:1144-
1156.
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37. Melamed IR, Stein MR, Wasserman RL et al. Recombinant human hyaluronidase 
facilitates dispersion of subcutaneously administered Gammagard Liquid and 
enables administration of a full monthly dose in a single site to patients with 
immunodeficiency diseases [abstract]. J.Allergy Clin.Immunol. 2008;121:S83.
38. Wasserman RL, Melamed I, Stein MR et al. Recombinant human hyaluronidase-
facilitated subcutaneous infusion of human immunoglobulins for primary 
immunodeficiency. J.Allergy Clin.Immunol. 2012;130:951-957.e11.
39. Varni JW, Seid M, Rode CA. The PedsQL: measurement model for the pediatric 
quality of life inventory. Med.Care 1999;37:126-139.
40. Rabin R, de Charro F. EQ-5D: A measure of health status from the EuroQol Group. 
Ann.Med. 2001;33:337-343.
41. Oken MM, Creech RH, Tormey DC et al. Toxicity and response criteria of the 
Eastern Cooperative Oncology Group. Am.J.Clin.Oncol. 1982;5:649-655.
42. World Health Organization. Toxicity grading scale for determining the severity of 
adverse events.  96. 2-20-2003.  World Health Organization (WHO). 
Link to Publisher´s Site: 
http://www.icssc.org/Documents/Resources/AEManual2003AppendicesFebruary_0
6_2003%20final.pdf
43. U.S.Department of Health and Human Services, Food and Drug Administration, 
and 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.  17. 2008.  U.S. Department of Health and Human Services, 
Food and Drug Administration (FDA). 
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44. Committee for Medicinal Products for Human Use. Guideline on the clinical 
investigation of human normal immunoglobulin for subcutaneous and/or 
intramuscular administration (SCIg/IMIg). EMA/CHMP/BPWP/410415/2011 rev 1, 
10. 7-23-2015.  European Medicines Agency (EMEA). 
Link to Publisher´s Site: 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/201
5/07/WC500190211.pdf
45. Goldstein B, Giroir B, Randolph A. International pediatric sepsis consensus 
conference: definitions for sepsis and organ dysfunction in pediatrics. 
Pediatr.Crit.Care Med. 2005;6:2-8.
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6.
Section 3 Synopsis, 
Section 8.2.3 Epoch 3
Description of Change: The sentence “These subjects complete the study 
termination/completion visit when the AE/SAE resolves and the anti-rHuPH20 
titer is < 2560.” was changed to “These subjects complete the study 
termination/completion visit when the AE/SAE resolves or the anti-rHuPH20 titer 
is < 2560.”
Purpose for Change: Only one condition must be met to complete the study.
7.
Section 3 Synopsis, 
Section 6.4.2 KIOVIG,
Description of Change: References to the Investigator´s Brochure (IB) for 
KIOVIG were deleted, the term “product information” was replaced by “SmPC”.
Purpose for Change: KIOVIG is a registered product. Reference information is 
provided in the SmPC, no IB will be made available for KIOVIG.
8.
Section 3 Synopsis, 
Section 8.7.3.3 Cuvitru
Description of Change: Reference to the SUBCUVIA product information was 
replaced by a reference to the Cuvitru SmPC.
Purpose for Change: Cuvitru will be used instead of SUBCUVIA.
Description of Change: The dosage frequency of product administration was 
changed from “Once every week or biweekly” to “daily to once every two weeks, 
at the investigator´s discretion”.
Purpose for Change: To match the dosing frequency suggestions of the SmPC for 
Cuvitru.
9.
Section 3 Synopsis, 
Section 9.1 Inclusion Criteria
Description of Change: “…and by diagnostic criteria according to Conley et al.2” 
was removed.
Purpose for Change: Not applicable.
10.
Section 3 Synopsis, 
Section 9.2 Exclusion Criteria
Description of Change: “…in the opinion of the investigator.” Was added at the 
end of the sentence describing it. 9.
Purpose for Change: To clarify assessment criteria for “severe dermatitis”.
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11.
Section 6.1.2 KIOVIG 100 mg/ml solution for infusion and Cuvitru
200 mg/ml solution for injection; 
Section 8.7.1.4 Cuvitru
Description of Change: The description of SUBCUVIA was replaced by the 
description of Cuvitru. 
Purpose for Change: To provide information on Cuvitru. SUBCUVIA may no 
longer be available in countries with participating sites at a certain stage of the 
study. To prevent issues with product supply, Cuvitru will be used instead.
12.
Section 6.1.2 KIOVIG 100 mg/ml solution for infusion and Cuvitru
200 mg/ml solution for injection; 
Section 8.7.1.4 Cuvitru
Description of Change: The description of SUBCUVIA was replaced by the 
description of Cuvitru. 
Purpose for Change: To provide information on Cuvitru. SUBCUVIA may no 
longer be available in countries with participating sites at a certain stage of the 
study. To prevent issues with product supply, Cuvitru will be used instead.
13.
Section 6.4.1 HyQvia
Description of Change: The reference to the IB for Immune Globulin Infusion 
10% (Human) with Recombinant Human Hyaluronidase (IGI, 10% with 
rHuPH20) as well as Prescribing Information for HyQvia was deleted.
Purpose for Change: HyQvia is a registered product. Reference information will 
be provided in the SmPC. An IB or local prescribing information will not be 
provided by the Sponsor.
14.
Section 8.2 Overall Study Design
Description of Change: “Female subjects of childbearing potential should employ 
birth control measures as advised by the investigator or per the site´s standard 
recommendations for the duration of the study.
Purpose for Change: Clarify expectations as to which birth control measures are 
considered adequate.
15.
Section 8.8 Source Data
Description of Change: “Source data for this study comprise the following” […]” 
was changed to “Source data for this study comprise, but are not limited to, the 
following: […]”.
Purpose for Change: For clarity.
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16.
Section 10.1 Informed Consent
Description of Change: A reference to Section 16.3. Informed Consent was added.
Wording (in italics) was added: “…is considered enrolled in the study and thus 
becomes a subject in the study”.
Purpose for Change: To cross-reference the procedure of obtaining informed 
consent, and to specifically define enrollment.
17.
Section 10.3 Screening and Study Visits
Description of Change: ”The study site is responsible for maintaining a screening 
log that includes all subjects who provided informed consent.” was replaced by 
“Screening will comprise all procedures to confirm subject eligibility. The 
investigator is responsible for maintaining a patient identification list that includes 
all enrolled subjects which includes the following information: subject´s full 
name, subject number, and site number.”
Purpose for Change: To define screening; for clarity.
Description of Change: The following paragraph was added “All screening 
procedures must be completed up to 31 days prior to the first infusion. If a subject 
is scheduled to receive a dose of IgG before eligibility is fully confirmed (eg due 
to the unavailability of lab results), the subject may continue receiving the IgG 
product used prior to enrolment. Subjects may be re-screened once.”
Purpose for Change: To specify timelines for screening, to provide an option to 
treat the subject in the time period between signing the informed consent and first
IP infusion, and to limit the number of re-screenings.
18.
Section 12.1.1.2 Suspected Unexpected Serious Adverse Reaction (SUSAR)
Description of Change: Section 12.1.1.2 was added. Former Section 12.1.2.3 
Safety Reporting was deleted.
Purpose for Change: To define SUSAR and clarify related reporting requirements.
19.
Section 12.1.2 Assessment of Adverse Events
Description of Change: Text in italics was added: “If an investigator becomes 
aware of an SAE occurring in a subject within 30 days after study completion, …”
Purpose for Change: To limit reportability of SAEs after study completion.
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20.
Section 12.7 Clinical Laboratory Parameters
Description of Change: A sentence “Blood drawing for trough levels will always 
take place before the infusion is administered.” was deleted from Section 12.7.5 
IgG Trough Levels and IgG Subclasses and Specific Antibodies, and was added to 
Section 12.7. instead.
Purpose for Change: To define the time point for blood drawing for all trough 
level measurements.
21.
Section 12.7.5 IgG Trough Levels and IgG Subclasses and Specific Antibody 
Tests
Description of Change: Types of specific antibodies were specified, and the time 
point for blood drawing was defined.
Purpose for Change: To clarify which types of specific antibodies will be 
measured, and to further clarify the time point of the blood draws.
22.
Section 15 Quality Control and Quality Assurance; 
Section 16 Ethics; 
Investigator Acknowledgement Pages
Description of Change: “… applicable regulatory requirements…” was changed 
to “…applicable national and local regulatory requirements…” throughout the 
sections´ text.
Purpose for Change: To further specify regulatory requirements and to match text 
to the latest applicable version of the Sponsor´s protocol template.
23.
Section 15.6 Non-Compliance with the Protocol
Description of Change: “… responsible EC is notified…” was changed to “… 
responsible EC and relevant competent authority is notified…”.
Purpose for Change: To further specify reporting requirements and to match text 
to the latest applicable version of the Sponsor’s protocol template.
24.
Section 16.1 Subject Privacy
Description of Change: Entire text of Section 16 was replaced.
Purpose for Change: To harmonize language with Shire´s requirements for 
standard privacy language after Baxalta becoming part of Shire.
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25.
Section 16.3 Informed Consent
Description of Change: Text in italics was changed or added: “All patients and/or 
their legally authorized representative must sign an informed consent form before 
enrollment into the study according to applicable national and local regulatory 
requirements and ICH GCP. The case history for each individual shall document 
that informed consent was obtained prior to participation in the study.”
Purpose for Change: To clarify expectations regarding the documentation of the 
IC process.
26.
Section 20.1 Study Flow Chart
Description of Change: A box “Screening” was added.
Purpose for Change: For clarity.
27.
Section 20.2 Table 6
Description of Change: HRQoL (PedsQL, EQ-5D Treatment Preference 
questionnaire, TSQM-9) assessments were removed from the table.
Purpose for Change: Subjects will not receive HyQvia during Epoch 3, therefore, 
no HRQoL assessments on HyQvia will be done
28.
Section 20.3 Table 6
Description of Change: Retention samples were deleted from the table.
Purpose for Change: No retention samples will be taken (section 12.7.9). 
29.
Section 20.3 Table 8
Description of Change: The same footnote as in Table 9 was added to Hemolysis 
Tests.
Purpose for Change: For clarity. 
30.
Section 20.3 Table 8
Description of Change: Text in footnote b. “.. tests described above …” was 
replaced by “tests described in section 12.7.4 ….”.
Purpose for Change: To correct reference.
31.
Section 20.3, Table 8
Description of Change: Specific antibody testing at visit month 6 was deleted.
Purpose for Change: The trough levels of specific antibodies will be measured 
only at the baseline and the study completion/termination visits.
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INVESTIGATOR ACKNOWLEDGEMENT
PRODUCT: HyQvia
STUDY TITLE: Post-Authorization Safety, Tolerability and Immunogenicity 
Evaluation of HyQvia in Pediatric Subjects with Primary Immunodeficiency Diseases
PROTOCOL IDENTIFIER: 161504
CLINICAL TRIAL PHASE 4
AMENDMENT 1: 2016 OCT 07
Replaces: ORIGINAL: 2016 MAR 16
ALL VERSIONS:
Amendment 1: 2016 OCT 07
ORIGINAL: 2016 MAR 16
Original: 2016 MAR 16OTHER ID(s)
NCT Number: Not Yet Available
EudraCT Number: 2016-003438-26
IND NUMBER: Not Applicable
By signing below, the investigator acknowledges that he/she has read and understands 
this protocol, and will comply with the requirements for obtaining informed consent from 
all study subjects prior to initiating any protocol-specific procedures, obtaining written 
initial and ongoing EC(s) protocol review and approval, understands and abides by the 
requirements for maintenance of source documentation, and provides assurance that this 
study will be conducted according to all requirements as defined in this protocol, Clinical 
Trial Agreement, ICH GCP guidelines, and all applicable national and local regulatory 
requirements.
Signature of Principal Investigator
Date
Print Name of Principal Investigator
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For non-commercial use only

PROTOCOL:
161504
Title:
Post-Authorization Safety, Tolerability and Immunogenicity 
Evaluation of HyQvia in Pediatric Subjects with Primary 
Immunodeficiency Diseases
Short Title:
Post-Authorization Safety, Tolerability and Immunogenicity 
Evaluation of HyQvia in Pediatric PIDD subjects
Study Phase:
Phase 4 
Drug:
HyQvia
IND Number:
Not Applicable
EUDRACT Number:
2016-003438-26
NCT Number
NCT03116347
Sponsor:
Baxalta US Inc.*
300 Shire Way, Lexington, MA 02421
UNITED STATES
AND
Baxalta Innovations GmbH*,
Industriestrasse 67, A-1221 Vienna 
AUSTRIA
*Baxalta is now part of Shire
Principal / 
Coordinating 
Investigator:
Multicenter
Protocol History:
Amendment 2: 2019 DEC 04
Replaces: Amendment 1: 2016 OCT 07
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.
For non-commercial use only

For non-commercial use only

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2. SERIOUS ADVERSE EVENT REPORTING
The investigator will comply with applicable laws/requirements for reporting serious 
adverse events (SAEs) to the ECs.
ALL SAEs, INCLUDING SUSARs, ARE TO BE REPORTED ON THE 
SERIOUS ADVERSE EVENT REPORT (SAER) FORM ANDTRANSMITTED TO 
THE SPONSOR WITHIN 24 HOURS AFTER BECOMING AWARE OF THE 
EVENT.
Drug Safety contact information: see SAE Report form.
Refer to SAE Protocol Sections and the study team roster for further information. 
For definitions and information on the assessment of these events, refer to the following:

AE, Section 12.1

SAE, Section 12.1.1.1

SUSARS, Section 12.1.1.2

Assessment of AEs, Section 12.1.2
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3. SYNOPSIS
INVESTIGATIONAL PRODUCT
Name of Investigational 
Product (IP)
1. HyQvia, Immune Globulin Infusion 10% (Human) with Recombinant 
Human Hyaluronidase PH20 (IGI, 10% with rHuPH20).
2. KIOVIG 100 mg/mL solution for infusion
3. Cuvitru 200 mg/mL solution for subcutaneous injection
(For better readability the names HyQvia, KIOVIG and Cuvitru will be 
used throughout the document.)
Name(s) of Active 
Ingredient(s)
Human Normal Immunoglobulin 
CLINICAL CONDITION(S)/INDICATION(S)

Primary Immunodeficiency Diseases (PIDD) 
PROTOCOL ID
161504
PROTOCOL TITLE
Post-Authorization Safety, Tolerability and Immunogenicity Evaluation 
of HyQvia in Pediatric Subjects with Primary Immunodeficiency Diseases
Short Title
Post-Authorization Safety, Tolerability and Immunogenicity Evaluation 
of HyQvia in Pediatric PIDD subjects
STUDY PHASE
Ph4 (post-authorization)
PLANNED STUDY PERIOD
Initiation
2016 
Primary Completion
2023 
Study Completion
2023 
Duration
Approximately seven years
STUDY OBJECTIVES AND PURPOSE
Study Purpose
The purpose of the study is to acquire additional data on safety, tolerability and immunogenicity of 
HyQvia in pediatric (age two to <18 years) subjects with Primary Immunodeficiency Diseases 
(PIDD).
Primary Objective
Safety of HyQvia treatment in pediatric subjects with PIDD who have received prior 
immunoglobulin therapy before enrollment into the study.
Secondary Objective(s)
Further safety assessments (e.g. immunogenicity), tolerability, characteristics of product 
administration and efficacy (immunoglobulin G [IgG] trough levels)
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STUDY DESIGN
Study Type/ Classification/ 
Discipline
Safety, Immunogenicity
Control Type
No control
Study Indication Type
Treatment
Intervention Model 
Single-group
Blinding/Masking
Open-label
Study Design
This study is a Phase 4, post-authorization, prospective, non-controlled, 
multicenter study to evaluate the safety, tolerability, and other 
parameters of subcutaneous (SC) treatment using HyQvia in 40 pediatric 
subjects with PIDD who have received immunoglobulin therapy before 
enrollment into this study. Subjects will have regular anti-recombinant 
human hyaluronidase PH20 (rHuPH20) antibody testing (binding and 
neutralizing anti-rHuPH20 antibody) throughout the study 
(approximately every three months).
Epoch 1: Pediatric patients with PIDD who are on non-HyQvia 
intravenous (IV) or SC treatment with immunoglobulin (IV-pretreated, 
SC pretreated) will be enrolled and treated with HyQvia subcutaneously 
with a dose or interval ramp-up period of up to six weeks. Subjects 
already treated with HyQvia (HyQvia pretreated) will be enrolled 
directly into Epoch 2. Epoch 1 infusions will be administered at the 
study site. 
Epoch 2: The ramp-up (Epoch 1) is followed by Epoch 2 with HyQvia 
treatment at the following intervals. For IV-pretreated subjects: every 
three or four weeks, depending on the subject’s previous IV dosing 
schedule. For SC-pretreated subjects: every three or four weeks, at the 
discretion of investigator and subject. For HyQvia pre-treated subjects: 
No change in frequency of administration. After one year in Epoch 2, 
the anti-rHuPH20 binding antibody assay results during that year will be 
used to decide the next steps in the study (see Section 20.1 Study Flow 
Chart). Subjects with anti-rHuPH20 antibody titer < 160 at all time-
points during the study will complete the study termination/completion 
visit at the next possible occasion. Subjects with anti-rHuPH20 antibody 
titer ≥ 160 during the study and/or at the last measurement will continue 
in Epoch 2 for an additional two years of HyQvia treatment and 
observation. 
The first two or three infusions during Epoch 2 will be administered at 
the study site. It is preferable that subsequent infusions be performed at 
home (or equivalent site) by the subject or caregiver, if in the opinion of 
the investigator, such treatment is safe and appropriate. 
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In that case, the investigator/designee must have trained the subject or 
caregiver and must be satisfied that the subject or caregiver is capable of 
self-administration of SC infusions at home before the subject or 
caregiver will be permitted to conduct the SC infusion at home.
Epoch 3: Epoch 3 is approximately one year safety follow-up, if needed; 
subjects whose anti-rHuPH20 antibody titer was ≥ 160 during Epoch 1 
or Epoch 2 and who experience either a related Serious Adverse Event 
(SAE) or a related severe Adverse Event (AE) will be followed 
accordingly.
Subjects in Epoch 3 will be treated with KIOVIG intravenously or 
Cuvitru subcutaneously, at the discretion of the investigator and the 
subject. 
In the event that a subject in Epoch 1 or in Epoch 2 experiences a related 
SAE or severe AE without anti-rHuPH20 antibody titer ≥ 160, the 
subject can (at the discretion of the investigator and subject) 1) be 
terminated from the study; or, 2) change directly to Epoch 3; or, 
3) continue in Epoch 1 or 2 with appropriate medical intervention such 
as decreasing the HyQvia infusion rate and/or premedication.
Subjects with antibody titer of ≥ 160 when entering Epoch 3 continue 
regular anti-rHuPH20 antibody testing (approximately every three 
months) for approximately one year. These subjects complete the study 
termination or completion visit when the AE or SAE resolves or the 
anti-rHuPH20 titer is <2560.
Infusions in Study Epoch 3 will be administered at home or at the study 
site.
The study termination/completion visit will be conducted at the study 
site.
Planned Duration of 
Subject Participation
Study Epoch 1 (Ramp-up): Up to six weeks for HyQvia-naïve subjects 
Study Epoch 2 (Final dosing): Up to three years
Study Epoch 3 (Safety Follow-up): Up to one year
The maximum subject participation period is approximately four years.
Primary Outcome Measure
1. Number and rate per infusion (excluding infections) of all severe related AEs
2. Number and rate per infusion (excluding infections) of related SAEs
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Secondary Outcome Measure(s) 
Efficacy
1. Trough levels of IgG (for Study Epochs 1 and 2) 
Safety 
1. Proportion of subjects who achieve a treatment interval of three or four weeks in Epoch 2 
2. Proportion of subjects who maintain a treatment interval of three or four weeks in Epoch 2 for 
12 months
3. Number and rate per infusion (excluding infections) of local AEs and Adverse Reactions (ARs)
4. Number and rate per infusion (excluding infections) of systemic AEs and ARs 
5. Number and rate per infusion (excluding infections) of all AEs and all ARs
6. Number and rate per infusion (excluding infections) of all temporally associated AEs 
7. Number and rate per infusion (excluding infections) of all causally related and/or temporally 
associated AEs
8. Number and rate per infusion (excluding infections) of all SAEs 
9. Number/proportion of subjects who develop positive titer (≥160) of binding or neutralizing 
antibodies to rHuPH20
10. Additional safety outcome measures include clinical laboratory outcomes: raw (actual) values and 
change from baseline, and vital signs: raw (actual) values and change from baseline
Mode of Product Administration (For Study Epochs 1 and 2)
1. Infusions
a. Number of infusions per month
b. Number of infusion sites (needle sticks) per infusion/month
c. Duration of infusion
d. Maximum infusion rate/site
e. Infusion volume/site
f.
Number/proportion of infusions that are discontinued, slowed, or interrupted due to an AE
2. Number of weeks to reach final dose interval (three weeks or four weeks)
3. Assessment of Treatment Preference Questionnaire
4. Assessment of Treatment Satisfaction Questionnaire for Medication: TSQM-9
5. Assessment of Health-related Quality of Life Questionnaires: Peds-QL, EQ-5D
Tertiary Outcome Measure(s) 
1. Number of acute serious bacterial infections
2. Number of all infections
3. Days not able to go to school/work or to perform normal daily activities due to infection or other 
illnesses
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4. Days on antibiotics
5. Number of hospitalizations, indication for the hospitalization (infection or non-infection) and days 
hospitalized
6. Number of acute physician visits (office and emergency room) due to infection or other illnesses
INVESTIGATIONAL PRODUCT(S), DOSE AND MODE OF ADMINISTRATION
Active 
Product
1. HyQvia Immune Globulin Infusion 10% (Human) with Recombinant Human 
Hyaluronidase
Subjects will be treated with HyQvia in Study Epoch 1 and Study Epoch 2.
Dosage Form: injectable
Mode of Administration: subcutaneous
Dosage Frequency:
Study Epoch 1 (Ramp-up): 
One treatment interval of one week, then one treatment interval of two weeks, 
then one treatment interval of three weeks (for subjects who are planned to be 
treated every four weeks)
Study Epoch 2 (Final dosing):
HyQvia dose once every three or four weeks:

For IV-pretreated subjects: every three or four weeks, depending on the 
subject’s previous IV dosing schedule. 

For SC-pretreated subjects: every three or four weeks, at the discretion of 
investigator and subject
Dose: HyQvia weekly dose will be equivalent to 100% (±5%) of pre-study 
treatment
Example for IgG dosing:
Pre-Study
Epoch 1 
(Ramp-Up)
Epoch 2 
(Final Dose)
Admin. 
Route
Dose
First 
Infusion at 
Baseline: 
1-Week Dose
Second 
Infusion at 
Week 1: 
2-Week Dose
Third 
Infusion at 
Week 3: 
3-Week Dose
IV
0.6 g/kg 
every 3 weeks
0.2 g/kg
0.4 g/kg
-
0.6 g/kg 
every 3 weeks
IV
0.6 g/kg 
every 4 weeks
0.15 g/kg
0.3 g/kg
0.45 g/kg
0.6 g/kg 
every 4 weeks
SC
0.1 g/kg 
every week
0.1 g/kg
0.2 g/kg
-
0.3 g/kg 
every 3 weeks
SC
0.1 g/kg 
every week
0.1 g/kg
0.2 g/kg
0.3 g/kg
0.4 g/kg 
every 4 weeks
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Infusion Rate:
Study Epoch 1 (Ramp-up): 

For subjects with a body weight (BW) of < 40 kg: 5 mL/h/site (at start) to 
80 mL/h/site (maximum, if tolerated)

For subjects with a BW of ≥ 40 kg: 10 mL/h/site (at start) to 240 mL/h/site 
(maximum, if tolerated)
Study Epoch 2 (Final dosing):

For subjects with a BW of < 40 kg: 10 mL/h/site (at start) to 160 mL/h/site 
(maximum, if tolerated)

For subjects with a BW of ≥ 40 kg: 10 mL/h/site (at start) to 300 mL/h/site 
(maximum, if tolerated)
If infusions have been tolerated after the subject has received two HyQvia 
infusions at the dose for the final infusion interval (three- or four-week dose),
then investigators may choose an infusion rate schedule at their own discretion.
2. KIOVIG
Subjects may be treated with KIOVIG in Study Epoch 3 (Safety Follow-up).
Dosage form: injectable
Mode of Administration: intravenous
The infusion rate and infusion volume per site will follow the suggestions of the 
KIOVIG SmPC. 
Dosage frequency: Once every three or four weeks 
Dose: The weekly dose will be equivalent to 100% (±5%) of the dose in the 
previous study epoch
3.
Cuvitru
Subjects may be treated with Cuvitru in Study Epoch 3 (Safety Follow-up).
Dosage form: Solution for injection
Mode of Administration: subcutaneous 
The infusion rate and infusion volume per site will follow the suggestions of the 
Cuvitru SmPC.
Dosage frequency: daily to once every two weeks, at the investigator´s discretion
Dose: The weekly dose will be equivalent to 100% (±5%) of the dose in the 
previous study epoch.
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SUBJECT SELECTION 
Targeted Accrual
Sample size: 40 pediatric subjects already on IgG treatment pre-study will be 
enrolled. The study will enroll approximately six subjects 2 to less than 6 years of 
age, 12 subjects 6 to <12 years of age, 22 subjects 12 to <18 years of age. The 
study will be conducted in the European Economic Area.
Study sites: Approximately 20
Number of Groups/ 
Arms/Cohorts
1
Inclusion Criteria
1. Subject must have a documented diagnosis of a form of primary humoral immunodeficiency 
involving a defect in antibody formation and requiring gammaglobulin replacement, as defined 
according to the International Union of Immunological Societies (IUIS) Scientific Committee 2015 
(Picard et al., 2015) prior to enrollment. The diagnosis must be confirmed by the sponsor´s 
Medical Director prior to first treatment with investigational product (IP) in the study. 
2. Subject is at least 2 years and below 18 years of age at the time of screening.
3. Subject has been receiving a consistent dose of IgG, administered in compliance with the 
respective product information for a period of at least three months prior to screening. The average 
minimum pre-study dose over that interval was equivalent to 300 mg/kg BW/4 weeks and a 
maximum dose equivalent to 1000 mg/kg BW/4 weeks.
4. Subject has a serum trough level of IgG >5 g/L at screening.
5. If female of childbearing potential, subject presents with a negative pregnancy test and agrees to 
employ adequate birth control measures for the duration of the study. 
6. Subject/legally authorized representative is willing and able to comply with the requirements of the 
protocol.
Exclusion Criteria
1. Subject has a known history of or is positive at screening for one or more of the following: 
hepatitis B surface antigen (HBsAg), polymerase chain reaction (PCR) for hepatitis C virus (HCV), 
PCR for human immunodeficiency virus (HIV) Type 1/2. 
2. Abnormal laboratory values at screening meeting any one of the following criteria (abnormal tests 
may be repeated once to determine if they are persistent):
a. Persistent alanine aminotransferase (ALT) and aspartate amino transferase (AST) >2.5 times 
the upper limit of normal (ULN) for the testing laboratory
b. Persistent severe neutropenia (defined as an absolute neutrophil count [ANC] 500/mm3)
3. Subject has anemia that would preclude phlebotomy for laboratory studies, according to standard 
practice at the site.
4. Subject has an ongoing history of hypersensitivity or persistent reactions (urticaria, breathing 
difficulty, severe hypotension, or anaphylaxis) following IV immunoglobulin, SC immunoglobulin, 
and/or Immune Serum Globulin (ISG) infusions.
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5. Subject has severe immunoglobulin A (IgA) deficiency (less than 7.0 mg/dL) with known anti-IgA 
antibodies and a history of hypersensitivity.
6. Subject has a known allergy to hyaluronidase.
7. Subject has active infection and is receiving antibiotic therapy for the treatment of infection at the 
time of screening.
8. Subject has a bleeding disorder or a platelet count less than 20,000/µL, or who, in the opinion of 
the investigator, would be at significant risk of increased bleeding or bruising as a result of SC 
therapy. 
9. Subject has severe dermatitis that would preclude adequate sites for safe product administration in 
the opinion of the investigator.
10. Subject has participated in another clinical study involving an IP or investigational device within 
30 days prior to enrollment or is scheduled to participate in another clinical study involving an IP 
or investigational device during the course of this study.
11. Subject is a family member or employee of the investigator.
12. If female, subject is pregnant or lactating at the time of enrollment.
STATISTICAL ANALYSIS
Sample Size Calculation
The planned sample size for the study is 40 pediatric subjects.
Planned Statistical Analysis
Statistical analyses and data displays will be mainly descriptive. Data from all enrolled subjects will be 
included in the analysis. All SAEs and non-serious AEs will be categorized according to Medical 
Dictionary for Regulatory Activities (MedDRA) system organ class and preferred term. All analyses 
will be performed using SAS® version 9.2 or higher (SAS Institute, Cary, NC, USA).
A single interim analysis is planned to be performed. The purpose of the analysis is to update the 
scientific community, on the interim safety, tolerability and immunogenicity of HyQvia in pediatric 
subjects with PIDD. Analysis is planned to be performed when 75% of all subjects (30 subjects if 40 are 
enrolled [dosed]) have completed 12 months of participation (1-year observation period) in Epoch 2. 
Data for the interim analysis will include, but are not limited to: safety/tolerability, infusion data, 
infections, and Healthcare Resource Utilization data. No statistical hypothesis testing will be performed 
in the interim analysis. No modifications to the study design, study conduct, or final analysis will be 
made during or after the interim analysis, and the analysis is not planned with the intention of deciding 
whether or not to terminate the study.
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4. TABLE OF CONTENTS
PROTOCOL SIGNATURE PAGE................................................................................. 2
Sponsor’s (Shire) Approval.......................................................................................... 2
Investigator’s Acknowledgement ................................................................................ 2
1. STUDY PERSONNEL.................................................................................................. 3
1.1 Authorized Representative (Signatory) / Responsible Party .............................. 3
1.2 Study Organization................................................................................................. 3
2. SERIOUS ADVERSE EVENT REPORTING........................................................... 4
3. SYNOPSIS..................................................................................................................... 5
4. TABLE OF CONTENTS ........................................................................................... 13
5. LIST OF ABBREVIATIONS .................................................................................... 19
6. BACKGROUND INFORMATION .......................................................................... 22
6.1 Description of Investigational Product ............................................................... 22
6.1.1 HyQvia............................................................................................................ 22
6.1.2 KIOVIG 100 mg/mL solution for infusion (Immune Globulin Infusion 
[IGI] 10%) and Cuvitru 200 mg/mL solution for subcutaneous injection23
6.1.3 Immunoglobulin Treatment.......................................................................... 24
6.1.4 Immunoglobulin and Hyaluronidase Treatment........................................ 26
6.2 Clinical Condition/Indication .............................................................................. 28
6.3 Findings from Nonclinical and Clinical Studies................................................. 28
6.3.1 Clinical Study 160602.................................................................................... 28
6.3.2 Clinical Study 160603.................................................................................... 29
6.3.2.1 Pharmacokinetic Properties .................................................................. 31
6.3.3 Clinical Study 160902.................................................................................... 32
6.3.3.1 Disposition of Subjects ........................................................................... 33
6.3.3.2 Extent of Exposure ................................................................................. 33
6.3.3.3 Efficacy .................................................................................................... 34
6.3.3.4 Safety........................................................................................................ 34
6.3.4 Clinical Study 161101.................................................................................... 36
6.3.5 HyQvia Pregnancy Registry 161301 ............................................................ 38
6.3.6 HyQvia PASS 161302 .................................................................................... 39
6.3.7 HyQvia Study 161406.................................................................................... 40
6.3.8 HYQVIA Study 161503................................................................................. 41
6.4 Evaluation of Anticipated Risks and Benefits of the Investigational Product(s) 
to Human Subjects................................................................................................ 42
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6.4.1 HyQvia............................................................................................................ 42
6.4.1.1 Pregnancy, Breast Feeding, Fertility .................................................... 43
6.4.2 KIOVIG.......................................................................................................... 43
6.4.3 Cuvitru............................................................................................................ 45
6.5 Compliance Statement.......................................................................................... 45
7. STUDY PURPOSE AND OBJECTIVES ................................................................. 45
7.1 Study Purpose ....................................................................................................... 45
7.2 Primary Objective................................................................................................. 45
7.3 Secondary Objectives ........................................................................................... 45
7.4 Tertiary Objectives............................................................................................... 45
8. STUDY DESIGN......................................................................................................... 46
8.1 Brief Summary...................................................................................................... 46
8.2 Overall Study Design............................................................................................ 46
8.2.1 Epoch 1............................................................................................................ 46
8.2.2 Epoch 2............................................................................................................ 47
8.2.3 Epoch 3............................................................................................................ 48
8.3 Duration of Study Period(s) and Subject Participation .................................... 48
8.4 Outcome Measures ............................................................................................... 49
8.4.1 Primary Outcome Measure........................................................................... 49
8.4.2 Secondary Outcome Measures ..................................................................... 49
8.4.2.1 Efficacy .................................................................................................... 49
8.4.2.2 Safety/Tolerability .................................................................................. 49
8.4.2.3 Mode of Product Administration .......................................................... 50
8.4.3 Tertiary Outcome Measures......................................................................... 50
8.4.4 Exploratory Outcomes Measure................................................................... 50
8.5 Randomization and Blinding............................................................................... 50
8.6 Study Stopping Rules............................................................................................ 51
8.7 Investigational Product(s) .................................................................................... 51
8.7.1 Packaging, Labeling, and Storage................................................................ 51
8.7.1.1 rHuPH20.................................................................................................. 51
8.7.1.2 IGI, 10%.................................................................................................. 51
8.7.1.3 KIOVIG (IGIV 10%) ............................................................................. 52
8.7.1.4 Cuvitru (IGSC 20%) .............................................................................. 52
8.7.2 Administration ............................................................................................... 52
8.7.3 Description of Treatment.............................................................................. 53
8.7.3.1 HyQvia..................................................................................................... 53
8.7.3.2 KIOVIG (IGI 10%)................................................................................ 55
8.7.3.3 Cuvitru (IGI 20%).................................................................................. 55
8.7.4 Investigational Product Accountability ....................................................... 56
8.8 Source Data ........................................................................................................... 56
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9. SUBJECT SELECTION, WITHDRAWAL, AND DISCONTINUATION .......... 57
9.1 Inclusion Criteria.................................................................................................. 57
9.2 Exclusion Criteria................................................................................................. 57
9.3 Withdrawal and Discontinuation ........................................................................ 58
10. STUDY PROCEDURES .......................................................................................... 60
10.1 Informed Consent ............................................................................................... 60
10.2 Subject Identification Code................................................................................ 60
10.3 Screening and Study Visits................................................................................. 60
10.4 Medications and Non-Drug Therapies.............................................................. 61
10.5 Subject Diary....................................................................................................... 62
10.6 Subject Completion/Discontinuation ................................................................ 63
10.7 Procedures for Monitoring Subject Compliance ............................................. 64
11. ASSESSMENT OF EFFICACY.............................................................................. 65
11.1 IgG Trough Levels.............................................................................................. 65
11.2 Treatment Preference Questionnaire................................................................ 65
11.3 Treatment Satisfaction Questionnaire for Medication.................................... 65
11.4 HRQoL Questionnaire ....................................................................................... 66
11.4.1 PedsQL.......................................................................................................... 66
11.4.2 EQ-5D ........................................................................................................... 66
12. ASSESSMENT OF SAFETY................................................................................... 67
12.1 Adverse Events.................................................................................................... 67
12.1.1 Definitions..................................................................................................... 67
12.1.1.1 Serious Adverse Event.......................................................................... 67
12.1.1.2 Suspected Unexpected Serious Adverse Reaction (SUSAR)............. 68
12.1.1.3 Non-Serious Adverse Event ................................................................. 68
12.1.1.4 Unexpected Adverse Events................................................................. 68
12.1.1.5 Preexisting Diseases.............................................................................. 69
12.1.2 Assessment of Adverse Events.................................................................... 69
12.1.2.1 Severity .................................................................................................. 70
12.1.2.2 Causality................................................................................................ 71
12.2 Urgent Safety Measures ..................................................................................... 72
12.3 Untoward Medical Occurrences........................................................................ 72
12.4 Non-Medical Complaints ................................................................................... 73
12.5 Medical, Medication, and Non-Drug Therapy History................................... 73
12.6 Physical Examinations........................................................................................ 73
12.7 Clinical Laboratory Parameters........................................................................ 74
12.7.1 Hematology and Clinical Chemistry.......................................................... 74
12.7.2 Urine Tests.................................................................................................... 74
12.7.3 Pregnancy Test............................................................................................. 74
12.7.4 Hemolysis Test.............................................................................................. 74
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12.7.5 IgG Trough Levels and IgG Subclasses and Specific Antibody Tests .... 75
12.7.6 Anti-rHuPH20 Antibodies .......................................................................... 75
12.7.7 Viral Pathogen Serology.............................................................................. 76
12.7.8 Assessment of Laboratory Values .............................................................. 76
12.7.8.1 Toxicity Grading Scale......................................................................... 76
12.7.8.2 Assessment of Abnormal Laboratory Values..................................... 76
12.7.9 Backup Samples and Biobanking............................................................... 77
12.8 Vital Signs............................................................................................................ 77
12.8.1 Screening....................................................................................................... 77
12.8.2 Infusion at Study Site .................................................................................. 77
12.8.3 Infusion at Home.......................................................................................... 77
12.8.4 End-of-Study ................................................................................................ 77
12.9 Acute Serious Bacterial Infections .................................................................... 78
12.9.1 Infection: Bacteremia/Sepsis(a).................................................................. 78
12.9.2 Infection: Bacterial Meningitis................................................................... 79
12.9.3 Infection: Osteomyelitis/Septic Arthritis................................................... 79
12.9.4 Infections: Bacterial Pneumonia(d) ........................................................... 80
12.9.5 Infection: Visceral Abscess ......................................................................... 81
13. STATISTICS............................................................................................................. 82
13.1 Sample Size and Power Calculations ................................................................ 82
13.2 Analysis Sets ........................................................................................................ 82
13.2.1 Full Analysis Set........................................................................................... 82
13.2.2 Per-Protocol Analysis Set............................................................................ 82
13.2.3 Safety Analysis Set....................................................................................... 82
13.3 Handling of Missing, Unused, and Spurious Data........................................... 82
13.4 Methods of Analysis............................................................................................ 83
13.4.1 Primary Outcome Measure......................................................................... 83
13.4.2 Secondary Outcome Measures ................................................................... 83
13.4.2.1 Efficacy .................................................................................................. 83
13.4.2.2 Safety...................................................................................................... 83
13.4.2.3 Mode of Product Administration (For Study Epochs 1 and 2) ........ 84
13.4.2.4 HRQoL................................................................................................... 85
13.4.3 Tertiary Outcome Measures....................................................................... 85
13.4.3.1 Infections ............................................................................................... 85
13.4.3.2 Healthcare Resource Utilization Endpoints....................................... 85
13.5 Planned Interim Analysis of the Study ............................................................. 86
13.5.1 Overview of Interim Analysis..................................................................... 86
13.5.2 Data for Interim Analysis............................................................................ 87
13.5.3 Methods of Interim Analysis....................................................................... 88
14. DIRECT ACCESS TO SOURCE DATA/DOCUMENTS .................................... 89
15. QUALITY CONTROL AND QUALITY ASSURANCE...................................... 90
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15.1 Investigator’s Responsibility.............................................................................. 90
15.1.1 Final Clinical Study Report ........................................................................ 90
15.2 Training ............................................................................................................... 90
15.3 Monitoring........................................................................................................... 90
15.4 Safety Monitoring ............................................................................................... 90
15.5 Auditing ............................................................................................................... 91
15.6 Non-Compliance with the Protocol ................................................................... 91
15.7 Laboratory and Reader Standardization ......................................................... 91
16. ETHICS ..................................................................................................................... 92
16.1 Subject Privacy ................................................................................................... 92
16.2 Ethics Committee and Regulatory Authorities................................................ 92
16.3 Informed Consent ............................................................................................... 92
17. DATA HANDLING AND RECORD KEEPING................................................... 94
17.1 Confidentiality Policy ......................................................................................... 94
17.2 Study Documentation and Case Report Forms ............................................... 94
17.3 Document and Data Retention........................................................................... 94
18. FINANCING AND INSURANCE........................................................................... 95
19. PUBLICATION POLICY........................................................................................ 95
20. SUPPLEMENTS....................................................................................................... 96
20.1 Study Flow Chart................................................................................................ 96
20.2 Schedule of Study Procedures and Assessments.............................................. 97
20.3 Clinical Laboratory Assessments .................................................................... 101
20.4 Toxicity Grading Scale for Laboratory Values.............................................. 105
21. REFERENCES........................................................................................................ 106
22. SUMMARY OF CHANGES.................................................................................. 114
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Tables
Table 1. Pharmacokinetic Parameters of HyQvia Compared to  Intravenous 
Administration of IGI 10%....................................................................................... 31
Table 2. Example for IgG dosing...................................................................................... 54
Table 3. STUDY EPOCH 1 – Ramp Up  Schedule of Study Procedures and Assessments
................................................................................................................................... 97
Table 4. STUDY EPOCH 2 – Year 1  Schedule of Study Procedures and Assessments. 98
Table 5. STUDY EPOCH 2 – Year 2 and Year 3 Schedule of Study Procedures and 
Assessments .............................................................................................................. 99
Table 6. STUDY EPOCH 3  Schedule of Study Procedures and Assessments.............. 100
Table 7. STUDY EPOCH 1 – Ramp Up  Clinical Laboratory Assessments.................. 101
Table 8. STUDY EPOCH 2 – Year 1  Clinical Laboratory Assessments ..................... 102
Table 9. STUDY EPOCH 2 – Year 2 and Year 3 Clinical Laboratory Assessments..... 103
Table 10. STUDY EPOCH 3 Clinical Laboratory Assessments .................................... 104
Table 11. Grading of Laboratory Parameters ................................................................. 105
Figures
Figure 1 Study Design for Clinical Study 161504........................................................... 96
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5. LIST OF ABBREVIATIONS
Abbreviation
Definition
ADR
Adverse drug reaction (i.e., related AE) 
AE
Adverse event
AR
Adverse reaction
AIDS
Acquired immune deficiency syndrome
ALP
Alkaline phosphatase
ALT 
Alanine amino transferase (SGPT)
ANC
Absolute neutrophil count
AST 
Aspartate amino transferase (SGOT)
AUC
Area under the curve
B19V
Parvovirus B19
BUN
Blood urea nitrogen
BW
Body weight
CHMP
Committee for Medicinal Products for Human Use
CLL
Chronic lymphocytic leukemia
CI
Confidence interval
Cmax
Maximum concentration
Cmin
Minimum concentration
CRF
Case report form
CSF
Cerebrospinal fluid
CT
Computed tomography
CXR
Chest x-ray
EC
Ethics committee
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic case report form
EDC
Electronic data capture
EDTA
Ethylenediamine tetracetic acid
ELISA
Enzyme-linked immunosorbent assay
EPR
Electronic Patient Reported 
EU
European Union
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Abbreviation
Definition
Fc
Crystallizable region of antibody
FDA
Food and Drug Administration
GCP
Good Clinical Practice
h, hr
Hour(s)
HAV
Hepatitis A virus
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HEV
Hepatitis E virus
Hgb
Hemoglobin
HIV 
Human immunodeficiency virus 
HRQoL
Health related quality of life
HSCT
Hematopoietic stem cell transplantation
ICF
Informed consent form
ICH
International Council for Harmonization
IgA
Immunoglobulin A
IgG
Immunoglobulin G
IGI
Immunoglobulin
IGIV
Immune globulin intravenous (human)
IGSC
Immune globulin subcutaneous (human)
IP
Investigational Product
ISG
Immune serum globulin
ISMC
Internal Safety Monitoring Committee
ITP
Idiopathic thrombocytopenic purpura 
IV
Intravenous
LDH
Lactate dehydrogenase 
MedDRA
Medical Dictionary for Regulatory Activities
min
Minute(s)
mL
Milliliter(s)
MM
Multiple myeloma
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Abbreviation
Definition
MMN
Multi-focal motor neuropathy
MRI
Magnetic resonance imaging
NMC
Non-medical complaint
PaCO2
Partial pressure (tension) of carbon dioxide
PASS
Post-authorization safety study
PCR
Polymerase chain reaction
PIDD
Primary immunodeficiency disease
PK
Pharmacokinetic(s)
RBC
Red blood cell (count)
rHuPH20
Recombinant human hyaluronidase PH20
SAP
Statistical analysis plan
S/D
Solvent/detergent
SAE
Serious adverse event
SAER
Serious adverse event report
SC
Subcutaneous
SCIG
Subcutaneous immunoglobulin G
SIC
Subject identification code
SmPC
Summary of product characteristics
Tmax
Time to maximum concentration
TRALI
Transfusion related acute lung injury
ULN
Upper limit of normal
VASBI
Validated acute serious bacterial infection
WBC
White blood cell (count)
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6. BACKGROUND INFORMATION
Purified human immunoglobulin G (IgG) preparations were first used in 1952 
for the treatment of patients with primary immunodeficiency diseases (PIDD), 
a class of disorders that result in increased susceptibility to infection, including 
both recurrent pyogenic infections secondary to defects of humoral immunity and 
opportunistic infections resulting from defects in cell-mediated immunity (Bruton, 1952, 
Rosen et al., 1995). Individuals with these disorders require replacement therapy with 
immunoglobulin products to prevent or reduce the severity of infections. In addition to 
PIDD syndromes, immunoglobulin preparations have been indicated for secondary 
immunodeficiencies, such as B-cell chronic lymphocytic leukemia (CLL), acquired 
immunodeficiency syndrome (AIDS), and immunodeficiency after bone marrow 
transplantation (Abdel-Mageed et al., 1999, Griffiths and Chapel, 1997, Rechtman, 1997, 
Wolin and Gale, 1997). Immunoglobulins are also effective in the management of 
autoimmune disorders, such as idiopathic thrombocytopenic purpura (ITP)
(George and Raskob, 1998, Imbach et al., 1995, McMillan, 2000), Kawasaki 
syndrome (Barron et al., 1990, Rosenfeld et al., 1995), and multi-focal motor 
neuropathy (MMN) (Hahn et al., 2013).
6.1 Description of Investigational Product
6.1.1 HyQvia
HyQvia 100 mg/mL solution for infusion for subcutaneous (SC) use is a dual vial unit
consisting of one vial of human normal immunoglobulin (Immune Globulin 10% or 
IG 10%) and one vial of recombinant human hyaluronidase PH20 (rHuPH20). 
The IG 10% component provides the therapeutic effect of this medicinal product. 
The rHuPH20 facilitates the dispersion and absorption of IG 10%.
Human normal immunoglobulin contains mainly IgG with a broad spectrum of 
opsonizing and neutralizing antibodies against infectious agents.
Human normal immunoglobulin contains the IgG antibodies present in the normal 
population. It is usually prepared from pooled human plasma from not fewer than 
1,000 donations. It has a distribution of IgG subclasses closely proportional to that in 
native human plasma. Adequate doses of human normal immunoglobulin may restore 
abnormally low IgG levels to the normal range.
rHuPH20 is a soluble recombinant form of human hyaluronidase that modifies the 
permeability of connective tissue through the hydrolysis of hyaluronan. 
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Hyaluronan is a polysaccharide found in the intercellular matrix of connective tissue and 
of certain specialized tissues. It is degraded by naturally occurring hyaluronidases 
and has a very fast natural turnover in SC tissue. As a permeation enhancer, rHuPH20 
depolymerizes hyaluronan, resulting in a temporary increase in the permeability of the 
interstitial matrix that facilitates more rapid dispersion and absorption and improved 
bioavailability of the IG 10%.
HyQvia therapeutic indications include:
Replacement therapy in adults, children and adolescents (0-18 years) in:

Primary immunodeficiency syndromes with impaired antibody production 

Hypogammaglobulinaemia and recurrent bacterial infections in patients with 
chronic lymphocytic leukaemia (CLL), in whom prophylactic antibiotics have 
failed or are contra indicated.

Hypogammaglobulinaemia and recurrent bacterial infections in multiple myeloma 
(MM) patients.

Hypogammaglobulinaemia in patients pre- and post allogeneic hematopoietic stem 
cell transplantation (HSCT).
6.1.2 KIOVIG 100 mg/mL solution for infusion (Immune Globulin Infusion 
[IGI] 10%) and Cuvitru 200 mg/mL solution for subcutaneous injection
KIOVIG is a liquid unmodified IgG preparation with an osmolality that is similar to 
physiologic osmolality and contains no added sugars, sodium, or preservatives. The 
manufacturing process includes three independent, validated viral inactivation or removal 
steps: solvent/detergent (S/D) treatment, nanofiltration and incubation at a low pH and 
elevated temperature. The product contains immunoglobulins with intact Fc regions 
(crystallizable region of the antibody) in isotonic solution including glycine for 
stabilization. KIOVIG is a ready-to-use 10% liquid preparation.
A detailed description of KIOVIG is provided in the Summary of Product Characteristics 
(SmPC). 
Cuvitru 200 mg/mL solution for subcutaneous injection is a ready-for-use sterile, liquid 
preparation of highly purified, concentrated, functionally intact human IgG.
Therapeutic indications include replacement therapy in adults, and children and 
adolescents (0-18 years) with
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
primary immunodeficiency syndromes with impaired antibody production

hypogammaglobulinaemia and recurrent bacterial infections in patients with 
chronic lymphocytic leukaemia (CLL), in whom prophylactic antibiotics have 
failed or are contra-indicated

hypogammaglobulinaemia and recurrent bacterial infections in multiple 
myeloma (MM) patients

hypogammaglobulinaemia in patient’s pre- and post-allogeneic haematopoietic 
stem cell transplantation (HSCT).
A detailed description of Cuvitru is provided in the SmPC, which is available in those 
countries where Cuvitru is registered. In countries where Cuvitru is not registered, an IB 
will be available.
6.1.3 Immunoglobulin Treatment
Defective antibody formation, with or without decreased levels of serum 
immunoglobulins, is the most common abnormality in the majority of PIDD. It leads to 
increased susceptibility to viral and bacterial infections, especially of the sinopulmonary 
and gastrointestinal tracts. Decreased immunoglobulin levels are found not only in the 
group made up predominantly of antibody defects (e.g., X-linked agammaglobulinemia, 
selective IgG subclass deficiency, common variable immunodeficiency, or X-linked 
hyperimmunoglobulin M syndrome), but also in the group of combined 
immunodeficiencies (e.g., severe combined immunodeficiency, Wiskott-Aldrich 
Syndrome) that have defects in both T- and B-cells (Picard et al., 2015). 
Immunoglobulin treatment to prevent infections is also performed in Secondary 
Immunodeficiencies, such as CLL or multiple myeloma (MM). CLL is the most frequent 
form of leukemia in Western countries. It is characterized by the clonal proliferation and 
accumulation of neoplastic B lymphocytes in the blood, bone marrow, lymph nodes, and 
spleen (Rozman and Montserrat, 1995). MM is a plasma-cell neoplasm that is 
characterized by skeletal destruction, renal failure, anemia, hypercalcemia but also 
recurrent infections (Kyle and Rajkumar, 2004). 
Individuals with PIDD require lifelong replacement therapy with immunoglobulin 
products to prevent or reduce severity of infections. Initially, immunoglobulin 
replacement therapy was given by the intramuscular route, however, since the early 
1980s in the US, the overwhelming majority of patients have been treated by the 
intravenous (IV) route. In the past several years SC administration has gained popularity. 
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Currently, the majority of immunoglobulin products in the US are licensed for IV 
administration; though, in December 2005, the first SC preparation was licensed by 
ZLB-Behring (Gardulf et al., 2006, Ochs et al., 2006). SC administration of 
immunoglobulin preparations for PIDD patients has been accepted in many countries 
worldwide and is the predominant mode in the Scandinavian countries, particularly in 
Sweden. The first attempts, in the late 1970s, used intramuscular preparations 
administered at slow infusion rates, but in later years rapid infusion rates have been used 
more successfully (Berger et al., 1980, Gardulf et al., 1993, Gustafson et al., 2008, 
Roord et al., 1982, Welch and Stiehm, 1983). 
All of the gammaglobulin preparations licensed for SC use are formulated at 10-20%. 
Commonly they are formulated at 16% and are similar to Cohn Fraction II, therefore, 
they cannot be infused intravenously. The higher concentration, relative to IV 
preparations that are formulated at 5% to 12%, allows for a smaller infusion volume. 
This method of immunoglobulin replacement therapy is considered to be effective, 
safe and also highly appreciated by patients, as it has a low risk of systemic adverse 
reactions (ARs). When given weekly or every other week, SC IgG leads to higher trough 
serum IgG concentrations than monthly IV infusions (at the same monthly dose) 
(Gardulf et al., 1995, Gardulf et al., 1991). After adequate training by healthcare 
professionals, SC infusions of immunoglobulin can easily be performed by many 
patients at home, thus increasing patient comfort and independence and reducing cost 
(Gardulf and Hammarström, 1996).
Immunoglobulin administered intravenously is immediately available in the blood, 
and slowly equilibrates to the extra-vascular compartment over three to five days 
(Schiff and Rudd, 1986). Subcutaneously administered immunoglobulin is slowly 
absorbed from the SC space into the blood and at the same time equilibrates with the 
extra-vascular compartment. Consequently, there is no high spike in the IgG 
concentration as is seen following IV infusion. A study in 1972 by Smith, et al., used 
pharmacokinetic (PK) modeling and determined that the bioavailability of SC and IM 
was 100% when compared to IV (Smith et al., 1972). More recent studies mandated by 
the Food and Drug Administration (FDA) showed that the bioavailability (measured as 
the area under the curve (AUC) of immune globulin concentration over time) of SC 
immunoglobulin is lower than that of IV immunoglobulin (Ochs et al., 2006, 
ZLB Behring, 2006). Accordingly, it is recommended that the dose of SC 
immunoglobulin be adjusted to 137-153% of the IV dose to provide a comparable 
IgG exposure (Ochs et al., 2006, Wasserman et al., 2011).
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Despite the technical difficulties of comparing AUC for two different routes and 
frequencies of administration, studies of intradermally administered immunoglobulin 
in ratsi suggest that there is decreased bioavailability through the SC route. This may 
be due to the mode of absorption of large protein molecules, which cannot readily 
diffuse through the capillary walls and must be absorbed via the lymphatics 
(Supersaxo et al., 1990).
The primary practical disadvantage of SC administration of immunoglobulin is that only 
small volumes can be infused at each site, necessitating the use of multiple sites on a 
weekly or biweekly (every-other-week) basis. Generally, using a 16% solution, 
approximately 20 mL can be infused per site; an adult patient receiving 400 mg/kg body 
weight (BW) thus would require at least three sites per week or 12 sites per month. 
Even though weekly or biweekly administration has the benefit of maintaining better IgG 
trough levels than monthly IV infusions, the requirement for multiple needle insertions 
may deter many patients.
6.1.4 Immunoglobulin and Hyaluronidase Treatment
The SC space is formed by a collagen and elastin network filled with a gel-like substance, 
hyaluronan or hyaluronic acid. It is largely responsible for the resistance to fluid flow 
through this tissue. Hyaluronidase derived from sheep or cows has been used for the last 
sixty years to depolymerize the hyaluronan and facilitate SC infusions of fluids for re-
hydration (Olsson and Löjgren, 1949). rHuPH20 is a 61 kd protein genetically engineered 
from the sequence of the naturally occurring human protein. It temporarily depolymerizes 
the hyaluronan, decreasing the resistance to fluid flow and thus facilitating infusions into 
the SC space. The high molecular weight hyaluronan has a rapid turnover and is restored 
within 24 to 48 h, leaving no observable histopathologic changesii. Weekly infusions into 
cynomolgus monkeys for 39 weeks in doses up to two mg/kg (> 1,000-fold higher than 
the HyQvia dose in humans) did not lead to adverse reactionsiii. Infusion of rHuPH20 
improved the absorption and bioavailability of intradermally injected IgG in rabbits, 
pegylated interferon and infliximab in rats, and increased the rate of infusion and comfort 
of infusions of lactated Ringer’s solution in the arms of adult human volunteers three- to 
four-fold (Thomas et al., 2007). Studies investigating the effects of rHuPH20 on SC 
infusions of large quantities of IgG in dogs and rabbits have been difficult to interpret due 
to the rapid absorption of IgG alone in this model. However, at higher doses of rHuPH20, 
bioavailability seemed to increase. The human SC compartment is much tighter than that 
of these animal species and thus, human studies were required. 
                                                
i
Halozyme Report Number R1005-0551
ii
Halozyme Report R08014
iii
Halozyme Report R09050
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rHuPH20 can facilitate absorption of small molecules such as insulin and morphine in 
humans; in phase 1 trials rHuPH20 improved the bioavailability of proteins such as 
infliximabiv and enabled drug dispensation and absorption at the administration site of 
rituximab and trastuzumab (Shpilberg and Jackisch, 2013). In a phase 1/2 clinical study 
of HyQvia (Study 160602) the average bioavailability of the IgG in seven subjects was 
92%, suggesting a significant improvement compared to SC administration in the absence 
of rHuPH20.
The immunogenicity of rHuPH20 has been monitored in a number of clinical trialsv
(Bass et al., 2018, Clemens PL et al., 2018, Riedl et al., 2016, Rosengren et al., 2015). 
No positive skin reactions were observed when rHuPH20 was administered to 
100 healthy volunteers in a skin allergy clinical trial (Yocum et al., 2007). In Study 
160603, a total of 13 subjects had at least one plasma sample that tested positive for 
rHuPH20-binding antibodies (positivity defined as a sample with a titer of ≥ 160) 
following HyQvia treatment. The peak of the observed positive titers ranged from 160 up 
to 81,920 and declined during the long-term extension study despite continued exposure 
to rHuPH20. None of these samples contained neutralizing antibodies. No local or 
systemic reactions were attributed to the presence of anti-rHuPH20 antibodies. Based 
upon data available to date, including data from long-term exposure in Study 160902 
(63 subjects received HyQvia for a total number of 187.7 subject-years), the incidence of 
the formation of anti-rHuPH20 binding antibodies is 18%, no neutralizing antibodies 
have been observed, no clinical signs or symptoms have been associated with positive 
anti-rHuPH20 binding antibody titers. In addition, there was no evidence of a lack of 
treatment effect when rHuPH20-binding antibodies were detected.
Antibodies reactive to rHuPH20 have also been identified in the normal population with a 
prevalence between 3 and 12% (Rosengren et al., 2015, Rosengren et al., 2018). No 
signal of associated infertility or autoimmune/inflammatory condition could be identified.
Non-clinical data for rHuPH20 or antibodies to rHuPH20 reveal no special hazard for 
humans based on conventional studies of safety pharmacology, repeated dose toxicity and 
developmental toxicity. Reversible effects on fertility have been reported in male and 
female guinea pigs immunized to produce antibodies to hyaluronidase. 
However, antibodies to hyaluronidase did not influence reproduction in mouse, rabbit, 
sheep, or cynomolgus monkey. 
                                                
iv
Halozyme Report R05109
v
Halozyme Report Number 10059.
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6.2 Clinical Condition/Indication 
Primary antibody deficiencies are characterized by decreased serum levels of 
immunoglobulin isotypes and increased susceptibility to infection by various 
microorganisms, including encapsulated bacteria. Treatment with immunoglobulins is 
indicated whenever there is a defect in antibody production, regardless of the actual level 
of IgG. Studies have clearly demonstrated that antibody replacement reduces the number 
and severity of patients’ symptoms and infections as immunoglobulins are able to 
neutralize infectious agents, enhance phagocytosis, and modulate the immune response. 
Antibody replacement can be accomplished either intravenously or subcutaneously.
6.3 Findings from Nonclinical and Clinical Studies
6.3.1 Clinical Study 160602
Phase I/II Determination of the Dose of Recombinant Human Hyaluronidase 
Required Enabling up to 600 mg/kg Body Weight of Immune Globin Intravenous 
(Human) 10% to be Administered Subcutaneously in a Single Infusion Site in 
Subjects with Primary Immunodeficiency Disease
This study was a prospective, open-label, non-controlled, two-arm, multicenter study 
with the aim of determining the dose of rHuPH20 necessary to infuse a full four-week 
dose of Immune globulin intravenous (IGIV) 10% in a single SC site with good 
tolerability (Melamed et al., 2008). An infusion was defined as having been tolerated if it 
caused no more than mild local adverse drug reactions (ADRs) (e.g., minimal swelling, 
redness, or pain) that the investigator did not assess as unacceptable for other medical 
reasons. All infusions were administered at the study site. 
A total of 11 adult subjects (four male, seven female) participated in the study. In Study 
Arm 1, four adult/adolescent subjects received only SC infusions of IGIV 10% to 
determine tolerability. After this initial assessment of tolerability, seven subjects (five 
female and two male) were enrolled in Study Arm 2 for determination of tolerability of 
SC infusions as described for Study Arm 1 and for comparison of PK parameters 
obtained after IV and SC administration of IGIV 10% in the initial phase of Study Arm 2. 
The only severe and potentially life-threatening adverse event (AE) that occurred in the 
study was an anaphylactic reaction that was attributed to an antibiotic drug taken 
immediately prior to onset of the symptoms. This serious adverse event (SAE) occurred 
more than 24 hours after an infusion and was not considered related to use of the study 
drugs by the investigator. The subject continued in the study without further reactions. 
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All other AEs, which occurred in four subjects in Study Arm 1 and six of seven subjects 
in Study Arm 2, were non-serious local AEs, of which the majority were mild and none 
were severe. Local AEs included infusion site erythema, infusion site pain, infusion site 
edema, infusion site warmth, injection site pruritus, infusion site swelling, and symptoms 
categorized as infusion site reactions. 
The primary safety endpoint was the proportion of SC infusions, which were not 
interrupted or stopped due to AEs. Two SC infusions, one in each study arm, had to be 
interrupted due to mild infusion site pain and mild chest pain, respectively. In one subject 
in Study Arm 2, the infusion rate had to be decreased due to a mild infusion site reaction. 
In conclusion, this study of SC use of IGIV 10% facilitated by prior injection of 
rHuPH20 yielded initial favorable results in terms of tolerability of a full four-week dose 
of IGIV 10% administered by SC infusion in a single infusion site and in terms of 
bioavailability of IgG after SC administration.
6.3.2 Clinical Study 160603
Efficacy, Tolerability and Pharmacokinetic Comparison of Immune Globulin 
Intravenous (Human) 10% (GAMMAGARD LIQUID, KIOVIG) Administered 
Intravenously or Subcutaneously Following Administration of Recombinant Human 
Hyaluronidase (rHuPH20) in Subjects with Primary Immunodeficiency Diseases
Study 160603 was a prospective, open-label, non-controlled, multi-center, Phase III study 
(Wasserman et al., 2012). The purpose of the study was to develop a SC treatment option 
for subjects with PIDD that allows SC administration of GAMMAGARD 
LIQUID/KIOVIG at the same frequency as IV administration. The study consisted of two 
study parts:

Study Epoch 1: IV treatment with GAMMAGARD LIQUID/KIOVIG

Study Epoch 2: SC treatment with GAMMAGARD LIQUID/KIOVIG after 
administration of 75 U rHuPH20 / g IgG at three- or four-week treatment intervals
Study Arm 1 was comprised of subjects who previously participated in Study 160601 and 
wished to also participate in this follow-up study; these subjects only completed Study 
Epoch 2. Study Arm 2 comprised all other subjects; these subjects completed Study 
Epoch 1 and Study Epoch 2.
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Eighty-nine subjects were enrolled in the study, of which 87 were treated via both IV and 
SC routes. Eighty-four subjects completed Study Epoch 1 and 68 subjects completed 
Study Epoch 2. Sixteen subjects withdrew or were discontinued from the study, including 
three subjects who withdrew during the ramp-up period at the beginning of HyQvia
treatment. Four adults withdrew due to local pain and swelling; in two of these subjects, 
the swelling extended from the abdominal site to the genitalia, causing transient 
discomfort. In one of the subjects, the swelling was accompanied by erythema. One 
other subject withdrew due to a perceived increase in infections. 
Of the 1,359 SC infusions with rHuPH20 during the ramp-upvi period and Epoch 2, 
90.1% were administered in the abdomen and 8.6% in the thighs. The median duration of
individual infusions was similar or lower when GAMMAGARD LIQUID/KIOVIG was 
administered SC with rHuPH20 than for IV administration. The percentage of subjects 
who had no infusions that required a reduction in flow rate, interruption, or had to be 
stopped due to tolerability concerns or AEs was similar between SC infusions with 
rHuPH20 (84.0%) and IV administration (88.5%).
The rate of infusions temporally associated with systemic AEs was lower for SC 
administration with rHuPH20 compared to IV administration, whereas the rate of 
infusions temporally associated with local AEs was higher for SC administration with 
rHuPH20. The trend toward less frequent systemic AEs and more frequent local AEs 
during SC administration with rHuPH20 compared to IV treatment was also evident in 
the nature of AEs reported in Medical Dictionary for Regulatory Activities (MedDRA) 
Preferred Terms. Of the AEs in Epoch 1 that were considered by the investigator to be 
possibly or probably related to GAMMAGARD LIQUID/KIOVIG, the most common 
were headache, chills, nausea, fatigue, pyrexia, and vomiting. The most common AEs 
possibly or probably related to both GAMMAGARD LIQUID/KIOVIG and rHuPH20 in 
Epoch 2 (excluding the ramp-up) were infusion site pain, infusion site erythema, infusion 
site discomfort, headache, infusion site pruritus, infusion site edema, and infusion site 
swelling. No severe headache was related to SC infusions with rHuPH20. AEs possibly 
or probably related to rHuPH20 but not GAMMAGARD LIQUID/KIOVIG in Epoch 2 
(excluding the ramp-up) included infusion site pain and infusion site pruritus. The 
majority of AEs were mild; very few severe AEs occurred. All SAEs were assessed as 
unrelated to the study drugs. A comparison of data from this study and Study 160601 
demonstrated no appreciable differences in the median rates of AEs temporally associated 
with or related to either or both study drugs.
                                                
vi
The treatment intervals and doses used for the initial infusions were gradually increased during the first
weeks of treatment (referred to as the ramp-up), in order to allow the subjects to adjust to increasing 
volumes administered SC.
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GAMMAGARD LIQUID/KIOVIG administered SC with rHuPH20 at 108% of the 
IV dose was effective in preventing bacterial infections in pediatric and adult subjects 
with PIDD. Analysis of the secondary endpoints demonstrated that GAMMAGARD 
LIQUID/KIOVIG given SC with rHuPH20 had higher bioavailability as determined by 
AUC per dose/kg than when infused SC without rHuPH20. Compared to IV infusion, 
SC administration with rHuPH20 was administered at the same dosing interval and 
resulted in similar IgG trough levels while eliciting fewer systemic ARs. Furthermore, 
SC infusion with rHuPH20 was the subjects’ preferred mode of treatment with 
GAMMAGARD LIQUID/KIOVIG.
6.3.2.1 Pharmacokinetic Properties
With administration of HyQvia, peak serum IgG levels are achieved in the recipient’s 
circulation after a delay of approximately three to five days.
Data from the clinical trial of HyQvia show that serum IgG trough levels can be 
maintained by dosing regimens of 320 to 1,000 mg/kg BW/four weeks given at intervals 
of three or four-weeks.
The PK of HyQvia was evaluated in this Phase 3 efficacy and safety study in 60 patients 
with PIDD aged 12 years and older. The pharmacokinetic results are presented in Table 1
below, as compared to data for IV administration of IGI 10% obtained in the same study.
Table 1. Pharmacokinetic Parameters of HyQvia Compared to 
Intravenous Administration of IGI 10%
Parameter
HyQvia
Median (95% Cle)
N=60
IGIV, 10%
Median (95% Cle)
N=68
Cmaxa[g/l]
15.5 (14.5; 17.1)
21.9 (20.7; 23.9)
Cminb [g/l]
10.4 (9.4 to 11.2)
10.1 (9.5 to 10.9)
AUCc per week [g*days/l]
90.52 (83.8 to 98.4)
93.9 (89.1 to 102.1)
Tmaxd [days]
5.0 (3.3 to 5.1)
0.1 (0.1 to 0.1)
Apparent clearance or clearance [mL/kg/day]
1.6 (1.4 to 1.79)
1.4 (1.2 to 1.4)
Terminal half-life [days]
45.3 (41.0 to 60.2)
35.7 (32.4 to 40.4)
a
Concentration maximum. 
b
Concentration minimum.
c
Area under the curve.
d
Time to maximum concentration.
e
Confidence interval.
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6.3.3 Clinical Study 160902
Long-Term Tolerability and Safety of Immune Globulin Subcutaneous (IGSC) 
Solution Administered Subcutaneously Following Administration of Recombinant 
Human Hyaluronidase (rHuPH20) in Subjects with Primary Immunodeficiency 
Diseases
The purpose of the study was to assess the long-term safety, tolerability, and 
practicability of the SC treatment with IGI, 10% facilitated with rHuPH20 in subjects 
with PIDD who completed Clinical Study Protocol 160603. The primary objective of this 
study was to evaluate the long-term tolerability and safety of IGI, 10% given SC after an 
SC administration of rHuPH20 in subjects with PIDD. The secondary objectives 
included: monitoring the long-term efficacy of IG, 10% given SC after an administration 
of rHuPH20 in subjects with PIDD, evaluating the effect of varying the dose frequency of 
IG, 10% rHuPH20 on IgG trough levels and assessing the practicability of treating PIDD 
with IGI, 10% given SC after an administration of rHuPH20 when treatment occurs in a 
home treatment environment.
In Study 160902, subjects began on the same doses of IGI, 10% and rHuPH20 that were 
used for the last infusions in Study Epoch 2 of Study 160603. In order to pursue the 
secondary objective “effect of varying the dose frequency of IGI, 10%/rHuPH20 on IgG 
trough levels”, subjects were requested to change their drug administration interval to a 
two-week drug interval (receiving a two-week dose) from a three- or four-week drug 
administration interval, provided both the subject and the investigator agreed that the 
change was appropriate. This new treatment interval started after three infusions on the 
three or four-week interval and was maintained for a minimum of four months. It was 
intended to allow for evaluation of whether a more frequent administration of IGI, 10% 
leads to improved IgG trough levels. After the four-month trial period, subjects could 
revert to their previous dose interval or continue on the two-week interval, depending on 
the subject’s preference.
On 01 August of 2012, the FDA requested administration of rHuPH20 drug product in all 
ongoing HyQvia clinical studies in the US to be suspended and patients were switched to 
treatment with KIOVIG/GAMMAGARD LIQUID only (Protocol Amendment 5). 
Subjects were treated with conventional IGIV or IGSC for 24 weeks, or, for those who 
had anti-rHuPH20 antibody titers ≥160 at the time rHuPH20 was discontinued, for 
48 weeks.
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6.3.3.1 Disposition of Subjects
Sixty-six subjects were screened for eligibility to participate in this study. Out of the 
66 patients who rolled over from Study 160603 into 160902, 63 subjects were treated 
with IGSC, 10% with rHuPH20; three subjects received IGIV, 10%. Of the 63 subjects 
under IGSC, 10% with rHuPH20 treatment, 15 withdrew or were discontinued from the 
study; 48 switched to the Safety Follow-up when Protocol Amendment 5 went into effect. 
Of the 15 subjects discontinued from IGSC, 10% with rHuPH20, four withdrew, one 
subject died, one subject had bone marrow transplant, six subjects had their clinical site 
closed out by sponsor, and three had their site elected to exit study. Of the 48 subjects 
switched to the Safety Follow-up period, one subject withdrew after experiencing an AE. 
In total, 50 subjects completed the study: 47 subjects from the Safety Follow-up and three 
subjects who received IGI, 10% IV or SC without rHuPH20 throughout the study. The 
majority of enrolled subjects were in the age range category of 16 to <65 years (47 out 
of 66), followed by 65 years and older (eight subjects), seven subjects in the range of 
12 to <16 years and four subjects in the range of two to <12 years. The median age was 
43.0 years. Of the 66 subjects who met all inclusion/exclusion criteria, 50 (75.8%) 
completed the study.
6.3.3.2 Extent of Exposure
IGSC, 10% with rHuPH20 was administered to 63 subjects prior to the Safety Follow-up 
period for a median treatment duration of 669 days (range: 60-729 days) and a mean 
(± SD) of 565.9 ± 211.8 days. The mean (± SD) dose received per week, per body mass, 
was 0.156 ± 0.051 g/kg/week. Across all age groups, the median initial rate of 
IGSC, 10% infusion with rHuPH20 was 10 mL/hr (range: 5-300) and the median 
maximum rate of infusion achieved was 300 mL/hr (range: 10-350). Across all age 
groups and infusion intervals, a median number of 1.09 infusions/month (range: 0.3-2.1) 
was administered. IGSC, 10% with rHuPH20 treatment required a median number of 
1.58 infusion sites/month (range 0.3-4.2) across all age groups and infusion intervals. For 
the majority of subjects in this study (41/66; 62.1%), the four-week infusion interval was 
the most frequently followed infusion interval. The two-week infusion interval was the 
most frequent interval for 15/66 (22.7%) subjects and 7/66 (10.6%) subjects most 
frequently followed a three-week infusion interval.
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6.3.3.3 Efficacy
Analysis of the efficacy results in this study indicates that rHuPH20-facilitated SC 
treatment with IGI, 10% is efficacious in the treatment of adult and pediatric subjects 
with PIDD, in terms of IgG trough levels, infection rates, and patient-related outcomes.
Two validated acute serious bacterial infections (VASBIs) occurred in 66 subjects under 
IGSC, 10% treatment with rHuPH20. The annual rate of VASBIs was statistically 
significantly lower than the threshold specified as providing substantial evidence of 
efficacy. 
The point estimate for the annualized rate of all infections was 2.86 (95% Confidence 
Interval [CI]: 2.36-3.43) during IGSC, 10% with rHuPH20 treatment.
IgG trough levels maintained under IGSC, 10% with rHuPH20 treatment did not 
substantially vary with infusion interval changes and were lower with the longest 
(four-week) infusion interval (median steady-state trough level: 10.90 g/L (two-week 
interval), 12.30 g/L (three-week interval), 9.76 g/L (four-week interval). 
Percent change of steady-state trough levels was 105.90% (mean and median) for 
subjects who switched from a three-week to a two-week infusion interval and a mean of 
113.23% (median 112.44%) for subjects who switched from a four-week to a two-week 
infusion interval.
The point estimate for the annualized rate of days off school/work was less than 
eight days per year. The rate of days on antibiotics was less than 65 days per year. The 
rate of hospitalizations was less than one per year and the rate of days hospitalized, less 
than one day per year. The rate of acute physician visits due to infection or other illness 
was less than five visits per year.
6.3.3.4 Safety
rHuPH20-facilitated SC treatment with IGI, 10% was safe and well tolerated by adult and 
pediatric subjects with PIDD.
No SAEs occurred that were considered by the investigator to be related to either of the 
study drugs. In total, 11 subjects experienced SAEs during the study. One subject 
experienced an SAE after study completion.
Throughout the study, the proportion of infusions requiring adjustment for tolerability 
concerns or for AEs was low (0.1% of infusions stopped, 0.6% of infusions interrupted; 
1% infusion rate reduced). 
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The most common related AEs under IGSC, 10% treatment facilitated by rHuPH20 were 
infusion site pain, infusion site pruritus, nausea, myalgia, infusion site erythema, 
headache, fatigue, asthenia, chills, infusion site discomfort, and pain. 
The rate of all AEs related to IGI, 10%, by infusion, was 0.13 during rHuPH20-facilitated 
IGSC, 10% treatment administration, and 0.22 during the Safety Follow-up period. 
During rHuPH20-facilitated IGSC, 10% treatment, the rate of all AEs related to 
rHuPH20, by infusion, was 0.01 and the rate of all AEs related to both IGI, 10% and 
rHuPH20 by infusion, was 0.06.
The rate of all causally related AEs by infusion was 0.20 during rHuPH20-facilitated 
IGSC, 10% treatment administration. The rate of all causally-related local AEs, by 
infusion, was 0.10 during rHuPH20-facilitated IGSC, 10% treatment administration. 
During rHuPH20-facilitated IGSC, 10% treatment, the rate of related systemic AEs by 
infusion, including or excluding infections was 0.1.
The rate of all temporally-associated AEs by infusion was 0.28 during 
rHuPH20-facilitated IGSC, 10% treatment. The rate of all temporally-associated local 
AEs by infusion was 0.10 during rHuPH20-facilitated IGSC, 10% treatment. During 
rHuPH20-facilitated IGSC, 10% treatment, the rate of temporally-associated systemic 
AEs by infusion including infections was 0.18 and excluding infections was 0.16. 
Throughout the study, 7.4 % of infusions were associated with one or more local AEs.
No subjects developed neutralizing antibodies in the entire duration of the follow-up 
including data obtained in Study 160603 starting with first exposure to IGSC, 10% 
facilitated by rHuPH20 and in Study 160902. 
A total of 13/66 subjects had anti-rHuPH20 antibody titers ≥160 in Study 160902. 
Eleven subjects had developed anti-rHuPH20 antibody titers ≥160 in Study 160603. Two 
subjects each newly developed one anti-rHuPH20 antibody titer of ≥160 in 
Study 160902. In the majority of subjects with anti-rHuPH20 antibody titers ≥160, the 
titers declined over time during continued IGSC, 10% with rHuPH20 treatment.
Assessment of hematology parameters, clinical chemistry parameters, urinalysis and 
specific antibody tests and viral pathogen serology did not raise any safety concerns with 
respect to the SC administration of IGI, 10% with rHuPH20. 
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6.3.4 Clinical Study 161101 
Tolerability, Safety and Administration Mode Evaluation of rHuPH20 Facilitated 
Subcutaneous Treatment with Immune Globulin Infusion (Human), 10% in 
Subjects with Primary Immunodeficiency Diseases
This US study was a Phase 2/3, prospective, non-controlled, multicenter study to evaluate 
tolerability and safety and other parameters of SC treatment using Immune Globulin 
Infusion (Human), 10% (IGI, 10%. IGI, 10% is the same product as IGIV 10% licensed 
in the EU as KIOVIG) with rHuPH20 in a total of approximately 60 PIDD subjects 
already pre-treated with immunoglobulin products (Gamunex administered IV, Hizentra 
or Privigen). 
PIDD patients already on IV or SC treatment were enrolled and treated with IGI, 10% 
and rHuPH20 subcutaneously with a dose/interval ramp-up of three weeks. The ramp-up 
period was Epoch 1.
The ramp-up was followed by Epoch 2, a six-month period of IGSC, 10% with rHuPH20 
treatment:

For IV-pretreated subjects: every three weeks or four weeks, depending on the 
subject’s previous IV dosing schedule

For SC-pretreated subjects: every three weeks or four weeks, at the discretion of 
investigator and subject
The rHuPH20 administration was discontinued as of 01 August 2012 at the request of the 
FDA. Those subjects who did not withdraw from the study completed the planned 
infusions using conventional IGIV or IGSC. The last subject completed the study on 
04 January 2013. 
A total of 37 subjects started the treatment. All but one of the subjects reached Epoch 2. 
During Epoch 2, nine subjects withdrew. At the time when rHuPH20 administration was 
stopped, one subject had completed Epoch 2. The remaining 26 were switched to 
Epoch 3. During Epoch 3, two subjects withdrew, 24 completed Epoch 3. Thus, 
25 subjects including the one subject who completed Epoch 2 without ever reaching 
Epoch 3 completed the study. 
Analysis of the efficacy results in this study indicate that rHuPH20-facilitated SC 
treatment with IGI, 10% was efficacious in the treatment of adults and pediatric subjects 
with PIDD, in terms of IgG trough levels, infection-rates, and subject related outcomes.
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Trough levels of total IgG at the end of Epoch 2 (geometric mean: 9.21 g/L [95% CI: 
8.28-10.25]) were comparable to the levels measured at screening (geometric mean: 
10.53 g/L [95% CI: 9.46-11.73]). 
No serious bacterial infections were reported in any subject throughout the study. The 
point estimate for the rate of all infections per year was 2.45 for Epoch 1 and Epoch 2 
combined.
The point estimate for the rate per month of days off either from work, school, or daily 
activity was less than one day/month. The rate of days on antibiotics was less than three 
days/month. No subjects were hospitalized during the study period and the rate of acute 
physician visit due to infection or other illness was less than one visit/month.
Analysis of the mode of infusion was inconclusive due to the premature stop of subject 
enrollment and early termination of Epoch 2, however the following results were 
observed.
Median number of infusions per month: 2.90 in Epoch 1; 1.09 in Epoch 2. Median 
number of infusion sites (needle sticks) per infusion/month: 2.90 in Epoch 1; 1.12 in 
Epoch 2. Median duration of infusion: less than two hours. Median maximum infusion 
rate: 240mL/h in Epoch 1; 300mL/h in Epoch 2. 
Treatment with IGI, 10% when administrated either SC with rHuPH20 (Epochs 1 and 2) 
or SC without rHuPH20 or IV (Epoch 3) was safe and well tolerated. No SAEs occurred 
that were considered by the investigator to be related to either of the study drugs.
During Epoch 1 and Epoch 2 combined, 59 related systemic AEs occurred. The rate of 
related systemic AEs/infusion, excluding infections (primary outcome) was 0.326 
(95% CI: 0.186-0.522) and the rate per number of subjects was 37.8% (14/37), for 
Epochs 1 and 2 combined. The rate per infusion of local AEs (including infections) 
related to IGI, 10% was 0.066 in Epoch 1, 0.028 in Epoch 2 and 0.006 in Epoch 3. 
The rate of local AEs related to rHuPH20 per infusion was 0.039 in Epoch 1 and 0.038 in 
Epoch 2. The rate of local AEs related to both rHuPH20 and IGI, 10% per infusion was 
0.776 in Epoch 1 and 0.745 in Epoch 2.
According to MedDRA preferred term classification, the most common AEs related to 
IGI, 10% with rHuPH20 in both Epoch 1 and Epoch 2 were “infusion site pain”, 
“infusion site erythema”, and “infusion site swelling”.
No patient developed neutralizing anti-rHuPH20 antibodies in the course of the study. 
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Assessment of hematology parameters, clinical chemistry parameters, and urinalysis did 
not raise any safety concerns with respect to the SC administration of IGI, 10% with 
rHuPH20.
6.3.5 HyQvia Pregnancy Registry 161301
Pregnancy Registry to collect Long-Term Safety Data from Women treated with 
HyQvia (Immune Globulin (Human) 10% with rHuPH20
This study is an ongoing non-interventional, prospective, uncontrolled, two-arm, open-
label, multicenter post-authorization pregnancy registry. Subjects who prior to the study 
received HyQvia at enrollment receive a licensed human normal immunoglobulin other 
than HyQvia or an alternative treatment during the study are assigned to Study Arm 1 
(Alternative Product Arm); subjects in countries where HyQvia treatment during 
pregnancy is not indicated are enrolled in this arm. Subjects who continue treatment with 
HyQvia during pregnancy are followed in Study Arm 2 (HyQvia Arm).
The study is conducted in the European Economic Area and North America. This 
pregnancy registry with regular assessment of antibodies against rHuPH20 was a 
commitment to the Committee for Medicinal Products for Human Use (CHMP) and the 
FDA in the course of the HyQvia Marketing Authorization Procedure. Further data shall 
be collected to evaluate safety of women who become pregnant during or after treatment 
with HyQvia as well as the physical and neurological development of the infant during 
the first two years of life.
The primary objective is to collect and assess clinical safety data regarding the possible 
effects of HyQvia on the course and outcome of the pregnancy, and on the growth and 
development of the fetus/infant. The secondary objectives are to collect any laboratory 
safety data and additional safety assessments obtained during the clinical management of 
the pregnancy or in the evaluation of the fetus in utero and the infant post-partum.
In this registry pregnant women who were ever treated with HyQvia were enrolled. In the 
European Union (EU) the therapeutic indications for HyQvia are PIDD, CLL, and 
myeloma. In the USA, HyQvia is licensed for the treatment of PIDD. Although the target 
population consisted mainly of women treated for the approved indications in the 
respective country, any woman who became pregnant after being exposed to HyQvia 
could participate in the registry.
Visits to the investigator (for example immunologist) and all other medical care were 
performed as was standard for the site and for the subject’s healthcare. 
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However, the pregnant subject was invited to return approximately every three months to 
the site for blood samples to be taken to assess antibodies against rHuPH20, as requested 
by the CHMP and the FDA.
As soon as the patient became aware of the pregnancy, she was to inform the treating 
physician. According to her treatment, the subject entered the study in one of the 
following two Study Arms.
Study Arm 1 (Alternative Product Arm): Subjects who stopped treatment with HyQvia 
were followed in Study Arm 1. The treating physician of the pregnant woman prescribed 
a licensed human normal immunoglobulin other than HyQvia for IV or SC infusion or an 
alternative treatment, at his/her discretion. 
Study Arm 2 (HyQvia Arm): Subjects who continued treatment with HyQvia according 
to their treatment regimen were followed in Study Arm 2.
The overall duration of the study is approximately six years from study initiation to study 
completion (i.e., end data collection). The participation period for the pregnant woman 
was from enrollment to study completion/termination visit after the delivery/end of 
pregnancy. The participation period for the infant is from enrollment until the age of 
two years to assess the development, unless prematurely discontinued. Enrollment and 
participation of the mothers has been completed.
6.3.6 HyQvia PASS 161302
Non-Interventional Post-Authorization Safety Study on the Long-Term Safety of 
HyQvia in Subjects treated with HyQvia
This is a non-interventional, prospective, uncontrolled, multi-center, open-label, 
post-authorization safety study (PASS) in the European Economic Area. The Post-
Authorization Safety Surveillance was a commitment to the CHMP in the course of the 
HyQvia Marketing Authorization Procedure. The study is ongoing. Subject enrollment 
has been completed.
The purpose of the study is to acquire additional data (including the assessment of anti-
rHuPH20 antibodies) on the long-term safety of HyQvia and to assess the prescribed 
treatment regimens and treatment administration in routine clinical practice.
The primary objective is to collect and assess safety data, in particular the occurrence of 
long-term changes in incidence and severity of related AEs in patients treated with 
HyQvia. 
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Secondary objectives are to collect data on the prescribed treatment regimen, 
anti-rHuPH20 antibodies and, as available, other laboratory safety assessments, total IgG, 
further safety assessments that are obtained during the routine clinical management of the 
subjects, treatment administration, and health-related quality of life (HRQoL) and health 
resource use assessments (optional).
Adult patients (≥ 18 years) who have been prescribed treatment with HyQvia are 
enrolled. Treatment regimens are prescribed at the discretion of the attending physician in 
accordance with routine clinical practice. Visits to the investigator and all other medical 
care are performed as is standard for the site and for the subject´s healthcare. In addition, 
however, the subject is requested to have additional blood samples drawn at the time of 
routine laboratory assessments approximately every three months, but no more often than 
four times a year, for the measurement of antibodies against rHuPH20.
The overall duration of the study is approximately six years from study initiation (i.e., 
first subject enrolled) to study completion (i.e., last subject last visit). .Enrollment started 
in 2014 and finished in 2016. The subject participation period is approximately three to 
six years from enrollment to subject completion (i.e., study termination/completion visit), 
depending on the time point of enrollment, unless prematurely discontinued. The study 
enrolled 111 subjects in total. The participation period is due to end in Q1 2020.
6.3.7 HyQvia Study 161406 
Non-Interventional Post-Marketing Safety Study on the Long-Term Safety of 
HyQvia (Global)
This prospective, uncontrolled, multi-center, open-label, post- HyQvia marketing 
authorization surveillance study with assessment of anti-rHuPH20 antibodies was agreed 
upon with the FDA in the course of the HyQvia Biologic License review and approval 
process.
The purpose of the study is to acquire additional data (including the assessment of 
anti-rHuPH20 antibodies) on the long-term safety of HyQvia and to assess the prescribed 
treatment regimens and treatment administration in a total of 250 adult evaluable subjects 
with PIDD under routine clinical conditions. Further data shall be collected in subjects 
with an anti-rHuPH20 antibody titer ≥ 160. Subject enrollment has been completed with a 
total of 264 subjects enrolled. The study is ongoing.
The primary objective is to collect and assess safety data, in particular the occurrence of 
long-term changes in incidence and severity of related AEs in patients treated with 
HyQvia.
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Secondary objectives are to collect data on anti-rHuPH20 antibodies and, as available, 
other laboratory safety assessments, total IgG, further safety assessments that are 
obtained during the routine clinical management of the subjects, the prescribed treatment 
regimen, treatment administration, HRQoL and health resource use assessments. 
6.3.8 HYQVIA Study 161503
Efficacy, Safety, Tolerability, Immunogenicity and Pharmacokinetic Evaluation of 
HYQVIA in Pediatric Subjects with Primary Immunodeficiency Diseases
Study 161503 is a phase 3, open-label, prospective, non-controlled, multicenter, USA-
only study to evaluate efficacy, safety, tolerability, immunogenicity, pharmacokinetics 
and other parameters of HYQVIA treatment in pediatric subjects with Primary 
Immunodeficiency Diseases (PIDD). 44 subjects aged 2 to <16 years who have received 
prior IV or SC immunoglobulin therapy have been enrolled in the USA, and enrollment 
has ended (planned sample size is 40 subjects). The first subject was enrolled (dosed) in 
Study 161503 on 17 Oct 2017 and the last subject was enrolled on 02 May 2019. Subjects 
will undergo regular testing for binding anti-rHuPH20antibodies approximately every 
three months; neutralizing antibodies and characterization of antibodies may also be 
done.
In Study Epoch 1, patients pre-treated (IV or SC) with non-HyQvia immunoglobulins are 
enrolled and treated with HyQvia SC in a dose or interval ramp-up during a period of up 
to six weeks with HYQVIA infusions administered at the study site.
In Epoch 2 subjects will receive HyQvia at intervals of either three or four weeks, 
depending on the subject’s previous IV dosing schedule, or at the investigator´s and 
subject´s discretion for SC pre-treated subjects. While the first two or three infusions will 
be administered at the study site, subsequent infusions should be performed at home. 
A PK assessment should be performed at the six-month visit. After one year in Epoch 2, 
subjects with a binding anti-rHuPH20 antibody titer < 160 at all time-points will exit the 
study. Subjects with a titer ≥ 160 will continue in Epoch 2 for another two years. Epoch 3 
is approximately one-year safety follow-up of up, if needed: subjects whose anti-
rHuPH20 antibody titer was ≥ 160 during Epoch 1 or 2 and who experience either a 
study drug related SAE or a related severe AE will be followed accordingly. Subjects 
in Epoch 3 continue regular testing for anti-rHuPH20 antibodies, for approximately 
one year. Subjects in Epoch 3 will be treated with GAMMAGARD LIQUID IV or SC at 
the study site or at home.
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Subjects who experience a related SAE or severe AE and have an anti-rHuPH20 antibody 
titer < 160 in Epoch 1 or 2 may either be terminated from the study, change directly to
Epoch 3, or continue in Epoch 1 or 2 with appropriate medical intervention such as 
decreasing the HyQvia infusion rate and/or premedication.
6.4 Evaluation of Anticipated Risks and Benefits of the Investigational Product(s) to 
Human Subjects
6.4.1 HyQvia
The clinical development program for HyQvia has demonstrated that IGI, 10% 
administered via SC treatment with rHuPH20 is efficacious and safe in persons with 
PIDD. The safety, tolerability, efficacy and bioavailability of HyQvia were investigated 
in one pivotal Phase III study (160603), and an extension study (160902) in patients with 
PIDD. One supportive clinical study (160602) in patients with PIDD using Gammagard 
Liquid administered subcutaneously was also conducted. Further information is provided 
in the SmPC for HyQvia.
The most common ARs observed in PIDD clinical trials in >5% of subjects were: local 
reactions, headache, antibody formation against rHuPH20, fatigue, nausea, pyrexia, and 
vomiting.
The safety and efficacy of chronic use of the rHuPH20 solution in HyQvia has not been 
established in conditions other than PIDD. Study 160603 compared the efficacy, PKs, 
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 PIDD receiving 
IGI, 10% with rHuPH20 in 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. 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.
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6.4.1.1 Pregnancy, Breast Feeding, Fertility
Subcutaneous immunoglobulin G (SCIG) products have been shown to cross the 
placenta, increasingly during the third trimester. Clinical experience with 
immunoglobulins suggests that no harmful effects on the course of pregnancy, or on the 
fetus and the neonate are to be expected. Development and reproductive toxicology 
studies have been conducted with rHuPH20in mice and rabbits. No adverse effects on 
pregnancy and fetal development were associated with anti-rHuPH20 antibodies. In these 
studies, maternal antibodies to rHuPH20were transferred to offspring in utero. The effects 
of antibodies to the rHuPH20component of HyQvia on the human embryo or on human 
fetal development are currently unknown. Immunoglobulins are excreted into the milk 
and may contribute to protecting the neonate from pathogens which have a mucosal 
portal of entry.
The safety of HyQvia for use in human pregnancy has not been established in controlled 
clinical trials and therefore should only be given with caution to pregnant or 
breastfeeding women.
There are currently no clinical safety data for HyQvia on fertility available. Clinical 
experience with immunoglobulins suggests that no harmful effects of IG 10% on fertility 
are to be expected. Animal studies do not indicate direct or indirect harmful effects of 
rHuPH20 with respect to reproductive potential at the doses used for facilitating 
administration of IG 10%.
See Section 6.4.2 for the known risks associated with IGI, 10%.
6.4.2 KIOVIG
IGI, 10% administered via IV treatment (KIOVIG) is efficacious and safe in the 
particular fields of therapeutic use and approved indications, i.e., PIDD, ITP and MMN, 
as demonstrated in the clinical development program for KIOVIG. Please see the SmPC 
for KIOVIG.
Serious ARs (defined as SAEs occurring during or within 72 hours of infusion or any 
casually related SAE occurring within the study period) which occurred in the clinical 
trials of KIOVIG were aseptic meningitis, pulmonary embolism, and blurred vision.
The most common ARs observed in ≥5% of patients were:

PIDD, IV administration: headache, fatigue, pyrexia, nausea, chills, rigors, pain in 
extremity, diarrhea, migraine, dizziness, vomiting, cough, urticaria, asthma, 
pharyngolaryngeal pain, rash, arthralgia, myalgia, edema peripheral, pruritus, and 
cardiac murmur.
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
PIDD, 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.
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 with immune globulin products, including IGI, 10%. Risk factors 
may include advanced age, prolonged immobilization, hypercoagulable conditions, 
history of venous or arterial thrombosis, use of estrogens, indwelling vascular catheters, 
hyperviscosity, and cardiovascular risk factors.
Renal dysfunction, acute renal failure, osmotic nephrosis, and death may occur in 
predisposed patients receiving immune globulin intravenous (IGIV) products including 
IGI, 10%. Renal dysfunction and acute failure occur more commonly with IGIV products 
containing sucrose. IGI, 10% does not contain sucrose.
IGI, 10% contains blood group antibodies (isoagglutinins) that may cause hemolysis. 
Delayed hemolytic anemia can develop subsequent to IGI, 10% therapy due to enhanced 
red blood cell (RBC) sequestration. Acute hemolysis, consistent with intravascular 
hemolysis, has been reported. The following risk factors may be related to the 
development of hemolysis: high doses (e.g., ≥ 2 g/kg, single administration or divided 
over several days) and non-O blood group. Underlying inflammatory state in an 
individual patient may increase the risk of hemolysis but its role is uncertain.
Contraindications to IGI treatment include anaphylactic or severe systemic 
hypersensitivity reactions to IG and IgA deficient patients with antibodies against IgA 
and a history of hypersensitivity. 
IGI, 10% has a high margin of safety. Screening against potentially infectious agents 
begins with the donor selection process and continues throughout plasma collection and 
preparation. Three validated, dedicated, independent, and effective virus 
inactivation/removal steps have been integrated into the manufacturing and formulation 
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processes, further increasing the margin of safety. In addition, careful screening and 
monitoring of subjects in this study will be utilized to minimize the above and other 
known risks associated with IG therapy (e.g., exclusion criteria, blood group typing at 
baseline, and laboratory monitoring for hemolysis). 
Further information is provided in the SmPC for KIOVIG.
6.4.3 Cuvitru
Information about Cuvitru is provided in the SmPC, which is available in those countries 
where Cuvitru is registered. In countries where Cuvitru is not registered, an IB will be 
available. 
6.5 Compliance Statement
This study will be conducted in accordance with this protocol, the International Council 
for Harmonisation Guideline for Good Clinical Practice E6 (ICH GCP, R2, November 
2016), Title 21 of the US Code of Federal Regulations , the EU Directives 2001/20/EC 
and 2005/28/EC, the Declaration of Helsinki and applicable national and local regulatory 
requirements.
7. STUDY PURPOSE AND OBJECTIVES
7.1 Study Purpose
The purpose of the study is to acquire additional data on safety, tolerability and 
immunogenicity of HyQvia in pediatric (age two to <18 years) subjects with PIDD.
7.2 Primary Objective
The primary objective of the study is to assess the safety of HyQvia treatment in pediatric 
subjects with PIDD who received immunoglobulin therapy prior to study enrollment.
7.3 Secondary Objectives
Secondary objectives of the study are further assessments (e.g. immunogenicity), 
tolerability, characteristics of product administration and efficacy (IgG trough levels). 
7.4 Tertiary Objectives
Tertiary objectives are further safety and efficacy assessments. The study objectives are 
described in more detail in Section 11, Section 12 and Section 20.2.
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8. STUDY DESIGN
8.1 Brief Summary
This study is a Phase 4, post-authorization, prospective, non-controlled, multicenter study 
to evaluate safety, tolerability, and other parameters of SC treatment using HyQvia in 
40 pediatric subjects with PIDD who received immunoglobulin therapy prior to study 
enrollment.
The purpose of the study is to acquire additional data on safety, tolerability and 
immunogenicity of HyQvia in pediatric subjects.
8.2 Overall Study Design
The overall study design is illustrated in Figure 1. Details on the procedures to be 
performed at each study visit can be found in Section 20.2 Schedule of Study Procedures 
and Assessments and Section 20.3 Clinical Laboratory Assessments. In this study 
40 pediatric subjects with PIDD will be enrolled, who have received prior 
immunoglobulin therapy. The study will enroll approximately six subjects aged 2 to 
<6 years, 12 subjects 6 to <12 years, and 22 subjects 12 to <18 years of age. The study 
will be conducted in the European Economic Area.
All subjects will have regular anti-rHuPH20 antibody testing (binding and neutralizing 
anti-rHuPH20 antibody) throughout the study (approximately every three months).
Female subjects of childbearing potential should employ birth control measures as 
advised by the investigator or per the site´s standard recommendations for the duration of 
the study.
8.2.1 Epoch 1
Pediatric patients with PIDD who are on non-HyQvia IV or SC treatment with 
immunoglobulin (IV-pretreated, SC-pretreated) will be enrolled and treated with HyQvia 
subcutaneously with a dose or interval ramp-up period of up to six weeks. Subjects 
already treated with HyQvia (HyQvia-pretreated) will be enrolled directly into Epoch 2. 
Epoch 1 infusions will be administered at the study site.
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8.2.2 Epoch 2
The ramp-up (Epoch 1) is followed by Epoch 2 with HyQvia treatment at the following 
intervals:

For IV-pretreated subjects: every three or four weeks, depending on the subject’s 
previous IV dosing schedule.

For SC-pretreated subjects: every three or four weeks, at the discretion of 
investigator and subject.

For HyQvia pre-treated subjects: No change in frequency of administration. 
Alternative treatment intervals, for example infusion every 2 weeks, may be considered 
for tolerability reasons at the discretion of the investigator, after informing the sponsor. 
After one year in Epoch 2, the anti-rHuPH20 binding antibody assay results during that 
year will be used to decide the next steps in the study (see Section 20.1 Study Flow 
Chart):

Subjects with anti-rHuPH20 antibody titer < 160 at all time-points during the study 
will complete the study termination/completion visit at the next possible occasion. 

Subjects with anti-rHuPH20 antibody titer ≥ 160 during the study and/or at the last 
measurement will continue in Epoch 2 for an additional two years of HyQvia 
treatment and observation. 
The first two to three infusions during Epoch 2 will be administered at the study site. It is 
preferable that subsequent infusions, be performed at home (or equivalent site) by the 
subject/caregiver, if in the opinion of the investigator, such treatment is safe and 
appropriate. In that case, the investigator/designee must have trained the subject or 
caregiver and must be satisfied that the subject or caregiver is capable of 
self-administration of SC infusions at home before the subject or caregiver will be 
permitted to conduct the SC infusion at home.
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8.2.3 Epoch 3
Epoch 3 is approximately one-year safety follow-up, if needed: subjects whose anti-
rHuPH20 antibody titer was ≥ 160 during Epoch 1 or Epoch 2 and who experience either 
a related SAE or a related severe AE will be followed accordingly.
In the event that a subject in Epoch 1 or in Epoch 2 experiences a related SAE or severe 
AE without anti-rHuPH20 antibody titer ≥ 160, the subject can (at the discretion of the 
investigator and subject): 1) be terminated from the study; or, 2) change directly to 
Epoch 3; or, 3) continue in Epoch 1 or 2 with appropriate medical intervention such as 
decreasing the HyQvia infusion rate and/or premedication.
Subjects with antibody titer of ≥ 160 when entering Epoch 3 continue regular 
anti-rHuPH20 antibody testing (approximately every three months) for approximately 
one year. These subjects complete the study termination/completion visit when the 
AE/SAE resolves or the anti-rHuPH20 titer is < 2,560.
Subjects in Epoch 3 will be treated with KIOVIG (IGI, 10%) intravenously or Cuvitru 
subcutaneously, at the discretion of the investigator and the subject.
Infusions in Study Epoch 3 will be administered at home or at the study site.
The study termination/completion visit will be conducted at the study site.
8.3 Duration of Study Period(s) and Subject Participation
The overall duration of the study is approximately seven years from study initiation (i.e., 
first subject enrolled) to study completion (i.e., last subject last visit). The recruitment 
period is expected to be approximately two years. 
The maximum subject participation period is approximately four years from enrollment 
to subject completion (i.e., study termination/completion visit), unless prematurely 
discontinued.
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8.4 Outcome Measures
8.4.1 Primary Outcome Measure
1.
Number and rate per infusion (excluding infections) of all severe related AEs
2. Number and rate per infusion (excluding infections) of related SAEs
8.4.2 Secondary Outcome Measures
8.4.2.1 Efficacy 
1.
Trough levels of IgG (for Study Epochs 1 and 2)
8.4.2.2 Safety/Tolerability
1.
Proportion of subjects who achieve a treatment interval of three or four weeks in 
Epoch 2 
2.
Proportion of subjects who maintain a treatment interval of three or four weeks in 
Epoch 2 for 12 months
3.
Number and rate per infusion (excluding infections) of local AEs and ARs
4.
Number and rate per infusion (excluding infections) of systemic AEs and ARs 
5.
Number and rate per infusion (excluding infections) of all AEs and all ARs
6.
Number and rate per infusion (excluding infections) of all temporally associated 
AEs 
7.
Number and rate per infusion (excluding infections) of all causally related and/or 
temporally associated AEs
8.
Number and rate per infusion (excluding infections) of all SAEs 
9.
Number/proportion of subjects who develop positive titer (≥160) of binding or 
neutralizing antibodies to rHuPH20
10. Additional safety outcome measures include.

Clinical laboratory outcomes: raw (actual) values and change from baseline

Vital signs: raw (actual) values and change from baseline
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8.4.2.3 Mode of Product Administration
For Study Epochs 1 and 2
1.
Infusions
a.
Number of infusions per month
b.
Number of infusion sites (needle sticks) per infusion/month
c.
Duration of infusion
d.
Maximum infusion rate/site
e.
Infusion volume/site
f.
Number/proportion of infusions that are discontinued, slowed, or interrupted 
due to an AE
2.
Number of weeks to reach final dose interval (3 weeks or 4 weeks)
3.
Assessment of Treatment Preference Questionnaire 
4.
Assessment of Treatment Satisfaction Questionnaire for Medication: TSQM-9
5.
Assessment of HRQoL Questionnaire: Peds-QL, EQ-5D
8.4.3 Tertiary Outcome Measures
1.
Number of acute serious bacterial infections
2.
Number of all infections
3.
Days not able to go to school or work or to perform normal daily activities due to 
infection or other illnesses per patient-year
4.
Days on antibiotics
5.
Number of hospitalizations, indication for the hospitalization (infection or non-
infection) and days hospitalized
6.
Number of acute physician visits (office and emergency room) due to infection or 
other illnesses
8.4.4 Exploratory Outcomes Measure
Not applicable.
8.5 Randomization and Blinding
This is a non-randomized, open-label, active treatment clinical study.
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8.6 Study Stopping Rules 
Stopping rules will not be established for this study as the pediatric subjects will be 
treated with a licensed human normal immunoglobulin, according to the routine standard 
at the study site for the duration of the study. 
8.7 Investigational Product(s)
8.7.1 Packaging, Labeling, and Storage
8.7.1.1 rHuPH20
Dosage Form: Injection, solution
Packaging: rHuPH20 drug product (160 U/mL) will be supplied as a clear, colorless, 
ready-for-use sterile liquid preparation in single-use glass vials. The product should be 
inspected visually for particulate matter and discoloration. The product should not be 
used if particulate matter and/or discoloration is observed.
Labeling: The product will be labeled according to the regulatory requirements for 
clinical studies.
Storage: rHuPH20 drug product must be stored under refrigerated conditions (2° to 8°C 
or 36° to 46°F). Do not freeze the product. Do not use if expiration date is exceeded.
8.7.1.2 IGI, 10%
Dosage Form: Injection, solution.
Packaging: IGI, 10% will be supplied as a ready-for-use sterile liquid preparation in 
single-use glass vials. IGI, 10% is a clear or slightly opalescent and colorless or pale 
yellow solution. The product should be inspected visually for particulate matter and 
discoloration. The product should not be used if particulate matter and/or discoloration is 
observed.
Labeling: IGI, 10% will be labeled according to regulatory requirements for clinical 
studies.
Storage: IGI, 10% must be stored under refrigerated conditions (2°C to 8°C or 36°F to 
46°F). Do not freeze the product. Do not use if expiration date is exceeded.
Prior to use, the vials must be removed from refrigeration and placed at room temperature 
for a minimum of 90 minutes to a maximum of 24 hours to equilibrate and should be kept 
at room temperature during administration. 
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If IGI, 10% is pooled in a bag, it must be used as soon as possible, but no longer than 
three hours from the time of pooling. 
8.7.1.3 KIOVIG (IGIV 10%)
Dosage Form: Injection, solution
Packaging: IGIV, 10% will be supplied as a ready-for-use sterile liquid preparation in 
single-use glass vials of 5 g (50 mL) and 10 g (100 mL).
Labeling: The study product will be labeled according to the valid regulatory 
requirements for clinical studies.
Storage: Refrigeration. IGIV, 10% must be stored under refrigerated conditions (2° to 
8°C or 36° to 46°F). Do not freeze the product. Do not use if expiration date is exceeded. 
Prior to use, the unopened vials must be removed from refrigeration and placed at room 
temperature for a minimum of 90 minutes to a maximum of 24 hours to equilibrate and 
should be kept at room temperature during administration.
8.7.1.4 Cuvitru (IGSC 20%)
Dosage form: Solution for injection
Packaging:
5, 10, 20 or 40 mL of solution in a vial (Type I glass) with a stopper (bromobutyl).
Pack size: 1 vial. Not all pack sizes may be available.
Labeling: The study product will be labeled according to the valid regulatory 
requirements for clinical studies.
Storage and Shelf Life: Do not store above 25°C. Do not freeze the product. 
Shelf Life: 2 years. Do not use if expiration date is exceeded. Keep the container in the 
outer carton in order to protect from light. Once opened, use immediately.
8.7.2 Administration
rHuPH20 will be administered at a dose ratio of approximately 80 U/g IgG before the 
infusion of IGI, 10%. The full vial of rHuPH20 associated with each vial of IGI, 10% 
should be used.
rHuPH20 should be injected at a rate of approximately1-2 mL/min, or faster if 
tolerated, through the same SC needle that will be used to infuse the IGI, 10%. 
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As soon as the rHuPH20 infusion is completed, but no longer than ten minutes after it is 
completed, the administration tubing to deliver IGI, 10% should be connected to the same 
SC needle set used to administer rHuPH20 in order to flush the remaining rHuPH20 into 
the SC tissue and start the infusion of immunoglobulin. 
8.7.3 Description of Treatment
8.7.3.1 HyQvia 
Subjects will be treated with HyQvia in Study Epoch 1 and Study Epoch 2.
Dosage Form: Injection
Mode of Administration: SC
Dosage Frequency:
Study Epoch 1 (Ramp-up):
One treatment interval of one week, then one treatment interval of two weeks, then one 
treatment interval of three weeks (for subjects in whom treatment is expected to be every 
four weeks).
Study Epoch 2 (Final dosing): 
Once every three or four weeks:
For IV-pretreated subjects: every three or four weeks, depending on the subject’s 
previous IV dosing schedule
For SC-pretreated subjects: every three or four weeks, at the discretion of investigator 
and subject
Dose: HyQvia weekly dose will be equivalent to 100% (±5%) of pre-study treatment.
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Table 2. Example for IgG dosing
Pre-Study
Epoch 1 
(Ramp-Up)
Epoch 2 
(Final Dose)
Admin. 
Route
Dose
First Infusion 
at Baseline: 
1-Week Dose
Second Infusion 
at Week 1: 
2-Week Dose
Third Infusion 
at Week 3: 
3-Week Dose
IV
0.6 g/kg 
every 3 weeks
0.2 g/kg
0.4 g/kg
-
0.6 g/kg 
every 3 weeks
IV
0.6 g/kg 
every 4 weeks
0.15 g/kg
0.3 g/kg
0.45 g/kg
0.6 g/kg 
every 4 weeks
SC
0.1 g/kg 
every week
0.1 g/kg
0.2 g/kg
-
0.3 g/kg 
every 3 weeks
SC
0.1 g/kg 
every week
0.1 g/kg
0.2 g/kg
0.3 g/kg
0.4 g/kg 
every 4 weeks
The dose (in grams IgG per kg body weight) should remain stable throughout the study. 
In order to maintain the same dose in g/kg when there has been an increase in body 
weight (kg), it will be necessary to increase the absolute dose (in g or mg) administered. 
The HYQVIA dose should be based on the most current weight measurement (taken at a 
site visit) - if the subject´s weight has increased by more than 5%, the absolute dose (in g 
or mg) should be adjusted at the next possible infusion. If there is a weight decrease, 
regardless of the percentage, the HYQVIA dose should not be changed. 
The final dose in g/kg may be increased if clinically indicated (e.g. increased incidence of 
infections, low IgG trough level (<5 g/L)) at the investigator´s discretion. If such an event 
arises, the sponsor should be informed, the rationale for such dose adjustment should be 
documented in the patient file, and the adjusted dose should be entered in the case report 
forms (CRFs).
Infusion Rate:
Study Epoch 1 (Ramp-up): 

For subjects with a BW of < 40 kg: 5 mL/h/site (at start) to 80 mL/h/site 
(maximum, if tolerated)

For subjects with a BW of ≥ 40 kg: 10 mL/h/site (at start) to 240 mL/h/site 
(maximum, if tolerated)
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Study Epoch 2 (Final dosing):

For subjects with a BW of < 40 kg: 10 mL/h/site (at start) to 160 mL/h/site 
(maximum, if tolerated)

For subjects with a BW of ≥ 40 kg: 10 mL/h/site (at start) to 300 mL/h/site 
(maximum, if tolerated)
If infusions have been tolerated after the subject has received two HyQvia infusions at the 
dose for the final infusion interval (three- or four-week dose), then the investigator may 
choose an infusion rate schedule at his/her own discretion.
8.7.3.2 KIOVIG (IGI 10%)
Subjects may be treated with KIOVIG in Study Epoch 3 (Safety Follow-up).
Dosage form: injectable
Mode of Administration: intravenous
The infusion rate and infusion volume per site will follow the suggestions of the KIOVIG 
SmPC. 
Dosage frequency: Once every three or four weeks 
Dose: The weekly dose will be equivalent to 100% (±5%) of the dose in the previous 
study Epoch.
8.7.3.3 Cuvitru (IGI 20%)
Subjects may be treated with Cuvitru in Study Epoch 3 (Safety Follow-up).
Dosage form: injectable
Mode of Administration: subcutaneous
The infusion rate and infusion volume per site will follow the suggestions of the Cuvitru 
SmPC, which is available in those countries where Cuvitru is registered. In Countries 
where Cuvitru is not registered, an IB will be available. 
Dosage frequency: daily to once every two weeks, at the investigator´s discretion
Dose: The weekly dose will be equivalent to 100% (±5%) of the dose in the previous 
study epoch.
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8.7.4 Investigational Product Accountability
The investigator will ensure that the investigational product(s) (IP[s]) are stored as 
specified in the protocol and that the storage area is secured, with access limited to 
authorized study personnel. The investigator will maintain records that the IP(s) was 
received, including the date received, drug identity code, date of manufacture or 
expiration date, amount received and disposition. IP(s) must be dispensed only at the 
study site or other suitable location (e.g. infusion center; home, as applicable per study 
design). Records will be maintained that includes the subject identification code (SIC), 
dispensation date, and amount dispensed. All remaining partially used and/or unused 
IP(s) will be returned to the sponsor or sponsor’s representative after study 
completion/termination, or destroyed with the permission of the sponsor in accordance 
with applicable laws and study site procedures. If IP(s) is to be destroyed, the investigator 
will provide documentation in accordance with sponsor’s specifications.
8.8 Source Data
Per ICH GCP, source data are defined as all information in original records and certified 
copies of original records of clinical findings, observations, or other activities in a clinical 
trial that are necessary for the reconstruction and evaluation of the trial. Source data are 
contained in source documents (original records or certified copies), which may be in 
paper and/or electronic format. Source data for this study comprise, but are not limited to, 
the following: hospital records, medical records, clinical and office charts, laboratory 
notes, memoranda, subjects' diaries or evaluation checklists, outcomes reported by 
subjects, pharmacy dispensing records, recorded data from automated instruments, copies 
or transcriptions certified after verification as being accurate copies, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, subject files, and records 
kept at the pharmacy, at the laboratories and at medico-technical departments involved in 
the clinical study.
No data will be entered directly into the electronic case report form (eCRF). 
For additional information on study documentation and eCRFs, see Section 17.2. The use 
of subject diaries is described in Section 10. 
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9. SUBJECT SELECTION, WITHDRAWAL, AND DISCONTINUATION
9.1 Inclusion Criteria
Subjects who meet ALL of the following criteria are eligible for this study:
1.
Subject must have a documented diagnosis of a form of primary humoral 
immunodeficiency involving a defect in antibody formation and requiring 
gammaglobulin replacement, as defined according to the IUIS (International Union 
of Immunological Societies) Scientific Committee 2015 (Picard et al., 2015) prior 
to enrollment. The diagnosis must be confirmed by the sponsor´s Medical Director 
prior to first treatment with IP in the study.
2.
Subject is at least two and below 18 years of age at the time of screening.
3.
Subject has been receiving a consistent dose of IgG, administered in compliance 
with the respective product information for a period of at least three months prior to 
screening. The average minimum pre-study dose over that interval was equivalent 
to 300 mg/kg BW/four weeks and a maximum dose equivalent to 1000 mg/kg 
BW/4 weeks.
4.
Subject has a serum trough level of IgG > 5 g/L at screening.
5.
If female of childbearing potential, subject presents with a negative pregnancy test 
and agrees to employ adequate birth control measures for the duration of the study. 
6.
Subject/legally authorized representative is willing and able to comply with the 
requirements of the protocol.
9.2 Exclusion Criteria
Subjects who meet ANY of the following criteria are not eligible for this study:
1.
Subject has a known history of or is positive at screening for one or more of the 
following: hepatitis B surface antigen (HBsAg), polymerase chain reaction (PCR) 
for hepatitis C virus (HCV), PCR for human immunodeficiency virus (HIV) 
Type 1/2. 
2.
Abnormal laboratory values at screening meeting any one of the following criteria 
(abnormal tests may be repeated once to determine if they are persistent):
a. Persistent alanine aminotransferase (ALT) and aspartate amino transferase 
(AST) >2.5 times the upper limit of normal (ULN) for the testing laboratory
b. Persistent severe neutropenia (defined as an absolute neutrophil count [ANC] 
≤500/mm3)
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3.
Subject has anemia that would preclude phlebotomy for laboratory studies, 
according to standard practice at the site.
4.
Subject has an ongoing history of hypersensitivity or persistent reactions (urticaria, 
breathing difficulty, severe hypotension, or anaphylaxis) following IV 
immunoglobulin, SC immunoglobulin, and/or Immune Serum Globulin (ISG) 
infusions.
5.
Subject has severe immunoglobulin A (IgA) deficiency (less than 7.0 mg/dL) with 
known anti-IgA antibodies and a history of hypersensitivity. . 
6.
Subject has a known allergy to hyaluronidase.
7.
Subject has active infection and is receiving antibiotic therapy for the treatment of 
infection at the time of screening.
8.
Subject has a bleeding disorder or a platelet count less than 20,000/µL, or who, in 
the opinion of the investigator, would be at significant risk of increased bleeding or 
bruising as a result of SC therapy. 
9.
Subject has severe dermatitis that would preclude adequate sites for safe product 
administration in the opinion of the investigator.
10. Subject has participated in another clinical study involving an IP or investigational 
device within 30 days prior to enrollment or is scheduled to participate in another 
clinical study involving an IP or investigational device during the course of this 
study.
11. Subject is a family member or employee of the investigator.
12. If female, subject is pregnant or lactating at the time of enrollment.
9.3 Withdrawal and Discontinuation
Any subject may voluntarily withdraw (i.e., reduce the degree of participation in the 
study) consent for continued participation and data collection. The reason for withdrawal 
will be recorded on the End of Study eCRF. Assessments to be performed at the 
termination visit (including in cases of withdraw or discontinuation) are described in 
Section 10.6 and Section 20.2.
Discontinuation (i.e., complete withdrawal from study participation) may be due to 
dropout (i.e., active discontinuation by subject) or loss to follow-up (i.e., discontinuation 
by subject without notice or action). Additionally, the investigator and sponsor have the 
discretion to discontinue any subject from the study if, in their judgment, continued 
participation would pose an unacceptable risk for the subject.
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Subjects also will be withdrawn from treatment or discontinued from further study 
participation for the following reasons:

The subject becomes pregnant. IP exposure will be discontinued. Attempts will be 
made to follow the subject through completion of the pregnancy and up to 1 year 
post-delivery, if feasible. The investigator will record a narrative description of the 
course of the pregnancy and its outcome.

The subject begins lactating. IP exposure will be discontinued. The investigator will 
record a narrative description of the course of the baby’s development.

The subject twice consecutively misses administration of IP. 

The subject does not comply with the protocol (per the investigator’s discretion).

The subject develops severe hypersensitivity reactions related to IP administration.

The subject uses prohibited medications (see Section 10.4) during the course of this 
study.

The subject participates in another clinical study involving an IP or device during 
the course of this study.
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10. STUDY PROCEDURES
10.1 Informed Consent
Any patient who provides informed consent (i.e., signs and dates the informed consent 
form and assent form, if applicable. See also Section 16.3) and meets all inclusion and 
none of the exclusion criteria, is considered enrolled in the study and thus becomes a 
subject in the study. 
10.2 Subject Identification Code
The following series of numbers will comprise the SIC: protocol identifier (e.g., 161504) 
to be provided by the sponsor, three-digit number study site number (e.g., 002) to be 
provided by the sponsor, and three-digit subject number (e.g., 003) reflecting the order of 
providing informed consent. For example, the third subject who signed an informed 
consent form at study site 02 will be identified as Subject 161504-002003. All study 
documents (e.g., case report forms [CRFs], clinical documentation, sample containers, 
drug accountability logs, etc.) will be identified with the SIC. Additionally, a uniquely 
coded SIC(s) is permitted as long as it does not contain a combination of information that 
allows identification of a subject (e.g., collection of a subject’s initials and birth date 
would not be permitted), in compliance with laws governing data privacy.
10.3 Screening and Study Visits
Screening will comprise all procedures to confirm subject eligibility. The investigator is 
responsible for maintaining a patient identification list that includes all enrolled subjects 
and which includes the following information: subject´s full name, subject number, and 
site number. The log also will serve to document the reason for screening failure. All 
screening data will be collected and reported in eCRFs, regardless of screening outcome. 
If a subject is re-screened, the End of Study eCRF for the prior screening should be 
completed, and a new ICF, new SIC and new eCRF are required for that subject.
The overall study design is illustrated in the Study Flow Chart (Section 20.1). Details on 
the procedures to be performed at each study visit, including screening, can be found in 
Section 20.2 Schedule of Study Procedures and Assessments and Section 20.3 Clinical 
Laboratory Assessments.
All screening procedures must be completed up to 31 days prior to the first infusion. If a 
subject is scheduled to receive a dose of IgG before eligibility is fully confirmed (e.g. due 
to the unavailability of lab results), the subject may continue receiving the IgG product 
used prior to enrollment. Subjects may be re-screened once. 
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Details on the treatment regimen including dose (total dose in mg/kg BW/week) and the 
infusion interval will be collected. Changes to the treatment regimen, including the 
reason for the change, will also be collected.
In addition, details on product administration such as infusion date and start/stop time, lot 
number, actual volume infused, maximum infusion rate achieved, number and location of 
infusion sites (needle sticks) per infusion, will be collected.
Details of the treatment regimen and product administration, if performed at the site, 
should be recorded on the CRF. Administration details for home treatment should be 
recorded by the subject/subject´s legally authorized representative in the subject diary.
10.4 Medications and Non-Drug Therapies 
The use of all antibiotic therapy must be associated with a corresponding AE, and 
documented accordingly.
The following medications and non-drug therapies are not permitted during the course of 
the study:

Prophylactic treatment with systemic antibacterial antibiotics is not allowed during 
the study. The use of systemic prophylactic antibacterial antibiotics by a subject 
will be considered a protocol deviation. However, prophylaxis for viral infections, 
fungi and parasites (including pneumocystis pneumonia) which are not treated by 
immunoglobulin, can be used and should be recorded as concomitant medication. 
Use of Trimethaprim-Sulfamethoxazole for pneumocystis prophylaxis is acceptable 
in doses typical for pneumocystis pneumonia, but not low dose daily therapy that 
can also be used for antibacterial prophylaxis. Brief (less than 72 hours), 
prophylaxis for surgery (including dental procedures) or injury is permitted but 
treatment and indication must be recorded.

Other IGIV or IGSC products

Pre-medication on the day of product administration:
In this study, subjects should not receive pre-medication for SC infusions unless an 
AR of at least moderate severity, not resolving with a reduction in the infusion rate, 
occurs during or after at least two infusions. Should this occur, subjects may be 
pretreated with antipyretics, corticosteroids or antihistamines at the discretion of the 
investigator. Topical anesthetics (e.g., EMLA) may be used if the needle insertion 
was intolerable in prior infusions. Subjects who have a history of using topical 
anesthetics (e.g., EMLA) may use these topical anesthetics for SC infusions. 
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The use of such pre-medications should be recorded on the concomitant medication 
record. 
10.5 Subject Diary 
An electronic subject diary will be provided to each subject/caregiver at enrollment to 
record the following information:

Occurrence of AEs (including infections). The investigator will provide guidance 
for the subject/caregiver regarding identification and documentation of AEs 

Concomitant medication use 

Details of the product administration as specified in Section 10.3

Days not able to attend school/work or to perform normal daily activities due to 
infection or other illness

Non-study-required out-patient visits (including urgent care visits to see healthcare 
providers) and hospitalizations
Subjects and/or their legally authorized representatives will be trained on use of the diary. 
The diary will be provided in electronic format and remain with the subject for the 
duration of the study. The investigator will review the diary for completeness and request 
missing information periodically and in a timely manner. Untoward events recorded in 
the diary will be reported as AEs according to the investigator’s discretion and clinical 
judgment.
Subject entries in the diary will serve as source records. During study participation the 
investigator has access to the database holding the subject diary data. After study closure, 
the investigator will receive the diary records for their subjects, including audit trail 
records, in PDF format. The data will be transmitted to the CRF by a validated transfer. 
Electronic Patient Reported (EPR) modules will be used to enable deployment of 
required subject diaries to subjects based on protocol requirements. EPRs can be 
programmed to allow a certain level of data validation at the time of data entry by the 
subject; this allows cleaning of subject reported data at the time of data collection. 
Additionally, EPR compliance reports enable monitoring of patient compliance, and 
proactive follow up if required. EPRs can be deployed in local languages as needed. 
Automated reminder e-mails are sent to subjects who do not complete required EPRs. 
Following a certain number of reminder e-mails, the link to that particular EPR is 
disabled; this ensures that EPRs are collected in a timely manner during the study.
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10.6 Subject Completion/Discontinuation
A subject is considered to have completed the study when he/she ceases active 
participation in the study because the subject has, or is presumed to have, completed all 
study procedures according to the protocol (with or without protocol deviations).
Reasons for completion/discontinuation will be reported on the 
Completion/Discontinuation eCRF, including: completed, screen failure, AE (e.g., death), 
discontinuation by subject (e.g., lost to follow-up [defined as three documented 
unsuccessful attempts to contact the subject], dropout), physician decision (e.g., 
pregnancy, progressive disease, non-compliance with IP/protocol violation(s), recovery), 
study terminated by sponsor, or other (reason to be specified by the investigator, e.g., 
technical problems). Regardless of the reason, all data available for the subject up to the 
time of completion/discontinuation should be recorded on the appropriate eCRF. 
Every effort will be made to have discontinued subjects complete the study 
completion/termination visit. If the completion/termination visit is done as an additional, 
unscheduled visit, the assessment results shall be recorded with the 
completion/termination visit. If a subject terminates participation in the study and does 
not return for the completion/termination visit, their last recorded assessments shall 
remain recorded with their last visit. The reason for discontinuation will be recorded, and 
the data collected up to the time of discontinuation will be used in the analysis and 
included in the clinical study report. If additional assessments are required, the 
assessments shall be recorded separately. Assessments to be performed at the termination 
visit (including in cases of withdraw or discontinuation) can be found in Section 20.2
Schedule of Study Procedures and Assessments and Section 20.3 Clinical Laboratory 
Assessments.
In the event of subject discontinuation due to an AE, clinical and/or laboratory 
investigations that are beyond the scope of the required study observations/assessments 
may be performed as part of the evaluation of the event. These investigations will take 
place under the direction of the investigator in consultation with the sponsor, and the 
details of the outcome may be reported to the appropriate regulatory authorities by the 
sponsor. 
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10.7 Procedures for Monitoring Subject Compliance
For study procedures that are to be performed under the direct supervision of the 
investigator/healthcare professional (e.g., infusion nurse) at the study site or infusion 
center, no separate procedures will be used to monitor subject compliance.
Training, evaluation, and verification of the subject’s (and/or caregiver’s) proficiency in 
performing self-infusion procedures by the investigator/designee, must be documented as 
a prerequisite before the subject (and/or caregiver) will be allowed to begin 
self-administration of SC infusions. A healthcare professional (e.g., infusion nurse) may 
be present to observe the subject’s self-administration. The subject (and/or caregiver) 
may be asked to return to the study site during the study so that the investigator/designee 
can further assess and document that the subject (and/or caregiver) is capable of 
continuing to independently perform self-infusion procedures.
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11. ASSESSMENT OF EFFICACY
11.1 IgG Trough Levels
IgG trough levels will be determined at several time points (see Section 20.3 Clinical 
Laboratory Assessments). Standard assay methods will be used for the determination of 
IgG and IgG subclasses. The measurement will be performed at the central laboratory. 
11.2 Treatment Preference Questionnaire
The treatment preference questionnaire, internally developed at Baxalta, is a self-
administered, non-validated scale assessing patient preference for various attributes of 
IgG therapy, such as ease of administration, frequency and duration of administration, 
and convenience. 
The treatment preference questionnaire will be administered at the study site using a 
translated version, as applicable. It is recommended that the subject complete the 
assessment using the same translated version throughout the course of the study. For 
subjects aged 13 to <18 years, the subject should complete the questionnaire themselves 
(observer: subject). For subjects under the age of 13, the parent should complete the 
questionnaire on behalf of their child (observer: parent). The same observer should be 
employed for the duration of subject participation. 
For detailed administration time points, see Section 20.2 Schedule of Study Procedures 
and Assessments.
11.3 Treatment Satisfaction Questionnaire for Medication
The Abbreviated Treatment Satisfaction Questionnaire for Medication (TSQM-9) is a 
9-item, validated, self-administered instrument to assess patients’ satisfaction with 
medication. The 3 domains assessed are effectiveness, convenience, and global 
satisfaction.
The TSQM-9 will be administered at the study site using a validated translated version, as 
applicable. It is recommended that the subject complete the assessment using the same 
translated version throughout the course of the study. For subjects aged 13 to <18 years, 
the subject should complete the questionnaire themselves (observer: subject). For subjects 
under the age of 13, the parent should complete the questionnaire on behalf of their child 
(observer: parent). The same observer should be employed for the duration of subject 
participation. 
For detailed administration time points, see Section 20.2 Schedule of Study Procedures 
and Assessments.
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11.4 HRQoL Questionnaire
11.4.1 PedsQL
The PedsQL is a validated questionnaire designed to measure generic HRQoL among a 
pediatric population. Both patient and proxy versions of the questionnaire are available. 
This questionnaire measures four domains, including; Physical functioning, Emotional
functioning, Social functioning and school functioning. A total score and domain scores 
can be calculated. Higher scores indicate better health status (Varni et al., 1999).
Quality of life (QoL) will be assessed separately for the age groups two to four years, and 
five to seven years, eight to 12 years (PEDS-QL, observer: parent), and 13 to <18 years 
(PEDS-QL, observer: subject) . The same observer should be employed for the duration 
of subject participation. 
Age will be defined as the age at screening, in order to determine which age-specific 
assessment is to be used. The same age-specific assessment is to be used for the duration
of the study. In the event that the language or age group is not available, the assessment 
in the closest age group will be used. In the event that the appropriate language is not 
available, the questionnaire will not be administered for that subject. For detailed 
administration time points, see Section 20.2 Schedule of Study Procedures and 
Assessments.
11.4.2 EQ-5D
The EQ-5D is a validated, self-administered assessment of overall health designed by the 
EuroQol Group (Rabin and de Charro, 2001). It is a descriptive system of HRQoL states 
consisting of 5 dimensions (mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression). Subjects are asked to describe their health state that day by choosing 
1 of 3 responses that reflect the levels of severity for each of the 5 dimensions: no 
problems, some or moderate problems, or extreme problems. The EQ-5D also includes a 
standard vertical 20-cm visual analogue scale (similar to a thermometer) for recording a 
subject’s rating of their current HRQoL state.
The EQ-5D will be administered at the study site using a validated translated version, as 
applicable. It is recommended that the subject complete the assessment using the same 
translated version throughout the course of the study. For subjects aged 13 to <18 years, 
the subject should complete the questionnaire themselves (observer: subject). For subjects 
under the age of 13, the parent should complete the questionnaire on behalf of their child 
(observer: parent). In the event that the appropriate language is not available, the 
questionnaire will not be administered for that subject. For detailed administration time 
points, see Section 20.2 Schedule of Study Procedures and Assessments.
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12. ASSESSMENT OF SAFETY
12.1 Adverse Events
12.1.1 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. 
Temporally associated AEs are all AEs which occur during the infusion or within 
72 hours of completion of infusion.
12.1.1.1 Serious Adverse Event 
A SAE is defined as an untoward medical occurrence that at any dose meets one or more 
of the following criteria:

Outcome is fatal/results in death (including fetal death)

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.

Requires inpatient hospitalization or results in prolongation of an existing 
hospitalization – inpatient hospitalization refers to any inpatient admission, 
regardless of length of stay.

Results in persistent or significant disability/incapacity (i.e., a substantial disruption 
of a person’s ability to conduct normal life functions)

Is a congenital anomaly/birth defect

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 
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Reviewed and confirmed seroconversion for HIV, hepatitis A virus (HAV), 
hepatitis B virus (HBV), HCV, hepatitis E virus (HEV), or parvovirus B19 
(B19V)
Thromboembolic events (e.g., deep vein thrombosis, pulmonary embolism, 
myocardial infarction, cerebrovascular accidents [e.g., stroke, transient 
ischemic event])
Hemolytic anemia
Uncomplicated pregnancies, following maternal or paternal exposure to IP are not 
considered an (S)AE; however, any pregnancy complication or pregnancy termination by 
therapeutic, elective, or spontaneous abortion shall be considered an SAE.
12.1.1.2 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.
12.1.1.3 Non-Serious Adverse Event
A non-serious AE is an AE that does not meet the criteria of an SAE.
12.1.1.4 Unexpected Adverse Events
An unexpected AE is an AE whose nature, severity, specificity, or outcome is not 
consistent with the term, representation, or description used in the Reference Safety 
Information. “Unexpected” also refers to the AEs that are mentioned in the investigator’s 
brochure 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. 
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The expectedness of AEs will be determined by the sponsor using the investigator’s 
brochure and/or prescribing information as the Reference Safety Information. 
This determination will include considerations such as the number of AEs previously 
observed, but not on the basis of what might be anticipated form the pharmacological 
properties of a product.
12.1.1.5 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.
12.1.2 Assessment of Adverse Events
Each AE from signing informed consent 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 12.1). Each AE will be evaluated by the 
investigator for:

Seriousness as defined in Section 12.1.1.1

Severity as defined in Section 12.1.2.1

Causal relationship to IP exposure or study procedure as defined in Section 12.1.2.2
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 
Report Form. 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.
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Deviations from the protocol-specified dosage (including overdosing or underdosing by 
more than 20%, abuse, and withdrawal), 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, lack of 
efficacy, and/or other observations because these events may be reportable to regulatory 
authorities.
Any pregnancy that occurs after administration of IP will be reported on a Pregnancy 
Report Form and followed-up at estimated date of delivery and one year post-delivery, if 
feasible. The investigator will record a narrative description of the course of the 
pregnancy and its outcome.
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 hours after awareness.
12.1.2.1 Severity
The investigator will assess the severity of each AE using his/her clinical expertise and 
judgment based on the most appropriate description below:

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.

Moderate

The AE produces limited impairment of function and may require therapeutic 
intervention.

The AE produces no sequela/sequelae.

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.
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These severity definitions will also be used to assess the severity of an AE with a 
study-related procedure(s), if necessary.
12.1.2.2 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 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:

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). 

Unlikely related (either one or both circumstances are met)

Has little or no temporal relationship to the IP 

A more likely alternative etiology exists

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
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: 
o
Reappearance of a similar reaction upon re-administration (positive 
rechallenge)
o
Positive results in a drug sensitivity test (skin test, etc.)
o
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
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For events assessed as not related or unlikely related and occurring within 72 hours 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.
12.2 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: 

Immediate change in study design or study procedures

Temporary or permanent halt of a given clinical trial or trials

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 one calendar day after the change is implemented. The sponsor 
will also ensure the responsible ethics committee(s) (ECs) and relevant competent 
authority(s) are notified of the urgent safety measures taken in such cases according to 
local regulations.
12.3 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 12.1). 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 non-serious 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. 
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12.4 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:

A failure of a product to exhibit its expected pharmacological activity and/or design 
function, e.g., reconstitution difficulty

Missing components

Damage to the product or unit carton

A mislabeled product (e.g., potential counterfeiting/tampering)

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 one business day. If requested, defective product(s) will be returned to the 
sponsor for inspection and analysis according to procedures.
12.5 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 12.1.2.1) 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 medications taken and non-drug therapies received from providing informed consent
until completion/termination will be recorded on the concomitant medications and 
non-drug therapies CRFs.
12.6 Physical Examinations
At screening and subsequent scheduled study visits (as described in Section 20.2), 
a 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. 
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If the abnormal value was not deemed an AE because it was due to an error, due to a 
preexisting disease (described in Section 12.1.1.5), not clinically significant, a symptom 
of a new/worsened condition already recorded as an AE, or due to another issue that will 
be specified, the investigator will record the justification on the source record.
12.7 Clinical Laboratory Parameters
For detailed sampling time points see Section 20.3 Clinical Laboratory Assessments. 
Blood and urine collection will occur pre-infusion (unless stated otherwise), and should 
be collected within one hour before the start of the infusion procedure, if possible.
12.7.1 Hematology and Clinical Chemistry
The hematology panel will consist of complete blood count (hemoglobin [Hgb], 
hematocrit, erythrocytes [i.e., RBC], and leukocytes [i.e., white blood cell count [WBC]) 
with differential (i.e., basophils, eosinophils, lymphocytes, monocytes, neutrophils) and 
platelet counts. 
The clinical chemistry panel will consist of sodium, potassium, chloride, bicarbonate, 
total protein, albumin, alanine aminotransferase ALT, aspartate amino transferase (AST), 
total bilirubin, alkaline phosphatase (ALP), blood urea nitrogen (BUN), serum creatinine, 
and glucose.
Hematology and clinical chemistry assessments will be performed on 
EDTA-anticoagulated whole blood and serum, respectively, at the central laboratory. 
12.7.2 Urine Tests
Urinalysis will include color, specific gravity, pH, protein, glucose, ketones, bilirubin, 
urobilinogen, blood, nitrite, leukocyte esterase, and microscopic examination. Urinalysis 
tests will be conducted at the central laboratory.
12.7.3 Pregnancy Test
For female subjects of childbearing potential, urine pregnancy test will be performed at a 
central laboratory, unless a serum pregnancy test is mandatory as specified by local 
regulatory/institutional requirements.
12.7.4 Hemolysis Test
Hemolysis test will consist of Hgb, lactate dehydrogenase (LDH), serum haptoglobin, 
plasma-free (unbound) Hgb, serum direct anti-globulin (direct Coomb’s) test (antibody 
elution to be performed if direct Coomb’s test is positive), reticulocyte count, as well as 
urine hemosiderin. 
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If there is a reduction in Hgb of two g/dL or more compared to baseline Hgb, every effort 
is to be made to perform a repeat test consisting of the hemolysis tests described above 
within 72 hours; if it is not feasible to do so, the hemolytic panel must be performed as 
soon as possible. At any time during the study, an unscheduled hemolytic panel may be 
performed in the event of suspected hemolytic anemia.
Hemolysis test will be performed at the central laboratory or other laboratories as 
appropriate (e.g., antibody elution in the event of positive direct Coomb’s test). Complete 
hematology and clinical chemistry assessments may be performed in order to obtain 
laboratory results required for a hemolytic panel.
12.7.5 IgG Trough Levels and IgG Subclasses and Specific Antibody Tests
IgG total and IgG subclass trough levels and trough levels of specific antibodies against 
Clostridium tetani toxoid, Haemophilus influenzae, and HBV will be determined on all 
subjects. Testing will be performed at the central laboratory using standard assay 
methods.
12.7.6 Anti-rHuPH20 Antibodies
All subjects will have regular anti-rHuPH20 antibody testing in pre-identified central 
laboratories for binding anti-rHuPH20 antibodies throughout the study approximately 
every three months (see Section 20.3). For subjects with an anti-rHuPH20 antibody titer 
≥160 neutralizing antibodies will also be measured.
At any time during the course of the study, subjects who have 1) two consecutive anti-
rHuPH20 antibody titers of ≥1:160 that are elevated from the subject’s baseline titers, 
and 2) a moderate or severe AE that may be a result of immune-mediated response to 
either immunoglobulin or rHuPH20 will be asked to return to the study site as soon as 
possible to undergo an additional panel of testing:

50% hemolytic complement activity of serum, 

serum complement component 3;

serum complement component 4;

(C1q) binding assay, and 

circulating immune complex Raji cell assay.
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12.7.7 Viral Pathogen Serology
Tests for viral pathogen serology include: HBsAg by enzyme-linked immunosorbent 
assay (ELISA), PCR for HCV and PCR for HIV-1/2. These assessments will be 
performed at the central laboratory at the time points specified in Section 20.3.
12.7.8 Assessment of Laboratory Values
12.7.8.1 Toxicity Grading Scale
The following laboratory values will be evaluated by the sponsor/sponsor’s representative 
according to the Common Toxicity Criteria of the Eastern Cooperative Oncology Group 
(ECOG), published by (Oken et al., 1982):

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 toxicity grading system (World Health Organization, 2003). 
The laboratory parameters and the corresponding grading scale are provided in 
Section 20.4. The toxicity scale is defined as: zero = none, one = mild, 
two = moderate, three = severe, four = life-threatening. Laboratory parameters not 
listed in Table 11 will not be graded. However, clinical significance of those 
abnormal laboratory values will be assessed as described in Section 12.7.8.2.
12.7.8.2 Assessment of Abnormal Laboratory Values 
The investigator’s assessment of each laboratory value will be recorded on the 
eCRF laboratory form. For each abnormal laboratory value, the investigator will 
determine whether the value is considered clinically significant or not. 
For clinically significant values, the investigator will indicate if the value constitutes an 
new AE (see definition in Section 12.1, and record the sign, symptom, or medical 
diagnosis on the AE CRF), is a symptom or related to a previously recorded AE, is due to 
a pre-existing disease (described in Section 12.1.1.5), or is due to another issue that will 
be specified. If the abnormal value was not clinically significant, the investigator will 
indicate the reason, i.e., because it is due to a preexisting disease, due to a lab error, or 
due to another issue that will be specified. Additional tests and other evaluations required 
to establish the significance or etiology of an abnormal value, or to monitor the course of 
an AE should be obtained when clinically indicated. Any abnormal value that persists 
should be followed at the discretion of the investigator. 
Any seroconversion result for HIV, HAV, HBV, HCV, HEV, or B19V shall be re-tested.
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12.7.9 Backup Samples and Biobanking
Backup samples taken and stored short-term may be used, for example, for re-testing, 
follow-up of an AE(s) or other test results, and/or assay development. After study testing 
is completed, the remaining samples may be stored in a coded form for no more than two 
years after the final study report has been completed and then the samples will 
subsequently be destroyed.
For this study, no samples will be taken or stored long-term in a biobank for future 
analyses.
12.8 Vital Signs
Vital signs will include body temperature (°C or °F), respiratory rate (breaths/min), pulse 
rate (beats/min), and systolic and diastolic blood pressure (mmHg). Height (in or cm) and 
weight (lb or kg) will also be collected.
Vital signs will be measured as described in Section 20.3.
12.8.1 Screening

All vital signs
12.8.2 Infusion at Study Site
1.
Within 30 min prior to infusion:

All vital signs. Height and weight can be taken at any time at this visit. 
2.
30 (± 5) min after initiation of infusion: 

All vital signs except height and weight
3.
During the infusion if a systemic AE occurs, to be assessed as needed:

All vital signs except height and weight 
4.
Within 30 min of completion of the infusion:

All vital signs except height and weight
12.8.3 Infusion at Home

No assessment of vital signs
12.8.4 End-of-Study 

All vital signs
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Vital sign values are to be recorded on the eCRF. For each abnormal vital sign value, the 
investigator will determine whether to report an AE (see definition in Section 12.1 and 
record the medical diagnosis [preferably], symptom, or sign on the AE CRF). Additional 
tests and other evaluations required to establish the significance or etiology of an 
abnormal value, or to monitor the course of an AE should be obtained when clinically 
indicated. Any abnormal value that persists should be followed at the discretion of the 
investigator.
12.9 Acute Serious Bacterial Infections
Acute serious bacterial infections will be defined as follows based on the US FDA 
Guidance for Industry to Support Marketing of Human IGIV as Replacement Therapy for 
Primary Humoral Immunodeficiency (Food and Drug Administration, 2008) and the 
EMA guideline on the clinical investigation of human normal immunoglobulin for SC 
and /or intramuscular administration (Committee for Medicinal Products for Human Use, 
2015). 
12.9.1 Infection: Bacteremia/Sepsis(a)
1.
Symptoms: chills, rigors
2.
Physical findings- fever, hypothermia, tachycardia, tachypnea, hypocarbia, 
hypotension (systolic blood pressure <90 mm Hg or a reduction of >40 mm Hg 
from baseline in the absence of other causes of hypotension), altered mental status, 
petechiae, purpura, oliguria, cutaneous vasodilation/vasoconstriction
3.
Laboratory tests: positive blood culture(b), leukocytosis (WBC count >12,000/mm3), 
differential WBC count demonstrating >10% immature (band) neutrophils, 
leukopenia, thrombocytopenia, coagulopathy, lactic acidosis
(a) Two of the following should be present to make the diagnosis of sepsis in adults: 
temperature >38°C oral/ > 39°C rectal or <36°C oral or < 37°C rectal; heart rate 
>90 beats/min; respiratory rate >20 breaths/min, or partial pressure of carbon dioxide 
(PaCO2) <32 mm Hg; WBC >12,000/mm3, <4,000/mm3, or >10% immature (band) 
forms. For pediatric patients, we recommend you employ the definition of sepsis using 
age-specific criteria as recommended by the International Consensus Conference on 
Pediatric Sepsis (Goldstein et al., 2005). 
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(b) Indwelling catheter- or vascular access device-related blood-borne infections are not 
included because evidence is lacking that these are preventable with IGI replacement 
therapy. For subjects without indwelling catheters or vascular access devices, a single 
blood culture positive for a pathogenic organism will meet the diagnostic criteria for 
bacteremia. Multiple blood cultures are typically obtained in cases of suspected 
bacteremia/sepsis, as per standard medical practice, and the finding of a single positive 
culture should prompt additional confirmatory cultures. Subjects meeting criteria for 
positive blood culture but without two or more of the sepsis criteria listed above will be 
classified as having bacteremia.
12.9.2 Infection: Bacterial Meningitis
1.
Symptoms: headache, stiff neck, mental status changes, irritability, decreased 
feeding (infants), photophobia, nausea/vomiting, rigors, seizures
2.
Physical findings: Kernig’s sign, Brudzinski’s sign, meningococcal rash, fever of 
>38 °C oral or >39°C rectal
3.
Laboratory tests: positive cerebrospinal fluid (CSF) Gram stain and/or culture 
and/or positive CSF bacterial antigen assay, positive blood culture(c), CSF 
leukocytosis with neutrophil predominance, decrease in CSF glucose
(c) A blood culture positive for growth of Streptococcus pneumoniae, Neisseria 
meningitides, or Haemophilus influenzae, in combination with CSF leukocytosis and/or 
decrease in CSF glucose, can serve to confirm the diagnosis of acute bacterial meningitis
12.9.3 Infection: Osteomyelitis/Septic Arthritis
1.
Symptoms: pain, decreased range of motion, tenderness, edema, redness, warmth 
over the involved site (local inflammatory symptoms/signs may be lacking in 
adults)
2.
Physical findings: evidence of soft tissue infection adjacent to the involved 
bone/joint; drainage from sinus tract from involved bone; fever of >38°C oral or 
>39°C rectal
3.
Laboratory tests: positive blood culture, positive probe to bone, positive bone 
aspirate culture, positive bone biopsy culture, positive bone histopathology, positive 
joint fluid Gram stain and culture
4.
Imaging studies: positive X-ray, nuclear medicine bone scan, magnetic resonance 
imaging (MRI) scan, or computed tomography (CT) scan showing bony destruction 
with radiolucent areas; for chronic osteomyelitis: sequestra, involucre
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12.9.4 Infections: Bacterial Pneumonia(d)
1.
Symptoms: productive cough/change in character of sputum, dyspnea or tachypnea, 
chills, chest pain, rigors, headache, fatigue, sweats, anorexia, myalgias
2.
Physical findings: rales; pulmonary consolidation as reflected by: dullness on 
percussion, bronchial breath sounds, egophony; fever >38°C oral or > 39°C rectal, 
or <36°C, hypothermia (temperature < 36°C oral or < 37°C rectal)
3.
Laboratory tests: leukocytosis; differential WBC count of >10% band neutrophils; 
leukopenia; hypoxemia (PaO2 < 60 mm Hg on room air); positive blood culture; 
Gram stain and culture of deep expectorated sputum(e), positive culture with or 
without positive Gram stain of transtracheal aspirate, pleural fluid culture, lung 
biopsy, bronchoscopy with BAL or protected brush sampling,
4.
Imaging studies: Pulmonary infiltrate with consolidation on chest X-Ray ([CXR]; 
new in comparison with baseline or previous CXR)
(d) For the diagnosis of pneumonia in adults, commonly at least two of the listed 
symptoms and/or signs should be present in conjunction with at least one laboratory and 
one imaging studies diagnostic elementvii. However, for the purposes of counting serious 
infection episodes in a clinical study of IGI, the finding of a new pulmonary infiltrate 
with consolidation on CXR is considered sufficient. To establish the diagnosis of 
bacterial pneumonia for pediatric patients, most of the same diagnostic criteria listed may 
be used, with the following exceptions: Because pediatric patients may not produce a 
sputum specimen for culture, blood cultures or serology may be substituted to identify the 
etiologic bacterial pathogen. In infants age three to 24 months, who tend to have a higher 
baseline temperature, fever is defined as a rectal temperature >38.3°C (101°F). In 
children >two years, fever is more commonly defined as a rectal temperature >38°C 
(100.4°F). In pediatric patients, elevations of WBC counts >15,000/mm3 are frequent but 
could be variable in patients with bacterial pneumonia, or leukopenia with WBC count 
<5000/mm3 may be observed, usually associated with severe infection
(e) We recommend a deep expectorated sputum Gram stain demonstrate the presence of 
microorganisms on examination of 10 to 20 oil immersion microscopic fields and <ten 
squamous epithelial cells and >25 polymorphonuclear leukocytes at tenX low power 
magnification to determine suitability of sputum culture.
                                                
vii Further evaluation, in particular laboratory evaluation (culture and white blood count with differential to 
evaluate for the presence of immature neutrophils) and chest x-rays, should be aggressively pursued 
whenever a bacterial pneumonia is suspected
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12.9.5 Infection: Visceral Abscess
1.
Symptoms: abdominal pain, anorexia, weight loss, cough/pleuritic chest pain 
(hepatic abscess), rigors (seldom present)
2.
Physical findings: intermittent fevers (temperature >38°C oral or >39°C rectal); 
abdominal tenderness; palpable mass; hepatomegaly; jaundice
3.
Laboratory tests: positive Gram stain and/or culture from the infected site, with 
isolation of an appropriate pathogen; positive blood culture; leukocytosis with 
accompanying left shift; differential WBC of >10% immature (band) neutrophils; 
elevated serum amylase concentration (pancreatic abscess); elevated alkaline 
phosphatase concentration (hepatic abscess) pyuria in renal abscess
4.
Imaging studies: typical findings on ultrasound, CT scan, MRI scan, or radionuclide 
scan
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13. STATISTICS
13.1 Sample Size and Power Calculations
The sample size selected for the study is primarily determined by the objective to collect 
safety data on HYQVIA in a sufficient number (about 40) of pediatric (age two to 
<18 years) subjects with PIDD who have received prior immunoglobulin therapy before 
enrollment into this study. In addition, the guideline of the CHMP on the clinical 
investigation of human normal immunoglobulin for SC and/or intramuscular 
administration (Committee for Medicinal Products for Human Use, 2015) indicates that 
at least 40 patients should be included to evaluate replacement therapy in primary 
immunodeficiency syndromes.
13.2 Analysis Sets
13.2.1 Full Analysis Set
All patients who provide informed consent (i.e., sign and date the ICF, if applicable), and 
meet enrollment eligibility (i.e., meets all inclusion criteria and do not meet any exclusion 
criteria) will be included in the full analysis set.
13.2.2 Per-Protocol Analysis Set
All patients in the full analysis set who have no major protocol deviations will be 
included in the per-protocol analysis set.
Protocol deviations will be classified as major or minor in accordance with applicable 
study sponsor’s standard operating procedure(s) and prior to statistical analysis in which 
the Per-protocol Analysis Set will be used. 
13.2.3 Safety Analysis Set
The safety analysis set will contain all subjects in the full analysis set who receive at least 
one dose of HyQvia.
13.3 Handling of Missing, Unused, and Spurious Data
The handling of missing, unused or spurious data will be described in the statistical 
analysis plan (SAP)
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13.4 Methods of Analysis
In this study no hypothesis will be tested. Detailed statistical analysis methods will be 
described in the SAP. Statistical analyses and data displays will be mainly descriptive.
Data from all enrolled subjects will be included in the analysis. If groups of sufficient 
sample size (such as age groups or PIDD types) are available, CIs may accompany the 
point estimates. All SAEs and non-serious AEs will be categorized according to 
MedDRA system organ class and preferred term. Tables will be prepared to list for each 
SAE and non-serious AE the number of events and the number of subjects who 
experienced one or more event. All analyses will be performed using SAS® version 9.2 or 
higher (SAS Institute, Cary, NC, USA). 
13.4.1 Primary Outcome Measure 

Number and rate per infusion (excluding infections) of all severe related AEs 

Number and rate per infusion (excluding infections) of related SAEs
For the endpoint of incidence of all severe related AEs and related SAEs, a point estimate 
and corresponding 95% CI (by the Wilson score method) for the proportion of subjects 
with one or more related SAEs will be provided. In addition, incidence of all severe 
related AEs and related SAEs will be calculated as rate per infusion and rate per 
subject-year, and will be analyzed for changes in frequency and for changes in severity 
over time. All SAEs will be listed. No statistical hypotheses will be tested.
13.4.2 Secondary Outcome Measures 
13.4.2.1 Efficacy 
Trough levels of IgG for Study Epoch 1 and 2: Descriptive statistics will be provided for 
the trough level of IgG for study Epoch 1 and 2. 
13.4.2.2 Safety 
The following secondary safety endpoints/outcome measures will be analyzed:

Proportion of subjects who achieve a treatment interval of three or four weeks in 
Epoch 2 

Proportion of subjects who maintain a treatment interval of three or four weeks in 
Epoch 2 for 12 months

Number and rate per infusion (excluding infections) of local AEs and ARs

Number and rate per infusion (excluding infections) of systemic AEs and ARs 

Number and rate per infusion (excluding infections) of all AEs and all ARs
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
Number and rate per infusion (excluding infections) of all temporally associated 
AEs 

Number and rate per infusion (excluding infections) of all causally related and/or 
temporally associated AEs

Number and rate per infusion (excluding infections) of all SAEs 

Number/proportion of subjects who develop positive titer (≥160) of binding or 
neutralizing antibodies to rHuPH20
Additional safety endpoints/outcome measures include:

Clinical laboratory outcomes: raw (actual) values and change from baseline

Vital signs: raw (actual) values and change from baseline
Descriptive methods, mainly frequency tables, will be used for all secondary safety 
endpoints. In addition, adverse events will be summarized in terms of AEs per subject 
(rate per subject) and AEs per subject-year (rate per subject-year). 
13.4.2.3 Mode of Product Administration (For Study Epochs 1 and 2)

Number of Infusions

Number of infusions per month 

Number of infusion sites (needle sticks) per infusion/month 

Duration of infusion (defined as time from the start of rHuPH20 infusion until the 
stop time of immunoglobulin infusion)

Maximum infusion rate/site

Infusion volume/site

Number/proportion of infusions that are discontinued, slowed, or interrupted due to 
an AE

Number of weeks to reach final dose interval (defined as three- or four-weeks 
infusion interval)
Nonparametric descriptive statistics (median, quartiles, and range) will be calculated and 
reported for the infusion administration variables. Frequency table will show the 
number/proportion of infusions discontinued, slowed or interrupted due to AE and total 
observation time in subject-years. 
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13.4.2.4 HRQoL

Treatment Preference Questionnaire

Treatment Satisfaction Questionnaire for Medication (TSQM-9)

HRQoL Questionnaire: Peds-QL, EQ-5D
Total and domain scores on each of the HRQoL measures will be calculated for each 
subject, at each data assessment time point. Descriptive statistics will be shown for each 
of the scores, at each data assessment time point.
13.4.3 Tertiary Outcome Measures 
13.4.3.1 Infections 

Number of acute serious bacterial infections

Number of all infections

Days on antibiotics
For the endpoint of incidence of acute serious bacterial infection and all infections a point 
estimate and 95% CI (by the Wilson score method) for the proportion of subjects with 
one or more infection will be calculated. In addition, incidence of all infection endpoints 
will be calculated as rate per infusion and rate per subject-year. Descriptive statistics will 
be performed and reported for the days on antibiotics. 
13.4.3.2 Healthcare Resource Utilization Endpoints

Days not able to go to school/work or to perform normal daily activities due to 
infection or other illness 

Number of hospitalizations, indication for the hospitalization (infection or 
non-infection) and days hospitalized

Number of acute physician visits (office and emergency room) due to infection or 
other illnesses
Healthcare resource utilization endpoints, including hospitalization, acute physician visits 
and days missed for school/work or normal daily activities, will be summed and 
annualized for reporting purposes. Descriptive statistics will be performed and reported.
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13.5 Planned Interim Analysis of the Study
13.5.1 Overview of Interim Analysis
Analysis details will be provided in the interim analysis (IA) SAP, which will be finalized 
prior data cut-off for interim analysis.
The primary objective of this study is to assess the safety of HyQvia treatment in 
pediatric subjects with PIDD who received immunoglobulin therapy prior to study 
enrollment. The purpose of the study is to acquire additional data on safety, tolerability 
and immunogenicity of HyQvia in pediatric (age 2 to <18 years) subjects with PIDD. 
A single IA is planned to be performed. The purpose of the IA is to update the scientific 
community, via publications and presentations, on the interim safety, tolerability and 
immunogenicity of HyQvia in pediatric subjects with PIDD. 
All of the following will apply to the IA, or apply as a result of the IA:

Analysis will include, but not limited to: safety/tolerability, infusion data, 
infections, and Healthcare Resource Utilization data, as defined below in 
Section 13.5.2.

Analysis is planned to be performed when 75% of all subjects (30 subjects if 40 are 
enrolled [dosed]) have completed 12 months of participation (1-year observation 
period) in Epoch 2.

Definition of completed 12 months of participation: Any subject who completes 
12 months in Epoch 2, or discontinues prematurely from Epoch 2, irrespective of 
reason for withdrawal, is considered as having completed 12 months of 
participation in Epoch 2. 

No statistical hypothesis testing will be performed.

No early stopping of study (the interim analysis is not planned with the intention of 
deciding whether or not to terminate the study).

No modifications to the study design, study conduct, or final analysis will be made 
during or after the interim analysis.

No interim clinical study report is planned.
The final analysis of all study data will be performed after database lock. Details will be 
provided in the final analysis SAP, which will be finalized prior to end of study.
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13.5.2 Data for Interim Analysis 
Data for interim analysis will include, but are not limed to the following: 
Safety/Tolerability 

Number and rate per infusion (excluding infections) of all severe related AEs. 
Note: This is 1 of 2 of the study primary outcome measures listed in Section 8.4. 

Number and rate per infusion (excluding infections) of related SAEs. 
Note: This is 2 of 2 of the study primary outcome measures listed in Section 8.4. 

Number and rate per infusion (excluding infections) of local AEs and ARs

Number and rate per infusion (excluding infections) of systemic AEs and ARs 

Number and rate per infusion (excluding infections) of all AEs and all ARs

Number and rate per infusion (excluding infections) of all SAEs 

Number and proportion of subjects who develop positive titer (≥160) of binding or 
neutralizing antibodies to rHuPH20

Number and proportion 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 and proportion of subjects with HyQvia-related AEs that were mild, 
moderate, or severe in severity, and number of events in each category

Number and proportion of subjects with any AEs, any serious and/or nonserious 
AEs, and any local and systemic AEs/SAEs, regardless of causality 

Number and proportion 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
Infections

Number of acute serious bacterial infections

Number of all infections
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Mode of Product Administration (For Study Epoch 1 and 2)

Number of Infusions

Number of infusions per month 

Number of infusion sites (needle sticks) per infusion/month 

Duration of infusion (defined as time from the start of rHuPH20 infusion until the 
stop time of immunoglobulin infusion)

Maximum infusion rate/site

Infusion volume/site

Number/proportion of infusions that are discontinued, slowed, or interrupted due to 
an AE 

Number of weeks to reach final dose interval (defined as three- or four-weeks 
infusion interval)
Healthcare Resource Utilization

Days not able to go to school/work or to perform normal daily activities due to 
infection or other illness 

Days on antibiotics

Number of hospitalizations, indication for the hospitalization (infection or 
non-infection) and days hospitalized

Number of acute physician visits (office and emergency room) due to infection or 
other illnesses
13.5.3 Methods of Interim Analysis
Continuous data (e.g., change from baseline) will be summarized using the following 
descriptive statistics: number of subjects (n), mean, median, standard deviation (SD), 
minimum value, maximum value. Categorical data (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. No statistical hypothesis testing will be 
performed. No CIs will be presented.
Baseline is defined as the last non-missing value before the initial dose of HyQvia.
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14. DIRECT ACCESS TO SOURCE DATA/DOCUMENTS
The investigator/study site will cooperate and provide direct access to study documents 
and data, including source documentation for monitoring by the study monitor, audits by 
the sponsor or sponsor’s representatives, review by the EC, and inspections by applicable 
regulatory authorities, as described in the Clinical Trial Agreement (CTA). If contacted 
by an applicable regulatory authority, the investigator will notify the sponsor of contact, 
cooperate with the authority, provide the sponsor with copies of all documents received 
from the authority, and allow the sponsor to comment on any responses, as described in 
the CTA.
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15. QUALITY CONTROL AND QUALITY ASSURANCE
15.1 Investigator’s Responsibility
The investigator will comply with the protocol (which has been approved/given favorable 
opinion by the EC), 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 study site 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. Sub-investigators or other 
authorized study personnel are eligible to sign for the investigator, except where the 
investigator’s signature is specifically required.
15.1.1 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.
15.2 Training
The study monitor will ensure that the investigator and study site 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 study site, and/or by instruction manuals. In addition, the study monitor will be 
available for consultation with the investigator and will serve as the liaison between the 
study site and the sponsor.
15.3 Monitoring
The study monitor is responsible for ensuring and verifying that each study site conducts 
the study according to the protocol, standard operating procedures, other written 
instructions/agreements, ICH GCP, and applicable national and local regulatory 
guidelines/requirements. The investigator will permit the study monitor to visit the study 
site at appropriate intervals, as described in the CTA. Monitoring processes specific to the 
study will be described in the clinical monitoring plan.
15.4 Safety Monitoring
The safety of the subjects in this study shall be monitored by an Internal Safety 
Monitoring Committee (ISMC). 
The ISMC is a group of individuals with pertinent expertise within the sponsor that 
reviews on a regular basis accumulating data from an ongoing clinical study. 
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For this study, the ISMC will be composed of appropriate sponsor representatives from 
the relevant functions (e.g., Global Drug Safety, Clinical Research, Medical Affairs, 
Clinical Development) with expertise/specialization in PIDD clinical care and research. 
Safety and safety-supported data will be provided to the ISMC. Details and procedural 
information will be provided in the ISMC Charter. The ISMC can stop a trial if it finds 
toxicities or if treatment is proven to be not beneficial.
15.5 Auditing
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 study site, as 
described in the CTA. Auditing processes specific to the study will be described in the 
audit plan.
15.6 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 one calendar day after the change is 
implemented. The sponsor will also ensure the responsible EC 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 and applicable regulatory authorities of any investigator termination.
15.7 Laboratory and Reader Standardization
Inter-laboratory standardization methods will be described in the data management plan 
as needed. 
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16. ETHICS 
16.1 Subject Privacy
The study protocol, documentation, data and all other information generated will be held 
in strict confidence and in accordance with applicable laws, regulations, and guidelines. 
No information concerning the study or the data will be released to any unauthorized 
third party, without prior written approval of the Sponsor.
Country-specific data protection and privacy regulations will be observed in collecting, 
forwarding, processing, and storing data from study participants.
16.2 Ethics Committee and Regulatory Authorities
Before patients participate in this study, the protocol, informed consent form, any 
promotional material/advertisements, and any other written information will be reviewed 
and approved/given favorable opinion by the ethics committee (EC) and applicable 
regulatory authorities. The IB, if applicable, will be provided for review. The EC’s 
composition or a statement that the EC’s composition meets applicable regulatory criteria 
will be documented. The study will commence only upon the sponsor’s receipt of 
approval/favorable opinion from the EC and, if required, upon the sponsor’s notification 
of applicable regulatory authority(s) approval, as described in the CTA. 
If the protocol or any other information given to the subject is amended, the revised 
documents will be reviewed and approved/given favorable opinion by the EC and 
applicable regulatory authorities, where applicable. The protocol amendment will only be 
implemented upon the sponsor’s receipt of approval and, if required, upon the sponsor’s 
notification of applicable regulatory authority(s) approval.
16.3 Informed Consent
Investigators will choose patients for participation considering the study eligibility 
criteria. The investigator will exercise no selectivity so that no bias is introduced from 
this source. 
All patients and/or their legally authorized representative must sign an informed consent 
form before enrollment into the study according to applicable national and local 
regulatory requirements and ICH GCP. The case history for each individual shall 
document that informed consent was obtained prior to participation in the study.
An assent form may be provided and should be signed by patients enrolled in the study. 
Before use, the informed consent form will be reviewed by the sponsor and approved 
by the EC and regulatory authority(s), where applicable, (see Section 16.2). 
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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 or their 
legally authorized representative(s) will be allowed sufficient time to consider 
participation in the study. By signing the informed consent form, patients or their legally 
authorized representative(s) 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 EC and regulatory authorities, 
where applicable, will be provided by the investigator to the subjects who consented to 
participate in the study. 
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17. DATA HANDLING AND RECORD KEEPING
17.1 Confidentiality Policy
The investigator will comply with the confidentiality policy as described in CTA. 
17.2 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” 
(see Section 8.8), records detailing the progress of the study for each subject, signed 
informed consent forms, correspondence with the EC and the study monitor/sponsor, 
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 eCRFs are provided by the sponsor, only authorized study site 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 study site in accordance with the data 
retention policy (see Section 17.3).
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. 
17.3 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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18. FINANCING AND INSURANCE
The investigator will comply with investigator financing, investigator/sponsor insurance, 
and subject compensation policies, if applicable, as described in the CTA.
19. PUBLICATION POLICY
The investigator will comply with the publication policy as described in the CTA. 
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20.2 Schedule of Study Procedures and Assessments
Table 3. STUDY EPOCH 1 – Ramp Up 
Schedule of Study Procedures and Assessments
Procedures/Assessments 
Routinely Performed Pre-
Infusion, Unless Stated 
Otherwise
Enrollment / 
Screening
Treatment Visit in Study Epoch 1 (Visit +/- 1 Day)
First Infusion: 
Baseline
2nd Infusion: Week 1 
(This Treatment is the End of Epoch 1 
if Subject is Planning for 3-Week 
Treatment Intervals)
3rd Infusion: Week 3 
(Only for Subjects Planning to 
Ramp Up to 4-Week Treatment 
Intervals)
Location
Site
Site
Site
Site
Informed Consenta
x
Eligibility Criteria
x
Infusion
x
x
x
Medical History
x
Concomitant Medications
x
x
x
x
Non-drug Therapies
x
x
x
x
Physical Exam
x
x
x
x
Adverse Events
x
x
x
Laboratoriesb
x
x
Vital Signs
x
x
x
x
HRQoL (PedsQL, EQ-5D)/, 
TSQM-9 Assessment
x
a
Occurs prior to any study-specific procedure.
b  For laboratory assessments, see Section 20.3
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Table 4. STUDY EPOCH 2 – Year 1 
Schedule of Study Procedures and Assessments
Procedures/ Assessments 
Routinely Performed Pre-
Infusion, Unless Stated 
Otherwise
Visit in Study Epoch 2 (Visit +/- 2 weeks)
Month 0
Month 3
Month 6 
Month 9 
Month 12a
Study Completion/
Termination Visit (at Next 
Infusion), if Applicable
Location
Site
Site
Site
Site
Site
Site
Informed Consent
Infusione
x
x
x
x
x
Concomitant Medications
x
x
x
x
x
x
Non-drug Therapies
x
x
x
x
x
x
Physical Exam
x
x
x
x
x
x
Adverse Events
x
x
x
x
x
x
Laboratoriesd
x
x
x
x
x
x
Vital Signs
x
x
x
x
x
x
HRQoL (PedsQL, EQ-5D), 
Treatment Preference 
Questionnaire, TSQM-9 
(x) b
x
(x) c
a   Further (additional) infusions may be administered after the 12 months visit until anti-rHuPH20-antibody results become available to determine the 
subject´s continuation in the study. AEs, concomitant medications, and non-drug therapies will continue to be recorded until EOS or continuation of 
Epoch 2 dependent on antibody assay result.
b
Only subjects who did not perform Epoch 1 will take these assessments in Epoch 2 at Month 0.
c
All subjects will complete assessments at the month 12 visit. Only subjects who prematurely exit the study will complete the questionnaires at the study 
termination visit. 
d
For laboratory assessments, see Section 20.3
e
Infusions (including home infusions) administered between scheduled site visits/site infusions may deviate up to +/- 3 days from original schedule
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Table 5. STUDY EPOCH 2 – Year 2 and Year 3
Schedule of Study Procedures and Assessments
Procedures/ Assessments 
Routinely Performed
Pre-Infusion, Unless 
Stated Otherwise
Visit in Study Epoch 2 (Visit +/- 2 Weeks)
Month 15
Month 18
Month 21
Month 24
Month 27
Month 30
Month 33
Month 36/
Study Completion/
Termination Visit, if 
Applicablea
Location
Site
Site
Site
Site
Site
Site
Site
Site
Infusionc
x
x
x
x
x
x
x
Concomitant Medications
x
x
x
x
x
x
x
x
Non-drug Therapies
x
x
x
x
x
x
x
x
Physical Exam
x
x
x
x
x
x
x
x
Adverse Events
x
x
x
x
x
x
x
x
Laboratoriesb
x
x
x
x
x
x
x
x
Vital Signs
x
x
x
x
x
x
x
x
HRQoL (PedsQL, EQ-5D), 
Treatment Preference 
Questionnaire, TSQM-9
x
x
a
In case a subject moves to Study Epoch 3, he/she will have the Study Completion/Termination Visit at the end of Epoch 3.
b
For laboratory assessments, see Section 20.3.
c
Infusions (including home infusions) administered between scheduled site visits/site infusions may deviate up to +/- 3 days from original schedule.
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Table 6. STUDY EPOCH 3 
Schedule of Study Procedures and Assessments 
Procedures/Assessments Routinely 
Performed Pre-Infusion, Unless 
Stated Otherwise
Visit in Study Epoch 3(Visit +/- 2 Weeks)
Month 0 
Month 3
Month 6 
Months 9 
Month 12/
Study Completion/
Termination Visita
Location
Site
Site
Site
Site
Site
Infusiond
x
x
x
x
Concomitant Medications
x
x
x
x
x
Non-drug Therapies
x
x
x
x
x
Physical Examb
x
x
x
x
x
Adverse Events
x
x
x
x
x
Laboratoriesc
x
x
x
x
x
Vital Signs
x
x
x
x
x
HRQoL (PedsQL, EQ-5D), Treatment 
Preference questionnaire, TSQM-9 
Assessment
x
x
a
Includes for cases of withdrawal or discontinuation.
b
Occurs prior to any study-specific procedure.
c
For laboratory assessments, see Section 20.3. 
d
Infusions (including home infusions) administered between scheduled site visits/site infusions may deviate up to +/- 3 days from original schedule.
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20.3 Clinical Laboratory Assessments
Table 7. STUDY EPOCH 1 – Ramp Up 
Clinical Laboratory Assessments 
Assessments 
Routinely Performed Pre-Infusion, 
Unless Stated Otherwise
Enrollment / 
Screening
Treatment Visit in Study Epoch 1 (Visit +/- 1 Day)
First Infusion: 
Baseline
Second Infusion: Week 1 
(This Treatment is the End of 
Epoch 1 if Subject is Planning 
for 3-Week Treatment 
Intervals)
Third Infusion: Week 3 
(Only for Subjects 
Planning to Ramp Up to 
4-Week Treatment 
Intervals)
Location
Site
Site
Site
Site
Hematology
x
Clinical Chemistry
x
Urinalysis
x
Pregnancy Test in females of 
childbearing potential – Urine
x
Viral Pathogen Serology
x
Hemolysis Test
Specific Antibody Tests
x
IgG Trough Levels and IgG Subclasses
x
Antibodies to rHuPH20
x
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Table 8. STUDY EPOCH 2 – Year 1 
Clinical Laboratory Assessments
Assessments 
Routinely Performed Pre-Infusion, 
Unless Stated Otherwise
Visit in Study Epoch 2 (Visit +/- 2 Weeks)
Month 0c
Month 3
Month 6 
Month 9 
Month 12 
Study Completion/
Termination Visit 
(at Next Infusion), if 
Applicable 
Location
Site
Site
Site
Site
Site
Site
Hematology
x
x
x
Clinical Chemistry
x
x
x
Urinalysis
x
x
x
Pregnancy Test in females of 
childbearing potential– Urine
x
Viral Pathogen Serology
x
Hemolysis Test
xa
Specific Antibody Tests
(x)b
x
IgG Trough Levels and IgG Subclasses
x
x
x
Antibodies to rHuPH20
x
x
x
x
x
a
If there is a reduction in Hgb of two g/dL or more compared to baseline Hgb, every effort is to be made to perform a repeat test consisting of the 
hemolysis tests described in section 12.7.4 within 72 hours in addition to the prescribed tests
b Only for subjects who did not perform Epoch 1
c
Month 0 will be considered to be the “Baseline” visit for subjects who do not participate in Epoch 1
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Table 9. STUDY EPOCH 2 – Year 2 and Year 3
Clinical Laboratory Assessments
Assessments 
Routinely Performed Pre-
Infusion, Unless Stated 
Otherwise
Visit in Study Epoch 2(Visit +/- 2 Weeks)
Month 15
Month 18
Month 21
Month 24
Month 27
Month 30
Month 33
Month 36/
Study Completion/
Termination Visit, 
if Applicablea
Location
Site
Site
Site
Site
Site
Site
Site
Site
Hematology
x
x
x
x
Clinical Chemistry
x
x
x
x
Urinalysis
x
x
x
x
Pregnancy Test in females of 
childbearing potential – Urine
x
Viral Pathogen Serology
x
Hemolysis Testsb
x
Specific Antibody Tests
x
IgG Trough Levels and IgG 
Subclasses
x
x
x
x
Antibodies to rHuPH20
x
x
x
x
x
x
x
x
a    In case a subject moves to Study Epoch 3, he/she will have the Study Completion/Termination Visit at the end of Epoch 3.
b   If there is a reduction in Hgb of two g/dL or more compared to baseline Hgb, every effort is to be made to perform a repeat test consisting of the 
hemolysis tests described in section 12.7.4 within 72 hours
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Table 10. STUDY EPOCH 3
Clinical Laboratory Assessments
Assessments Routinely Performed Pre-
Infusion, Unless Stated Otherwise
Visit in Study Epoch 3 (Visit +/- 2 Weeks)
Month 0
Month 3
Month 6
Months 9
Month 12/
Study Completion/
Termination Visit
Location
Site
Site
Site
Site
Site
Hematology
x
x
x
Clinical Chemistry
x
x
x
Urinalysis
x
x
x
Pregnancy Test in females of childbearing 
potential – Urine
x
Viral Pathogen Serology
x
Hemolysis Test
x
Specific Antibody Tests
x
IgG Trough Levels and IgG Subclasses
x
x
x
Antibodies to rHuPH20
x
x
x
x
x
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20.4 Toxicity Grading Scale for Laboratory Values
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. Normal
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
Normal
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; BUN=blood urea nitrogen; 
ECOG=Eastern Cooperative Oncology Group; LDH=lactate dehydrogenase; N/A=not applicable; ULN=upper limit of normal; 
WBC=white blood cell; WHO=World Health Organization; WNL=within normal limits. 
a Grade refers to severity:  1=mild, 2=moderate, 3=severe, 4=life-threatening or disabling, 5 (not shown in the table)=death. Grading scale criteria taken 
from ECOG (Oken et al., 1982) and WHO (World Health Organization, 2003) guidelines, with the exception of LDH that uses the same thresholds as 
defined for ALT and AST
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22. SUMMARY OF CHANGES
Protocol 161504: Amendment 2  2019 DEC 04
Replaces: Amendment 1: 2016 OCT 07
In this section, changes from the previous version of the Protocol 161504, Amendment 1, 
dated 2016 OCT 07, are described and their rationale is given.
1.
Throughout the document
Description of Change: Minor grammatical, editorial and/or administrative changes 
have been made. 
Rationale for Change: To improve the readability and/or clarity of the protocol. 
2.
Throughout the document
Description of Change: Updated sections with the recent references.
Rationale for Change: To update the protocol with the recent publications for 
rHUPH20.
3.
Title Page
Description of Change: Updated address of the US Sponsor, added NCT number.
Rationale for Change: Administrative.
4.
Protocol Signature Page and Section 1.1
Description of Change: Updated name of sponsor signatory.
Rationale for Change: Administrative.
5.
Synopsis and Section 8.3 
Description of Change: Revised completion and duration to 2023 scenario in case
LSI goes until Epoch 2 Year 3 and then 1 year in Epoch 3.
Rationale for Change: Duration of study periods and subject participation changed 
according to the current timelines.
6.
Synopsis and Section 8.1, Section 8.2 and Section 13.5.2
Description of Change: Removed wording "approximately" 40 subjects and added
"if 40 are enrolled (dosed)".
Rationale for Change: To avoid confusion regarding the number of patients 
enrolled and obtain accuracy.
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7.
Synopsis and Section 8.2.3 Epoch 3
Description of Change: Emphasized that Epoch 3 should last approximately 1 year 
and the removal of “or until the anti-rHuPH20 antibody titer declines to < 2,560 for 
at least two consecutive measurements, whichever comes first.” 
Rationale for Change: To clarify that safety follow up and the antibody testing 
continue for one year, not less, for all subjects who switch to Epoch 3.
8.
Synopsis, Section 8.4.2.2 and Section 13.4.2.2
Description of Change: Provided additional information/clarification on safety 
outcome measures “additional safety outcome measures include clinical laboratory 
outcomes: raw (actual) values and change from baseline, and vital signs : raw 
(actual) values and change from baseline”.
Rationale for Change: To clarify that the laboratory values and vital signs collected 
routinely as safety assessments are among the outcome measures.
9.
Synopsis and Section 13.5, Section 13.4.2
Description of Change: Added planned Interim Analysis.
Rationale for Change: The purpose of the analysis is to update the scientific 
community, on the interim safety, tolerability and immunogenicity of HyQvia in 
pediatric subjects with PIDD.
10. Section 6.1.1 HyQvia 
Description of Change: Updated the Europe indication for HyQvia.
Rationale for Change: To update the HyQvia indication; for the current version.
11. Section 6.1.2, Section 6.4.3, Section 8.7.3.3
Description of Change: Added “A detailed description of Cuvitru is provided in the 
SmPC, which is available in those countries where Cuvitru is registered. In 
countries where Cuvitru is not registered, an IB will be available.“
Rationale for Change: Needed for countries where sites are open but Cuvitru is not 
registered; therefore, reference for the Cuvitru Investigator Brochure is added. 
12. Section 6.3.5, Section 6.4.1.1, Section 9.3, Section 12.1.2 HYQVIA Pregnancy 
Registry 161301
Description of Change: Description of the current study status, wording was 
updated to reflect the most recent study status, the Pregnancy registry has closed 
enrollment. 
Rationale for Change: To provide update on the current study status.
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13. Section 6.3.6 HyQvia PASS 161302
Description of Change: Description of the current study status, wording was 
updated to reflect the most recent study status, the study has closed enrollment. 
Rationale for Change: To provide update on the current study status.
14. Section 6.3.7 HyQvia Study 161406
Description of Change: Description of the current study status, wording was 
updated to reflect the most recent study status, the study has closed for enrollment.
Rationale for Change: To provide update on the current study status.
15. Section 6.3.8 HYQVIA Study 161503
Description of Change: Additional HYQVIA study conducted in US; description of 
the current study 161503 status, wording was updated to reflect the most recent 
study status.
Rationale for Change: To provide update on the current study status.
16. Section 6.5 Compliance Statement
Description of Change: Updated to current version of GCP E6 guideline 
(Nov 2016) and added Declaration of Helsinki.
Rationale for Change: To reflect the most current guidelines.
17. Section 8.2.2: Study Design
Description of Change: Added description to allow shorter infusion intervals 
(2 weeks, instead of 3 or 4 weeks) if preferable due to tolerability, at the discretion 
of the investigator.
Rationale for Change: Infusion intervals to allow more flexibility for the needs of 
pediatric patients.
18. Section 8.7.3.1 Description of HYQVIA Treatment
Description of Change: Provided additional clarification that the mg/kg dose of 
each subject should remain stable during the study, and that in the event of weight 
gain the absolute dose (g or mg) should be increased to maintain the mg/kg dose 
stable. In the event of increased infections or low trough level, the mg/kg dose may 
be increased, after documentation is provided in the medical file and added that 
dose may be increased if clinically indicated.
Rationale for Change: To clarify when dose adjustments are required.
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19. Section 12.7: Clinical Laboratory Parameters
Description of Change: Sentence was changed from “Blood and urine collection, if 
appropriate, will occur within one hour before the start of the infusion procedure.” 
To “Blood and urine collection will occur pre-infusion (unless stated otherwise) 
and should be collected within one hour before the start of the infusion procedure, 
if possible.”
Rationale for Change: To provide additional clarification that sample collection 
should occur pre-infusion but may be performed outside the specified time if 
required, to accommodate needs of young children.
20. Section 12.7.1 Hematology and Clinical Chemistry
Description of Change: The clinical chemistry panel was updated (new text in 
italics) to read: “total protein, total bilirubin, serum creatinine”. AST, LDH and 
LDH isoenzyme measurement was added.
Rationale for Change: To accurately define tests, and to monitor for potential 
hemolysis.
21. Section 12.7.6 Anti-rHuPH20 Antibodies
Description of Change: Text was changed to separately describe testing for 
neutralizing and for binding anti-rHuPH20 antibodies.
Rationale for Change: To provide improved clarity.
22. Section 15.4 Safety Monitoring
Description of Change: Changed Internal Safety Review Board (ISRB) to Internal 
Safety Monitoring Committee (ISMC) and added procedural details.
Rationale for Change: Administrative update.
23. Section 20.2: General comments for Schedule of Study Procedures and 
Assessments
Description of Change: Inserted cells and updated missing footnotes.
Rationale for Change: To distinguish between baseline and other treatments and to 
update administrative changes such as missing footnotes.
24. Section 20.2 Schedule of Study Procedures and Assessments (Table 3 and 
Table 7)
Description of Change: A margin of ±1 day for the scheduling of treatment visits in 
Epoch 1 was defined.
Rationale for Change: To allow a limited amount of flexibility in the scheduling of 
study drug infusions, and to prevent related protocol deviations.
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25. Section 20.2 Table 4, Table 5, Table 6
Description of Change: Added a footnote: § Infusions (including home infusions) 
administered between scheduled site visits/site infusions may deviate up to +/- 3 
days from original schedule.
Rationale for Change: To allow limited flexibility in the scheduling of study site 
visits.
26. Section 20.2 Table 3 and Table 4
Description of Change: The Treatment Preference Questionnaire will not be 
completed at Baseline (Epoch 1); and addition of footnotes (b) and (c) to Table 4 
(Epoch 2). 
Rationale for Change: To clarify the guidance regarding when the assessments 
should be performed. 
27. Section 20.2 Table 8
Description of Change: Added a footnote: specific antibody tests will be done only 
for subjects who did not perform Epoch 1, and month 0 will be considered to be 
“baseline” visit for subject who didn’t participate in Epoch 1.
Rationale for Change: To clarify that for some subjects Month 0 of Epoch 2 will be 
considered as baseline for those subjects who didn’t have to participate in Epoch 2; 
therefore also specific antibody tests have to be performed. 
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