Long-Term Tolerability and Safety of Immune Globulin Infusion 10% (Human) With Recombinant Human Hyaluronidase (HYQVIA/HyQvia) for the Treatment of Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP)
Phase: PHASE3
Conditions: Chronic Inflammatory Demyelinating Polyradiculoneuropathy
Sponsor: Baxalta now part of Shire

For non-commercial use only

PROTOCOL: 161505
TITLE:
Long-Term Tolerability and Safety of Immune Globulin Infusion 
10% (Human) with Recombinant Human Hyaluronidase 
(HYQVIA/HyQvia) for the Treatment of Chronic Inflammatory 
Demyelinating Polyradiculoneuropathy (CIDP)
SHORT TITLE:
Long-Term Tolerability and Safety of HYQVIA/HyQvia in CIDP
STUDY PHASE:
IIIb
DRUG:
Immune Globulin Infusion 10% (Human) with Recombinant 
Human Hyaluronidase (HYQVIA/HyQvia)
IND NUMBER:
014381
EUDRACT 
NUMBER:
2016 000374 37
NCT NUMBER:
NCT02955355
SPONSOR:
Takeda Development Center Americas, Inc.
95 Hayden Ave , Lexington, MA 02421, USA
AND
Baxalta Innovations GmbH*
Industriestrasse 67, A-1221 Vienna 
* Baxalta is now part of Shire, a wholly-owned subsidiary of
Takeda Pharmaceutical Company Limited
PRINCIPAL/
COORDINATING
INVESTIGATOR:
TBD
PROTOCOL 
HISTORY:
Amendment 4: 2022 Jan 11
Replaces: Amendment 3: 2019 AUG 05
Amendment 2: 2018 NOV 14
Amendment 1: 2016 JUN 27
Original: 2016 JAN 20
This document contains confidential and proprietary information of Takeda 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 Takeda.
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PROTOCOL SIGNATURE PAGE
Sponsor’s (Takeda) Approval
Signature:
Date:
, MD 
12-Jan-2022
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Investigator’s Acknowledgement
I have read this protocol for Study 161505.
Title: Long-Term Tolerability and Safety of Immune Globulin Infusion 10% (Human) 
with Recombinant Human Hyaluronidase (HYQVIA/HyQvia) for the Treatment of 
Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP)
I have fully discussed the objective(s) of this study and the contents of this protocol with 
the sponsor’s representative.
I understand that the information in this protocol is confidential and should not be 
disclosed, other than to those directly involved in the execution or the scientific/ethical 
review of the study, without written authorization from the sponsor. It is, however, 
permissible to provide the information contained herein to a subject in order to obtain 
their consent to participate.
I agree to conduct this study according to this protocol and to comply with its 
requirements, subject to ethical and safety considerations and guidelines, and to conduct 
the study in accordance with International Council for Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use guidelines on Good 
Clinical Practice and with the applicable regulatory requirements.
I understand that failure to comply with the requirements of the protocol may lead to the 
termination of my participation as an investigator for this study.
I understand that the sponsor may decide to suspend or prematurely terminate the study at 
any time for whatever reason; such a decision will be communicated to me in writing. 
Conversely, should I decide to withdraw from execution of the study I will communicate 
my intention immediately in writing to the sponsor.
Investigator Name and Address:
(please hand print or type)
Signature:
Date:
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1. STUDY PERSONNEL
1.1 Authorized Representative (Signatory) / Responsible Party
, MD
, Plasma Derived Therapies
Takeda Development Center Americas
1.2 Study Organization
The name and contact information of the responsible party and individuals involved with 
the study (eg, investigator(s), sponsor’s medical expert and study monitor, sponsor’s 
representative(s), laboratories, steering committees, and oversight committees [including 
ethics committees (ECs)], as applicable) will be maintained by the sponsor and provided 
to the investigator.
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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 SUSPECTED UNEXPECTED SERIOUS ADVERSE 
REACTIONS (SUSARS), 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
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

Non-Medical Complaints, Section 12.4
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3. SYNOPSIS
INVESTIGATIONAL PRODUCT
Name of Investigational Product 
(IP)
Immune Globulin Infusion 10% (Human) with Recombinant Human 
Hyaluronidase (IGI, 10% with rHuPH20; HYQVIA/HyQviai)
Name(s) of Active Ingredient(s)
Immune Globulin Infusion 10% (Human) for HYQVIA/HyQvia
CLINICAL CONDITION(S)/INDICATION(S)

Chronic Inflammatory Demyelinating Polyradiculoneuropathy(CIDP)
PROTOCOL ID
161505
PROTOCOL TITLE
Long-Term Tolerability and Safety of Immune Globulin Infusion 
10% (Human) with Recombinant Human Hyaluronidase 
(HYQVIA/HyQvia) for the Treatment of Chronic Inflammatory 
Demyelinating Polyradiculoneuropathy (CIDP)
Short Title
Long-Term Tolerability and Safety of HYQVIA/HyQvia in CIDP
STUDY PHASE
Phase IIIb
PLANNED STUDY PERIOD
Initiation
2016 Q2/3
Primary Completion
Dependent on approval of HYQVIA/HyQvia in countries 
participating in study. 
Study Completion
Dependent on approval of HYQVIA/HyQvia in countries 
participating in study. 
Duration
Dependent on approval of HYQVIA/HyQvia in countries 
participating in study. 
STUDY OBJECTIVES AND PURPOSE
Study Purpose
The purpose of this study is to assess the long-term safety, tolerability, and immunogenicity of the 
subcutaneous (SC) treatment with Immune Globulin Subcutaneous (IGSC) facilitated with rHuPH20 
(HYQVIA/HyQvia) in subjects with CIDP who have completed Baxalta Clinical Study Protocol 161403 
Epoch 1 without CIDP worsening.
Primary Objective
1. To evaluate the long-term safety, tolerability, and immunogenicity of HYQVIA/HyQvia
Exploratory Objective(s)
1. To assess the long-term effect of HYQVIA/HyQvia on clinical outcome measures, including 
prevention of relapse, change in functional ability, hand grip strength, and musclestrength
2. To assess the long-term effect of HYQVIA/HyQvia on quality of life, health utility, health resource 
utilization (HRU), treatment satisfaction, treatment preference, and subject global impression of 
change
                                                
i HYQVIA and HyQvia are registered trademarks of Baxalta US Inc./Baxalta Innovations GmbH.
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3. To evaluate improvement in functional impact on everyday tasks as measured by a pre-specified 
subscore of R-ODS
STUDY DESIGN
Study Type
Long-term Safety, Tolerability, Immunogenicity, Efficacy, 
Pharmacoeconomics
Control Type
No control
Study Indication Type
Treatment
Intervention Model
Single-group, non-randomized
Blinding/Masking
Open-label
Study Design
This study is a Phase IIIb, open-label, multicenter study to assess the 
long-term safety, tolerability, and immunogenicity of HYQVIA/HyQvia 
(IGI, 10% with rHuPH20 administered subcutaneously) for maintenance 
therapy to prevent relapse. This study is an extension of Baxalta Clinical 
Study 161403, a Phase III Efficacy, Safety, and Tolerability Study of 
HYQVIA/HyQvia and GAMMAGARD LIQUID/KIOVIG in CIDP.
Enrollment into this study is open to subjects who have completed Study 
161403 Epoch 1 without CIDP worsening and who have provided 
informed consent. Subjects must meet all eligibility criteria (see section 
‘SUBJECT SELECTION’) in order to participate in this Extension 
Study. As of December 3, 2021, a total of 121 subjects completed the 
pivotal study (161403), 77 of whom rolled over into the extension study 
(161505). There are 11 ongoing subjects in the pivotal study with 
potential to roll over into the extension study.  Hence, it is estimated that 
a maximum of 88 subjects will be eligible for study participation.
In this Extension Study, eligible subjects will receive HYQVIA/HyQvia 
in an open-label fashion until relapse or until predetermined study end 
for the specific country from which the subject is participating (see 
section ‘Planned Duration of Subject Participation’, below).
Dose of HYQVIA/HyQvia and Dosing Regimen:
Subjects will continue to receive the same dose and dosing regimen of 
HYQVIA/HyQvia in the Extension Study as the subject’s full dose 
received in Epoch 1 of the Phase III Study 161403.
The study product components of HYQVIA/HyQvia will be 
administered sequentially. SC infusion of rHuPH20 solution at a dose of 
80 U/g Immunoglobulin G (IgG) will be administered first, to be 
followed by SC infusion of IGI, 10% within 10 minutes of completion of 
the infusion of rHuPH20 solution.
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Entry into Extension Study:
Enrollment into the Extension Study (signed informed consent) may take 
place immediately prior to or during the subject’s study completion visit 
in Study 161403. The termination visit of Study 161403 is to serve as the 
baseline visit for the Extension Study. Therefore, informed consent for 
the Extension Study must be obtained on the day of or prior to 
conducting the end-of-treatment assessments in Study 161403 in order
for those assessments to serve as the baseline assessments in the 
Extension Study. Subject’s eligibility for entrance into the Extension 
Study must be determined prior to the first investigational product (IP) 
infusion in the Extension Study, which will occur at the next visit (the 
first treatment visit in the Extension Study). The first administration in 
the Extension Study will take place at the subject’s next scheduled 
dosing (every 2, 3, or 4 weeks). The dose will be the same as that 
administered in Study 161403. The first infusion will be at the subject’s 
full dose; there will be no ramp-up of dose.
After the first 12 weeks of treatment in the Extension Study, the dosing 
interval of HYQVIA/HyQvia may be adjusted for subject preference 
provided that it is safe to do so at the investigator’s discretion. If 
medically necessary, the interval and/or dose may be changed at any 
time, at the investigator’s discretion.
Administration and Study Site Visits:
As some subjects were receiving placebo treatment and have not been 
exposed to HYQVIA/HyQvia while participating in Study 161403, all 
subjects will have at least the first 2 infusion visits in the Extension 
Study at the study site to facilitate safety monitoring.
Subjects from Study 161403:
The first 2 infusions in the Extension Study will be conducted at the 
investigator’s site. Thereafter and per investigator’s discretion, the SC 
infusions for subjects rolling over from Study 161403 may take place at 
the study site, infusion center, or at the subject’s home or other suitable 
location, as acceptable per local regulations and standard practices of the 
study site and if product can be shipped from the pharmacy to the 
respective locations.
The ability of the subject (and/or caregiver) to perform infusion 
procedures independently is a prerequisite for self-administration in 
general. As needed, retraining and verification of the subject’s (and/or 
caregiver’s) proficiency in independently self-administering infusions 
will be provided and must be documented.
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Whilst HYQVIA/HyQvia infusions will occur at 2-, 3-, or 4-week 
intervals, at home or in clinic, Study Site Visits are only mandatory for 
the first and second dose and then every 12 weeks (±5 days) in the 
Extension Study. However, an unscheduled visit can occur at any time 
should the need arise.
Planned Duration of Subject 
Participation
Each subject will have the opportunity to receive HYQVIA/HyQvia until 
approval of HyQvia marketing authorization for the treatment of CIDP 
in either US or EU (whichever comes later) unless one of the following 
criteria is met:  
Early subject discontinuation from treatment or study due to CIDP 
worsening that, at the discretion of the investigator, would preclude 
further treatment with IP
1. Country-specific predetermined date, as may be mandated by 
regulations.
2. Sponsor’s decision to early discontinue further participation of a 
subject in the study
3. Early study termination at the sponsor’s discretion, for any reason
4. Upon unblinding of study 161403, subjects who did not have CIDP 
worsening while on placebo treatment during Epoch 1 should 
discuss options regarding continued participation in this long-term 
clinical trial with the investigator
5. Subject becomes pregnant during the study
Outcome Measures
Primary Outcome Measures 
Safety/Tolerability
1. Number (percentage) of subjects experiencing any treatment-emergent serious and/or non- serious 
adverse events (SAEs and/or AEs, respectively), regardless of causality
2. Number (percentage) of subjects experiencing causally related SAEs and/or AEs
3. Number (percentage) of subjects with serious and/or non-serious adverse reactions (Ars) plus 
suspected ARs
4. Rate of AEs that may be a result of immune-mediated response to either immunoglobulin, rHuPH20, 
or other factors as listed in Table 12-1, expressed as number of events per infusion and per subject-
year
5. Number (percentage) of treatment-emergent SAEs and/or AEs associated with infusions, regardless 
of causality
6. Number (percentage) of causally related SAEs and/or AEs associated with infusions
7. Number (percentage) of AEs temporally associated with infusions (defined as AEs occurring during 
or within 72 hours after completion of an infusion)
8. Number (percentage) of serious and/or non-serious ARs plus suspected ARs associated with infusions
9. Number (percentage) of infusions associated with 1 or more systemic AEs
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10. Number (percentage) of infusions associated with 1 or more local infusion site reactions
11. Number and proportion of infusions for which the infusion rate was reduced and/or the infusion was 
interrupted or stopped due to intolerability and/or AEs
12. Rates of systemic and local AEs, regardless of causality, expressed as number of events per infusion, 
per subject, and per subject-year
13. Rates of causally related systemic and local AEs, expressed as number of events per infusion, per 
subject, and per subject-year
14. Rates of systemic and local ARs plus suspected ARs, expressed as number of events per infusion, per 
subject, and per subject-year
15. Number of subjects with AE(s) that led to discontinuation from study
16. Number and rate per infusion of moderate or severe AEs that may be a result of immune- mediated 
response to either immunoglobulin, rHuPH20, or other factors as defined in Table 12-1
(Section 12.7.10)
17. Number (percentage) of subjects experiencing  treatment-emergent local infusion site reactions
18. Number (percentage) of subjects with treatment-emergent with local tolerability* events during the 
first 8 weeks of  open-label Extension Study 161505 among subjects originally randomized to placebo 
(no ramp up), versus during the 8 week-ramp-up period for subjects originally randomized to 
HYQVIA in double-blind Study 161403. * Subjects for which infusion rate was reduced and/or the 
infusion was interrupted or stopped due to intolerability and/or AEs.
19. Number (percentage) of subjects experiencing local infusion reactions, as a function of dosing 
interval, infusion rate per site, and infusion volume per site.  
20. Number (percentage) of subjects whose anti-hyaluronidase antibody titers rise by ≥ 4 fold from the 
original baseline value from study 161403 using combined data from both studies (161403 and 
161505).
Immunogenicity
1. Incidence of binding antibodies to rHuPH20
2. Incidence of neutralizing antibodies to rHuPH20
3. Number of subjects with a decline of anti-rHuPH20 antibody titers to the antibody titer level at 
baseline in Study 161403 and/or to <160 at the study completion or early discontinuation
4. For subjects who have >10,000 titer of binding antibodies to rHuPH20: neutralizing antibodies and 
cross reactivity with Hyal-1, 2 and 4
Exploratory Outcomes 
Efficacy
1. Relapse (defined as a worsening of functional disability defined as an increase of ≥1 adjusted 
Inflammatory Neuropathy Cause and Treatment [INCAT] disability scores in 2 consecutive 
timepoints, relative to baseline)
2.
 
 
 
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3. Time to relapse
4. Percentage of subjects with change in Rasch-built Overall Disability Scale (R-ODS) score by 
>4 points from baseline
5. Change in adjusted INCAT disability score from baseline
6. Percentage of subjects with change in hand grip strength score by >8 kPa from baseline
7. Change in Medical Research Council (MRC) sum score from baseline
8. Change from baseline in functional impact on everyday tasks as measured by R-ODS sub-components
Subject Reported Outcomes and Health Economics
1. Short Form-36 (SF-36) scores and changes from baseline over various time periods
2. EuroQoL (Quality of Life)-5 Dimensions (EQ-5D-3L) scores and changes from baseline over various 
time periods
3. HRU, including days off school/work, unscheduled physician visits, hospitalization, and emergency 
room visits, plus the total number of acute physician visits (office and emergency room due to CIDP 
exacerbation, any CIDP-related issue, any cause), over various time periods
4. Treatment satisfaction
5. Treatment preference
6. Subject global impression of change
Other
1. Trough serum IgG levels
INVESTIGATIONAL PRODUCT(S), DOSE AND MODE OF ADMINISTRATION
Active Product
HYQVIA/HyQvia
(Sequential SC administration of rHuPH20 solution followed by IGI, 10%)
1.
rHuPH20 
Dose: 80 U/g IgG
Dosing Frequency: Every 2, 3, or 4 weeks
Dosage form: Injection, solution
Mode of Administration: One to 3 infusion sites per infusion day are 
allowed. The infusion rate of rHuPH20 may be started at the previous 
infusion rate tolerated in the 161403 study. Infusion rates may be increased 
as tolerated by the subject and at the discretion of the investigator.
2.
IGI, 10%
Dose: Same monthly equivalent dose as the individual subject’s IgG 
treatment in Study 161403.
Dosing Frequency: Every 2, 3, or 4 weeks
Dosage form: Injection, solution
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Mode of Administration: SC infusion, to be administered via a peristaltic 
infusion pump with programmable infusion rates and infusion volumes at 
1 to 3 infusion sites per infusion day, with step-wise increases in infusion 
rate. IGI 10% solution may be administered at 1, 2, or 3 infusion sites. 
The recommended site(s) for the infusion of HYQVIA/HyQvia are the 
middle to upper abdomen and thighs.
For the initial 2 infusions, it may be delivered at an infusion rate of 10 to 
240 mL/h per infusion site for subjects ≥40 kg and 5 to 80 mL/h per 
infusion site for subjects <40 kg, as tolerated by the subject and/or at the 
discretion of the investigator.
For subsequent administrations, infusion rate may be increased as tolerated 
by the subject and at the discretion of the investigator.
Due to a manufacturer (CME America) recall on the Body Guard 323 pump 
and pump tubing, a replacement pump (for US and CANADA only) will 
be the Q Core – Sapphire pump. 
The Body Guard 323 pump and pump tubing will continue to be used in 
EU/ROW. Details on the infusion parameters for each pump is provided in 
the Investigator Site Infusion Manual.
Prior to subjects being allowed to infuse at these higher infusion rates in the 
home setting, this should first be conducted under medical supervision in 
the clinic setting.
At high infusion rates, above 750 mL/h (if trifurcated needle set for 
3 infusion sites is used), the pump occlusion alarm may be activated due to 
high back pressure, stopping the pump. If this occurs then reduce the 
infusion rate to allow proper pump function.
One to 3 sites can be used at the discretion of the investigator and subject 
based on tolerability and total IgG dose volume for the individual subject.
IGI, 10% solution may be administered at 1 or 2 infusion sites with a 
maximum infusion volume of up to 600 mL per infusion site for subjects 
weighing ≥40 kg. If using 3 infusion sites, the maximum is 400 mL/site 
since on any given infusion day, the maximum infusion volume should not 
exceed 1200 mL for subjects weighing ≥40 kg.
IGI 10% solution may be administered at 1 or 2 infusion sites with a 
maximum infusion volume of up to 300 mL per infusion site for subjects 
<40 kg, as tolerated. If using 3 infusion sites, the maximum is 200 mL/site 
since on any given infusion day, the maximum infusion volume should not 
exceed 600 mL for subjects weighing <40 kg.
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If a subject’s IgG dose per kg of body weight on a given day exceeds 
1.3 g/kg/day or exceeds the SC maximum infusion volume the subject can 
tolerate, not to exceed 1200 mL/day, the HYQVIA/HyQvia dose may be 
administered over multiple days as divided doses with 48 to 72 hours 
recommended between doses (eg, Day 1 and Day 3 of a given infusion 
cycle, but left to the investigator’s discretion) to allow absorption of 
infusion fluid at infusion site(s).
Note: The volume (mL) of infusion solution to be administered will be 
calculated using the subject’s body weight measured at baseline. 
Adjustment based on body weight changes during the course of the 
study is not planned, however it may be done if deemed medically 
necessary by the investigator (eg, clinically significant body weight change). 
After baseline, for study visits where the subject’s body weight is measured 
(see Table 21-1, Section 21.2 Schedule of Study Procedures and 
Assessments, for detailed timepoints), it is to be measured on site using the 
same scale/instrument throughout the study for that individual subject.
At a few selected study sites, subjects may be asked to permit still 
photographs of the infusion sites, which will be used for educational and 
demonstration purposes, both within and external to the study. Only the 
infusion site will be photographed, and no identifying features will be 
included. The site staff will be instructed on how to collect the still 
photographs. Subjects who agree will sign a separate consent.
SUBJECT SELECTION
Targeted Accrual
Maximum 88 subjects
Number of Groups/ 
Arms/Cohorts
1
Inclusion Criteria
Subjects who meet ALL of the following criteria are eligible for this study:
1.
Has completed Epoch 1 of Study 161403 without CIDPworsening.
2.
If female of childbearing potential, the subject must have a negative pregnancy test at baseline and 
agree to employ adequate birth control measures (eg, birth control pills/patches, intrauterine device 
[IUD], or diaphragm or condom [for male partner] with spermicidal jellyor foam) throughout the 
course of the study.
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Exclusion Criteria
Subjects who meet ANY of the following criteria are not eligible for this study:
1.
Subject has a serious medical condition such that in the opinion of the investigator the subject’s 
safety or medical care would be impacted by participation in this ExtensionStudy.
2.
New medical condition that developed during participation in Study 161403 that in the judgment of 
the investigator could increase risk to the subject or interfere with the evaluation of investigational 
medicinal product and/or conduct of thestudy.
3.
Subject is scheduled to participate in another, non-Baxalta clinical study involving an IP or 
investigational device during the course of this study.
4.
The subject is nursing or intends to begin nursing during the course of thestudy.
5.
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(with the 
exception of Study 161403) involving an IP or investigational device during the course of this study.
6.
The subject is a family member or employee of the investigator.
STATISTICAL ANALYSIS
Sample Size Calculation
Not applicable
Planned Statistical Analysis
Data will be analyzed descriptively .
Analysis Populations
Safety Set: The Safety (SAF) analysis set will be defined as all subjects who are enrolled in the Extension 
Study and received at least one dose of study medication. This will be the primary analysis set for all 
safety analyses. Descriptive analyses based on the Safety Set that are to be presented by treatment that a 
subject received during Study 161403 Epoch 1.
Safety Analysis
Descriptive statistics will be performed for all safety and tolerability outcome measures that are described 
in the section Primary Outcome Measures.
Immunogenicity
The number and percentage of subjects who meet each of the following criteria will be summarized: 
(1) subjects who have binding and/or neutralizing antibodies to rHuPH20, (2) subjects who have rHuPH20 
antibody titers that decline toward normal (titer <160) during continuous exposure to rHuPH20, (3) 
subjects who have a >10,000 titer of binding antibodies to rHuPH20 neutralizing antibodies and cross 
reactivity with Hyal-1,2 and 4. All immunogenicity analyses will be performed on the SAF analysis set.
Exploratory Efficacy
Exploratory efficacy analyses will be presented for the SAF analysis set. Subject relapse rates will be 
characterized by 6-month and cumulative relapse rates at the end of each consecutive 6-month study 
period and at the end of the study, as well as a Kaplan-Meier estimate of the median time to relapse. 
Point estimates and appropriate two-tailed, 95% confidence intervals will be provided. 
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Scores and changes from baseline in R-ODS, adjusted INCAT disability, hand grip strength, and MRC 
sum will be summarized by visit, using basic descriptive statistics. Baseline will be defined as the score at 
the study completion (end-of- SC treatment) visit in Study 161403.
Trough Serum IgG Levels
Trough plasma concentrations of IgG will be summarized and based on the SAF set, using the sample size, 
mean, SD, median, minimum, maximum, geometric mean, and SD of the geometric mean.
Subject-Reported Outcomes and Health Economics
The SF-36 section scores, EQ-5D-3L visual analog scale (VAS) scores, Treatment Satisfaction (TSQM-9) 
scores, and their respective changes from baseline will be summarized by visit using descriptive statistics 
for continuous data. The EQ-5D-3L item scores, Treatment Preference results, and Patient Global 
Impressionof Change (PGIC) scores will be summarized by the number and percentage of subjects who 
gave each possible response.
Health Resource Utilization (HRU) (such as days off school/work, unscheduled physician visits, 
hospitalization and emergency room visits, number of acute physician visits (office and emergency room 
visits due to CIDP exacerbation, any CIDP-related issue, any cause) over various time periods (pre-SC to 
End of Extension Study, baseline Extension Study to End of Extension Study) will be summarized by the 
number and percentage of subjects who experienced each type of event, with descriptive statistics for the 
number of events of each type.
Data will be analyzed descriptively.
Interim Analysis
An interim analysis is planned to be performed based on an interim data cut-off to occur within 30 days 
after the last subject in study 161403 had its last visit in Epoch 1. The data are planned to be included in 
future regulatory submissions. Outcome measures to be analyzed will include, but may not be limited to:
•
Number of subjects with a relapse (defined as a worsening of functional disability defined as an 
increase of ≥1 adjusted INCAT disability scores in 2 consecutive timepoints, relative to baseline)
•
Time to relapse
•
Change in R-ODS score from baseline
•
Change in adjusted INCAT disability score from baseline
•
Change in hand grip strength score from baseline
•
Change in MRC sum score from baseline
•
Cumulative treatment-emergent serious and non-serious AEs
•
Rates of causally related systemic and local AEs, expressed as number of events per infusion, per 
subject, and per subject-year
•
Infusions for which the infusion rate was reduced and/or the infusion was interrupted or stopped due 
to intolerability and/or AEs, for both local and systemic AEs
•
Anti-rHuPH20 binding and neutralizing antibody titers
•
Any relevant information that may support safety evaluation
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No corrections for multiplicity will be applied as this interim analysis is of a purely descriptive nature.
In addition to the interim analysis, Study 161505 safety data available at time of data cut for 
Study 161403 interim safety analysis (details in study protocol) will be summarized, in order to assess 
the long-term safety of HYQVIA.
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4. TABLE OF CONTENTS
PROTOCOL SIGNATURE PAGE................................................................................. 2
Sponsor’s (Takeda) Approval...................................................................................... 2
Investigator’s Acknowledgement ................................................................................ 3
1. STUDY PERSONNEL.................................................................................................. 4
1.1 Authorized Representative (Signatory) / Responsible Party .............................. 4
1.2 Study Organization................................................................................................. 4
2. SERIOUS ADVERSE EVENT REPORTING........................................................... 5
3. SYNOPSIS..................................................................................................................... 6
4. TABLE OF CONTENTS ........................................................................................... 17
5. LIST OF ABBREVIATIONS .................................................................................... 22
6. BACKGROUND INFORMATION .......................................................................... 25
6.1 Description of Investigational Product ............................................................... 29
6.1.1 HYQVIA/HyQvia........................................................................................... 29
6.1.1.1 Recombinant Human Hyaluronidase ................................................... 29
6.1.1.2 Immune Globulin Infusion 10% (Human)........................................... 30
6.1.2 Dose Justification........................................................................................... 31
6.2 Clinical Condition/Indication .............................................................................. 31
6.3 Population To Be Studied..................................................................................... 31
6.4 Findings from Nonclinical and Clinical Studies................................................. 31
6.5 Evaluation of Anticipated Risks and Benefits of the Investigational Product(s)
to Human Subjects................................................................................................ 31
6.5.1 HYQVIA/HyQvia........................................................................................... 31
6.5.2 GAMMAGARD LIQUID/KIOVIG............................................................. 33
6.6 Compliance Statement.......................................................................................... 34
7. STUDY PURPOSE AND OBJECTIVES ................................................................. 35
7.1 Study Purpose ....................................................................................................... 35
7.2 Primary Objective................................................................................................. 35
7.3 Exploratory Objectives......................................................................................... 35
8. STUDY DESIGN......................................................................................................... 36
8.1 Brief Summary...................................................................................................... 36
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8.2 Overall Study Design............................................................................................ 36
8.3 Duration of Study Period(s) and Subject Participation .................................... 38
8.4 Outcome Measures ............................................................................................... 38
8.4.1 Primary Outcome Measures......................................................................... 38
8.4.1.1 Safety/Tolerability .................................................................................. 38
8.4.1.2 Immunogenicity ...................................................................................... 40
8.4.2 Exploratory Outcomes Measure................................................................... 40
8.4.2.1 Exploratory Efficacy-Type Outcomes Measures................................. 40
8.4.2.2 Subject-Reported Outcomes and Health Economics........................... 41
8.4.2.3 Other........................................................................................................ 41
8.5 Randomization and Blinding............................................................................... 41
8.6 Study Stopping Rules............................................................................................ 41
8.7 Investigational Product(s) .................................................................................... 41
8.7.1 Packaging, Labeling, and Storage................................................................ 41
8.7.1.1 rHuPH20.................................................................................................. 41
8.7.1.2 IGI, 10%.................................................................................................. 42
8.7.2 Preparation and Storage of Pooled Products .............................................. 42
8.7.3 Administration ............................................................................................... 43
8.7.4 Description of Treatment.............................................................................. 45
8.7.5 Investigational Product Accountability ....................................................... 45
8.8 Source Data ........................................................................................................... 46
9. SUBJECT SELECTION, WITHDRAWAL, AND DISCONTINUATION .......... 47
9.1 Inclusion Criteria.................................................................................................. 47
9.2 Exclusion Criteria................................................................................................. 47
9.3 Withdrawal and Discontinuation ........................................................................ 47
10. STUDY PROCEDURES .......................................................................................... 49
10.1 Informed Consent and Enrollment ................................................................... 49
10.2 Subject Identification Code................................................................................ 49
10.3 Screening and Study Visits................................................................................. 49
10.3.1 Screening and Baseline Period.................................................................... 49
10.3.1.1 Rescreening ........................................................................................... 51
10.3.2 Treatment Period......................................................................................... 51
10.3.2.1 SC Infusion Visits (Including HomeInfusions).................................. 51
10.3.2.2 Unscheduled Visit for RelapseAssessment......................................... 53
10.3.3 Study Completion/Early Termination Visit .............................................. 53
10.4 Management of Infusion-Related AEs .............................................................. 53
10.5 Medications and Non-Drug Therapies.............................................................. 54
10.5.1 Immunizations.............................................................................................. 55
10.5.2 Pre-Medications for Infusion Administration........................................... 55
10.6 Subject Diary and Patient Reported Outcomes............................................... 56
10.7 Subject Completion/Discontinuation ................................................................ 57
10.8 Procedures for Monitoring Subject Compliance ............................................. 58
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10.9 Alternative Approaches to Study Procedures and Data Collection Due to 
COVID-19 Related Factor ................................................................................... 58
11. ASSESSMENT OF EFFICACY.............................................................................. 61
11.1 The Inflammatory Neuropathy Cause and Treatment (INCAT) Disability 
Scale........................................................................................................................ 61
11.2 Rasch-Built Overall Disability Scale (R-ODS)................................................. 62
11.3 Hand Grip Strength............................................................................................ 62
11.4 Medical Research Council SumScore............................................................... 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 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 Adverse Reactions Plus Suspected AdverseReactions ...................... 66
12.1.1.6 Pre-existing Diseases............................................................................. 66
12.1.2 Assessment of Adverse Events.................................................................... 66
12.1.2.1 Severity .................................................................................................. 68
12.1.2.2 Causality................................................................................................ 68
12.1.2.3 Safety Reporting ................................................................................... 69
12.2 Urgent Safety Measures ..................................................................................... 70
12.3 Untoward Medical Occurrences........................................................................ 70
12.4 Non-Medical Complaints ................................................................................... 71
12.5 Medical, Medication, and Non-Drug Therapy History................................... 71
12.6 Physical Examinations........................................................................................ 72
12.7 Clinical Laboratory Parameters........................................................................ 72
12.7.1 Hematology and Clinical Chemistry.......................................................... 72
12.7.2 Hemolytic Panel............................................................................................ 73
12.7.3 Hemoglobin A1C (HbA1C)......................................................................... 73
12.7.4 Serum Iron, Ferritin, and Total Iron Binding Capacity .......................... 73
12.7.5 Viral Serology Tests..................................................................................... 73
12.7.6 Urine Tests.................................................................................................... 74
12.7.7 Pregnancy Test............................................................................................. 74
12.7.8 Assessment of Laboratory Values .............................................................. 74
12.7.8.1 Toxicity Grading Scale......................................................................... 74
12.7.8.2 Assessment of Abnormal Laboratory Values..................................... 75
12.7.9 Trough Serum IgG....................................................................................... 75
12.7.10 Anti-rHuPH20 Antibodies......................................................................... 76
12.7.11 Immunogenicity Panel ............................................................................... 76
12.7.11.1 Guidance on Reporting and Assessing rHuPH20 antibody test 
results....................................................................................................... 78
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12.7.12 Back-up Samples and Biobanking ........................................................... 78
12.8 Vital Signs............................................................................................................ 79
13. OTHER ASSESSMENTS ........................................................................................ 80
13.1 Short Form-36 Health Survey............................................................................ 80
13.2 EuroQoL (Quality of Life)-5 Dimensions (EQ-5D-3L) ................................... 80
13.3 Health Resource Utilization ............................................................................... 80
13.4 Abbreviated Treatment Satisfaction Questionnaire for Medication(TSQM-9)
................................................................................................................................ 81
13.5 Treatment Preference ......................................................................................... 81
13.6 Patient Global Impression of Change ............................................................... 81
14. STATISTICS............................................................................................................. 82
14.1 Sample Size and Power Calculations ................................................................ 82
14.2 Datasets and Analysis Cohorts........................................................................... 82
14.3 Handling of Missing, Unused, and Spurious Data ........................................... 82
14.4 Methods of Analysis............................................................................................ 84
14.4.1 Primary Outcome Measure......................................................................... 84
14.4.1.1 Safety/Tolerability ................................................................................ 84
14.4.1.2 Tolerability............................................................................................ 87
14.4.1.3 Immunogenicity .................................................................................... 87
14.4.2 Exploratory Outcome Measures................................................................. 87
14.4.2.1 Exploratory Efficacy ............................................................................ 87
14.4.2.2 Subject-Reported Outcomes and HealthEconomics......................... 88
14.4.2.3 Trough Serum IgG Levels.................................................................... 88
14.5 Planned Interim Analysis of the Study ............................................................. 89
15. DIRECT ACCESS TO SOURCE DATA/DOCUMENTS .................................... 90
16. QUALITY CONTROL AND QUALITY ASSURANCE...................................... 91
16.1 Investigator’s Responsibility.............................................................................. 91
16.1.1 Final Clinical Study Report ........................................................................ 91
16.2 Training ............................................................................................................... 91
16.3 Monitoring........................................................................................................... 91
16.4 Auditing ............................................................................................................... 91
16.5 Non-Compliance with the Protocol ................................................................... 92
16.6 Laboratory and Reader Standardization ......................................................... 92
17. ETHICS ..................................................................................................................... 93
17.1 Subject Privacy ................................................................................................... 93
17.2 Ethics Committee and Regulatory Authorities................................................ 93
17.3 Informed Consent ............................................................................................... 93
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17.4 Data MonitoringCommittee .............................................................................. 94
18. DATA HANDLING AND RECORD KEEPING................................................... 95
18.1 Confidentiality Policy ......................................................................................... 95
18.2 Study Documentation and Case Report Forms ............................................... 95
18.3 Document and Data Retention........................................................................... 95
19. FINANCING AND INSURANCE........................................................................... 96
20. PUBLICATION POLICY........................................................................................ 96
21. SUPPLEMENTS....................................................................................................... 97
21.1 Study Flow Chart................................................................................................ 97
21.2 Schedule of Study Procedures and Assessments.............................................. 98
21.3 Clinical Laboratory Assessments .................................................................... 101
21.4 Toxicity Grading Scale for Laboratory Values.............................................. 103
21.5 Contraceptive Methods for Female Subjects of ChildbearingPotential...... 105
22. SUMMARY OF CHANGES.................................................................................. 107
23. REFERENCES........................................................................................................ 110
Tables
Table 12-1 List of Conditions/Symptoms That May be a Result of Immune-Mediated 
Response to Either Immunoglobulin, rHuPH20, or Other Factors........................... 77
Table 12-2 ImmunogenicityPanel ................................................................................... 77
Table 21-1 Schedule of Study Procedures and Assessments........................................... 98
Table 21-2 Clinical Laboratory Assessments ................................................................ 101
Table 21-3 Grading of Laboratory Parameters .............................................................. 103
Figures
Figure 21-1 Study Flow Chart for Study 161505 ............................................................ 97
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5. LIST OF ABBREVIATIONS
Abbreviation
Definition
AAN
American Academy of Neurology
ADA
Antibody detection assay
AE(s)
Adverse event(s)
AIDS
Acquired immunodeficiency syndrome
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
ANC
Absolute neutrophil count
AR(s)
Adverse reaction(s)
AST
Aspartate aminotransferase
B19V
Parvovirus B19
BMI
Body mass index
BUN
Blood urea nitrogen
C3
Complement component 3
C4
Complement component 4
CH50
50% hemolytic complement activity of serum
CHO
Chinese hamster ovary
CIC
Circulating immune complex
CIDP
Chronic inflammatory demyelinating polyradiculoneuropathy
CMAP
Compound motor action potential
CPK
Creatine phosphokinase
CRF(s)
Case report form(s)
CTA
Clinical Trial Agreement
CTFG
Clinical Trial Facilitation Group
DADS
Distal acquired demyelinating symmetric neuropathy
DMC
Data monitoring committee
DNA
Deoxyribonucleic acid
EC(s)
Ethics committee(s)
ECOG
Eastern Cooperative Oncology Group
ECRF/eCRF
Electronic case report form
EDC
Electronic data capture
EDTA
Ethylenediaminetetraacetic acid
EFNS/PNS
European Federation of Neurological Societies/Peripheral Nerve Society
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Abbreviation
Definition
EMA
European Medicines Agency
EQ-5D
EuroQoL (Quality of Life)-5 Dimensions
FDA
Food and Drug Administration
GAMMAGARD LIQUID/ 
KIOVIG
Immune Globulin Infusion (Human), 10% Solution
GCP
Good Clinical Practice
GGT
Gamma-glutamyl transferase
HAV
Hepatitis A virus
HbA1C
Hemoglobin A1C; also known as glycosylated or glycated hemoglobin
HBV
Hepatitis B virus
Hct
Hematocrit 
HCV
Hepatitis C virus
HEV
Hepatitis E virus
Hgb
Hemoglobin 
HIV
Human immunodeficiency virus 
HRQOL
Health-related quality of life
HRU
Health Resource Utilization
HYQVIA/HyQvia
Immune Globulin Infusion 10% (Human) with Recombinant Human 
Hyaluronidase (IGI, 10% with rHuPH20)
IB
Investigator's brochure
ICH
International Council for Harmonisation
IgA
Immunoglobulin A
IGI, 10%
Immune Globulin Infusion (Human), 10% Solution
IGIV or IVIg
Intravenous immunoglobulin G
IgG
Immunoglobulin G
IgM
Immunoglobulin M
IGSC
Subcutaneous immunoglobulin G
INCAT
Inflammatory Neuropathy Cause and Treatment 
IP(s)
Investigational product(s)
ITP
Idiopathic thrombocytopenic purpura
IV
Intravenous
LDH
Lactate dehydrogenase
MADSAM
Multifocal acquired demyelinating sensory and motor neuropathy
MCS
Mental component summary score
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Abbreviation
Definition
MedDRA
Medical Dictionary for Regulatory Activities
MMN
Multi-focal motor neuropathy
MRC
Medical Research Council
NMC 
Non-medical complaint
PCS
Physical component summary score
PE
Plasma exchange
PGIC
Patient Global Impression of Change
PID
Primary immunodeficiency disease
RBC
Red blood cell
rHuPH20
Recombinant human hyaluronidase
R-ODS
Rasch-built Overall Disability Scale 
RSI
Reference Safety Information
SAE(s)
Serious adverse event(s)
SAER
Serious adverse event report
SAP
Statistical analysis plan
SC
Subcutaneous
SD
Standard deviation
SF-36
Short Form-36 health survey
SIC
Subject identification code
SUSAR(s)
Suspected unexpected serious adverse reaction(s)
TEAE(s)
Treatment-emergent adverse event(s)
TIBC
Total Iron Binding Capacity
TRALI
Transfusion related acute lung injury
TSQM-9
Abbreviated treatment satisfaction questionnaire for medication
ULN
Upper limit of normal
US
United States
WBC
White blood cell
WHO
World Health Organization
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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 disease (PID), 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 PID syndromes, 
immunoglobulin preparations have been indicated for secondary immunodeficiencies, 
such as B-cell chronic lymphocytic leukemia, 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). Clinical studies in 
neurological indications have also shown significant results with intravenous (IV) 
immunoglobulin (IGIV) preparations in the treatment of chronic inflammatory 
demyelinating polyradiculoneuropathy (CIDP) (Hughes et al., 2008, Léger et al., 2013).
CIDP is a progressive chronic sensory and motor neuropathy with a relapsing and 
remitting or progressive course of more than 2 months, characterized by proximal 
weakness, positive sensory symptoms, areflexia without wasting, and impaired sensation 
with a preferential loss of vibration or joint position sense (European Federation of 
Neurological Societies, 2010, Köller et al., 2005). Worldwide estimates of the prevalence 
of CIDP range from 1.9 to 8.9/100,000 with an annual incidence of 0.15-1.6/100,000
(Iijima et al., 2008, Laughlin et al., 2009, Lunn et al., 1999, McLeod et al., 1999, 
Mygland and Monstad, 2001). A report in Neurology in 2009 cited a United States (US) 
prevalence of CIDP of 8.9/100,000 and an annual incidence of 1.6/100,000 new cases 
each year (Laughlin et al., 2009). CIDP has an estimated prevalence in Europe of 
3.7/100,000 (Orphanet Report Series, 2014).
European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) 
guidelines published in 2010 utilize clinical, electrodiagnostic, and supportive criteria 
for the diagnosis of CIDP (European Federation of Neurological Societies, 2010). CIDP 
is defined as having either a typical or an atypical clinical presentation. Typical CIDP 
presents as a symmetric proximal and distal weakness with sensory involvement of all 
extremities. The clinical course is either slowly progressive or relapsing and remitting. 
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Tendon reflexes are diminished or absent in all extremities. Cranial nerve involvement 
is less commonly seen. Balance can be impaired due to loss of proprioception 
(Koski, 2002). Sensory symptoms may include numbness, tingling, and painful 
paresthesias (Dyck et al., 1975, McCombe et al., 1987). Atypical CIDP, according to the 
EFNS/PNS guidelines, includes CIDP with pure motor or pure sensory impairment 
or with distal, multifocal, or focal distributions (European Federation of Neurological 
Societies, 2010). Atypical presentations of CIDP may include the presence of normal 
tendon reflexes in unaffected limbs. CIDP with a predominantly distal presentation is 
described as distal acquired demyelinating symmetric neuropathy (DADS) (Note: DADS 
without immunoglobulin M [IgM] paraprotein is generally considered to be a variant of 
CIDP). Lewis-Sumner Syndrome, also known as multifocal acquired demyelinating 
sensory and motor neuropathy (MADSAM), is the asymmetric variant of CIDP. For 
this study, pure sensory CIDP (including chronic immune sensory polyradiculopathy 
affecting the central process of the primary sensory neuron) and focal CIDP (eg, 
involvement of the brachial or lumbosacral plexus or of one or more peripheral nerves in 
one upper or lower limb) will be exclusionary; the study outcome measures are not fitting 
to assess clinical change in patients with those variants of CIDP. In order to meet the 
clinical diagnostic criteria for CIDP (whether typical or atypical), other causes for a 
neuropathy must be excluded (European Federation of Neurological Societies, 2010). 
The EFNS/PNS guidelines and the American Academy of Neurology (AAN) require 
electrodiagnostic testing with findings consistent with demyelination for a diagnosis of 
CIDP (Cornblath et al., 1991, European Federation of Neurological Societies, 2010, 
Hahn et al., 2005, Köller et al., 2005). Major electrodiagnostic features consistent with 
CIDP include one or more of the following: prolonged distal motor latencies, reduced 
motor conduction velocity, delay or absence of F waves, partial motor conduction block, 
abnormal temporal dispersion, and distal compound motor action potential (CMAP) 
increase (European Federation of Neurological Societies, 2010, Köller et al., 2005, 
Koski, 2002). Supportive criteria in the diagnosis of CIDP may include findings from 
examination of cerebrospinal fluid, magnetic resonance imaging, nerve biopsy and/or 
response to immunotherapy treatment (European Federation of Neurological Societies, 
2010).
While CIDP can occur in all ages, it occurs more often in the middle-aged and elderly 
population with a male predominance (Hughes, 2003). The peak incidence of CIDP is 
between the ages of 30 to 60 years (Dalakas, 2011). Approximately 60% of patients have 
a chronic progressive form and are typically older. Approximately 30% have a relapsing 
remitting course and these patients tend to be younger.
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There is a significant burden of disease associated with CIDP. Patients with CIDP have 
weakness and gait disturbances that result in tripping and falling, difficulty with stairs, 
difficulty rising from a seat, and difficulty with maintaining balance. Walking may 
require a cane or a walker or the patient may be confined to a wheelchair or bed.
Weakness and clumsiness of the upper extremities result in impaired dexterity in carrying 
out tasks such as personal hygiene, dressing, buttoning a shirt, or picking up objects.
Patients can have difficulty showering or going to the bathroom. Paresthesias can 
result in painful symptoms such as aching, jabbing, and searing or burning pain
(Ulane and Brannagan, 2012).
Although the exact etiology of CIDP is unknown, it is regarded as an autoimmune 
disorder. On nerve biopsy, a demyelinating neuropathy is seen with inflammatory 
changes and infiltration of macrophages and T-cells. Demyelination, remyelination, 
and onion bulb formation is present (Hughes, 2003, Köller et al., 2005, Koski, 2002).
Axonal loss can also be seen. Long-term demyelination leads to axonal loss, and it is the 
amount of axonal loss that determines the level of disability and long-term prognosis
(Köller et al., 2005, Koski, 2002, Ulane and Brannagan, 2012). Treatment is 
recommended for all CIDP patients who demonstrate significant clinical symptoms in 
order to prevent continuing demyelination and secondary axon loss leading to permanent 
disability (Köller et al., 2005).
Conventional therapy for CIDP includes corticosteroids, plasma exchange (PE), and 
IGIV. IGIV has been the most studied treatment and the only approved therapy for CIDP
for both induction and maintenance therapy (Eftimov et al., 2013, Harbo et al., 2009b, 
Hughes et al., 2001, Hughes et al., 2008, Kuitwaard et al., 2010, Léger et al., 2013, 
Mendell et al., 2001, Nobile-Orazio et al., 2012, Patwa et al., 2012, van Schaik et al., 
2002).  In clinical guidelines for treatment of CIDP, corticosteroids (Eftimov et al., 2012, 
Hughes et al., 2001, Nobile-Orazio et al., 2012, van Schaik et al., 2010) and PE 
(Dyck et al., 1986, Hahn et al., 1996, Mehndiratta and Hughes, 2012) are also first-line 
therapies for induction therapy and maintenance therapy (European Federation of 
Neurological Societies, 2010, Patwa et al., 2012).
The EFNS/PNS 2010 guidelines recommend that either corticosteroids or IGIV 
should be considered for the initial treatment of CIDP. PE may be similarly effective 
but less tolerated because associated adverse events (AEs) are not uncommon. 
Since IGIV may provide rapid improvement, it is often the first choice. 
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If the response is inadequate to the initial treatment or there is a problem with tolerability 
of maintenance treatment, the EFNS/PNS 2010 guidelines recommend that the other first-
line therapies (IGIV, steroids, or PE) be tried before considering combination treatments. 
Adding an immunosuppressant or immunomodulatory drug may be considered, but there 
is insufficient evidence to recommend a particular immunosuppressant/ 
immunomodulatory agent (Cocito et al., 2011a, European Federation of Neurological 
Societies, 2010). However, while corticosteroids are effective in treating the symptoms of 
CIDP, there are significant problems with safety and tolerability associated with 
corticosteroid treatment, particularly when givenchronically (Gorson, 2012). 
Subcutaneous (SC) administration of immunoglobulin G (IGSC) has been the 
predominant mode in the Scandinavian countries for many years (Gardulf et al., 1991)
and has become increasingly widespread with tens of thousands of SC infusions given 
during the last decade in patients with primary and secondary antibody deficiencies
(Grunebaum et al., 2002). To date, several publications have reported the therapeutic 
efficacy of IGSC administration in patients with CIDP (Cocito et al., 2014, Cocito et al., 
2011b, Köller et al., 2006, Lee et al., 2008, Markvardsen et al., 2013) IGSC replacement 
therapy is considered to be effective, safe, and also highly appreciated by patients 
(Misbah et al., 2009, Nicolay et al., 2006) and to have a low risk of systemic adverse 
reactions (ARs) (Gardulf et al., 1995, Gardulf et al., 1993, Gardulf et al., 1991). 
Some of the proposed advantages of IGSC over IGIV include: 1) superior systemic AE 
profile and improved tolerability, 2) an alternative for patients with poor venous access, 
3) option for home treatment, and thus reduced burden on resources and healthcare costs 
(Gardulf and Hammarström, 1996),  4) improved health-related quality of life (HRQOL), 
5) ease of administration and flexibility of dosing, and 6) increased convenience and 
compliance. The main disadvantages with conventional IGSC therapy are: 1) the limited 
volume of fluid that can bedelivered subcutaneously, and 2) the low bioavailability 
(65%-69%) (Berger et al., 2013) of the conventional IGSC therapy. These limitations in 
turn require more frequent dosing typically to be weekly to several times a week 
(Markvardsen et al., 2014) and, in the case of large doses, administration at multiple sites 
to deliver the entire dose (Harbo et al., 2009a, Harbo et al., 2010, Markvardsen et al., 
2014).
Immune Globulin Infusion 10% (Human) with Recombinant Human 
Hyaluronidase (IGI, 10% with rHuPH20; tradenames: HYQVIA/HyQvia) was 
developed to address the major limitation of conventional IGSC therapy. 
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HYQVIA/HyQvia significantly enhances SC administration in PID by offering improved 
bioavailability (as compared to conventional IGSC therapy) without requiring greater 
doses than those administered by IV (Schiff et al., 2008).
In addition, HYQVIA/HyQvia allows the SC administration of standard PID monthly 
dosing volumes and the utilization of infusion rates equal to IV administration while 
preserving the advantages of SC administration (Schiff et al., 2008). These advantages 
may be particularly relevant to neurology indications, including immune-mediated 
neuropathies for IgG usage, that require immunomodulatory doses up to 5 times higher 
than immune replacement doses.
One clinical study with HYQVIA/HyQvia in CIDP is currently ongoing: Study 161403, 
a Phase III Efficacy, Safety, and Tolerability Study of HYQVIA/HyQvia and 
GAMMAGARD LIQUID/KIOVIG. It is a Phase III multicenter, double-blind, placebo 
controlled study.
This clinical study is being performed to investigate the long-term tolerability and safety 
of rHuPH20-facilitated IGSC therapy in subjects with CIDP, who have completed 
Baxalta Clinical Study 161403 Epoch 1 without CIDP worsening.
6.1 Description of Investigational Product
6.1.1 HYQVIA/HyQvia
HYQVIA/HyQvia is a product that contains both Immune Globulin Infusion 10% 
(Human) (IGI, 10%) and recombinant human hyaluronidase (rHuPH20) packaged as two 
separate vials. Further information is provided in the Investigator’s Brochure (IB) for 
IGI, 10% with rHuPH20.
6.1.1.1 Recombinant Human Hyaluronidase
rHuPH20 (molecular weight of ~61 kDa) is produced from genetically engineered 
Chinese Hamster Ovary (CHO) cells containing a deoxyribonucleic acid (DNA) plasmid 
encoding for a soluble fragment of human hyaluronidase PH20. rHuPH20 is a soluble 
recombinant form of human hyaluronidase that modifies the permeability of connective 
tissue through the hydrolysis of hyaluronan. rHuPH20 acts locally and transiently within 
the SC space to increase the tissue dispersion and absorption of other injected drugs and 
fluids. rHuPH20 is locally catabolized. In SC tissue, rHuPH20 has a half-life of less than 
30 minutes, and in the systemic circulation a half-life of less than 5 minutes (Halozyme 
data on file). Hyaluronan is a gel-like polysaccharide that limits the movement of fluids 
and other molecules in the SC tissue. It is degraded by naturally occurring hyaluronidase 
and has a very fast turnover (half-life of approximately 0.5 days) in SC tissue. 
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The addition of rHuPH20 accelerates the depolymerization of hyaluronan, resulting in a 
decreased resistance to fluid flow and a transient increase in permeability of the local SC 
tissue. The interstitial matrix and normal permeability of the SC tissue is restored within 
24 to 48 hours due to the naturally occurring rapid regeneration of hyaluronan in the 
body.
rHuPH20 drug product is supplied as a sterile, clear, colorless, ready-for-use solution in 
the label strength of 160 U/mL, containing the additional excipients sodium chloride, 
sodium phosphate, albumin human, ethylenediaminetetraacetic acid (EDTA) disodium, 
calcium chloride, and sodium hydroxide and/or hydrochloric acid added for pH 
adjustment. rHuPH20 solution contains 0.1% human albumin with an approximate pH of 
7.4 and osmolality of 290 to 350 mOsm. rHuPH20 solution is preservative-free. rHuPH20 
solution provides for high margins of safety with respect to viruses, due to 
comprehensive virus testing at the Master Cell Bank, Working Cell Bank and bulk 
harvest stage, effective virus reduction during the purification process, and the use of 
pharmaceutical grade human albumin as an excipient with no other materials of human or 
animal origin involved in the manufacturing process.
6.1.1.2 Immune Globulin Infusion 10% (Human)
The manufacturing process of IGI, 10% is in compliance with the US 21 Code of 
Federal Regulations and Recommendations and Guidelines published by the US Food 
and Drug Administration (FDA) and/or the European Medicines Agency (EMA). 
IGI, 10% is manufactured from human plasma by employing a modified Cohn-Oncley 
cold alcohol fractionation process, as well as cation and anion exchange chromatography.
Screening against potentially infectious agents (such as hepatitis A virus [HAV], hepatitis 
B virus [HBV], hepatitis C virus [HCV], human immunodeficiency virus [HIV], and 
parvovirus B19 [B19V]) begins with the donor selection process and continues 
throughout plasma collection and preparation. To further improve the margin of safety, 
three validated, dedicated, independent, and effective virus inactivation/removal steps 
have been integrated into the manufacturing and formulation processes, namely 
solvent/detergent treatment, nanofiltration, and incubation at a low pH and elevated 
temperature in the final formulation.
The finished medicinal product, IGI, 10%, is a purified, functionally intact IgG solution 
formulated with 0.25 M glycine (for a stabilizing effect) at 10% weight/volume (w/v) 
protein concentration and a pH of 4.6 to 5.1. The preparation is an isotonic solution 
containing approximately 100 mg of protein per mL, of which at least 98% is IgG with an 
IgG subclass distribution representative of native human plasma. The product contains no 
preservatives.
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6.1.2 Dose Justification
The IgG dosing regimen for HYQVIA/HyQvia will be the same as in Study 161403.
6.2 Clinical Condition/Indication 
For maintenance therapy of CIDP to prevent neuromuscular disability and impairment.
6.3 Population To Be Studied
This study will enroll subjects who have completed Study 161403 Epoch 1 without CIDP 
worsening and who have agreed to enter this Extension Study. It is estimated that a 
maximum of 88 subjects will be eligible for enrollment into the study.
6.4 Findings from Nonclinical and Clinical Studies
Findings from non-clinical and clinical studies for HYQVIA/HyQvia are detailed in the 
IGI, 10% with rHuPH20 IB.
6.5 Evaluation of Anticipated Risks and Benefits of the Investigational Product(s) to 
Human Subjects
6.5.1 HYQVIA/HyQvia
The clinical development program for HYQVIA/HyQvia has demonstrated that IGI, 10% 
administered via SC treatment with rHuPH20 is efficacious and safe in PID. The safety, 
tolerability, efficacy, and bioavailability of HYQVIA/HyQvia were investigated in one 
pivotal Phase III study (160603) and an Extension Study (160902) in subjects with PID. 
One supportive clinical study (160602) in subjects with PID using GAMMAGARD 
LIQUID/KIOVIG (IGI, 10%) administered subcutaneously was also conducted. Further 
information is provided in the IB for IGI, 10% with rHuPH20 as well as Prescribing 
Information for HYQVIA and the Summary of Product Characteristics (SmPC) for 
HyQvia.
The most common ARs observed in PID 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/HyQvia 
has not been established in conditions other than PID. Study 160603 compared the 
efficacy, pharmacokinetics, 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. 
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Eighteen percent (15 of 83) of subjects with PID receiving IGI, 10% with rHuPH20 in 
Baxter Study 160603 and Study 160902 developed non-neutralizing antibodies to 
rHuPH20. The clinical significance of these antibodies is not known. The clinical data 
from Baxter 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 (See Section 12.7.10 for details).
Pregnancy, Breast Feeding, Fertility
IGSC 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 rHuPH20 in mice and 
rabbits. No adverse effects on pregnancy and fetal development were associated with 
anti-rHuPH20 antibodies. In these studies, maternal antibodies to rHuPH20 were 
transferred to offspring in utero. The effects of antibodies to the rHuPH20 component of 
HyQvia on the human embryo or on human fetal development are currently unknown.
Immunoglobulins are excreted into the milk and may contribute to protecting the neonate 
from pathogens that have a mucosal portal of entry. 
For subjects in the European Union (EU): 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.
For subjects in US: HyQvia should be given to a pregnant or nursing woman only if 
clearly indicated.
There are currently no clinical safety data for HyQvia on fertility available. Clinical 
experience with immunoglobulins suggests that no harmful effects of IGI 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 IGI 10%.
Subjects who become pregnant during the study should be withdrawn from the study.
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See Section 6.5.2 for the known risks associated with IGI, 10%.
6.5.2 GAMMAGARD LIQUID/KIOVIG
GAMMAGARD LIQUID/KIOVIG will not be used as an investigational drug in 
this study. However, GAMMAGARD LIQUID/KIOVIG—also known as IGI, 10%—
is the immunoglobulin product in HYQVIA/HyQvia. Information on this product is 
therefore also presented:
IGI, 10% administered via IV treatment (GAMMAGARD LIQUID/KIOVIG) 
is efficacious and safe in the particular fields of therapeutic use and approved 
indications, ie, PID, ITP, and MMN, as demonstrated in the clinical development 
program for GAMMAGARD LIQUID/KIOVIG. 
Please see the IB for IGI, 10% for further information, as well as the Prescribing 
Information for GAMMAGARD LIQUID and the SmPC for KIOVIG.
Serious ARs (defined as serious adverse events [SAEs] occurring during or within 
72 hours of infusion or any casually related SAE occurring within the study period) that 
occurred in the clinical trials of GAMMAGARD LIQUID/KIOVIG were aseptic 
meningitis, pulmonary embolism, and blurred vision.
The most common ARs observed in ≥5% of subjects were: 

PID, IV administration: headache, fatigue, pyrexia, nausea, chills, rigors, pain in 
extremity, diarrhea, migraine, dizziness, vomiting, cough, urticaria, asthma, 
pharyngolaryngeal pain, rash, arthralgia, myalgia, oedema peripheral, pruritus, and 
cardiac murmur.

PID, SC administration: infusion site (local) event, headache, fatigue, heartrate 
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.
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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, 
hyper viscosity, and cardiovascular risk factors.
Renal dysfunction, acute renal failure, osmotic nephrosis, and death may occur in 
predisposed patients receiving 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 (eg, ≥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, 10% treatment include anaphylactic or severe systemic 
hypersensitivity reactions to IG, and immunoglobulin A (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 
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 (eg, exclusion criteria, blood group typing at 
baseline, and laboratory monitoring for hemolysis).
Further information is provided in the Prescribing Information for GAMMAGARD 
LIQUID, SmPC for KIOVIG, and the IB for IGI, 10%.
6.6 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 Clinical Trial Regulation
EU No. 536/2014 and 2005/28/EC, the Declaration of Helsinki, and applicable national 
and local regulatory requirements.
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7. STUDY PURPOSE AND OBJECTIVES
7.1 Study Purpose
The purpose of this study is to assess the long-term safety, tolerability, and 
immunogenicity of the SC treatment with IGSC facilitated with rHuPH20 
(HYQVIA/HyQvia) in subjects with CIDP who have completed Baxalta Clinical 
Study 161403 Epoch 1 without CIDP worsening.
7.2 Primary Objective
1.
To evaluate the long-term safety, tolerability, and immunogenicity of 
HYQVIA/HyQvia.
7.3 Exploratory Objectives
1.
To assess the long-term effect of HYQVIA/HyQvia on clinical outcome 
measures, including prevention of relapse, change in functional ability, hand grip 
strength, and muscle strength.
2.
To assess the long-term effect of HYQVIA/HyQvia on quality of life, health 
utility, health resource utilization (HRU), treatment satisfaction, treatment 
preference, and subject global impression of change.
3.
To evaluate improvement in functional impact on everyday tasks as 
measured by a pre-specified subscore of R-ODS
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8. STUDY DESIGN
8.1 Brief Summary
This study is a Phase IIIb, open-label, multicenter study to assess the long-term safety, 
tolerability, and immunogenicity of HYQVIA/HyQvia (IGI, 10% with rHuPH20 
administered subcutaneously) for maintenance therapy to prevent relapse. This study is 
an extension of Baxalta Clinical Study 161403, a Phase III Efficacy, Safety, and 
Tolerability Study of HYQVIA/HyQvia and GAMMAGARD LIQUID/KIOVIG in 
CIDP.
8.2 Overall Study Design 
The overall study design is illustrated in Figure 21-1. Details on the procedures to be 
performed at each study visit can be found in Section 21.2 Schedule of Study Procedures 
and Assessments and Section 21.3 Clinical Laboratory Assessments.
Enrollment into this study is open to subjects who have completed Study 161403 Epoch 1 
without CIDP worsening and who have provided informed consent.
Subjects must meet all eligibility criteria (see Section 9) in order to participate in this 
Extension study. It is estimated that a maximum of 88 subjects will be eligible for study 
participation.
In this Extension Study, eligible subjects will receive HYQVIA/HyQvia in an open-label 
fashion until relapse or until predetermined study end for the specific country from which 
the subject is participating as described in Section 8.3.
Dose of HYQVIA/HyQvia and Dosing Regimen:
Subjects will continue to receive the same dose and dosing regimen of HYQVIA/HyQvia 
in the Extension Study as the subject’s full dose received in Epoch 1 of the Phase III 
pivotal study (Study 161403).
Entry into Extension Study:
Enrollment into the Extension Study (signed informed consent) may take place prior to 
or during the subject’s study completion visit in Study 161403. The termination visit 
of Study 161403 is to serve as the baseline visit for the Extension Study. Therefore, 
the informed consent for the Extension Study must be obtained on the day of or prior 
to conducting the end-of-treatment assessments in Study 161403 in order for those 
assessments to serve as the baseline assessments in the Extension Study. 
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Subject’s eligibility for entrance into the Extension Study must be determined prior to 
the first investigational product (IP) infusion in the Extension Study, which will occur at 
the next visit (the first treatment visit in the Extension Study). The first administration in 
the Extension Study will take place at the subject’s next scheduled dosing (every 2, 3, or 
4 weeks). The dose will be the same as that administered in Study 161403. The first 
infusion will be at the subject’s full dose; there will be no ramp-up of dose.
After the first 12 weeks of treatment in the Extension Study, the dosing interval of 
HYQVIA/HyQvia may be adjusted for subject preference, provided that it is safe to do so 
at the investigator’s discretion. If medically necessary, the interval and/or dose may be 
changed at any time, at the investigator’s discretion.
Administration and Study Site Visits:
As some subjects were receiving placebo treatment and have not been exposed to 
HYQVIA/HyQvia while participating in the 161403 protocol, all subjects will have at 
least the first 2 infusion visits in this Extension Study at the study site to facilitate safety 
monitoring.
Subjects from Study 161403:
The first 2 infusions in the Extension Study will be conducted at the investigator’s site. 
Thereafter and per investigator’s discretion, the SC infusions for subjects rolling over 
from Study 161403 may take place at the study site, infusion center, or at the subject’s 
home or other suitable location, as acceptable per local regulations and standard practices 
of the study site and if product can be shipped from the pharmacy to the respective 
locations.
The ability of the subject (and/or caregiver) to independently perform infusion procedures
is a prerequisite for self-administration. As needed, retraining and verification of the 
subject’s (and/or caregiver’s) proficiency in independently self-administering infusions 
will be provided and must be documented.
Whilst HYQVIA/HyQvia infusions will occur at 2-, 3-, or 4-week intervals, at home or in 
clinic, Study Site Visits are only mandatory at 1 week after the first and second dose and 
then every 12 weeks (±5 days) in the Extension Study. However, an unscheduled visit 
can occur at any time should the need arise.
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8.3 Duration of Study Period(s) and Subject Participation
Each subject will have the opportunity to receive HYQVIA/HyQvia until approval of 
HyQvia marketing authorization for the treatment of CIDP in either US or EU (whichever 
comes later) unless 1 of the following criteria is met:
2.
Early subject discontinuation from treatment or study due to CIDP worsening that 
at the discretion of the investigator would preclude further treatment with IP.
3.
Country-specific predetermined date, as may be mandated by regulations.
4.
Sponsor’s decision to early discontinue further participation of a subject in the 
study.
5.
Early study termination at the sponsor’s discretion, for any reason.
6.
Upon unblinding of study 161403, subjects who did not have CIDP worsening 
while on placebo treatment during Epoch 1 should discuss options regarding 
continued participation in this long-term clinical trial with the investigator.
7.
Subject becomes pregnant during the study.
8.4 Outcome Measures
8.4.1 Primary Outcome Measures
8.4.1.1 Safety/Tolerability
The primary outcome measure is safety/tolerability (each of these analyzed over time 
period, eg, first year, second year, third year, etc.) and immunogenicity.
1.
Number (percentage) of subjects experiencing any treatment-emergent SAEs and/or 
AEs, regardless of causality.
2.
Number (percentage) of subjects experiencing causally related SAEs and/or AEs.
3.
Number (percentage) of subjects with serious and/or non-serious ARs plus 
suspected ARs.
4.
Rate of AEs that may be a result of immune-mediated response to either 
immunoglobulin, rHuPH20, or other factors as listed in Table 12-1, expressed as 
number of events per infusion and per subject-year.
5.
Number (percentage) of treatment-emergent SAEs and/or AEs associated with 
infusions, regardless of causality
6.
Number (percentage) of causally related SAEs and/or AEs associated with 
infusions
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7.
Number (percentage) of AEs temporally associated with infusions (defined as AEs 
occurring during or within 72 hours after completion of an infusion)
8.
Number (percentage) of serious and/or non-serious ARs plus suspected ARs 
associated with infusions
9.
Number (percentage) of infusions associated with 1 or more systemic AEs.
10. Number (percentage) of infusions associated with 1 or more local infusion site 
reactions.
11. Number and proportion of infusions for which the infusion rate was reduced and/or 
the infusion was interrupted or stopped due to intolerability and/or AEs.
12. Rates of systemic and local AEs, regardless of causality, expressed as number of 
events per infusion, per subject, and per subject-year.
13. Rates of causally related systemic and local AEs, expressed as number of events per 
infusion, per subject, and per subject-year.
14. Rates of systemic and local ARs plus suspected ARs, expressed as number of 
events per infusion, per subject, and per subject-year.
15. Number of subjects with an AE(s) that led to discontinuation from study.
16. Number and rate per infusion of moderate or severe AEs that may be a result of 
immune-mediated response to either immunoglobulin, rHuPH20, or other factors as 
defined in Table 12-1 (Section 12.7.11).
17. Number (percentage) of subjects experiencing treatment-emergent local infusion 
site reactions. All local infusion site treatment-emergent AEs are to be reported as 
adverse reactions.
18. Number (percentage) of subjects with treatment-emergent with local tolerability* 
events during the first 8 weeks of open-label Extension study 161505 among 
subjects originally randomized to placebo (no ramp up), versus during the 8 week-
ramp-up period for subjects originally randomized to active HYQVIA in double-
blind Study 161403.
* Subjects for which infusion rate was reduced and/or the infusion was interrupted 
or stopped due to intolerability and/or AEs.
19. Number (percentage) of subjects with local infusion reactions, as a function of 
dosing interval, infusion rate per site, and infusion volume per site.
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20. Number (percentage) of subjects whose anti-hyaluronidase antibody titers rise by 
≥4 fold from the original baseline value from Study 161403 using combined data 
from both studies (161403 and 161505).
8.4.1.2 Immunogenicity
1.
Incidence of binding antibodies to rHuPH20.
2.
Incidence of neutralizing antibodies to rHuPH20.
3.
Number of subjects with a decline of anti-rHuPH20 antibody titers to the antibody 
titer level at baseline in Study 161403 and/or to <160 at the study completion or 
early discontinuation.
4.
For subjects who have >10,000 titer of binding antibodies to rHuPH20: neutralizing 
antibodies and cross reactivity with Hyal-1,2 and 4.
8.4.2 Exploratory Outcomes Measure
8.4.2.1 Exploratory Efficacy-Type Outcomes Measures
1.
Relapse (defined as a worsening of functional disability defined as an increase of 
≥1 adjusted Inflammatory Neuropathy Cause and Treatment [INCAT] disability 
scores in 2 consecutive timepoints, relative to baseline).
2.
 
 
 
 
 
3.
Time to relapse.
4.
Percentage of subjects with change in Rasch-built Overall Disability Scale 
(R-ODS) score by >4 points from baseline.
5.
Change in adjusted INCAT disability score from baseline.
6.
Percentage of subjects with change in hand grip strength score >8 kPa from 
baseline.
7.
Change in Medical Research Council (MRC) sum score from baseline.
8.
Change from baseline in functional impact on everyday tasks as measured by R-
ODS sub-components.
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8.4.2.2 Subject-Reported Outcomes and Health Economics
1.
Short Form-36 (SF-36) scores and changes from baseline over various time periods.
2.
EuroQoL (Quality of Life)-5 Dimensions (EQ-5D-3L) scores and changes from 
baseline over various time periods.
3.
HRU, including days off school/work, unscheduled physician visits, hospitalization, 
and emergency room visits, plus the total number of acute physician visits (office 
and emergency room due to CIDP exacerbation, any CIDP-related issue, any 
cause), over various time periods.
4.
Treatment satisfaction.
5.
Treatment preference.
6.
Subject global impression of change.
8.4.2.3 Other 
1.
Trough serum IgG levels
8.5 Randomization and Blinding
This is a non-randomized, open-label, active treatment clinical study. No comparator is 
planned.
8.6 Study Stopping Rules
There will be no specific stopping rules for this study; however, the study may be 
terminated by the sponsor at any time. The safety of the subjects in this study shall be 
monitored by an external, independent Data Monitoring Committee (DMC) (see 
Section 17.4).
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.
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Storage: rHuPH20 drug product 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.
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.
8.7.2 Preparation and Storage of Pooled Products
Vials of rHuPH20 solution and bag(s) of pooled IGI, 10% solution will be supplied for 
infusions.
The vials of rHuPH20 must be stored under refrigerated conditions (2°C to 8°C or 36°F 
to 46°F). Prior to administration, the vials of rHuPH20 should be taken out of 
temperature-controlled storage to allow for equilibration to room temperature, which may 
take up to 60 minutes. Detailed instructions for transferring rHuPH20 solution into 
syringes for infusion will be provided in infusion manuals.
IGI, 10% for administration are to be prepared using aseptic techniques under controlled 
air environment in accordance with United States Pharmacopeia (USP) guideline 797 or 
its equivalent per regional or institutional standard practices. Administration of the 
pooled products must be completed within 5 days from the time of preparation. Once the 
pooled products are prepared, the infusion must be started within 3 hours from the time of 
preparation. When administration of pooled products will begin more than 3 hours from 
preparation, they must be kept at 2°C to 8°C (36F to 46F). Pooled products should be 
taken out of the temperature-controlled storage before administration to allow for 
equilibration to room temperature. It may take 60 minutes or longer for the pooled
products to reach room temperature. The infusion shall be started no later than 3 hours 
after removal from the temperature-controlled storage.
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In case IGI, 10% solutions for administration have to be prepared using aseptic 
techniques without controlled air environment (Laminar Flow hood) in accordance with 
USP guideline 797 or its equivalent per regional or institutional standard practices and 
within the Pharmacy Manual, the study drug must only be administered to study subjects 
at the study site or by home infusion (as per country regulations) and immediately 
following preparation and after reaching room temperature.
All solutions for infusion must be administered room temperature.
All solutions for infusion will be labeled according to regulatory requirements for clinical 
studies.
8.7.3 Administration
Mode of administration:
rHuPH20 solution and IGI, 10% solution will be administered subcutaneously in a 
sequential order, with IGI, 10% infusion being initiated within approximately 10 minutes 
of completing the infusion of the rHuPH20 solution. 1, 2, or 3 infusion sites may be used.
It is recommended to use a 24G thin-walled, single, bifurcated, or trifurcated SC needle 
set labeled for high flow and a peristaltic infusion pump with variable rate programming 
capability, to infuse both study drugs. 
rHuPH20: One to 3 infusion sites per infusion day are allowed. The infusion rate of 
rHuPH20 may be started at the previous infusion rate tolerated in the 161403 study. 
Infusion rates may be increased as tolerated by the subject and at the discretion of the 
investigator. 
IGI, 10% solution: SC infusion, to be administered via a peristaltic infusion pump with 
programmable infusion rates and infusion volumes in  1 to 3 infusion sites per infusion 
day, with step-wise increases in infusion rate. IGI 10% solution may be administered at 
1, 2, or 3 infusion sites. The recommended site(s) for the infusion of HYQVIA/HyQvia 
are the middle to upper abdomen and thighs.
For the initial 2 infusions, it may be delivered at an infusion rate of 10 to 240 mL/h per 
infusion site for subjects ≥40 kg and 5 to 80 mL/h per infusion site for subjects <40 kg, as 
tolerated bythe subject and/or at the discretion of the investigator. 
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Due to a manufacturer (CME America) recall on the Body Guard 323 pump and pump 
tubing, a replacement pump (for US and CANADA only) will be the Q Core – Sapphire 
pump. 
The Body Guard 323 pump and pump tubing will continue to be used in 
EU/ROW. Details on the infusion parameters with each pump is provided in the 
Investigator Site Infusion Manual.
Prior to subjects being allowed to infuse at these higher infusion rates than specified in 
Infusion Manual in the home setting, this should first be conducted under medical 
supervision in the clinic setting. At high infusion rates above 750 mL/h (if trifurcated 
needle set for 3 infusion sites is used), the pump occlusion alarm may be activated due to 
high back pressure, stopping the pump. If this occurs, then reduce the infusion rate to 
allow proper pump function. These rates should not be exceeded unless the investigator 
determines that higher infusion rates could be attempted and as long as the higher 
infusion rates are attempted under medical supervision in the clinic setting, prior to 
allowing their use in the home setting.
Site of administration: Bifurcated and trifurcated needle sets are to be used for 2 and 
3 infusions, respectively. The recommended site(s) for the infusion of HYQVIA/HyQvia 
are the middle to upper abdomen and the thighs. 
Volume of infusion per site: IGI 10% solution may be administered at 1, 2, or 3 infusion 
sites with a maximum infusion volume of up to 300 mL per infusion site for subjects 
weighing <40 kg, as tolerated. On a given infusion day, the maximum infusion volume 
should not exceed 1200 mL for subjects weighing ≥40 kg or 600 mL for subjects 
weighing <40 kg. One to 3 sites can be used at the discretion of the investigator and 
subject based on tolerability and total IgG dose volume for the individual subject. Should 
the total infusion volume that is to be administered exceed either 1200 mL for subjects 
≥40 kg or 600 mL for subjects <40kg, or exceed the maximum infusion volume a subject 
can tolerate on a given infusion day, then the total dose may be administered over 
multiple days as divided doses a recommended 48 to 72 h apart (eg, Day 1 and Day 3 of a 
given infusion cycle, but left to the investigator’s discretion) to allow the infused fluid to 
be absorbed.
Note: The volume (mL) of infusion solution to be administered will be calculated using 
the subject’s body weight measured at baseline. Adjustment based on body weight 
changes during the course of the study is not planned, however it may be done if deemed 
medically necessary by the investigator (eg, clinically significant body weight change).
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After baseline, for study visits where the subject’s body weight is measured (see 
Table 21-2, Section 21.2 Schedule of Study Procedures and Assessments for detailed 
timepoints), it is to be measured on site using the same scale/instrument throughout the 
study for that individual subject.
At a few selected study sites, subjects may be asked to permit still photographs of the 
infusion sites, which will be used for educational and demonstration purposes, both 
within and external to the study. Only the infusion site will be photographed, and no 
identifying features will be included. The Site Staff will be instructed how to collect the  
still photographs. Subjects who agree will sign a separate consent.
8.7.4 Description of Treatment
Treatment: HYQVIA/HyQvia with rHuPH20
Treatment Period: Until relapse or discontinuation as described in Section 9.3.
Dose: Subjects will continue to receive the same dose and dosing regimen of 
HYQVIA/HyQvia in the Extension Study as the subject’s full dose received in Epoch 1 
of the Phase III pivotal study (Study 161403). All attempts should be made to maintain 
the original infusion schedule for subjects. If a subject receives a dose out of window, the 
dose will still be given prior to the next infusion, if possible. Subjects should return to the 
original planned visit schedule even if an infusion was given out of window.
The study product components of HYQVIA/HyQvia will be administered sequentially. 
SC infusion of rHuPH20 solution at a dose of 80 U/g IgG will be administered first, to be 
followed by SC infusion of IGI, 10% within 10 minutes of completion of the infusion of 
rHuPH20 solution.
8.7.5 Investigational Product Accountability
The investigator/designee (or the central pharmacy, as applicable) will ensure that 
the IP(s) is stored as specified in the protocol and that the storage area is secured, 
with access limited to authorized study personnel. The investigator/designee (or the 
central pharmacy, as applicable) 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 (eg, infusion center or home, as applicable per study 
design). Records will be maintained that include the subject identification code 
(SIC), dispensation date, and amount dispensed. 
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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/designee (or the central pharmacy, as 
applicable) will provide documentation in accordance with the 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 include but are not limited to: 
hospital records, medical records, clinical and office charts, laboratory notes, memoranda, 
subjects' diaries (including electronic diaries and the Infusion Data worksheet) 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 onto the case report from (CRF). 
For additional information on study documentation and CRFs, see Section 18.2. The use 
of subject diaries is described in Section 10.6. 
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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.
Has completed Epoch 1 of Study 161403 without CIDP worsening.
2.
If female of childbearing potential, the subject must have a negative pregnancy test 
at baseline and agree to employ adequate birth control measures (eg, birth control 
pills/patches, intrauterine device, or diaphragm or condom [for male partner] with 
spermicidal jelly or foam) throughout the course of the study.
9.2 Exclusion Criteria
Subjects who meet ANY of the following criteria are not eligible for this study:
1.
Subject has a serious medical condition such that the subject’s safety or medical 
care would be impacted by participation in this Extension Study 
2.
New medical condition that developed during participation in Study 161403 that, in 
the judgment of the investigator, could increase risk to the subject or interfere with 
the evaluation of investigational medicinal product (IMP) and/or conduct of the 
study
3.
Subject is scheduled to participate in another non-Baxalta clinical study involving 
an IP or investigational device during the course of this study
4.
The subject is nursing or intends to begin nursing during the course of the study
5.
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 (with the exception of Study 161403) involving an IP or 
investigational device during the course of this study
6.
The subject is a family member or employee of the investigator
9.3 Withdrawal and Discontinuation
Any subject may voluntarily withdraw (ie, 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 CRF. Assessments to be performed at the termination visit 
(including in cases of withdraw or discontinuation) are described in Section 10.7 and 
Section 21.2.
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Discontinuation (ie, complete withdrawal from study participation) may be due to 
dropout (ie, active discontinuation by subject) or loss to follow-up (ie, 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.
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 the infant up 
to 2 years post-delivery, if feasible. The investigator will record a narrative 
description of the course of the pregnancy and its outcome. (See also 
Section 12.1.2)

The subject begins nursing. IP exposure will be discontinued. The investigator will 
record a narrative description of the course of the infant’s development.

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 10.5) during the course of this 
study.

The subject participates in another clinical study involving an IP or device during 
the course of this study.
Each subject will have the opportunity to receive HYQVIA/HyQvia until approval of 
HyQvia marketing authorization in either US or EU (whichever comes later) unless 1 of 
the following criteria is met:

Early subject discontinuation from treatment or study due to CIDP worsening that 
at the discretion of the investigator would preclude further treatment with IP

Country-specific predetermined date, as may be mandated by regulations.

Sponsor's decision to early discontinue further participation of a subject in the study

Early study termination at the sponsor's discretion, for any reason 

Upon unblinding of study 161403, subjects who did not have CIDP worsening 
while on placebo treatment during Epoch 1 should discuss options regarding 
continued participation in this long-term clinical trial with the investigator.

Subject becomes pregnant during the study.
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10. STUDY PROCEDURES
10.1 Informed Consent and Enrollment
Any patient who provides informed consent (ie, signs and dates the informed consent 
form [ICF] and assent form, if applicable) is considered a subject in the study.
10.2 Subject Identification Code
The following series of numbers will comprise the SIC: protocol identifier (eg, 161505) 
to be provided by the sponsor, 3-digit study site number (eg, 002) to be provided by the 
sponsor, and 3-digit subject number (eg, 003) reflecting the order of providing informed 
consent (ie, signing the ICF). For example, the third subject who signed an ICF at study 
site 002 will be identified as Subject 161505-002003. All study documents (eg, 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 
(eg, 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 CRFs, regardless of 
screening outcome. 
The overall study design is illustrated in Figure 21-1. Details on the procedures to be 
performed at each study visit, including screening (baseline), can be found in 
Section 21.2 Schedule of Study Procedures and Assessments and Section 21.3 Clinical 
Laboratory Assessments.
10.3.1 Screening and Baseline Period
A subject’s eligibility will be determined during at the screening/baseline period.
In order to be eligible to participate in this extension study, subjects must have completed 
Epoch 1 of Study 161403 without CIDP worsening.
For subjects enrolling from Study 161403 Epoch 1, enrollment into the Extension Study 
(signed informed consent) may take place prior to or during the subject’s study 
completion visit in Study 161403. Since the Study 161403 termination visit is to serve as 
the baseline visit for the Extension Study, the informed consent for the Extension Study 
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must be obtained on the day of or prior to conducting the end-of-treatment assessments in 
Study 161403 in order for those assessments to serve as the baseline assessments in the 
Extension Study.
Subject’s eligibility for entrance into the Extension Study must be determined prior to the 
first IP infusion in the Extension Study, which will occur at the next visit (the first 
treatment visit in the Extension Study).
For all subjects, the following procedures will also be performed at baseline:

Medical history

Vital signs as well as weight

Physical exam

INCAT disability score

R-ODS

Hand grip strength

MRC sum score 

SF-36

EQ-5D-3L

HRU

Treatment satisfaction

Treatment preference

AEs

Laboratory assessments as outlined in Table 21-2

Hemoglobin A1C (HbA1C) assessment if required 

Concomitant medications
At least the first 2 infusions should be performed at the site under supervision of the 
investigator/designee for the assessment if the subject is ready for independent infusions. 
Subsequent infusions may be self-administered at home or other suitable location. Details 
are provided in Section 8.2. Infusions that coincide with post-baseline study visits may be 
performed at the site; however, such infusions should be self-administered.
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10.3.1.1 Rescreening
Not applicable.
10.3.2 Treatment Period
During the treatment phase of this extension study, subjects will receive 
HYQVIA/HyQvia in an open-label fashion until approval of HyQvia marketing 
authorization for the treatment of CIDP in either US or EU (whichever comes later) 
unless one of the criteria in Section 9.3 is met. For detailed procedures and assessments, 
see Table 21-1 and Table 21-2.
10.3.2.1 SC Infusion Visits (Including HomeInfusions)
Packaging, labeling, and storage of IPs are described in Section 8.7.1, and preparation 
and storage of pooled IP solutions are described in Section 8.7.2. Route and rate of 
administration are described in Section 8.7.3. Description of treatment, including 
treatment period, doses, and dosage frequency, are detailed in Section 8.7.4.
The number of infusion visits during the SC treatment period will vary across subjects, 
depending on whether their infusion cycles are every 2, 3, or 4 weeks.
Subjects will continue to receive the same dose and dosing regimen of HYQVIA/HyQvia 
in the Extension Study as the subject’s full dose received in Epoch 1 of the Phase III 
pivotal study (Study 161403).
The study product components of HYQVIA/HyQvia will be administered sequentially. 
SC infusion of rHuPH20 solution at a dose of 80 U/g IgG will be administered first, to be 
followed by SC infusion of IGI, 10% within 10 minutes of completion of the infusion of 
rHuPH20 solution.
The first administration in the Extension Study will take place at the subject’s next 
scheduled dosing (every 2, 3, or 4 weeks). The dose will be the same as that administered 
in Study 161403. The first infusion will be at the subject’s full dose; there will be no 
ramp-up of dose.
After the first 12 weeks of treatment in the Extension Study, the dosing interval of 
HYQVIA/HyQvia may be adjusted for subject preference provided that it is safe to do so 
at the investigator’s discretion. If medically necessary, the interval and/or dose may be 
changed at any time, at the investigator’s discretion.
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For each SC infusion on each infusion day, the following infusion-related information 
will be recorded on the Infusion Data worksheet and in the subject’s electronic diary 
(manuals containing detailed instructions will be provided to the sites and subjects):

Date of the infusion

Location of the infusion (eg, study site/infusion center,home)

Start and stop times of the infusion for rHuPH20 solution and the pooled study 
product (IGI, 10%)

Any unplanned infusion rate change(s), infusion interruption(s), and/or 
discontinuation(s), as well as reason(s) for the event(s).
If an infusion is interrupted and restarted after an interruption, the time the 
infusion is interrupted, restarted, and ends, as well as the rate of infusion upon 
restart, will berecorded.

Planned infusion volume (mL) (total of rHuPH20 solution plus the IGI, 10%)

Actual volume infused (mL) (total of rHuPH20 solution plus the IGI, 10%)

Number of infusion sites

Maximum infusion rate tolerated

Length of SC needle used (mm)

Whether a healthcare professional (eg, infusion nurse) was present during the 
infusion

The individual who administered the infusion (subject, caregiver, or nurse)

Any infusion-related interventions performed by the healthcareprofessional 
(eg, infusion nurse) and reason(s) forintervention 

Any AE(s) that occur during or after the infusion

Use of any medications or non-drug therapies to treatAE(s)

Any changes to the subject’s concomitant medications or non-drug therapies
Telephone follow-up will be conducted by the investigator/designee following each 
infusion visit (24 to 72 hours + 1 business day) to monitor for changes in a subject’s 
functional status (according to the same criteria used in Study 161403) and to document 
AEs, concomitant medications, and non-drug therapies, which may have occurred within 
this period after the completion of an infusion (or after the completion of the last day of 
dosing for an infusion that was administered over multiple consecutive days).
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10.3.2.2 Unscheduled Visit for RelapseAssessment
Subjects who relapse (defined as an increase in adjusted INCAT disability score by 
≥1 point relative to the baseline score of this extension study on 2 consecutive INCAT 
assessments) will be discontinued from the extension study.
At any time during the SC treatment period, unscheduled visit(s) to the study site will be 
allowed for subjects who experience CIDP worsening to perform INCAT, R-ODS, hand 
grip strength, and MRC sum scoreassessments.
10.3.3 Study Completion/Early Termination Visit
Subjects may end their active participation in the SC treatment period in 1 of 2 ways. For 
a detailed schedule of study procedures and assessments, see Section 21.2.
1.
Subjects may be requested to complete treatment in the study, which may be as 
soon as the subject participating country gets market authorization for the treatment 
of CIDP in either US or EU (whichever comes later). Study completion 
assessments are to be conducted on the day of the final infusion. This will mark the 
subjects’ completion of the study.
2.
A subject may withdraw their participation in the study or be discontinued from the 
study prior to completing treatment. These subjects will be asked to undergo an 
early termination visit at the study site prior to discontinuation from the study.
10.4 Management of Infusion-Related AEs
It is the investigator’s responsibility to monitor the safety and well-being of the subject 
and to assure that all infusions are conducted in the prescribed and timely manner 
throughout the study, regardless of the location of administration. Subjects and caregivers 
will be provided with information about the typical signs and symptoms of possible AEs 
and when the subject/caregiver should immediately call the investigator or go to the 
emergency room/department for immediate treatment.
The occurrence of certain AEs, such as headache, chills, or body aches, may be reduced 
by slowing the infusion rate.
Any suspicion of allergic, hypersensitivity, or anaphylactic reaction(s) requires 
immediate discontinuation of the infusion and administration of appropriate medical 
treatment in accordance with the local standard of care.
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Any rate reductions, interruptions, or discontinuation of an infusion and, if applicable, 
any medications and/or non-drug therapies used to treat AE(s) must be recorded in the 
appropriate CRF(s). The use of any pre-medication(s) must be recorded in theappropriate 
CRF(s). See Section 10.5.2 for further information about pre-medication prior to SC and 
IV infusions in this study.
10.5 Medications and Non-Drug Therapies 
Steroids are commonly used in clinical practice as one of the first-line therapies for the 
treatment of CIDP. The use of steroids, however, may confound the interpretation and 
analysis of the efficacy outcome measures in this study. Therefore, the guidelines listed 
below concerning the use of steroids in this study are to be followed:

Systemic corticosteroids at doses >10 mg/prednisolone/day or its equivalent are not 
permitted throughout the course of the study if given for worsening of CIDP.

Low-dose systemic corticosteroids (≤10 mg prednisolone/day or its equivalent) are 
permitted; however, the dosage should remain stable unless a change is deemed 
medically necessary.
In the event a change in low-dose systemic corticosteroid dose or the addition 
of a low-dose systemic corticosteroid is necessary during the study, it must be 
approved by the Medical Monitor prior to the addition/change being made, 
whenever possible. It must be determined whether continuing in the study 
may pose increased risk to the subject due to the condition requiring treatment 
and/or whether the condition may impede the subject’s participation in the 
study or confound the results of the study.

Non-systemic corticosteroids (eg, topical, ophthalmic, or inhaled glucocorticoids) 
are allowed at any time before screening and during the course of the study.
Immunomodulatory/immunosuppressive agents (such as azathioprine and 
methotrexate) have been reported to be beneficial and may be considered for use as an 
add-on therapy in clinical practice when the response to corticosteroids, IGIV, or PE is 
inadequate (European Federation of Neurological Societies, 2010). However, clinical 
efficacy of these agents remains to be proven. Nevertheless, to avoid confounding effects 
on the interpretation of the efficacy outcome measures in this study, the use of 
immunomodulatory/immunosuppressive agents during the course of the study is not
permitted.
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PE has been shown to provide short-term clinical benefits in improving neurological 
disability in CIDP. Thus, use of PE during the course of the study is not permitted to 
avoid confounding effect on the interpretation of the efficacy outcome measures in this 
study.
Other medications that are not permitted during the course of the study include the 
following:
Other IgG products
For questions about medications and non-drug therapies that are not listed, please consult 
the Medical Monitor.
10.5.1 Immunizations
Passive transfer of antibodies (such as via IgG treatment) may transiently impair the 
immune responses to live attenuated virus vaccines, such as mumps, rubella, and varicella 
for up to 6 months and for 1 year or more to measles (rubeola). Subjects should be 
instructed that when they are receiving vaccinations that they are to inform the 
immunizing healthcare professional of this potential interaction between IgG treatment 
and vaccinations, and that the subject is receiving IgG therapy. Annual influenza vaccines 
are permitted.
10.5.2 Pre-Medications for Infusion Administration
For subjects who are prone to infusion-related AEs, if the same type of mild-to-moderate, 
non-serious AE(s) expected to be related to infusion (eg, headache, chills, fever, flushing, 
malaise) occur(s) during or after 2 or more infusions, the subject may be pre-medicated 
for subsequent infusion(s) at the discretion of the investigator in accordance with the 
standard of care at the investigative site. Subjects may be pre-medicated with 
acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), antihistamines and/or 
topical corticosteroids. If any of these agents do not adequately prevent the infusion-
related AE(s), consult with the Medical Monitor.
Topical anesthetics (eg, EMLA) may be used if the needle insertion was intolerable in 
prior infusions. Subjects who have a history of using topical anesthetics (eg, EMLA) for 
IV infusions may also use these topical anesthetics for SC infusions.
The use of any pre-medications should be recorded in the appropriate CRF(s).
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10.6 Subject Diary and Patient Reported Outcomes

An electronic subject diary will be provided to each subject at baseline to record the 
following information throughout the study: Occurrence of signs/symptoms 
indicative of AEs

Use of concomitant medications and non-drugtherapies

Infusion records (see Section 10.3.1 and Section 10.3.2.1)

HRU (such as days off school/work, unscheduled physician visits [including urgent 
care visits to see healthcare providers], hospitalizations, and emergency room 
visits). HRU does not include visits and days off from work/school for study-
related outpatient procedures and assessments.

R-ODS

Infusion-related information (see Section 10.3.2.1)
Subjects, caregivers, and/or subjects’ legally authorized representatives will be trained on 
use of the diary. In cases where the subject or the caregiver are not self-administering 
therapy, site staff will have an option in the diary to enter the infusion data only. The 
diary will be provided in electronic format and remain with the subject for the duration of 
the study. The investigator/designee will review the diary data for completeness and 
request missing information periodically and in a timely manner.
Untoward medical 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 for subject-reported data. An 
Infusion Data worksheet will serve as an additional source document. During study 
participation, the investigator has access to the database holding the subject diary data. 
After study closure, the investigator/designee will receive the diary records for their 
subjects, including audit trail records, in PDF format. The third party eDiary vendor data 
will be imported via a validated transfer to Data Management and incorporated via SAS 
into the final SAS data transfers.
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10.7 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 CRF, including: completed, screen failure, AE (eg, death), 
discontinuation by subject (eg, lost to follow-up [defined as 3 documented unsuccessful 
attempts to contact the subject], dropout), physician decision (eg, pregnancy, progressive 
disease, non-compliance with IP/protocol violation(s), recovery), study terminated by 
sponsor, or other (reason to be specified by the investigator, eg, 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 CRF. 
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 21.2
Schedule of Study Procedures and Assessments and Section 21.3 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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10.8 Procedures for Monitoring Subject Compliance
For study procedures that are to be performed under the direct supervision of the 
investigator/healthcare professional (eg, infusion nurse) at the study site or infusion 
center, no separate procedures will be used to monitor subject compliance.
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 (eg, 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-infusionprocedures.
10.9 Alternative Approaches to Study Procedures and Data Collection Due to 
COVID-19 Related Factor
This amendment aims to ensure subject safety, confidentiality, and study integrity in the 
context of healthcare delivery challenges presented by the COVID-19 pandemic. This 
guidance takes references from the FDA Guidance on Conduct of Clinical Trials of 
Medical Products during COVID-19 Public Health Emergency - Guidance for Industry, 
Investigators, and Institutional Review Boards, March 2020, updated 30 August 2021, 
and the EMA Guidance on the Management of Clinical Trials During the COVID-19 
(Coronavirus) Pandemic, Version 3 (28 April 2020).
As the COVID-19 pandemic outbreak may peak in different regions at different times and 
restrictions implemented by local laws and recommendations may vary, any decision on 
procedural changes should be made on a case by case basis following consultation with 
the medical monitor, with patient safety as the priority.
Procedural changes due to COVID-19 may include the following:
1. The subject (or subject’s legal representative on behalf of the subject) may withdraw 
from the study. All attempts will be made to determine the underlying reason for the 
withdrawal and, where possible, the primary underlying reason will be recorded. If a 
subject chooses to withdraw from study participation due to personal concerns 
related to the COVID-19 pandemic (other than a COVID-19-related adverse event), 
this will be specified as the reason for subject withdrawal in the eCRF. This 
approach may apply to screening and randomization failures as well.
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2. Due to COVID-19-related factors, delayed or missing infusions could put a study 
subject at risk of developing CIDP worsening (as defined by ≥1-point increase in 
adjusted INCAT score). The allowable period for treatment COVID-19 related 
treatment lapse is set to 14 days to allow the study subjects to timely switch to 
alternative treatments (such as steroids) that can be more easily administered at 
home settings. In the case where a subject is stable as of 14 days past the scheduled 
infusion date, an additional 7 days may be allowed on a case-by-case basis by the 
Takeda medical monitor (totaling up to 21-day lapse).
3. Alternative study drug delivery to trial participants may be necessary to avoid 
unnecessary patient visits to sites while providing needed study drug. Additional 
study drug may be dispensed during a scheduled study visit or study drug may be 
shipped directly from investigational sites to participants’ residences by a contracted 
logistics provider or distributor in compliance with national laws or temporary 
national emergency measures and Takeda processes.
4. The study site staff may administer the IP and/or collect labs at home, as necessary 
when COVID-19 is at risk at the hospital setting. All infusion visits may be 
conducted at the clinic or by home healthcare visits to extend flexibility to patients 
during the COVID-19 public health emergency. Study drug may be administered by 
a trained health care professional as part of home nursing or home health care. 
Infusion training, infusion material, personal protective equipment, lab kits and tools 
to collect the lab samples will be provided to the subject and the health care 
professional. Home healthcare visits conducted by the study staff will be 
documented in the study records and eCRF.
5. For home healthcare visits managed by the study site, collection of clinical 
laboratory samples may be performed by a delegated qualified health care 
professional who can visit the trial participant’s residence.
6. Unscheduled remote visits via virtual communications (eg, TeleHealth application) 
may be performed as a safety check on subject well-being, as deemed necessary. 
Safety and efficacy assessments may be conducted by phone (e.g., collection of AEs 
and monitoring), video conferencing (Telehealth or Telemedicine, physician), or site 
staff visiting the subject’s residence. All efficacy assessments including the INCAT 
assessment will be performed by appropriately certified or trained staff (as 
applicable). Local visits and telemedicine must comply with national and local laws 
and regulations. The type of alternative visit must be recorded on the eCRF.
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7. In the event a monitor cannot visit the site in a timely manner due to the COVID-19 
pandemic, alternative monitoring approaches such as remote source data verification 
(SDV) or telephone contact may be used to ensure data quality and integrity and 
maintain patient safety. Alternative monitoring approaches should be used only 
where allowed by applicable local regulations and permitted by the IRB/IEC.
8. Subjects who are anxious to travel to the study due to COVID-19 may be offered 
free transportation to the study site at off-hospital hours to conduct infusion visits in 
a safe and isolated section of the clinic. Transfer of study participants to 
investigational sites away from risk zones or closer to their home may be permitted.
9. Missing visits, missing data, alternative visits, and deviations from the protocol-
specified procedures (e.g., not collecting a protocol-specified specimen, such as post 
dose bloodwork) will be recorded as related to COVID-19.
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11. ASSESSMENT OF EFFICACY 
11.1 The Inflammatory Neuropathy Cause and Treatment (INCAT) Disability Scale
The INCAT 10-points disability scale (Hughes et al., 2001) is the most widely used 
assessment tool to measure the functional activity level of patients with CIDP. The 
INCAT disability scale consists of upper and lower extremity components, with a 
maximum of 5 points for the upper extremities (arm disability) and a maximum of 
5 points for the lower extremities (leg disability), which are summed for an overall 
INCAT disability score ranging from 0 to 10 points, where 0 is normal (eg, no upper limb 
problems and walking not affected) and 10 is severely incapacitated (eg, inability to 
move either arm for any purposeful movement and restricted to wheelchair, unable to 
stand and walk a few steps withhelp).
The INCAT disability score is considered to be an effective and responsive tool to assess 
clinical response to treatment in CIDP (Hughes et al., 2008, Merkies et al., 2010).
An adjusted INCAT disability score is the same as the INCAT disability score, with 
the only exception in the exclusion of changes from 0 (normal) to 1 (minor symptoms) 
(or vice versa) in upper limb function since this reflects only a symptomatic change 
and is not considered to be a clinically meaningful change of functional ability 
(Hughes et al., 2008). A ≥1-point change in the adjusted INCAT disability score is 
considered to be a clinically significant response to treatment and has been used as the 
primary efficacy outcome measure in a number of clinical trials in CIDP, including the 
pivotal trials for other IGIV products (Hughes et al., 2008, Léger et al., 2013).
The INCAT disability scale will be administered at the study site by the 
investigator/designee using a validated translated version, as applicable. It is 
recommended that the investigator/designee complete the assessment using the same 
translated version throughout the course of their participation in the study.
In order to reduce the possibility of bias, investigators/designees who perform INCAT
assessments must not have access to information regarding any AE(s) experienced by the 
particular subject they are evaluating. The investigator/designee who administers the 
INCAT to a particular subject should remain constant throughout the study for that
particular subject and should be the same individual that administers the MRC to that 
subject. For detailed administration timepoints, see Section 21.2 Schedule of Study 
Procedures and Assessments.
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11.2 Rasch-Built Overall Disability Scale (R-ODS)
The R-ODS is a patient self-reported, linearly-weighted overall disability scale that was 
specifically designed to capture activity and social participation limitations in patients 
with immune-mediated peripheral neuropathies including CIDP (van Nes et al., 2011).
The R-ODS is composed of 24 items for which subjects are asked to rate their 
functioning (ie, no difficulty, some difficulty, or could not do) related to a variety of 
everyday tasks at the moment of completion. The R-ODS has a high internal/external 
validity, acceptable reliability scores, and high discriminant validity. In a recent 
publication, the R-ODS was reported to be a more responsive scale in capturing clinically 
meaningful changes over time in newly diagnosed or relapsing patients with Guillain 
Barré Syndrome (GBS) and CIDP compared with the widely used ordinal-based INCAT
(Draak et al., 2014).
The R-ODS will be directly recorded in the subject’s electronic diary using a translated 
version, as applicable. It is recommended that the subject completes the assessment using 
the same translated version throughout the course of their participation in the study. For 
detailed administration timepoints, see Section 21.2 Schedule of Study Procedures and 
Assessments.
11.3 Hand Grip Strength
Grip strength, a measure of a subject’s distal strength and upper limb function, is 
commonly used in clinical practice to monitor the subject’s clinical and functional status, 
as well as response to treatment (Merkies et al., 2000). Hand grip strength measurement 
using devices such as a hand dynamometer is of particular relevance in subjects with 
peripheral neuropathies in which distal weakness predominates.
In this study, hand grip strength will be assessed as a measure of motor function using the 
Vigorimeter (Martin, Tuttlingen, Germany), an instrument that is commonly used in 
patients with immune-mediated neuropathies. The instrument has good validity, 
reliability, and responsiveness, and has been shown to capture both meaningful 
improvement and deterioration earlier than the INCAT disability scale.
Hand grip strength will be administered at the study site by the investigator/designee. For 
detailed administration timepoints, see Section 21.2 Schedule of Study Procedures and 
Assessments.
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11.4 Medical Research Council SumScore
The MRC sum score will serve as a measure of muscle strength (Kleyweg et al., 1991).  
To obtain an MRC sum score, the following muscles on each side of the body are 
examined, and the strength of each muscle is rated according to the MRC scale: deltoids, 
biceps, wrist extensors, iliopsoas, quadriceps, and anterior tibialis. The MRC scale ranges 
from 0 to 5, where: 

0 = no visible contraction;

1 = visible contraction without movement of the limb;

2 = movement of the limb but not against gravity;

3 = movement against gravity over (almost) the full range;

4 = movement against gravity and resistance; and,

5 = normal.
All scores from both the left and right side of the body are summed to obtain the MRC 
sum score. The MRC sum score ranges from 0 (paralysis) to 60 (normal strength).
The MRC scale will be administered at the study site by the investigator/designee. The 
investigator/designee who performs the MRC scale evaluation for a particular subject 
should remain constant throughout the study for that particular subject and should be the 
same individual that administers the INCAT to that subject. In order to reduce the 
possibility of bias, investigators/designees who perform MRC scale assessments must not 
have access to information regarding any AE(s) experienced by the particular subject 
they are evaluating. For detailed administration timepoints, see Section 21.2 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 (eg, an abnormal laboratory finding), 
symptom (eg, rash, pain, discomfort, fever, dizziness, etc.), disease (eg, peritonitis, 
bacteremia, etc.), or outcome of death temporally associated with the use of an IP, 
whether or not considered causally related to the IP. 
In accordance with ICH E9, a treatment-emergent adverse event (TEAE) is defined as 
any event not present prior to the initiation of the treatments or any event already present 
that worsens in either intensity or frequency following exposure to the treatments.
12.1.1.1 Serious Adverse Event 
A serious adverse event (SAE) is defined as an untoward medical occurrence that at any 
dose meets one or more of the following criteria:

Outcome is fatal/results in death (including fetaldeath)

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 (ie, 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 beimmediately

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, HAV, HBV,HCV, hepatitis 
E virus (HEV), orB19V
Thromboembolic events (eg, deep vein thrombosis, pulmonary embolism, 
myocardial infarction, cerebrovascular accidents [eg, stroke, transient 
ischemic event])
Hemolytic anemia
Uncomplicated pregnancies, following maternal exposure to IP, are not considered as 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 (SUSAR). 
The event(s) must meet all of the following:

Suspected adverse reaction

Serious

Unexpected

Assessed as related to study treatment
Once determined to meet the criteria for a SUSAR, a SAE should be submitted to 
regulatory agencies expeditiously. 
The reporting of SUSARs is described in Section 12.1.2.3.
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 adverse event is an AE whose nature, severity, specificity, or outcome 
is not consistent with the term, representation, or description used in the Reference 
Safety Information (RSI). “Unexpected” also refers to the AEs that are mentioned in 
the IB and/or prescribing information as occurring with a class of drugs or as 
anticipated from the pharmacological properties of the product but are not 
specifically mentioned as occurring with the particular product under investigation. 
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The expectedness of AEs will be determined by the sponsor using the IB and/or 
prescribing information as the RSI. This determination will include considerations such 
as the number of AEs previously observed, but not on the basis of what might be 
anticipated from the pharmacological properties of a product.
12.1.1.5 Adverse Reactions Plus Suspected AdverseReactions
An AR plus suspected AR is any AE that meets any of the following criteria:

an AE considered by either the investigator and/or the sponsor to be possibly or 
probably related to IP administration, or

an AE that begins during infusion of IP or within 72 hours following the end of IP 
infusion, or

an AE for which causality assessment is missing orindeterminate.
12.1.1.6 Pre-existing Diseases
Pre-existing diseases that are present before entry in to 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
For the purposes of this study, the following non-serious events experienced after the first 
IP exposure are not reportable on the AE CRF, unless otherwise specified; nor will they 
be included in the analysis of AEs:

CIDP relapse or worsening reflective of disease progression and meeting ≥1 point 
increase in the adjusted INCAT disability score will be collected and recorded on 
the appropriate CRF(s).

Infusion site swelling following SC infusion of IGI, 10% solution that is reported 
by subjects will be captured and reported as adverse events. Infusion of a large 
quantity of fluid into the SC space would be expected to cause some degree of 
swelling.

Pre-existing conditions related to hospitalizations and elective surgeries planned 
prior to study entry are not considered SAEs or AEs provided they are documented 
in the subject’s medicalrecords.
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All other AEs from the first IP exposure until study completion/discontinuation date will 
be described on the AE CRF using the medical diagnosis (preferred), or, if no diagnosis 
could be established at the time of reporting the AE, a symptom or sign, in standard 
medical terminology in order to avoid the use of vague, ambiguous, or colloquial 
expressions (see definition in Section 12.1.1). 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 (ie, recovering/resolving, recovered/resolved, 
recovered/resolved with sequelae, not recovered/not resolved, fatal, unknown) and, if 
applicable, action taken (ie, dose increased, dose not changed, dose reduced, drug 
interrupted, drug withdrawn, not applicable, or unknown) will also be recorded on the AE 
CRF. Recovering/resolving AEs will be followed until resolution, medically stabilized, or 
30 days after the study completion/termination visit, whichever comes first. Follow-up 
information will be recorded in the appropriate CRF(s) as applicable unless the database 
has already locked. If the severity rating for an ongoing AE changes before the event 
resolves, the original AE report will be revised (ie, the event will not be reported as a 
separate AE). During the course of any AE, the highest severity rating will be reported. 
Deviations from the protocol-specified dosage (including overdosing, underdosing, 
abuse, and withdrawal) that result in AEs meeting criteria for SAEs, treatment errors 
(including incorrect route of administration, use of an incorrect product, and deviations 
from the protocol-defined dosing schedule), failures of expected pharmacologicalactions, 
and unexpected therapeutic or clinical benefits will be followed with regard to occurrence 
of AEs and/or other observations because these events may be reportable to regulatory 
authorities.
Any pregnancy that occurs after administration of IP will be reported on a Pregnancy 
Report Form. Attempts will be made to follow the subject through completion of the 
pregnancy and the infant up to 2 years 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 after study completion, 
the SAE must be reported on the provided SAE Report Form within 24 hours after 
awareness; no additional reporting on CRFs is necessary.
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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:
1.
Mild

The AE is a transient discomfort and does not interfere in a significant manner 
with the subject’s normal functioning level.

The AE resolves spontaneously or may require minimal therapeutic 
intervention.
2.
Moderate

The AE produces limited impairment of function and may require therapeutic 
intervention.

The AE produces no sequela/sequelae.
3.
Severe

The AE results in a marked impairment of function and may lead to temporary 
inability to resume usual life pattern.

The AE produces sequela/sequelae, which require (prolonged) therapeutic 
intervention.
These severity definitions will also be used to assess the severity of an AE with a study-
related procedure(s), if necessary.
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, eg, 
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 concurrentdrugs
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Is not associated with the IP (ie, does not follow a reasonable temporal 
relationship to the administration of IP or has a much more likely alternative 
etiology)

Unlikely related (either 1 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 ofIP
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
The sponsor will ensure that all relevant information about SUSARs that are fatal or 
life-threatening, as well as all other serious unexpected ARs, are reported to regulatory 
authorities within the timeframes mandated by the applicable regulations (eg, ICH 
Guideline E2A, the European Clinical Trial Directive [2005/28/EC], and Clinical Trial 
Regulation EU No. 536/2014). The sponsor will comply with applicable laws/ 
requirements for reporting SUSARs and all other SAEs to the ECs and investigators.
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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 1 calendar day after the change is implemented. The sponsor will 
also ensure the responsible EC(s) 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 (ie, 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, eg reconstitution difficulty

Missing components

Damage to the product or unit carton

A mislabeled product (eg, potential counterfeiting/tampering)

A bacteriological, chemical, or physical change or deterioration of the product 
causing it to malfunction, present a hazard, or fail to meet label claims
Any NMCs of the product will be documented on an NMC form and reported to the 
sponsor within 1 business day. If requested, defective product(s) will be returned to the 
sponsor for inspection and analysis according to procedures.
12.5 Medical, Medication, and Non-Drug Therapy History
At baseline, 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.
Medical history related to CIDP (such as time of first symptoms and time since diagnosis, 
as available), as well as medication history (eg, use of steroid and/or 
immunomodulatory/immunosuppressive agents) and/or non-drug therapies (eg, PE) 
related to the treatment of CIDP from 6 months (or 3 months for PE) prior to baseline 
throughout the study, will be recorded on the appropriate CRF(s).
All other 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 baseline and other study visits (as described in Table 21-1), 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 baseline, if an abnormal condition is detected, the 
condition will be described on the medical history CRF. At study visits, if a new 
abnormal or worsened abnormal pre-existing condition is detected, the condition will be 
described on the AE CRF. If the abnormal value was not deemed an AE because it was 
due to an error, due to a pre-existing disease (described in Section 12.1.1.6), 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 timepoints, see Section 21.3 Clinical Laboratory Assessments.
12.7.1 Hematology and Clinical Chemistry
The hematology panel will consist of Hgb, hematocrit (Hct), erythrocytes (ie, RBC 
count), and leukocytes (ie, white blood cell [WBC] count) with differential (ie, basophils, 
eosinophils, lymphocytes, monocytes, neutrophils) and platelet counts, as well as 
absolute neutrophil count (ANC), and absolute lymphocyte count.
The clinical chemistry panel will consist of sodium, potassium, chloride, bicarbonate, 
total protein, albumin, alanine aminotransferase (ALT), aspartate aminotransferase 
(AST), total bilirubin, direct bilirubin, alkaline phosphatase (ALP), gamma-glutamyl-
transferase (GGT), lactate dehydrogenase (LDH), creatine phosphokinase (CPK), blood 
urea nitrogen (BUN), creatinine, amylase, lipase, aldolase, and glucose.
Samples for hematology and clinical chemistry assessments will be collected in the 
appropriate matrix as specified in the laboratory manual. With the exception of baseline 
and early termination visits, samples for hematology and clinical chemistry collected 
during the treatment period must be collected prior to IP administration. At any time 
during the study, unscheduled hematology and/or clinical chemistry test(s) may be 
performed as part of AE/safety investigation or may be repeated once in the event of 
abnormalities in test results due to errors.
Hematology and clinical chemistry assessments will be performed at the central 
laboratory following standardized assay procedures.
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12.7.2 Hemolytic Panel
The hemolytic anemia panel will consist of Hgb, 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, and urine hemosiderin. 
The Hgb result obtained from the baseline visit will serve as the baseline Hgb value for 
the duration of the current study. For subsequent tests in the current protocol, if there is a 
reduction in Hgb of 1 g/dL or more compared to baseline Hgb, every effort is to be made 
to perform a hemolytic panel within 72 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.
Hemolytic tests will be performed at the central laboratory or other laboratories as 
appropriate (eg, 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.
12.7.3 Hemoglobin A1C (HbA1C)
Hemoglobin A1C (HbA1C) measurements will be performed only in subjects diagnosed 
with diabetes mellitus. During the study, HbA1C will be measured at baseline, first 
treatment visit, at Weeks 48 and 96, and as deemed medically necessary and at the 
end- of-treatment visit of each treatment period (or during the early termination visit in 
subjects who discontinue early on the study) to monitor glycemic control in these 
subjects.
12.7.4 Serum Iron, Ferritin, and Total Iron Binding Capacity
Serum iron, ferritin, and total iron binding capacity (TIBC) will be monitored every 
12 months and at the end- of-treatment visit. At any time during the study, the iron panel 
may be performed as part of AE/safety evaluation. Serum iron, ferritin, and TIBC tests 
will be performed at the central laboratory.
12.7.5 Viral Serology Tests
The need for HIV and Hepatitis serology should be determined by the PI based 
upon clinical assessment and interval medical history. Serum samples may be 
collected for viral serology testing for HAV antibody, hepatitis B surface antigen
(HBsAg), HCV antibody, and HIV-1/HIV-2 antibody. Additional tests, such as 
hepatitis B surface antibody [HBsAb], hepatitis B core antibody [HBcAb], and/or 
nucleic acid tests, may be performed as considered necessary by the PI. 
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Subjects with immunity to hepatitis B from active vaccination are those with negative 
HBsAg, positive hepatitis B surface antibody [HBsAb], and negative HBcAb. Subjects 
with past infection are defined as those with negative HBsAg, positive HBsAb, and 
positive HBcAb.
Unscheduled serology testing may be performed in the event of suspected hepatitis/HIV 
infection. Any seroconversion result for HBV, HCV, or HIV shall be re-tested and 
additional tests for investigation may be conducted, in particular in the event of absence 
of clear alternative etiology.
See Section 21.3 for detailed sample collection timepoints.
12.7.6 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. Urinalysis should be completed before 
the first IP dose is given.
12.7.7 Pregnancy Test
For female subjects of childbearing potential, a urine pregnancy test will be performed, 
unless a serum pregnancy test is mandatory as specified by local regulatory/institutional 
requirements.
12.7.8 Assessment of Laboratory Values
12.7.8.1 Toxicity Grading Scale
The Common Toxicity Criteria of the Eastern Cooperative Oncology Group (ECOG) 
(Eastern Cooperative Oncology Group, 2006), published by Oken et al., 1982, will be 
used to grade the following laboratory values:

ALP, ALT, AST, BUN, Hgb, lymphocytes, neutrophils, platelet count, serum 
creatinine, serum total bilirubin, and WBC.

Grading for LDH will use the same thresholds as defined for ALT and AST.

Sodium and potassium will be graded using the thresholds taken from 
the World Health Organization (WHO) toxicity grading system 
(World Health Organization, 2003). 
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The laboratory parameters and the corresponding grading scale are provided in 
Section 21.4. The toxicity scale is defined as: 0 = none, 1 = mild, 2 = moderate, 
3 = severe, 4 = life-threatening (U.S.Department of Health and Human Services et al., 
2008).
Laboratory parameters not listed in Table 21-3 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 
appropriate eCRF/laboratory form. For each abnormal laboratory value, the investigator 
will determine whether the laboratory value (except hyaluronidase antibody values) is 
considered clinically significant or not. For clinically significant values, the investigator 
will indicate if the value constitutes a 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 12.1.1.6), 
or is due to another issue that will be specified. If the abnormal value was not clinically 
significant, the investigator will indicate the reason, ie, because it is due to a pre-existing 
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.
12.7.9 Trough Serum IgG
Following baseline assessment, trough serum IgG samples must be collected on the day 
of the site-administered (see Table 21-1) IP administration (or on the first day of IP 
infusion if the IP dose is to be administered as divided doses over multiple days in an 
infusion cycle) just prior to the start of the infusion.
Blood samples are to be collected and processed according to the directions provided in 
the laboratory manual. Each serum sample will be split into duplicate aliquots of 
approximately equal volume, one of which will serve as a retention (back-up) sample.
Total IgG level in serum will be determined using a validated nephelometric assay 
method at a specialty laboratory.
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12.7.10 Anti-rHuPH20 Antibodies
The potential for immune response to rHuPH20 will be monitored in all subjects who 
have received rHuPH20 administration. Serum samples for the detection of anti-
rHuPH20 binding and neutralizing antibodies will be collected at baseline, Weeks 12, 24, 
36, 48, 60, 72, 84, and 96, and every 12 weeks, and at the Study Completion/Termination
Visit.
Blood samples for the detection of anti-rHuPH20 binding neutralizing antibodies will be 
collected and processed according to the directions provided in the laboratory manual. At 
each collection timepoint, serum samples will be collected into separate tubes labeled for 
binding antibodies and neutralizing antibodies. Each will then be split into duplicate 
aliquots of approximately equal volume, one of which will serve as a retention (back-up) 
sample. All subjects will be monitored for the formation of anti-rHuPH20 antibodies 
using validated anti-rHuPH20 antibody detection assay (ADA) (also known as the 
Screening and Confirmatory Binding Assay). Samples with antibody titers ≥1:160 will be 
analyzed for the presence of neutralizing antibodies using a validated assay based on 
neutralization of rHuPH20 activity. Samples with rHuPH20-binding antibody titers 
>10,000 titer will be tested for cross reactivity with Hyal-1, 2 and 4.
12.7.11 Immunogenicity Panel
At baseline (Week 0 predose) of the pivotal Phase III Study 161403, samples had to be 
collected for the following tests to be conducted: 50% hemolytic complement activity of 
serum (CH50), serum complement component 3 (C3), serum complement component 
4 (C4), C1q binding assay, and circulating immune complex (CIC) Raji cell assay.
At any time during the course of the extension study, subjects who have (a) 2 consecutive 
anti-rHuPH20 antibody titers of ≥1:160 that are elevated from the subject’s baseline 
titers, and (b) a moderate or severe AE that may be a result of immune-mediatedresponse 
to either immunoglobulin, rHuPH20, or other concomitant medications (see Table 12-1) 
will be asked to return to the study site as soon as possible to undergo an additional panel 
of testing outlined in Table 12-2.
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Table 12-1
List of Conditions/Symptoms That May be a Result of Immune-Mediated Response 
to Either Immunoglobulin, rHuPH20, or Other Factors
Allergic reactions
•
Urticaria
•
New-onset bronchospasm
•
Oedema of tongue, lips, face(angioedema)
•
Anaphylaxis
•
Stevens-Johnson syndrome
•
Erythema multiforme
•
Toxic epidermal necrolysis
Immune complex mediated reactions – Local
•
Induration/nodule at the site of administration that persists for more than 48hours
•
Excessive inflammation at the site of administration - severe redness,heat, swelling, and/or pain
•
Tissue necrosis/ulceration at the site of administration
•
Dystrophic or fibrotic changes at the site of administration
•
Pigmented skin changes at the site of drug administration
Immune complex mediated reactions – Systemic
•
Arthritis
•
Vasculitis (purpuricrash)
•
Glomerulonephritis - hematuria, red cell casts in urine, progressive renal dysfunction
Table 12-2
Immunogenicity Panel
1.
Repeat test for anti-rHuPH20 binding antibody titers
2.
Test (or repeat test, as applicable) for the presence of neutralizing anti-rHuPH20 antibodies
3.
Assessment of cross reactivity to human HYAL1, HYAL2, and HYAL4
- only for subjects whose anti-rHuPH20 binding antibody titer exceeds 1:10,000
4.
Hematology panel with manual differential (see Section 12.7.1)
5.
Clinical chemistry panel (see Section 12.7.1)
6.
CH50
7.
Serum C3
8.
Serum C4
9.
C1q binding assay
10.
CIC Raji cell assay
11.
Blood draw for additional testing as necessary
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Blood samples are to be collected and processed according to the directions provided in 
the laboratory manual. The tests should be performed at the central laboratory and/or 
specialty laboratories as appropriate.
12.7.11.1 Guidance on Reporting and Assessing rHuPH20 antibody test results
All hyaluronidase antibody test results (titers, and binding or neutralizing) will be 
assessed for clinical significance by the investigator in the electronic data capture (EDC) 
database but are not to be reported as AEs. 
For AEs occurring during the SC infusion of hyaluronidase the investigator and sponsor 
will independently assess relatedness, also taking into account quantitative and qualitative 
test results for hyaluronidase antibodies.
For AEs occurring upon or after subsequent SC infusion of the immunoglobulin 
component an assessment of causality is confounded by the presence of the consecutively 
administered IMPs. The overlap is transient due to the short half-life of hyaluronidase of
about 30 minutes in the SC space. The investigator and sponsor will independently 
evaluate the relatedness of an AE to one or the other component during this period.
12.7.12 Back-up Samples and Biobanking
Back-up samples should be taken and stored appropriately for repeat or additional 
analysis, if necessary. These samples may be used short-term for re-testing, further 
evaluation of an AE, or follow-up of other test results. The following samples are 
planned:

Serum IgG samples (back-up aliquots)

Anti-rHuPH20 binding antibody samples (back-up aliquots)

Anti-rHuPH20 neutralizing antibody samples (back-upaliquots)
Baseline and end-of-trial serum/plasma back-up samples will be stored for possible 
testing of pathogens for no more than 2 years after the final study report has been 
completed.
Other back-up samples that remain after study testing is done may be stored and used for 
additional testing (eg, further evaluation of an abnormal test, investigation of an AE or 
suspected seroconversion). Samples will be stored in a coded form for no more than 
2 years after the final study report has been completed and subsequently the samples will 
be destroyed. The need for HIV and hepatitis serology should be determined by the PI 
based upon clinical assessment and interval medical history. For detailed sampling 
timepoints, see Table 21-2.
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12.8 Vital Signs
Vital signs will include body temperature (°C or °F), respiratory rate (breaths/minute), 
pulse rate (beats/minute), and resting systolic and diastolic blood pressure (mmHg). 
Blood pressure will be measured when subjects are in the supine/sitting position. Vital 
signs will be measured at baseline, periodically at each infusion visit, and at study 
completion/early termination visit (See Section 21.2 Schedule of Study Procedures and 
Assessments detailed collection timepoints).
For the initial 2 SC infusions, vital signs are to be monitored and recorded at any time 
prior to infusion, in the event of occurrence of AE(s), and within 60 minutes of 
completion of an infusion. During subsequent infusion visits, vital signs will be taken 
only in the event of an AE that occurs during an infusion and when a healthcare 
professional (eg, infusion nurse) is present to take the measurements. In these cases, vital 
signs will be taken at the onset of an AE (or as soon as the AE is reported) and within 
60 minutes of completion of an infusion. Additional vital signs may be taken as deemed 
medically necessary to monitor the AE. Subjects/caregivers will be instructed that if a 
healthcare professional is not present at an infusion and the subject experiences an AE 
necessitating stopping of the infusion, the subject/caregiver should immediately contact 
the investigator or go to the emergency room/department.
Body height (in or cm) will be obtained from the baseline visit in Study 161403. Weight 
(lb or kg), as well as body mass index (BMI), will be collected at baseline of Study 
161505. Subsequently, body weight will be re-measured every 24 weeks and in the event 
of clinically significant change in body weight (see Section 21.2 for detailed 
measurement timepoints). All body weight measurements are to be taken at the study site 
using the same scale/instrument throughout the study for that individual subject. 
Subject’s self-reported weights will not be used at any time during the course of the 
study.
Vital sign values are to be recorded on the appropriate CRF. For each abnormal vital sign 
value, the investigator will determine whether or not 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.
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13. OTHER ASSESSMENTS
13.1 Short Form-36 Health Survey
Quality of life measures are useful in assessing the relative burden of disease as well as 
the degree to which treatment has made a difference in the well-being of an individual. 
The SF-36 health survey will be utilized to assess changes in HRQOL and functional 
health (Ware et al., 2000). The SF-36 health survey is a standardized, validated 
instrument designed to be self-administered by subjects aged 14 years and older and is 
composed of items grouped into 8 domains. The domains reflected in the physical 
component summary score (PCS) are physical functioning, role-physical, bodily pain, 
and general health. The domains captured in the mental component summary score 
(MCS) include social functioning, role- emotional, vitality, and mental health.
The SF-36 health survey 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 detailed 
administration timepoints, see Section 21.2 Schedule of Study Procedures and 
Assessments.
13.2 EuroQoL (Quality of Life)-5 Dimensions (EQ-5D-3L)
The EQ-5D is a validated, self-administered assessment of overall health designed by 
the EuroQol Group, 1990. 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-3L 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 detailed administration 
timepoints, see Section 21.2 Schedule of Study Procedures and Assessments. 
13.3 Health Resource Utilization
The HRU items will assess subjects’ utilization of health services such as days off from 
school/work, unscheduled physician visits (including urgent care visits to see healthcare 
providers), hospitalizations, and emergency room visits. HRU does not include visits and 
days off from school/work for study-related outpatient procedures and assessments.
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The HRU items will be directly recorded in the subject’s electronic diary on an ongoing 
basis during the study. If a translated version is used, it is recommended that the subject 
complete the assessment using the same translated version throughout the course of the 
study. For detailed administration timepoints, see Section 21.2 Schedule of Study 
Procedures and Assessments.
13.4 Abbreviated Treatment Satisfaction Questionnaire for Medication(TSQM-9)
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 detailed administration 
timepoints, see Section 21.2 Schedule of Study Procedures and Assessments.
13.5 Treatment Preference
The treatment preference questionnaire 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 
detailed administration timepoints, see Section 21.2 Schedule of Study Procedures and 
Assessments.
13.6 Patient Global Impression of Change
The Patient Global Impression of Change (PGIC) scale is a single item recorded at study 
completion/termination that evaluates the subject’s perspective on whether or not they 
have improved since the beginning of treatment. The PGIC is used as an ‘anchor’ in the 
determination of clinically meaningful change. Subjects rate their perception of 
improvement or deterioration since the beginning of treatment on a 7-point scale ranging 
from “very much worse” to “very much improved”.
The PGIC scale will be completed using a translated version, as applicable. It is 
recommended that the subject complete the item using the same translated version 
throughout the course of the study.
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14. STATISTICS
Detailed statistical analysis methods will be described in the statistical analysis plan 
(SAP).
14.1 Sample Size and Power Calculations
Not applicable. This study is an extension to Study 161403. As indicated in Section 7.1, 
the purpose of this study is to assess the long-term safety, tolerability, and 
immunogenicity of HYQVIA in subjects with CIDP who have completed Study 161403 
Epoch 1 without CIDP worsening. Enrollment in Study 161505 is open to subjects 
who have completed Study 161403 Epoch 1 without CIDP worsening and who have 
provided informed consent. 
 
 
 
 
 
14.2 Datasets and Analysis Cohorts
Safety Set: The Safety (SAF) analysis set will include all subjects who are enrolled in the 
Extension Study and received at least one dose of study medication. This will be the 
primary analysis set for all safety analyses. Descriptive analyses based on the Safety Set 
that are to be presented by treatment received during Study 161403 Epoch 1.
14.3 Handling of Missing, Unused, and Spurious Data
Missing or incomplete AE start/stop dates, relationship to study medication, severity, and 
seriousness will be imputed. Missing or partial AE start dates will be imputed for the 
purpose of determining treatment emergence. If an AE start date is completely missing, 
the AE will be considered treatment-emergent in the extension study. If a partial AE start 
date is supplied, then the later of (1) the first infusion date in the Extension Study or (2) 
the earliest date that is consistent with the available data will be used as an imputed start 
date for determining treatment emergence. If an AE has a missing causality assessment, 
the relationship of the AE to treatment will be counted as “related”. If an AE has a 
missing severity assessment, the severity will be imputed as “unknown”, except that if the 
subject also had a severe AE categorized under the same preferred term, then the AE of 
unknown severity will be imputed as a severe AE. Events of unknown seriousness will be 
tabulated as SAEs; however, every effort will be made to avoid data lock with events for 
which a determination of seriousness remains missing. The Medical Monitoring Plan 
presents details of how this effort will be executed.
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If an infusion record is completely missing, or the planned infusion date cannot be 
determined from the recorded data, then the infusion will be imputed as “Not done”. 
Otherwise, any infusion that has some amount of recorded data will be assumed to have 
been completed, unless the available data indicate otherwise. If the infusion dose level is 
missing, it will be imputed as unchanged from the previous infusion. If an infusion start 
date and/or time is missing or incomplete, a date and time of infusion will be imputed.
Missing antibody data will be imputed as “No new development of antibodies”. No 
specific values will be imputed for quantitative summaries.
Missing INCAT assessments that pertain to determination of relapse status will be 
imputed as “No relapse”.
Missing Ig trough levels will not be imputed for any quantitative analysis.
Missing or incomplete start and stop dates for prior/concomitant medications and non-
drug therapies will be imputed to support determination of prior and concomitant 
medication status.
Missing or incomplete assessment dates (or date-times if needed to support calculations) 
will be imputed for time to event analyses.
The SAP will provide more detailed imputation rules for the handling of missing and 
incomplete dates and times of assessments and events.
Clinical laboratory values that contain non-numeric values due to assay results that were 
above or below the limit of quantitation will be imputed at the upper or lower limit of the 
assay, respectively, if needed for any analysis.
Data will not be imputed in any quantitative summaries by timepoint or visit. Both 
scheduled and unscheduled assessments will be used in all event-based analyses (relapse, 
occurrence of AEs, etc.). Unscheduled visit data will not be used in any “by-visit” 
descriptive summaries.
Data such as (but not limited to) laboratory tests that were not specified for collection in 
the protocol will be reviewed on a case-by-case basis for handling decisions during the 
study. Full documentation of data related to subject safety will be the primary 
consideration in establishing how such data will be handled.
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Data points that appear to be spurious (eg, outliers, values incompatible with life) will be 
queried and either corrected or explained, if possible. Outliers will not be excluded from, 
or identified in, any analysis unless otherwise specified. Any data points that are specified 
for exclusion will be documented in table footnotes or cross-referenced to an appropriate 
listing.
14.4 Methods of Analysis
Analysis of all outcome measures in this non-comparative study will focus on estimation 
and descriptive statistics overall for all subjects in the SAF analysis set. There are no 
statistical hypotheses to be tested and no planned statistical testing. However, results may 
be presented by 161403 Epoch 1 actual treatment and overall, where applicable.
Continuous measures will be summarized using the number of subjects in the sample (n), 
mean, standard deviation (SD), median, minimum, and maximum. Categorical outcomes 
will be summarized using the number and percentage of subjects. Event rates will be 
estimated in several different ways, depending on the outcome measure, as explained in 
the remainder of this section. All collected data will be listed or provided in Clinical Data 
Interchange Standards Consortium (CDISC)-compliant datasets.
14.4.1 Primary Outcome Measure
14.4.1.1 Safety/Tolerability
Clinically important treatment-emergent abnormalities in vital signs, laboratory 
assessments, and physical examination results will be reported as AEs. All AEs will be 
coded using Medical Dictionary for Regulatory Activities (MedDRA) version 18.1 
(Sep 2015) and reported by body system (ie, MedDRA system organ class), preferred 
term, and treatment received in the previous study (Study 161403).
All analyses of AEs will be performed using data from the SAF analysis set. All TEAEs, 
SAEs, ARs/suspected ARs, AEs that could be related to possible immune-mediated 
responses to one or more study medication components, AEs that are temporally related 
to infusion, and other subsets of AEs will be reported using (1) the number and 
percentage of subjects who experienced a particular type of event at any time during the 
study, (2) the number and rate of reports of a specified type of event per subject-year of 
time at risk, and/or (3) the number and rate of reports of a specified type of event per
infusion.
Any ongoing TEAE that occurred during Study 161403 will be reported in the 
continuation study as medical history. If this specific ongoing AE becomes worse after 
the first infusion in the continuation study, this AE will be reported as a new TEAE. 
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All AEs that occur after the last infusion in Study 161403 and before the first infusion in 
the continuation study will be reported as a new TEAE and analyzed based on the 
treatment in the Study 161403.
Note that infusion site swelling following SC infusion of IGI, 10% or 0.25% albumin 
placebo solution that is reported by subjects will be captured and reported as adverse 
events.
The purpose of examining all TEAEs without regard to causality is to identify any 
potential new signals that may arise. The following summaries of all TEAEs are planned:
1.
The number and percentage of subjects who had any TEAE, any serious TEAE, any
TEAE leading to early withdrawal, any TEAE with onset during and within 
72 hours after infusion, any moderate or severe TEAE, any localized TEAE, any 
moderate or severe localized TEAE, or any TEAE leading to death will be 
summarized in a single table.
2.
The number and percentage of subjects who had a TEAE, serious TEAE, TEAE 
leading to early withdrawal, TEAE that occurred in >5% of subjects, or TEAE that 
occurred during or within 72 hours after infusion will be summarized overall and 
by treatment, MedDRA system organ class, and preferred term in a separate table 
for each specified group ofevents.
3.
The total number of reports, and event rates expressed as number of events (reports) 
per infusion, per subject, and per subject-year of time at risk, willbe summarized 
overall and by treatment, MedDRA system organ class, and preferred term in 
separate tables for all TEAEs, serious TEAEs, and TEAEs that occurred during and 
within 72 hours after infusion.
4.
The number and percentage of subjects with TEAEs will be summarized in 
descending order of overall frequency.
5.
The number and percentage of subjects with TEAEs will be summarized overall 
and by treatment, MedDRA system organ class, preferred term, and maximum
severity.
6.
The number of reports of TEAEs that occurred during and within 72 hours after 
infusion will be summarized overall and by treatment, MedDRA system organ 
class, preferred term, and severity.
7.
The number and percentage of subjects with treatment-emergent local infusion site 
reactions and number of reports of reactions will be summarized overall and by 
treatment. Note: All local infusion site treatment-emergent AEs are to be reported 
as adverse reactions. 
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8.
The number and percentage of subjects with local infusion reactions, as a function 
of dosing interval, infusion rate per site, and infusion volume per site, will be 
summarized overall and by treatment.
9.
The number and percentage of subjects whose anti-hyaluronidase antibody titers 
rise by ≥ 4 fold from the original baseline value from Study 161403 using 
combined data from both studies (161403 and 161505) will be summarized, and 
such rises will be correlated with TEAEs using descriptive statistics.
The purpose of examining ARs/suspected ARs is to obtain a clear picture of AEs that are 
recognized as causally related to the study medication. The following summaries of ARs 
and suspected ARs are planned:
1.
The number and percentage of subjects who had any AR/suspected AR, any serious 
AR/suspected AR, an AR/suspected AR leading to early withdrawal, an 
AR/suspected AR with onset during or within 72 hours after infusion, any moderate 
or severe AR/suspected AR, any localized AR/suspected AR, any moderate or 
severe localized AR/suspected AR, or any AR/suspected AR leading to death will 
be summarized overall and by treatment in a single table.
2.
The number and percentage of subjects who had an AR/suspected AR, serious 
AR/suspected ARs, AR/suspected AR leading to early withdrawal, AR/suspected 
AR that occurred in >5% of subjects, or AR/suspected AR that occurred during or 
within 72 hours after infusion will be summarized overall and by treatment, 
MedDRA system organ class, and preferred term in separate tables for each 
specified group ofevents.
3.
The total number of reports of ARs/suspected ARs, and the event rates expressed as 
number of events (reports) per infusion, per subject, and per subject-year of time at 
risk, will be summarized overall and by treatment, MedDRA system organ class, 
and preferred term in separate tables for all ARs/suspected ARs, serious 
ARs/suspected ARs, and ARs/suspected ARs that occurred during and within 72 
hours afterinfusion.
4.
The number and percentage of subjects with ARs/suspected ARs will be 
summarized overall and by treatment and preferred term, in descending order of 
overall frequency.
5.
The number and percentage of subjects with ARs/suspected ARs will be 
summarized overall and by treatment, MedDRA system organ class, preferred term, 
and maximum severity.
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The number of reports of ARs/suspected ARs that occurred during and within 72 hours 
after infusion will be summarized overall and by treatment, MedDRA system organ class, 
preferred term, and severity. A single table that includes all temporally associated TEAEs 
(regardless of causality) and all AEs that are causally related but not temporally 
associated will be generated to support the product insert. The table will include the 
number and percentage of subjects, and the number of reports, for each relevant type of 
event.
14.4.1.2 Tolerability
The number and percentage of infusions in which the infusion rate is reduced and/or the 
infusion is interrupted or stopped due to intolerability and/or AEs will be reported for all 
AEs and both local and systemic AEs.
In addition, the local tolerability* during the first 8 weeks of  open-label study 161505 
among subjects originally randomized to placebo (no ramp up), versus during the 8 week-
ramp-up period for subjects originally randomized to active HYQVIA in double-blind 
study 161403 will be summarized.
*In terms of number and percentage of subjects for which infusion rate was reduced 
and/or the infusion was interrupted or stopped due to intolerability and/or AEs.
Note: AE implies TEAE. 
14.4.1.3 Immunogenicity
The development and course of immunogenicity will be described by the number and 
percentage of subjects who meet each of the following criteria: (1) subjects who have 
binding and/or neutralizing antibodies to rHuPH20, (2) subjects who have rHuPH20 
antibody titers that decline toward normal (<160) during continuous exposure to 
rHuPH20, (3) subjects who have a >10,000 titer of binding antibodies to rHuPH20: 
neutralizing antibodies and cross reactivity with Hyal-1,2 and 4. All immunogenicity 
analyses will be performed on the SAF analysis set.
14.4.2 Exploratory Outcome Measures 
14.4.2.1 Exploratory Efficacy
Exploratory efficacy analyses will be presented for the SAF analysis set. 
Subject relapse rates will be characterized by 6-month and cumulative relapse rates 
at the end of each consecutive 6-month study period and at the end of the study, as 
well as a Kaplan-Meier estimate of the median time to relapse. Point estimates 
and appropriate two-tailed, 95% confidence intervals will be provided. 
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Subject relapse is defined as a worsening of functional disability, as indicated by an 
increase of ≥1 adjusted INCAT disability scores in 2 consecutive timepoints relative to 
baseline score of this extension study.
Scores and changes from baseline in R-ODS, adjusted INCAT disability, hand grip 
strength, a pre-specified subset of R-ODS, and MRC sum will be summarized by visit, 
using basic descriptive statistics. The percentage of subjects whose R-ODS scores change
from baseline by ≥4 points, and the percentage of subjects whose hand grip strength score 
changes from baseline by ≥8 kPa, will also be reported. Baseline will be defined as the 
score at the study completion (end-of-SC treatment) visit in Study 161403.
14.4.2.2 Subject-Reported Outcomes and HealthEconomics
The SF-36 section scores, the EQ-5D-3L, Visual Analog Scale (VAS) scores, Treatment 
Satisfaction (TSQM-9) scores, and their respective changes from baseline will be 
summarized by visit using descriptive statistics for continuous data.
The EQ-5D-3L item scores, Treatment Preference results, and PGIC scores will be 
summarized by the number and percentage of subjects who gave each possible response.
Information collected on the HRU form includes days off school/work, unscheduled 
physician visits, hospitalization, and emergency room visits. These events plus the total 
number of acute physician visits (office and emergency room visits due to CIDP 
exacerbation, any CIDP-related issue, any cause) will be summarized over various time 
periods (pre-SC to end of Extension Study, baseline Extension Study to end of Extension 
Study). The number and percentage of subjects who experienced each of these types of 
events during the Extension Study will be reported. Descriptive statistics for the number 
of events of each type will be presented for subjects who experienced each event.
14.4.2.3 Trough Serum IgG Levels
Trough plasma concentrations of IgG will be summarized and based on the SAF set, 
using the sample size, mean, SD, median, minimum, maximum, geometric mean, and SD 
of the geometric mean.
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14.5 Planned Interim Analysis of the Study
An interim analysis is planned to be performed based on an interim data cut-off to occur 
within 30 days after the last subject in study 161403 had its last visit in Epoch 1. The data 
are planned to be included in future regulatory submissions. Data to be analyzed 
descriptively will include but may not be limited to:

Number of subjects with arelapse

Time to relapse

Percentage of subjects with change in R-ODS score by >4 points from baseline

Change in adjusted INCAT disability score from baseline

Percentage of subjects with change in hand grip strength score by >8 kPa from 
baseline

Change in MRC sum score from baseline

Cumulative treatment-emergent serious and non-seriousAEs

Rates of causally related systemic and local AEs, expressed as number of events per 
infusion, per subject, and persubject-year

Infusions for which the infusion rate was reduced and/or the infusionwas 
interrupted or stopped due to intolerability and/or AEs, for both local and systemic
AEs

Anti-rHuPH20 binding and neutralizing antibodytiters

Any relevant information that may support safetyevaluation
No corrections for multiplicity will be applied as this interim analysis is of a purely 
descriptive nature. In addition to the interim analysis, Study 161505 safety data available 
at time of data freeze for Study 161403 interim safety analysis (details in study protocol) 
will be analyzed descriptively, in order to assess the long-term safety of HYQVIA.
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15. 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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16. QUALITY CONTROL AND QUALITY ASSURANCE
16.1 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 Clinical Trial 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.
16.1.1 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.
16.2 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.
16.3 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.
16.4 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.
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16.5 Non-Compliance with the Protocol
The investigator may deviate from the protocol only to eliminate an apparent immediate 
hazard to the subject. In the event(s) of an apparent immediate hazard to the subject, the 
investigator will notify the sponsor immediately by phone and confirm notification to the 
sponsor in writing as soon as possible, but within 1 calendar day after the change is 
implemented. The sponsor (Baxalta) will also ensure the responsible EC 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.
16.6 Laboratory and Reader Standardization
Inter-laboratory standardization methods will be described in the data management plan 
as needed. A standardization program will be implemented to provide standardized 
training to raters and to monitor inter-rater reliability as part of the clinical quality 
assurance program. Clinical assessments (eg, INCAT, hand grip strength, MRC sum 
score) will be conducted in accordance with standardized procedures.
All required training and certification for specified study assessments will be documented 
in a training plan that will include the responsibilities of the sponsor/designee and the 
process of certification for the specified study assessments.
Laboratory assessments will be performed at a central laboratory using standardized 
procedures. Measurements of trough serum IgG levels and anti-rHuPH20 antibodies will 
be performed at the respective specialty laboratories.
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17. ETHICS
17.1 Subject Privacy
The investigator will comply with applicable subject privacy regulations/guidance as 
described in the CTA.
17.2 Ethics Committee and Regulatory Authorities
Before patients participate in this study, the protocol, ICF, 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), 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.
17.3 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 ICF before 
entering into the study according to applicable national and local regulatory requirements 
and ICH GCP. Before use, the ICF will be reviewed by the sponsor and approved by the 
EC and regulatory authority(s), where applicable (see Section 17.2). The ICF 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 ICF, subjects 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 ICF, after 
approval by the applicable EC and regulatory authorities will be provided by the 
investigator to the subjects who consented to participate in the study.
17.4 Data MonitoringCommittee
This study will be monitored by an external, independent DMC. The DMC is a group of 
individuals with pertinent expertise that reviews, on a regular basis, accumulating data 
from an ongoing clinical study. For this study, the DMC will be composed of recognized 
experts in the fields of immune-mediated neuropathy clinical care and research, 
IG/antibody therapy, and/or clinical immunogenicity assessments of therapeutic proteins, 
all of whom who are not participating in this study. The DMC may recommend to stop 
the study if it finds toxicities or if treatment is proven to be not beneficial.
The DMC will be responsible for reviewing the data obtained in the study, including (but 
not necessarily limited to) SAEs, AEs, clinically significant abnormal laboratory test 
results, anti-rHuPH20 antibody data, and any relevant information that may have an 
impact on the safety of the participants or the ethics of the study. 
The membership, responsibilities, interactions, and operations of the DMC will be 
detailed in the DMC Charter.
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18. DATA HANDLING AND RECORD KEEPING
18.1 Confidentiality Policy
The investigator will comply with the confidentiality policy as described in the CTA. 
18.2 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 
ICFs, correspondence with the EC and the study monitor/sponsor, baseline information, 
CRFs, SAE reports (SAERs), laboratory reports (if applicable), and data clarifications 
requested by the sponsor.
The investigator will comply with the procedures for data recording and reporting. Any 
corrections to paper study documentation must be performed as follows: 1) the first entry 
will be crossed out entirely, remaining legible; and 2) each correction must be dated and 
initialed by the person correcting the entry; the use of correction fluid and erasing are 
prohibited.
The investigator is responsible for the procurement of data and for the quality of data 
recorded on the CRFs. CRFs will be provided in electronic form.
If electronic format CRFs are provided by the sponsor, only authorized 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 18.3).
The handling of data by the sponsor, including data quality assurance, will comply with 
regulatory guidelines (eg, 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.
18.3 Document and Data Retention 
The investigator will retain study documentation and data (paper and electronic forms) in 
accordance with applicable national and local regulatory requirements and the document 
and data retention policy, as described in the CTA.
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19. FINANCING AND INSURANCE
The investigator will comply with investigator financing, investigator/sponsor insurance, 
and subject compensation policies, if applicable, as described in the CTA.
20. PUBLICATION POLICY
The investigator will comply with the publication policy as described in the CTA. 
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21. SUPPLEMENTS
21.1 Study Flow Chart
Figure 21-1
Study Flow Chart for Study 161505
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21.2 Schedule of Study Procedures and Assessments
Table 21-1
Schedule of Study Procedures and Assessments
Procedures/ 
Assessments
Termination 
Visit Study 
161403/
Baseline Visit 
in Extension 
Studya
First 
Treatment 
Visit in 
Extension 
Study
Interval Study Visits
Study 
Completion/ 
Termination 
Visit
Unscheduled 
Visit
Week
-4, -3, -2
0
+4,
+3,
+2b
12
24
36
48
60c
72c
84c
96 and every 
12 Wksc
Country 
Dependent
Any
Informed Consentd
X
Eligibility Criteria
X
Medical History
X
Body Weight
X
Every 24 weeks and in the event of clinically significant change in body weight
Infusione
Every 2, 3, or 4 weeksf
Vital Signs
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical Exam
X
X
X
X
X
X
X
X
X
X
X
X
INCAT Disability 
Score
X
Xk
Xk
Xk
Xk
Xk
Xk
Xk
Xk
X
X
Hand Grip Strength
X
Xk
Xk
Xk
Xk
Xk
Xk
Xk
Xk
X
X
MRC
Sum Score
X
Xk
Xk
Xk
Xk
Xk
Xk
Xk
Xk
X
X
R-ODS
X
Xk
Xk
Xk
Xk
Xk
Xk
Xk
Xk
X
X
SF-36
X
X
X
X
Every other 
visit (ie, every 
24 weeks)
X
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Table 21-1
Schedule of Study Procedures and Assessments
Procedures/ 
Assessments
Termination 
Visit Study 
161403/
Baseline Visit 
in Extension 
Studya
First 
Treatment 
Visit in 
Extension 
Study
Interval Study Visits
Study 
Completion/ 
Termination 
Visit
Unscheduled 
Visit
Week
-4, -3, -2
0
+4,
+3,
+2b
12
24
36
48
60c
72c
84c
96 and every 
12 Wksc
Country 
Dependent
Any
EQ-5D
X
X
X
X
Every other 
visit (ie, every 
24 weeks)
X
HRU
X
X
X
X
X
X
X
X
X
X
X
X
Treatment 
Satisfaction
X
X
X
X
Every other 
visit (ie, every 
24 weeks)
X
Treatment Preference
X
X
X
X
Every other 
visit (ie, every 
24 weeks)
X
PGIC
X
Adverse Eventsj
X
X
X
X
X
X
X
X
X
X
X
X
X
Post-Infusion 
Telephone Follow-upj
Every 2, 3, or 4 weeks (24 to 72 hours + 1 business day after each infusion visit)
Laboratory 
Assessmentg
X
Xa
X
X
X
X
X
X
X
X
X
X
Xh
HbA1Ci
X
X
X
X
X
Concomitant 
Medicationsj
X
X
X
X
X
X
X
X
X
X
X
X
X
Continued on Next Page
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Continued
Abbreviations: EQ-5D=EuroQoL (Quality of Life)-5 Dimensions; HbA1C=hemoglobin A1C; HRU=Health Resource Utilization; INCAT=Inflammatory 
Neuropathy Cause and Treatment disability scale; MRC=Medical Research Council; PGIC=Patient Global Impression of Change scale; R-ODS=Rasch-
built Overall Disability Scale; SF-36=Short Form-36 health survey.
a
To occur in conjunction with Termination Visit in Study 161403 except for Urinalysis. This test requires an additional sampling since it is not part of the 
Termination Visit in Study 161403. If another assessment is not available at a termination visit, it will be performed at the first infusion visit.
b ±5 days.
c
Study visits should occur approximately 4 times per year (approximately every 12 weeks±5 days) but do not need to coincide with an infusion.
d Occurs at prior to baseline. If assessments at End of Study Visit in Study 161403 are to be used as baseline for the Extension Study, then informed 
consent must be obtained on the day of or prior to conducting the end-of-treatment assessments in Study 161403.
e
The first 2 infusions will be conducted at the investigator’s site. Subsequent infusions may be self-administered at an infusion center or other suitable
location. For details, see Section 8.2. Infusions that coincide with post-baseline study visits may be performed at the site; however, such infusions should 
be self-administered.
f
Subjects will continue to receive HYQVIA/HyQvia infusions every 2, or 3, or 4 weeks (±3 days) following the schedule of their previous study. All
attempts should be made to maintain the original infusion schedule for subjects. If a subject receives a dose out of window, the dose will still be given
prior to the next infusion, if possible. Subjects should return to the original planned visit schedule if an infusion was given out of window.
g For laboratory assessments, see Section 21.3 below.
h As required
i
During the study, HbA1C will be measured for subjects with diabetes mellitus at baseline, first treatment visit, at Weeks 48 and 96 and as deemed 
medically necessary.
j
Telephone follow-up will be conducted by the investigator/designee following each infusion visit (after 24h but within 72 h + 1 business day) to monitor 
for changes in a subject’s functional status and to document AEs, concomitant medications, and non-drug therapies, which may have occurred within 
this period after the completion of an infusion (or after the completion of the last day of dosing for an infusion that was administered over multiple 
consecutive days).
k To be performed prior to the start of the infusion
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21.3 Clinical Laboratory Assessments
Table 21-2
Clinical Laboratory Assessments
Assessments
Termination Visit 
Study 161403/
Baseline Visit in 
Extension Studya
First Infusion 
Visit
Interval/Study Visits
Study Completion/ 
Termination Visit
Unscheduled 
Visit
Week
-4, -3, -2
0
+4,
+3,
+2
12
24
36
48
60b
72b
84b
96 and 
every 
12 wksb
Country Dependent
Any
Hematologyc
X
X
X
X
X
X
X
X
X
X
X
Xd
Clinical 
Chemistrye
X
X
X
X
X
X
X
X
X
X
X
Xd
Serum iron, 
ferritin, and TIBC
X
X
X
X
Xd
Urinalysisf
X
X
X
X
X
X
X
Xd
Pregnancy Test–
Urine
X
X
X
X
X
X
Xd
Viral Pathogen 
Serology
Xd
Xd
Xd
Serum IgGg
X
X
X
X
X
X
X
X
X
X
Xd
Binding 
Antibodies to 
rHuPH20h
X
X
X
X
X
X
X
X
X
X
Xd
Neutralizing 
Antibodies to 
rHuPH20i
X
X
X
X
X
X
X
X
X
X
Xd
Hemolysis Panelj
Xk
Xk
Xk
Xk
Xk
Xk
Xk
Xk
Xk
Xk
Xd,k
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Continued
Abbreviations: Hgb=hemoglobin; IgG=immunoglobulin G; IP=Investigational Product; rHuPH20=recombinant human hyaluronidase; 
TIBC=total iron binding capacity.
a
To occur in conjunction with termination visit in Study 161403 except for urinalysis. This test requires an additional sampling since it is not part of the 
termination visit in Study 161403. If another assessment is not available at a termination visit, it will be performed at the first infusion visit.
b
Study visits should occur approximately 4 times per year (approximately every 12 weeks ±5 days) but do not need to coincide with an infusion.
C
Hematology assessments: complete blood count (hemoglobin, hematocrit, erythrocytes [i.e., red blood cell count], and leukocytes [ie, white blood cell
count]) with differential (ie, basophils, eosinophils, lymphocytes, monocytes, neutrophils) and platelet counts. In addition, absolute neutrophil counts 
and lymphocyte counts will bedetermined.
d
As optional: The need for HIV and Hepatitis serology should be determined by the PI based upon:
• Clinical assessment and interval medical history.
e
Clinical chemistry assessments: sodium, potassium, chloride, bicarbonate, total protein, albumin, alanine aminotransferase, aspartate aminotransferase, 
bilirubin, alkaline phosphatase, blood urea nitrogen, creatinine, creatine phosphokinase, gamma-glutamyl-transferase, amylase, lipase, aldolase, lactate 
dehydrogenase, and glucose.
f
Urinalysis assessments: protein, glucose, blood, bilirubin, urobilinogen, specific gravity, pH, color, ketones, nitrite, leukocyte esterase, and microscopic
analysis.
g
To be collected before the administration of Investigational Product (IP) at that visit (if IP administration is scheduled), for trough levels.
h
In some subjects with high anti-rHuPH20 antibodies and who consent to participate, additional assessments for further evaluation of safety may be
performed.
i
In the event of an antibody titer of 1:160 or greater.
j
Hemolysis Panel: The hemolytic anemia panel will consist of hemoglobin (Hgb), lactate dehydrogenase, 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. The hemolytic anemia panel be conducted only in the event of a drop in Hgb of 1 g/dL or more compared to baseline value.
k 
The Hgb result obtained from the baseline visit in the Extension Study will serve as the baseline Hgb value for the duration of the Extension Study. In 
the event of a drop in Hgb of 1 g/dL or more compared to previous Hgb, every effort is to be made to perform a hemolytic panel within 72 hours. At 
any time during the study, an unscheduled hemolytic panel may be performed in the event of suspected hemolytic anemia.
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21.4 Toxicity Grading Scale for Laboratory Values
Table 21-3
Grading of Laboratory Parameters
Analyte
Direction WNL is 
Grade 0
No 
Grade 1
Units
Grade 0a
Grade 1a
Grade 2a
Grade 3a
Grade 4a
Source
Low
High
Low
High
Low
High
Low
High
Low
High
ALP
Increase
YES
NO
ULN
.
.
.
2.5
2.6
5.0
5.1
20
20.1
.
ECOG
ALT
Increase
YES
NO
ULN
.
.
.
2.5
2.6
5.0
5.1
20
20.1
.
ECOG
AST
Increase
YES
NO
ULN
.
.
.
2.5
2.6
5.0
5.1
20
20.1
.
ECOG
LDH
Increase
YES
NO
ULN
.
.
.
2.5
2.6
5.0
5.1
20
20.1
.
N/A
BUN
Increase
NO
NO
ULN
0.0
1.4
1.5
2.5
2.6
5.0
5.1
10
10.1
.
ECOG
Hemoglobin
Decrease
YES
NO
g/dL
.
.
.
10.0
8.0
9.9
6.5
7.9
0.0
6.4
ECOG
Lymphocytes Decrease
NO
NO
x10^3/uL 2.0
.
1.5
1.9
1.0
1.4
0.5
0.9
0.0
0.4
ECOG
Neutrophils
Decrease
NO
NO
x10^3/uL 2.0
.
1.5
1.9
1.0
1.4
0.5
0.9
0.0
0.4
ECOG
Platelet Count Decrease
YES
NO
x10^3/uL .
.
.
75.0
50.0
74.9
25
49.9
0.0
24.9
ECOG
Potassium
Decrease
NO
NO
mmol/L
3.5
.
3.0
3.4
2.5
2.9
2.0
2.4
0.0
1.9
WHO
Potassium
Increase
NO
NO
mmol/L
0.0
5.5
5.6
6.0
6.1
6.5
6.6
7.0
7.1
.
WHO
Serum 
Creatinine
Increase
YES
NO
ULN
.
.
.
1.4
1.5
3.0
3.1
6.0
6.1
.
ECOG
Sodium
Decrease
NO
NO
mmol/L
136
.
130
135
123
129
116
122
0.0
115
WHO
Sodium
Increase
NO
NO
mmol/L
0.0
145
146
150
151
157
158
165
166
.
WHO
Serum Total 
Bilirubin
Increase
YES
YES
ULN
.
.
.
.
.
1.4
1.5
3.0
3.1
.
ECOG
WBC
Decrease
NO
NO
x10^3/uL 4.0
.
3.0
3.9
2.0
2.9
1.0
1.9
0.0
0.9
ECOG
Continued on Next Page
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Continued
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
The toxicity scale is defined as: 0 = none, 1 = mild, 2 = moderate, 3 = severe, 4 = life-threatening (U.S.Department of Health and Human Services et 
al., 2008). Grading scale criteria taken fromECOG (Eastern Cooperative Oncology Group, 2006) 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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21.5 Contraceptive Methods for Female Subjects of ChildbearingPotential
No clinical studies have been conducted with GAMMAGARD LIQUID/KIOVIG or 
HYQVIA/HyQvia in pregnant women.
Animal reproduction studies have not been conducted with GAMMAGARD 
LIQUID/KIOVIG (IGI 10%) and IGI 10% component of HYQVIA/HyQvia. It is also not 
known whether IGI 10% can cause fetal harm when administered to a pregnant woman or 
can affect reproduction capacity. However, clinical experience with immunoglobulins 
suggests that no harmful effects of IGI 10% on fertility are to be expected.
Development and reproductive toxicology studies have been conducted with rHuPH20 in 
mice and rabbits. No adverse effects on pregnancy were associated with anti-rHuPH20 
antibodies. In these studies, maternal antibodies to rHuPH20 were transferred to offspring 
in utero. The effects of antibodies to the rHuPH20 component of HYQVIA on the human 
embryo or on human fetal development are unknown.
In this study, subjects who are women of childbearing potential must agree to utilize a 
highly effective contraceptive measure throughout the course of the study and for 30 days 
after the last administration of IP. In accordance with the Clinical Trial Facility Group 
(CTFG) recommendations related to contraception and pregnancy testing in clinical trials 
(version 2014-09-15) (Clinical Trial Facilitation Group (CTFG), 2014), birth control 
methods that may be considered as highly effective include the following:

Combined (estrogen- and progestogen-containing) hormonalcontraception 
associated with inhibition of ovulation:
oral
intravaginal
transdermal

Progestogen-only hormonal contraception associated with inhibition of ovulation:
oral
injectable
implantableii

Intrauterine device (IUD) ii

Intrauterine hormone-releasing system (IUS)ii
                                                
ii Contraception methods that are considered to have low user dependency
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
Bilateral tubal occlusionii

Vasectomized partner(s)ii

Sexual abstinence during the entire study period
Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal 
(coitus interruptus), spermicides only, and lactational amenorrhoea method (LAM) are 
not acceptable methods of contraception. Female condom and male condom should not 
be used together.
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22. SUMMARY OF CHANGES
In this section, major changes from the previous version of the protocol, 
dated 2019 AUG 05, are described and their rationale is given.
1.
Protocol Title Page, Protocol Signature Page
Description of Change: Sponsor entity and sponsor information changed
Purpose of Change:  Administrative update of sponsor information.
2.
Section 2
Description of Changes: Serious Adverse Event Reporting description changed.
Purpose of Change: Administrative error in the protocol template update.
3.
Synopsis, Section 6.3, Section 8.2
Description of Change: target accrual updated to 88  throughout the protocol.
Purpose of Change: The pivotal trial (study 161403) was closed to recruitment on 
August 17, 2021. As of December 3, 2021, a total of 121 subjects completed the 
pivotal study and 77 of them rolled over into the extension study (161505). There 
are 11 ongoing subjects in the pivotal study with potential to roll over into the 
extension study. Hence, a maximum of 88 subjects are expected to be enrolled into 
the extension study
4.
Synopsis, Section 7.3, Section 8.4.2.1, Section 14.4.2.1
Description of Change: Addition of exploratory objective: To evaluate 
improvement in functional impact on everyday tasks as measured by a pre-specified 
subscore of R-ODS
Purpose of Change: to provide a more patientcentric assessment of treatment 
benefit.
5.
Synopsis, Section 8.4.1.1
Description of Change: Safety/ Tolerability outcome measures description changed 
Purpose of Change: The wording of the safety/tolerability outcome measures was 
changed to align with safety/tolerability outcome measures in 161403 study 
protocol.
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6.
Synopsis, Section 8.4.2.1
Description of Change: clarification of definition of CIDP worsening defined as 
≥8 kPa decrease in the mean hand grip strength in the ‘most affected hand’ instead 
of ‘one hand’ 
Purpose of Change: to align with the changes in the 161403 study protocol.
7.
Synopsis, Section 8.7.3
Description of Change:  Change that the Site will be instructed how to collect the 
still photographs. 
Purpose of the change: To avoid having a third party to collect the still 
photographs. The site staff will take the still photographs.
8.
Synopsis, Section 8.7.3
Description of Change: Mode of Administration description wording changed to 
clarify type of pump used for the study and infusion parameter are referenced in the 
study Site Infusion Manual.
Purpose of Change: The addition of the Q Core pump was necessary due to the US 
recall of the BodyGuard  323 pump.
9.
Synopsis, Section 14
Description of Change:

Added additional information as to maximum enrollment based on actual accrual 
and relapse rate in study 161403.

Clarify throughout the section that analyses will be presented by actual treatment 
received in Study 161403 Epoch 1 and overall, where applicable.

Removed “subgroup” from “treatment subgroup” to align with 161403 study 
protocol.

Update the planned interim analysis timing.

Clarify that no correction for multiplicity will be applied as this interim analysis 
is of purely descriptive nature. 
Purpose of Change: 
Maximum enrollment updated to reflect actual accrual and relapse rate in study  
161403. Addition of analyses will be presented by actual treatment received in 
study 161403 and overall to provide clarification. Update planned interim analysis 
timing to support regulatory submission.
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10.
Synopsis, Section 14.5
Description of change: Timing of planned interim data cut-off was changed to 
occur within 30 days after the last subject in study 161403 had its last visit in 
Epoch 1 instead of six months of database lock of 161403.
Purpose of change: The sponsor will submit available data from this study with the 
planned regulatory submission of the final results of the 161403 pivotal study.
11.
Section 10.9
Description of Change: Added a new section ‘Alternative Approaches to Study 
Procedures and Data Collection Due to COVID-19 Related Factor’ to address 
possible impact of COVID-19 pandemic on operational details such as site visits 
for subjects/study staff, IP administration at home, laboratory sample collection at 
home, remote visits via virtual communication etc. 
Purpose of Change:  to reflect changes made in response to the COVID-19 
pandemic.
12.
Sections 13.2 and 14.4.2
Description of Changes: EQ-5D was replaced by EQ-5D-3L.
Purpose of Change: To clarify that EQ-5D-3L version of EQ-5D has been used in 
the study for data capture and analysis. 
13.
Table 21-1
Description of Change: footnotes and description h, i, j, k changed
Purpose of Change: Correction of misalignment in prior amendment 3, 
2019 Aug 05, addition of footnote k in alignment with 161403 study protocol.
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McMillan, R. 2000. The pathogenesis of chronic immune (idiopathic) thrombocytopenic 
purpura. Semin Hematol, 37, 5-9.
Mehndiratta, M. M. & Hughes, R. A. 2012. Plasma exchange for chronic inflammatory 
demyelinating polyradiculoneuropathy. Cochrane Database Syst. Rev, 9,
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M., Simpson, D. M., Parry, G. J., Rivner, M. H., Thornton, C. A., Bromberg, M. 
B., Tandan, R., Harati, Y., Giuliani, M. J. & Working Group on Peripheral 
Neuropathy 2001. Randomized controlled trial of IVIg in untreated chronic 
inflammatory demyelinating polyradiculoneuropathy. Neurology, 56, 445-449.
Merkies, I. S., Schmitz, P. I., Samijn, J. P., Meche, F. G., Toyka, K. V. & van Doorn, P. 
A. 2000. Assessing grip strength in healthy individuals and patients with immune-
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Merkies, I. S., van Nes, S. I., Hanna, K., Hughes, R. A. & Deng, C. 2010. Confirming the 
efficacy of intravenous immunoglobulin in CIDP through minimum clinically 
important differences: shifting from statistical significance to clinical relevance. J 
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& Ochs, H. D. 2009. Subcutaneous immunoglobulin: Opportunities and outlook. 
Clin Exp Immunol, 158 Suppl 1, 51-59.
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Mygland, A. & Monstad, P. 2001. Chronic polyneuropathies in Vest-Agder, Norway. Eur 
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Tamburin, S., Macchia, R., Cavaletti, G., Giannini, F., Sabatelli, M. & IMC Trial 
Group 2012. Intravenous immunoglobulin versus intravenous methylprednisolone 
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the American Academy of Neurology. Neurology, 78, 1009-1015.
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Rosen, F. S., Cooper, M. D. & Wedgwood, R. J. 1995. The primary immunodeficiencies. 
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Rosenfeld, E. A., Shulman, S. T., Corydon, K. E., Mason, W., Takahashi, M. & Kuroda, 
C. 1995. Comparative safety and efficacy of two immune globulin products in 
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egulatoryInformation/Guidances/Blood/ucm078526.pdf
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Kuitwaard, K., Faber, C. G. & Merkies, I. S. J. 2011. Rasch-built Overall 
Disability Scale (R-ODS) for immune-mediated peripheral neuropathies. 
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van Schaik, I. N., Eftimov, F., van Doorn, P. A., Brusse, E., van den Berg, L. H., Van der 
Pol, W. L., Faber, C. G., van Oostrom, J. C., Vogels, O. J., Hadden, R. D., Kleine, 
B. U., van Norden, A. G. W., Verschuuren, J. J. G. M., Dijkgraaf, M. G. W. & 
Vermeulen, M. 2010. Pulsed high-dose dexamethasone versus standard 
prednisolone treatment for chronic inflammatory demyelinating 
polyradiculoneuropathy (PREDICT study): a double-blind, randomised, 
controlled trial. Lancet Neurol, 9, 245-253.
van Schaik, I. N., Winer, J. B., de Haan, R. & Vermeulen, M. 2002. Intravenous 
immunoglobulin for chronic inflammatory demyelinating 
polyradiculoneuropathy: A systemic review. Lancet Neurol, 1, 491-498.
Ware, J. E., Kosinski, M. & Dewey, J. E. 2000. How to score version 2 of the SF-36®
Health Survey. Lincoln, RI.
Wolin, M. J. & Gale, R. P. 1997. IVIG in bone marrow transplantation. In: Lee, M. L. & 
Strand, V. (eds.) Intravenous Immunoglobulins in Clinical Practice. First Edition 
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World Health Organization 2003. Toxicity grading scale for determining the severity of 
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_06_2003%20final.pdf
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22. SUMMARY OF CHANGES
Protocol 161505: Amendment 3: 2019 AUG 05
Replaces: Amendment 2: 2018 NOV 14
In this section, major changes from the previous version of the protocol, 
dated 2018 NOV 14, are described and their rationale is given.
1.
Throughout the document
Description of Change: Minor grammatical and/or administrative changes that do 
not substantively affect the study conduct or subject safety have been made; also, 
references have been updated.
Purpose for Change: To improve the readability and/or clarity of the protocol.
2.
Synopsis, Section 8.4.1.1, Section 14.4.1.1, Section 14.4.1.2  
Description of Change: Addition of Outcome Measure in Primary Outcome 
Measures under Safety/Tolerability. Included local infusion site reactions to be 
reported as AEs.
Purpose for Change: To address the feedback received from FDA on 19 Jun 2019.
3.
Synopsis, Section 8.4.2.3, Section 14.4.2.3
Description of Change: Addition of “Other” Outcome Measure in Exploratory 
Outcome Measures - measurement of serum trough IgG levels.
Purpose for Change: It was inadvertently not included in the previous versions and 
added in this version to maintain consistency with study 161403.
4.
Synopsis, Section 9.3
Description of Change: Addition of “pregnancy” to list of reasons why subject 
would not receive HYQVIA/HyQvia until approval 
Purpose for Change: It was inadvertently not included in the previous versions and 
added in this version to maintain consistency with study 161403. 
5.
Sections 12.1.2, 14.4.1
Description of Change: It was added that infusion site swelling following SC 
infusion of IGI, 10% or 0.25% albumin placebo solution that is reported by subjects 
will be captured and reported as adverse events.
Purpose of Change: To maintain consistency with study 161403.
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6.
Section 10.3.1, 12.7.3, Table 21-1, footnote ‘h’.
Description of Change: Hemoglobin A1C (HbA1C) measurements will be 
performed only in subjects diagnosed with diabetes mellitus. 
Purpose of Change: To reflect administrative updates; to improve the readability 
and/or clarity of the protocol.
7.
Section 14.5 
Description of Change: An interim analysis is planned to be performed 6 months 
after unblinding of Study 161403 (unblinding of Epoch 1) and the data are planned 
to be included in future regulatory registrations. 
Purpose of Change: To address the feedback received from FDA on 19 Jun 2019. 
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22. SUMMARY OF CHANGES
Protocol 161505: Amendment 2: 2018 NOV 14
Replaces: Amendment 1: 2016 JUN 27
In this section, major changes from the previous version of the protocol, dated 
2016 JUN 27, are described and their rationale is given.
1.
Throughout the document
Description of Change: Minor grammatical, operational, and/or administrative 
changes that do not substantively affect the study conduct or subject safety have 
been made, which are not individually listed.
Purpose for Change: To reflect administrative updates; to improve the readability 
and/or clarity of the protocol.  Other minor changes have been made to align with 
the current protocol template and for consistency with applicable revised text in the 
recent Study 161403 Amendment 3 (31 January 2018), and to reflect updates to 
expected enrollment.
2.
Throughout the document
Description of Change: All references to Study 161601 have been deleted, which 
are not individually listed in this Summary of Changes.
Purpose for Change: Study 161601 is no longer a source for this extension study.
3.
Throughout the document
Description of Change: All references to the “HYQVIA/HyQvia Pregnancy 
Registry” have been deleted.
Purpose for Change: This registry has been closed; pregnancies will continue to be 
handled and reported using the standard safety reporting processes.
4.
Synopsis, (PLANNED STUDY PERIOD)
Description of Change: Correction made to the following text:
Primary Completion
Dependent on approval of HYQVIA/HyQvia in countries 
participating in study. This is expected to be no later than end of 
2021.
Study Completion
Dependent on approval of HYQVIA/HyQvia in countries 
participating in study. This is expected to be no later than end of 
2021.
Duration
Dependent on approval of HYQVIA/HyQvia in countries 
participating in study; total study duration (first subject in to last 
subject out): 5.5 years maximum (2.5 years maximum treatment 
per subject, or up to 3 years if mandated by regulations)
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corrected to:
Primary Completion
Dependent on approval of HYQVIA/HyQvia in countries 
participating in study. This is expected to be no later than end of 
2021.
Study Completion
Dependent on approval of HYQVIA/HyQvia in countries 
participating in study. This is expected to be no later than end of 
2021.
Duration
Dependent on approval of HYQVIA/HyQvia in countries 
participating in study. ; total study duration (first subject in to last 
subject out): 5.5 years maximum (2.5 years maximum treatment 
per subject, or up to 3 years if mandated by regulations)
Purpose for Change: The expected duration of the study has been revised 
upwards.
5.
Synopsis, (Planned Duration of Subject Participation); 
Section 8.3 (Duration of Study Periods and Subject Participation); 
Section 9.3 (Withdrawal and Discontinuation); 
Section 10.3.2 (Treatment Period)
Description of Change: Correction made to the following text:
Planned Duration of 
Subject Participation
Each subject will have the opportunity to receive 
HYQVIA/HyQvia for a maximum of 2.5 years unless one of the 
following criteria is met:
1.
Early subject discontinuation from treatment or study due to 
CIDP worsening that, at the discretion of the investigator, 
would preclude further treatment with IP
2.
Country-specific predetermined date, as may be mandated by 
regulations. This can be earlier than 2.5 years or later (up to 
3 years) (eg, United Kingdom [UK], Israel)
3.
Sponsor’s decision to early discontinue further participation 
of a subject in the study
4.
Early study termination at the sponsor’s discretion, for any 
reason
5.
Early discontinuation for subjects who did not have CIDP 
worsening while on placebo treatment during Epoch 1 in Study 
161403 will be offered HYQVIA/HyQvia following 
unblinding of Study 161403 treatment allocation 
6.
Subject becomes pregnant during the study
corrected to:
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Planned Duration of 
Subject Participation
Each subject will have the opportunity to receive 
HYQVIA/HyQvia until approval of HyQvia marketing 
authorization for the treatment of CIDP in either US or EU 
(whichever comes later) for a maximum of 2.5 years unless one 
of the following criteria is met:
1. Early subject discontinuation from treatment or study due to 
CIDP worsening that, at the discretion of the investigator, 
would preclude further treatment with IP
2. Country-specific predetermined date, as may be mandated by 
regulations. This can be earlier than 2.5 years or later (up to 3 
years) (eg, United Kingdom [UK], Israel)
3. Sponsor’s decision to early discontinue further participation of 
a subject in the study
4. Early study termination at the sponsor’s discretion, for any 
reason
5. Upon unblinding of study 161403, subjects who did not have 
CIDP worsening while on placebo treatment during Epoch 1 
should  discuss options regarding continued participation in 
this long-term clinical trial with the investigator
6. Subject becomes pregnant during the study
Purpose for Change: Correction and clarification. The expected duration of the 
study was revised upwards.  Point number 5 was re-worded to clarify the conduct 
of the study.
6.
Synopsis, (INVESTIGATIONAL PRODUCT(S), DOSE AND MODE OF 
ADMINISTRATION)
Description of Change: Revised text as follows:
“Mode of Administration: SC infusion, to be administered via a peristaltic infusion 
pump with programmable infusion rates and infusion volumes at 1 to 3 infusion 
sites per infusion day, with step-wise increases in infusion rate. IGI 10% solution 
may be administered at 1, 2, or 3 infusion sites.  The recommended site(s) for the 
infusion of HYQVIA/HyQvia are the middle to upper abdomen and thighs.
…
For tThe initial 2 infusions, are given it may be delivered at an infusion rate of 
10 to 240 mL/h per infusion site for subjects ≥40 kg and 5 to 80 mL/h per infusion 
site for subjects <40 kg, as tolerated by the subject and/or at the discretion of the 
investigator.
…
Prior to subjects being allowed to infuse at these higher infusion rates in the 
home setting, this should first be conducted under medical supervision in the 
clinic setting.
…
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The recommended site(s) for the infusion of HYQVIA/HyQvia are the middle to 
upper abdomen and thighs. These rates should not be exceeded unless the 
investigator determines that higher infusion rates could be attempted as long as the 
higher infusion rates are attempted under medical supervision in the clinic setting, 
prior to allowing their use in the home setting.
One to 3 sites can be used at the discretion of the investigator and subject 
based on tolerability and total IgG dose volume for the individual subject.
IGI, 10% solution may be administered at 1 or 2 infusion sites with a 
maximum infusion volume of up to 600 mL per infusion site for subjects 
weighing ≥40 kg. If using 3 infusion sites, the maximum is 400 mL/site since on 
any given infusion day, the maximum infusion volume should not exceed 
1200 mL for subjects weighing ≥40 kg.
IGI 10% solution may be administered at 1 or 2 infusion sites with a 
maximum infusion volume of up to 300 mL per infusion site for subjects 
<40 kg, as tolerated. If using 3 infusion sites, the maximum is 200 mL/site since 
on any given infusion day, the maximum infusion volume should not exceed 
600 mL for subjects weighing <40 kg.
If a subject’s IgG dose per kg of body weight on a given day exceeds 
1.3 g/kg/day or exceeds the SC maximum infusion volume the subject can 
tolerate, not to exceed 1200 mL/day, the HYQVIA/HyQvia dose may be 
administered over multiple days as divided doses with 48 to 72 hours 
recommended between doses (eg, Day 1 and Day 3 of a given infusion cycle, 
but left to the investigator’s discretion) to allow absorption of infusion fluid at 
infusion site(s).
IGI, 10% solution may be administered at 1, 2, or 3 infusion sites with a maximum 
infusion volume of up to 300 mL per infusion site for subjects weighing <40 kg, as 
tolerated. On a given infusion day, the maximum infusion volume should not 
exceed 1200 mL for subjects weighing ≥40 kg or 600 mL for subjects weighing 
<40 kg. One to 3 sites can be used at the discretion of the investigator and subject 
based on tolerability and total IgG dose volume for the individual subject. Should 
the total infusion volume that is to be administered exceed either 1200 mL for 
subjects ≥40 kg or 600 mL for subjects <40kg, or exceed the maximum infusion 
volume a subject can tolerate on a given infusion day, then the total dose may be 
administered over multiple days as divided doses 48 to 72 h apart (eg, Day 1 and 
Day 3 of a given infusion cycle) to allow the infused fluid to be absorbed.”
Purpose for Change: For consistency within the protocol body and to align with 
pivotal Study 161403.
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7.
Synopsis, Section 8.4.2 (Exploratory Outcome Measures)
Description of Change: Pharmacokinetic and administration-related outcomes 
deleted.  
Purpose for Change: Not applicable to this study. 
8.
Synopsis, Section 8.7.3 (Administration)
Description of Change: 
Revised rHuPH20 administration text to clarify that the initial infusion rate is to 
carry over from Study 161403.  Added text to clarify that the recommended 
intervals between divided doses were optional and that this was to be left to the 
investigator’s discretion.  Revised text to align between synopsis and body.
9.
Synopsis, Section 8.7.3 (Administration)
Revised text: 
rHuPH20:
One to 3 infusion sites per infusion day are allowed. The initial 2 SC infusions are 
given at an The infusion rate of 60 to 120 mL/h per infusion site (or a total of 120 
to 240 mL/h, or a total of 180 to 360 mL/h over 2 and 3 sites, respectively). 
Bifurcated and trifurcated needle sets are to rHuPH20 may be used for 2 and 3 
infusion sites, respectively. For subsequent administrationsstarted at the previous
infusion rate tolerated in the 161403 study. Infusion rates may be increased as 
tolerated by the subject and at the discretion of the investigator, but not to exceed 
300 mL/h per infusion site (or not to exceed a total of 600 mL/h or of 900 mL/h 
over 2 and 3 sites, respectively). SC infusion of IGI, 10% solution will begin within 
10 minutes of completion of SC infusion of rHuPH20 solution.
IGI, 10% solution: SC infusion, to be administered via a peristaltic infusion pump 
with programmable infusion rates and infusion volumes at 1 to 3 infusion sites per 
infusion day, with step-wise increases in infusion rate. IGI 10% solution may be 
administered at 1, 2, or 3 infusion sites. The recommended site(s) for the 
infusion of HYQVIA/HyQvia are the middle to upper abdomen and thighs.
TheFor the initial 2 infusionsare given at, it may be delivered an infusion rate of 
10 to 240 mL/h per infusion site for subjects ≥40 kg and 5 to 80 mL/h per infusion 
site for subjects <40 kg, as tolerated bythe subject and/or at the discretion of the
investigator. 
For subsequent administrations, infusion rate may be increased as tolerated by the 
subject and at the discretion of the investigator up to 300 mL/h per infusion site (or 
up to a total of 600 mL/h over 2 sites if bifurcated needle set is used, or up to a total 
of 900 mL/h over 3 sites if trifurcated needle set is used) for subjects ≥40 kg. 
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For subjects weighing <40 kg, infusion rates of up to 160 mL/h per infusion site (or 
up to a total of 320 and 480 mL/h over 2 and 3 sites if bifurcated and trifurcated 
need set is, respectively). Prior to subjects being allowed to infuse at these 
higher infusion rates in the home setting, this should first be conducted under 
medical supervision in the clinic setting. At high infusion rates above 750 mL/h 
(if trifurcated needle set for 3 infusion sites is used), the pump occlusion alarm may 
be activated due to high back pressure, stopping the pump. If this occurs, then 
reduce the infusion rate to allow proper pump function.
Site of administration: Bifurcated and trifurcated needle sets are to be used for 2 
and 3 infusions, respectively. The recommended site(s) for the infusion of 
HYQVIA/HyQvia are the right and left middle to upper abdomen and the right and 
left thighs. These rates should not be exceeded unless the investigator determines 
that higher infusion rates could be attempted and soas long as the higher infusion 
rates are attempted under medical supervision in the clinic setting, prior to allowing 
their use in the home setting.
Site of administration: Bifurcated and trifurcated needle sets are to be used 
for 2 and 3 infusions, respectively. The recommended site(s) for the infusion of 
HYQVIA/HyQvia are the middle to upper abdomen and the thighs. 
Volume of infusion per site: IGI, 10% solution may be administered at 1, 2, or 3 
infusion sites with a maximum infusion volume of up to 600 mL for subjects 
weighing ≥40 kg or up to 300 mL per infusion site for subjects weighing <40 kg, as 
tolerated. . On a given infusion day, the maximum infusion volume should not 
exceed 1200 mL for subjects weighing ≥40 kg or 600 mL for subjects weighing 
<40 kg. One to 3 sites can be used at the discretion of the investigator and subject 
based on tolerability and total IgG dose volume for the individual subject. If a 
subject’s IgG dose perShould the total infusion volume that is to be 
administered exceed either 1200 mL for subjects ≥40 kg of body weight on a 
given day exceeds 1.3 g/kg/day, or exceeds the SC 600 mL for subjects <40kg, or 
exceed the maximum infusion volume thea subject can tolerate not to exceed 1200 
mL/on a given infusion day, then the HYQVIA/HyQviatotal dose may be 
administered over multiple days as divided doses witha recommended 48 to 
72 hours between dosesh apart (eg, Day 1 and Day 3 of a given infusion cycle, but 
left to the investigator’s discretion) to allow absorption of infusion the infused 
fluid at infusion site(s).to be absorbed.
Note: The volume (mL) of infusion solution to be administered will be calculated 
using the subject’s body weight measured at baseline. Adjustment based on body 
weight changes during the course of the study is not planned, however it may be 
done if deemed medically necessary by the investigator (eg, clinically significant 
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body weight change). After baseline, for study visits where the subject’s body 
weight is measured (see Table 21 2, Section 21.2 Schedule of Study Procedures and 
Assessments for detailed timepoints), it is to be measured on site using the same 
scale/instrument throughout the study for that individual subject. 
At a few selected study sites, subjects may be asked to permit still photographs 
of the infusion sites, which will be used for educational and demonstration 
purposes, both within and external to the study. Only the infusion site will be 
photographed, and no identifying features will be included. A third party 
company will manage the collection of still photographs. Subjects who agree 
will sign a separate consent.
Purpose for Change: Information for sites.
10. Synopsis, Section 13.5 (Treatment Preference)
Description of Change: Deleted: 
At a few selected study sites, subjects will be asked to utilize two new approved 
devices to facilitate an easier administration process for the delivery of Immune 
Globulin Infusion 10% (Human) with Recombinant Human Hyaluronidase 
(HYQVIA/HyQvia).  The subject or Caregiver will be required to demonstrate a 
new self proficiency checklist to assure the understanding of how to utilize the new 
devices.  The subject will be asked to perform a an extra patient satisfaction, and 
treatment preference survey prior to starting the use of the new devices and then at 
final termination visit as currently planned.  Subjects who agree will sign a separate 
consent. (synopsis)
An additional treatment preference questionnaire will be requested for a select 
number of subjects prior to the use of two new approved devices to facilitate an 
easier administration process for the delivery of Immune Globulin Infusion 10% 
(Human) with Recombinant Human Hyaluronidase (HYQVIA/HyQvia).
(Section 13.5)
Purpose for Change: No longer relevant to this study. 
11. Synopsis, Section 14.5 (Planned Final Analysis of the Study)
Description of Change: Added: In addition to the interim analysis, Study 161505 
safety data available at time of data cut for Study 161403 interim safety 
analysis (details in study protocol) will be summarized, in order to assess the 
long-term safety of HYQVIA.
Deleted: Data from the analyses will be used to monitor the safety and tolerability 
of the IP in the study and to update the scientific community on the progress of the 
study at the scientific meetings.
Purpose for Change: Not relevant to this study. 
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12. Section 6 (BACKGROUND INFORMATION)
Description of Change: Revised text as follows “CIDP is an acquired progressive 
chronic sensory and motor neuropathy with a relapsing and remitting or progressive 
course of more than 2 months, characterized by proximal weakness, positive 
sensory symptoms, areflexia without wasting, and impaired sensation with a 
preferential loss of vibration or joint position sense.15,16”
Purpose for Change: Correction.
13. Section 6.1.1.1 (Recombinant Human Hyaluronidase [rHuPH20])
Description of Change: Additional half-life information was added for rHuPH20.
Purpose for Change: To support the additional text added on reporting and 
assessing antibody titer results.
14. Section 6.6 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 ICH GCP R2, November 2016),, Title 21 of the US Code of Federal 
Regulations, the EU Clinical Trial Regulation EU No. 536/2014 and 2005/28/EC, 
the Declaration of Helsinki, and applicable national and local regulatory 
requirements.
Purpose for Change: Updated regulatory statute.
15. Section 8.8 (Source Data), 
Section 10.3.2.1 (SC Infusion Visits [Including Home Infusions]), and 
Section 10.6 (Subject Diary and Patient Reported Outcomes)
Description of Change: added new text “Infusion Data worksheet”
Purpose for Change: Clarification for sites.
16. Section 10.3 (Screening and Study Visits)
Description of Change:  Deleted: “If a subject is re screened, the End of Study CRF 
should be completed and a new ICF, new SIC, and new CRF are required for that 
subject.”
Purpose for Change: Clarification for sites.
17. Section 10.3.2 (Treatment Period)
Description of Change:  Added text “For detailed procedures and assessments, see 
Table 21 1 and Table 21 2.”
Purpose for Change: Clarification for sites.
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18. Section 10.3.3 (Study Completion/Early Termination Visit)
Description of Change:  Revised text:
1.  Subjects may be requested to complete treatment in the study, may be as 
soon as the subject participating country gets market authorization for the 
treatment of CIDP in either US or EU (whichever comes later). a maximum of 
2.5 years of treatment (or up to 3 years if mandated by regulations). Study 
completion assessments are to be conducted on the day of the final infusion. This 
will mark the subjects’ completion of the study.
2.  A subject may withdraw their participation in the study or be discontinued from 
the study prior to completing treatment for 2.5 years (or up to 3 years if mandated 
by regulations). These subjects will be asked to undergo an early termination visit 
at the study site prior to discontinuation from the study.
Purpose for Change: Revised study duration upwards.
19. Section 10.5.1 (Immunizations)
Description of Change: Added text clarifying that seasonal influenza vaccines are 
permitted during the study.  
Purpose for Change: Clarification for sites.
20. Section 10.6 (Subject Diary and Patient Reported Outcomes):
Description of Change: added: In cases where the subject or the caregiver are 
not self-administering therapy, site staff will have an option in the diary to 
enter the infusion data only.
…
…. for patient reported data. An Infusion Data worksheet will serve as an 
additional source document.
Purpose for Change: Clarification for sites.
21. Section 12.1.2.3 (Safety Reporting):
Description of Change: revised text “The sponsor will ensure that all relevant 
information about SUSARs that are fatal or life threatening, as well as all other 
serious unexpected ARs, are reported to regulatory authorities within the 
timeframes mandated by the applicable regulations (eg, ICH Guideline E2A, and
the European Clinical Trial Directive [2001/20/EC2005/28/EC], and Clinical 
Trial Regulation EU No. 536/2014). The sponsor will comply with applicable 
laws/requirements for reporting SUSARs and all other SAEs to the ECs and 
investigators.” 
Purpose for Change: Updated regulatory statutes.
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22. Section 12.7.5 (Viral Serology Tests – new section)
Added text: 
Viral Serology Tests
The need for HIV and Hepatitis serology should be determined by the PI based 
upon clinical assessment and interval medical history. Serum samples may be 
collected for viral serology testing for HAV antibody, hepatitis B surface antigen 
(HBsAg), HCV antibody, and HIV-1/HIV-2 antibody. Additional tests, such as 
hepatitis B surface antibody [HBsAb], hepatitis B core antibody [HBcAb], and/or 
nucleic acid tests, may be performed as considered necessary by the PI. Subjects 
with immunity to hepatitis B from active vaccination are those with negative 
HBsAg, positive hepatitis B surface antibody [HBsAb], and negative HBcAb. 
Subjects with past infection are defined as those with negative HBsAg, positive 
HBsAb, and positive HBcAb.
Unscheduled serology testing may be performed in the event of suspected 
hepatitis/HIV infection. Any seroconversion result for HBV, HCV, or HIV shall be 
re-tested and additional tests for investigation may be conducted, in particular in the 
event of absence of clear alternative etiology.
See Section 21.3 for detailed sample collection timepoints.
Purpose for Change: Guidance for sites.
23. Section 12.7.8 Trough Serum IgG
Description of Change:  “Following baseline assessment, trough serum IgG 
samples must be collected on the day of the site-administered (see Table 21-1) IP 
administration (or on the first day of IP infusion if the IP dose is to be administered 
as divided doses over multiple days in an infusion cycle) just prior to the start of the 
infusion.”
Purpose for Change: To clarify that trough serum IgG will only be taken before 
infusions done at sites (and not at home or other infusions).
24. Section ADDED:  
12.7.10.1 Guidance on Reporting and Assessing rHuPH20 (hyaluronidase) 
antibody test results
All hyaluronidase antibody test results (titers, and binding or neutralizing) 
will be assessed for clinical significance by the investigator in the EDC 
database but are not to be reported as adverse events. 
For adverse events occurring during the subcutaneous infusion of 
hyaluronidase the investigator and sponsor will independently assess 
relatedness, also taking into account quantitative and qualitative test results 
for hyaluronidase antibodies.
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For AEs occurring upon or after subsequent SC infusion of the 
immunoglobulin component an assessment of causality is confounded by the 
presence of the consecutively administered IMPs. The overlap is transient due 
to the short half-life of hyaluronidase of about 30 minutes in the SC space. The 
investigator and sponsor will independently evaluate the relatedness of an 
adverse event to one or the other component during this period.
Purpose for Change: Text was added to clarify that neutralizing antibodies do not 
have to be reported as AEs.
25. Section 12.7.11 (Back-up Samples and Biobanking)
Description of Change: Added text “The need for  HIV and hepatitis serology 
should be determined by the PI based upon clinical assessment and interval medical 
history.”
Purpose for Change: Clarification for sites.
26. Section 12.8 (Vital Signs)
Description of Change: The following clause was removed “subject’s electronic 
diary (as applicable)”. 
Purpose for Change: Vital signs are not collected in the electronic diary.
27. Section 14.1 (Sample Size and Power Calculations)
Description of Change: The following text was revised: Not applicable. This 
study is an extension to Study 161403. As indicated in Section 7.1, the purpose 
of this study is to assess the long-term safety, tolerability, and immunogenicity 
of HYQVIA in subjects with CIDP who have completed Study 161403 Epoch 1 
without CIDP worsening. Enrollment in Study 161505 is open to subjects who 
have completed Study 161403 Epoch 1 without CIDP worsening and who have 
provided informed consent. The planned enrollment is 174 subjects, of whom 
approximately 148 subjects were assumed will complete the study; therefore, a 
maximum of 148 subjects are expected to enroll in the extension.
The purpose of this non comparative study is to collect long term data on safety, 
tolerability, and immunogenicity from subjects who completed Study 161403 
Epoch 1 without CIDP worsening. An estimated maximum of 149 subjects are 
expected to qualify for enrollment in this study, based on the planned enrollment 
and anticipated discontinuation rate in Study 161403. The study is not statistically 
powered. 
Purpose for Change: Clarification.
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28. Section 8.6 (Study Stopping Rules), 
Section 17.4 (Data Monitoring Committee) 
Description of Change: Description of the Internal Safety Review Board (ISRB) 
was deleted and replaced with new text describing the Data Monitoring Committee
(DMC).
Purpose for Change: Administrative change.
29. Sections 21.2 (Schedule of Study Procedures and Assessments) and 
Section 21.3 (Clinical Laboratory Assessments) 
Description of Change: Added table row and text to table footnotes specifying that 
an extra urinalysis sample may be needed. Added footnote to clarify timing of 
telephone follow-ups. Modified footnote text to clarify that the need for HIV and 
hepatitis serology should be determined by the PI based upon clinical assessment 
and interval medical history.
Purpose for Change: Clarification.
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22. SUMMARY OF CHANGES 
Protocol 161505: Amendment 1: 2016 JUN 27
Replaces: Original: 2016 JAN 20
In this section, changes from the previous version of the protocol, dated 2016 JAN 20, are 
described and their rationale is given.
1. Throughout the document
Description of Change: Minor grammatical and/or administrative changes that do 
not substantively affect the study conduct or subject safety have been made. 
Purpose for Change: To improve the readability and/or clarity of the protocol. 
2. Section 2.0 Serious Adverse Event Reporting, Section 12.1.2.3 Safety Reporting, 
Section 12.3 Untoward Medical Occurrences
Description of Change: All SAEs, including SUSARS, are to be reported on the 
Serious Adverse Event Report (SAER) Form and transmitted to the Sponsor 
within 24 hours after becoming aware of an event. Most of Section 12.1.2.3 was 
deleted. Section 12.3 was updated from eCRF reporting to SAE Report Form 
reporting.
Purpose for Change: The EDC system cannot pull all information on to the form 
which is required for Baxalta GDS. EDC should be re-programmed. Most of the 
text in Section 12.1.2.3 was no longer needed as it describes processes for 
electronic SAE reporting. Section 12.3 updates were made to reflect the changes 
from eCRF reporting of SAEs to paper reporting.
3. Throughout the document
Description of Change: The study protocol has been amended to incorporate 
subjects who participated in Study 161601, a Phase II Safety, Tolerability and 
Immunogenicity Study of HYQVIA/HyQvia in CIDP. Relevant text was changed 
to maintain consistency throughout the document with additional text added to 
indicate that subjects may have participated in Study 161601 or Study 161403.
Purpose for Change: To specify that eligible subjects may also be recruited from 
Study 161601.
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4. Throughout the document
Description of Change: The maximum treatment duration was clarified to extend 
up to 3 years if mandated by regulations.
Purpose of Change: To comply with regulations for trial duration in certain 
countries (eg, United Kingdom, Israel).
5. Synopsis, Section 8.2 Overall Study Design
Description of Change: Text was added to clarify the location(s) for infusion for 
subjects entering from Study 161403 and Study 161601, including study site 
infusion center, subject’s home, other suitable locations, and the conditions for 
these options.
Purpose for Change: To clarify the possible locations for subjects and specify the 
differences for subjects enrolled from Study 161403 and Study 161601 to receive 
the study infusion.
6. Synopsis, Section 8.2 Overall Study Design, Section 8.3 Duration of Study 
Periods and Subject Participation, Section 9.3 Withdrawal and Discontinuation
Description of Change: The following criterion was deleted: “Study termination 
upon commercial availability of HYQVIA/HyQvia in the subject’s country (or 
decision is made to not seek market authorization in that country)” and additional 
details specifying other reasons for extension of study participation. Related text 
in Section 8.2 was updated to reflect the changes in Section 8.3. 
Purpose for Change: This reason for subject discontinuation is no longer 
applicable.
7. Synopsis, Section 8.7.3 Administration
Description of Change: Text was added to clarify the determination of infusion 
rate based on subject weight, and to specify the differences for administration 
with single, bifurcated, or trifurcated SC needle sets.
Purpose for Change: To clarify infusion rate for each subject based on body 
weight and address how to proceed following an occlusion alarm; and how the 
volume is distributed over multiple sites.
8. Synopsis, Section 6.3 Population to be Studied, Section 8.2 Overall Study Design, 
Section 14.1 Sample Size and Power Calculations
Description of Change: The number of potential subjects was increased from 124 
to 149.
Purpose of Change: To acknowledge the potential to accrue 149 subjects.
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9. Section 5 List of Abbreviations, Section 15 Direct Access to Source 
Data/Documents, Quality Control and Quality Assurance, Section 17 Ethics, 
Section 18 Data Handling and Record Keeping, Section 19 Financing and 
Insurance, Section 20 Publication Policy
Description of Change: An abbreviation for the term Clinical Trial Agreement 
(CTA) was added, and the text was updated accordingly.
Purpose for Change: Updates to align with new template text.
10. Section 6 Background Information
Description of Change: A description of Study 161403 was added.
Purpose for Change: To update the background information to include an 
additional parent study for Study 161505.
11. Section 6.5.2 GAMMAGARD LIQUID/KIOVIG
Description of Change: The following text was added “GAMMAGARD 
LIQUID/KIOVIG will not be used as an investigational drug in this study. 
However, GAMMAGARD LIQUID/KIOVIG—also known as IGI, 10%—is the 
immunoglobulin product in HYQVIA/HyQvia. Information on this product is 
therefore also presented:”
Purpose for Change: To add clarification as both drugs are used in some of the 
parent studies.
12. Section 8.2 Overall Study Design
Description of Change: The word “relapse” was clarified to “study end”, and the 
phrase “predetermined study end for the specific country in which the subject is 
participating” was clarified to “premature termination for any reason described in 
Section 8.3.”
Purpose for Change: To provide a complete list of study termination criteria.
13. 16.1 Investigator’s Responsibility, Section 16.3 Monitoring, 16.4 Auditing, 17.3 
Informed Consent, 18.3 Document and Data Retention 
Description of Change: The phrase “national and local” was added to define the 
regulatory requirements.
Purpose for Change: To comply with updated template text.
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14. Section 8.7.2 Preparation and Storage of Pooled Products
Description of Change: The following text was added “In case IGI, 10% and 
0.25% albumin placebo solutions for administration have to be prepared using 
aseptic techniques without controlled air environment (Laminar Flow hood) in 
accordance with USP guideline 797 or its equivalent per regional or institutional 
standard practices and within the Pharmacy Manual, the study drug must only be 
administered to study subjects at the study site and immediately following 
preparation and after reaching room temperature.” Additionally, clarification was 
made to change specify the infusion will be administered at room temperature.
Purpose of Change: This will allow unblinded staff (nurse) to prepare the study 
drug, and ensure the infusions are stored and administered at the correct 
temperatures.
15. Synopsis, Section 8.7.3 Administration
Description of Change: Recommendations were modified to include a trifurcated 
SC needle set.
Purpose for Change: To add the option to administer the investigational product 
simultaneously at 3 body sites using a trifurcated needle set.
16. Section 10.1 Informed Consent and Enrollment, Section 10.2 Subject 
Identification Code, Section 10.3 Screening and Study Visits, 12.5 Medical, 
Medication, and Non-Drug Therapy History
Description of Change: Language was modified to clarify that each individual 
providing informed consent is considered a subject.
Purpose for Change: To comply with updated template text.
17. Throughout the document, Section 10.3.1 Screening and Baseline Period
Description of Change: The screening period or visit is referred to as “baseline”
throughout the document for consistency, and the statement “which may last up to 
4 weeks” has been deleted.
Purpose of Change: To clarify screening procedures for the Extension Study.
18. Section 10.5 Medications and Non-Drug Therapies
Description of Change: “Other medications that are not permitted during the 
course of the study” was clarified to include “Other IgG products” only.
Purpose of Change: To clarify that the only IgG product a subjects may take is the 
investigational product.
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19. Section 10.6 Subject Diary and Patient Reported Outcomes
Description of Change: A bullet point was added for “Infusion-related 
information (see Section 10.3.2.1)”, and additional information was added on how 
the diary data would be imported and validated.
Purpose for Change: To add additional outcomes listed in Section 10.3.2.1 not 
considered “Infusion records”, and to add clarification on the data transfer.
20. Section 11.3 Hand Grip Strength
Description of Change: The description of the JAMAR® PLUS + Hand 
Dynamometer has been replaced by a description of the Vigorimeter. 
Purpose for Change: The specific instrument used to measure hand grip strength 
was changed from the JAMAR® PLUS + Hand Dynamometer to the Vigorimeter.
21. Section 12.1.1.1 Serious Adverse Event
Description of Change: “Uncomplicated pregnancies” were clarified to refer to 
only those following maternal exposure to the investigational product.
Purpose for Change: To clarify that uncomplicated pregnancies following paternal 
exposure to the investigational product are not considered AEs.
22. Section 12.1.1.2 Suspected Unexpected Serious Adverse Reaction (SUSAR)
Description of Change: Standard template language was added to define 
SUSARs.
Purpose for Change: To define SUSARs per Baxalta protocol template 
requirements.
23. Section 12.7.8 Trough Serum IgG
Description of Change: The following language was deleted “The baseline trough 
serum IgG sample will be collected prior to the last SC infusion during the Study 
Completion (end of SC treatment) Visit in the 161403 study.”
Purpose for Change: To clarify when baseline trough serum IgG samples will be 
collected regardless of parent study participation by each subject.
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24. Section 12.7.11 Backup Samples/Biobanking
Description of Change: The following language was added: “Baseline and end-of-
trial serum/plasma backup samples will be stored for possible testing of pathogens 
for no more than 2 years after the final study report has been completed. Other 
backup samples that remain after study testing is done may be stored and used for 
additional testing (eg, further evaluation of an abnormal test, investigation of an
AE or suspected seroconversion). Samples will be stored in a coded form for no 
more than 2 years after the final study report has been completed and 
subsequently the samples will be destroyed.”
Purpose for Change: Updated based on regulatory feedback.
25. Section 16.6 Laboratory and Reader Standardization
Description of Change: The following phrase was added “Inter-laboratory 
standardization methods will be described in the data management plan as 
needed.”
Purpose for Change: To allow for use of the appropriate standardization methods 
as needed.
26. Section 17.4 Data Monitoring Committee
Description of Change: Language was added to indicate that individuals on the 
internal safety review board may not be actively recruiting subjects and that the 
board may recommend stopping the study based on safety signals or medical 
concerns or if the treatment is proven to be not beneficial.
Purpose for Change: To clarify the roles of individuals on the internal safety 
review board.
27. Figures and Tables
Description of Change: Titles were edited for brevity and clarity.
Purpose for Change: To improve understandability.
28. Section 12.7.9 Anti-rHuPH20 Antibodies, Section 12.7.10 Immunogenicity Panel, 
Section 21.1 Study Flow Chart, Section 21.1 Schedule of Study Procedures and 
Assessments, Section 21.3 Clinical Laboratory Assessments
Description of Change: Study visit numbers were updated according to addition 
of subjects from Study 161601.
Purpose for Change: To accurately reflect at which weeks study visits would 
occur.
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29. Synopsis, Section 14.4 Method of Analysis, Section 14.5 Planned Interim 
Analysis of the Study
Description of Change: The planned statistical analysis was updated. Subgroup 
analysis was removed and changed to single group analysis.
Purpose for Change: Decision on subgroup analysis will be determined in the 
SAP.
30. Section 14.4.2.1 Exploratory Efficacy
Description of Change: The phrase “Kaplan Meier” was deleted.
Purpose for Change: Biostatistics team members re-evaluated the most 
appropriate study testing.
31. Synopsis, 8.7.3 Administration
Description of Change: The maximum infusion volume was define as 1200 mL/d.
Purpose for Change: To clarify the maximum infusion volume of the 
investigational product.
32. Table 21.2 Schedule of Study Procedures and Assessments, Table 21.2 Schedule 
of Study Procedures and Assessments
Description of Change: Cells were merged on the row marked “Infusion”. Two 
footnotes were added to clarify that infusions will be administered according to 
the schedule of each subject’s previous study (every 2, 3, or 4 weeks), and to 
specify the visit windows.
Reason for Change: To improve clarity of the table.
33. Section 8.7.4 Description of Treatment, Table 21.1 Schedule of Study Procedures 
and Assessments
Description of Change: The following sentences were added “All attempts should 
be made to maintain the original infusion schedule for subjects. If a subjects 
receives a dose out of window, the dose will still be given prior to the next 
infusion, if possible. Patients should return to the original planned visit schedule 
even if an infusion was given out of window.”
Reason for Change: To clarify that each subject should be kept on the same 
infusion schedule as in the parent study.
34. Table 21.1 Schedule of Study Procedures and Assessments
Description of Change: Footnote a was added to the column marked “First 
Treatment Visit in Extension Study” and row marked “Laboratory Assessment”.
Purpose for Change: To improve clarity.
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35. Table 21.2 Clinical Laboratory Assessments
Description of Change: The following sentence was added to footnote j: “The 
hemolytic anemia panel be conducted only in the event of a drop in Hgb of 1 g/dL 
or more compared to baseline value.”
Purpose for Change: To clarify that the hemolytic panel will be conducted only if 
there is a decrease in hemoglobin.
36. Section 10.2 Subject Identification Code
Description of Change: The study site and subject numbers were clarified to be 3-
digit numbers.
Purpose for Change: To clarify the subject identification code that will be used by 
this study to conform to other related studies.
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