A Phase III Study to Evaluate the Efficacy, Safety, and Tolerability of Immune Globulin Infusion 10% (Human) With Recombinant Human Hyaluronidase (HYQVIA/HyQvia) and Immune Globulin Infusion (Human), 10% (GAMMAGARD LIQUID/KIOVIG) for the Treatment of Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP)
Phase: PHASE3
Conditions: Chronic Inflammatory Demyelinating Polyradiculoneuropathy
Sponsor: Baxalta now part of Shire

NCT Number: NCT02549170
Title: A Phase III Study to Evaluate the Efficacy, Safety, and Tolerability of 
Immune Globulin Infusion 10% (Human) with Recombinant Human 
Hyaluronidase (HYQVIA/HyQvia) and Immune Globulin Infusion (Human), 10% 
(GAMMAGARD LIQUID/KIOVIG) for the Treatment of Chronic Inflammatory 
Demyelinating Polyradiculoneuropathy (CIDP) 
Study Number: 161403
Document Version and Date: Protocol Amendment #6, 20-MAY-2021
Certain information within this document has been redacted (ie, specific content is masked 
irreversibly from view) to protect either personally identifiable information or company 
confidential information. 
A summary of changes to previous protocol versions is appended to the end of the 
document. 
Clinical Study Protocol

This document contains confidential and proprietary information of Shire and is disclosed pursuant to 
confidentiality and non-disclosure obligations. This information should be used solely for the purposes for 
which it was provided and should not be copied, shared with, or disclosed to any third party without the 
express written consent of Shire.
PROTOCOL: 161403
TITLE:
A Phase III Study to Evaluate the Efficacy, Safety, and 
Tolerability of Immune Globulin Infusion 10% (Human) with 
Recombinant Human Hyaluronidase (HYQVIA/HyQvia) and 
Immune Globulin Infusion (Human), 10% (GAMMAGARD 
LIQUID/KIOVIG) for the Treatment of Chronic Inflammatory 
Demyelinating Polyradiculoneuropathy (CIDP)
SHORT TITLE:
Phase III Efficacy, Safety, and Tolerability Study of 
HYQVIA/HyQvia and GAMMAGARD LIQUID/KIOVIG in 
CIDP
STUDY PHASE:
Phase 3
DRUG:
Immune Globulin Infusion 10% (Human) with Recombinant 
Human Hyaluronidase (HYQVIA/HyQvia) 
and 
Immune Globulin Infusion (Human), 10% 
(GAMMAGARD LIQUID/KIOVIG)
IND NUMBER:
014381
EUDRACT NUMBER:
2014-005496-87
NCT Number:
NCT02549170
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:
N/A
PROTOCOL 
HISTORY:
AMENDMENT 6:  2021 MAY 20
Replaces: AMENDMENT 5: 2019 MAY 10
ALL VERSIONS:
Amendment 6: 2021 MAY 20
Amendment 5: 2019 MAY 10
Amendment 4: 2019 FEB 13
Amendment 3: 2018 JAN 31
Amendment 2: 2016 APR 22
Amendment 1: 2015 AUG 25
Original: 2015 MAY 27
For non-commercial use only

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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:

Adverse events (AE), Section 12.1

SAE, Section 12.1.1.1

SUSARs, Section 12.1.1.2

Assessment of AEs, Section 12.1.2
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3. SYNOPSIS
INVESTIGATIONAL PRODUCT
Name of Investigational 
Product(s) (IP[s])
1. Immune Globulin Infusion 10% (Human) with Recombinant Human 
Hyaluronidase (IGI, 10% with rHuPH20; HYQVIA/HyQviai)
2. Immune Globulin Infusion (Human), 10% Solution (IGI, 10%; 
GAMMAGARD LIQUID/KIOVIGii; IGI, 10% when administered 
intravenously is also referred to as IGIV 10%)
3. 0.25% human albumin in Lactated Ringer’s (LR) solution (placebo) with 
rHuPH20
Name(s) of Active 
Ingredient(s)
1. Immune Globulin Infusion 10% (Human) for HYQVIA/HyQvia
2. Immune Globulin Infusion (Human), 10% Solution for GAMMAGARD 
LIQUID/KIOVIG
(The active ingredient is identical in both IPs.)
CLINICAL CONDITION/INDICATION

Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP)
PROTOCOL ID
161403
PROTOCOL TITLE
A Phase III Study to Evaluate the Efficacy, Safety, and Tolerability of 
Immune Globulin Infusion 10% (Human) with Recombinant Human 
Hyaluronidase (HYQVIA/HyQvia) and Immune Globulin Infusion (Human), 
10% (GAMMAGARD LIQUID/KIOVIG) for the Treatment of Chronic 
Inflammatory Demyelinating Polyradiculoneuropathy (CIDP)
Short Title
Phase III Efficacy, Safety, and Tolerability Study of HYQVIA/HyQvia and 
GAMMAGARD LIQUID/KIOVIG in CIDP
STUDY PHASE
Ph3
PLANNED STUDY PERIOD
Initiation
Q4 2015
Primary Completion
Q1 2022
Study Completion
Q1 2022
Duration
The maximum overall duration of this study is estimated to be approximately 
72 months from study initiation (ie, first subject enrolled) to study completion 
(ie, last subject last visit), including:

An enrollment period of approximately 64 months

A screening/baseline period of up to 8 weeks

Epoch 1 (subcutaneous [SC] treatment period) of 6 months

Epoch 2 (intravenous [IV] treatment period) of 6 months for subjects who 
relapse during Epoch 1
                                                
i HYQVIA and HyQvia are registered trademarks of Takeda Development Center Americas / Baxalta 
Innovations GmbH
ii GAMMAGARD LIQUID and KIOVIG are registered trademarks of Takeda Development Center 
Americas / Baxalta Innovations GmbH
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STUDY OBJECTIVES AND PURPOSE
Study Purpose

The purpose of this study is to provide evidence for the use of HYQVIA/HyQvia as a maintenance 
therapy option that enables self-infusion of a full therapeutic dose every 2 to 4 weeks in patients with 
CIDP. 

In addition, this study aims to provide evidence for the use of GAMMAGARD LIQUID/KIOVIG as 
an IV immunoglobulin treatment option in patients with CIDP.
Study Objectives
Epoch 1: SC Treatment Period with HYQVIA/HyQvia vs Placebo with rHuPH20
Primary Objective
1. To evaluate the efficacy of HYQVIA/HyQvia as a maintenance therapy for CIDP to prevent relapse 
of neuromuscular disability and impairment.
Secondary Objectives
1. To assess the time to CIDP relapse during maintenance therapy with HYQVIA/HyQvia, compared 
to placebo.
2. To assess the effect of HYQVIA/HyQvia on activities of daily living (ADL).
3. To assess the safety and tolerability of HYQVIA/HyQvia.
4. To monitor for the presence of binding and neutralizing anti-rHuPH20 antibodies following 
HYQVIA/HyQvia administration.
Tertiary Objectives
1. To evaluate the effects of HYQVIA/HyQvia on additional clinical outcome measures, including 
change in functional ability, hand grip strength, and muscle strength.
2. To evaluate improvement in functional impact on everyday tasks as measured by a pre-specified 
subscore of R-ODS
3. To assess the effect of HYQVIA/HyQvia on quality of life, health utility, health resource utilization 
(HRU), treatment satisfaction, treatment preference, and patient global impression of change 
(PGIC).
4. To assess the effect of HYQVIA/HyQvia on the total number or appearance of new demyelinating 
abnormalities on electrodiagnostic studies.
Epoch 2: IV Treatment Period with GAMMAGARD LIQUID/KIOVIG
Primary Objective
1. To evaluate the efficacy of GAMMAGARD LIQUID/KIOVIG for the treatment of CIDP to 
improve neuromuscular disability and impairment.
Secondary Objective
1. To assess the safety and tolerability of GAMMAGARD LIQUID/KIOVIG.
2. To assess the effect of GAMMAGARD LIQUID/KIOVIG on ADL.
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Tertiary Objectives
1. To assess the time to improvement during GAMMAGARD LIQUID/KIOVIG treatment.
2. To evaluate the effects of GAMMAGARD LIQUID/KIOVIG on additional clinical outcome 
measures, including change in functional ability, ADL, hand grip strength, and muscle strength in 
subjects with CIDP.
3. To assess the effect of GAMMAGARD LIQUID/KIOVIG on quality of life, health utility, HRU, 
treatment satisfaction, treatment preference, and patient global impression of change.
4. To assess the effect of GAMMAGARD LIQUID/KIOVIG on the total number or appearance of 
new demyelinating abnormalities on electrodiagnostic studies. 
STUDY DESIGN
Study Type/ 
Classification/ Discipline
Efficacy, Safety, Tolerability
Control Type
Epoch 1 (SC treatment period) – Concurrent (Placebo)
Epoch 2 (IV treatment period) – No control
Study Indication Type
Treatment
Intervention model 
Parallel
Blinding/Masking
Epoch 1 (SC treatment period) – Double-blind
Epoch 2 (IV treatment period) – Open-label
Study Design
This is a Phase III, prospective, multicenter study to evaluate the efficacy, 
safety, and tolerability of HYQVIA/HyQvia (IGI, 10% with rHuPH20 
administered subcutaneously) for maintenance therapy to prevent relapse and 
GAMMAGARD LIQUID/KIOVIG (IGIV 10% administered intravenously) 
for the treatment of CIDP. This study will enroll adult subjects with a
confirmed diagnosis of CIDP and who have remained on a stable dosing 
regimen (monthly equivalent dose of 0.4 to 2.4 g/kg body weight [BW] with a 
dosing interval of 2 to 6 weeks) of IV immunoglobulin G (IGIV) therapy for 
at least 12 weeks prior to screening. Randomization to Epoch 1 will be 
stopped by the sponsor prior to achieving the originally planned total of 
174 randomized subjects. At least 120 subjects will be randomized and dosed 
so that adequate statistical power (90%) will still be achieved, based on 
revised sample size assumptions. It is estimated that 15% of subjects will be 
prematurely discontinued from the study.
The overall study design is illustrated in Section 21.1 Study Flow Chart. 
Schematics for study assessments and visits are detailed in Section 21.2. 
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. 
After informed consent has been obtained, subjects will undergo screening 
and baseline procedures for the determination of eligibility. During the 
screening/baseline period, subjects will continue to receive their own IGIV 
treatment at the same dose and dosing frequency as prescribed prior to their
entry into this study.
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Epoch 1: SC Treatment Period
In this double-blind, placebo-controlled phase of the study (Epoch 1), 
eligible subjects will be randomized in a 1:1 ratio to receive either 
HYQVIA/HyQvia or 0.25% albumin placebo solution with rHuPH20 in 
a double-blind fashion for a period of 6 months or until relapse. 
The dosing regimen for HYQVIA/HyQvia or 0.25% albumin placebo with 
rHuPH20 will be the same as the subject’s pre-randomization monthly 
equivalent immunoglobulin G (IgG) dose (or at matching infusion volume for 
subjects in the placebo group) when administered at a dosing frequency of 
every 2, 3, or 4 weeks.iii No conversion factor will be applied when switching 
from pre-randomization IGIV to HYQVIA/HyQvia (or 0.25% albumin 
placebo solution with rHuPH20) treatment; that is, the monthly IgG dose of 
HYQVIA/HyQvia (or matching infusion volume for subjects in the placebo 
group) will be the same as the subject’s pre-randomization monthly dose of 
IGIV. The number of infusion visits and clinic visits during the SC treatment 
period will vary across subjects depending on whether their infusion cycles 
are every 2, 3, or 4 weeks (see Table 21-1, Table 21-2, and Table 21-3).
The study product components of HYQVIA/HyQvia (or 0.25% albumin 
placebo solution with rHuPH20) will be administered sequentially. SC 
infusion of rHuPH20 solution at a dose of 80 U/g IgG (or its equivalent at 
80 U/10 mL of the 0.25% albumin placebo solution) will be administered 
first, to be followed by SC infusion of IGI, 10% or placebo solution within 
10 minutes of completion of the infusion of rHuPH20 solution. To gradually 
increase the SC infusion volume, a dose ramp-up schedule will be employed 
until the subject’s full dose is reached (see Table 8-3). The first SC 
administration will take place 2 weeks (±3 days) following the subject’s last 
pre-randomization IGIV administration.
Initial SC infusions (during the ramp-up period and, at a minimum, the first 
full-dose infusion) will be administered at the study site or infusion center to 
monitor for safety and tolerability, to determine the infusion rate and infusion 
volume per infusion site that can be tolerated by the subject, and to provide 
training to the subject (and/or, as applicable, a caregiver who may assist the 
subject with self -administration) on self-infusion procedures. 
                                                
iii
Subjects receiving pre-randomization IGIV treatment every 2, 3, or 4 weeks will receive 
HYQVIA/HyQvia or placebo with rHuPH20 administration at the same IgG dose (or matching infusion 
volume for subjects in the placebo group) and dosing frequency during the study. Adjustment to dosing 
interval as a subject’s treatment is being switched from pre-randomization IGIV to SC IGI, 10% or 
placebo infusion will not be allowed, except for (i) subjects with pre-randomization IGIV dosing every 
5 or 6 weeks (for these subjects the dosing interval in the study will be converted to 2, 3, or 4 weeks 
while maintaining the same monthly equivalent IgG dose [or matching infusion volumes for subjects in 
the placebo group]), or (ii) subjects for whom the IgG dose (or matching infusion volume for subjects in 
the placebo group) that is to be administered exceeds a SC maximum infusion volume that a subject can 
tolerate.
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At the investigator’s discretion, the remainder of the SC infusions 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. The ability of the subject (and/or caregiver) to perform infusion 
procedures independently is a prerequisite for self-administration. Training and 
the investigator/designee’s evaluation of the subject’s (and/or caregiver’s) 
proficiency in independently self-administering infusions must be documented.
Assessments will be conducted to monitor for changes in the subject’s 
functional ability (Inflammatory Neuropathy Cause and Treatment 
[INCAT] disability score (Hughes et al., 2001)) and other clinical 
outcome measures, including ADL (Rasch-built Overall Disability Scale 
[R-ODS] (van Nes et al., 2011)), hand grip strength (Merkies et al., 2000), 
and muscle strength (Medical Research Council [MRC] sum score 
(Kleyweg et al., 1991)); to collect trough serum IgG levels; as well as 
for safety laboratory assessments. Additionally, patient reported 
outcome (PRO) measures will be collected, including quality of life 
(Short Form-36 [SF-36] (Ware et al., 2000)), health utility status (EuroQoL 
[Quality of Life]-5 Dimensions [EQ-5D] scores (The EuroQol Group, 1990)), 
HRU, treatment satisfaction, treatment preference, and PGIC. An electronic 
diary  (DIARYpro) will be utilized to capture data records related to 
infusions, adverse events (AEs), concomitant medications, and PRO 
measures such as the R-ODS and HRU. 
At any time during the SC treatment period, unscheduled visit(s) for INCAT 
assessments will be allowed for subjects who experience CIDP worsening, in 
order to determine whether the worsening meets the definition of relapse 
(ie, worsening in functional disability by ≥1 point relative to the pre-SC 
treatment baseline score in 2 consecutive adjusted INCAT disability 
scoresiv,(Hughes et al., 2008). Open label treatment with IGIV will be 
provided for any subjects (regardless of their treatment assignment in 
Epoch 1) who meet the definition of relapse and enter into Epoch 2, in order 
to restore functional ability. An INCAT assessment will be performed at the 
time the subject is being evaluated for relapse, and again just prior to initiation 
of IGIV treatment in Epoch 2. The pre-IV treatment baseline INCAT 
assessment will be used to confirm the subject’s adjusted INCAT disability 
score has increased by ≥1 point relative to the pre-SC treatment baseline 
score, at which time the final determination of whether a subject has met 
relapse criteria will be made. Subjects who relapse during Epoch 1 may 
choose not to enter into- Epoch 2. For these subjects, INCAT assessment will 
be repeated during the early termination visit, and this INCAT disability score 
will serve to confirm whether the subject has met the relapse criteria.
                                                
iv The adjusted INCAT disability score is identical to the INCAT disability score with the exception that 
upper extremity score changes from 0 (normal) to 1 (minor symptoms) or from 1 to 0 are excluded in 
determining the adjusted score, given that these changes do not reflect functional motor disability.
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Epoch 2: IV Treatment Period
Epoch 2 is the open-label phase of this study with the aim of providing IGIV 
treatment for subjects who meet relapse criteria during Epoch 1, in order to 
restore functional ability.

Subjects will receive GAMMAGARD LIQUID/KIOVIG (all subjects 
with the exception of those at US sites) or GAMUNEX®-Cv (subjects at 
US sites only). IGIV treatment will consist of an induction dose of 
2 g/kg BW, followed by maintenance infusions at the same monthly dose 
as the subject’s pre-randomization IGIV dosing regimen when 
administered every 3 weeks for a total of 6 months. The dose level of 
IGIV treatment may be adjusted at the discretion of the investigator, as 
medically necessary and/or as tolerated by the subject. Adjustment to the 
dosing interval of every 3 weeks is not allowed.
All subjects will be asked to return to the study site every 3 weeks (ie, every 
infusion visit) until study completion or early discontinuation, for follow-up 
monitoring of their functional ability as well as other clinical, safety, PRO 
measures, and trough serum IgG levels.
Planned Duration of 
Subject Participation
Approximately 8 to 14 months 
Study participation duration will be approximately 8 months for subjects who 
complete the SC treatment period (Epoch 1) without relapse. Study 
participation may be extended by 6 months for those subjects who relapse 
during the SC treatment period and undergo IV treatment (Epoch 2).
Epoch 1: SC Treatment Period
Primary Outcome Measure
1.
Relapse rate (proportion of subjects who experience a worsening of functional disability defined as 
an increase of ≥1 point relative to the pre-SC treatment baseline score in 2 consecutive adjusted 
INCAT disability scores)
Secondary Outcome Measures
Efficacy
1.
Proportion of subjects who experience a worsening of functional disability defined as an increase 
of ≥1 point relative to the pre-SC treatment baseline score in 2 consecutive adjusted INCAT 
disability scores OR who experience CIDP worsening (defined as a ≥8 kPa decrease in the hand 
grip strength in the more affected hand) OR ≥4 points decrease in R-ODS relative to the pre-SC 
treatment baseline score at 2 consecutive time points (at the time of withdrawal from the SC 
treatment period)
2.
Time to relapse
3.
Change from pre-SC treatment baseline in R-ODS
                                                
v
GAMUNEX®-C is approved for the treatment of CIDP and is a registered trademark of Grifols 
Therapeutics Inc.
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Safety
1.
Number (percentage) of subjects experiencing any treatment-emergent serious and/or nonserious 
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 nonserious adverse reactions (ARs) plus 
suspected ARs
4.
Number (percentage) with treatment-emergent SAEs and/or AEs associated with infusions, 
regardless of causality
5.
Number (percentage) of causally related SAEs and/or AEs associated with infusions
6.
Number (percentage) of AEs temporally associated with infusions (defined as AEs occurring during 
or within 72 h after completion of an infusion) 
7.
Number (percentage) of serious and/or nonserious ARs plus suspected ARs associated with 
infusions
8.
Number (percentage) of treatment-emergent systemic AEs associated with infusions
9.
Number (percentage) of treatment-emergent local infusion site reactions associated with infusions
10. 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
11. Rates of systemic and local AEs, regardless of causality, expressed as number of events per 
infusion, per subject, and per subject-year
12. Rates of causally related systemic and local AEs, expressed as number of events per infusion, per 
subject, and per subject-year
13. Rates of systemic and local ARs plus suspected ARs, expressed as number of events per infusion, 
per subject, and per subject-year
14. Number of subjects who have developed binding and/or neutralizing antibodies to rHuPH20
Note: Adverse events in this section refer to treatment-emergent AEs, if not specified.
Tertiary Outcome Measures
Efficacy
1.
Change from pre-SC treatment baseline in adjusted INCAT disability score
2.
Change from pre-SC treatment baseline in hand grip strength score 
3.
Change from pre-SC treatment baseline in functional impact on everyday tasks as measured by R-
ODS sub-components
4.
Change from pre-SC treatment baseline in MRC sum score
5.
Change from prescreen baseline in the total number or appearance of new demyelinating 
abnormalities on electrodiagnostic studies.
Patient Reported Outcomes
1.
Change from pre-SC treatment baseline in SF-36 scores 
2.
Change from pre-SC treatment baseline in EQ-5D scores 
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3.
HRU (such as days off school/work, unscheduled physician visits, hospitalization, and emergency 
room visits) 
4.
Treatment satisfaction
5.
Treatment preference
6.
PGIC
Other
1.
Trough serum IgG levels.
Epoch 2: IV Treatment Period
Primary Outcome Measure
1.
Responder rate (proportion of subjects with clinically meaningful improvement in functional 
ability defined as a decrease of ≥1 point in the adjusted INCAT disability score at the completion 
of the IV treatment period [6 months] or at the last study visit of the IV treatment period, relative 
to the pre-IV treatment baseline score)
Secondary Outcome Measures
Safety
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 nonserious ARs plus suspected ARs
4.
Number (percentage) of treatment-emergent SAEs and/or AEs associated with infusions, 
regardless of causality
5.
Number (percentage) of causally related SAEs and/or AEs associated with infusions
6.
Number (percentage) of AEs temporally associated with infusions (defined as AEs occurring 
during or within 72 h after completion of an infusion) 
7.
Number (percentage) of serious and/or nonserious ARs plus suspected ARs associated with 
infusions
8.
Number (percentage) of treatment-emergent systemic AEs associated with infusions
9.
Number (percentage) of treatment-emergent local infusion site reactions associated with infusions
10. 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
11. Rates of systemic and local AEs, regardless of causality, expressed as number of events per 
infusion, per subject, and per subject-year
12. Rates of causally related systemic and local AEs, expressed as number of events per infusion, per 
subject, and per subject-year
13. Rates of systemic and local ARs plus suspected ARs, expressed as number of events per infusion, 
per subject, and per subject-year
Note: Adverse events in this section refer to treatment-emergent AEs, if not specified.
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Efficacy
1.
Proportion of subjects with clinically meaningful improvement in functional ability defined as a 
decrease of ≥1 point in the adjusted INCAT disability score at 2 consecutive time points OR who 
experience CIDP improvement (defined as ≥8 kPa increase in the hand grip strength in the more 
affected hand OR ≥4 points increase in R-ODS) at the completion of the IV treatment period 
[6 months] or at the last study visit of the IV treatment period, relative to the pre-IV treatment 
baseline score 
Tertiary Outcome Measures
Efficacy
1.
Proportion of subjects whose adjusted INCAT disability score has returned to pre-SC baseline 
(or better) during or at the completion of the IV treatment period [6 months] or at the last study 
visit of the IV treatment period, after previously worsening by ≥1 point during Epoch 1
2.
Proportion of subjects whose hand grip strength in the more affected hand has returned to pre-SC 
baseline (or better) during or at the completion of the IV treatment period [6 months] or at the last 
study visit of the IV treatment period, after previously worsening by ≥8 kPa during Epoch 1
3.
Proportion of subjects whose R-ODS score has returned to the pre-SC baseline (or better) during 
or at the completion of the IV treatment period [6 months] or at the last study visit of the IV 
treatment period, after previously worsening by ≥4 points during Epoch 1
4.
Time to improvement in functional ability (defined as a decrease of ≥1 point in the adjusted 
INCAT score)
5.
Change from pre-IV treatment baseline in adjusted INCAT disability score 
6.
Change from pre-IV treatment baseline in R-ODS 
7.
Change from pre-IV treatment baseline in hand grip strength score 
8.
Change from pre-IV treatment baseline in MRC sum score 
9.
Proportion of subjects who require an increase in IGIV 10% dose due to worsening of CIDP
10. Proportion of subjects who returned to pre-randomization adjusted INCAT disability score
11. Change from pre-IV baseline in the total number or appearance of new demyelinating 
abnormalities on electrodiagnostic studies.
Patient Reported Outcomes
1.
Change from pre-IV treatment baseline in SF-36 scores 
2.
Change from pre-IV treatment baseline in EQ-5D scores 
3.
HRU (such as days off school/work, unscheduled physician visits, hospitalization, and emergency 
room visits)
4.
Treatment satisfaction
5.
Treatment preference
6.
PGIC
Other
1.
Trough serum IgG levels
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INVESTIGATIONAL PRODUCTS, DOSE AND MODE OF ADMINISTRATION
Active Treatment
Epoch 1: 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, except during the ramp-up period 
(see Table 8-3 for IP administration schedule during the ramp-up period)
Dosage form: Injection, solution
Mode of Administration:  
The rHuPH20 solution will be administered subcutaneously via a peristaltic 
infusion pump with programmable infusion rates and infusion volumes at 1, 2, or 
3 infusion sites per infusion day.
Due to a manufacturer (CME America) recall on the Body Guard 323 pump and 
pump tubing, a replacement pump (for US 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 will be noted in the Investigator Site 
Infusion Manual.
2.
IGI, 10%/ IGIV 10%
IGI, 10% when administered intravenously is also referred to as IGIV 10%.
Dose: Same monthly equivalent dose as the individual subject’s pre-randomization 
IgG treatment
Dosing Frequency: Every 2, 3, or 4 weeksiii, except during the ramp-up period 
(see Table 8-3 for IP administration schedule during the ramp-up period)
Dosage form: Injection, solution
Mode of Administration:
The SC infusion of IGI, 10% solution will begin within 10 minutes of completion 
of SC infusion of rHuPH20 solution via a peristaltic infusion pump with 
programmable infusion rates and infusion volumes at 1, 2, or 3 infusion sites per 
infusion day. A step-wise infusion rate escalation  regimen is suggested (see 
Section 8.7.3, Table 8-1, and Table 8-2) 
Due to a  manufacturer (CME America) recall on the Body Guard 323 pump and 
pump tubing, a replacement pump (for US 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 parameter will be noted in the Investigator Site 
Infusion Manual.
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If a subject’s total IgG dose on a given day exceeds 1200 mL for subjects weighing 
≥40 kg or 600 mL for subjects weighing <40 kg, or exceeds the SC maximum 
infusion volume the subject can tolerate, the HYQVIA/HyQvia dose may be 
administered over multiple days as divided doses with 48 to 72 h between doses 
(eg, Day 1 and Day 3 of a given infusion cycle) to allow absorption of infusion 
fluid at infusion site(s).
Epoch 2: GAMMAGARD LIQUID/KIOVIG
1.
GAMMAGARD LIQUID/KIOVIG (IGI 10%) 
(for all subjects with the exception of those at US sites)
Dose: Induction dose of 2 g/kg BW, followed by maintenance infusions at the 
same monthly equivalent dose as the individual subject’s pre-randomization IGIV 
treatment. The IG dose may be adjusted at the discretion of the investigator, as 
medically necessary and/or as tolerated by the subject, with a maximum dose of 
100 g/1000 mL/day.
Dosing Frequency: Every 3 weeks (adjustment to the dosing interval is not 
allowed)
Dosage form: Injection, solution
Mode of Administration:
IV infusion (to be administered via a peristalic variable rate infusion pump). 
Due to a  manufacturer (CME America) recall on the Body Guard 323 pump and 
pump tubing, a replacement pump (for US 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 will be noted in the Investigator 
Site Infusion Manual. The recommended starting infusion rate is 0.5 mL/kg BW/h, 
which may be gradually increased up to 5.4 mL/kg BW/h as tolerated by the 
subject. Induction dose (2 g/kg BW) is to be administered over 2 to 5 consecutive 
days. Maintenance infusions at the same monthly equivalent dose as the individual 
subject’s pre-randomized IGIV doses are to be administered over 2 to 
5 consecutive days, every 3 weeks.
Note: For subjects at the US sites, GAMUNEX®-C will be used. 
GAMUNEX®-C will be used as the IGIV treatment for subjects at US sites who 
relapse in Epoch 1 and enter into Epoch 2. Please refer to GAMUNEX®-C 
Prescribing Information for directions for use and storage instructions.
Dose: Induction dose of 2 g/kg BW, followed by maintenance infusions at the 
same monthly equivalent dose as the individual subject’s pre-randomization IGIV 
treatment. The IG dose may be adjusted at the discretion of the investigator, as 
medically necessary and/or as tolerated by the subject, with a maximum dose of 
100 g/1000 mL/day.
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Dosing Frequency: Every 3 weeks (adjustment to the dosing interval is not 
allowed)
Dosage form: Injection, solution
Mode of Administration:
IV infusion (to be administered via a peristalic variable rate  infusion pump). 
The recommended initial infusion rate is 2 mg/kg/min (0.02 mL/kg/min).
If the infusion is well tolerated, the rate may be gradually increased to a 
maximum of  8 mg/kg/min (0.08 mL/kg/min);see GAMUNEX-C Prescribing 
Information. For patients judged to be at risk for renal dysfunction or thrombosis, 
GAMUNEX-C is recommended to be administered at the minimum infusion 
rate practicable. Induction dose (2 g/kg BW) is to be administered over 2 to 
4 consecutive days, maintenance infusion of 1 g/kg (10 mL/kg) administered 
over 1 day or divided into 2 doses of 0.5 g/kg (5 mL/kg) given on 2 consecutive 
days, every 3 weeks.
EU/ROW -Maximum infusion rate is 500 mL/hr when using the Body Guard 
pump.
Placebo Treatment
Epoch 1: Placebo (0.25% human albumin in LR solution) with rHuPH20
(Sequential SC administration of rHuPH20 solution followed by 0.25% human 
albumin solution in LR solution)
1.
rHuPH20
Dose: 80 U/10 mL of the 0.25% albumin placebo solution
Dosing Frequency: Every 2, 3, or 4 weeksiii, except during the ramp-up period 
(see Table 8-3 for IP administration schedule during the ramp-up period)
Dosage form: Injection, solution
Mode of Administration:
The rHuPH20 solution will be administered subcutaneously via a peristaltic 
infusion pump with programmable infusion rates and infusion volumes at 1, 2, or 
3 infusion sites per infusion day
Due to a  manufacturer  (CME America) recall on the Body Guard 323 pump and 
pump tubing, a replacement pump (for US 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 will be noted in the Investigator Site 
Infusion Manual.
0.25% Human albumin in LR Solution
Dose: At matching infusion volume as the subject’s pre-randomization monthly 
equivalent IgG dose
Dosing Frequency: Every 2, 3, or 4 weeksiii, except during the ramp-up period 
(see Table 8-3 for IP administration schedule during the ramp-up period)
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Dosage form: Injection, solution
Mode of Administration:
SC infusion of 0.25% albumin placebo  solution will begin within 10 minutes of 
completion of SC infusion of rHuPH20 solution via a peristaltic infusion pump 
with programmable infusion rates and infusion volumes at 1, 2, or 3 infusion sites 
per infusion day. A step-wise infusion rate escalation  regimen is suggested (see 
Section 8.7.3, Table 8-1, and Table 8-2) 
Due to a manufacturer (CME America) recall on the Body Guard 323 pump and 
pump tubing, a replacement pump (for US 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 will be noted in the Investigator Site 
Infusion Manual.
If a subject’s total placebo dose (ie, infusion volume of the 0.25% albumin placebo 
solution) on a given day exceeds 1200 mL for subjects weighing ≥40 kg or 600 mL 
for subjects weighing <40 kg, or exceeds the SC maximum infusion volume the 
subject can tolerate, placebo dose may be administered over multiple days as 
divided doses with 48 to 72 h between doses (eg, Day 1 and Day 3 of a given 
infusion cycle) to allow absorption of infusion fluid at infusion site(s).
SUBJECT SELECTION 
Targeted Accrual
Randomization to Epoch 1 will be stopped by the sponsor prior to achieving the 
originally planned total of 174 randomized subjects. At least 120 subjects will be 
randomized and dosed so that adequate statistical power (90%) will still be 
achieved, based on revised sample size assumptions. It is estimated that 15% of 
subjects will be prematurely discontinued from the study.
Number of 
Groups/Arms/
Cohorts
Epoch 1 (SC treatment period) –2 groups (HYQVIA/HyQvia vs 0.25% albumin 
placebo with rHuPH20)
Epoch 2 (IV treatment period) – 1 group (open-label GAMMAGARD 
LIQUID/KIOVIG for all subjects with the exception of those at US sites, or 
GAMUNEX®-C for subjects at the US sites)
Inclusion Criteria
Subjects who meet ALL of the following criteria are eligible for this study:
1. Males or females of age ≥18 years old at the time of screening.
2. Subject has a documented diagnosis of definite or probable CIDP (focal atypical CIDP and pure 
sensory atypical CIDP will be excluded), as confirmed by a neurologist specializing/experienced 
in neuromuscular diseases to be consistent with the European Federation of Neurological 
Societies/Peripheral Nerve Society (EFNS/PNS) 2010 criteria (European Federation of 
Neurological Societies, 2010). Fulfillment of electrodiagnostic criteria must be confirmed by 
an independent qualified/experienced central reader.
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3. Subject has responded to IgG treatment in the past (partial or complete resolution of neurological 
symptoms and deficits), and must currently be on stable doses of IGIV treatment within the dose 
range equivalent to a cumulative monthly dose of 0.4 to 2.4 g/kg BW (inclusive) administered 
intravenously for at least 12 weeks prior to screening. The dosing interval of IGIV treatment must 
be between 2 and 6 weeks (inclusive). Variations in the dosing interval of up to ±7 days or monthly 
dose amount of up to ±20% between subject’s pre study IgG infusions are within acceptable limits.
4. INCAT disability score between 0 and 7 (inclusive). Subjects with INCAT scores of 0, 1 (whether 
from upper or lower extremities), or 2 (if at least 1 point is from an upper extremity) at screening 
and/or baseline will be required to have a history of significant disability as defined by an INCAT 
disability score of 2 (must be exclusively from the lower extremities) or greater documented in the 
medical record. Subjects will be eligible if one of the below eligibility criteria are met: 
a. Screening and Baseline INCAT disability score of between 3 and 7 inclusive.
b. Screening and/or Baseline INCAT disability score of 2 (both points are from lower extremities)
c. Screening and/or Baseline INCAT disability score of 2 (both points are not from lower 
extremities) 
AND has at least a score of 2 or greater documented in the medical record prior to screening. 
If a score was greater than 2 documented in the medical record prior to screening at least 
2 points must be from lower extremities.
d. Screening and/or Baseline INCAT disability score of 0 or 1 AND has at least a score of 2 or 
greater (both from lower extremities) documented in the medical record prior to screening, at 
least 2 points must be from lower extremities.
5. If female of childbearing potential, the subject must have a negative pregnancy test at screening and 
agree to employ a highly effective contraceptive measure throughout the course of the study and for 
at least 30 days after the last administration of investigational product (IP).
6. Subject is willing and able to sign an Informed Consent Form (ICF).
7. Subject is willing and able to comply with the requirements of the protocol.
Exclusion Criteria
Subjects who meet ANY of the following criteria are NOT eligible for this study:
1. Subjects with focal atypical CIDP or pure sensory atypical CIDP.
2. Any neuropathy of other causes, including:
a. Hereditary demyelinating neuropathies, such as hereditary sensory and motor neuropathy 
(HSMN) (Charcot-Marie-Tooth [CMT] disease), and hereditary sensory and autonomic 
neuropathies (HSANs).
b. Neuropathies secondary to infections, disorders, or systemic diseases such as Borrelia 
burgdorferi infection (Lyme disease), diphtheria, systemic lupus erythematosus, POEMS 
(polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes) syndrome, 
osteosclerotic myeloma, diabetic and non-diabetic lumbosacral radiculoplexus neuropathy,
lymphoma, and amyloidosis.
c. Multifocal acquired demyelinating sensory and motor neuropathy (MADSAM)
d. Multifocal motor neuropathy (MMN)
e. Drug-, biologic-, chemotherapy-, or toxin-induced peripheral neuropathy
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3. Immunoglobulin M (IgM) paraproteinemia, including IgM monoclonal gammopathy with high titer 
antibodies to myelin-associated glycoprotein.
4. Presence of prominent sphincter disturbance.
5. Any central demyelinating disorders such as multiple sclerosis.
6. Any chronic or debilitating disease, or central nervous disorder that causes neurological 
symptoms or may interfere with assessment of CIDP or outcome measures, including (but 
not limited to) arthritis, stroke, Parkinson’s disease, and diabetic peripheral neuropathy. 
(Subjects with clinically diagnosed diabetes mellitus who do not have diabetic peripheral 
neuropathy and who have adequate glycemic control with hemoglobin A1C [HbA1C] level of 
<7.5% at screening will be eligible for the study, provided the electrodiagnostic criteria are 
consistent with the diagnosis of a definite or probable CIDP consistent with the EFNS/PNS 2010 
criteria and the subject agrees to maintain adequate glycemic control.)
7. Congestive heart failure (New York Heart Association [NYHA] class III/IV), unstable angina, 
unstable cardiac arrhythmias, or uncontrolled hypertension (defined as diastolic blood pressure 
>100 mmHg and/or systolic blood pressure >160 mmHg).
8. History of deep vein thrombosis or thromboembolic events (eg, cerebrovascular accident, 
pulmonary embolism) within 12 months prior to screening.
9. Condition(s) which could alter protein catabolism and/or IgG utilization (eg, protein-losing 
enteropathies, nephrotic syndrome).
10. Known history of chronic kidney disease, or glomerular filtration rate (GFR) of 
<60 mL/min/1.73m2 estimated based on the Chronic Kidney Disease Epidemiology Collaboration 
(CKD-EPI) equation (Levey et al., 2009) at the time of screening.
11. Subject with active malignancy requiring chemotherapy and/or radiotherapy, or history of 
malignancy with less than 2 years of complete remission prior to screening. Exceptions to this 
exclusion are: adequately treated basal cell or squamous cell carcinoma of the skin, carcinoma in 
situ of the cervix, and stable prostate cancer not requiring treatment.
12. Clinically significant anemia that precludes repeated blood sampling during the study, or 
hemoglobin (Hgb) level of <10.0 g/dL at the time of screening.
13. Known history of hypersensitivity or ARs such as urticaria, breathing difficulty, severe 
hypotension, or anaphylaxis following administration of human blood products such as human IgG, 
albumin, or other blood components.
14. Known allergy to hyaluronidase of human (including recombinant human hyaluronidase) or animal 
origin (such as bee or wasp venom).
15. Known history of or immunoglobulin A (IgA) deficiency (<8 mg/dL) at the time of screening.
16. Abnormal laboratory values at screening meeting any one of the following criteria:
a. Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) > 2.5 × upper 
limit of normal (ULN)
b. Platelet count <100,000 cells/µL
c. Absolute neutrophil count (ANC) <1000 cells/µL
17. Ongoing/active infection with hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus 
(HCV), or human immunodeficiency virus (HIV) Type 1/2 infection at the time of screening. 
(Subjects with immunity to hepatitis B from either active vaccination or from previous natural 
infection are eligible to participate in the study.)
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18. The subject has received or is currently receiving treatment with 
immunomodulatory/immunosuppressive agents within 6 months prior to screening.
19. The subject has received or is currently receiving treatment with any corticosteroids dose within 
8 weeks prior to screening, regardless of indication. 
20. The subject has undergone plasma exchange (PE) within 3 months prior to screening.
21. The subject has any disorder or condition that in the investigator’s judgment may impede the 
subject’s participation in the study, pose increased risk to the subject, or confound the results of the 
study.
22. The subject is nursing or intends to begin nursing during the course of the study.
23. 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 the HYQVIA/HyQvia extension study in CIDP) involving an IP or investigational 
device during the course of this study.
24. The subject is a family member or employee of the investigator.
25. Subjects with acquired or inherited thrombophilic disorders. These will include the specific types of 
acquired or inherited thrombophilic disorders that could put subjects at risk of developing 
thrombotic events. Examples include
a.
Hereditary Thrombophilias: 
i. Factor V Leiden mutation
ii. Prothrombin 20210A mutation
iii. Protein C deficiency 
iv. Protein S deficiency 
v. Antithrombin deficiency 
b.
Acquired thrombophilias
i. Antiphospholipid antibody syndrome 
ii. Activated protein C Resistance acquired 
iii. Homocystinemia
STATISTICAL ANALYSIS
This statistical analysis section provides:

Sample size estimation (along with the underlying assumptions) and the planned statistical analysis 
for HYQVIA/HyQvia during the placebo-controlled, randomized, SC treatment period.

Sample size estimation (along with the underlying assumptions) and the planned statistical analysis 
for GAMMAGARD LIQUID/KIOVIG during the open-label, IV treatment period.
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Epoch 1: SC Treatment with HYQVIA/HyQvia vs Placebo with rHuPH20
Sample Size and Power
Summary
The original planned sample size of 174 randomized subjects was estimated on the basis of the treatment 
effect observed in the GAMUNEX®-C pivotal (ICE) study (Hughes et al., 2008) and an assumed 
remission rate of 45% (Viala et al., 2010).
 
 
 
 
 
Randomization to Epoch 1 will be stopped by the sponsor prior to achieving the original planned sample 
size of 174 randomized subjects. It is expected that at least 120 subjects will be randomized and dosed 
which, based on the revised sample size assumptions using more recent scientific literature, will be 
sufficient to achieve 90% power.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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 based on additional information provided by more recent scientific literature, the original 
sample size assumptions are no longer considered to be accurate and a larger difference in relapse rates of 
29% is now expected compared with the originally assumed 18%. Whilst the assumed relapse rates still 
remain close to the original assumptions, the percentage of subjects on long-term IgG therapy that no 
longer need therapy (the “remission rate”) has been revised from 45% to 19%, leading to an increase in 
the expected treatment effect.
 
Power Calculation
 
 
 
 
 
 
the difference in the relapse rates between the 
HYQVIA/HyQvia and placebo groups is expected to be 29%, where a sample size of 120 randomized and 
dosed subjects (60 subjects per group) will provide 90% power. This power estimate is based on a 
continuity-corrected chi-squared test, equal allocation, a 15% drop-out rate, a two-sided 5% significance 
level and a difference in relapse rates of 29% (39% Placebo – 10% HYQVIA/HyQvia = 29%) and was 
derived based on 100,000 simulation runs and with dropouts imputed as no relapse, as per the planned 
primary analysis.
                                                
vi
www fda.gov/media/146188/download
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Assumptions of Screen Failure Rate and Dropout Rates
The following screening and dropout rate assumptions are made:
a) Screening: A 25% screen failure rate is assumed based on the screen failure rates reported in the 
following clinical studies: 
(1) In the PRIMA study (Léger et al., 2013), 3 of 31 (10%) enrolled subjects were excluded during 
screening; 
(2) In the ICE study (Hughes et al., 2008), 31 of 148 (21%) enrolled subjects were excluded during 
screening.
(3) In the PATH study (van Schaik et al., 2018), 31 of 276 (11%) enrolled subjects were excluded 
during screening 
(4) In the FORCIDP study (Hughes et al., 2018), 53 of 159 (33%) enrolled subjects were excluded 
during screening
b) Dropout Rate: A 15% dropout rate in the treatment period is assumed based on the following clinical 
studies:
(1) In the PRIMA study (Léger et al., 2013), 3 of 28 (11%) subjects were 
prematurely discontinued 
from the study due to serious adverse events and insufficient clinical response. 
(2) In the ICE study (Hughes et al., 2008), 21 of 74 (28%) subjects who initially responded to IGIV 
treatment in the first period and cross-over periods were prematurely discontinued during the extended 
treatment period due to relapse or insufficient response, AE, and other reasons. 
(3) In the PATH study (van Schaik et al., 2018), 16 of 172 (9%) subjects were prematurely 
discontinued from the study due to serious adverse events and withdrawal of consent for other reasons.
(4) In the FORCIDP study (Hughes et al., 2018), 9 of 106 (8%) subjects were prematurely 
discontinued from the study due to serious adverse events, protocol violation, and withdrawal of 
consent for other reasons.
Planned Statistical Analysis
Analysis Sets
The Epoch 1 Safety Set will include all subjects who received any double-blind study medication.
A Modified Intent-to-Treat (MITT) analysis set will include all randomized subjects who received any 
double-blind study medication; this will be the primary efficacy analysis set for Epoch 1 data. 
A Per-Protocol (PP) analysis set will include all randomized subjects who received any double-blind 
study medication, and had no major protocol deviations during Epoch 1 that may have a significant 
impact on the primary outcome measure; this will be used for sensitivity and/or supportive analyses.
Analysis of Primary Outcome Measure
A relapse is defined as worsening of functional disability by ≥1 point (increase) relative to the pre-SC 
treatment baseline score in 2 consecutive adjusted INCAT disability scores.
The null hypothesis is that relapse rates are not different between the HYQVIA/HyQvia and placebo with 
rHuPH20 treatment groups. The primary efficacy outcome measure is the Epoch 1 relapse rate in the 
MITT analysis set. The primary analysis is a comparison of relapse rates in the two treatment groups, 
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using a continuity-corrected chi-square test conducted at the 5% level of statistical significance, with 
missing outcomes imputed as no relapse. The estimated relapse rates will be presented for each planned 
treatment group, along with the 95% confidence interval (CI) computed using the Wilson score method. 
Sensitivity analyses will include comparisons of the relapse rates in (1) the MITT analysis Set with 
missing imputed as a relapse, (2) an MITT Observed Cases analysis (missing outcomes excluded), 
(3) the PP Set with missing imputed as no relapse, and (4) MITT analysis set with missing imputed as no 
relapse, where relapse is alternatively defined as an increase in adjusted INCAT disability score of 
≥1 point relative to the pre-SC treatment baseline score, on a single INCAT assessment; this sensitivity 
analysis removes the requirement for the increase by ≥1 point relative to the pre-SC treatment baseline 
score to be confirmed at a secondary confirmatory INCAT evaluation (to be performed as early as the 
same day of the first INCAT evaluation and no later than 7 days afterwards) in order to classify a subject 
as having relapsed. These sensitivity analyses will use similar statistical methods to the primary analysis.
Analysis of Secondary Outcome Measures
Efficacy
Clinical worsening of CIDP, defined as subject relapse or ≥8 kPa decrease in the hand grip strength in 
the more affected hand OR ≥4 points decrease in R-ODS relative to the pre-SC treatment baseline score 
at 2 consecutive time points at the time of withdrawal from the SC treatment period, will be analyzed 
using the same methods as the primary endpoint.
Time to relapse, defined as time from the date of the first SC administration of HYQVIA/HyQvia or 
placebo with rHuPH20 to the date of relapse, will be compared between treatment groups using the 
Wilcoxon survival test. Additionally, the survival function will be estimated using the Kaplan-Meier 
curve. The analysis will be performed using data from the MITT analysis set with the planned Epoch 1 
treatment.
The change in ADL (R-ODS) from baseline to the end of the treatment period will be analyzed using an 
analysis of covariance (ANCOVA) model to test the treatment effect, with baseline R-ODS as a 
covariate. The last non-missing change in Epoch 1 will be used from subjects who discontinued early.
If an analysis of overall discontinuation rates shows a differential dropout rate between treatments that is 
significant at the 5% level, then a repeated-measures analysis of the change in ADL (R-ODS) will be 
used to investigate the robustness of results of the ANCOVA with last observation carried forward 
(LOCF) imputation in the MITT analysis set. The repeated-measure analysis will employ a restricted 
maximum likelihood (REML)-based, mixed-model repeated measure (MMRM) model which contains 
fixed terms for treatment group and planned timepoint, with baseline R-ODS as a covariate and subject as 
a random factor; additional details will be provided in the statistical analysis plan (SAP). These analyses 
will be performed in the MITT population.
Safety
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA), and reported by 
body system, preferred term, and treatment group. Clinically significant, treatment-emergent changes in 
physical exams, vital signs, electrocardiograms (ECGs), and clinical laboratory measurements will be 
recorded as AEs; therefore, safety analyses will be primarily based on analysis of AEs, including ARs 
plus suspected ARs. Safety endpoints will be summarized descriptively in the Epoch 1 Safety Set using 
actual treatment.
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Treatment-emergent AEs (TEAEs), serious TEAEs, and other AE-related outcome measures will be 
described by the number and percentage of subjects in each treatment group who experienced a particular 
type of event. Additionally, event rates will be expressed as number of events (reports) per infusion, per 
subject, and per subject-year. Both systemic event and events that are localized to the infusion site(s) will 
be examined. The relationship of AEs to infusions will be described further in terms of the number and 
proportion of infusions that were associated with an AE, and the number and proportion of infusions that 
were not completed as planned (interrupted, discontinued) due to an AE.
The first occurrence of any TEAE and the first occurrence of any treatment-emergent SAE will be 
analyzed using a Cox PH model to obtain an overall hazard ratio (HR) for treatment, adjusted for time in 
study (ie, duration of treatment). Separate HR’s for the relationship of AEs with treatment will be 
computed for subjects who had total treatment durations of 0 to 4 weeks, 5 to 8 weeks, 9 to 12 weeks, and 
13 to 26 weeks at the time of the data cut-off. These analyses will address the potential impact of any 
imbalance in AE rates due to differential dropout rates in Epoch 1 between HYQVIA/HyQvia and 
placebo with rHuPH20, and will characterize the relationship of AEs to treatment, overall and over time. 
Point estimates and CIs will be reported.
Similar analyses will be performed for ARs plus suspected ARs.
Summaries of subject deaths during study (if any) and of AEs leading to discontinuation will be provided.
For laboratory measurements, data will be summarized by treatment group and time point. Summaries of 
continuous measurements will include sample size, mean, standard deviation (SD), minimum, and 
maximum. For categorical measurements, the proportion of observations in each category will be 
presented.
Subjects are defined as having elevated rHuPH20 antibody titers if they have two consecutive anti-
rHuPH20 antibody titers of ≥1:160 which are elevated from the subject’s baseline titers. 
If at least 5 subjects in each treatment group have elevated titers, then an exploratory analysis will be 
conducted to assess if there is any evidence of relationship between anti-rHuPH20 antibody titer 
(elevated, not elevated) and the occurrence of AEs of interest.  In addition, an exploratory analysis of 
any treatment emergent abnormal titer or rises above baseline in anti-rHuPH20 antibody titer will be 
performed to assess if there is any evidence of relationship between anti-rHuPH20 antibody titer 
(elevated, not elevated) and the occurrence of AEs. 
Analysis of Tertiary Outcome Measures
Treatment satisfaction, treatment preference, PGIC, HRU (such as days off school/work, unscheduled 
physician visits, hospitalization, and emergency room visits) and changes from pre-IV treatment baseline 
in adjusted INCAT disability scores, hand grip strength scores, MRC sum scores, SF-36 scores, and 
EQ-5D scores will be summarized in the MITT analysis set, by planned treatment group, using 
descriptive statistics (sample size, mean, SD, median, minimum, maximum) for continuous measures 
or the number and percentage of subjects for categorical measures. 
Improvement in functioning in daily tasks will be evaluated using subset of  R-ODS scores. The subset 
scoring will be outlined in the SAP. In addition, a separate psychometric statistical plan (PSAP) will be 
finalized prior to Epoch 1 data lock to confirm the targeted subscale is fit-for-purpose and the subset 
scoring’s validity and reliability.
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Trough plasma concentrations of IgG will be summarized for the Safety set, by actual treatment, using 
the sample size, mean, SD, median, minimum, maximum, geometric mean, and SD of the geometric 
mean.
In addition, potential correlation between serum IgG trough levels on or after day 120 or at the time of 
CIDP symptom relapse and relapse status (relapse, no relapse) will be assessed as an exploratory 
analysis.
Electrodiagnostic (EDX) studies obtained before and after Epoch-1 (Epoch-1 baseline and exit) will be 
used to determine resolution of previously identified demyelinating abnormalities (DA) or occurrence of 
new DA. The total number of DA at Epoch-1 baseline and Epoch-1 exit, as well as their change, and the 
number of new DA in exit EDX will be summarized using descriptive statistics (sample size, mean, SD, 
median, minimum, maximum) for continuous measures or the number and percentage of subjects for 
categorical measures. 
Epoch 2: IV Treatment with GAMMAGARD LIQUID/KIOVIG
Sample Size Calculation
Historical Responder Rate for Placebo: In the ICE study (Hughes et al., 2008), 0 out of 12 treatment-
experienced patients in the placebo group responded to treatment, yielding an estimated responder rate of 
0% with the upper bound of the two-sided 95% CI of 24%, based on the Wilson score method. Therefore, 
for comparison to historical controls, the placebo rate is at most 24% with 97.5% confidence.
Sample Size: Assuming that 19% of enrolled IGIV-pretreated subjects are in remission (and thus would 
not relapse upon withdrawal of treatment) and based on the probability of relapse of 48% for the placebo 
group, a relapse rate of 39% ([1 - 0.19] × 48%) in the SC placebo treatment group is assumed. These 
remission and placebo relapse rate estimates are based on random effect meta-analyses of the relevant 
literature, as detailed for the Epoch 1 sample size calculation.
Randomization to Epoch 1 will be stopped by the sponsor prior to achieving the originally planned total 
of 174 randomized subjects. At least 120 subjects will be randomized and dosed in Epoch 1. Therefore, 
with at least 60 subjects randomized to the SC placebo treatment group in Epoch 1, and allowing for a 
15% drop-out rate in Epoch 1, it is expected that 19 or more subjects (60 x [1–0.15] x 0.39) will relapse 
and subsequently receive GAMMAGARD LIQUID/KIOVIG (or Gammunex-C in the US) treatment in 
Epoch 2. Assuming a responder rate of 65% to GAMMAGARD LIQUID/KIOVIG based on responder 
rates of 55% and 77% observed in the subset of treatment-experienced subjects in the ICE study 
(Hughes et al., 2008) and the PRIMA study (Léger et al., 2013), respectively, the estimated sample size 
of at least 19 subjects will provide more than 90% power to reject the null hypothesis that the responder 
rate is at most 24% at the two-sided 5% significance level and allowing for a 15% drop-out rate in 
Epoch 2.
Planned Statistical Analysis
Analysis Sets
The Epoch 2 Safety Set will include all subjects who had a relapse in Epoch 1, entered Epoch 2, and 
received IGIV treatment with either GAMMAGARD LIQUID/KIOVIG or GAMUNEX®-C in Epoch 2.
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The E1:Placebo Relapse / E2:GGL/KIOVIG Set will include a subset of subjects who had a relapse while 
on placebo in Epoch 1, entered Epoch 2, and were treated with GAMMAGARD LIQUID/KIOVIG in 
Epoch 2. This is the primary analysis set for Epoch 2 (the IV treatment period) non-safety data.
The E1:Placebo Relapse / E2:IGIV Set will include all subjects who had a relapse while on placebo in 
Epoch 1, entered Epoch 2, and were treated with IGIV (GAMMAGARD LIQUID/KIOVIG or 
GAMUNEX®-C). This is a secondary analysis set for Epoch 2 (the IV treatment period) non-safety data.
The E1:HYQVIA/HyQvia Relapse / E2:GGL/KIOVIG Set will include all subjects who had a relapse 
while on HYQVIA/HyQvia in Epoch 1, entered Epoch 2, and were treated with GAMMAGARD 
LIQUID/KIOVIG in Epoch 2. This is an exploratory analysis set for Epoch 2 (the IV treatment period) 
non-safety data.
The E1:HYQVIA/HyQvia Relapse / E2:IGIV Set will include all subjects who had a relapse while on 
HYQVIA/HyQvia in Epoch 1, entered Epoch 2, and were treated with IGIV (GAMMAGARD 
LIQUID/KIOVIG or GAMUNEX®-C) in Epoch 2. This is an exploratory analysis set for Epoch 2 (the 
IV treatment period) non-safety data.
Analysis of Primary Outcome Measure
A responder is defined as a subject who demonstrated an improvement of functional disability by 
≥1 point (decrease) in the adjusted INCAT disability score at the completion of IV treatment period 
(6 months) or the last study visit of the IV treatment period, relative to the pre-IV treatment baseline.
The null hypothesis is that the response rate to GAMMAGARD LIQUID/KIOVIG among subjects who 
relapsed in Epoch 1 while on placebo with rHuPH20 treatment of the current study is not higher than 
24%. If the lower limit of the two-sided 95% Wilson Score CI of the responder rate in the E1:Placebo 
Relapse / E2:GGL/KIOVIG set exceeds the assumed historical-control placebo response rate of 24%, 
then the null hypothesis will be rejected and the current study will be interpreted as providing evidence of 
the efficacy of GAMMAGARD LIQUID/KIOVIG. This analysis will be performed on the E1:Placebo 
Relapse – E2: GGL/KIOVIG analysis set as the primary analysis set.
Analysis of Secondary Outcome Measures
Safety
Epoch 2 safety set, including SAEs, TEAEs, ARs plus suspected ARs, deaths, and discontinuations due to 
AE will be analyzed using methods similar to Epoch 1. Analyses will be performed in the Epoch 2 Safety 
Set using the actual treatment. Safety endpoints will be summarized descriptively by IGIV treatment (ie, 
GAMMAGARD LIQUID/KIOVIG and GAMUNEX®-C separately).
Efficacy
Clinically meaningful improvement of CIDP, defined as one or more of the following: subject response
(response defined as a decrease of ≥1 point in the adjusted INCAT disability score) at 2 consecutive time 
points; ≥8 kPa increase in the hand grip strength in the more affected hand; ≥4 points increase in R-ODS 
at the completion of the IV treatment period [6 months] or at the last study visit of the IV treatment 
period, relative to the pre-IV treatment baseline score, will be presented using descriptive statistics.
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Analysis of Tertiary Outcome Measures
All tertiary outcome measures will be summarized descriptively.
Planned Interim Analyses of the Study
Two interim analyses are planned: 

Interim Safety Analysis, which is Epoch 1 and Epoch 2 safety analysis

Formal Interim Analysis, which is the final analysis of Epoch 1 data
The purpose and timing of each analysis are defined below.
Interim Safety Analysis
An interim safety analysis will be performed during the early conduct of the study to provide a 
preliminary assessment of potential immune response to rHuPH20 in CIDP subjects. 
The interim safety analysis will include a minimum of 30 subjects who have been treated with 
HYQVIA/HyQvia (ie, a total of approximately 60 randomized subjects), and followed up for a minimum 
of 30 days following the second full-dose administration.
Formal Interim Analysis (Epoch 1 Final Analysis)
Formal Interim Analysis will be performed to evaluate the efficacy of HyQvia versus placebo as a 
maintenance therapy for CIDP to prevent relapse of neuromuscular disability and impairment. All of the 
following will apply:

Analysis will be performed when all subjects have completed participation in Epoch 1.

Definition of completed participation: Any subject who completes Epoch 1, or discontinues 
prematurely from Epoch 1, irrespective of reason for withdrawal, is considered as having completed 
participation in Epoch 1.

At the completion of Epoch 1, all Epoch 1 data will be locked, treatment assignment will be 
unblinded, and all Epoch 1 data will be analyzed as preplanned in the study SAP. The analysis will 
be considered the final analysis of Epoch 1 data. All available Epoch 2 data will be included in 
subject data listings along with Epoch 1 data and will not be analyzed. 

No multiplicity adjustment for the control of Type 1 error (false positive conclusion) will be made, 
as the analysis of Epoch 1 data will include all Epoch 1 data for all subjects who have completed
participation in Epoch 1.

The study SAP will be finalized and approved prior to Epoch 1 data lock and treatment unblinding.
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4. TABLE OF CONTENTS
PROTOCOL SIGNATURE PAGE................................................................................. 2
Sponsor’s (Shire) Approval.......................................................................................... 2
Investigator’s Acknowledgement ................................................................................ 2
1. STUDY PERSONNEL.................................................................................................. 3
1.1 Authorized Representative (Signatory) / Responsible Party .............................. 3
1.2 Study Organization................................................................................................. 3
2. SERIOUS ADVERSE EVENT REPORTING........................................................... 4
3. SYNOPSIS..................................................................................................................... 5
4. TABLE OF CONTENTS ........................................................................................... 30
5. LIST OF ABBREVIATIONS .................................................................................... 37
6. BACKGROUND INFORMATION .......................................................................... 40
6.1 Description of Investigational Products.............................................................. 44
6.1.1 Epoch 1............................................................................................................ 44
6.1.1.1 HYQVIA/HyQvia ................................................................................... 44
6.1.1.2 Placebo Control....................................................................................... 46
6.1.2 Epoch 2............................................................................................................ 46
6.1.2.1 GAMMAGARD LIQUID/KIOVIG...................................................... 46
6.1.3 Dose Justification........................................................................................... 47
6.1.3.1 Epoch 1 .................................................................................................... 47
6.1.3.2 Epoch 2 .................................................................................................... 48
6.2 Clinical Condition/Indication .............................................................................. 49
6.3 Population To Be Studied..................................................................................... 49
6.4 Findings from Nonclinical and Clinical Studies................................................. 50
6.5 Evaluation of Anticipated Risks and Benefits of the Investigational Products 
to Human Subjects................................................................................................ 50
6.5.1 HYQVIA/HyQvia........................................................................................... 50
6.5.2 GAMMAGARD LIQUID/KIOVIG............................................................. 51
6.5.3 Placebo Control.............................................................................................. 53
6.6 Compliance Statement.......................................................................................... 53
7. STUDY PURPOSE AND OBJECTIVES ................................................................. 54
7.1 Study Purpose ....................................................................................................... 54
7.2 Epoch 1: SC Treatment Period............................................................................ 54
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7.2.1 Primary Objective.......................................................................................... 54
7.2.2 Secondary Objectives .................................................................................... 54
7.2.3 Tertiary Objectives........................................................................................ 54
7.3 Epoch 2: IV Treatment Period ............................................................................ 55
7.3.1 Primary Objective.......................................................................................... 55
7.3.2 Secondary Objective...................................................................................... 55
7.3.3 Tertiary Objectives........................................................................................ 55
8. STUDY DESIGN......................................................................................................... 56
8.1 Brief Summary...................................................................................................... 56
8.2 Overall Study Design............................................................................................ 56
8.3 Duration of Study Periods and Subject Participation....................................... 59
8.4 Outcome Measures ............................................................................................... 59
8.4.1 Epoch 1: SC Treatment Period..................................................................... 59
8.4.1.1 Primary Outcome Measure ................................................................... 59
8.4.1.2 Secondary Outcome Measures .............................................................. 59
8.4.1.3 Tertiary Outcome Measures.................................................................. 61
8.4.2 Epoch 2: IV Treatment Period ..................................................................... 61
8.4.2.1 Primary Outcome Measure ................................................................... 61
8.4.2.2 Secondary Outcome Measures .............................................................. 62
8.4.2.3 Tertiary Outcomes Measures ................................................................ 63
8.5 Randomization and Blinding............................................................................... 64
8.5.1 Blinding........................................................................................................... 64
8.5.2 Unblinding...................................................................................................... 65
8.6 Study Stopping Rules............................................................................................ 65
8.6.1 Operational procedures for study stopping................................................. 66
8.6.2 Trial integrity................................................................................................. 66
8.7 Investigational Products....................................................................................... 66
8.7.1 Packaging, Labeling, and Storage................................................................ 66
8.7.1.1 rHuPH20.................................................................................................. 66
8.7.1.2 IGI, 10% / IGIV 10%............................................................................. 67
8.7.1.3 Placebo Solution...................................................................................... 67
8.7.1.4 GAMUNEX®-C (US Only)..................................................................... 68
8.7.2 Preparation and Storage of Pooled Products.............................................. 68
8.7.3 Administration ............................................................................................... 69
8.7.3.1 Epoch 1 .................................................................................................... 69
8.7.3.2 Epoch 2 .................................................................................................... 71
8.7.4 Description of Treatment.............................................................................. 72
8.7.4.1 Epoch 1 .................................................................................................... 72
8.7.4.2 Epoch 2 .................................................................................................... 74
8.7.4.3 Weight-Based Determination of Infusion Volume............................... 74
8.7.5 Investigational Product Accountability ....................................................... 75
8.8 Source Data ........................................................................................................... 75
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9. SUBJECT SELECTION, WITHDRAWAL, AND DISCONTINUATION .......... 76
9.1 Inclusion Criteria.................................................................................................. 76
9.2 Exclusion Criteria................................................................................................. 77
9.3 Withdrawal and Discontinuation ........................................................................ 80
10. STUDY PROCEDURES .......................................................................................... 81
10.1 Informed Consent and Enrollment ................................................................... 81
10.2 Subject Identification Code................................................................................ 81
10.3 Screening and Study Visits................................................................................. 81
10.3.1 Screening and Baseline Period.................................................................... 81
10.3.1.1 Rescreening ........................................................................................... 84
10.3.2 Randomization ............................................................................................. 86
10.3.3 Epoch 1: SC Treatment Period................................................................... 86
10.3.3.1 SC Infusion Visits ................................................................................. 86
10.3.3.2 SC Treatment Interim Visit................................................................. 88
10.3.3.3 Unscheduled Visit for Relapse Assessment ........................................ 88
10.3.3.4 End-of-SC Treatment Period............................................................... 89
10.3.4 Epoch 2: IV Treatment Period ................................................................... 89
10.3.4.1 Baseline.................................................................................................. 89
10.3.4.2 IV Infusion Visits.................................................................................. 90
10.3.4.3 IV Treatment Interim Visit.................................................................. 91
10.3.4.4 End of IV Treatment Period................................................................ 91
10.4 Management of Infusion-Related AEs.............................................................. 91
10.5 Medications and Non-Drug Therapies.............................................................. 92
10.5.1 Immunizations.............................................................................................. 93
10.5.2 Pre-Medications for Infusion Administration........................................... 93
10.6 Subject Diary and Patient Reported Outcomes............................................... 94
10.7 Subject Completion/Discontinuation ................................................................ 95
10.8 Procedures for Monitoring Subject Compliance ............................................. 95
10.9 Alternative Approaches to Study Procedures and Data Collection Due to 
COVID-19 Related Factor ................................................................................... 96
11. ASSESSMENT OF EFFICACY............................................................................ 100
11.1 The Inflammatory Neuropathy Cause and Treatment (INCAT) Disability 
Scale...................................................................................................................... 100
11.2 Rasch-Built Overall Disability Scale (R-ODS)............................................... 101
11.3 Hand Grip Strength.......................................................................................... 101
11.4 Medical Research Council (MRC) Sum Score............................................... 102
12. ASSESSMENT OF SAFETY................................................................................. 103
12.1 Adverse Events.................................................................................................. 103
12.1.1 Definitions................................................................................................... 103
12.1.1.1 Serious Adverse Event........................................................................ 103
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12.1.1.2 Suspected Unexpected Serious Adverse Reaction (SUSAR)........... 104
12.1.1.3 Nonserious Adverse Event ................................................................. 104
12.1.1.4 Unexpected Adverse Events............................................................... 105
12.1.1.5 Adverse Reactions Plus Suspected Adverse Reactions.................... 105
12.1.1.6 Preexisting Diseases............................................................................ 105
12.1.2 Assessment of Adverse Events.................................................................. 105
12.1.2.1 Severity ................................................................................................ 107
12.1.2.2 Causality.............................................................................................. 108
12.2 Urgent Safety Measures ................................................................................... 109
12.3 Untoward Medical Occurrences...................................................................... 109
12.4 Non-Medical Complaints ................................................................................. 110
12.5 Medical, Medication, and Non-Drug Therapy History................................. 110
12.6 Physical Examinations...................................................................................... 111
12.7 Clinical Laboratory Parameters...................................................................... 111
12.7.1 Hematology and Clinical Chemistry........................................................ 111
12.7.1.1 Glomerular Filtration Rate................................................................ 112
12.7.2 Hemolytic Panel ......................................................................................... 112
12.7.3 Hemoglobin A1C (HbA1C)....................................................................... 113
12.7.4 Serum Iron, Ferritin, and Total Iron Binding Capacity (TIBC) .......... 113
12.7.5 Serum IgA................................................................................................... 113
12.7.6 Viral Serology Tests................................................................................... 113
12.7.7 Urine Tests.................................................................................................. 114
12.7.8 Pregnancy Test........................................................................................... 114
12.7.9 Assessment of Laboratory Values ............................................................ 114
12.7.9.1 Toxicity Grading Scale....................................................................... 114
12.7.9.2 Assessment of Abnormal Laboratory Values................................... 115
12.7.10 Trough Serum IgG .................................................................................. 115
12.7.11 Anti-rHuPH20 Antibodies ...................................................................... 116
12.7.12 Immunogenicity Panel............................................................................. 116
12.7.12.1 Guidance on Reporting and Assessing rHuPH20 (hyaluronidase) 
antibody test results.............................................................................. 118
12.7.13 Backup Samples/Biobanking .................................................................. 119
12.8 Vital Signs.......................................................................................................... 120
13. OTHER ASSESSMENTS ...................................................................................... 121
13.1 Electrodiagnostic studies (EMG)..................................................................... 121
13.2 Short Form-36 Health Survey (SF-36)............................................................ 122
13.3 EQ-5D ................................................................................................................ 122
13.4 Health Resource Utilization ............................................................................. 122
13.5 Abbreviated Treatment Satisfaction Questionnaire for Medication (TSQM-9)
.............................................................................................................................. 123
13.6 Treatment Preference....................................................................................... 123
13.7 Patient Global Impression of Change............................................................. 123
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14. STATISTICS........................................................................................................... 124
14.1 Epoch 1: SC Treatment Period........................................................................ 124
14.1.1 Sample Size and Power Calculations ....................................................... 124
14.1.1.1 Summary ............................................................................................. 124
14.1.1.2 Rationale.............................................................................................. 124
14.1.1.3 Power calculation................................................................................ 128
14.1.1.4 Assumptions of Screen Failure Rate and Dropout Rates................ 128
14.1.2 Datasets and Analysis Cohorts ................................................................. 129
14.1.3 Handling of Missing, Unused, and Spurious Data.................................. 129
14.1.4 Methods of Analysis................................................................................... 129
14.1.4.1 Primary Outcome Measure ............................................................... 129
14.1.4.2 Secondary Outcome Measures .......................................................... 130
14.1.4.3 Tertiary Outcome Measures.............................................................. 132
14.2 Epoch 2: IV Treatment Period ........................................................................ 133
14.2.1 Sample Size and Power Calculations ....................................................... 133
14.2.1.1 Upper Limit of Response Rate from Historical Control................. 133
14.2.1.2 Power Calculation............................................................................... 134
14.2.2 Datasets and Analysis Cohorts ................................................................. 134
14.2.3 Handling of Missing, Unused, and Spurious Data.................................. 135
14.2.4 Methods of Analysis................................................................................... 135
14.2.4.1 Primary Outcome Measure ............................................................... 135
14.2.4.2 Secondary Outcome Measures .......................................................... 135
14.2.4.3 Tertiary Outcome Measures.............................................................. 136
14.3 Planned Interim Analyses of the Study........................................................... 137
14.3.1 Interim Safety Analysis ............................................................................. 137
14.3.2 Formal Interim Analysis (Epoch 1 Final Analysis) ................................ 138
15. DIRECT ACCESS TO SOURCE DATA/DOCUMENTS .................................. 139
16. QUALITY CONTROL AND QUALITY ASSURANCE.................................... 140
16.1 Investigator’s Responsibility............................................................................ 140
16.1.1 Final Clinical Study Report ...................................................................... 140
16.2 Training ............................................................................................................. 140
16.3 Monitoring......................................................................................................... 140
16.4 Auditing ............................................................................................................. 140
16.5 Non-Compliance with the Protocol ................................................................. 141
16.6 Laboratory and Reader Standardization ....................................................... 141
17. ETHICS ................................................................................................................... 142
17.1 Subject Privacy ................................................................................................. 142
17.2 Ethics Committee and Regulatory Authorities.............................................. 142
17.3 Informed Consent ............................................................................................. 142
17.4 Data Monitoring Committee............................................................................ 143
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17.5 Description of Ethical Considerations Relating to the Trial......................... 143
18. DATA HANDLING AND RECORD KEEPING................................................. 149
18.1 Confidentiality Policy ....................................................................................... 149
18.2 Study Documentation and Case Report Forms ............................................. 149
18.3 Document and Data Retention......................................................................... 149
19. FINANCING AND INSURANCE......................................................................... 150
20. PUBLICATION POLICY...................................................................................... 150
21. SUPPLEMENTS..................................................................................................... 151
21.1 Study Flow Chart.............................................................................................. 151
21.2 Schedule of Study Procedures and Assessments............................................ 152
21.3 Clinical Laboratory Assessments .................................................................... 168
21.4 Toxicity Grading Scale for Laboratory Values.............................................. 179
21.5 Contraceptive Methods for Female Subjects of Childbearing Potential..... 180
22. SUMMARY OF CHANGES.................................................................................. 182
23. REFERENCES........................................................................................................ 187
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Tables
Table 8-1. Recommended SC Infusion Rates for IGI, 10% (or Placebo) for 
Subjects ˂40kg BW .................................................................................................. 69
Table 8-2. Recommended SC Infusion Rates for IGI, 10% (or Placebo) for 
Subjects ≥40kg BW .................................................................................................. 70
Table 8-3. SC Dosing Ramp-Up Schedule  During the Transition from IV to SC Dosing
................................................................................................................................... 73
Table 12-1. List of Conditions/Symptoms Which May be a Result of  Immune-Mediated 
Response to Either Immunoglobulin, rHuPH20,  or Other Concomitant Medications
................................................................................................................................. 117
Table 12-2. Immunogenicity Panel................................................................................. 118
Table 21-1. Schedule of Study Procedures and Assessments: SC Treatment Period 
(Epoch 1) –  Every 2 Weeks Dosing Regimen ....................................................... 152
Table 21-2. Schedule of Study Procedures and Assessments: SC Treatment Period 
(Epoch 1) –  Every 3 Weeks Dosing Regimen ....................................................... 157
Table 21-3. Schedule of Study Procedures and Assessments: SC Treatment Period 
(Epoch 1) –  Every 4 Weeks Dosing Regimen ....................................................... 161
Table 21-4. Schedule of Study Procedures and Assessments: IV Treatment Period 
(Epoch 2) –  Every 3 Weeks Dosing Regimen ....................................................... 165
Table 21-5. Clinical Laboratory Assessments: SC Treatment Period (Epoch 1) – Every 2 
Weeks Dosing Regimen.......................................................................................... 168
Table 21-6. Clinical Laboratory Assessments: SC Treatment Period (Epoch 1) – Every 3 
Weeks Dosing Regimen.......................................................................................... 171
Table 21-7. Clinical Laboratory Assessments: SC Treatment Period (Epoch 1) – Every 4 
Weeks Dosing Regimen.......................................................................................... 174
Table 21-8. Clinical Laboratory Assessments – IV Treatment Period (Epoch 2) .......... 177
Table 21-9. Grading of Laboratory Parameters .............................................................. 179
Figures
Figure 6-1. Pharmacokinetic Comparison of Mean IgG Concentration-Time Profiles  of 
IGI, 10% Following rHuPH20-Facilitated SC (HYQVIA/HyQvia) or IV 
(GAMMAGARD LIQUID/KIOVIG) Administration ............................................. 48
Figure 21-1. Study Design for Clinical Study 161403 ................................................... 151
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5. LIST OF ABBREVIATIONS
Abbreviation
Definition
ADL
Activities of daily living
AE(s)
Adverse event(s)
ALT
Alanine aminotransferase
ANC
Absolute neutrophil count
AR(s)
Adverse reaction(s)
AST
Aspartate aminotransferase
BW
Body weight
CI
Confidence interval
CIDP
Chronic inflammatory demyelinating polyradiculoneuropathy
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
Cmax
Peak or maximum concentration
CRF(s)
Case report form(s)
CTA
Clinical Trial Agreement
DIARYpro
Electronic diary
DMC
Data monitoring committee
EC(s)
Ethics committee(s)
ECRF/eCRF
Electronic case report form
EFNS/PNS
European Federation of Neurological Societies/Peripheral Nerve Society
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
GFR
Glomerular filtration rate
H
Hour 
HAV
Hepatitis A virus
HbA1C
Hemoglobin A1C; also known as glycosylated or glycated hemoglobin
HBcAb
Hepatitis B core antibody
HBsAb
Hepatitis B surface antibody
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
HCV
Hepatitis C virus
Hgb
Hemoglobin 
HIV
Human immunodeficiency virus 
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Abbreviation
Definition
HR
Hazard ratio
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 disability scale
IP(s)
Investigational product(s)
IRT
Interactive Response Technology System
IV
Intravenous
LDH
Lactate dehydrogenase
LR
Lactated Ringer’s
MADSAM
Multifocal acquired demyelinating sensory and motor neuropathy
MITT
Modified Intent-to-Treat
MMN
Multifocal motor neuropathy
MMRM
Mixed-model repeated measure
MRC
Medical Research Council
NMC 
Non-medical complaint
PE
Plasma exchange
PGIC
Patient Global Impression of Change
PID
Primary immunodeficiency disease
PK
Pharmacokinetic(s)
PP
Per-Protocol
PRO
Patient Reported Outcome
RBC
Red blood cell
rHuPH20
Recombinant human hyaluronidase
R-ODS
Rasch-built Overall Disability Scale 
SAE(s)
Serious adverse event(s)
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Abbreviation
Definition
SAER
Serious adverse event report
SAP
Statistical analysis plan
SC
Subcutaneous
Scr
Serum creatinine
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
Tmax 
Time to maximum concentration
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 multifocal motor neuropathy (MMN) (Hahn et al., 2013). Clinical studies in 
neurological indications have also shown significant results with intravenous (IV) 
immunoglobulin G (IGIV) preparations in the treatment of chronic inflammatory 
demyelinating polyradiculoneuropathy (CIDP) (Hughes et al., 2008, Léger et al., 2013).
Chronic inflammatory demyelinating polyradiculoneuropathy (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 (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 to 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).
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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. 
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) (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).
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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.
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 results in impaired dexterity in 
carrying out task 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).
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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. 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 given chronically (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, van Schaik et al., 
2018). This now includes long-term safety and efficacy IGSC up to 48 weeks and 
consistent with PATH study (van Schaik et al., 2019). The meta-analysis of Five studies, 
compassing 176 placebo subjects, measured maintained stability or deterioration as the 
primary endpoint results found deterioration was observed in 57% of these subjects 
randomized to placebo, but 43% (95% CI: 35, 50) did not relapse (placebo effect) 
(Lewis et al., 2020). IGSC replacement therapy is considered to be effective, safe, and 
also highly appreciated by patients  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 adverse event 
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 be delivered subcutaneously, and 2) the low 
bioavailability (65%-69%) (Berger et al., 2013) of the conventional IGSC therapy.
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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. 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-medicated neuropathies for IgG usage, that require immunomodulatory doses up 
to five-times higher than immune replacement doses.
This clinical study is being performed to investigate rHuPH20-facilitated IGSC therapy in 
patients with CIDP (Epoch 1) as well as to study the efficacy of GAMMAGARD 
LIQUID/KIOVIG in CIDP (Epoch 2). 
The COVID-19 pandemic has disrupted on-going drug development efforts including this 
study. More importantly it has resulted in several new issues directly impacting the 
treatment of dysimmune neuropathies (Eftimov et al., 2020).
6.1 Description of Investigational Products
6.1.1 Epoch 1
6.1.1.1 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. The Immune Globulin Infusion, 10% (Human) component of 
HYQVIA/HyQvia is manufactured by the same process and at the same manufacturing 
facilities as GAMMAGARD LIQUID, Immune Globulin Infusion (Human), 10%.
Further information is provided in the Investigator’s Brochure (IB) for Immune Globulin 
Infusion 10% (Human) with Recombinant Human Hyaluronidase (IGI, 10% with 
rHuPH20).
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6.1.1.1.1 Recombinant Human Hyaluronidase (rHuPH20)
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.1.1.1.2 Immune Globulin Infusion 10% (Human) (IGI, 10%)
Immune Globulin Infusion 10% (Human) (IGI, 10%), the therapeutically active 
component of HYQVIA/HyQvia, is identical to that in GAMMAGARD 
LIQUID/KIOVIG.
 
 
 
 
 
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6.1.1.2 Placebo Control
Human albumin 0.25% in Lactated Ringer’s (LR) solution (also known as Ringer’s 
Lactate or Hartmann’s solution or Compound Sodium Lactate Solution for Infusion in 
some participating countries) will be used as the placebo control for IGI, 10% in this 
study. The placebo solution will be administered in the same sequential manner with 
rHuPH20 solution as for HYQVIA/HyQvia.
Lactated Ringer’s solution is a physiological, isotonic solution that will be better tolerated 
in the SC tissue at a large volume than other crystalloid solutions such as normal saline. 
Human albumin at a very low concentration (0.25%) is added to match the appearance 
(eg, color) and foaming characteristics to that of IGI, 10% solution. Human albumin is 
compatible with LR. Human albumin is not known to have any therapeutic activity for 
the treatment of CIDP.
6.1.2 Epoch 2
6.1.2.1 GAMMAGARD LIQUID/KIOVIG
GAMMAGARD LIQUID/KIOVIG Immune Globulin Infusion (Human), 10% Solution; 
IGI, 10% is a liquid solution containing 10% human normal immunoglobulin. IGI, 10% 
when administered intravenously is also referred to as IGIV 10%.
Note: For subjects at the US sites, GAMUNEX®-C will be used.
Please see Section 6.1.1.1.2 for product description. Further information is provided in 
the IB for Immune Globulin Infusion (Human), 10% Solution (IGI, 10%).
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6.1.3 Dose Justification
6.1.3.1 Epoch 1
In Epoch 1 (SC treatment period), the IgG dosing regimen for HYQVIA/HyQvia or the 
0.25% albumin placebo with rHuPH20 will be the same as the subject’s pre-
randomization monthly equivalent IGIV dose (or at matching infusion volume for 
subjects in the placebo group) when administered at a dosing frequency of every 2, 3, or 
4 weeks.
 
 
 
 
 
 
 
 
 
 
 
 
A concentration-time profile of mean serum IgG levels at steady-state following 
administration of GAMMAGARD LIQUID/KIOVIG or HYQVIA/HyQvia administered 
every 4 weeks is shown in Figure 6-1. HYQVIA/HyQvia infusions were given at an 
adjusted dose of 108% of IV dose to provide equivalent area under the IgG 
concentration-time curve (AUC) at steady state. This illustrates (a) the expected 
difference in Cmax and Tmax for the two modes of administration, (b) the superimposition 
of IgG concentration-time curves during the elimination phase following SC and IV 
administration, and (c) comparable trough IgG levels after SC and IV administration. For 
this reason, no dose conversion factor will be applied; that is, subjects entering the study 
will receive the same IgG monthly equivalent dose as their own pre-study IGIV treatment 
regimen that was effective in maintaining the subject’s CIDP condition.
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In Epoch 2, subjects will receive GAMMAGARD LIQUID/KIOVIGvii. The first infusion 
will be given at 2 g/kg BW, followed by maintenance infusions at the same monthly 
equivalent dose that the subject had been stabilized on prior to enrollment into this study. 
Adjustments in the IGIV dose based on clinical response and/or subject’s tolerability are 
allowed. The Epoch 2 IGIV treatment regimen with provision for dose adjustments is 
consistent with the recommendations provided in the EFNS/PNS 2010 guidelines on the 
management of CIDP.
6.2 Clinical Condition/Indication

Epoch 1: For maintenance therapy of CIDP to prevent relapse of neuromuscular 
disability and impairment.

Epoch 2: For the treatment of CIDP to improve neuromuscular disability and 
impairment.
6.3 Population To Be Studied
This study will enroll adult CIDP patients who have demonstrated a response to IGIV 
therapy and who remain on stable doses of IGIV. The study will evaluate the efficacy of 
HYQVIA/HyQvia as a maintenance therapy in Epoch 1 (SC treatment phase) of the 
study. Eligible subjects must have:
1.
a documented diagnosis of definite or probable typical/ atypical CIDP (with the 
exclusion of focal atypical CIDP or pure sensory atypical CIDP), in accordance 
with the EFNS/PNS 2010 guidelines (European Federation of Neurological 
Societies, 2010).
2.
responded to IgG treatment in the past, and must be currently on stable doses of 
IgG treatment within the dose range equivalent to a cumulative monthly dose of 
0.4 to 2.4 g/kg BW administered IV for at least 12 weeks prior to screening.
3.
an Inflammatory Neuropathy Cause and Treatment (INCAT) disability score 
(Hughes et al., 2001) between 0 and 7 (see more details in Section 9.1).
Epoch 2 (IV treatment phase) of the study will include subjects who relapse (see 
definition in Section 8.2) during the randomized “SC treatment phase”, regardless of their 
treatment assignment in Epoch 1.
This study is not planned to enroll treatment-naïve subjects.
                                                
vii At US sites only, subjects who relapse in Epoch 1 will receive GAMUNEX®-C in Epoch 2.
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It is estimated that 232 subjects need to be enrolled into the study in order to achieve 
174 randomized subjects (assuming a 25% screen failure rate). Of the 174 randomized 
subjects, it is estimated that 15% of subjects could discontinue early from the study 
(dropout) such that approximately 148 evaluable subjects will complete the study. (See 
sample size calculations in Section 14.1 for more details.)
6.4 Findings from Nonclinical and Clinical Studies
Findings from nonclinical and clinical studies for HYQVIA/HyQvia are detailed in the 
IGI, 10% with rHuPH20 IB. 
Findings from nonclinical and clinical studies for GAMMAGARD LIQUID/KIOVIG are 
detailed in the IGI, 10% IB.
6.5 Evaluation of Anticipated Risks and Benefits of the Investigational Products to 
Human Subjects
6.5.1 HYQVIA/HyQvia
 
 
 
 
 Further information is provided in the IB for 
Immune Globulin Infusion 10% (Human) with Recombinant Human Hyaluronidase 
(IGI, 10% with rHuPH20) as well as Prescribing Information for HYQVIA and 
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. 
 
 
 
 
 
 
 
 
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No clinical studies have been conducted with HyQvia in pregnant women. HyQvia 
should not be used by women who are pregnant or are planning to become pregnant and 
an alternate treatment should be considered. It is recommended that women of 
childbearing potential take appropriate measures to prevent pregnancy during HyQvia 
treatment (see Section 21.5 for a list of highly effective contraceptive measures). If a 
woman becomes pregnant, treatment with HyQvia should be stopped. 
IGI, 10%, the therapeutically active component of HYQVIA/HyQvia, is identical to that 
in GAMMAGARD LIQUID/KIOVIG. See Section 6.5.2 for the known risks associated 
with IGI, 10%.
6.5.2 GAMMAGARD LIQUID/KIOVIG
IGI, 10% administered via IV treatment (GAMMAGARD LIQUID/KIOVIG) is 
efficacious and safe in the particular fields of therapeutic use and approved indications, 
ie, PID, ITP and MMN, as demonstrated in the clinical development program for 
GAMMAGARD LIQUID/KIOVIG. Please see the IB for Immune Globulin Infusion 
(Human), 10% Solution (IGI, 10%) for further information, as well as the Prescribing 
Information for GAMMAGARD LIQUID and the SmPC for KIOVIG.
Serious ARs (defined as SAEs occurring during or within 72 hours (h) of infusion or any 
casually related SAE occurring within the study period) which occurred in the clinical 
trials of GAMMAGARD LIQUID/KIOVIG were aseptic meningitis, pulmonary 
embolism, and blurred vision. The most common ARs observed in ≥5% of patients were:

PID, IV administration: headache, fatigue, pyrexia, nausea, chills, rigors, pain in 
extremity, diarrhea, migraine, dizziness, vomiting, cough, urticaria, asthma, 
laryngeal pain, rash, arthralgia, myalgia, oedema peripheral, pruritus, and cardiac 
murmur.
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
PID, SC administration: infusion site (local) event, headache, fatigue, heart rate 
increased, pyrexia, abdominal pain upper, nausea, vomiting, asthma, blood pressure 
systolic increased, diarrhea, ear pain, aphthous stomatitis, migraine, oropharyngeal 
pain, and pain in extremity.

MMN, IV administration: headache, chest discomfort, muscle spasms, muscular 
weakness, nausea, oropharyngeal pain, and pain in extremity.
Rare but serious events may occur with IGI products, including hypersensitivity, 
thrombosis, renal dysfunction/failure, hyperproteinemia, increased serum viscosity, and 
hyponatremia hemolysis, hemolysis, transfusion related acute lung injury (TRALI), and 
aseptic meningitis syndrome. 
Thrombosis may occur with immune globulin products, including IGI, 10%. Risk factors 
may include advanced age, prolonged immobilization, hypercoagulable conditions, 
history of venous or arterial thrombosis, use of estrogens, indwelling vascular catheters, 
hyperviscosity, and cardiovascular risk factors.
Renal dysfunction, acute renal failure, osmotic nephrosis, and death may occur in 
predisposed patients receiving 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 treatment include anaphylactic or severe systemic 
hypersensitivity reactions to IG and IgA deficient patients with antibodies against IgA 
and a history of hypersensitivity.
IGI, 10% has a high margin of safety. Screening against potentially infectious 
agents begins with the donor selection process and continues throughout plasma 
collection and preparation. Three validated, dedicated, independent, and effective 
virus inactivation/removal steps have been integrated into the manufacturing and 
formulation processes, further increasing the margin of safety. 
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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 Immune Globulin Infusion (Human), 
10% Solution (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 Directives 
(2001/20/EC; 2005/28/EC),  the Declaration of Helsinki (October 2013), and applicable 
national and local regulatory requirements.
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7. STUDY PURPOSE AND OBJECTIVES
7.1 Study Purpose
The purpose of the study is to provide evidence for the use of HYQVIA/HyQvia as a 
maintenance therapy option that enables self-infusion of a full therapeutic dose every 2 to 
4 weeks in patients with CIDP. 
In addition, this study aims to provide evidence for the use of GAMMAGARD 
LIQUID/KIOVIG as an IV immunoglobulin treatment option in patients with CIDP.
7.2 Epoch 1: SC Treatment Period
7.2.1 Primary Objective
1.
To evaluate the efficacy of HYQVIA/HyQvia as a maintenance therapy for CIDP to 
prevent relapse of neuromuscular disability and impairment.
7.2.2 Secondary Objectives
1.
To assess the time to CIDP relapse during maintenance therapy with 
HYQVIA/HyQvia, compared to placebo.
2.
To assess the effect of HYQVIA/HyQvia on activities of daily living (ADL).
3.
To assess the safety and tolerability of HYQVIA/HyQvia.
4.
To monitor for the presence of binding and neutralizing anti-rHuPH20 antibodies 
following HYQVIA/HyQvia administration.
7.2.3 Tertiary Objectives
1.
To evaluate the effects of HYQVIA/HyQvia on additional clinical outcome 
measures, including change in functional ability, hand grip strength, and muscle 
strength.
2.
To evaluate improvement in functional impact on everyday tasks as measured by a 
pre-specified subscore of R-ODS
3.
To assess the effect of HYQVIA/HyQvia on quality of life, health utility, health 
resource utilization (HRU), treatment satisfaction, treatment preference, and patient 
global impression of change (PGIC).
4.
To assess the effect of HYQVIA/HyQvia on the total number or appearance of new 
demyelinating abnormalities on electrodiagnostic studies.
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7.3 Epoch 2: IV Treatment Period
7.3.1 Primary Objective
1.
To evaluate the efficacy of GAMMAGARD LIQUID/KIOVIG for the treatment of 
CIDP to improve neuromuscular disability and impairment.
7.3.2 Secondary Objective
1.
To assess the safety and tolerability of GAMMAGARD LIQUID/KIOVIG.
2.
To assess the effect of GAMMAGARD LIQUID/KIOVIG on ADL.
7.3.3 Tertiary Objectives
1.
To assess the time to improvement during GAMMAGARD LIQUID/KIOVIG 
treatment.
2.
To evaluate the effects of GAMMAGARD LIQUID/KIOVIG on additional clinical 
outcome measures, including change in functional ability, ADL, hand grip strength, 
and muscle strength in subjects with CIDP.
3.
To assess the effect of GAMMAGARD LIQUID/KIOVIG on quality of life, health 
utility, HRU, treatment satisfaction, treatment preference, and patient global 
impression of change.
4.
To assess the effect of GAMMAGARD LIQUID/KIOVIG on the total number or 
appearance of new demyelinating abnormalities on electrodiagnostic studies.
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8. STUDY DESIGN
8.1 Brief Summary
This is a Phase III, prospective, multicenter study to evaluate the efficacy, safety, and 
tolerability of HYQVIA/HyQvia (IGI, 10% with rHuPH20 administered subcutaneously) 
for maintenance therapy to prevent relapse and GAMMAGARD LIQUID/KIOVIG 
(IGIV 10% administered intravenously) for the treatment of CIDP. This study will enroll 
adult subjects with a confirmed diagnosis of CIDP and who have remained on a stable 
dosing regimen (a monthly equivalent dose of 0.4 to 2.4 g/kg body weight [BW] with a 
dosing interval of 2 to 6 weeks) of IGIV therapy for at least 12 weeks prior to screening.
8.2 Overall Study Design
The overall study design is illustrated in Figure 21-1. Schematics for study assessments 
and visits are detailed in Section 21.2. 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.
After informed consent has been obtained, subjects will undergo screening and baseline 
procedures for the determination of eligibility. During the screening/baseline period, 
subjects will continue to receive their own IGIV treatment at the same dose and dosing 
frequency as prescribed prior to their entry into this study.
Epoch 1: SC Treatment Period
In this double-blind, placebo-controlled phase of the study (Epoch 1), eligible subjects 
will be randomized in a 1:1 ratio to receive either HYQVIA/HyQvia or the 0.25% 
albumin placebo solution with rHuPH20 in a double-blind fashion for a period of 
6 months or until relapse. The dosing regimen for HYQVIA/HyQvia or 0.25% albumin 
placebo with rHuPH20 will be the same as the subject’s pre-randomization monthly 
equivalent IgG dose (or at matching infusion volume for subjects in the placebo group) 
when administered at a dosing frequency of every 2, 3, or 4 weeks (see Section 8.7.4.1
for more information). No conversion factor will be applied when switching from 
pre-randomization IGIV to HYQVIA/HyQvia (or 0.25% albumin placebo with rHuPH20) 
treatment; that is, the monthly IgG dose of HYQVIA/HyQvia (or matching infusion 
volume for subjects in the placebo group) will be the same as the subject’s 
pre-randomization monthly dose of IGIV. The number of infusion visits and clinic visits 
during the SC treatment period will vary across subjects depending on whether their 
infusion cycles are every 2, 3, or 4 weeks (see Table 21-1, Table 21-2, and Table 21-3).
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The study product components of HYQVIA/HyQvia (or 0.25% albumin placebo with 
rHuPH20) will be administered sequentially. Subcutaneous infusion of rHuPH20 solution 
at a dose of 80 U/g IgG (or its equivalent at 80 U/10 mL of the 0.25% albumin placebo 
solution) will be administered first, to be followed by SC infusion of IGI, 10% or 
0.25% albumin placebo solution within 10 minutes of completion of the infusion of 
rHuPH20 solution. To gradually increase the SC infusion volume, a dose ramp-up 
schedule will be employed until the subject’s full dose is reached (see Table 8-3).* 
The first SC administration will take place 2 weeks (±3 days) following the subject’s last 
pre-randomization IGIV administration.
*Week 1 should be calculated from last day of dosing for an infusion dose that is to be 
administered over multiple days.
Initial SC infusions (ie, infusions during the ramp-up period and, at a minimum, the first 
full-dose infusion) must be administered at the study site or infusion center to monitor for 
safety and tolerability, to determine the infusion rate and infusion volume per infusion 
site that can be tolerated by the subject, and to provide training to the subject (and/or, as 
applicable, to a caregiver who may assist the subject with self-infusion) on self-infusion 
procedures. At the investigator’s discretion, the remainder of the SC infusions 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. The ability of 
the subject (and/or caregiver) to perform infusion procedures independently is a 
prerequisite for self-administration. Training and the investigator/designee’s evaluation of 
the subject’s (and/or caregiver’s) proficiency in independently self-administering 
infusions must be documented.
Assessments will be conducted to monitor for changes in the subject’s functional ability 
(INCAT disability score (Hughes et al., 2001), ADL (Rasch-built Overall Disability Scale 
[R-ODS] (van Nes et al., 2011), hand grip strength (Merkies et al., 2000), and muscle 
strength (Medical Research Council [MRC] sum score (Kleyweg et al., 1991). Additional 
assessments will include trough serum IgG levels, as well as safety laboratory 
assessments. Patient reported outcome (PRO) measures will be collected including: 
quality of life (Short Form-36 [SF-36] (Ware et al., 2000)), health utility status (EuroQoL 
[Quality of Life]-5 Dimensions [EQ-5D] scores (The EuroQol Group, 1990), HRU, 
treatment satisfaction, treatment preference, and PGIC. An electronic diary (DIARYpro) 
will be utilized to capture data records related to infusions, AEs, concomitant 
medications, and PRO measures such as the R-ODS and HRU.
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At any time during the SC treatment period, unscheduled visit(s) for INCAT assessments 
will be allowed for subjects who experience CIDP worsening, in order to determine 
whether the worsening meets the definition of relapse (ie, worsening in functional 
disability by ≥1 point relative to the pre-SC treatment baseline in 2 consecutive adjusted 
INCAT disability scoresiv,(Hughes et al., 2008). Open-label treatment with IGIV will be 
provided for any subjects (regardless of their treatment assignment in Epoch 1) who meet 
the definition of relapse and enter into Epoch 2, in order to restore functional ability. An 
INCAT assessment will be performed at the time the subject is being evaluated for 
relapse, and again just prior to initiation of IGIV treatment in Epoch 2. The pre-IV 
treatment baseline INCAT assessment will be used to confirm the subject’s adjusted 
INCAT disability score has increased by ≥1 point relative to the pre-SC treatment 
baseline score, at which time the final determination of whether a subject has met relapse 
criteria will be made. Subjects who relapse during Epoch 1 may choose not to enter into 
Epoch 2. For these subjects, INCAT assessment will be repeated during the early 
termination visit and this INCAT disability score will serve to confirm whether the 
subject has met the relapse criteria.
Epoch 2: IV Treatment Period
Epoch 2 is the open-label phase of this study that aims to provide IGIV treatment for 
subjects who meet relapse criteria during Epoch 1, in order to restore functional ability.
Subjects will receive GAMMAGARD LIQUID/KIOVIG (all subjects with the exception 
of those at US sites) or GAMUNEX®-Cv (subjects at US sites only). IGIV treatment will 
consist of an induction dose of 2 g/kg BW, followed by maintenance infusions at the 
same monthly dose as the subject’s pre-randomization IGIV dosing regimen when 
administered every 3 weeks for a total of 6 months. The dose level of IGIV treatment 
may be adjusted at the discretion of the investigator, as medically necessary and/or as 
tolerated by the subject. Adjustment to the dosing interval of every 3 weeks is not 
allowed. All subjects will be asked to return to the study site every 3 weeks (ie, every 
infusion visit) until study completion or early discontinuation, for follow-up monitoring 
of their functional ability as well as other clinical, safety, PRO measures, and trough 
serum IgG levels.
At any time during the IV treatment period, unscheduled visit(s) for INCAT assessments 
will be allowed for subjects who experience CIDP worsening, in order to determine 
whether the worsening meets the definition of relapse (ie, worsening in functional 
disability by ≥1 point relative to the pre-SC treatment baseline in 2 consecutive adjusted 
INCAT disability scores). Subjects who relapse during Epoch 2, will have a close-out 
visit and terminate participation in the study, in order to have the opportunity to receive 
other/additional treatment.
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8.3 Duration of Study Periods and Subject Participation
The maximum overall duration of this study is estimated to be approximately 72 months 
from study initiation (ie, first subject enrolled) to study completion (ie, last subject last 
visit), including:

An enrollment period of approximately 64 months

Subject participation duration of approximately 8 to 14 months from enrollment 
(ie, signing informed consent) to study completion (ie, last study visit), unless 
prematurely discontinued
For subjects who complete the SC treatment period (Epoch 1) without relapse, the 
duration of study participation will be approximately 8 months, including:

A screening/baseline period of up to 8 weeks

A SC treatment period (Epoch 1) of 6 months
For subjects who relapse during the SC treatment period and subsequently enter into the 
IV treatment period (Epoch 2), the duration of study participation will be approximately 
14 months, including:

A screening/baseline period of up to 8 weeks

A SC treatment period (Epoch 1) of 6 months

An IV treatment period (Epoch 2) of 6 months
8.4 Outcome Measures
8.4.1 Epoch 1: SC Treatment Period
8.4.1.1 Primary Outcome Measure
1.
Relapse rate (proportion of subjects who experience a worsening of functional 
disability defined as an increase of ≥1 point relative to the pre-SC treatment 
baseline score in 2 consecutive adjusted INCAT disability scores)
8.4.1.2 Secondary Outcome Measures
8.4.1.2.1 Efficacy
1.
Proportion of subjects who experience a worsening of functional disability defined 
as one or more of the following: an increase of ≥1 point relative to the pre-SC 
treatment baseline score in 2 consecutive adjusted INCAT disability scores; who 
experience CIDP worsening (defined as a ≥8 kPa decrease in the hand grip strength 
in the more affected hand); ≥4 points decrease in R-ODS relative to the pre-SC 
treatment baseline score (at the time of withdrawal from the SC treatment period)
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2.
Time to relapse 
3.
Change from pre-SC treatment baseline in R-ODS score
8.4.1.2.2 Safety
1.
Number (percentage) of subjects experiencing any treatment-emergent serious 
and/or nonserious 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 nonserious ARs plus suspected 
ARs
4.
Number (percentage) with treatment-emergent SAEs and/or AEs associated with 
infusions, regardless of causality
5.
Number (percentage) of causally related SAEs and/or AEs associated with 
infusions
6.
Number (percentage) of AEs temporally associated with infusions (defined as AEs 
occurring during or within 72 h after completion of an infusion) 
7.
Number (percentage) of serious and/or nonserious ARs plus suspected ARs 
associated with infusions
8.
Number (percentage) of treatment-emergent systemic AEs associated with 
infusions
9.
Number (percentage) of treatment-emergent local infusion site reactions associated 
with infusions
10. 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
11. Rates of systemic and local AEs, regardless of causality, expressed as number of 
events per infusion, per subject, and per subject-year
12. Rates of causally related systemic and local AEs, expressed as number of events per 
infusion, per subject, and per subject-year
13. Rates of systemic and local ARs plus suspected ARs, expressed as number of 
events per infusion, per subject, and per subject-year
14. Number of subjects who have developed binding and/or neutralizing antibodies to 
rHuPH20
Note: Adverse events in this section refer to treatment-emergent AEs, if not 
specified.
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8.4.1.3 Tertiary Outcome Measures
8.4.1.3.1 Efficacy
1.
Change from pre-SC treatment baseline in adjusted INCAT disability score
2.
Change from pre-SC treatment baseline in hand grip strength score 
3.
Change from pre-SC treatment baseline in functional impact on everyday tasks as 
measured by R-ODS sub-components
4.
Change from pre-SC treatment baseline in MRC sum score
5.
Change from prescreen baseline in the total number or appearance of new 
demyelinating abnormalities on electrodiagnostic studies.
8.4.1.3.2 Patient Reported Outcomes
1.
Change from pre-SC treatment baseline in SF-36 scores 
2.
Change from pre-SC treatment baseline in EQ-5D scores 
3.
HRU (such as days off school/work, unscheduled physician visits, hospitalization, 
and emergency room visits)
4.
Treatment satisfaction
5.
Treatment preference
6.
Patient global impression of change
8.4.1.3.3 Other
1.
Trough serum IgG levels
8.4.2 Epoch 2: IV Treatment Period
8.4.2.1 Primary Outcome Measure
1.
Responder rate (proportion of subjects with clinically meaningful improvement in 
functional ability defined as a decrease of ≥1 point in the adjusted INCAT disability 
score at the completion of the IV treatment period [6 months] or at the last study 
visit of the IV treatment period, relative to the pre-IV treatment baseline score) 
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8.4.2.2 Secondary Outcome Measures
8.4.2.2.1 Safety
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 nonserious ARs plus suspected 
ARs
4.
Number (percentage) of treatment-emergent SAEs and/or AEs associated with 
infusions, regardless of causality
5.
Number (percentage) causally related SAEs and/or AEs associated with infusions
6.
Number (percentage) of AEs temporally associated with infusions (defined as AEs 
occurring during or within 72 h after completion of an infusion) 
7.
Number (percentage) serious and/or nonserious ARs plus suspected ARs associated 
with infusions 
8.
Number (percentage) of treatment-emergent systemic AEs associated with 
infusions
9.
Number (percentage) of treatment-emergent local infusion site reactions associated 
with infusions
10. 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
11. Rates of systemic and local AEs, regardless of causality, expressed as number of 
events per infusion, per subject, and per subject-year
12. Rates of causally related systemic and local AEs, expressed as number of events per 
infusion, per subject, and per subject-year
13. Rates of systemic and local ARs plus suspected ARs, expressed as number of 
events per infusion, per subject, and per subject-year
Note: Adverse events in this section refer to treatment-emergent AEs, if not 
specified.
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8.4.2.2.2 Efficacy
1.
Proportion of subjects with clinically meaningful improvement in functional ability 
defined as one or more of the following: a decrease of ≥1 point in the adjusted 
INCAT disability score at 2 consecutive time points; who experience CIDP 
improvement (defined as ≥8 kPa increase in hand grip strength in the more affected 
hand; ≥4 points increase in R-ODS) at the completion of the IV treatment period 
[6 months] or at the last study visit of the IV treatment period, relative to the pre-IV 
treatment baseline score
8.4.2.3 Tertiary Outcomes Measures
8.4.2.3.1 Efficacy
1.
Proportion of subjects whose adjusted INCAT disability score has returned to 
pre-SC baseline (or better) during or at the completion of the IV treatment period 
[6 months] or at the last study visit of the IV treatment period, after previously 
worsening by ≥1 point during Epoch 1
2. Proportion of subjects whose hand grip strength in the more affected hand has 
returned to pre-SC baseline (or better) during or at the completion of the IV 
treatment period [6 months] or at the last study visit of the IV treatment period, after 
previously worsening by ≥8 kPa during Epoch 1
3. Proportion of subjects whose R-ODS score has returned to the pre-SC baseline (or 
better) during or at the completion of the IV treatment period [6 months] or at the 
last study visit of the IV treatment period, after previously worsening by ≥4 points 
during Epoch 1
4. Time to improvement in functional ability (defined as a decrease of ≥1 point in the 
adjusted INCAT score)
5. Change from pre-IV treatment baseline in adjusted INCAT disability score 
6. Change from pre-IV treatment baseline in R-ODS 
7. Change from pre-IV treatment baseline in hand grip strength score 
8. Change from pre-IV treatment baseline in MRC sum score 
9. Proportion of subjects who require an increase in IGIV 10% dose due to worsening 
of CIDP
10. Proportion of subjects who returned to pre-randomization adjusted INCAT 
disability score
11. Change from pre-IV baseline in the total number or appearance of new 
demyelinating abnormalities on electrodiagnostic studies.
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8.4.2.3.2 Patient Reported Outcomes
1.
Change from pre-IV treatment baseline in SF-36 scores
2.
Change from pre-IV treatment baseline in EQ-5D scores
3.
HRU (such as days off school/work, unscheduled physician visits, hospitalization, 
and emergency room visits)
4.
Treatment satisfaction assessed by Treatment Satisfaction Questionnaire for 
Medication (TSQM-9)
5.
Treatment preference
6.
Patient global impression of change
8.4.2.3.3 Other
1.
Trough serum IgG levels
8.5 Randomization and Blinding
This study comprises of 2 epochs: a randomized, double-blind, placebo-controlled SC 
treatment period (Epoch 1) and an open-label IV treatment period (Epoch 2). In order to 
minimize/avoid bias, subjects meeting all eligibility criteria (including baseline INCAT 
assessment) will be randomly assigned to one of two SC treatment regimens 
(HYQVIA/HyQvia or 0.25% albumin placebo with rHuPH20) at a ratio of 1:1. 
Each subject will be assigned a unique randomization code for the duration of the study. 
There will be no re-randomization for those subjects who relapse during Epoch 1 and 
subsequently enter into Epoch 2, as all subjects will receive open-label IGIV treatment 
during Epoch 2. Subjects who were withdrawn or discontinued early from the study after 
randomization will not be replaced. Randomization codes will be generated by the 
sponsor or the sponsor’s representatives, and maintained by a centralized randomization 
service.
8.5.1 Blinding
Epoch 1 is blinded and Epoch 2 is open-label. During Epoch 1, treatment assignment will 
not be revealed to the subject, the investigator and site personnel, the sponsor and 
sponsor’s representatives, except for unblinded study personnel. Unblinded personnel 
will be responsible for maintaining any unblinded records in a secure, access-controlled 
location/system. To avoid inadvertent unblinding, results of serum IgG levels obtained 
after exposure to IP(s) will be withheld from the subject, the investigator and site 
personnel, and all blinded study personnel with the sponsor and sponsor’s representatives 
until all subjects have completed participation in Epoch 1. Any subject who completes 
Epoch 1, or discontinues prematurely from Epoch 1, irrespective of reason for 
withdrawal, is considered as having completed participation in Epoch 1.
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8.5.2 Unblinding
Access to unblinding data during study conduct will be controlled to ensure that the 
scientific integrity and regulatory utility of the study are appropriately maintained and 
protected. 
Unblinding for Interim Safety Analysis:
For the interim safety analysis described in Section 14.3.1, treatment assignment will be 
unblinded and all data will be analyzed as preplanned in the study SAP; similarly for any 
other interim analysis.
Unblinding for Epoch 1 Final Analysis:
At the completion of Epoch 1, all Epoch 1 data will be locked, treatment assignment will 
be unblinded, and all data will be analyzed as preplanned in the study Statistical Analysis 
Plan (SAP). The analysis, described in Section 14.3.2 of this protocol, will be considered 
the final analysis of Epoch 1 data.
Unblinding for Other Purposes during Study Conduct:
Treatment assignment is not to be revealed before the study is completed/terminated, 
except for purposes of the Epoch 1 final analysis and the interim safety analysis, as noted 
above, and in emergency cases when unblinding is necessary for the clinical management 
of an SAE. In such events, the investigator may unblind via the Interactive Response 
Technology System (IRT) at any time (ie, 24 hours per day, 7 days per week) to obtain 
the treatment assignment. Details of unblinding procedures will be provided to study 
sites. 
8.6 Study Stopping Rules
A Data Monitoring Committee (DMC) will be established to monitor the study for any 
safety or medical concerns, and may recommend stopping the study based on the criteria 
defined in the DMC charter (see Section 17.4). The study may be terminated by the 
sponsor at any time.
In addition to the threat and future uncertainty caused by the COVID-19 pandemic, the 
study has had considerable recruitment challenges as a result of low CIDP prevalence, 
unwillingness of patients to discontinue their existing effective CIDP treatments, 
increasing competition in the CIDP trial landscape, and the reluctance of physicians and 
patients to be exposed to placebo given the existence of efficacious treatments for CIDP.
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As a result of these special circumstances, randomization to Epoch 1 will be stopped by 
the sponsor prior to achieving the originally planned total of 174 randomized subjects 
(i.e., such that 148 subjects would have been expected to complete Epoch 1). Based on 
updated sample size assumptions as a result of the changed scientific landscape since the 
study was originally planned, it is expected that adequate statistical power (90%) will still 
be achieved (Sections 14.1.1 and 14.2.1.2).
8.6.1 Operational procedures for study stopping
The following actions will be taken:

Randomization to Epoch 1 will be closed prior to achieving the originally planned 
total of 174 randomized subjects.

All subjects randomized will be permitted to complete Epoch 1 and may enter 
Epoch 2 if they relapse on Epoch 1, in accordance with study procedures.  Any 
patient entering into Epoch 2 will be followed for the protocol specified time or 
discontinuation. 
8.6.2 Trial integrity
It is important to note that the sponsor decision to stop randomization to Epoch 1 prior to 
achieving the originally planned target of 174 subjects is completely independent of 
observed study data and that trial integrity is completely maintained. This trial 
modification is therefore without risk of introducing bias into the interpretation of trial 
findings. 
8.7 Investigational Products
8.7.1 Packaging, Labeling, and Storage
8.7.1.1 rHuPH20
Dosage Form: Injection, solution
Packaging: rHuPH20 drug product (160 U/mL) will be supplied as a clear, colorless, 
ready-for-use sterile liquid preparation in single-use glass vials. The product should be 
inspected visually for particulate matter and discoloration. The product should not be 
used if particulate matter and/or discoloration is observed.
Labeling: The product will be labeled according to the regulatory requirements for 
clinical studies.
Storage: rHuPH20 drug product must be stored under refrigerated conditions (2° to 8°C 
or 36° to 46°F). Do not freeze the product. Do not use if expiration date is exceeded.
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8.7.1.2 IGI, 10% / IGIV 10%
IGI, 10% when administered intravenously is also referred to as IGIV 10%.
Dosage Form: Injection, solution.
Packaging: IGI, 10% / IGIV 10% will be supplied as a ready-for-use sterile liquid 
preparation in single-use glass vials. IGI, 10% / IGIV 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% / IGIV 10% will be labeled according to regulatory requirements for 
clinical studies.
Storage: IGI, 10% / IGIV 10% must be stored under refrigerated conditions (2° to 8°C or 
36° to 46°F). Do not freeze the product. Do not use if expiration date is exceeded.
8.7.1.3 Placebo Solution
Human albumin 0.25% in LR solution will be used as the placebo control in this study. 
Human albumin 0.25% solution will be prepared at the pharmacy by appropriate dilution 
of a concentrated human albumin product (e.g., 200 to 250 g/L or 25%) with LR solution.
Do not dilute human albumin solution with sterile water for injection.
Both human albumin product and LR solution should be inspected visually for particulate 
matter and discoloration. The products should not be used if particulate matter and/or 
discoloration is observed.
Dosage Form: Injection, solution.
Packaging: Human albumin product will be supplied as a transparent or slightly 
opalescent solution, which may have a greenish tint or may vary from a pale straw to an 
amber color in rest of world, and clear, slightly viscous solution, almost colorless, yellow 
to brown or green in US and Canada.
LR solution is a ready-for-use, sterile, clear, or almost colorless solution.
Labeling: Human albumin solution will be labeled according to regulatory requirements 
for clinical studies.
Storage: Store human albumin product according to information provided in the specific 
product label. Store LR solution at room temperature. Do not freeze the product. Do not 
use if expiration date is exceeded.
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8.7.1.4 GAMUNEX®-C (US Only)
GAMUNEX®-C will be used as the IGIV treatment for subjects at US sites who relapse 
in Epoch 1 and enter into Epoch 2. Please refer to GAMUNEX®-C Prescribing 
Information for directions for use and storage instructions.
8.7.2 Preparation and Storage of Pooled Products
Vials of rHuPH20 solution and bag(s) of pooled IGI, 10%/0.25% albumin placebo 
solution will be supplied for infusions.
The vials of rHuPH20 must be stored under refrigerated conditions (2° to 8°C or 36° 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% and 0.25% albumin placebo solutions for administration must 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 h from the time of preparation. 
When administration of pooled products will begin more than 3 h from preparation, they 
must be kept at 2° to 8°C (36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 h after removal from the 
temperature-controlled storage. 
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 and immediately following preparation and after reaching room 
temperature.
All solutions for infusion must be administered at room temperature. 
All solutions for infusion will be labeled according to regulatory requirements for clinical 
studies.
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For instructions on preparation and administration of GAMUNEX®-C, please refer to the 
GAMUNEX®-C Prescribing Information.
8.7.3 Administration
8.7.3.1 Epoch 1
Mode of administration:
The rHuPH20 solution will be administered subcutaneously via a peristaltic infusion 
pump with programmable infusion rates and infusion volumes at 1, 2, or 3 infusion sites 
per infusion day
Due to a manufacturer (CME America) recall on the Body Guard 323 pump and pump 
tubing, a replacement pump (for US 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 will be noted in the Investigator Site Infusion Manual.
The rHuPH20 solution and IGI, 10%/0.25% albumin placebo solution will be 
administered in a sequential order, with IGI, 10%/0.25% albumin placebo infusion being 
initiated within approximately 10 minutes of completing the infusion of the rHuPH20 
solution.
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 for both rHuPH20 and IGI, 10% /placebo solution.
IGI, 10%/placebo solution:
IGI,10/Placebo solution is administered second, within 10 minutes of the rHuPH20 being 
completed.
Table 8-1. Recommended SC Infusion Rates for IGI, 10% (or Placebo) for 
Subjects ˂40kg BW
Infusion Rate Per Infusion Site (mL/h)
First 2 
Infusions
Next 2 
Infusions
All Subsequent Infusions
First 5 – 15 min
5
10
Infusion rates may be adjusted and an abbreviated infusion 
rate ramp-up scheme may be employed at the investigator’s 
discretion and based on subject’s tolerability level, but not to 
exceed 160 mL/h per infusion site  For details of using 
Bifurcated and Trifucated infusion sets  and infusion rates 
recommended see the Investigator Site Infusion Manual
Next 5 - 15 min
10
20
Next 5 - 15 min
20
40
Next 5 - 15 min
40
80
Remainder of infusion
80
160
Abbreviation: BW = Body weight; SC=Subcutaneous
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Table 8-2. Recommended SC Infusion Rates for IGI, 10% (or Placebo) for 
Subjects ≥40kg BW
Infusion Rate Per Infusion Site (mL/h)
First 2 
Infusions
Next 2 
Infusions
All Subsequent Infusions
First 5 – 15 min
10
10
Infusion rates may be adjusted and an abbreviated 
infusion rate ramp-up scheme may be employed at 
the investigator’s discretion and based on subject’s 
tolerability level, but not to exceed 300 mL/h per 
infusion site.
For details of using Bifurcated and Trifucated 
infusion sets  and infusion rates recommended see 
the Investigator Site Infusion Manual
Next 5 - 15 min
30
30
Next 5 - 15 min
60
120
Next 5 - 15 min
120
240
Remainder of infusion
240
300
Abbreviation: BW = Body weight; SC=Subcutaneous 
Site of administration: The recommended site(s) for SC infusion are the right and left 
middle to upper abdomen and the right and left thighs, at the subject’s preference. If 
2 infusion sites are used concurrently, the 2 or 3 infusion sites should be on opposite sides 
of the middle to upper abdomen at least 10 cm apart or on opposite thighs. Avoid bony 
prominences, visible blood vessels, scars, and areas that are inflamed or infected. For 
large IgG doses (or matching infusion volume for subjects in the placebo group), the 
entire dose may be administered over multiple days as divided doses at least 48 to 72 h 
apart for tenderness, erythema, or swelling that may result from the previous infusion to 
subside.
Volume of infusion per site: IGI, 10% or 0.25% albumin placebo solution may be 
administered at 1, 2, or 3 infusions sites with a maximum infusion volume of 600 mL for 
subjects weighing ≥40 kg or up to 300 mL for subjects weighing <40 kg (or as tolerated) 
at each infusion site. 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. 
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.
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8.7.3.2 Epoch 2
Subjects will receive GAMMAGARD LIQUID/KIOVIG (all subjects with the exception 
of those at US sites) or GAMUNEX®-C (subjects at US sites only).
Mode of administration: IV infusion
Rate of administration: GAMMAGARD LIQUID/KIOVIG will be administered 
intravenously with a step-wise increase in infusion rate regulated using a peristaltic 
infusion pump with programmable infusion rates and infusion volumes. 
Due to a manufacturer (CME America) recall on the Body Guard 323 pump and pump 
tubing, a replacement pump (for US only) will be  the Q Core – Sapphire pump. 
IV infusion (to be administered via a peristalic variable rate infusion pump). 
The Body Guard 323 pump and pump tubing will  continue to be used in EU/ROW.  
Details on the infusion parameters will be noted in the Investigator Site Infusion Manual.
The recommended starting infusion rate is 0.5 mL/kg BW/h, which may be gradually 
increased up to 5.4 mL/kg BW/h as tolerated by the subject. Induction dose (2 g/kg BW) 
is to be administered over 2 to 5 consecutive days. Maintenance infusions at the same 
monthly equivalent dose as the individual subject’s pre-randomized IGIV doses are to be 
administered over 2 to 5 consecutive days, every 3 weeks.
It is recommended that, for the initial 2 infusions, IGIV 10% should be infused at starting 
infusion rate of 0.5 mL/kg BW/h. The infusion rate may be gradually increased up to 
5.4 mL/kg BW/h, at the discretion of the investigator and if tolerated by the subject. For 
all subsequent infusions, the starting infusion rate and the increases in the infusion rate 
may be determined by the investigator or in accordance with institutional standardized 
infusion rate protocols. The maximum infusion rate should not exceed 5.4 mL/kg BW/h 
at any time. In the EU, the maximum infusion rate for Body Guard 323 pump is 
500 mL/hr.
GAMUNEX®-C will be administered in accordance with the GAMUNEX®-C Prescribing 
Information and based on the subject’s pre-study IGIV treatment history, including initial 
and maximum tolerated rate(s) of administration.
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8.7.4 Description of Treatment
8.7.4.1 Epoch 1
Treatment: Either HYQVIA/HyQvia or placebo (0.25% human albumin in LR solution) 
with rHuPH20, based on treatment assignment
Treatment Period: 6 months, or until relapse
Dose:

rHuPH20 solution: 80 U rHuPH20/g IgG, or 80 U rHuPH20/10 mL of the 
0.25% albumin placebo solution. If the IGI, 10%/0.25% albumin placebo solution 
is given at a single site, the entire dose of recombinant rHuPH20 should be given at 
the site. When using bifurcated or trifurcated needle set, IGI, 10%/placebo is to be 
divided between 2 or 3 sites, respectively. Additionally, rHuPH20 dose should be 
divided between 2 or 3 sites by maintaining the ratio of 80 U rHuPH20 per 10 mL 
of IGI 10% or placebo (0.25% human albumin in LR solution).

IGI, 10% or placebo: Same as the subject’s pre-randomization monthly equivalent 
IgG dose for subjects receiving IGI, 10%, or at matching infusion volume for 
subjects in the placebo group. No conversion factor will be applied when switching 
from pre-randomization IGIV to IGI, 10% or 0.25% albumin placebo with 
rHuPH20 treatment; that is, the monthly IgG dose of IGI, 10% (or matching 
infusion volume for subjects in the placebo group) will be the same as the subject’s 
pre-randomization monthly dose of IGIV.
Dosing frequency: Every 2, 3, or 4 weeks, except during the ramp-up period. See 
Table 8-3 below for dosing schedule during the ramp-up period.
1.
Subjects on pre-randomization IGIV treatment schedule every 2, 3, or 4 weeks will 
continue to receive HYQVIA/HyQvia or 0.25% albumin placebo with rHuPH20 
administration at the same dosing frequency during the study. Adjustment to dosing 
interval is not allowed, except due to intolerability.
2.
Adjustment to the dosing frequency as the subject transitions from pre-
randomization IGIV to SC IGI, 10% or 0.25% albumin placebo will only be 
allowed in the following cases:
a.
For subjects with pre-randomization IGIV dosing every 5 or 6 weeks, the 
dosing interval in the study will be converted to 2, 3, or 4 weeks while 
maintaining the same monthly equivalent IgG dose (or matching infusion 
volumes for subjects in the placebo group). The choice of 2-, 3-, or 4-week 
interval will be at the discretion of the investigator and based on the subject’s 
tolerability.
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b.
For subjects with an IgG dose (or matching infusion volume for subjects in 
the placebo group) that exceeds the SC maximum infusion volume that a 
given subject can tolerate, HYQVIA/HyQvia or 0.25% albumin placebo with 
rHuPH20 may be administered at a 2-, 3-, or 4-week dosing interval at the 
discretion of the investigator and as tolerated by the subject while maintaining 
the same monthly equivalent dose.
Ramp-up Schedule: During the transition from pre-randomization IV to SC dosing, a 
dose ramp-up schedule to gradually increase the SC infusion volume will be employed 
until the subject’s full dose is reached (see Table 8-3). The first SC administration 
(1-week dose) will take place 2 weeks (±3 days) following the subject’s last pre-
randomization IGIV administration, regardless of the pre-randomization IGIV dosing 
interval.
Table 8-3. SC Dosing Ramp-Up Schedule 
During the Transition from IV to SC Dosing
Dosing 
Schedule
Study Visits
S / BL Period 
(up to 8 Wks) 
SC Treatment Period 
(6 Months)
Pre-SC 
BL
W1a
(2 Wks After 
Pre-SC BL)
W2 W3 W4 W5 W6 W7
W8 W9 W10 W11 W12
Q2W
Last full IGIV 
dose
1-W
1-W 2-W (full dose) and every 2 weeks thereafter
Q3W
1-W
1-W 2-W
--
3-W (full dose) and every 3 weeks thereafter
Q4W
1-W
1-W 2-W
--
3-W
--
--
4-W (full dose) and every 
4 weeks thereafter
Abbreviations: S = Screening; BL = Baseline; Pre-SC BL = Pre-subcutaneous treatment baseline visit; 
wks = weeks; W = Week; 1-W = 1-week dose; 2-W = 2-week dose; 3-W = 3-week dose; 
4-W = 4-week dose; --: No infusion will be administered for the particular week as marked.
a W1 indicates when the first administration of HYQVIA/HyQvia or 0.25% albumin placebo with 
rHuPH20 is given. The first SC administration will take place 2 weeks (±3 days) following the subject’s 
last pre-randomization IGIV administration.
As an example, a monthly dose of 1.6 g/kg (equivalent to 0.4 g/kg per week) would be administered 
according to the following SC ramp-up regimens (as applicable):
0.8 g/kg BW Q2W: 0.4 g/kg BW during Week 1 and Week 2 visits, 0.8 g/kg BW (full dose) during 
Week 3 visit and every 2 weeks thereafter (Week 5, Week 7,…,Week 27).
1.2 g/kg BW Q3W: 0.4 g/kg BW during Week 1 and Week 2 visits, 0.8 g/kg BW during Week 3 
visit, 1.2 g/kg BW (full dose) during Week 5 visit and every 3 weeks thereafter (Week 8, 
Week 11,…,Week 26).
1.6 g/kg BW Q4W: 0.4 g/kg BW during Week 1 and Week 2 visits, 0.8 g/kg BW during Week 3 
visit, 1.2 g/kg BW during Week 5 visit, 1.6 g/kg BW (full dose) during Week 8 visit and every 
4 weeks thereafter (Week 12, Week 16,…,Week 28).
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8.7.4.2 Epoch 2
Treatment: GAMMAGARD LIQUID/KIOVIG (all subjects with the exception of those 
at US sites) or GAMUNEX®-C (subjects at US sites only)
Treatment period: 6 months
Dosing and dosing frequency:
GAMMAGARD LIQUID/KIOVIG: 
The first IGIV dose will be 2 g/kg BW given as divided doses over 2 to 5 consecutive 
days (for GAMMAGARD LIQUID/KIOVIG), followed by maintenance infusions at the 
same monthly dose as the individual subject’s pre-randomization IGIV doses are to be 
administered over 2 to 5 days (for GAMMAGARD LIQUID/KIOVIG) every 3 weeks.
GAMUNEX-C: 
The recommended initial infusion rate is 2 mg/kg/min (0.02 mL/kg/min). If the infusion 
is well tolerated, the rate may be gradually increased to a maximum of 8 mg/kg/min 
(0.08 mL/kg/min) In the EU, the maximum infusion rate for the Body Guard 323 is 
500 mL/hr; see GAMUNEX-C prescribing information. For patients judged to be at risk 
for renal dysfunction or thrombosis, this drug is recommended to be administered at the 
minimum infusion rate practicable. Induction dose (2 g/kg BW) is to be administered 
over 2 to 4 consecutive days, maintenance infusion of 1 g/kg (10 mL/kg) administered 
over 1 day or divided into 2 doses of 0.5 g/kg (5 mL/kg) given on 2 consecutive days, 
every 3 weeks
The dose level of IGIV treatment may be adjusted at the discretion of the investigator, as 
medically necessary and/or as tolerated by the subject, with a maximum dose of 
100 g/1000 mL/day. There will be no adjustments to the dosing interval of every 3 weeks.
8.7.4.3 Weight-Based Determination of Infusion Volume 
In both Epoch 1 and Epoch 2, the volume (mL) of infusion solution to be administered 
will be calculated using the subject’s BW measured at screening. Adjustment based on 
BW changes during the course of the study is not planned, however may be done if 
deemed medically necessary by the investigator (eg, clinically significant BW change). 
After screening, for study visits where the subject’s BW is measured, (see 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. 
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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; home, as applicable per study design). Records will be maintained that 
includes the subject identification code (SIC), dispensation date, and amount dispensed.
All remaining partially used and/or unused IP(s) will be returned to the sponsor or 
sponsor’s representative after study completion/termination or destroyed with the 
permission of the sponsor in accordance with applicable laws and study site procedures. 
If IP(s) is to be destroyed, the investigator/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) 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 form (CRF). All data entered in to 
the CRF should be able to be verified by a corresponding source document.
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.
Males or females of age ≥18 years old at the time of screening.
2.
Subject has a documented diagnosis of definite or probable CIDP (focal atypical 
CIDP and pure sensory atypical CIDP will be excluded), as confirmed by a 
neurologist specializing/experienced in neuromuscular diseases to be consistent 
with the EFNS/PNS 2010 criteria (European Federation of Neurological Societies, 
2010). Fulfillment of electrodiagnostic criteria must be confirmed by an 
independent qualified/experienced central reader.
3.
Subject has responded to IgG treatment in the past (partial or complete resolution of 
neurological symptoms and deficits), and must currently be on stable doses of IGIV 
treatment within the dose range equivalent to a cumulative monthly dose of 0.4 to 
2.4 g/kg BW (inclusive) administered intravenously for at least 12 weeks prior to 
screening. The dosing interval of IGIV treatment must be between 2 and 6 weeks 
(inclusive). Variations in the dosing interval of up to ±7 days or monthly dose 
amount of up to ±20% between subject’s pre study IgG infusions are within 
acceptable limits
4.
INCAT disability score between 0 and 7 (inclusive). Subjects with INCAT scores 
of 0, 1 (whether from upper or lower extremities), or 2 (if at least 1 point is from an 
upper extremity) at screening and/or baseline will be required to have a history of 
significant disability as defined by an INCAT disability score of 2 (must be 
exclusively from the lower extremities) or greater documented in the medical 
record. Subjects will be eligible if one of the below eligibility criteria are met: 
a.
Screening and Baseline INCAT disability score of between 3 and 7 inclusive.  
Screening and/or Baseline INCAT disability score of 2 (both points are from 
lower extremities)
b.
Screening and/or Baseline INCAT disability score of 2 (both points are not 
from lower extremities) AND has at least a score of 2 or greater documented in 
the medical record prior to screening. If a score was greater than 2 documented 
in the medical record prior to screening at least 2 points must be from lower 
extremities.
c.
Screening and/or Baseline INCAT disability score of 0 or 1 AND has at least a 
score of 2 or greater (both from lower extremities) documented in the medical 
record prior to screening, at least 2 points must be from lower extremities.
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5.
If female of childbearing potential, the subject must have a negative pregnancy test 
at screening and agree to employ a highly effective contraceptive measure (see 
Section 21.5 for more details) throughout the course of the study and for at least 
30 days after the last administration of investigational product (IP).
6.
Subject is willing and able to sign an Informed Consent Form (ICF).
7.
Subject is willing and able to comply with the requirements of the protocol.
9.2 Exclusion Criteria
Subjects who meet ANY of the following criteria are NOT eligible for this study:
1.
Subjects with focal atypical CIDP or pure sensory atypical CIDP.
2.
Any neuropathy of other causes, including:
a.
Hereditary demyelinating neuropathies, such as hereditary sensory and motor 
neuropathy (HSMN) (Charcot-Marie-Tooth [CMT] disease), and hereditary 
sensory and autonomic neuropathies (HSANs)
b.
Neuropathies secondary to infections, disorders, or systemic diseases such as 
Borrelia burgdorferi infection (Lyme disease), diphtheria, systemic lupus 
erythematosus, POEMS (polyneuropathy, organomegaly, endocrinopathy, 
M-protein, and skin changes) syndrome, osteosclerotic myeloma, diabetic and 
non-diabetic lumbosacral radiculoplexus neuropathy, lymphoma, and 
amyloidosis.
c.
Multifocal acquired demyelinating sensory and motor neuropathy (MADSAM)
d.
Multifocal motor neuropathy (MMN)
e.
Drug-, biologic-, chemotherapy-, or toxin-induced peripheral neuropathy
3.
Immunoglobulin M (IgM) paraproteinemia, including IgM monoclonal 
gammopathy with high titer antibodies to myelin-associated glycoprotein
4.
Presence of prominent sphincter disturbance.
5.
Any central demyelinating disorders such as multiple sclerosis.
6.
Any chronic or debilitating disease, or central nervous disorder that causes 
neurological symptoms or may interfere with assessment of CIDP or outcome 
measures, including (but not limited to) arthritis, stroke, Parkinson’s disease, 
and diabetic peripheral neuropathy.
(Subjects with clinically diagnosed diabetes mellitus who do not have diabetic 
peripheral neuropathy and who have adequate glycemic control with hemoglobin 
A1C [HbA1C] level of <7.5% at screening will be eligible for the study, provided 
the electrodiagnostic criteria are consistent with the diagnosis of a definite or 
probable CIDP consistent with the EFNS/PNS 2010 criteria and the subject agrees 
to maintain adequate glycemic control.)
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7.
Congestive heart failure (New York Heart Association [NYHA] class III/IV), 
unstable angina, unstable cardiac arrhythmias, or uncontrolled hypertension 
(defined as diastolic blood pressure >100 mmHg and/or systolic blood 
pressure >160 mmHg).
8.
History of deep vein thrombosis or thromboembolic events (eg, cerebrovascular 
accident, pulmonary embolism) within 12 months prior to screening.
9.
Condition(s) which could alter protein catabolism and/or IgG utilization (eg, 
protein-losing enteropathies, nephrotic syndrome).
10. Known history of chronic kidney disease, or glomerular filtration rate (GFR) of 
<60 mL/min/1.73m2 estimated based on the Chronic Kidney Disease Epidemiology 
Collaboration (CKD-EPI) equation (Levey et al., 2009) at the time of screening.
11. Subject with active malignancy requiring chemotherapy and/or radiotherapy, or 
history of malignancy with less than 2 years of complete remission prior to 
screening. Exceptions to this exclusion are: adequately treated basal cell or 
squamous cell carcinoma of the skin, carcinoma in situ of the cervix, and stable 
prostate cancer not requiring treatment.
12. Clinically significant anemia that precludes repeated blood sampling during the 
study, or hemoglobin (Hgb) level of <10.0 g/dL at the time of screening.
13. Known history of hypersensitivity or ARs such as urticaria, breathing difficulty, 
severe hypotension, or anaphylaxis following administration of human blood 
products such as human IgG, albumin, or other blood components.
14. Known allergy to hyaluronidase of human (including recombinant human 
hyaluronidase) or animal origin such as bee or wasp venom.
15. Known history of, or immunoglobulin A (IgA) deficiency (<8 mg/dL) at the time of 
screening.
16. Abnormal laboratory values at screening meeting any one of the following criteria:
a.
Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) 
> 2.5 x upper limit of normal (ULN)
b.
Platelet count <100,000 cells/µL
c.
Absolute neutrophil count (ANC) <1000 cells/µL
17. Ongoing/active infection with hepatitis A virus (HAV), hepatitis B virus (HBV), 
hepatitis C virus (HCV), or human immunodeficiency virus (HIV) Type 1/2 
infection at the time of screening. (Subjects with immunity to hepatitis B from 
either active vaccination or from previous natural infection are eligible to 
participate in the study.)
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18. The subject has received or is currently receiving treatment with 
immunomodulatory/immunosuppressive agents within 6 months prior to screening.
19. The subject has received or is currently receiving treatment with any corticosteroids 
dose within 8 weeks  prior to screening, regardless of indication. 
20. The subject has undergone plasma exchange (PE) within 3 months prior to 
screening.
21. The subject has any disorder or condition that in the investigator’s judgment may 
impede the subject’s participation in the study, pose increased risk to the subject, or 
confound the results of the study.
22. The subject is nursing or intends to begin nursing during the course of the study. 
23. 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 the HYQVIA/HyQvia extension study in 
CIDP) involving an IP or investigational device during the course of this study.
24. The subject is a family member or employee of the investigator.
25. Subjects with acquired or inherited thrombophilic disorders. These will include the 
specific types of acquired or inherited thrombophilic disorders that could put 
subjects at risk of develop thrombotic events. Examples include 
a.
Hereditary Thrombophilias: 
i.
Factor V Leiden mutation
ii.
Prothrombin 20210A mutation
iii.
Protein C deficiency 
iv.
Protein S deficiency 
v.
Antithrombin deficiency 
b. Acquired thrombophilias
i.
Antiphospholipid antibody syndrome 
ii.
Activated protein C Resistance acquired 
iii.
Homocystinemia
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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 appropriate 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.
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 may also be withdrawn from treatment or discontinued from further study 
participation for the following reasons:
1.
The subject becomes pregnant. IP exposure will be discontinued. If the subject has 
been exposed to rHuPH20, attempts will be made to follow the subject through 
completion of the pregnancy and the infant up to 1 year postdelivery, if feasible. 
The investigator will record a narrative description of the course of the pregnancy 
and its outcome. (See also Section 12.1.2)
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.
3.
The subject frequently misses administration of IP (more than 2 consecutive 
infusions after reaching full dose).
4.
The subject develops severe hypersensitivity reactions related to IP administration.
5.
The subject uses prohibited medications (see Section 10.5) during the course of this 
study.
6.
The subject participates in another clinical study involving an IP or device during 
the course of this study.
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10. STUDY PROCEDURES
10.1 Informed Consent and Enrollment
Any patient who provides informed consent (ie, signs and dates the informed consent 
form 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 subject identification code (SIC): 
protocol identifier (eg, 161403) to be provided by the sponsor, 2- or 3-digit number study 
site number (eg, 02) to be provided by the sponsor, and 3- or 4-digit subject number 
(eg, 0003) reflecting the order of providing informed consent. For example, the third 
subject who signed an informed consent form at study site 02 will be identified as 
Subject 161403-020003. 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 an enrollment/screening log that includes all 
subjects who provided informed consent. The log will also serve to document the reason 
for screening failure. All screening data will be collected and reported in CRFs, 
regardless of screening outcome. 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.
The overall study design is illustrated in Section 21.1 Study Flow Chart. Schematics for 
study assessments and visits are detailed in Section 21.2. Details on the procedures to be 
performed at each study visit, including screening, 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 the screening/baseline period, which 
may last up to 8 weeks.
In order to be eligible to participate in this study, subjects must have a documented 
diagnosis of definite or probable CIDP in accordance with the EFNS/PNS 2010 criteria 
(European Federation of Neurological Societies, 2010). Subjects with focal atypical 
CIDP and pure sensory atypical CIDP will not be eligible. To fulfill the electrodiagnostic 
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criteria, nerve conduction studies will be performed on all subjects, which will be used 
for confirmation of CIDP diagnosis. The subject’s previous electrodiagnostic records 
including those obtained at the time of diagnosis, if available, can be used for initial 
screening. If a previous evaluable nerve conduction report is available, an additional 
study at the time of screening is not mandatory but highly recommended. This is 
recommended because according to recent data it would be possible to determine whether 
the subject is going to need IgG for control of his disease or if the subject is in remission 
by reviewing these 2 separate tests.
Standardized procedures and selection of nerve segments for assessments are detailed in 
the nerve conduction manual. All nerve conduction study records will be reviewed by an 
independent central reader who specializes in neuromuscular diseases in order to 
confirm the diagnosis of definite or probable CIDP in accordance to the EFNS/PNS 2010 
guideline on management of CIDP (European Federation of Neurological Societies, 
2010). Nerve conduction records obtained at screening (if available) or pre-study 
(if not available at screening) will serve as the baseline for comparison to post-
screening/baseline records to identify any new demyelinating findings during the 
course of the study.
Nerve conduction studies will be repeated during the end of Epoch 1 visit for those 
subjects who did not relapse following 6 months of SC treatment, or at the time of relapse 
(ie, during the pre-IV baseline visit prior to initiation of IGIV treatment for those entering 
into Epoch 2), or during early termination visit for those who will be discontinued from 
the study. For subjects who undergo Epoch 2, nerve conduction studies will be repeated 
during the end of Epoch 2 treatment visit for those subjects who responded to and 
completed 6 months of IGIV treatment, or during early termination visit for those who 
will be discontinued from the study due to relapse or other reasons. It is recommended 
that the same nerve segments will be assessed as those examined at the time of CIDP 
diagnosis and/or during screening nerve conduction studies.
All eligible subjects must be on a stable dosing regimen of IGIV treatment at a monthly 
equivalent dose of 0.4 to 2.4 g/kg BW with a dosing interval between 2 and 6 weeks 
for at least 12 weeks prior to screening. Subjects with changes to IGIV prescribed 
dosing regimen (dose or dosing interval) related to unstable CIDP disease conditions 
or changes to other CIDP-related immunomodulatory/immunosuppressive agents 
within 8 weeks of screening are not allowed to enter into the study. These subjects 
may be rescreened when their CIDP conditions and IGIV dosing regimen remain stable 
for at least 3 months. The subject’s monthly equivalent IGIV dose will be calculated 
based on the subject’s pre-study IGIV dosing records within 12 weeks prior to screening. 
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Variations in the dosing interval of up to ±7 days or monthly dose amount of up to ±20% 
between subject’s pre-study IgG infusions are within acceptable limits.
A subjects’ medical history pertaining to CIDP will include time of first CIDP symptoms 
and time since CIDP diagnosis, as available. Use of any IgG products, PE, steroids, 
and/or immunomodulatory/immunosuppressive agents for up to 6 months prior to 
screening will be recorded (including product, dose, dosing frequency, route of 
administration, treatment start and stop dates) on the medication and non-drug therapy 
CRF(s). Other medical, medication and/or non-drug therapy history will also be recorded 
(see Section 12.5).
Diabetes mellitus is a common comorbidity in CIDP patient population. Some patients 
may develop diabetic peripheral neuropathy, which may be associated with similar 
clinical presentation and demyelinating abnormalities as CIDP and thus may confound 
assessment of disease activities and study outcome measures. Thus, CIDP subjects who 
also have diabetic peripheral neuropathy will not be eligible to participate in this study. 
CIDP subjects with clinically diagnosed diabetes mellitus who do not have diabetic 
peripheral neuropathy at screening will be allowed, provided that the subject has adequate 
glycemic control as verified by HbA1C test result of <7.5% at the time of screening and 
agrees to maintain adequate glycemic control throughout the course of the study. 
Glycemic control will be monitored (only in those subjects with clinically diagnosed 
diabetes mellitus) throughout the course of the study (see Section 12.7.3 for more 
details).
A 12-lead electrocardiogram (ECG) will be performed at screening for the determination 
of eligibility (e.g., exclusion of clinically significant cardiac abnormalities, such as 
unstable cardiac arrhythmias, and detection of other clinically significant cardiac 
abnormalities that may indicate an underlying condition that may impede the subject’s 
participation in the study, pose increased risk to the subject, or confound the results of the 
study).
Screening blood pressure measurements may be repeated in the event of exclusionary 
values obtained during initial measurement, in order to verify eligibility. The following 
screening laboratory tests may be repeated once at least 1 week apart in the event of 
abnormal laboratory values or suspected erroneous values: serum creatinine (for the 
determination of GFR), Hgb, AST, ALT, platelet count, and absolute neutrophil count.
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During the screening/baseline period, subjects will continue to receive their own IGIV 
treatment and adhere to the same dose and dosing frequency as prescribed by their 
physician prior their entry into this study (referred to as “pre-randomization” IGIV 
infusions) for the duration of the screening/baseline period. Adjustments to the subject’s 
IGIV dose and/or dosing frequency during screening/baseline period are not allowed. The 
following information will be recorded for subject’s pre-randomization IGIV infusions 
that occur after enrollment, but prior to randomization:

Date and time of infusion, product name

Dose administered

Dosing interval

AE(s)

Concomitant medications and/or non-drug therapies
The INCAT disability scale assessment will be performed during screening and the 
pre-SC treatment baseline visit to assess the subject’s level of functional abilities. The 
screening INCAT should be conducted as soon as possible for initial determination of 
whether a subject’s INCAT disability score falls within the inclusionary range of 0 to 
7 (inclusive) (see additional description in Section 9.1). However, the final determination 
of eligibility for the INCAT inclusion criterion will take the pre-SC treatment baseline 
INCAT disability score into consideration. The baseline INCAT disability score must 
also be within the range of 0 to 7 (inclusive) (see additional description in Section 9.1). 
Additionally, as only subjects whose CIDP condition remains stable on IGIV treatment 
will be enrolled into the study, any clinically significant changes in the subject’s 
functional ability (eg, 1 or more point worsening on the adjusted INCAT disability score) 
between screening and baseline assessments should be reviewed and the subject’s final 
eligibility determination will made in consultation with the Medical Monitor.
10.3.1.1 Rescreening
Subjects may be rescreened only once. Subjects who have failed screening based on the 
following reasons may be rescreened, after the cause underlying the initial screen failure 
has been resolved: 
1.
Subjects whose ineligibility is associated with a time period specified in the 
Inclusion Criteria (see Section 9.1) or Exclusion Criteria (see Section 9.2)
• Inclusion criterion #3: Changes to IGIV dose and/or dosing interval within 
12 weeks prior to screening. 
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• Exclusion criterion #18/19: the subject has received or is currently receiving 
treatment with any corticosteroids dose within 8 weeks prior to screening, 
regardless of indication, or any immunomodulatory/immunosuppressive agents 
within 6 months prior to screening.
• Exclusion criterion #20: Recently treated with previous PE within 3 months 
prior to screening.
• Exclusion criterion #23: Recent participation in another clinical study involving 
an IP or investigational device within 30 days prior to enrollment
2.
Subjects with screening laboratory abnormalities meeting exclusion criterion #16.
3.
Subjects who have been erroneously determined to be ineligible to participate in 
this study.
4.
Subjects with other reasons for initial screen failure may be rescreened at the 
discretion of the investigator.
All subjects must sign a new ICF prior to rescreening procedures. Subjects who are 
rescreened will be assigned a new SIC and new CRFs are required for that subject.
The following screening procedures will be performed at rescreening:

Demographics 

Medical, medication and non-drug therapy history

Vital signs as well as height, weight, and body mass index (BMI)

Physical exam

Screening laboratory assessments

INCAT disability score

R-ODS

Hand grip strength

MRC sum score
When completing a rescreen, the following procedure(s) do not need to be performed if 
they were already conducted during the initial screening, unless a reason exists to repeat 
the procedure(s) (eg, there is an erroneous result from the initial screening or a medical 
condition necessitates a repeat):

12-lead ECG

Electrodiagnostic test
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10.3.2 Randomization
Randomization is to take place after a subject has completed all the screening procedures 
and, at a minimum, baseline INCAT assessments, and met all eligibility criteria, but 
before the first SC administration in Epoch 1.
10.3.3 Epoch 1: SC Treatment Period
During the SC treatment phase of this study, subjects will receive either 
HYQVIA/HyQvia or 0.25% albumin placebo with rHuPH20 in a double-blind fashion for 
a period of 6 months or until relapse.
10.3.3.1 SC Infusion Visits
Packaging, labeling, and storage of IPs are described in Section 8.7.1 and preparation and 
storage of pooled IP solutions is 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 8.7.4.1.
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. 
The first SC administration of HYQVIA/HyQvia or 0.25% albumin placebo with 
rHuPH20 will take place 2 weeks (±3 days) following the last pre-randomization IGIV 
administration. To gradually increase the SC infusion volume, a dose ramp-up schedule 
will be utilized until the subject’s full dose is reached (see Table 8-3).
The SC infusions during the ramp-up period and, at a minimum, the first full-dose 
infusion will be administered under direct supervision at the study site or infusion center 
to monitor for safety and tolerability. In addition, this will allow for the determination of 
the infusion rate and infusion volume per infusion site that can be tolerated by the 
subject. At the investigator’s discretion, the remainder of the SC infusions may then 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.
HYQVIA/HyQvia or 0.25% albumin placebo with rHuPH20 will be administered by 
an appropriately trained healthcare professional (eg, infusion nurse), self-administered 
by the subject, and/or, as applicable, by a caregiver who may assist the subject with self-
administration. The ability of the subject (and/or caregiver) to perform infusion 
procedures independently is a prerequisite for self-administration. Training will be 
provided to the subject (and/or caregiver) by the investigator/designee.
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The investigator/designee must assess and be satisfied that the subject (and/or caregiver) 
is/are capable of independently performing self-infusion procedures per the infusion 
manual and will adhere to the IP administration schedule. Training of the subject (and/or 
caregiver), as well as the investigator/designee’s evaluation of the subject’s (and/or 
caregiver’s) proficiency in independently self-administering the treatment, must be 
documented. The subject (and/or caregiver) may be asked to return to the study site 
during the SC treatment period so that the investigator/designee can further assess and 
document that the subject (and/or caregiver) continues to be capable of independently 
performing self-infusion procedures. The infusions may be carried out by the subject 
(and/or caregiver) in the presence of a healthcare professional. The healthcare 
professional may intervene only if necessary. Such intervention and the reason for 
intervention will be documented. 
For each SC infusion on each infusion day, the following infusion related information 
will be recorded in the subject’s DIARYpro (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%/0.25% albumin placebo solution)

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 be recorded.

Planned infusion volume (mL) 
(total of rHuPH20 solution plus the IGI, 10%/0.25% albumin placebo solution)

Actual volume infused (mL) 
(total of rHuPH20 solution plus the IGI, 10%/0.25% albumin placebo solution)

Number of infusion sites 

Maximum infusion rate tolerated

Length of SC needle used (mm)

Whether a healthcare professional (e.g., infusion nurse) was present during the 
infusion 

The individual who administered the infusion (subject, caregiver, or nurse)
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
Any infusion-related interventions performed by the healthcare professional (eg, 
infusion nurse) and reason(s) for intervention

Any AE(s) that occur during or after the infusion

Use of any medications or non-drug therapies to treat AE(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 (after 24 h 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 72 h 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).
10.3.3.2 SC Treatment Interim Visit
Subjects will be asked to return to the study site for interim assessments during the 
following week:

Every 2 weeks dosing schedule: Week 15 (+/- 1 infusion visit)

Every 3 weeks dosing schedule: Week 14 (+/- 1 infusion visit)

Every 4 weeks dosing schedule: Week 16 (+/- 1 infusion visit)
The interim visit assessments must be completed prior to the SC infusion on the day of 
infusion (preferred) or within 3 days prior to the infusion visit due to scheduling 
availability. Details on the procedures and assessments to be performed at the interim 
visit can be found in Section 21.2 and Section 21.3.
10.3.3.3 Unscheduled Visit for Relapse Assessment
Subjects who relapse (defined as an increase in adjusted INCAT disability score by 
≥1 point relative to the pre-SC treatment baseline score, on 2 consecutive INCAT 
assessments) will be offered open-label IGIV treatment in Epoch 2.
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 score assessments. For subjects whose adjusted INCAT 
disability score has increased by ≥1 point compared to the pre-SC treatment baseline 
score, INCAT, R-ODS, hand grip strength, and MRC sum score assessments will be 
repeated at the pre-IV treatment baseline visit for those subjects who will enter into 
Epoch 2 or at the early termination visit for those who choose not to enter into Epoch 2 
and will be discontinued early from the study.
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10.3.3.4 End-of-SC Treatment Period
Subjects may end their active participation in the SC treatment period in one of three 
ways. For a detailed schedule of procedures and assessments, see Section 21.2.
1.
Subjects may complete the entire 6-month SC treatment period without relapse. 
These subjects will be asked to undergo an End-of-Epoch 1 visit at the study site. 
End of SC treatment assessments are to be conducted on the day of the final 
infusion in the SC treatment period. This will mark the subjects’ completion of the 
study.

Subjects may opt to participate in an open-label extension study for the 
evaluation of long-term safety, tolerability, immunogenicity, and efficacy of 
HYQVIA/HyQvia in CIDP. Subjects who are interested will be asked to 
provide informed consent for the extension study prior to conducting any of the 
End-of-SC Treatment Period (study completion) procedures.
2.
A subject may withdraw their participation in the study or be discontinued from the 
study prior to completing the entire 6-month SC treatment period, or a subject may 
relapse and choose not to enter into Epoch 2 for IV treatment. These subjects will 
be asked to undergo an early termination visit at the study site prior to 
discontinuation from the study.
3.
Subjects may experience relapse of their CIDP as determined by 2 consecutive 
INCAT assessments performed at the site. These subjects will be offered IGIV 
treatment in Epoch 2. Subjects who will be going on to receive IV treatment will 
undergo an end-of-SC treatment/pre-IV treatment baseline assessment visit at the 
study site. (In these cases, an early termination visit for the SC treatment period is 
not applicable and does not need to be conducted). These pre-IV treatment baseline 
assessments must be completed prior to the first IV treatment. 
10.3.4 Epoch 2: IV Treatment Period
10.3.4.1 Baseline
Open-label treatment with IGIV will be provided for subjects who meet the definition 
of relapse during the SC treatment period as determined by 2 consecutive INCAT 
assessments performed at the site. An INCAT assessment will be performed at the time 
the subject is being evaluated for relapse, and again just prior to initiation of IGIV 
treatment. Subjects will be asked to complete a pre-IV treatment baseline assessment 
visit at the study site. These assessments will also serve as the end-of-SC treatment 
assessments. Details on the procedures and assessments to be performed at the pre-IV 
treatment baseline visit can be found in Section 21.2 and Section 21.3. Pre-IV treatment 
baseline assessments must be completed prior to initiation of treatment with IGIV. 
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The pre-IV treatment baseline INCAT assessment will be used to confirm the subject’s 
adjusted INCAT disability score has increased by ≥1 point relative to the pre-SC 
treatment baseline score, at which time the final determination of whether a subject has 
met relapse criteria will be made. IGIV treatment will be initiated only after CIDP relapse 
is confirmed.
10.3.4.2 IV Infusion Visits 
Packaging, labeling and storage of IPs are described in Section 8.7.1 and preparation and 
storage of pooled IP solutions is 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.
In Epoch 2, subjects will receive IV infusions of GAMMAGARD LIQUID/KIOVIG (all 
subjects with the exception of those at US sites) or GAMUNEX®-C (US only) every 
3 weeks (±3 days) for a total of 6 months. Following the completion of the pre-IV 
treatment baseline assessments including INCAT disability scale and other clinical 
outcome measures, subject may receive the first IGIV infusion as soon as practically 
feasible. 
All IV treatment infusions will be performed at the study site/infusion center. In addition, 
subjects will undergo follow-up assessments at the study site every 3 weeks (ie, every 
infusion visit) until their study completion or early withdrawal/discontinuation.
For each IV infusion, the following infusion-related information will be recorded in the 
subject’s DIARYpro (manuals containing detailed instructions will be provided to the 
sites and subjects):

Date, start and end time of the infusion on each day of infusion

Planned and actual infusion volume on each of infusion day

Maximum tolerated infusion rate 

Any changes in infusion rates (with the exception of pre-programmed infusion rate 
changes/ramp-up), interruption(s) and/or discontinuation of an infusion 

Any unplanned infusion rate change(s), infusion interruption(s), and/or 
discontinuation, 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 be recorded.

Any AE(s) that occur during or after infusion
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
Use of any medications or non-drug therapies to treat AE(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 (after 24 h 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 72 h 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).
10.3.4.3 IV Treatment Interim Visit
Interim assessments are to be conducted during Week 13 (+/- 1 infusion visit) during the 
IV treatment period. Details on the procedures and assessments to be performed at the 
interim visit can be found in Section 21.2 and Section 21.3.
10.3.4.4 End of IV Treatment Period
Subjects may end their active participation in the IV treatment period, and thus the study, 
in one of two ways. For a detailed schedule of procedures and assessments, see 
Section 21.2 and Section 21.3.
1.
Subjects may complete the entire 6-month IV treatment period. These subjects will 
be asked to undergo an End-of-Epoch 2 visit at the study site. End of IV treatment 
assessments are to be conducted pre-infusion on the day of the final infusion in the 
IV treatment period. This will mark the subjects’ completion of the study.
2.
A subject may withdraw their participation in their study or be discontinued from 
the study prior to completing the entire 6-month IV treatment period. 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 post-randomization 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.
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Any suspicion of allergic, hypersensitivity, or anaphylactic reaction(s) requires 
immediate discontinuation of the infusion and administration of appropriate medical 
treatment in accordance with the local standard of care.
Any rate reductions, interruptions or discontinuation of an infusion and, if applicable, any 
medications and/or non-drug therapies used to treat AE(s), must be recorded in the 
appropriate CRF(s). The use of any pre-medication(s) must be recorded in the appropriate 
CRF(s). 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: 
1.
Subject who have received or is currently receiving treatment with any 
corticosteroids dose within 8 weeks prior to screening, regardless of indication are 
not permitted.
2.
Non-systemic corticosteroids (e .g, 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 within 6 months before screening (for 
corticosteroids: within 8 weeks prior to screening, for details see Section 9.2 Exclusion 
Criteria) and during the course of the study is not permitted.
Plasma exchange has been shown to provide short-term clinical benefits in improving 
neurological disability in CIDP. Thus, use of PE within 3 months before screening and 
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:
1.
Other IgG products
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
With the exception of the subject’s IGIV treatment during the 
screening/baseline period; however, following randomization, use of the 
subject’s pre-randomization IGIV will no longer be permitted
2.
Hyperimmune serum
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 may have recently been exposed to IgG therapy due 
to blinded study product in Epoch 1. Subjects being treated in Epoch 2 should also inform 
the healthcare professional that the subject is receiving IGIV treatment.
10.5.2 Pre-Medications for Infusion Administration
Subjects who are prone to AEs occurring in conjunction with infusions of IGIV products 
are often pre-medicated with antipyretics (e.g., acetaminophen), non-steroidal anti-
inflammatory drugs [NSAIDs], antihistamines, and/or corticosteroids. In this study, pre-
medications to prophylactically treat infusion-related AEs should be avoided, if possible, 
for both SC and IV infusions. Reactions experienced by subjects with pre-study IGIV 
treatment do not automatically necessitate the use of pre-medication(s) for SC infusions 
and/or IV infusions in this study. In addition, reactions that occurred with SC infusions 
(Epoch 1) do not necessitate automatic pre-medication for IV infusions (Epoch 2).
For subjects who are prone to infusion-related AEs, if the same type of mild-to-moderate, 
nonserious AE(s) expected to be related to infusion (e.g., 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, 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.
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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 (e.g., 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).
10.6 Subject Diary and Patient Reported Outcomes
An electronic subject diary (DIARYpro) will be provided to each subject at screening to 
record the following information throughout the study:
1.
Occurrence of signs/symptoms indicative of AEs
2.
Use of concomitant medications and non-drug therapies
3.
Infusion records (see Section 10.3.1, Section 10.3.3.1, and Section 10.3.4.2)
4.
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.
5.
R-ODS
Subjects and caregivers 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 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 patient reported data. 
An Infusion Data Collection 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 data will be imported via 
a validated transfer to Data Management. 
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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 with the protocol (with or without protocol deviations).
Reasons for completion/discontinuation will be reported on the 
Completion/Discontinuation CRF, including: completed, screen failure, AE, 
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, 
death). 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. 
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.
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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 SC treatment period so that the 
investigator/designee can further assess and document that the subject (and/or caregiver) 
is still capable of continuing to independently perform self-infusion procedures.
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. 
Amendment 6 provides flexibility to study participants to opt for home healthcare (HHC) 
solutions as permitted by local regulations. 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 03 June 2020, and the EMA Guidance on the Management 
of Clinical Trials During the COVID19 (Coronavirus) Pandemic, Version 3 (28 April 
2020).
The unpredictable clinical trial landscape due to the COVID-19 outbreak poses a risk to 
the conduct of the trial. Quarantines, site closures, travel limitations and site personnel or 
trial participants infected with COVID-19 have resulted in slowed recruitment and 
potential protocol deviations, with significant delays in achieving the planned recruitment 
target anticipated. 
In the current COVID-19 environment, the requirement for a confirmatory INCAT for 
diagnosis of CIDP relapse poses a risk to the patient’s safety as it requires an additional 
visit to the study site. Site closures, travel restrictions, and scheduling conflicts with the 
INCAT raters further pose a risk. As a result, Amendment 6 includes a sensitivity analysis  
where relapse is defined as an increase in adjusted INCAT disability score of ≥1 point 
relative to the pre-SC treatment baseline score, on a single INCAT assessment; this 
sensitivity analysis removes the requirement for the increase by ≥1 point relative to the 
pre-SC treatment baseline score to be confirmed at a secondary confirmatory INCAT 
evaluation (to be performed as early as the same day of the first INCAT evaluation and no 
later than 7 days afterwards) in order to classify a subject as having relapsed. The 
rationale for the proposed change includes: 1) Inability to perform a second INCAT could 
result in misclassification of subject who have experienced clinically significant CIDP
For non-commercial use only
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worsening consistent with a relapse as no relapse. Hence, the requirement for 
confirmatory INCAT poses a risk to the integrity of the study; 2) INCAT is not sensitive 
to small fluctuations in clinical symptoms; it captures only significant deterioration. For 
that reason, clinical worsening severe enough to be captured by the INCAT score is not 
expected to rapidly reverse without an alternative treatment. The clinical implication of 
this is that repeated INCAT assessments within a small time window would reveal similar 
results; 3) Prior studies of CIDP that used INCAT required only one assessment for end 
point ascertainment (Lancet Neurol 2008 ;7 :136-144; Lancet Neurol. 2018;17(8):689; 
Neurol Neuroimmunol Neuroinflamm 2019;6:e590; Lancet Neurol 2018;17: 35–46). 
The proposed change in the amendment is expected to make the results of ADVANCE-1 
comparable with the literature.
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 in amendment-6 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.
2. The protocol amendment #5 dated 10 May 2019 specifies that the investigator and 
the sponsor have the discretion to discontinue any subject from the study if the 
subject frequently misses administration of IP (more than 2 consecutive infusions 
after reaching full dose). Missing two consecutive infusions could result in a lapse in 
treatment for up to 12 weeks depending on the assigned dosing regimen. Such a long 
lapse due to COVID-19-related factors could put a study subject at risk of 
developing CIDP worsening (as defined by ≥1-point increase in adjusted INCAT 
score). The sponsor will reduce the allowable period for treatment lapse 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). 
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3. Subjects who discontinued from screening due to COVID-19-related factors but 
were otherwise qualified to participate in the trial may be rescreened once if the 
Takeda medical monitor agrees.
4. 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.
5. The study site staff may administer the IP and/or collect labs at home, as necessary 
when COVID is at risk at the hospital setting. IP infusions during the ramp-up 
period will be performed at the clinic. All other 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.
6. 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.
7. 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.
8. 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.
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9. 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.
10. 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 (e.g., no upper 
limb problems and walking not affected) and 10 is severely incapacitated (e.g., inability 
to move either arm for any purposeful movement and restricted to wheelchair, unable 
to stand and walk a few steps with help). 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 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 Hand Grip 
Strength assessment and MRC to that subject. For detail, 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 comprised 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 (DIARYpro) using 
a translated version, as applicable. It is recommended that the subject complete the 
assessment using the same translated version throughout the course of their participation 
in the study. To further measure patient centric benefit of HyQvia in CIDP an alternative 
scoring algorithm will be applied to evaluate benefit of functional impact on everyday 
tasks. Specifics of the alternative scoring (in addition to the full score) will be pre-
specified in the SAP, along with psychometric evidence supporting the alternative 
scoring algorithm, based on data from the current trial.
For detailed administration timepoints, see Section 21.2. DIARYpro will be dispensed to 
the subjects at screening. R-ODS data collected during screening will not be used for 
analysis.
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. 
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Recently the Vigorimeter was proposed as one of the cardinal assessment tools in 
addition to the R-ODS (Vanhoutte et al., 2013a, Vanhoutte et al., 2013b). 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.
11.4 Medical Research Council (MRC) Sum Score
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 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 and Hand Grip strength assessment 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.
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:
1.
Outcome is fatal/results in death (including fetal death)
2.
Is life-threatening – defined as an event in which the subject was, in the judgment 
of the investigator, at risk of death at the time of the event; it does not refer to an 
event that hypothetically might have caused death had it been more severe.
3.
Requires inpatient hospitalization or results in prolongation of an existing 
hospitalization – inpatient hospitalization refers to any inpatient admission, 
regardless of length of stay.
4.
Results in persistent or significant disability/incapacity (ie, a substantial disruption 
of a person’s ability to conduct normal life functions)
5.
Is a congenital anomaly/birth defect
6.
Is a medically important event – a medical event that may not be immediately life-
threatening or result in death or require hospitalization but may jeopardize the 
subject or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the definitions above. Examples of such events are: 

Intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias, or convulsions that do not result in 
hospitalization, or development of drug dependence or drug abuse
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
Reviewed and confirmed seroconversion for HIV, HAV, HBV, HCV, HEV, 
or B19V

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. Any pregnancy that occurs after maternal administration of medicinal product 
will be reported on a Pregnancy Report Form and 1 year postdelivery, if feasible. Any 
pregnancy complication or pregnancy termination by therapeutic, elective, or 
spontaneous abortion shall be considered an SAE.
12.1.1.2 Suspected Unexpected Serious Adverse Reaction (SUSAR)
Any suspected adverse reaction to study treatment (ie, including active comparators) that 
is both serious and unexpected.
The event(s) must meet all of the following:

Suspected adverse reaction

Serious

Unexpected

Assessed as related to study treatment
Once determined to meet the criteria for a SUSAR, a SAE should be submitted to 
regulatory agencies expeditiously. 
The sponsor will ensure that all relevant information about suspected unexpected serious 
adverse reactions (SUSARs) that are fatal or life-threatening, as well as all other serious 
unexpected ARs, are reported to regulatory authorities within the timeframes mandated 
by the applicable regulations (eg ICH Guideline E2A and the European Clinical Trial 
Directive (2001/20/EC). The sponsor will comply with applicable laws/requirements for 
reporting SUSARs and all other SAEs to the ECs and investigators.
12.1.1.3 Nonserious Adverse Event
A nonserious AE is an AE that does not meet the criteria of an SAE. 
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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. The expectedness of AEs will 
be determined by the sponsor using the IB and prescribing information as the RSI. This 
determination will include considerations such as the number of AEs previously 
observed, but not on the basis of what might be anticipated from the pharmacological 
properties of a product.
12.1.1.5 Adverse Reactions Plus Suspected Adverse Reactions
An AR plus suspected AR is any AE that meets any of the following criteria:

An AE considered by either the investigator and/or the sponsor to be possibly or 
probably related to IP administration, or 

An AE that begins during infusion of IP or within 72 h following the end of IP 
infusion, or

An AE for which causality assessment is missing or indeterminate.
12.1.1.6 Preexisting Diseases
Preexisting diseases that are present before entry into the study are described in the 
medical history, and those that manifest with the same severity, frequency, or duration 
after IP exposure, will not be recorded as AEs. However, when there is an increase in the 
severity, duration, or frequency of a preexisting disease, the event must be described on 
the AE CRF.
12.1.2 Assessment of Adverse Events
For the purposes of this study, the following nonserious events experienced after the first 
IP exposure are not reportable, unless otherwise specified; on the AE CRF nor will they 
be included in the analysis of AEs:
1.
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).
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2.
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. 
Infusion of a large quantity of fluid into the SC space would be expected to cause 
some degree of swelling (except the US sites, as per FDA request, infusion-site 
swelling will be reported as AEs). 
3.
Preexisting 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 medical records.
All other AE from the first IP exposure until study completion/discontinuation date will 
be described on the AE CRF using the medical diagnosis (preferred), or, if no diagnosis 
could be established at the time of reporting the AE, a symptom or sign, in standard 
medical terminology in order to avoid the use of vague, ambiguous, or colloquial 
expressions (see definition in Section 12.1). Each AE will be evaluated by the 
investigator for:
1.
Seriousness as defined in Section 12.1.1.1
2.
Severity as defined in Section 12.1.2.1
3.
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 
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 adverse events meeting criteria for SAEs, treatment 
errors (including incorrect route of administration, use of an incorrect product, and 
deviations from the protocol-defined dosing schedule), failures of expected 
pharmacological actions, and unexpected therapeutic or clinical benefits will be followed 
with regard to occurrence of AEs, and/or other observations because these events may be 
reportable to regulatory authorities.
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Any pregnancy that occurs after maternal administration of IP will be reported on a 
Pregnancy Report Form and followed-up at estimated date of delivery and 1 year 
postdelivery, if feasible. Any pregnancy complication or pregnancy termination by 
therapeutic, elective, or spontaneous abortion shall be considered an SAE.
If an investigator becomes aware of an SAE occurring in a subject within 30 days after 
study completion, the SAE must be reported on the provided SAE Report Form within 
24 h after awareness; no additional reporting on CRFs is necessary. Thereafter, AEs of 
any nature are to be reported using standard forms such as the Council for International 
Organizations of Medical Sciences (CIOMS) form or MedWatch form, etc.
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.
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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:
1.
Not related (both circumstances must be met)

Is due to underlying or concurrent illness, complications, concurrent 
treatments, or effects of concurrent drugs

Is not associated with the IP (ie, does not follow a reasonable temporal 
relationship to the administration of IP or has a much more likely alternative 
etiology). 
2.
Unlikely related (either 1 or both circumstances are met)

Has little or no temporal relationship to the IP 

A more likely alternative etiology exists
3.
Possibly related (both circumstances must be met)

Follows a reasonable temporal relationship to the administration of IP

An alternative etiology is equally or less likely compared to the potential 
relationship to the IP
4.
Probably related (both circumstances must be met)

Follows a strong temporal relationship to the administration of IP, which may 
include but is not limited to the following: 
Reappearance of a similar reaction upon re-administration (positive 
rechallenge)
Positive results in a drug sensitivity test (skin test, etc.)
Toxic level of the IP as evidenced by measurement of the IP 
concentrations in the blood or other bodily fluid

Another etiology is unlikely or significantly less likely
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For events assessed as not related or unlikely related and occurring within 72 h after 
completion of IP administration, the investigator shall provide the alternative etiology. 
These causality definitions will also be used to assess the relationship of an AE with a 
study-related procedure(s), if necessary.
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:
1.
Immediate change in study design or study procedures
2.
Temporary or permanent halt of a given clinical trial or trials
3.
Any other immediate action taken in order to protect clinical trial participants from 
immediate hazard to their health and safety
The investigator may take appropriate urgent safety measures in order to protect subjects 
against any immediate hazard to their health or safety. The measures should be taken 
immediately and may be taken without prior authorization from the sponsor. In the 
event(s) of an apparent immediate hazard to the subject, the investigator will notify the 
sponsor immediately by phone and confirm notification to the sponsor in writing as soon 
as possible, but within 1 calendar day after the change is implemented. The sponsor will 
also ensure the responsible ethics committees and relevant competent authorities are 
notified of the urgent safety measures taken in such cases according to local regulations.
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 nonserious untoward medical occurrence experienced 
by a subject undergoing study-related procedure(s) before the first IP exposure will be 
recorded on the AE CRF; these events will not be considered as AEs and will not be 
included in the analysis of AEs. 
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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:
1.
A failure of a product to exhibit its expected pharmacological activity and/or design 
function, eg reconstitution difficulty
1.
Missing components
2.
Damage to the product or unit carton
3.
A mislabeled product (eg, potential counterfeiting/tampering)
4.
A bacteriological, chemical, or physical change or deterioration of the product 
causing it to malfunction or to present a hazard or fail to meet label claims
Any NMCs of the product will be documented on an NMC form and reported to the 
sponsor within 1 business day. If requested, defective product(s) will be returned to the 
sponsor for inspection and analysis according to procedures.
12.5 Medical, Medication, and Non-Drug Therapy History
At screening, the subject’s medical history will be described for the following body 
systems including severity (defined in Section 12.1.2.1) or surgery and start and end 
dates, if known: eyes, ears, nose, and throat; respiratory; cardiovascular; gastrointestinal; 
musculoskeletal; neurological; endocrine; hematopoietic/lymphatic; dermatological; and 
genitourinary. 
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 screening 
throughout the study, will be recorded on the appropriate CRF(s).
All other medications taken and non-drug therapies received from enrollment until 
completion/termination will be recorded on the concomitant medications and non-drug 
therapies CRFs.
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12.6 Physical Examinations
At screening and subsequent study visits (as described in Table 21-1, Table 21-2, and 
Table 21-3, and Table 21-4), a physical examination will be performed on the following 
body systems: general appearance, head and neck, eyes and ears, nose and throat, chest, 
lungs, heart, abdomen, extremities and joints, lymph nodes, skin, and neurological. At 
screening, if an abnormal condition is detected, the condition will be described on the 
medical history CRF. At study visits, if a new abnormal or worsened abnormal pre-
existing condition is detected, the condition will be described on the AE CRF. If the 
abnormal value was not deemed an AE because it was due to an error, due to a 
preexisting disease (described in Section 12.1.1.6), 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, 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 ANC, 
and absolute lymphocyte account. Measurements for Hgb and hematocrit will be 
performed at different time points according to Section 21.3 (Table 21-5, Table 21-6, 
Table 21-7, and Table 21-8). Epoch 2 E2W3 is required for those subjects taking 
Gamunex-C.
The clinical chemistry panel will consist of sodium, potassium, chloride, bicarbonate, 
total protein, albumin, ALT, AST total bilirubin, direct bilirubin, alkaline phosphatase 
(ALP), gamma-glutamyl-transferase (GGT), lactate dehydrogenase (LDH), creatine 
phosphokinase (CPK), blood urea nitrogen (BUN), creatinine, and glucose. At any time 
when the LDH test result is 2x ULN or greater, LDH isoenzymes panel will be 
performed.
Samples for hematology and clinical chemistry assessments will be collected in the 
appropriate matrix as specified in the laboratory manual. With the exception of 
screening and early termination visits, samples for hematology and clinical chemistry 
collected during 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.
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Hematology and clinical chemistry assessments will be performed at the central 
laboratory following standardized assay procedures.
12.7.1.1 Glomerular Filtration Rate
For eligibility determination (exclusion criterion #10), serum creatinine obtained as part 
of the clinical chemistry panel will be used for the estimation of GFR according to the 
CKD-EPI creatinine equation (2009), as follows (Levey et al., 2009):
GFR = 141 x min(Scr/κ, 1)α x max(Scr/κ, 1)-1.209 x 0.993Age x 1.018 [if female] x 
  
1.159 [if black]
where
Scr is serum creatinine (mg/dL)
κ = 0.7 if female
κ = 0.9 if male
α = -0.329 if female
α = -0.411 if male
min = The minimum of Scr/κ or 1
max = The maximum of Scr/κ or 1
12.7.2 Hemolytic Panel
The first hemolytic panel will be measured at Epoch 1 Week 1 (E1W1). The Hgb result 
obtained from the E1W1 will serve as the baseline Hgb value for the duration of the 
study. In case of absence of E1W1 result for any reason screening Hgb result serve as the 
baseline Hgb value. Hemoglobin and LDH values can be taken from the hematology and 
clinical chemistry panels, if conducted on the same day as the hemolytic panel. For 
subsequent tests, if there is a reduction in Hgb of ≥1 g/dL compared to baseline Hgb, 
every effort is to be made to perform a hemolytic panel within 72 hours. If it is not 
feasible to do so, the hemolytic panel must be performed as soon as possible but at the 
next scheduled visit, at latest. At any time during the study, an unscheduled hemolytic 
panel may be performed in the event of suspected hemolytic anemia. Any LDH test result 
of 2x ULN or greater will trigger analysis of the sample for LDH isoenzymes.
It is not necessary to repeat the hemolytic panel if the drop of ≥1 g/dL Hgb remains 
constant 72 hours after the first full dose of the IP or after an unscheduled visit blood 
draw, unless it drops further. It is recommended that the investigator uses good medical 
judgement in assessing subjects with an unexplained decrease in serum Hgb as other 
medical conditions beside hemolysis can cause this, and therefore may require additional 
investigations.
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The hemolytic anemia panel will consist of Hgb, LDH, serum haptoglobin, plasma-free 
(unbound) Hgb, serum direct anti-globulin (direct Coombs) test (antibody elution to be 
performed if direct Coombs test is positive), reticulocyte count, as well as urine 
hemosiderin.
Hemolytic tests will be performed at the central laboratory or other laboratories as 
appropriate (eg, antibody elution in the event of positive direct Coombs test). 
Complete hematology and clinical chemistry assessments may be performed in order to 
obtain laboratory results required for a hemolytic panel.
12.7.3 Hemoglobin A1C (HbA1C)
HbA1C measurements will be performed only in subjects with clinically diagnosed 
diabetes mellitus at screening to support eligibility determination. During the study, 
HbA1C will be measured at baseline, during the interim visit, and at the end of treatment 
visit of each treatment period (or during 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 (TIBC)
During each of the treatment periods, serum iron, ferritin, and TIBC will be monitored. 
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 Serum IgA
Serum IgA level will be measured for the determination of eligibility. Serum IgA 
measurement will be performed at the central laboratory using an assay with a lower 
quantification limit of 8 mg/dL.
12.7.6 Viral Serology Tests
Serum samples will 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 necessary to confirm eligibility determination. 
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. All viral testing will be performed at the central laboratory at screening 
for eligibility determination (exclusion criterion #17).
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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.
In addition, the serum retention samples collected at baseline (Epoch 1 Week 1 predose), 
periodically following initiation of treatment, and at the end of each treatment 
period/early termination visit will be stored and may be used for possible testing of 
pathogens identified in the future. See Section 21.3 for detailed sample collection 
timepoints.
12.7.7 Urine Tests
Urinalysis will include color, specific gravity, pH, protein, glucose, ketones, bilirubin, 
urobilinogen, blood, nitrite, leukocyte esterase, and microscopic examination. Urinalysis 
tests will be conducted at the central laboratory.
12.7.8 Pregnancy Test
For female subjects of childbearing potential, urine pregnancy test will be performed, 
unless a serum pregnancy test is mandatory as specified by local regulatory/institutional 
requirements.
12.7.9 Assessment of Laboratory Values
12.7.9.1 Toxicity Grading Scale
The Common Toxicity Criteria of the Eastern Cooperative Oncology Group, 2006, 
published by Oken et al., 1982, will be used to grade the following laboratory values:

ALP, ALT, AST, BUN, Hgb, lymphocytes, neutrophils, platelet count, serum 
creatinine, serum total bilirubin, and WBC. 
Grading for LDH will use the same thresholds as defined for ALT and AST. 

Sodium and potassium will be graded using the thresholds taken from the 
World Health Organization (WHO) toxicity grading system 
(World Health Organization, 2003).
The laboratory parameters and the corresponding grading scale are provided in 
Section 21.4. 
The toxicity scale is defined as: 0 = none, 1 = mild, 2 = moderate, 3 = severe, 
4 = life-threatening (Food and Drug Administration, 2008).
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Laboratory parameters not listed in Table 21-9 will not be graded. However, clinical 
significance of those abnormal laboratory values will be assessed as described in 
Section 12.7.9.2.
12.7.9.2 Assessment of Abnormal Laboratory Values 
The investigator’s assessment of each laboratory value will be recorded on the 
appropriate CRF/laboratory form. For each abnormal laboratory value, the 
investigator will determine whether the value is considered clinically significant or not. 
For clinically significant values, the investigator will indicate if the laboratory value 
(except hyaluronidase antibody values) 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 preexisting disease, due to a lab error, or due to another issue that 
will be specified. Additional tests and other evaluations required to establish the 
significance or etiology of an abnormal value, or to monitor the course of an AE should 
be obtained when clinically indicated. Any abnormal value that persists should be 
followed at the discretion of the investigator.
12.7.10 Trough Serum IgG
The screening/baseline trough serum IgG sample will be collected prior to the last pre-
randomization IGIV dosing during the screening/baseline period. If due to scheduling 
difficulties, blood sampling at other pre-randomization IGIV infusions will be allowed. 
However, serum IgG samples must be collected prior to start of the pre-randomization 
IGIV infusion (or prior to the first day of IGIV infusion if the IGIV dose is divided over 
multiple days in an infusion cycle).
During Epoch 1 and Epoch 2 (as applicable), trough serum IgG samples must be 
collected on the day of the 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) prior 
to the start of the infusion. 
Blood samples are to be collected and processed according to 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 (backup) sample. 
Serum IgG trough levels must also be collected on each subject on or after day 120 or at 
the time of CIDP symptom relapse.
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Total IgG level in serum will be determined using a validated nephelometric assay 
method at a specialty laboratory.
12.7.11 Anti-rHuPH20 Antibodies
The potential for immune response to rHuPH20 will be monitored in all subjects 
(regardless of treatment assignment to the active or placebo treatment group) who have 
received rHuPH20 administration in Epoch 1. Serum samples for the detection of anti-
rHuPH20 binding and neutralizing antibodies will be collected at baseline (Epoch 1 
Week 1 prior to IP administration), during early time course (ie, at 2, 4, and 7 to 8 weeks 
since start of treatment), during the Epoch 1 interim visit (ie, at 13 to 15 weeks since start 
of treatment; the precise week of sample collection depends on the subject’s dosing 
frequency and scheduling), and at the end-of-SC treatment visit (ie, 25 to 27 weeks since 
start of treatment; the precise week of sample collection depends on the subject’s dosing 
frequency and scheduling)/early termination visit. In the event that no safety concerns are 
observed, the early sampling time points (i.e., at 2, 4, and 7 to 8 weeks since treatment 
initiation) may be waived or modified upon recommendation by the DMC and 
notification by the sponsor or sponsor’s representative. See Section 21.3.
During Epoch 2, serum samples will be collected for continued monitoring for the 
detection of anti-rHuPH20 binding and neutralizing antibodies during the pre-IV baseline 
visit, Epoch 2 interim visit, and at the end of Epoch 2 treatment/early termination visit.
Blood samples for the detection of anti-rHuPH20 binding neutralizing antibodies will be 
collected and processed according to 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 (backup) 
sample. All subjects will be monitored for the formation of anti-rHuPH20 antibodies 
using validated anti-rHuPH20 antibody detection (ADA) assay (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.
12.7.12 Immunogenicity Panel
At baseline (Week 1 predose), samples will be collected for the following tests to be 
conducted: 50% hemolytic complement activity of serum (CH50), serum complement 
component 3 (C3), serum complement component 4 (C4), C1q binding assay, and 
circulating immune complex (CIC) Raji cell assay.
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At any time during the course of the study, subjects who have (a) two consecutive anti-
rHuPH20 antibody titers of ≥1:160 which are elevated from the subject’s baseline titers, 
and (b) a moderate or severe AE which may be a result of immune-mediated response to 
either immunoglobulin, rHuPH20, 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.
Table 12-1. List of Conditions/Symptoms Which May be a Result of 
Immune-Mediated Response to Either Immunoglobulin, rHuPH20, 
or Other Concomitant Medications
Allergic reactions

Urticaria

New-onset bronchospasm

Oedema of tongue, lips, face (angioedema)

Anaphylaxis

Stevens-Johnson syndrome

Erythema multiforme

Toxic epidermal necrolysis
Immune complex mediated reactions – Local

Induration/nodule at the site of administration that persists for more than 48 h

Excessive inflammation at the site of administration severe redness, heat, swelling, and/or pain

Tissue necrosis/ulceration at the site of administration

Dystrophic or fibrotic changes at the site of administration 

Pigmented skin changes at the site of drug administration
Immune complex mediated reactions – Systemic

Arthritis

Vasculitis (purpuric rash)

Glomerulonephritis hematuria, red cell casts in urine, progressive renal dysfunction
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Table 12-2. Immunogenicity Panel
1.
Repeat test for anti-rHuPH20 binding antibody titers
5.
Test (or repeat test, as applicable) for the presence of neutralizing anti rHuPH20 antibodies
6.
Assessment of cross reactivity to human HYAL1, HYAL2, and HYAL4
only for subjects whose anti-rHuPH20 binding antibody titer exceeds 1:10,000
7.
Hematology panel with manual differential (see Section 12.7.1)
8.
Clinical chemistry panel (see Section 12.7.1)
9.
CH50
10.
Serum C3
11.
Serum C4
12.
C1q binding assay
13.
CIC Raji cell assay
14.
Blood draw for additional testing as necessary
Blood samples are to be collected and processed according to the directions provided in 
the laboratory manual. The tests should be performed at the central laboratory and/or 
specialty laboratories as appropriate.
12.7.12.1 Guidance on Reporting and Assessing rHuPH20 (hyaluronidase) antibody 
test results
Epoch 1: Hyaluronidase is administered as Investigational Medicinal Product (IMP) in 
Epoch 1. 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 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.
For adverse events occurring upon or after subsequent subcutaneous 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.
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Epoch 2: No hyaluronidase is administered during Epoch 2. 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 in Epoch 2 the investigator and sponsor will independently 
assess relatedness, also taking into account the cumulative quantitative and qualitative 
test results for hyaluronidase antibodies.
12.7.13 Backup Samples/Biobanking
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12.8 Vital Signs
Vital signs will include body temperature (°C or °F), respiratory rate (breaths/min), pulse 
rate (beats/min), 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 screening, periodically throughout each treatment period, and at study 
completion/early termination visit (See Section 21.2 Schedule of Study Procedures and 
Assessments detailed collection timepoints).
For the initial 3 SC infusions, vital signs are to be monitored and recorded at any time 
prior to infusion, in the event of occurrence of AE(s), and within 60 minutes of 
completion of an infusion. During subsequent infusion visits, vital signs will be taken 
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 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) and weight (lb or kg), as well as BMI will be collected at 
screening. Subsequently, BW will be re-measured during each treatment period (see 
Section 21.2 for detailed measurement timepoints). All BW 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 Electrodiagnostic studies (EMG)
Electrodiagnostic (EDX) studies that were conducted prior to initiation of SC (Epoch-1) 
treatment (baseline EDX study) will be used to ensure that subjects meet EFNS/PNS 
diagnostic criteria (van den Bergh et al, 2010) for inclusion into Epoch-1. In addition, 
EDX studies will be repeated prior to initiation (baseline EDX study) and at the 
completion (exit EDX study) of Epoch-1 and Epoch-2 to provide  additional information 
regarding disease activity while on therapy. For purposes of comparison, the same nerve 
segments will be evaluated at the exit and baseline studies. EDX studies will be 
performed according to standard practice, using supramaximal percutaneous nerve 
stimulation to determine compound muscle action potential (CMAP) and sensory nerve 
action potential (SNAP) amplitudes. At a minimum, two limbs and four motor nerves 
(median , ulnar, peroneal, tibial nerves) per limb will be examined (please see the Nerve 
Conduction Study Manual for details). EDX studies will be reviewed by an evaluator at 
the Central Reading Site (Cornell University). The results of the evaluation and whether 
the subject meets inclusion criteria, will be reported back to the study site within two 
business days of submission.  For each subject, the EDX studies will be analyzed for total 
number and specific types of demyelinating abnormalities (DA) in each study, resolution 
of original DA seen in screening EDX and new DA in exit EDX.  Demyelinating 
abnormalities will be determined following EFNS/PNS criteria and include: 

Prolonged distal motor latency

Partial motor conduction block 

Probable partial motor conduction block 

Temporal dispersion 

Prolonged distal CMAP duration 

Conduction velocity slowing

Prolonged F-wave minimal latency
All EDX assessments will be done blinded to the treatment assignment by a central lab 
located at the Cornell University. For further information regarding EDX testing, please 
refer to the Nerve Conduction Studies Manual. 
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13.2 Short Form-36 Health Survey (SF-36)
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 Short Form (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.
13.3 EQ-5D
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 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.
13.4 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. Health Resource Utilization 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 DIARYpro on an on-going 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. DIARYpro will be dispensed to the subjects at screening. 
HRU data collected during screening will not be used for analysis.
13.5 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.
13.6 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.
13.7 Patient Global Impression of Change
The PGIC scale is a single item 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. For detailed administration timepoints, see 
Section 21.2 Schedule of Study Procedures and Assessments.
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14. STATISTICS
This statistical analysis section provides:

Sample size estimation (along with the underlying assumptions) and the planned 
SAP for HYQVIA/HyQvia during the placebo-controlled, randomized, SC 
treatment period.

Sample size estimation (along with the underlying assumptions) and the planned 
SAP for GAMMAGARD LIQUID/KIOVIG during the open-label IV period.
Detailed statistical analysis methods will be described in the SAP.
14.1 Epoch 1: SC Treatment Period
14.1.1 Sample Size and Power Calculations
14.1.1.1 Summary
The original planned sample size of 174 randomized subjects was estimated on the 
basis of the treatment effect observed in the GAMUNEX®-C pivotal (ICE) study 
(Hughes et al., 2008) and an assumed remission rate of 45% (Viala et al., 2010).
Based on additional information provided by more recent scientific literature, the original 
sample size assumptions are no longer considered to be relevant and a larger treatment 
difference in relapse rates of 29% is now expected compared with the originally assumed 
18% difference.  Whilst the assumed relapse rates still remain close to the original 
assumptions, the percentage of subjects on long-term IgG therapy that no longer need 
therapy (the “remission rate”) has been revised from 45% to 19%, leading to an increase 
in the expected treatment effect.
As discussed in Section 8.6, randomization to Epoch 1 will be stopped by the sponsor 
prior to achieving the original planned sample size of 174 randomized subjects. It is 
expected that at least 120 subjects will be randomized and dosed which, based on the 
revised sample size assumptions using more recent scientific literature, will be sufficient 
to achieve 90% power.
 
 
 
 
 
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14.1.1.3 Power calculation
 
 
 
 
 
 
the difference in the relapse rates 
between the HYQVIA/HyQvia and placebo groups is expected to be 29%, where a 
sample size of 120 randomized and dosed subjects (60 subjects per group) will provide 
90% power. This power estimate is based on a continuity-corrected chi-squared test, 
equal allocation, a 15% drop-out rate, a two-sided 5% significance level and a difference 
in relapse rates of 29% (39% Placebo – 10% HYQVIA/HyQvia = 29%) and was derived 
based on 100,000 simulation runs and with dropouts imputed as no relapse, as per the 
planned primary analysis.
14.1.1.4 Assumptions of Screen Failure Rate and Dropout Rates
The following screening and dropout rate assumptions are made:
a)
Screening: A 25% screen failure rate is assumed based on the screen failure rates 
reported in the following clinical studies: 
(1) In the Privigen® PRIMA study (Léger et al., 2013), 3 of 31 (10%) enrolled 
subjects were excluded during screening; 
(2) In the ICE study (Hughes et al., 2008), 31 of 148 (21%) enrolled subjects were 
excluded during screening.
(3) In the PATH study (van Schaik et al., 2018), 31 of 276 (11%) enrolled subjects 
were excluded during screening 
(4) In the FORCIDP study (Hughes et al., 2018), 53 of 159 (33%) enrolled subjects 
were excluded during screening
b)
Dropout Rate: A 15% dropout rate in the treatment period is assumed based on the 
following clinical studies: 
(1) In the PRIMA study (Léger et al., 2013), 3 of 28 (11%) subjects were 
prematurely discontinued from the study due to serious adverse events and 
insufficient clinical response. 
(2) In the ICE study (Hughes et al., 2008), 21 of 74 (28%) subjects who initially 
responded to IGIV treatment in the first period and cross-over periods were 
prematurely discontinued during the extended treatment period due to relapse or 
insufficient response, AE, and other reasons. 
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(3) In the PATH study (van Schaik et al., 2018), 16 of 172 (9%) subjects were 
prematurely discontinued from the study due to serious adverse events and 
withdrawal of consent for other reasons.
(4) In the FORCIDP study (Hughes et al., 2018), 9 of 106 (8%) subjects were 
prematurely discontinued from the study due to serious adverse events, protocol 
violation, and withdrawal of consent  for other reasons.
14.1.2 Datasets and Analysis Cohorts
The Epoch 1 Safety Set will include all subjects who received any double-blind study 
medication. Analyses based on the Epoch 1 Safety Set will use the actual treatment that a 
subject received during Epoch 1.
A Modified Intent-to-Treat (MITT) analysis set will include all randomized subjects who 
received any double-blind study medication; this will be the primary efficacy analysis set 
for Epoch 1 data. Analyses based on the MITT analysis set will use the Epoch 1 planned 
(ie, as randomized) treatment. 
A Per-Protocol (PP) analysis set will include all randomized subjects who received any 
double-blind study medication, and had no major protocol deviations during Epoch 1 that 
may have a significant impact on the primary outcome measure; this will be used for 
sensitivity and/or supportive analyses. Analyses based on the PP analysis set will use the 
Epoch 1 planned (ie, as randomized) treatment. Such protocol deviations will be 
determined prior to Epoch 1 data lock and treatment unblinding.
14.1.3 Handling of Missing, Unused, and Spurious Data
Rules for handling missing data will be described in the SAP.
14.1.4 Methods of Analysis
14.1.4.1 Primary Outcome Measure
A relapse is defined as worsening of functional disability by ≥1 point (increase) relative 
to pre-SC treatment baseline in 2 consecutive adjusted INCAT disability scores.
The null hypothesis is that relapse rates are not different between the HYQVIA/HyQvia 
and placebo with rHuPH20 treatment groups. The primary efficacy outcome measure is 
the Epoch 1 relapse rate in the MITT analysis set. The primary analysis is a comparison 
of relapse rates in the two treatment groups, using a continuity-corrected chi-square test 
conducted at the 5% level of statistical significance, with missing outcomes imputed as 
no relapse. The estimated relapse rates will be presented for each planned treatment 
group, along with the 95% CI computed using the Wilson score method. 
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Sensitivity analyses will include comparisons of the relapse rates in (1) the MITT 
analysis Set with missing imputed as a relapse, (2) an MITT Observed Cases analysis 
(missing outcomes excluded), (3) the PP Set with missing imputed as no relapse, 
(4) MITT analysis set with missing imputed as no relapse, where relapse is alternatively 
defined as an increase in adjusted INCAT disability score of ≥1 point relative to the pre-
SC treatment baseline score, on a single INCAT assessment; this sensitivity analysis 
removes the requirement for the increase by ≥1 point relative to the pre-SC treatment 
baseline score to be confirmed at a secondary confirmatory INCAT evaluation (to be 
performed as early as the same day of the first INCAT evaluation and no later than 7 days 
afterwards) in order to classify a subject as having relapsed. Justification for this 
sensitivity analysis in the context of the Covid-19 pandemic is given in Section 10.9. 
These sensitivity analyses will use similar statistical methods to the primary analysis.
14.1.4.2 Secondary Outcome Measures
14.1.4.2.1 Efficacy
Clinical worsening of CIDP, defined as one or more of the following: subject relapse; 
≥8 kPa decrease in the hand grip strength in the more affected hand; ≥4 points decrease in 
R-ODS relative to the pre-SC treatment baseline score at the time of withdrawal from the 
SC treatment period, will be analyzed using the same methods as the primary endpoint.
Time to relapse, defined as time from the date of the first SC administration of 
HYQVIA/HyQvia or placebo with rHuPH20 to the date of relapse, will be compared
between treatment groups using the Wilcoxon survival test. Additionally, the survival 
function will be estimated using the Kaplan-Meier curve. The analysis will be performed 
using data from the MITT analysis set with the planned Epoch 1 treatment.
The change in ADL (R-ODS) from baseline to the end of the treatment period will be 
analyzed using an analysis of covariance (ANCOVA) model to test the treatment effect, 
with baseline R-ODS score as a covariate. The last non-missing change in Epoch 1 will 
be used from subjects who discontinued early. If an analysis of overall discontinuation 
rates shows a differential dropout rate between treatments that is significant at the 
5% level, then a repeated-measures analysis of the change in ADL (R-ODS) will be used 
to investigate the robustness of results of the ANCOVA with last observation carried 
forward (LOCF) imputation in the MITT analysis set. The repeated-measure analysis will 
employ a restricted maximum likelihood (REML)-based, mixed-model repeated measure 
(MMRM) model which contains fixed terms for treatment group and planned timepoint, 
with baseline R-ODS as a covariate and subject as a random factor; additional details will 
be provided in the SAP. These analyses will be performed in the MITT population.
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14.1.4.2.2 Safety
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA), 
and reported by body system, preferred term, and treatment group. Clinically significant, 
treatment-emergent changes in physical exams, vital signs, ECGs, and clinical laboratory 
measurements will be recorded as AEs; therefore, safety analyses will be primarily based 
on analysis of AEs, including ARs plus suspected ARs. Safety endpoints will be 
summarized descriptively in the Epoch 1 Safety Set using actual treatment.
Treatment-emergent AEs (TEAEs), serious TEAEs, and other AE-related outcome 
measures will be described by the number and percentage of subjects in each treatment 
group who experienced a particular type of event. Additionally, event rates will be 
expressed as number of events (reports) per infusion, per subject, and per subject-year. 
Both systemic event and events that are localized to the infusion site(s) will be examined. 
The relationship of AEs to infusions will be described further in terms of the number and 
proportion of infusions that were associated with an AE, and the number and proportion 
of infusions that were not completed as planned (interrupted, discontinued) due to an AE.
In addition, the incidence (number of percentage of subjects) of local infusion site 
reactions will be provided by geographic region (US, non-US) and overall.  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 first occurrence of any TEAE and the first occurrence of any treatment-emergent 
SAE will be analyzed using a Cox PH model to obtain an overall hazard ratio (HR) 
for treatment, adjusted for time in study (ie, duration of treatment). Separate HR’s 
for the relationship of AEs with treatment will be computed for subjects who had 
total treatment durations of 0 to 4 weeks, 5 to 8 weeks, 9 to 12 weeks, and 13 to 
26 weeks at the time of the data cut-off. 
These analyses will address the potential impact of any imbalance in AE rates due to 
differential dropout rates in Epoch 1 between HYQVIA/HyQvia and placebo with 
rHuPH20, and will characterize the relationship of AEs to treatment, overall and over 
time. Point estimates and CIs will be reported.
Similar analyses will be performed for ARs plus suspected ARs.
Summaries of subject deaths during study (if any) and of AEs leading to discontinuation 
will be provided.
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For the purpose of summaries and listings the durations of AEs will be calculated as 
follows: (stop day – start day) + 1 day, which yields the number of days on which the AE 
was present.
For each body system and overall, the number and proportion of subjects that 
experienced an AE will be presented by treatment group.
For laboratory measurements, data will be summarized by treatment group and time 
point. Summaries of continuous measurements will include sample size, mean, standard 
deviation (SD), minimum, and maximum. For categorical measurements, the proportion 
of observations in each category will be presented.
Subjects are defined as having elevated rHuPH20 antibody titers if they have two 
consecutive anti-rHuPH20 antibody titers of ≥1:160 which are elevated from the subject’s 
baseline titers. If at least 5 subjects in each treatment group have elevated titers, then an 
exploratory analysis will be conducted to assess if there is any evidence of relationship 
between anti-rHuPH20 antibody titer (elevated, not elevated) and the occurrence of AEs 
of interest.
In addition, an exploratory analysis of any treatment emergent abnormal titer or rises 
above baseline in anti-rHuPH20 antibody titer will be performed to assess if there is any 
evidence of relationship between anti-rHuPH20 antibody titer (elevated, not elevated) and 
the occurrence of AEs. 
14.1.4.3 Tertiary Outcome Measures
Treatment satisfaction, treatment preference, PGIC, HRU (such as days off school/work, 
unscheduled physician visits, hospitalization, and emergency room visits) and changes 
from pre-IV treatment baseline in adjusted INCAT disability scores, hand grip strength 
scores, MRC sum scores, SF-36 scores and EQ-5D scores will be summarized in the 
MITT analysis set, by planned treatment group, using descriptive statistics (sample size, 
mean, SD, median, minimum, maximum) for continuous measures or the number and 
percentage of subjects for categorical measures.
R-ODS will also be evaluated as described in the secondary outcome measures above 
using a targeted subscale measuring impact on ability to complete everyday tasks. In 
addition, a separate psychometric statistical plan (PSAP) will be finalized prior to 
Epoch 1 data lock to confirm the targeted subscale is fit-for-purpose and the subset 
scoring’s validity and reliability. 
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EDX studies will be obtained prior to initiation (baseline EDX study) and at the 
completion of the trial (exit EDX study). Repeat EDX studies are expected to reveal 
resolution of previously identified demyelinating abnormalities (DA) or occurrence of 
new DA that reflects ongoing disease activity. The total number of DA at Epoch-1 
baseline and Epoch-1 exit, as well as their change, and the number of new DA in exit 
EDX will be summarized using descriptive statistics (sample size, mean, SD, median, 
minimum, maximum) for continuous measures or the number and percentage of subjects 
for categorical measures. The minimum data requirement is the availability of bilateral 
tibial, peroneal, median and ulnar measurements at both baseline and exit studies in 
every subject. Only subjects with complete baseline and exit EDX (i.e. with all 
56 measurements) will be included into the analyses.
Trough plasma concentrations of IgG will be summarized for the Safety set, by actual 
treatment, using the sample size, mean, SD, median, minimum, maximum, geometric 
mean, and SD of the geometric mean.
In addition, potential correlation between serum IgG trough levels after day 120 (every 
2-week dosing E1W27/EOE1T; every 3-week dosing E1W26/EOE1T, every 4-week 
dosing E1W28/EOE1T) or at the time of CIDP symptom relapse (E1ET or Pre-IV 
BL/E2W1) and relapse status (relapse, no relapse) will be assessed as an exploratory 
analysis.
14.2 Epoch 2: IV Treatment Period
14.2.1 Sample Size and Power Calculations
14.2.1.1 Upper Limit of Response Rate from Historical Control
In Epoch 2 (the IV treatment period), the study population will comprise of IGIV 
experienced subjects who have relapsed while on the placebo control during Epoch 1 
(the SC treatment period). Therefore, the historical control should match those 
conditions. The historical placebo response rate observed in the subset of 
treatment -experienced subjects in the GAMUNEX®-C pivotal (ICE) study has been 
chosen (Hughes et al., 2008). In the ICE study, none of the 12 IGIV-experienced subjects 
randomized to placebo were responders- representing a responder rate of 0% (0/12). 
The upper bound of the two-sided 95% CI using the Wilson score method is 24%. 
Therefore, the CI limit to exceed for the present study is 24%.
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14.2.1.2 Power Calculation
Assuming that 19% of enrolled IGIV-pretreated subjects are in remission (and thus would 
not relapse upon withdrawal of treatment) and based on the probability of relapse of 48% 
for the placebo group, a relapse rate of 39% ([1 - 0.19] × 48%) in the SC placebo 
treatment group is assumed. These remission and placebo relapse rate estimates are based 
on random effect meta-analyses of the relevant literature, as detailed for the Epoch 1 
sample size calculation (Section 14.1.1).
Randomization to Epoch 1 will be stopped by the sponsor prior to achieving the 
originally planned total of 174 randomized subjects. At least 120 subjects will be 
randomized and dosed in Epoch 1. Therefore, with at least 60 subjects randomized to the 
SC placebo treatment group in Epoch 1, and allowing for a 15% drop-out rate in Epoch 1, 
it is expected that 19 or more subjects (60 x [1–0.15] x 0.39) will relapse and 
subsequently receive GAMMAGARD LIQUID/KIOVIG treatment in Epoch 2. 
Assuming a responder rate of 65% to GAMMAGARD LIQUID/KIOVIG based on 
responder rates of 55% and 77% observed in the subset of treatment-experienced subjects 
in the ICE study (Hughes et al., 2008) and the PRIMA study (Léger et al., 2013), 
respectively, the estimated sample size of at least 19 subjects will provide more than 90% 
power to reject the null hypothesis that the responder rate is at most 24% at the two-sided 
5% significance level and allowing for a 15% drop-out rate in Epoch 2.
14.2.2 Datasets and Analysis Cohorts
The Epoch 2 Safety Set will include all subjects who had a relapse in Epoch 1, entered 
Epoch 2, and received IGIV treatment with either GAMMAGARD LIQUID/KIOVIG or 
GAMUNEX®-C in Epoch 2.
The E1:Placebo Relapse / E2:GGL/KIOVIG Set will include a subset of subjects who 
had a relapse while on placebo in Epoch 1, entered Epoch 2, and were treated with 
GAMMAGARD LIQUID/KIOVIG in Epoch 2. This is the primary analysis set for 
Epoch 2 (the IV treatment period) non-safety data.
The E1:Placebo Relapse / E2:IGIV Set will include all subjects who had a relapse while 
on placebo in Epoch 1, entered Epoch 2, and were treated with IGIV (GAMMAGARD 
LIQUID/KIOVIG or GAMUNEX®-C). This is a secondary analysis set for Epoch 2 
(the IV treatment period) non-safety data.
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The E1: HYQVIA/HyQvia Relapse / E2:GGL/KIOVIG Set will include all subjects who 
had a relapse while on HYQVIA/HyQvia in Epoch 1, entered Epoch 2, and were treated 
with GAMMAGARD LIQUID/KIOVIG in Epoch 2. This is an exploratory analysis set 
for Epoch 2 (the IV treatment period) non-safety data.
The E1:HYQVIA/HyQvia Relapse / E2:IGIV Set will include all subjects who had a 
relapse while on HYQVIA/HyQvia in Epoch 1, entered Epoch 2, and were treated with 
IGIV (GAMMAGARD LIQUID/KIOVIG or GAMUNEX®-C) in Epoch 2. This is an 
exploratory analysis set for Epoch 2 (the IV treatment period) non-safety data.
14.2.3 Handling of Missing, Unused, and Spurious Data
Rules for handling missing data will be described in the SAP.
14.2.4 Methods of Analysis
14.2.4.1 Primary Outcome Measure
The primary outcome measure in Epoch 2 is the response rate. A responder is defined as 
a subject who demonstrated an improvement of functional disability by ≥1 point 
(decrease) in the adjusted INCAT disability score at the completion of IV treatment 
period (6 months) or the last study visit of the IV treatment period, relative to pre-IV 
treatment baseline.
The null hypothesis is that the response rate to GAMMAGARD LIQUID/KIOVIG 
among subjects who relapsed in Epoch 1 while on placebo with rHuPH20 treatment of 
the current study is not higher than 24%. If the lower limit of the two-sided 95% Wilson 
Score CI of the responder rate in the E1:Placebo Relapse / E2:GGL/KIOVIG set exceeds 
the assumed historical-control placebo response rate of 24%, then the null hypothesis will 
be rejected and the current study will be interpreted as providing evidence of the efficacy 
of GAMMAGARD LIQUID/KIOVIG. This analysis will be performed on the 
E1:Placebo Relapse – E2: GGL/KIOVIG analysis set as the primary analysis set. 
14.2.4.2 Secondary Outcome Measures 
14.2.4.2.1 Clinical Improvement of CIDP
Clinically meaningful improvement of CIDP, defined as one or more of the following: 
subject response (defined as a decrease of ≥1 point in the adjusted INCAT disability 
score at 2 consecutive time points); ≥8 kPa increase in the hand grip strength in the more 
affected hand; ≥4 points increase in R-ODS at the completion of the IV treatment period 
[6 months] or at the last study visit of the IV treatment period, relative to the pre-IV 
treatment baseline score, will be presented using descriptive statistics.
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14.2.4.2.2 Time to Response
The median time to response will be presented for the GAMMAGARD 
LIQUID/KIOVIG Placebo Relapse analysis set. Additionally, INCAT will be 
summarized by time point. Summary statistics will include sample size, mean, standard 
deviation, minimum, and maximum.
As a supportive analysis, these analyses will be repeated on the Full Placebo Relapse 
analysis set.
14.2.4.2.3 Safety
Epoch 2 safety set, including SAEs, TEAEs, ARs plus suspected ARs, deaths, and 
discontinuations due to AE will be analyzed using methods similar to Epoch 1. Analyses 
will be performed in the Epoch 2 Safety Set using the actual treatment. Safety endpoints 
will be summarized descriptively by IGIV treatment (ie, GAMMAGARD 
LIQUID/KIOVIG and GAMUNEX®-C separately).
For the purpose of summaries and listings the durations of AEs will be calculated as 
follows: (stop day – start day) + 1 day, which yields the number of days on which the AE 
was present.
For each body system and overall, the number and proportion of subjects that 
experienced an AE will be presented by IGIV treatment (ie, GAMMAGARD 
LIQUID/KIOVIG and GAMUNEX®-C separately). 
Laboratory measurements will be summarized by time point and IGIV treatment (ie, 
GAMMAGARD LIQUID/KIOVIG and GAMUNEX®-C separately). Summaries of 
continuous measurements will include sample size, mean, SD, minimum, and maximum. 
For categorical measurements, the proportion of observations in each category will be 
presented.
14.2.4.3 Tertiary Outcome Measures 
Responder rates for the E1:HYQVIA/HyQvia Relapse – E2:IGIV analysis set and the 
E1:HYQVIA/HyQvia Relapse – E2:GGL/KIOVIG analysis set will be summarized by 
sample size and proportion. As the expected sample size for the Full HYQVIA/HyQvia 
Relapse analysis set is only 5, no CIs will be constructed.
All other tertiary outcome measures will be summarized descriptively.
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14.3 Planned Interim Analyses of the Study
Two interim analyses are planned:

Interim Safety Analysis, which is Epoch 1 and Epoch 2 safety analysis. 

Formal Interim Analysis, which is the final analysis of Epoch 1 data.
The purpose and timing of each analysis are defined below.
14.3.1 Interim Safety Analysis
An interim safety analysis will be performed during early conduct of the study in order to 
closely monitor safety and determine the anti-rHuPH20 antibody response in CIDP 
subjects. Data from the interim safety analysis will be independently reviewed by the 
DMC, and the Interim Safety Analysis Report along with the DMC recommendation will 
be used to update regulatory authorities.
The interim safety analysis will include a minimum of 30 subjects who have been treated
with HYQVIA/HyQvia (ie, a total of approximately 60 randomized subjects), and 
followed up for a minimum of 30 days following the second full-dose administration. 
Safety data to be reviewed at the interim safety analysis will include, but may not be 
limited to:

Cumulative treatment-emergent serious and nonserious AEs

Cumulative ARs plus suspected ARs

Anti-rHuPH20 binding and neutralizing antibody titers

Clinically significant abnormal clinical laboratory test results

Any relevant information that may support safety evaluation
Safety data will be summarized descriptively by Epoch 1 treatment (actual) for the 
Epoch 1 Safety set. If more than 5 subjects have relapsed prior to the cut-off date for the 
Interim Safety Analysis, then safety data will also be presented for the Epoch 2 Safety 
set. 
The first occurrence of any TEAE and the first occurrence of any treatment-emergent 
SAE will be analyzed using a Cox Proportional Hazard model to obtain an overall 
HR for treatment, adjusted for time in study (ie, duration of treatment). 
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Separate HR’s for the relationship of AEs with treatment will be computed for subjects 
who had total treatment durations of 0 to 4 weeks, 5 to 8 weeks, 9 to 12 weeks, and 13 to 
26 weeks at the time of the data cut-off. These analyses will address the potential impact 
of any imbalance in AE rates due to differential dropout rates in Epoch 1 between 
HYQVIA/HyQvia and placebo with rHuPH20, and will characterize the relationship of 
AEs to treatment, overall and over time. Point estimates and CIs will be reported.
Subjects are defined as having elevated rHuPH20 antibody titers if they have two 
consecutive anti-rHuPH20 antibody titers of ≥1:160 which are elevated from the subject’s 
baseline titers. If at least 5 subjects in each treatment group have elevated titers, then an 
exploratory analysis will be conducted to assess if there is any evidence of relationship 
between anti-rHuPH20 antibody titer (elevated, not elevated) and the occurrence of AEs 
of interest.
In addition, an exploratory analysis of any treatment emergent abnormal titer or rises 
above baseline in anti-rHuPH20 antibody titer will be performed to assess if there is any 
evidence of relationship between anti-rHuPH20 antibody titer (elevated, not elevated) and 
the occurrence of AEs. 
In addition, the proportion of subjects who experience a worsening of functional 
disability defined as an increase of ≥1 point relative to the pre-SC treatment baseline 
score in 2 consecutive adjusted INCAT disability scores OR who experience CIDP 
worsening (defined as ≥8 kPa decrease in the hand grip strength in the more affected 
hand) OR ≥4 points decrease in R-ODS relative to the pre-SC treatment baseline score 
(at the time of withdrawal from the SC treatment period) will be evaluated.
14.3.2 Formal Interim Analysis (Epoch 1 Final Analysis)
Formal Interim Analysis will be performed to evaluate the efficacy of HyQvia versus 
placebo as a maintenance therapy for CIPD to prevent relapse of neuromuscular disability 
and impairment. All of the following will apply:

Analysis will be performed when all subjects have completed participation in 
Epoch 1.

Definition of completed participation: Any subject who completes Epoch 1, or 
discontinues prematurely from Epoch 1, irrespective of reason for withdrawal, is 
considered as having completed participation in Epoch 1.

At the completion of Epoch 1, all Epoch 1 data will be locked, treatment 
assignment will be unblinded, and all Epoch 1 data will be analyzed as preplanned 
in the study SAP. The analysis will be considered the final analysis of Epoch 1 data. 
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All available Epoch 2 data will be included in subject data listings along with 
Epoch 1 data and will not be analyzed.

No multiplicity adjustment for the control of Type 1 error (false positive 
conclusion) will be made, as the analysis of Epoch 1 data will include all Epoch 1 
data for all subjects who have completed participation in Epoch 1.

The study SAP will be finalized and approved prior to Epoch 1 data lock and 
treatment unblinding.
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 CTA. The investigator is ultimately responsible for the conduct of all 
aspects of the study at the study site and verifies by signature the integrity of all data 
transmitted to the sponsor. The term “investigator” as used in this protocol as well as in 
other study documents, refers to the investigator or authorized study personnel that the 
investigator has designated to perform certain duties. Subinvestigators 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 and Takeda Development Center Americas) 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
A central reader will be used to confirm CIDP diagnosis for eligibility determination 
based on review of electrodiagnostic records and other relevant medical records in 
accordance with EFNS/PNS 2010 guideline. Electrodiagnostic test if repeated during 
screening will be conducted in accordance with standardized procedures.
A standardization program will be implemented to provide standardized training to raters 
and to monitor inter-rater reliability as part of 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 enrollment of patients into this study, the protocol, informed consent form, any 
promotional material/advertisements, and any other written information to be provided 
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(ies) approval, as described in the CTA.
If the protocol or any other information given to the subject is amended, the revised 
documents will be reviewed and approved/given favorable opinion by the EC and 
applicable regulatory authorities, where applicable. The protocol amendment will only be 
implemented upon the sponsor’s receipt of approval and, if required, upon the sponsor’s 
notification of applicable regulatory authority(ies) approval.
17.3 Informed Consent
Investigators will choose patients for enrollment considering the study eligibility criteria. 
The investigator will exercise no selectivity so that no bias is introduced from this source.
All patients must sign an informed consent form before entering into the study according 
to applicable national and local regulatory requirements and ICH GCP. Before use, the 
informed consent form will be reviewed by the sponsor and approved by the EC and 
regulatory authority(ies), where applicable, (see Section 17.2). The informed consent 
form will include a comprehensive explanation of the proposed treatment without any 
exculpatory statements, in accordance with the elements required by ICH GCP and 
applicable national and local regulatory requirements. Patients will be allowed sufficient 
time to consider participation in the study. By signing the informed consent form, patients 
agree that they will complete all evaluations required by the study, unless they withdraw 
voluntarily or are terminated from the study for any reason.
The sponsor will provide to the investigator in written form any new information 
that significantly bears on the subjects’ risks associated with IP exposure. 
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The informed consent will be updated, if necessary. This new information and/or revised 
informed consent form, that have been approved by the applicable EC and regulatory 
authorities, where applicable, will be provided by the investigator to the subjects who 
consented to participate in the study (see Section 17.3).
17.4 Data Monitoring Committee
This study will be monitored by an independent, external 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, 
as well as an unblinded statistician; all of whom who are not participating in this study. 
The DMC may recommend to stop the trial if it finds toxicities or if treatment is proven 
to be not beneficial.
The DMC will be responsible for monitoring the data obtained in the study, including 
(but not necessarily limited to) periodic review of 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 
trial. In addition, the DMC will be responsible for reviewing interim safety analysis. If no 
significant trends of treatment-emergent hemolytic anemia or safety concerns related to 
potential immune response to rHuPH20 are detected, the initial frequent clinical 
laboratory assessment and/or anti-rHuPH20 antibody sampling schedule may be 
waived/modified upon recommendation by the DMC and notification by the 
sponsor/sponsor’s representative. Based on data reviews, the DMC will make a 
recommendation to continue the study as is, temporarily suspend the study, or 
terminate the study. 
The membership, responsibilities, interactions, and operations of the DMC will be 
detailed in the DMC Charter.
17.5 Description of Ethical Considerations Relating to the Trial
The need for a placebo-controlled study, with reference to articles 16 and 7 of the 
Declaration of Helsinki is discussed below. This Section 17.5 is intended to fulfill the 
requirements as laid down in article 22 of the Declaration of Helsinki.
Article 16 states “In medical practice and in medical research, most interventions involve 
risks and burdens. Medical research involving human subjects may only be conducted if 
the importance of the objective outweighs the risks and burdens to the research subjects.”
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The study design follows the current clinical practice as set forward in the current 
EFNS/PNS guidelines (European Federation of Neurological Societies, 2010), to 
periodically evaluate the need for continuous IgG therapy and to provide IGIV as an 
effective treatment of those subjects who relapse during the periodic evaluation (see 
below under risks of serious or irreversible harm). We consider the addition of a 
treatment option and the prospect of self-infusion, and therefore empowerment of the 
patient, besides the availability of immediate rescue treatment, justifies the risks and 
burden to the research subjects.
Article 7 states “Medical research is subject to ethical standards that promote and ensure 
respect for all human subjects and protect their health and rights.”
Our protocol is not different from the medical practice as promoted by the current 
EFNS/PNS guidelines, as stated above.
According to the Declaration of Helsinki article 33, conducting a placebo-controlled trial 
is possible if:

Compelling methodological reasons exist 

The patient will not be subject to additional risks of serious or irreversible harm

No proven intervention exists
This placebo-controlled study is designed in accordance with the current version of the 
Declaration of Helsinki:

Compelling methodological reasons exist
The safety and efficacy of intravenous immunoglobulin G (IGIV) treatment in CIDP is 
considered a proven intervention, however HyQvia (a rHuPH20-facilitated subcutaneous 
immunoglobulin G [IGSC]) is a new product that is administered subcutaneously (rather 
than intravenously) resulting in a unique PK, bioavailability and safety profile. The 
safety, tolerability, and efficacy of HyQvia as a treatment option for CIDP have yet to be 
demonstrated.
During protocol development, a non-inferiority, active-comparator, double-masked- (for
masking both IGIV and IGSC) design has been considered due to concerns about the
ethics of including a placebo group when an effective IGIV treatment is available.
Sample size for the active-comparator study design was estimated according to the 
US FDA Guidance for Industry: Non-Inferiority Clinical Trials (U.S. Department of 
Health and Human Services et al., 2010). An active-control relapse rate of 14% was 
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assumed, based on data from the ICE study (Hughes et al., 2008). Non-inferiority 
margins calculated using the preferred 95%-95% rule and the 90%-95% alternative rule 
were 1.15 and 1.37, respectively.
Using the 95% to 95% rule and non-inferiority margin of 1.15, it was determined that a 
sample size of 4,286 subjects per treatment arm would be required to show 
non-inferiority using a 1-tailed, 97.5% CI. Preservation of up to 80% of the control effect 
would increase this sample size to 107,144 per treatment arm.
Using the 90% to 95% rule and non-inferiority margin of 1.37, it was determined that a 
sample size of 705 subjects per treatment arm would be required to show non-inferiority 
using a 1-tailed, 97.5% CI. Preservation of up to 80% of the control effect would increase 
this sample size to 26,786 subjects per group. 
In both cases, these required calculated sample sizes will be increased for relapse rates 
lower than 14%. On the other hand, a non-inferiority margin greater than 1.37, which 
would result in lower sample size, is not clinically acceptable.
CIDP is a rare disease with a worldwide prevalence ranging from 1.9 to 8.9/100,000 with 
an annual incidence of 0.15 to 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 sample size of 
705 per treatment arm (ie, total of 1,410 randomized subjects in a study) or greater is not 
feasible to recruit in this patient population.
Another drawback of an active-comparator, non-inferiority study is that it requires the 
use of a double-masked-design for masking since currently only intravenous 
immunoglobulin products are approved for the treatment of CIDP (therefore, the 
active comparator to HyQvia which is a SC administration must be IGIV). To protect 
the blind, the double-masked-design will involve simultaneous intravenous and 
subcutaneous infusions, which means doubling an already large infusion volume due 
to large IgG doses typically required to treat CIDP patients. To illustrate, the mean 
monthly dose of IgG in CIDP is 1.3 g/kg BW, which is equivalent to approximately 
1000 mL of IgG 10% solution for an 80-kg patient. Some CIDP patients may require 
monthly doses as high as 2.4 g/kg BW (ie, approximately 2000 mL). Double-masked-
design means administering twice the infusion volumes (equivalent to 2000 to 
4000 mL). Such high volumes subject the patients to undue safety risks 
including fluid overload, edema and potentially congestive heart failure. 
Additionally, total infusion administration time will markedly increase, 
adding unnecessary burden to the patients participating in the study.
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Therefore, it is concluded that an active-comparator, non-inferiority design for a study in 
CIDP is not feasible. As an alternative, it is proposed to keep the current placebo-
controlled design, with close monitoring for early detection for signs of relapse and 
provision of IGIV rescue therapy immediately without delay. The study protocol has been 
reviewed and discussed with the independent DMC comprised of 2 physicians/clinical 
researchers who are recognized experts in the CIDP and an independent biostatistician. 
The DMC agreed that the placebo-controlled study as designed that includes relapse risk 
mitigation measures and management are acceptable and ethical.

The patient will not be subject to additional risks of serious or irreversible 
harm
The progression of CIDP occurs over a long period of time. Bouchard et al. in a review of 
100 CIDP patients found that in long-standing disease the cumulative loss of axons 
correlates with a poor prognosis (Bouchard et al., 1999).
With newer therapies for CIDP (IGIV), the prognosis of CIDP has been improved. In an 
institutional-based evaluation (Hahn et al., 2005), 88% of patients returned to normal or 
had only minor non-disabling symptoms remaining (modified Rankin score of 0 or 1); 
64% of these patients had discontinued all medication and were in full remission for 
5.7 years. Many of these patients required aggressive therapy during the early stage of the 
disease, often with combination of several therapeutic modalities (including prednisone, 
PE and IGIV). It is concluded that even severe relapse can be treated adequately with 
excellent response and recovery. In the proposed study, subjects with modest relapse will 
be immediately rescued.
The EFNS/PNS guidelines (European Federation of Neurological Societies, 2010) for the 
management of CIDP encourage physicians to periodically reduce a subject’s treatment 
dose and/or dosing frequency (even to the point of temporarily discontinuing the 
subject’s treatment) to assess the patient’s need for continued therapy:
“If a patient becomes stable on a regimen of intermittent IVIg, the dose (or, perhaps, 
frequency) of IVIg should be reduced periodically to establish the need for ongoing 
therapy because patients may need less IVIg than they receive or in fact none at all.”
The proposed (161403) study design including a placebo arm (in essence, withdrawing 
IGIV therapy) is consistent with the EFNS/PNS recommendation to evaluate the need for 
continuous therapy and to provide IGIV as an effective treatment of those subjects who 
relapse.
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Treatment withdrawal or use of placebo control has been commonly employed in recent 
or ongoing clinical studies of IGIV treatment in CIDP. In a previous study (ICE study of 
Gamunex-C) (Hughes et al., 2008), subjects were exposed to placebo twice during the 
trial. There were no reports of permanent disability or axonal injury. Likewise, in a recent 
study (PRIMA study of Privigen) (Léger et al., 2013), subjects who had been receiving 
IGIV were also mandated to withdraw their IGIV treatment for up to 10 weeks until 
disease deterioration (≥1 adjusted INCAT disability score) occurred before subjects 
were allowed to be enrolled in the study to receive IGIV study drug (Privigen). In a 
currently ongoing CIDP study (PATH study of Hizentra; NCT01545076; EudraCT 
Number 2011-003448-28) being conducted in multiple EU countries, all subjects are at 
least once exposed to drug withdrawal with half of the subjects (randomized to placebo 
group) being exposed to drug withdrawal for a second time. In the current proposed 
161403 study, subjects will not be required to withdraw their IGIV treatment at study 
entry. In fact, subjects will be required to continue on their own IGIV therapy during 
screening and baseline period until randomization. At randomization, half of the
participants will be exposed to placebo (ie, subjected to IG treatment cessation) until 
CIDP worsening defined as ≥1 point increases in the adjusted INCAT disability score, 
which is the same criteria as that used in the other CIDP clinical trials mentioned above.
In the proposed clinical trial, the sponsor is taking multiple mitigation steps to assure the 
prevention of serious or irreversible harm, safety of the patients and to prevent 
axonal/permanent injury. The following are the measures to mitigate the above risk:
1.
During the proposed 161403 study, the subject’s CIDP disease condition will be 
closely and frequently monitored. Subjects will be provided with a DIARYpro to 
report their level of activities of daily living on a weekly basis by filling out a 
24item questionnaire (R-ODS). R-ODS has been demonstrated to have a 
significantly higher responsiveness compared to the INCAT disability scale, and is 
recommended to be the primary instrument for the assessment of the subject’s 
activity and functional levels (Vanhoutte et al., 2013a). Subject’s self-reported 
R-ODS scores can be readily accessible for frequent review by the investigator. 
Any clinical signs of CIDP worsening would be readily captured, thus reducing the 
possibility of untreated relapse and/or delay in treatment of relapse.
2.
Additionally, subjects will be instructed to contact the study site/investigator in 
the event of suspected CIDP worsening (“feeling worse”). At any time, 
unscheduled visit to the study site will be arranged as soon as possible to evaluate 
if the CIDP worsening meets the definition of relapse by INCAT assessments. 
Subjects with confirmed CIDP relapse in Epoch 1 will be offered IGIV rescue 
immediately without any mandatory waiting period, thus minimizing the possibility 
of causing axonal injury/permanent damage.
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3.
Patients whose disease progresses by ≥1 adjusted INCAT disability score will be 
rescued with IGIV at a dose of 2 gram/kg BW. This definition of disease 
progression (by ≥1 adjusted INCAT disability score) correlates with a very modest
clinical progression. The protocol-specified IGIV treatment (an induction dose of 
2 g/kg BW followed by maintenance infusions every 3 weeks) is consistent with 
the recommended treatment guidelines (EFNS/PNS 2010 (European Federation of 
Neurological Societies, 2010)) and has been established to be effective in large 
clinical trials for more than 1 IGIV products (eg, ICE study (Hughes et al., 2008)
and PRIMA study (Léger et al., 2013)). The maintenance IGIV dose to be used in 
rescuing the subjects who relapsed during Epoch 1 is the same as the subject’s pre-
study IGIV maintenance treatment which has been shown to be effective in 
maintaining the disease in remission. Additionally, recognizing subjects at times 
may need a higher IGIV dose following CIDP relapse, the protocol allows IGIV 
dose adjustments (increases) in order to restore the subject’s functional ability to 
baseline level. These measures will assure that subjects participating in the study 
would not suffer additional axonal injury or permanent disability.
4.
The proposed study will have a DMC, composed of independent neurologists with 
expertise in the field of peripheral neuropathy. The Board will review all safety 
data, as well as data assessing response to rescue therapy of a relapse, in a fully 
unblinded fashion. The Board will alert the sponsor in case of a safety signal and 
will recommend actions to be taken that may include termination of the study.
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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 
informed consent forms, correspondence with the EC and the study monitor/sponsor, 
enrollment and screening information, CRFs, SAE reports (SAERs), laboratory reports 
(if applicable), and data clarifications requested by the sponsor. 
The investigator will comply with the procedures for data recording and reporting. Any 
corrections to paper study documentation must be performed as follows: 1) the first entry 
will be crossed out entirely, remaining legible; and 2) each correction must be dated and 
initialed by the person correcting the entry; the use of correction fluid and erasing are 
prohibited.
The investigator is responsible for the procurement of data and for the quality of data 
recorded on the CRFs. CRFs will be provided in electronic form.
If electronic format CRFs are provided by the sponsor, only authorized 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 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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21.2 Schedule of Study Procedures and Assessments
Table 21-1. Schedule of Study Procedures and Assessments: SC Treatment Period (Epoch 1) –
Every 2 Weeks Dosing Regimen
Study Period
Screening/
Pre-SC BLa
(Up to 
8 Weeks)
SC Treatment Periodb
(6 Months)
Uc ETd
Study Visits
S
Pre-
SC 
BL
Ramp-Up
SC Infusions Every 2 Weeks (±3 Days)
E1
W1e
E1
W2e
E1
W3
E1 W3 
+72 hrs
E1 
W4f
E1
W5v
E1
W7
E1
W9
E1
W11
E1
W13
E1W15/ 
E1Intg
E1
W17
E1
W19
E1
W21
E1
W23
E1
W25
E1W27/
EOE1T
Informed Consenth
X
Eligibility Determination
X
X
Demographics
X
Medical, Medication, and 
Non-Drug Therapy 
History
X
Body Height
X
Body Weight
X
Xg
X
Body mass index
X
Xg
Vital Signsi
X
Xj
Xj
Xj
Xj
Xj
Xj
Xj
Xj
Xg,j
Xj
Xj
Xj
Xj
Xj
Xj
X
Physical Exam
X
Xk
Xg,k
Xk
X
12-Lead ECG
X
X
X
Electrodiagnostic Test/ 
Nerve Conduction Studies
Xl
Xk
X
Screening and Safety 
Labsm
X
Xk
Xk
Xn
X
Xk
Xg,k
Xk
X
INCAT Disability Score
X
Xk,o
Xk
Xk
Xk
Xg,k
Xk
Xk
Xk
X
X
Hand Grip Strength
Xk
Xg,k
Xk
X
X
MRC sum scorep
Xk
Xg,k
Xk
X
X
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Table 21-1. Schedule of Study Procedures and Assessments: SC Treatment Period (Epoch 1) –
Every 2 Weeks Dosing Regimen
Study Period
Screening/
Pre-SC BLa
(Up to 
8 Weeks)
SC Treatment Periodb
(6 Months)
Uc ETd
Study Visits
S
Pre-
SC 
BL
Ramp-Up
SC Infusions Every 2 Weeks (±3 Days)
E1
W1e
E1
W2e
E1
W3
E1 W3 
+72 hrs
E1 
W4f
E1
W5v
E1
W7
E1
W9
E1
W11
E1
W13
E1W15/ 
E1Intg
E1
W17
E1
W19
E1
W21
E1
W23
E1
W25
E1W27/
EOE1T
R-ODS
Xk
Xq
X
X
SF-36
X
X
X
EQ-5D
X
X
X
HRUr
X
Treatment Satisfaction
X
X
X
Treatment Preference
X
X
X
PGIC
X
X
Subject’s pre-
randomization IgG 
Treatment
X
Randomization
Xs
IP Administration
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Infusion self-
administration 
proficiency checklistt
X
Post-Infusion Telephone 
Follow-upu
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum IgGm
Xk
Xk
Xg,k
Xk
X
Anti-rHuPH20 
Antibodiesm
Xk
Xk
Xk
Xk
Xg,k
Xk
X
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Table 21-1. Schedule of Study Procedures and Assessments: SC Treatment Period (Epoch 1) –
Every 2 Weeks Dosing Regimen
Study Period
Screening/
Pre-SC BLa
(Up to 
8 Weeks)
SC Treatment Periodb
(6 Months)
Uc ETd
Study Visits
S
Pre-
SC 
BL
Ramp-Up
SC Infusions Every 2 Weeks (±3 Days)
E1
W1e
E1
W2e
E1
W3
E1 W3 
+72 hrs
E1 
W4f
E1
W5v
E1
W7
E1
W9
E1
W11
E1
W13
E1W15/ 
E1Intg
E1
W17
E1
W19
E1
W21
E1
W23
E1
W25
E1W27/
EOE1T
Plasma/Serum Retention 
Samplesm
Xk
Xk
Xk
Xk
Xg,k
Xk
X
Adverse Events
X
Concomitant Medications 
and Non-Drug Therapies
X
Abbreviations:  AE = adverse event; CIDP = Chronic inflammatory demyelinating polyradiculoneuropathy; E1W = Epoch 1 week number; E1Int = Epoch 1 
interim visit; ECG = Electrocardiogram; EOE1T = End-of-Epoch 1 treatment visit; EQ-5D = EuroQoL (Quality of Life)-5 Dimensions Questionnaire; 
ET = Early termination visit; IgG = Immunoglobulin G; IGIV = Intravenous immunoglobulin G; INCAT = Inflammatory Neuropathy Cause and 
Treatment; h = hours; HRU = Health resource utilization; MRC = Medical Research Council; PGIC = Patient global impression of change scale; 
IP = Investigational product; Pre-SC BL = Pre-subcutaneous treatment baseline visit; rHuPH20 = Recombinant human hyaluronidase 
R-ODS = Rasch-built Overall Disability Scale; S=Screening; SC = Subcutaneous; SF-36 = Short Form-36 Survey; 
U = Unscheduled visit for relapse assessment.
a
The Pre-SC treatment baseline visit is to take place on the day of the subject’s last pre-randomization IGIV infusion, which is to be administered at the 
study site. The first SC administration of HYQVIA/HyQvia or placebo with rHuPH20 will take place 2 weeks (±3 days) following the last 
pre-randomization IGIV administration regardless of the subject’s pre-randomization IGIV dosing interval. For the rest of the SC period, SC 
administrations are calculated from Week 1 and not the Pre-SC BL Visit.
b
During the SC treatment period, subjects who relapse (defined as an increase in adjusted INCAT disability score by ≥1 point relative to the pre-SC 
treatment baseline score, on 2 consecutive INCAT assessments) will be offered open-label IGIV treatment. Subjects who will receive IV treatment will 
undergo an end-of-SC treatment/pre-IV treatment baseline assessment visit (instead of the ET visit). For the schedule of study procedures and 
assessments during the IV treatment period, see Table 21-4. For any deviation from allowable study visit windows (±2 or ±3 day windows), subjects 
would be required to be brought back to the original planned visit date of the next visit in order to ensure subject safety. All other assessment or 
procedure visits, which do not have a visit window or a reference note in the protocol, should follow visit windows of ±3 days. There will be no visit 
window allowed in the ramp up period after Visit 1 (Week 1).
Continued on Next Page
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Continued
c
At any time during the SC treatment period, unscheduled visit(s) may take place for a subject whose CIDP is worsening to assess whether the subject has 
an increase in the adjusted INCAT disability score by ≥1 point relative to the pre-SC treatment baseline score. INCAT assessment will be repeated during 
the pre-IV treatment baseline visit or early termination visit, as applicable, to confirm the subject’s adjusted INCAT disability score has increased by 
≥1 point relative to the pre-SC treatment baseline score, at which time the final determination of whether a subject has met relapse criteria will be made.
d
The early termination visit is to be conducted for subjects who are being prematurely discontinued from the SC treatment period and will not undergo IV 
treatment period.
e
The Week 1 infusion visit takes place 2 weeks (±3 days) after the subject’s last pre-randomization IGIV administration (Pre-SC BL visit). Week 1 should 
be calculated from the last day of dosing for an infusion dose that is to be administered over multiple days. For the rest of the SC period, the reference to 
calculate the visit  is Week 1 and not the Pre-SC BL Visit (Exception:  Week 3+72 h, Week 4 (please see note f) and Week 5 that are calculated from 
Week 3 due to safety assessments in the protocol). During the ramp-up period, treatment will be given as a 1-week equivalent dose during the Week 1 
and Week 2 infusion visits. The full (2-week) dose will be administered beginning at Week 3. 
f
To be collected 7 (±2) days (ie, 5 – 9 days) after the Week 3 infusion, the subject’s first full-dose infusion of IP (HYQVIA/HyQvia or placebo with 
rHuPH20). 
g
Subjects on a dosing schedule of every 2 weeks will be asked to return to the study site for interim assessments of the assessments that are to be 
conducted on the day of infusion ( ±3 days) during Week 15. 
h
Written informed consent must be obtained prior to any study procedures including screening.
i
Vital signs include pulse rate, resting systolic and diastolic blood pressure, body temperature, and respiratory rate. Vital signs are to be taken at baseline 
(prior to infusion during E1W1 visit), during the initial 3 SC infusion visits, the interim visit, and at the end-of-SC treatment visit.
j
For the initial 3 SC infusions, vital signs are to be monitored and recorded at any time prior to infusion, in the event of occurrence of AE(s), and within 
60 minutes of completion of an infusion. During subsequent infusion visits, vital signs will be taken 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. See further details in Section 12.8.
k
To be performed prior to the start of the infusion (or prior to the first day of dosing for an infusion dose that is to be administered over multiple days).
l
If available, subjects’ previous nerve conduction study records consistent with electrodiagnostic criteria for Definite or Probable CIDP per 
EFNS/PNS 2010 guideline on management of CIDP may be used during initial screening for eligibility assessment. An additional study at the time of 
screening is not mandatory but highly recommended. Subjects’ nerve conduction study record(s) must be reviewed by an independent central reader to 
confirm and document the diagnosis of CIDP based on electrodiagnostic criteria. 
m
For detailed sampling timepoints, see Table 21-5. Whenever there is an overlap of a safety visit and an infusion visit, the safety laboratory assessments 
should be performed first prior to the IP infusion. 
n
To be collected at 72 (±24) h (ie, 48 – 96 hrs) after the Week 3 infusion, the subject’s first full-dose infusion of IP (HYQVIA/HyQvia or placebo with 
rHuPH20).
o
The baseline INCAT disability score will be used to confirm subject eligibility for the inclusion criterion of an INCAT disability score between 0 and 
7 (inclusive) (ie, Inclusion Criterion #4), at which time the final determination of eligibility will be made. 
p
The MRC sum score is obtained by examining the following muscles on each side of the body: deltoids, biceps, wrist extensors, iliopsoas, quadriceps, 
and anterior tibialis, and rating the strength of each muscle according to the MRC scale. All scores from muscles on both left and right side of the body 
are summed to obtain the MRC sum score.
Continued on Next Page
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Continued
q
Beginning with the E1W1 visit, the R-ODS will be completed at least once weekly. If R-ODS assessment coincides with an infusion visit, the R-ODS is 
to be performed prior to the start of the infusion (or prior to the first day of dosing for an infusion dose that is to be administered over multiple days). 
eDiary (DIARYpro) will be dispensed to the subjects at screening. R-ODS data collected during screening will not be used for analysis.
r
The health resource utilization (HRU) questionnaire includes days off school/work, unscheduled physician visits, hospitalization, and emergency room 
visits. Beginning with the Pre-SC BL visit, HRU items will be recorded on an ongoing basis during the study. Note: The data entered by subjects for 
HRU during screening in the DIARYpro will not be used for analysis.
s
Randomization can occur between the last day of IGIV and Week 1 assessments (once last IGIV is fully administered and eligbility is confirmed).
t
SC infusions will be administered by an appropriately trained healthcare professional (eg, infusion nurse), self-administered by the subject, and/or, as 
applicable, by a caregiver who may assist the subject with self-administration. Training, evaluation, and verification of the subject’s (and/or caregiver’s) 
proficiency in performing self-infusion procedures by the investigator/designee must be documented as a prerequisite before the subject (and/or 
caregiver) will be allowed to begin self-administration of SC infusions at home or other suitable locations. A proficiency checklist will be completed by 
the investigator/designee once training begins and until the subject’s (and/or caregiver’s) proficiency is demonstrated. The subject (and/or caregiver) may 
be asked to return to the study site during the SC treatment period so that the investigator/designee can further assess and document that the subject 
(and/or caregiver) continues to be capable of independently performing self-infusion procedures. 
u
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 
72 h 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).
v
A minimum of a 3 day interval is required between E1W4 and E1W5 visits.
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Table 21-2. Schedule of Study Procedures and Assessments: SC Treatment Period (Epoch 1) –
Every 3 Weeks Dosing Regimen
Study Period
Screening/
Pre-SC BLa
(Up to 8 Weeks)
SC Treatment Periodb
(6 Months)
Uc ETd
Study Visits
S
Pre-SC 
BL
Ramp-Up
SC Infusions Every 3 Weeks (±3 Days)
E1
W1e E1
W2e E1
W3e E1
W5
E1 W5 
+72 hrs
E1 
W6f
E1 
W7v E1
W8
E1
W11
E1W14/
E1Intg
E1
W17
E1
W20
E1
W23
E1W26 
/EOE1T
Informed Consenth
X
Eligibility Determination
X
X
Demographics
X
Medical, Medication, and 
Non-Drug Therapy History
X
Body Height
X
Body Weight
X
Xg
X
Body mass index
X
Xg
Vital Signsi
X
Xj
Xj
Xj
Xj
Xj
Xj
Xg,j
Xj
Xj
Xj
Xj
X
Physical Exam
X
Xk
Xg,k
Xk
X
12-Lead ECG
X
X
X
Electrodiagnostic Test/Nerve 
Conduction Studies
Xl
Xk
X
Screening and Safety Labsm
X
Xk
Xk
Xk
Xn
X
X
Xg,k
Xk
X
INCAT Disability Score
X
Xk,o
Xk
Xk
Xk
Xg,k
Xk
Xk
Xk
Xk
X
X
Hand Grip Strength
Xk
Xg,k
Xk
X
X
MRC sum scorep
Xk
Xg,k
Xk
X
X
R-ODS
Xk
Xq
X
X
SF-36
X
X
X
EQ-5D
X
X
X
HRUr
X
Treatment Satisfaction
X
X
X
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Table 21-2. Schedule of Study Procedures and Assessments: SC Treatment Period (Epoch 1) –
Every 3 Weeks Dosing Regimen
Study Period
Screening/
Pre-SC BLa
(Up to 8 Weeks)
SC Treatment Periodb
(6 Months)
Uc ETd
Study Visits
S
Pre-SC 
BL
Ramp-Up
SC Infusions Every 3 Weeks (±3 Days)
E1
W1e E1
W2e E1
W3e E1
W5
E1 W5 
+72 hrs
E1 
W6f
E1 
W7v E1
W8
E1
W11
E1W14/
E1Intg
E1
W17
E1
W20
E1
W23
E1W26 
/EOE1T
Treatment Preference
X
X
X
PGIC
X
X
Subject’s pre-randomization 
IgG Treatment
X
Randomization
Xs
IP Administration
X
X
X
X
X
X
X
X
X
X
X
Infusion self-administration 
proficiency checklistt
X
Post-Infusion Telephone 
Follow-upu
X
X
X
X
X
X
X
X
X
X
X
Serum IgGm
Xk
Xk
Xg,k
Xk
X
Anti-rHuPH20 Antibodiesm
Xk
Xk
Xk
Xk
Xg,k
Xk
X
Plasma/Serum Retention 
Samplesm
X
Xk
Xk
Xk
Xg,k
X
X
Adverse Events
X
Concomitant Medications and 
Non-Drug Therapies
X
Abbreviations:  E1W = Epoch 1 week number; E1Int = Epoch 1 interim visit; ECG = Electrocardiogram; EOE1T = End-of-Epoch 1 treatment visit; 
EQ-5D = EuroQoL (Quality of Life)-5 Dimensions Questionnaire; ET = Early termination visit; HRU = Health resource utilization; 
IgG = Immunoglobulin G; IGIV = Intravenous immunoglobulin G; INCAT = Inflammatory Neuropathy Cause and Treatment; 
IP = Investigational product; MRC = Medical Research Council; PGIC = Patient global impression of change scale; 
Pre-SC BL = Pre-subcutaneous treatment baseline visit; rHuPH20 = Recombinant human hyaluronidase; R-ODS = Rasch-built Overall Disability Scale; 
S = Screening; SC = Subcutaneous; SF-36 = Short Form-36 Survey; U = Unscheduled visit for relapse assessment
Continued on Next Page
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Continued
a
The Pre-SC treatment baseline visit is to take place on the day of the subject’s last pre-randomization IGIV infusion, which is to be administered at the 
study site. The first SC administration of HYQVIA/HyQvia or placebo with rHuPH20 will take place 2 weeks (±3 days) following the last pre-
randomization IGIV administration regardless of the subject’s pre-randomization IGIV dosing interval. For the rest of the SC period, SC administrations 
are calculated from Week 1 and not the Pre-SC BL Visit 
b
During the SC treatment period, subjects who relapse (defined as an increase in adjusted INCAT disability score by ≥1 point relative to the pre-SC 
treatment baseline score, on 2 consecutive INCAT assessments) will be offered open-label IGIV treatment. Subjects who will receive IV treatment will 
undergo an end-of-SC treatment/pre-IV treatment baseline assessment visit (instead of the ET visit). For the schedule of study procedures and 
assessments during the IV treatment period, see Table 21-4. For any deviation from allowable study visit windows (±2 or ±3 day windows), subjects 
would be required to be brought back to the original planned visit date of the next visit in order to ensure subject safety. All other assessment or 
procedure visits, which do not have a visit window or a reference note in the protocol, should follow visit windows of ±3 days. There will be no visit 
window allowed in the ramp-up period after Visit 1 (Week 1).
c
At any time during the SC treatment period, unscheduled visit(s) may take place for a subject whose CIDP is worsening to assess whether the subject has 
an increase in the adjusted INCAT disability score by ≥1 point relative to the pre-SC treatment baseline score. INCAT assessment will be repeated during 
the pre-IV treatment baseline visit or the early termination visit, as applicable, to confirm the subject’s adjusted INCAT disability score has increased by 
≥1 point relative to the pre-SC treatment baseline score, at which time the final determination of whether a subject has met relapse criteria will be made.
d
The early termination visit is to be conducted for subjects who are being prematurely discontinued from the SC treatment period and will not undergo IV 
treatment period.
e
The Week 1 infusion visit takes place 2 weeks (±3 days) after the subject’s last pre-randomization IGIV administration (Pre-SC BL visit). Week 1 should 
be calculated from the last day of dosing for an infusion dose that is to be administered over multiple days. For the rest of the SC period, the reference to 
calculate the visit is Week 1 and not the Pre-SC BL Visit (Exception: Week 5+72 h, Week 6 (please see note f) and Week 7 that are calculated from 
Week 5 due to safety assessments in the protocol). During the ramp-up period, treatment will be given as 1-week equivalent dose during the Week 1 and 
Week 2 infusion visits, and then a 2-week equivalent dose during Week 3. The full (3-week) dose will be administered beginning at Week 5.
f
To be collected 7 (±2) days (ie, 5 – 9 days) after the Week 5 infusion, the subject’s first full-dose infusion of IP (HYQVIA/HyQvia or placebo with 
rHuPH20).
g
Subjects on a dosing schedule of every 3 weeks will be asked to return to the study site for interim assessments of the assessments that are to be 
conducted on the day of infusion (±3 days) during Week 14.
h
Written informed consent must be obtained prior to any study procedures including screening.
i
Vital signs include pulse rate, resting systolic and diastolic blood pressure, body temperature, and respiratory rate. Vital signs are to be taken at baseline 
(prior to infusion during E1W1 visit), during the initial 3 SC infusion visits, the interim visit, and at the end-of-SC treatment visit.
j
For the initial 3 SC infusions, vital signs are to be monitored and recorded at any time prior to infusion, in the event of occurrence of AE(s), and within 
60 minutes of completion of an infusion. During subsequent infusion visits, vital signs will be taken 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. See further details in Section 12.8.
k
To be performed prior to the start of the infusion (or prior to the first day of dosing for an infusion dose that is to be administered over multiple days).
Continued on Next Page
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Continued
l
If available, subjects’ previous nerve conduction study records consistent with electrodiagnostic criteria for Definite or Probable CIDP per EFNS/PNS 
2010 guideline on management of CIDP may be used during initial screening for eligibility assessment. An additional study at the time of screening is 
not mandatory but highly recommended. Subjects’ nerve conduction study record(s) must be reviewed by an independent central reader to confirm and 
document the diagnosis of CIDP based on electrodiagnostic criteria.
m
For detailed sampling timepoints, see Table 21-5. Whenever there is an overlap of a safety visit and an infusion visit, the safety laboratory assessments 
should be performed first prior to the IP infusion. 
n
To be collected 72 (±24) h (ie, 48 – 96 h) after the Week 5 infusion, the subject’s first full-dose infusion of IP (HYQVIA/HyQvia or placebo with 
rHuPH20).
o
The baseline INCAT disability score will be used to confirm subject eligibility for the inclusion criterion of an INCAT disability score between 
0 and 7 (inclusive) (ie, Inclusion Criterion #4), at which time the final determination of eligibility will be made. 
p
The MRC sum score is obtained by examining the following muscles on each side of the body: deltoids, biceps, wrist extensors, iliopsoas, quadriceps, 
and anterior tibialis, and rating the strength of each muscle according to the MRC scale. All scores from muscles on both left and right side of the body 
are summed to obtain the MRC sum score.
q
Beginning with the Epoch 1 Week 1 (E1W1) visit, the R-ODS will be completed at least once weekly. If R-ODS assessment coincides with an infusion 
visit, the R-ODS is to be performed prior to the start of the infusion (or prior to the first day of dosing for an infusion dose that is to be administered over 
multiple days). eDiary (DIARYpro) will be dispensed to the subjects at screening. R-ODS data collected during screening will not be used for analysis. 
r
The health resource utilization (HRU) questionnaire includes days off school/work, unscheduled physician visits, hospitalization, and emergency room 
visits. Beginning with the Pre-SC BL visit, HRU items will be recorded on an ongoing basis during the study. Note: The data entered by subjects for 
HRU during screening in the DIARYpro will not be used for analysis.
s
Randomization can occur between the last day of IGIV and Week 1 assessments (once last IGIV is fully administered and eligbility is confirmed).
t
SC infusions will be administered by an appropriately trained healthcare professional (eg, infusion nurse), self-administered by the subject, and/or, as 
applicable, by a caregiver who may assist the subject with self-administration. Training, evaluation, and verification of the subject’s (and/or caregiver’s) 
proficiency in performing self-infusion procedures by the investigator/designee must be documented as a prerequisite before the subject (and/or 
caregiver) will be allowed to begin self-administration of SC infusions at home or other suitable locations. A proficiency checklist will be completed by 
the investigator/designee once training begins and until the subject’s (and/or caregiver’s) proficiency is demonstrated. The subject (and/or caregiver) may 
be asked to return to the study site during the SC treatment period so that the investigator/designee can further assess and document that the subject 
(and/or caregiver) continues to be capable of independently performing self-infusion procedures.
u
Telephone follow-up will be conducted by the investigator/designee following each infusion visit (after 24 h 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 
72 h 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).
v
A minimum of a 3 day interval is required between E1W6 and E1W7 visits.
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Table 21-3. Schedule of Study Procedures and Assessments: SC Treatment Period (Epoch 1) –
Every 4 Weeks Dosing Regimen
Study Period
Screening/
Pre-SC BLa
(Up to 8 Weeks)
SC Treatment Periodb
(6 Months)
Uc ETd
Study Visits
S
Pre-SC 
BL
Ramp-Up
SC Infusions Every 4 Weeks (±3 Days)
E1
W1e
E1
W2e
E1
W3e E1
W5e E1
W8
E1 W8 
+72 hrs
E1
W9f
E1 
W10v
E1
W12
E1W16/
E1Intg
E1
W20
E1
W24
E1W28/
EOE1T
Informed Consenth
X
Eligibility Determination
X
X
Demographics
X
Medical, Medication, and Non-Drug 
Therapy History
X
Body Height
X
Body Weight
X
Xg
X
Body mass index
X
Xg
Vital Signsi
X
Xj
Xj
Xj
Xj
Xj
Xj
Xg,j
Xj
Xj
Xj
X
Physical Exam
X
Xk
Xg,k
Xk
X
12-Lead ECG
X
X
X
Electrodiagnostic Test/Nerve 
Conduction Studies
Xl
Xk
X
Screening and Safety Labsm
X
Xk
Xk
Xk
Xn
X
X
Xg,k
Xk
X
INCAT Disability Score
X
Xk,o
Xk
Xk
Xk
Xg,k
Xk
Xk
Xk
X
X
Hand Grip Strength
Xk
Xg,k
Xk
X
X
MRC sum scorep
Xk
Xg,k
Xk
X
X
R-ODS
Xk
Xq
X
X
SF-36
X
X
X
EQ-5D
X
X
X
HRUr
X
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Table 21-3. Schedule of Study Procedures and Assessments: SC Treatment Period (Epoch 1) –
Every 4 Weeks Dosing Regimen
Study Period
Screening/
Pre-SC BLa
(Up to 8 Weeks)
SC Treatment Periodb
(6 Months)
Uc ETd
Study Visits
S
Pre-SC 
BL
Ramp-Up
SC Infusions Every 4 Weeks (±3 Days)
E1
W1e
E1
W2e
E1
W3e E1
W5e E1
W8
E1 W8 
+72 hrs
E1
W9f
E1 
W10v
E1
W12
E1W16/
E1Intg
E1
W20
E1
W24
E1W28/
EOE1T
Treatment Satisfaction
X
X
X
Treatment Preference
X
X
X
PGIC
X
X
Subject’s pre-randomization IgG 
Treatment
X
Randomization
Xs
IP Administration
X
X
X
X
X
X
X
X
X
X
Infusion self-assessment proficiency 
checklistt
X
Post-Infusion Telephone Follow-upu
X
X
X
X
X
X
X
X
X
X
Serum IgGm
Xk
Xk
Xg,k
Xk
X
Anti-rHuPH20 Antibodiesm
Xk
Xk
Xk
Xk
Xg,k
Xk
X
Plasma/Serum Retention Samplesm
Xk
Xk
Xk
Xk
Xg,k
Xk
X
Adverse Events
X
Concomitant Medications and Non-
Drug Therapies
X
Abbreviations:  E1Int = Epoch 1 interim visit; E1W = Epoch 1 week number; ECG = Electrocardiogram; EOE1T = End-of-Epoch 1 visit; 
ET = Early termination visit; EQ-5D = EuroQoL (Quality of Life)-5 Dimensions Questionnaire; HRU = Health resource utilization; 
IgG = Immunoglobulin G; INCAT = Inflammatory Neuropathy Cause and Treatment; IP = Investigational product; MRC = Medical Research Council; 
PGIC = Patient global impression of change scale; Pre-SC BL = Pre-subcutaneous treatment baseline visit; rHuPH20 = Recombinant human hyaluronidase 
R-ODS = Rasch-built Overall Disability Scale; S = Screening; SC = Subcutaneous; SF-36 = Short Form-36 Survey; 
U = Unscheduled visit for relapse assessment.
Continued on Next Page
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Continued
a
The Pre-SC treatment baseline visit is to take place on the day of the subject’s last pre-randomization IGIV infusion, which is to be administered at the 
study site. The first SC administration of HYQVIA/HyQvia or placebo with rHuPH20 will take place 2 weeks (±3 days) following the last pre-
randomization IGIV administration regardless of the subject’s pre-randomization IGIV dosing interval. For the rest of the SC period, SC administrations 
are calculated from Week 1 and not the Pre-SC BL Visit.
b
During the SC treatment period, subjects who relapse (defined as an increase in adjusted INCAT disability score by ≥1 point) will be offered open-label 
IGIV treatment. Subjects who will receive IV treatment will undergo an end-of-SC treatment/pre-IV treatment baseline assessment visit (instead of the 
ET visit). For the schedule of study procedures and assessments during the IV treatment period, see Table 21-4. For any deviation from allowable study 
visit windows (±2 or ±3 day windows), subjects would be required to be brought back to the original planned visit date of the next visit in order to ensure 
subject safety. All other assessment or procedure visits, which do not have a visit window or a reference note in the protocol, should follow visit 
windows of ±3 days. There will be no visit window allowed in the ramp-up period after Visit 1 (Week 1).
c. At any time during the SC treatment period, unscheduled visit(s) may take place for a subject whose CIDP is worsening to assess whether the subject has 
an increase in the adjusted INCAT disability score by ≥1 point relative to the pre-SC treatment baseline score. INCAT assessment will be repeated during 
the pre-IV treatment baseline visit or early termination visit, as applicable, to confirm the subject’s adjusted INCAT disability score has increased by 
≥1 point relative to the pre-SC treatment baseline score, at which time the final determination of whether a subject has met relapse criteria will be made.
d
The early termination visit is to be conducted for subjects who are being prematurely discontinued from the SC treatment period and will not undergo IV 
treatment period.
e
The Week 1 infusion visit takes place 2 weeks (±3 days) after the subject’s last pre-randomization IGIV administration (Pre-SC BL visit). Week 1 should 
be calculated from the last day of dosing for an infusion dose that is to be administered over multiple days. For the rest of the SC period, the reference to 
calculate the visit  is Week 1 and not the Pre-SC BL Visit (Exception: Week 8+72 h, Week 9 (please see note f) and Week 10 that  are calculated from
Week 8 due to safety assessments in the protocol). During the ramp-up period, treatment will be given as 1-week equivalent dose during the Week 1 and 
Week 2 infusion visits, followed by a 2-week equivalent dose during Week 3, and then a 3-week equivalent dose during Week 5. The full (4-week) dose 
will be administered beginning at Week 8.
f
To be collected 7 (±2) days (ie, 5 – 9 days) after the Week 8 infusion, the subject’s first full-dose infusion of IP (HYQVIA/HyQvia or placebo with 
rHuPH20). 
g
Subjects on a dosing schedule of every 4 weeks will be asked to return to the study site for interim assessments of the assessments that are to be 
conducted on the day of infusion ( ± 3 days) during Week 16.
h
Written informed consent must be obtained prior to any study procedures including screening.
i
Vital signs include pulse rate, resting systolic and diastolic blood pressure, body temperature, and respiratory rate. Vital signs are to be taken at baseline 
(prior to infusion during E1W1 visit), during the initial 3 SC infusion visits, the interim visit, and at the end-of-SC treatment visit.
j
For the initial 3 SC infusions, vital signs are to be monitored and recorded at any time prior to infusion, in the event of occurrence of AE(s), and within 
60 minutes of completion of an infusion. During subsequent infusion visits, vital signs will be taken 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. See further details in Section 12.8.
k
To be performed prior to the start of the infusion (or prior to the first day of dosing for an infusion dose that is to be administered over multiple days).
Continued on Next Page
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Continued
l
If available, subjects’ previous nerve conduction study records consistent with electrodiagnostic criteria for Definite or Probable CIDP per 
EFNS/PNS 2010 guideline on management of CIDP may be used during initial screening for eligibility assessment. An additional study at the time of 
screening is not mandatory but highly recommended. Subjects’ nerve conduction study record(s) must be reviewed by an independent central reader to 
confirm and document the diagnosis of CIDP based on electrodiagnostic criteria.
m
For detailed sampling timepoints, see Table 21-5. Whenever there is an overlap of a safety visit and an infusion visit, the safety laboratory assessments 
should be performed first prior to the IP infusion.
n
To be collected 72 (±24) h (ie, 48 – 96 h) after the Week 8 infusion, the subject’s first full-dose infusion of IP (HYQVIA/HyQvia or placebo with 
rHuPH20).
o
The baseline INCAT disability score will be used to confirm subject eligibility for the inclusion criterion of an INCAT disability score between 
0 and 7 (inclusive) (ie, Inclusion Criterion #4), at which time the final determination of eligibility will be made. 
p
The MRC sum score is obtained by examining the following muscles on each side of the body: deltoids, biceps, wrist extensors, iliopsoas, quadriceps, 
and anterior tibialis, and rating the strength of each muscle according to the MRC scale. All scores from muscles on both left and right side of the body 
are summed to obtain the MRC sum score.
q
Beginning with the Epoch 1 Week 1 (E1W1) visit, the R-ODS will be completed at least once weekly. If R-ODS assessment coincides with an infusion 
visit, the R-ODS is to be performed prior to the start of the infusion (or prior to the first day of dosing for an infusion dose that is to be administered over 
multiple days). eDiary (DIARYpro) will be dispensed to the subjects at screening. R-ODS data collected during screening will not be used for analysis.
r
The health resource utilization (HRU) questionnaire includes days off school/work, unscheduled physician visits, hospitalization, and emergency room 
visits. Beginning with the Pre-SC BL visit, HRU items will be recorded on an ongoing basis during the study. Note: The data entered by subjects for 
HRU during screening in the DIARYpro will not be used for analysis.
s
Randomization can occur between the last day of IGIV and Week 1 assessments (once last IGIV is fully administered and eligbility is confirmed).
t
SC infusions will be administered by an appropriately trained healthcare professional (eg, infusion nurse), self-administered by the subject, and/or, as 
applicable, by a caregiver who may assist the subject with self-administration. Training, evaluation, and verification of the subject’s (and/or caregiver’s) 
proficiency in performing self-infusion procedures by the investigator/designee must be documented as a prerequisite before the subject (and/or 
caregiver) will be allowed to begin self-administration of SC infusions at home or other suitable locations. A proficiency checklist will be completed by 
the investigator/designee once training begins and until the subject’s (and/or caregiver’s) proficiency is demonstrated. The subject (and/or caregiver) may 
be asked to return to the study site during the SC treatment period so that the investigator/designee can further assess and document that the subject 
(and/or caregiver) continues to be capable of independently performing self-infusion procedures.
u
Telephone follow-up will be conducted by the investigator/designee following each infusion visit (after 24 h 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 
72 h 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).
v
A minimum of a 3 day interval is required between E1W9 and E1W10 visits.
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Table 21-4. Schedule of Study Procedures and Assessments: IV Treatment Period (Epoch 2) –
Every 3 Weeks Dosing Regimen
Study Period
IV Treatment Period 
(6 Months)
IV Infusions Every 3 Weeks (±3 Days)
Uc
ET
Study Visits
Pre-IV BL/
E2W1a
E2W3 E2W4 E2W7 E2W10
E2W13/
E2Intb
E2W16 E2W19 E2W22 E2W25/
EOE2T
Body weight
X
Xb
X
Vital Signsd
X
X
X
X
X
X
X
X
X
X
Physical Exam
X
X
X
12-Lead ECG
X
X
X
Nerve Conduction Studies
Xe
Xe
X
Safety Labsf
Xe
X
Xb,e
Xe
X
INCAT Disability Scoreg
Xe,h
Xe
Xe
Xe
Xb,e
Xe
Xe
Xe
Xe
X
X
Hand Grip Strength
Xe
Xe
Xe
Xe
Xb,e
Xe
Xe
Xe
Xe
X
X
MRC sum scorei
Xe
Xe
Xe
Xe
Xb,e
Xe
Xe
Xe
Xe
X
X
R-ODSe
Xj
X
X
SF-36
X
X
X
EQ-5D
X
X
X
HRUk
X
Treatment Satisfaction
X
X
X
Treatment Preference
X
X
X
PGIC
X
X
X
IP Administrationl
Xl
X
X
X
X
X
X
X
X
Post-Infusion Telephone Follow-upm
X
X
X
X
X
X
X
X
X
Serum IgGe
X
Xb
X
X
Anti-rHuPH20 Antibodiese
X
Xb
X
X
Plasma/Serum Retention Samplese
X
Xb
X
X
Adverse Events
X
For non-commercial use only

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Table 21-4. Schedule of Study Procedures and Assessments: IV Treatment Period (Epoch 2) –
Every 3 Weeks Dosing Regimen
Study Period
IV Treatment Period 
(6 Months)
IV Infusions Every 3 Weeks (±3 Days)
Uc
ET
Study Visits
Pre-IV BL/
E2W1a
E2W3 E2W4 E2W7 E2W10
E2W13/
E2Intb
E2W16 E2W19 E2W22 E2W25/
EOE2T
Concomitant Medications and Non-
Drug Therapies
X 
Abbreviations:  IV = Intravenous; Pre-IV BL = Pre-intravenous treatment baseline visit; E2W = Epoch 2 week number; E2Int = Epoch 2 interim visit; 
EOE2T = End-of-Epoch 2 treatment visit; U = Unscheduled visit for relapse assessment ; ET = Early termination visit; ECG = Electrocardiogram; 
INCAT = Inflammatory Neuropathy Cause and Treatment; MRC = Medical Research Council; R-ODS = Rasch-built Overall Disability Scale; 
SF-36 = Short Form-36 Survey; EQ-5D = EuroQoL (Quality of Life)-5 Dimensions Questionnaire; HRU = Health Resource Utilization; 
PGIC = Patient global impression of change scale; IP = Investigational product; IgG = Immunoglobulin G; rHuPH20 = Recombinant human 
hyaluronidase.
a
For subjects who meet the definition of relapse during the SC treatment period and are to receive IGIV treatment, the pre-IV treatment baseline 
assessments will also serve as the end-of-SC treatment assessments. 
b
Interim assessments are to be conducted on the day of infusion (or within 3 days prior to the day of infusion will be acceptable) during Week 13 
(±1 infusion visit, ie, Week 10. Week 13, Week 16).
c
At any time during the IV treatment period, unscheduled visit(s) for INCAT assessments will be allowed for subjects who experience CIDP worsening, 
in order to determine whether the worsening meets the definition of relapse (ie, worsening in functional disability by ≥1 point relative to the pre-SC 
treatment baseline in 2 consecutive adjusted INCAT disability scores). Subjects who relapse during Epoch 2, will have a close-out visit and terminate 
participation in the study, in order to have the opportunity to receive other/additional treatment
d
Vital signs include pulse rate, resting systolic and diastolic blood pressure, body temperature, and respiratory rate. Vital signs are to be monitored and 
recorded on each day of infusion (at any time prior to infusion, prior to each infusion rate change, in the event of occurrence of AE(s), and within 
60 minutes of completion of an infusion).
e
To be performed prior to infusion (or prior to the first day of dosing for an infusion dose that is to be administered over multiple days).
f
For detailed sampling timepoints, see Table 21-8.
g
In case the first INCAT evaluation indicating relapse (during Epoch 1) occurs during a study visit and not at an unscheduled visit, and the second 
(confirmatory) INCAT evaluation (Pre-IV BL Epoch 2) is performed on the same day, and in addition the Investigator’s preference is to administer the 
rescue medication (E2W1) also on the same day—repetition of same laboratory assessments should be avoided, except for Serum IgG, which must be 
collected at the time of relapse (eg, combining E1W15 at 2 weekly dose regimen, E1W14 at 3 weekly dose regimen, or E1W16 at 4 weekly dose regimen 
together with Pre-IV BL Epoch 2 and E2W1 all on the same day). In this case laboratory assessments of Epoch 1 study visit are the same as the ones in 
E2W1 before IP. These laboratory assessments should then be performed only once for subject’s safety regarding blood volume taken.
Continued on Next Page
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Continued
h
At any time during the SC treatment period, unscheduled visit(s) may take place for a subject whose CIDP is worsening to assess whether the subject has 
met relapse criteria (ie, an increase in adjusted INCAT disability score by ≥1 point relative to the pre-SC treatment baseline score, on 2 consecutive 
INCAT assessments). The pre-IV treatment baseline INCAT disability score will be used to confirm the subject’s adjusted INCAT disability score has 
increased by ≥1 point relative to the pre-SC treatment baseline score, at which time the final determination of whether a subject has met relapse criteria 
will be made. If INCAT evaluation indicates relapse during the SC treatment, the second confirmatory INCAT evaluation (Pre-IV BL Epoch 2) can be 
performed as early as the same day of the first INCAT evaluation and no later than 7 days after the first INCAT evaluation and by the same rater.
i
The MRC sum score is obtained by examining the following muscles on each side of the body: deltoids, biceps, wrist extensors, iliopsoas, quadriceps, 
and anterior tibialis, and rating the strength of each muscle according to the MRC scale. All scores from muscles on both left and right side of the body 
are summed to obtain the MRC sum score.
j
The R-ODS will be completed at least once weekly. If R-ODS assessment coincides with an infusion visit, the R-ODS is to be performed prior to the 
start of the infusion (or prior to the first day of dosing for an infusion dose that is to be administered over multiple days).
k
The HRU questionnaire includes days off school/work, unscheduled physician visits, hospitalization, and emergency room visits. HRU items will be 
recorded on an ongoing basis during the study. 
l
GAMMAGARD Liquid/KIOVIG or GAMUNEX-C (for US sites only), can be given as a rescue medication on Epoch 2, after the second INCAT 
evaluation, as early as the same day and no later than 7 days, at the discretion of the Investigator When administration of the rescue medication (E2W1) 
does not occur on same day as second (confirmatory) INCAT evaluation (Pre-IV BL Epoch 2), then Table 21-4 all study procedures and assessments 
should be performed at ‘Pre-IV BL’ Epoch 2 day and Table 21-8, all clinical laboratory assessments should be performed (before infusion) at ‘E2W1’ 
visit day.
m
Telephone follow-up will be conducted by the investigator/designee following each infusion visit (after 24 h 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 
72 h 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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21.3 Clinical Laboratory Assessments
Table 21-5. Clinical Laboratory Assessments: SC Treatment Period (Epoch 1) – Every 2 Weeks Dosing Regimen
Study Period
Screening/
Pre-SC BL
(Up to 
8 Weeks)
SC Treatment Perioda
(6 Months)
ETc
Study Visits
S
Pre-
SC 
BL
Ramp-Up
SC Infusions Every 2 Weeks (±3 Days)
E1
W1d
E1
W2
E1
W3d
E1 W3 
+72 hrs
E1
W4e
E1
W5d
E1
W7
E1
W9d
E1
W11
E1
W13
E1W15/
E1Intb,d
E1
W17
E1
W19
E1
W21
E1
W23
E1
W25
E1W27/
EOE1Td
Hematology Panelf
X
X
X
Xg
X
X
X
X
X
Clinical Chemistry Panelh
X
X
X
X
X
HbA1Ci
X
X
X
X
X
Blood type
X
Serum iron, ferritin, and 
TIBC
X
X
X
Hemolytic Panelj
X
X (as applicable)
Serum Immunoglobulin A
X
HAV Antibody, HBsAg, 
HCV Antibody, and HIV-
1/HIV-2 Antibody
X
Serum IgGk
Xl
X
X
X
X
Anti-rHuPH20 Antibodies 
– Binding Antibodies
X
X
X
X
X
X
X
Anti-rHuPH20 Antibodies 
– Neutralizing Antibodies
X
X
X
X
X
X
X
CH50, serum C3, serum 
C4, C1q binding assay, 
and CIC Raji cell assay
X
Immunogenicity Panelm
X (as applicable)
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Table 21-5. Clinical Laboratory Assessments: SC Treatment Period (Epoch 1) – Every 2 Weeks Dosing Regimen
Study Period
Screening/
Pre-SC BL
(Up to 
8 Weeks)
SC Treatment Perioda
(6 Months)
ETc
Study Visits
S
Pre-
SC 
BL
Ramp-Up
SC Infusions Every 2 Weeks (±3 Days)
E1
W1d
E1
W2
E1
W3d
E1 W3 
+72 hrs
E1
W4e
E1
W5d
E1
W7
E1
W9d
E1
W11
E1
W13
E1W15/
E1Intb,d
E1
W17
E1
W19
E1
W21
E1
W23
E1
W25
E1W27/
EOE1Td
Plasma and Serum 
Retention Samples
X
Xi
X
X
X
X
X
Urinalysisn
X
Pregnancy Testo
X
X
X
Abbreviations:  ALP = alkaline phosphatase; ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = aspartate aminotransferase; 
BUN = blood urea nitrogen; CIC = Circulating immune complex; CPK = creatine phosphokinase; E1Int = Epoch 1 interim visit; 
E1W = Epoch 1 week number; EOE1T = End-of-Epoch 1 treatment visit; ET = Early termination visit; GGT = gamma-glutamyl-transferase; 
HAV = Hepatitis A virus; HbA1C = Hemoglobin A1C; HBsAg = Hepatitis B surface antigen; HcT = hematocrit, Hgb = hemoglobin; 
HCV = Hepatitis C virus; HIV = Human immunodeficiency virus; IgG = Immunoglobulin G; IP = investigational product; IV = intravenous;
LDH = lactate dehydrogenase; Pre-SC BL = Pre-subcutaneous treatment baseline visit; RBC = red blood cell; rHuPH20 = Recombinant human 
hyaluronidase; S = Screening; SC = Subcutaneous; TIBC = Total iron binding capacity; ULN = upper limit of normal; WBC = white blood cell.
a
During the SC treatment period, subjects who relapse (defined as an increase in adjusted INCAT disability score by ≥1 point relative to the 
pre-SC treatment baseline score, on 2 consecutive INCAT assessments) will be offered open-label IGIV treatment. For the schedule of study procedures 
and assessments during the IV treatment period, see Table 21-4. For any deviation from allowable study visit  windows (±2 or ±3 day windows), subjects 
would be required to be brought back to the original planned visit date of the next visit in order to ensure subject safety. All other assessment or 
procedure visits, which do not have a visit window or a reference note in the protocol, should follow  visit windows of ±3 days. There will be no visit 
window allowed in the ramp-up period after Visit 1 (Week 1).
b
The interim visit is to take place on the day of infusion (or within 3 days prior to infusion will be acceptable due to scheduling availability) during 
Week 15 (±1 infusion visit).
c
The early termination visit is to be conducted for subjects who are being prematurely discontinued from the SC treatment period and will not undergo IV 
treatment.
d
Samples must be collected prior to IP administration (ie, prior to initiation of rHuPH20 administration) on the day of infusion (or prior to IP 
administration on the first day of dosing for an infusion dose that is to be administered over multiple days).
Continued on Next Page
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Continued
e
To be collected 7 (±2) days (ie, 5 – 9 days) after the Week 3 infusion, the first full-dose infusion of IP (HYQVIA/HyQvia or placebo with rHuPH20).
f
The hematology panel will consist of complete blood count (Hgb, Hct, erythrocytes [ie, RBC] count), leukocytes [ie, WBC] count with differential (ie, 
basophils, eosinophils, lymphocytes, monocytes, and neutrophils), ANC, absolute lymphocyte count, and platelet count, a reticulocyte count to the 
hemolytic panel to be run in the event of a 1 g/dL or more drop in Hgb from baseline.
g
In addition to the predose sample (see footnote d), sample for hematology is also to be collected 72 (±24) h (ie, 48 to 96 h) after the first full-dose 
infusion (Week 3) of IP (HYQVIA/HyQvia or placebo with rHuPH20). 
h
The clinical chemistry panel will consist of sodium, potassium, chloride, bicarbonate, total protein, albumin, total bilirubin, direct bilirubin, ALT, AST, 
ALP, GGT, LDH, CPK, BUN, creatinine, and glucose. At any time when the LDH test result is 2× ULN or greater, LDH isoenzymes panel will be 
performed.
i
For subjects with clinically diagnosed diabetes mellitus only.
j
The hemolytic anemia panel will consist of Hgb, LDH, serum haptoglobin, plasma-free (unbound) Hgb, serum direct anti-globulin (direct Coombs) test 
(antibody elution to be performed if direct Coombs test is positive), reticulocyte count, as well as urine hemosiderin. The lab results obtained predose 
during the E1W1 visit will serve as the baseline values. In case of absence of E1W1 result for any reason screening Hgb result serve as the baseline Hgb 
value. Hgb and LDH values can be taken from the hematology and clinical chemistry panels, if conducted on the same day as the hemolytic panel. For 
subsequent tests, if there is a reduction in Hgb of 1 g/dL or more compared to baseline Hgb, every effort is to be made to perform a hemolytic panel 
within 72 h; if it is not feasible to do so, the hemolytic panel must be performed as soon as possible, but at the next scheduled visit, at the latest . At any 
time during the study, an unscheduled hemolytic panel may be performed in the event of suspected hemolytic anemia. 
k
Prior to start of infusion (as applicable).
l
To be collected prior to the start of the subject’s last pre-randomization IGIV infusion.
m
At any time during the course of the study. For those subjects who have (a) two consecutive anti-rHuPH20 antibody titers of ≥1:160 which are elevated 
from the subject’s baseline titers, and (b) a moderate or severe AE which may be a result of immune-mediated response to either immunoglobulin, 
rHuPH20, 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.
n
Urinalysis includes color, specific gravity, pH, protein, glucose, ketones, bilirubin, urobilinogen, blood, nitrite, leukocyte esterase, and microscopic 
examination.
o
For female subjects of childbearing potential only. Urine pregnancy test will be performed, unless serum pregnancy test is mandatory as specified by 
local regulatory/institutional requirements.
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Table 21-6. Clinical Laboratory Assessments: SC Treatment Period (Epoch 1) – Every 3 Weeks Dosing Regimen
Study Period
Screening/
Pre-SC BL
(Up to 8 
Weeks)
SC Treatment Perioda
(6 Months)
ETc
Ramp-Up
SC Infusions Every 3 Weeks (±3 Days)
Study Visits
S
Pre-
SC 
BL
E1
W1d E1
W2
E1
W3d
E1
W5d E1W5 
+72 hrs
E1 
W6e
E1 
W7
E1
W8 d
E1
W11
E1
W14/
E1Intb,d
E1
W17
E1
W20
E1
W23
E1
W26/
EOE1Td
Hematology Panelf
X
X
X
X
Xg
X
X
X
X
X
Clinical Chemistry Panelh
X
X
X
X
X
HbA1Ci
X
X
X
X
X
Blood Type
X
Serum iron, ferritin, and TIBC
X
X
X
Hemolytic Panelj
X
X (as applicable)
Serum Immunoglobulin A
X
HAV Antibody, HBsAg, 
HCV Antibody, and 
HIV-1/HIV-2 Antibody
X
Serum IgG
Xk
X
X
X
X
Anti-rHuPH20 Antibodies –
Binding Antibodies
X
X
X
X
X
X
X
Anti-rHuPH20 Antibodies –
Neutralizing Antibodies
X
X
X
X
X
X
X
CH50, serum C3, serum C4, C1q 
binding assay, and CIC Raji cell 
assay
X
Immunogenicity Panell
X (as applicable)
Plasma/Serum Retention Samples
X
X
X
X
X
X
X
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Table 21-6. Clinical Laboratory Assessments: SC Treatment Period (Epoch 1) – Every 3 Weeks Dosing Regimen
Study Period
Screening/
Pre-SC BL
(Up to 8 
Weeks)
SC Treatment Perioda
(6 Months)
ETc
Ramp-Up
SC Infusions Every 3 Weeks (±3 Days)
Study Visits
S
Pre-
SC 
BL
E1
W1d E1
W2
E1
W3d
E1
W5d E1W5 
+72 hrs
E1 
W6e
E1 
W7
E1
W8 d
E1
W11
E1
W14/
E1Intb,d
E1
W17
E1
W20
E1
W23
E1
W26/
EOE1Td
Urinalysism
X
Pregnancy Testn
X
X
X
Abbreviations:  ALP = alkaline phosphatase; ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = aspartate aminotransferase; 
BUN = blood urea nitrogen; CIC = Circulating immune complex; CPK = creatine phosphokinase; E1Int = Epoch 1 interim visit; 
E1W = Epoch 1 week number; GGT = gamma-glutamyl transferase; HAV = Hepatitis A virus; HBsAg = Hepatitis B surface antigen; 
Hct = hematocrit; HCV = Hepatitis C virus; Hgb = hemoglobin; HIV = Human immunodeficiency virus; EOE1T = End-of-Epoch 1 treatment visit; 
ET = Early termination visit; HbA1C = Hemoglobin A1C; IgG = Immunoglobulin G; LDH = lactate dehydrogenase; 
Pre-SC BL = Pre-subcutaneous treatment baseline visit; RBC = red blood cell; rHuPH20 = Recombinant human hyaluronidase; S = Screening; 
SC = Subcutaneous; TIBC = Total iron binding capacity; ULN = upper limit of normal; WBC = white blood cell.
a
During the SC treatment period, subjects who relapse (defined as an increase in adjusted INCAT disability score by ≥1 point relative to the pre-SC 
treatment baseline score, on 2 consecutive INCAT assessments) will be offered open-label IGIV treatment. For the schedule of study procedures and 
assessments during the IV treatment period, see Table 21-4. For any deviation from allowable study visit windows (±2 or ±3 day windows), subjects 
would be required to be brought back to the original planned visit date of the next visit in order to ensure subject safety. All other assessment or 
procedure visits, which do not have a visit window or a reference note in the protocol, should follow visit windows of ±3 days. There will be no visit 
window allowed in the Ramp-up period after Visit 1 (Week 1).
b
The interim visit is to take place on the day of infusion (or within 3 days prior to infusion will be acceptable due to scheduling availability) during 
Week 14 (±1 infusion visit). 
c
The early termination visit is to be conducted for subjects who are being prematurely discontinued from the SC treatment period and will not undergo IV 
treatment.
d
Samples must be collected prior to IP administration (ie, prior to initiation of rHuPH20 administration) on the day of infusion (or prior to IP 
administration on the first day of dosing for an infusion dose that is to be administered over multiple days).
e
To be collected 7 (±2) days (ie, 5 – 9 days) after the subject’s Week 5 infusion, the first full-dose infusion of IP (HYQVIA/HyQvia or placebo with 
rHuPH20).
Continued on Next Page
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Continued
f
The hematology panel will consist of complete blood count (Hgb, Hct, erythrocytes [ie, RBC count]), leukocytes [ie, WBC count] with differential (ie, 
basophils, eosinophils, lymphocytes, monocytes, and neutrophils), ANC, absolute lymphocyte count, and platelet count, a reticulocyte count to the 
hemolytic panel to be run in the event of a 1 g/dL or more drop in hemoglobin from baseline.
g
In addition to the predose sample (see footnote d), sample for hematology is also to be collected 72 (±24) h (ie, 48 – 96 h) after the subject’s Week 5 
infusion, the first full-dose infusion of IP (HYQVIA/HyQvia or placebo with rHuPH20).
h
The clinical chemistry panel will consist of sodium, potassium, chloride, bicarbonate, total protein, albumin, total bilirubin, direct bilirubin, ALT, AST, 
ALP, GGT, LDH, CPK, BUN, creatinine, and glucose. At any time when the LDH test result is 2× ULN or greater, LDH isoenzymes panel will be 
performed. 
i
For subjects with clinically diagnosed diabetes mellitus only.
j
The hemolytic anemia panel will consist of Hgb, LDH, serum haptoglobin, plasma-free (unbound) Hgb, serum direct anti-globulin (direct Coombs) test 
(antibody elution to be performed if direct Coombs test is positive), reticulocyte count, as well as urine hemosiderin. The lab results obtained predose 
during the Epoch 1 Week 1 (E1W1) visit will serve as the baseline values. In case of absence of E1W1 result for any reason screening Hgb result serve as 
the baseline Hgb value. Hgb and LDH values can be taken from the hematology and clinical chemistry panels, if conducted on the same day as the 
hemolytic panel. For subsequent tests, if there is a reduction in Hgb of ≥1 g/dL compared to baseline Hgb, every effort is to be made to perform a 
hemolytic panel within 72 h; if it is not feasible to do so, the hemolytic panel must be performed as soon as possible, but at the next scheduled visit, at the 
latest. At any time during the study, an unscheduled hemolytic panel may be performed in the event of suspected hemolytic anemia. 
k
To be collected prior to the subject’s last pre-randomization IGIV infusion. 
l
At any time during the course of the study. For those subjects who have (a) two consecutive anti-rHuPH20 antibody titers of ≥1:160 which are elevated 
from the subject’s baseline titers, and (b) a moderate or severe AE which may be a result of immune-mediated response to either immunoglobulin, 
rHuPH20, 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.
m
Urinalysis includes color, specific gravity, pH, protein, glucose, ketones, bilirubin, urobilinogen, blood, nitrite, leukocyte esterase, and microscopic 
examination.
n
For female subjects of childbearing potential only. Urine pregnancy test will be performed, unless serum pregnancy test is mandatory as specified by 
local regulatory/institutional requirements.
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Table 21-7. Clinical Laboratory Assessments: SC Treatment Period (Epoch 1) – Every 4 Weeks Dosing Regimen
Study Period
Screening/
Pre-SC BL
(Up to 8 Weeks)
SC Treatment Perioda
(6 Months)
ETc
Study Visits
S
Pre-SC 
BL
Ramp-Up
SC Infusions Every 4 Weeks (±3 Days)
E1
W1d
E1
W2
E1
W3d
E1
W5 d
E1
W8 d E1 W8 
+72 hrs
E1 
W9e
E1
W10
E1
W12
E1W16/
E1Intb,d
E1
W20
E1
W24
E1W28/
EOE1Td
Hematology Panelf
X
X
X
X
Xg
X
X
X
X
X
Clinical Chemistry Panelh
X
X
X
X
X
HbA1Ci
X
X
X
X
X
Blood Type
X
Serum iron, ferritin, and TIBC
X
X
X
Hemolytic Panelj
X
X (as applicable) 
Serum Immunoglobulin A
X
HAV Antibody, HBsAg, HCV 
Antibody, and HIV-1/HIV-2 
Antibody
X
Serum IgG
Xk
X
X
X
X
Anti-rHuPH20 Antibodies –
Binding Antibodies
X
X
X
X
X
X
X
Anti-rHuPH20 Antibodies –
Neutralizing Antibodies
X
X
X
X
X
X
X
CH50, serum C3, serum C4, C1q 
binding assay, and CIC Raji cell 
assay
X
Immunogenicity Panell
X (as applicable)
Plasma/Serum Retention Samples
X
X
X
X
X
X
X
Urinalysism
X
Pregnancy Testn
X
X
X
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Abbreviations:  ALP = alkaline phosphatase; ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = aspartate aminotransferase; 
BUN = blood urea nitrogen; CIC = Circulating immune complex; CPK = creatine phosphokinase; E1Int = Epoch 1 interim visit; 
E1W = Epoch 1 week number; EOE1T = End-of-Epoch 1 treatment visit; ET = Early termination visit; GGT = gamma-glutamyl transferase; 
HAV = Hepatitis A virus; HbA1C = Hemoglobin A1C; HbsAg = Hepatitis B surface antigen; Hct = hematocrit; HCV = Hepatitis C virus; 
Hgb = hemoglobin; HIV = Human immunodeficiency virus; IgG = Immunoglobulin G; Pre-SC BL = Pre-subcutaneous treatment baseline visit; 
RBC = red blood cell; rHuPH20 = Recombinant human hyaluronidase; S = Screening; SC = Subcutaneous; TIBC = Total iron binding capacity; 
ULN = upper limit of normal; WBC = white blood cell.
a
During the SC treatment period, subjects who relapse (defined as an increase in adjusted INCAT disability score by ≥1 point) will be offered open-label 
IGIV treatment. For the schedule of study procedures and assessments during the IV treatment period, see Table 21-4. For any deviation from allowable 
study visit windows (±2 or ±3 day windows), subjects would be required to be brought back to the original planned visit date of the next visit in order to 
ensure subject safety. All other assessment or procedure visits, which do not have a visit window or a reference note in the protocol, should follow visit 
windows of ±3 days. There will be no visit window allowed in the ramp-up period after Visit 1 (Week 1).
b
The interim visit is to take place on the day of infusion (or within 3 days prior to infusion will be acceptable due to scheduling availability) during 
Week 16 (±1 infusion visit).
c
The early termination visit is to be conducted for subjects who are being prematurely discontinued from the SC treatment period and will not undergo IV 
treatment.
d
Samples must be collected prior to IP administration (ie, prior to initiation of rHuPH20 administration) on the day of infusion (or prior to IP 
administration on the first day of dosing for an infusion dose that is to be administered over multiple days).
e
To be collected 7 (±2) days (ie, 5 – 9 days) after the subject’s Week 8 infusion visit, the first full-dose infusion of IP (HYQVIA/HyQvia or placebo with 
rHuPH20).
f
The hematology panel will consist of complete blood count (Hgb, Hct, erythrocytes [ie, RBC count]), leukocytes [ie, WBC count] with differential (ie, 
basophils, eosinophils, lymphocytes, monocytes, and neutrophils), ANC, absolute lymphocyte count, and platelet count, a reticulocyte count to the 
hemolytic panel to be run in the event of a 1 g/dL or more drop in hemoglobin from baseline.
g
In addition to the predose sample (see footnote d), sample for hematology is also to be collected 72 (±24) h (ie, 48 – 96 h) after the subject’s Week 8 
infusion, the first full-dose infusion of IP (HYQVIA/HyQvia or placebo with rHuPH20).
h
The clinical chemistry panel will consist of sodium, potassium, chloride, bicarbonate, total protein, albumin, total bilirubin, direct bilirubin, ALT, AST, 
ALP, GGT LDH, CPK, BUN, creatinine, and glucose. At any time when the LDH test result is 2× ULN or greater, LDH isoenzymes panel will be 
performed.
i
For subjects with clinically diagnosed diabetes mellitus only.
j
The hemolytic anemia panel will consist of Hgb, LDH, serum haptoglobin, plasma-free (unbound) Hgb, serum direct anti-globulin (direct Coombs) test 
(antibody elution to be performed if direct Coombs test is positive), reticulocyte count, as well as urine hemosiderin. The lab results obtained predose 
during the Epoch 1 Week 1 (E1W1) visit will serve as the baseline values. In case of absence of E1W1 result for any reason screening Hgb result serve as 
the baseline Hgb value. Hgb and LDH values can be taken from the hematology and clinical chemistry panels, if conducted on the same day as the 
hemolytic panel. For subsequent tests, if there is a reduction in Hgb of ≥1 g/dL compared to baseline Hgb, every effort is to be made to perform a 
hemolytic panel within 72 h; if it is not feasible to do so, the hemolytic panel must be performed as soon as possible, but at the next scheduled visit, at the 
latest. At any time during the study, an unscheduled hemolytic panel may be performed in the event of suspected hemolytic anemia. 
Continued on Next Page
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Continued
k
To be collected prior to the subject’s last pre-randomization IGIV infusion. 
l
At any time during the course of the study. For those subjects who have (a) two consecutive anti-rHuPH20 antibody titers of ≥1:160 which are elevated 
from the subject’s baseline titers, and (b) a moderate or severe AE which may be a result of immune-mediated response to either immunoglobulin, 
rHuPH20, 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.
m
Urinalysis includes color, specific gravity, pH, protein, glucose, ketones, bilirubin, urobilinogen, blood, nitrite, leukocyte esterase, and microscopic 
examination.
n
For female subjects of childbearing potential only. Urine pregnancy test will be performed, unless serum pregnancy test is mandatory as specified by
local regulatory/institutional requirements.
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Table 21-8. Clinical Laboratory Assessments – IV Treatment Period (Epoch 2)
Study Period
IV Treatment Period 
(6 Months)
IV Infusions Every 3 Weeks (±3 Days)
ETc
Study Visits
Pre-IV BL/
E2W1a,d
E2W3d
E2W4
E2W7
E2W10
E2W13/ 
E2Intb,d
E2W16 E2W19 E2W22
E2W25/ 
EOE2Td
Hematology Panele
X
X
X
X
X
Clinical Chemistry Panelf
X
X
X
X
HbA1Cg
X
X
X
X
Serum iron, ferritin, and TIBC
X
X
Hemolytic Panelh
X (as applicable)
Serum IgG
X
X
X
X
Anti-rHuPH20 Antibodies – Binding 
Antibodies
X
X
X
X
Anti-rHuPH20 Antibodies –
Neutralizing Antibodies
X
X
X
X
Immunogenicity Paneli
X (as applicable) 
Plasma/Serum Retention Samples
X
X
X
X
Pregnancy Testj
X
X
Abbreviations:  ALP = alkaline phosphatase; ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = aspartate aminotransferase; 
BUN = blood urea nitrogen; CIC = Circulating immune complex; CPK = creatine phosphokinase; E2Int = Epoch 2 interim visit; 
EOE2T = End-of-Epoch 2 treatment visit; ET = Early termination visit; E2W= Epoch 2 week number; GGT = gamma-glutamyl transferase; 
HbA1C = Hemoglobin A1C; Hct = hematocrit; IgG = Immunoglobulin G; IV = Intravenous; LDH = lactate dehydrogenase; 
Pre-IV BL = Pre-intravenous treatment baseline visit; RBC = red blood cell; rHuPH20 = Recombinant human hyaluronidase; 
TIBC = Total iron binding capacity; ULN = upper limit of normal; WBC = white blood cell.
Continued on Next Page
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Continued
a
For subjects who meet the definition of relapse during the SC treatment period and are to receive IV treatment, the pre-IV treatment baseline assessments will 
also serve as the end-of-SC treatment assessments. The pre-IV treatment baseline assessments can be conducted on the same day of the first IGIV 10% infusion; 
however, all samples must be collected prior to infusion (or prior to the first day of dosing for an infusion that is to be administered over multiple consecutive 
days). 
In case the first INCAT evaluation indicating relapse (during Epoch 1) occurs during a study visit and not at an unscheduled visit, and the second (confirmatory) 
INCAT evaluation (Pre-IV BL Epoch 2) is performed on the same day, and in addition the Investigator’s preference is to administer the rescue medication 
(E2W1) also on the same day—repetition of same lab assessments should be avoided (eg, combining E1W15 at 2 weekly dose regimen, E1W14 at 3 weekly dose 
regimen, or E1W16 at 4 weekly dose regimen together with Pre-IV BL Epoch 2 and E2W1 all on the same day). In this case laboratory assessments of Epoch 1 
study visit are the same as the ones in E2W1 before IP. These laboratory assessments should then be performed only once for subject’s safety regarding blood 
volume taken.
When administration of the rescue medication (E2W1) does not occur on same day as second (confirmatory) INCAT evaluation (Pre-IV BL Epoch 2), then 
Table 21-4 all study procedures and assessments should be performed at ‘Pre-IV BL’ Epoch 2 day and Table 21-8, all clinical laboratory assessments should be 
performed (before infusion) at ‘E2W1’ visit day.
b
The Epoch 2 interim visit is to take place during Week 13 (±1 infusion visit).
c
The early termination (ET) visit is to be conducted for subjects who are being prematurely discontinued from the IV treatment period.
d
Samples must be collected prior to infusion. Samples must be collected prior to infusion on the day of infusion (or prior to infusion on the first day of dosing for 
an infusion dose that is to be administered over multiple days).
e
The hematology panel will consist of complete blood count (Hgb, Hct, erythrocytes [ie, RBC count]), leukocytes [ie, WBC count] with differential (ie, basophils, 
eosinophils, lymphocytes, monocytes, and neutrophils), ANC, absolute lymphocyte count, and platelet count.
f
The clinical chemistry panel will consist of sodium, potassium, chloride, bicarbonate, total protein, albumin, total bilirubin, direct bilirubin, ALT, AST, ALP, 
GGT, LDH, CPK, BUN, creatinine, and glucose. At any time when the LDH test result is 2× ULN or greater, LDH isoenzymes panel will be performed.
g
For subjects with clinically diagnosed diabetes mellitus only.
h
The hemolytic anemia panel will consist of Hgb, LDH, serum haptoglobin, plasma-free (unbound) Hgb, serum direct anti-globulin (direct Coombs) test (antibody 
elution to be performed if direct Coombs test is positive), reticulocyte count, as well as urine hemosiderin. The lab results obtained from the Epoch 1 Week 1 
(E1W1) will serve as the baseline values. In case of absence of E1W1 result for any reason screening Hgb result serve as the baseline Hgb value. Hgb and LDH 
values can be taken from the hematology and clinical chemistry panels, if conducted on the same day as the hemolytic panel. For subsequent tests, if there is a 
reduction in Hgb of 1 ≥g/dL  compared to baseline Hgb, every effort is to be made to perform a hemolytic panel within 72 h; if it is not feasible to do so, the 
hemolytic panel must be performed as soon as possible, but at the next scheduled visit, at the latest. At any time during the study, an unscheduled hemolytic 
panel may be performed in the event of suspected hemolytic anemia. Epoch 2 E2W3 is required for those subjects taking Gamanx-C.
i
At any time during the course of the study. For those subjects who have (a) two consecutive anti-rHuPH20 antibody titers of ≥1:160 which are elevated from the 
subject’s baseline titers, and (b) a moderate or severe AE which may be a result of immune-mediated response to either immunoglobulin, rHuPH20, 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.
j
For female subjects of childbearing potential only. Urine pregnancy test will be performed, unless serum pregnancy test is mandatory as specified by local 
regulatory/institutional requirements.
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21.4 Toxicity Grading Scale for Laboratory Values
Table 21-9. Grading of Laboratory Parameters
Analyte
Direction WNL is Grade 0
No
Grade 1
Units
Grade 0a
Grade 1a
Grade 2a
Grade 3a
Grade 4a
Source
Low
High
Low
High
Low
High
Low
High
Low
High
ALP
Increase
YES
NO
ULN
.
.
.
2.5
2.6
5.0
5.1
20
20.1
.
ECOG
ALT
Increase
YES
NO
ULN
.
.
.
2.5
2.6
5.0
5.1
20
20.1
.
ECOG
AST
Increase
YES
NO
ULN
.
.
.
2.5
2.6
5.0
5.1
20
20.1
.
ECOG
LDH
Increase
YES
NO
ULN
.
.
.
2.5
2.6
5.0
5.1
20
20.1
.
N/A
BUN
Increase
NO
NO
ULN
0.0
1.4
1.5
2.5
2.6
5.0
5.1
10
10.1
.
ECOG
Hemoglobin
Decrease
YES
NO
g/dL
.
.
.
10.0
8.0
9.9
6.5
7.9
0.0
6.4
ECOG
Lymphocytes
Decrease
NO
NO
x10^3/uL
2.0
.
1.5
1.9
1.0
1.4
0.5
0.9
0.0
0.4
ECOG
Neutrophils
Decrease
NO
NO
x10^3/uL
2.0
.
1.5
1.9
1.0
1.4
0.5
0.9
0.0
0.4
ECOG
Platelet 
Count
Decrease
YES
NO
x10^3/uL
.
.
.
75.0
50.0
74.9
25
49.9
0.0
24.9
ECOG
Potassium
Decrease
NO
NO
mmol/L
3.5
.
3.0
3.4
2.5
2.9
2.0
2.4
0.0
1.9
WHO
Potassium
Increase
NO
NO
mmol/L
0.0
5.5
5.6
6.0
6.1
6.5
6.6
7.0
7.1
.
WHO
Serum Creatinine Increase
YES
NO
ULN
.
.
.
1.4
1.5
3.0
3.1
6.0
6.1
.
ECOG
Sodium
Decrease
NO
NO
mmol/L
136
.
130
135
123
129
116
122
0.0
115
WHO
Sodium
Increase
NO
NO
mmol/L
0.0
145
146
150
151
157
158
165
166
.
WHO
Serum 
Total Bilirubin
Increase
YES
YES
ULN
.
.
.
.
.
1.4
1.5
3.0
3.1
.
ECOG
WBC
Decrease
NO
NO
x10^3/uL
4.0
.
3.0
3.9
2.0
2.9
1.0
1.9
0.0
0.9
ECOG
Abbreviations:  ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
LDH = lactate dehydrogenase; BUN = blood urea nitrogen; ULN = upper limit of normal; ECOG = Eastern Cooperative Oncology Group; 
WHO = World Health Organization; WNL = within normal limits.
a
The toxicity scale is defined as: 0 = none, 1 = mild, 2 = moderate, 3 = severe, 4 = life-threatening (Food and Drug Administration, 2008).
Grading scale criteria taken from ECOG (Eastern Cooperative Oncology Group, 2006) and WHO (World Health Organization, 2003) guidelines, with the 
exception of LDH that use the same thresholds as defined for ALT and AST.
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21.5 Contraceptive Methods for Female Subjects of Childbearing Potential
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 recombinant 
human hyaluronidase in mice and rabbits. No adverse effects on pregnancy were 
associated with anti-rHuPH20 antibodies. In these studies, maternal antibodies to 
recombinant human hyaluronidase were transferred to offspring in utero. The effects of 
antibodies to the rHuPH20 component of HYQVIA on the human embryo or on human 
fetal development are unknown. 
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 Facilitation Group 
(CTFG) recommendations related to contraception and pregnancy testing in clinical trials 
(version 2014-09-15) (Heads of Medicines Agencies and Clinical Trial Facilitation Group 
(CTFG), 2014), birth control methods which may be considered as highly effective 
include the following:
•
Combined (estrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation:
oral
intravaginal
transdermal
•
Progestogen-only hormonal contraception associated with inhibition of ovulation:
oral
injectable
implantableviii
•
Intrauterine device (IUD)viii
                                                
viii Contraception methods that are considered to have low user dependency.
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•
Intrauterine hormone-releasing system (IUS)viii
•
Bilateral tubal occlusionviii
•
Vasectomised partner(s)viii
•
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 
Protocol 161403: Amendment 6 2021 MAY 20
Replaces: Amendment 5: 2019 MAY 10
In this section, changes other than grammatical, formatting and/or administrative changes 
from the previous version of the protocol (dated 2019 MAY 10) are described and their 
rationales are given.
1.
Synopsis, Section 8.3
Description of Change: Maximum overall duration of the study was changed from 
68 months to 72 months and enrollment period was changed from 61 months to 64 
months.
Purpose of Change: To reflect changes made in response to sponsor decision for 
ending the study enrollment.
2.
Synopsis, Sections 7.2.3, 13
Description of Change: The following tertiary objectives were added for Epoch 1:
- To evaluate improvement in functional impact on everyday tasks as measured by a 
pre-specificed subscore of R-ODS
- To assess the effect of HYQVIA/HyQvia on the total number or appearance of new 
demyelinating abnormalities on electrodiagnostic studies.
Purpose of Change: to better assess treatment benefit in patients.
3.
Synopsis, Section 7.3.3
Description of Change: The following tertiary objective was added for Epoch 2:
- To assess the effect of GAMMAGARD LIQUID/KIOVIG on the total number or 
appearance of new demyelinating abnormalities on electrodiagnostic studies.
Purpose of Change: To better assess treatment effects.
4.
Synopsis [study design ], Sections 8.6, 14.1.1, 14.2.1.2
Description of Change: Details related to stopping randomization on Epoch 1.
Purpose of Change: Randomization to Epoch 1 will be stopped by the sponsor prior 
to achieving the original planned total of 174 randomized subjects. Sample size 
assumptions revised based on more recent scientific literature.
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5.
Synopsis [study design (Epoch 1: SC Treatment Period)] 
Description of Change: Addition of text added to collect trough serum IgG levels and 
additional patient reported outcome (PRO) measures.
Purpose of Change: Updates.
6.
Synopsis [study design (Epoch 1: SC Treatment Period)], Section 8
Description of Change: Details related to IP administration at site, infusion related 
data to be recorded and subject/caregiver’s training were added.
Purpose of Change: Updates.
7.
Synopsis, Section 8.4.1.3.1
Description of Change: Following tertiary outcome measures were added for
Epoch 1:
- Change from pre-SC treatment baseline in functional impact on everyday tasks as 
measured by R-ODS sub-components
- Change from pre-screen baseline in the total number or appearance of new 
demyelinating abnormalities on electrodiagnostic studies.
Purpose of Change: Better assess treatment benefits for patients.
8.
Synopsis, Section 8.4.2.3.1
Description of Change: Following tertiary outcome measure was added for Epoch 2:
- Change from pre-IV baseline in the total number or appearance of new 
demyelinating abnormalities on electrodiagnostic studies.
Purpose of Change: Better assess treatment effects.
9.
Synopsis (Mode of administration), Section 8.7.3
Description of Change: Details related to the mode of administration of rHuPH20, 
IGI, 10% and placebo treatment were revised to specify the use of peristalic pump. 
Duration to be maintained between rHuPH20 and 0.25% albumin placebo infusions 
was specified. Region specific details related to the use of peristalic pump were 
added. Reference to Site Infusion Manual was added to check recommended infusion 
rates.
Purpose of Change:  Change made due to the pump recall in the US of the body 
guard.
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10. Synopsis, Section 8.7.3.2, Section 8.7.4.2
Description of Change: Specifications of infusion pump (ie peristalic variable rate 
infusion pump) to be used for IV infusion of GAMMAGARD LIQUID/KIOVIG/ 
GAMUNEX®-C in Epoch 2 were added. Maximum infusion rate for Body Guard 
pump was specified.
Purpose of Change: Change made due to the pump recall in the US of the body 
guard.
11. Synopsis, Section 8
Description of Change: Details related to the mode of administration of placebo 
treatment (0.25% human albumin in LR solution and rHuPH20) were revised to 
specify the use of peristalic infusion pump, region specific details related to the 
peristalic pump and duration between rHuPH20 and 0.25% albumin placebo solution 
infusions.
Purpose of Change: Change made due to the pump recall in the US of the body 
guard. Synopsis (Statistical Analysis)
12. Synopsis (planned statistical analysis), Section 14.1.4.3
Description of Change:  Details related to statistical analysis of R-ODS score and 
demyelinating abnormalities based on electrodiagnostic studies (tertiary outcome 
measures) were added. 
Purpose of Change: To document additional endpoints.
13. Synopsis
Description of Change: The following footnote was removed:
At high infusion rates above 750 mL/h, 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.
Purpose of Change:  Update.
14. Section 5. List of Abbreviations.
Description of Change: New abbreviations added.
Purpose of Change: Updates.
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15. Section 6
Description of Change: Literature references describing therapeutic efficacy and 
safety of IGSC treatment and impact of COVID-19 pandemic on ongoing drug-
development efforts were added. 
Purpose of Change: To reflect changes made in response to the COVID-19 
pandemic.
16. Section 8.5.2 Unblinding
Description of Change: Language updated to reflect updated study procedure.
Purpose of Change: Update.
17. Sections 8.6, 8.6.1 Study Stopping Rules
Description of Change: Language updated to reflect new stopping rule changes.
Purpose of Change: Stopping the study due to the impact caused by COVID-19 
pandemic.
18. Section 8.6.2 Trial Integrity
Description of Change: This is a new section added to the amendment # 6.
Purpose of Change:  To clarify that despite study stopping before achieving 
originally planned total number of subjects, trial integrity is maintained.
19. 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.
20. Section 11.2
Description of Change: Specified that an alternative scoring algorithm would be 
applied to R-ODS (in addition to the full score) to measure the patient centric benefit 
of HyQvia.
Purpose of Change:  introduce patient-centric endpoint.
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21. Section 13.1
Description of Change: Added a new section to describe Electrodiagnostic studies 
Purpose of Change: introduce new endpoint to further assess treatment effect.
22. Section 14.1.3
Description of Change: Clarified that rules for handling missing data will be 
described in the SAP.
Purpose of Change:  Update.
23. Synopsis (Analysis of Primary Outcome Measure), Section 14.1.4.1 
Description of Change: Added a sensitivity analysis with alternative relapse 
definition due to expected missed confirmation visits during Covid-19 pandemic.
Purpose of change: Update
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23. REFERENCES
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Protocol amendment #6: 161403-protocol-amend-6-2021may20  
Amendment to amendment #5: 2019 MAY 10; 23 items 
1. Synopsis, Section 8.3 Description of Change: Maximum overall duration of the study was changed 
from 68 months to 72 months and enrollment period was changed from 61 months to 64 months. 
Purpose of Change: To reflect changes made in response to sponsor decision for ending the study 
enrollment.  
2. Synopsis, Sections 7.2.3, 13 Description of Change: The following tertiary objectives were added 
for Epoch 1: - To evaluate improvement in functional impact on everyday tasks as measured by a 
pre-specificed subscore of R-ODS - To assess the effect of HYQVIA/HyQvia on the total number or 
appearance of new demyelinating abnormalities on electrodiagnostic studies. Purpose of Change: to 
better assess treatment benefit in patients.  
3. Synopsis, Section 7.3.3 Description of Change: The following tertiary objective was added for 
Epoch 2: - To assess the effect of GAMMAGARD LIQUID/KIOVIG on the total number or appearance 
of new demyelinating abnormalities on electrodiagnostic studies. Purpose of Change: To better 
assess treatment effects.  
4. Synopsis [study design ], Sections 8.6, 14.1.1, 14.2.1.2 Description of Change: Details related to 
stopping randomization on Epoch 1. Purpose of Change: Randomization to Epoch 1 will be stopped 
by the sponsor prior to achieving the original planned total of 174 randomized subjects. Sample size 
assumptions revised based on more recent scientific literature.  
5. Synopsis [study design (Epoch 1: SC Treatment Period)] Description of Change: Addition of text 
added to collect trough serum IgG levels and additional patient reported outcome (PRO) measures. 
Purpose of Change: Updates.  
6. Synopsis [study design (Epoch 1: SC Treatment Period)], Section 8 Description of Change: Details 
related to IP administration at site, infusion related data to be recorded and subject/caregiver’s 
training were added. Purpose of Change: Updates.  
7. Synopsis, Section 8.4.1.3.1 Description of Change: Following tertiary outcome measures were 
added for Epoch 1: - Change from pre-SC treatment baseline in functional impact on everyday tasks 
as measured by R-ODS sub-components - Change from pre-screen baseline in the total number or 
appearance of new demyelinating abnormalities on electrodiagnostic studies. Purpose of Change: 
Better assess treatment benefits for patients.  
8. Synopsis, Section 8.4.2.3.1 Description of Change: Following tertiary outcome measure was added 
for Epoch 2: - Change from pre-IV baseline in the total number or appearance of new demyelinating 
abnormalities on electrodiagnostic studies. Purpose of Change: Better assess treatment effects.  
9. Synopsis (Mode of administration), Section 8.7.3 Description of Change: Details related to the 
mode of administration of rHuPH20, IGI, 10% and placebo treatment were revised to specify the use 
of peristalic pump. Duration to be maintained between rHuPH20 and 0.25% albumin placebo 
infusions was specified. Region specific details related to the use of peristalic pump were added. 
Reference to Site Infusion Manual was added to check recommended infusion rates. Purpose of 
Change: Change made due to the pump recall in the US of the body guard. Synopsis, Section 8.7.3.2, 
Section 8.7.4.2 Description of Change: Specifications of infusion pump (ie peristalic variable rate 
infusion pump) to be used for IV infusion of GAMMAGARD LIQUID/KIOVIG/ GAMUNEX®-C in Epoch 2 
were added. Maximum infusion rate for Body Guard pump was specified. Purpose of Change: 
Change made due to the pump recall in the US of the body guard.  
For non-commercial use only

11. Synopsis, Section 8 Description of Change: Details related to the mode of administration of 
placebo treatment (0.25% human albumin in LR solution and rHuPH20) were revised to specify the 
use of peristalic infusion pump, region specific details related to the peristalic pump and duration 
between rHuPH20 and 0.25% albumin placebo solution infusions. Purpose of Change: Change made 
due to the pump recall in the US of the body guard. Synopsis (Statistical Analysis)  
12. Synopsis (planned statistical analysis), Section 14.1.4.3 Description of Change: Details related to 
statistical analysis of R-ODS score and demyelinating abnormalities based on electrodiagnostic 
studies (tertiary outcome measures) were added. Purpose of Change: To document additional 
endpoints.  
13. Synopsis Description of Change: The following footnote was removed: At high infusion rates 
above 750 mL/h, 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. Purpose of 
Change: Update.  
14. Section 5. List of Abbreviations. Description of Change: New abbreviations added. Purpose of 
Change: Updates.  
15. Section 6 Description of Change: Literature references describing therapeutic efficacy and safety 
of IGSC treatment and impact of COVID-19 pandemic on ongoing drug development efforts were 
added. Purpose of Change: To reflect changes made in response to the COVID-19 pandemic.  
16. Section 8.5.2 Unblinding Description of Change: Language updated to reflect updated study 
procedure. Purpose of Change: Update.  
17. Sections 8.6, 8.6.1 Study Stopping Rules Description of Change: Language updated to reflect new 
stopping rule changes. Purpose of Change: Stopping the study due to the impact caused by COVID-
19 pandemic.  
18. Section 8.6.2 Trial Integrity Description of Change: This is a new section added to the 
amendment # 6. Purpose of Change: To clarify that despite study stopping before achieving 
originally planned total number of subjects, trial integrity is maintained.  
19. 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. 
 20. Section 11.2 Description of Change: Specified that an alternative scoring algorithm would be 
applied to R-ODS (in addition to the full score) to measure the patient centric benefit of HyQvia. 
Purpose of Change: introduce patient-centric endpoint.  
21. Section 13.1 Description of Change: Added a new section to describe Electrodiagnostic studies 
Purpose of Change: introduce new endpoint to further assess treatment effect.  
22. Section 14.1.3 Description of Change: Clarified that rules for handling missing data will be 
described in the SAP. Purpose of Change: Update.  
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23. Synopsis (Analysis of Primary Outcome Measure), Section 14.1.4.1 Description of Change: Added 
a sensitivity analysis with alternative relapse definition due to expected missed confirmation visits 
during Covid-19 pandemic. Purpose of change: Update 
Protocol amendment #5: 161403-protocol-amend-5-2019may10 
Amendment to amendment #4: 2019 FEB 13; 12 items 
1. Synopsis and throughout the document Description of Change: References to the electronic diary 
were changed to DIARYpro after an initial explanation. Purpose of Change: For clarity.  
2. Synopsis, Section 9.2, Section 10.3.1, Section 10.5 Description of Change: Exclusion criterion 19 
was adapted to preclude use of any corticosteroids within 8 weeks prior to screening, regardless of 
indication. 
  
3. Synopsis, Section 14.3.2 Description of Change: The following outcome measure was added: In 
addition, potential correlation between serum IgG trough levels after day 120 (every 2-week dosing 
E1W27/EOE1T; every 3-week dosing E1W26/EOE1T, every 4-week dosing E1W28/EOE1T) or at the 
time of CIDP symptom relapse (E1ET or Pre-IV BL/E2W1) and relapse status (relapse, no relapse) will 
be assessed as an exploratory analysis. 
  
4. Synopsis, Section 14.1.4 Description of Change: The following outcome measure was added: In 
addition, potential correlation between serum IgG trough levels on or after day 120 or at the time of 
CIDP symptom relapse and relapse status (relapse, no relapse) will be assessed as an exploratory 
analysis. This change was also reflected in Section 12.7.10. 
  
5. List of Abbreviations Description of Change: DIARYpro was added, and eDiary was added. Purpose 
of Change: For increased clarity and better readability of the protocol.  
6. Section 6.6 Description of Change: It was clarified that the study will be conducted in accordance 
with EU Directives (2001/20/EC; 2005/28/EC). Purpose of Change: To correct the guideline currently 
in place.  
7. Section 8.8 Description of Change: All data entered in to the CRF should be able to be verified by a 
corresponding source document. Purpose of Change: Clarification requested by sites.  
8. Section 11.1, Section 11.4 Description of Change: It was clarified in the text that the same 
individual should administer the Hand Grip test as who administers the INCAT and the MRC, for 
consistency. Purpose of Change: To improve intructions to the Investigators. 
9. Synopsis, Section 12.1.2 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. 
  
10. Section 14.1.4.2.2 Description of Change: Following text language has been included: In addition, 
the incidence (number of percentage of subjects) of local infusion site reactions will be provided by 
geographic region (US, non-US) and overall. 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. 
  
11. Section 21.2 Description of Change: Xs were removed from Body Mass Index collections at three 
time points: E1W26ET/E1W27ET/E1W28ET visits. Purpose of Change: To correct a previous error in 
the protocol.  
For non-commercial use only

12. Section 21.2, Section 21.3 Description of Change: The footnote “g” was corrected per Protocol 
Amendment 4 (2019 FEB 13). Purpose of Change: This change was inadvertently not noted in the 
Summary of Changes in Protocol Amendment 4. 
Protocol amendment #4: 161403-protocol-amend-4-2019feb13 
Amendment to amendment #3: 161403-protocol-amend-3-2018jan31 (17 items) 
1. Synopsis, Section 8.3 Description of Change: Overall duration of the study has been extended to 
68 months and enrollment period has been extended to 61 months. Purpose of Change: To 
accomplish subject recruitment.  
2. Synopsis Description of Change: Reference to GAMUNEX® -C Prescribing Instruction (for storage 
condition) has been included in the Synopsis. Purpose of Change: To provide clarity on the storage 
condition of GAMUNEX® -C for US sites who might be using GAMUNEX® -C in Epoch 2.  
3. Synopsis, Section 8.7.4.2 Description of Change: The mode of administration of GAMUNEX-C – this 
has been amended. Purpose of Change: To make it in line with the Prescribing Instruction.  
4. List of Abbreviations Description of Change: Moved the abbreviation “IWRS” up to match the 
alphabetical order. Removed duplicate entry of the abbreviation “Lactate Ringers”. Removed “CFR” 
from the list as it was used only once in the document. Additionally, usage of definitions or 
abbreviations is updated throughout the document. Purpose of Change: For better readability of the 
protocol.  
5. Inclusion criteria Description of Change: The cross-reference to section 21.4 has been updated to 
correct section 21.5, in inclusion criterion#5. Purpose of Change: The cross-reference to section 21.4 
in inclusion criterion #5 was incorrect in Protocol amendment # 3. 
6. Synopsis, Section 9.2 Exclusion Criteria Description of Change: The phrase “multifocal acquired 
demyelinating sensory and motor neuropathy (MADSAM)” has been removed from the hereditary 
demyelinating neuropathies in Exclusion criterion# 2a, and included as a separate exclusion 
criterion#2c. Purpose of Change: To improve intructions to the Investigators for clearer directions on 
eligibility.  
7. Synopsis, Section 9.2 Exclusion Criteria Description of Change: An exclusion criterion for 
“thrombophilic disorders” has been added as exclusion criterion#25, in the synopsis and section 9.2 
of the protocol. Purpose of Change: To improve intructions to the Investigator for clearer directions 
on eligibility.  
8. Section 8.5.2 Unblinding Description of Change: Following text language has been included 
“Access to unblinding data during study conduct will be controlled to ensure that the scientific 
integrity and regulatory utility of the study are appropriately maintained and protected. Unblinding 
for Epoch 1 Final Analysis:At the completion of Epoch 1, all Epoch 1 data will be locked, treatment 
assignment will be unblinded, and all data will be analyzed as preplanned in the study Statis tical 
Analysis Plan (SAP). The analysis, described in Section 14.3.1 of this protocol, will be considered the 
final analysis of Epoch 1 data. Unblinding for Interim Safety Analysis: For the interim safety analysis 
described in Section 14.3.2, treatment assignment will be unblinded and all data will be analyzed as 
preplanned in the study SAP; similarly for any other interim analysis. Unblinding for Other Purposes 
during Study Conduct:Treatment assignment is not to be revealed before the study is 
completed/terminated, except for purposes of the Epoch 1 final analysis and the interim safety 
analysis, as noted above, and in emergency cases when unblinding is necessary for the clinical 
management of an SAE. In such events, the investigator may unblind via the integrated web 
For non-commercial use only

response system (IWRS) at any time (ie, 24 hours per day, 7 days per week) to obtain the treatment 
assignment. Details of unblinding procedures will be provided to study sites.” Purpose of 
Change:Addition of unblinding language from the Amendment 2 (dated 2016 APR 22), and provide 
additional information.  
9. Section 8.7.1.3 Placebo solution Description of Change: Storage temperature of Lactated Ringers 
solution has been included. Purpose of Change: To improve the clarity and readability of the 
protocol.  
10. Section 8.7.3.1 Epoch 1 Description of Change: Language was updated to include “for both 
rHuPH20 and IGI,10% /placebo solution”. Purpose of change: To improve clarity in the protocol.  
11. Section 8.7.4.1 Epoch 1 Description of Change: Minor corrections were made, such as the 
spelling of “albumin” was corrected, and “rHu” was added before PH20 for clarity. Purpose of 
Change: To improve clarity in the protocol.  
12. Section 6.5.1, Section 9.3, Section 12.1.1.1, Section 12.1.2 Description of Change:Language 
pertaining to pregnancy has been removed, and also the followup period was updated to 1 year 
postdelivery instead of 2 years postdelivery. Additional clarification added in section 12.1.1.1. 
Purpose of Change: Enrollment to Pregnancy registry has been closed.  
13. Section 12.7.1 Hematology and Clinical Chemistry Description of Change: the following text was 
removed: “In the event that no safety concerns are raised, Two weeks following the first infusion, at 
the time of the first full dose, approximately 72 h, and 7 and 14 days following the first full dose in 
Epoch 1 and E2W3 in Epoch 2 sampling time points may be waived or modified upon 
recommendation by the DMC and notification by the sponsor/sponsor’s representative”. New text 
added: “Epoch 2 E2W3 is required for those subjects taking Gamunex-C”. 
 
  
14. Section 12.7.2 Hemolytic Panel Description of Change: Following paragraph has been moved up 
to the beginning of the Hemolytic panel. “The first hemolytic panel will be measured at Epoch 1 
Week 1 (E1W1). The Hgb result obtained from the E1W1 will serve as the baseline Hgb value for the 
duration of the study. In case of absence of E1W1 result for any reason screening Hgb result serve as 
the baseline Hgb value.Hemoglobin and LDH values can be taken from the hematology and clinical 
chemistry panels, if conducted on the same day as the hemolytic panel. For subsequent tests, if 
there is a reduction in Hgb of ≥ 1 g/dL compared to baseline Hgb, every effort is to be made to 
perform a hemolytic panel within 72 hours.; if it is not feasible to do so, the hemolytic panel must be 
performed as soon as possible but at the next scheduled visit, at latest. At any time during the study, 
an unscheduled hemolytic panel may be performed in the event of suspected hemolytic anemia. Any 
LDH test result of 2 × ULN or greater will trigger analysis of the sample for LDH isoenzymes.” Purpose 
of Change: to improve the clarity and readability of the protocol.  
15. Section 12.7.2 Hemolytic Panel Description of Change: Following paragraph has been added to 
this section. “It is not necessary to repeat the hemolytic panel if the drop of ≥1 g/dL Hgb remains 
constant 72 hours after the first full dose of investigational product or after an unscheduled visit 
blood draw, unless it drops further. It is recommended that the investigator uses good medical 
judgement in assessing subjects with an unexplained decrease in serum Hgb as other medical 
conditions beside hemolysis can cause this, and therefore may require additional investigations.” 
Purpose of Change: To improve the clarity of the protocol and and reflect the same instructions 
provided to sites in previous, ‘memos’ to sites.  
For non-commercial use only

16. Section 21 Schedule of Assessments Description of Change: Footnotes for R-ODS and HRU in 
Table 21-1 through Table 21-3 were updated to state “The data entered by subjects for HRU during 
screening in the DIARYpro will not be used for analysis”. Additionally, the relevant texts for R-ODS 
and HRU has been updated throughout the document to reflect the same clarification. Purpose of 
Change: To improve the assessments and clarity of the protocol.  
17. Section 21 Schedule of Assessments Description of Change: INCAT disability score frequency of 
assessment was changed to approximately every 4 weeks in the Schedule of Study Procedures and 
Assessments Tables 21-1, Table 21-2 and Table 21-3. Corresponding footnote in each of the tables 
was also updated accordingly to reflect the change. 
 
 
 
 
Protocol amendment #3: 161403-protocol-amend-3-2018jan31 
Amendment to amendment #2: 161403-protocol-amend-2-2016Apr22 (68 items) 
 
1. Throughout the document Description of Change: Minor editorial/grammatical and/or 
administrative changes that do not substantively affect the study conduct or patient safety have 
been made. Purpose for Change: To improve the readability and/or clarity of the protocol. 
2. Section 1 Study Personnel Description of Change: Authorized representative was updated. 
Purpose for Change: Change in personnel.  
3. Synopsis, 8.3 Duration of Study Periods and Subject Participation Description of Change: New 
estimates of study completion and duration were added. Purpose for Change: Updated the 
estimates to be in line with the extended enrollment period.  
4. Synopsis, 6.3 Population To Be Studied, 8.1 Brief Summary, 9.1 Inclusion Criteria, 10.3.1 Screening 
and Baseline Period, 10.3.1.1 Rescreening Description of Change: The description of the stable 
dosing regimen of IGIV therapy was updated from 3 months to 12 weeks. Purpose for Change: For 
consistency in reporting times in weeks and for greater accuracy.  
5. Synopsis; 9.1 Inclusion Criteria Description of Change: Removed the time limit on INCAT scores 
and replaced it with documentation in medical records. Purpose for Change: The exclusion of 
individuals whose last INCAT score was documented 24 months prior is arbitrary and excludes 
potential study participants who might otherwise qualify as long as they meet the other 
inclusion/exclusion criteria.  
6. Synopsis; 9.1 Inclusion Criteria, 21.3 Schedule of Study Procedures and Assessments Table 21-1, 
Table 21-2, Table 21-3 Description of Change: Definition of stability was added to the inclusion 
criteria. Purpose for Change: This was added to make the definition of stability more easily available 
for the Investigator.  
7. Synopsis, 9.1 Inclusion Criteria Description of Change: Detail of INCAT scoring was added to 
Inclusion 4. Purpose for Change: To improve instructions to the Investigator for clearer directions on 
eligibility.  
8. Synopsis, 9.2 Exclusion Criteria Description of Change: “MADSAM” was added to the list of 
hereditary demyelinating neuropathies. Purpose for Change: Added for clarity for the investigators.  
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9. Synopsis; 14.3 Planned Interim Safety Analysis of the Study Description of Change: In addition to 
the previously planned interim safety analysis, a formal IA of all Epoch 1 data was added. Details for 
this additional IA were added. Purpose for Change: The previous IA described was for safety, the 
additional IA is for submission purposes.  
10. Synopsis Description of Change: Minor edits were made to the safety outcome measures 8, and 9 
to align with the protocol body. Purpose for Change: To align with the protocol body text.  
11. Synopsis; 8.4.1.2.2 Safety, 8.4.2.2.1 Safety Description of Change: A note was added to safety 
outcome measures “Note: Adverse events in this section refer to treatment-emergent AEs, if not 
specified.” Purpose for Change: To clarify the type of AEs that will be evaluated.  
12. Synopsis, 8.7.4.2 Epoch 2 Description of Change: Maintenance infusions were specified for 
GAMMAGARD LIQUID/KIOVIG and GAMUNEX® -C. A maximum dose was also added. Purpose for 
Change: The mode of administration section for GAMMAGARD LIQUID/KIOVIG and GAMUNEX® -C 
was updated to more clearly state the timing of the maintenance infusions. The maximum dose was 
added to ensure the safety of the subjects and align with clinical practice.  
13. Synopsis Description of Change: The timing for subsequent doses for GAMMAGARD was updated 
from 1 to 2 days, to 2 to 5 days. Purpose for Change: To be more accurate to how investigators will 
dose.  
14. Synopsis, 8.7.4.2 Epoch 2 Description of Change: The clause “every 3 weeks” was added to the 
mode of administration section on GAMMAGARD LIQUID/KIOVIG. Purpose for Change: To emphasize 
that this was a fixed dose schedule.  
15. Synopsis, 14.1.2 Datasets and Analysis Cohorts Description of Change: The definition of PP 
analysis set was updated. Purpose for Change: For consistency within the company and between the 
final and interim analyses.  
16. 6 Background Information Description of Change: A new reference was added to the sentence 
summarizing current publications on CIDP. Purpose for Change: A relevant recent publication was 
published and was felt useful to add.  
17. 6.1.1.1.1 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.  
18. 6.1.1.2 Placebo Control Description of Change: The following parenthetical was added after 
Lactated Ringer’s solution “(also known as Ringer’s Lactate or Hartmann’s solution or Compound 
Sodium Lactate Solution for Infusion in some participating countries)”. Purpose for Change: To clarify 
the possible names of the placebo control in various countries.  
19. 6.2 Clinical Condition/Indication Description of Change: “Relapse of” was added to the clinical 
condition in Epoch 1. Purpose for Change: To align with the synopsis.  
20. 6.5.2 GAMMAGARD LIQUID/KIOVIG Description of Change: The term pharyngolaryngeal pain was 
updated to laryngeal pain. Purpose for Change: To align with the current MedDRA preferred term.  
21. 6.6 Compliance Statement Description of Change: “The Declaration of Helsinki (October 2013)” 
was removed. Purpose for Change: To align with the newest template language.  
22. 8.2 Overall Study Design, Schedule of Study Procedures and Assessments Table 21-1, Table 21-2, 
Table 21-3 Description of Change: A reference point was added for Week 1. “Week 1 should be 
For non-commercial use only

calculated from the last day of dosing for an infusion dose that is to be administered over multiple 
days.” Purpose for Change: To ensure consistency from all sites on determining Week 1.  
23. 8.5.1 Blinding Description of Change: Specifications that Epoch 1 is blinded and Epoch 2 is open 
label were added, as well as a definition of completion was added for Epoch 1 subjects. Purpose for 
Change: To align with the changes in unblinding added into Section 8.5.2.  
24. 8.5.2 Unblinding Description of Change: Language was updated from the standard unblinding 
language to describe that treatment assignments will be unblinded after Epoch 1. Purpose for 
Change: The study will be unblinded after the completion of Epoch 1.  
25. 8.7.1.3 Placebo Solution Description of Change: Additional text was added describing the placebo 
packaging, including the coloration and dilution. Purpose for Change: Label language was slightly 
different between the US and Canada compared to the rest of world. This additional text was to help 
clarify for the sites based on these differences.  
26. 10.3.1 Screening and Baseline Period Description of Change: “Product name” was added to the 
list of information captured for pre-randomization IGIV infusions. Purpose for Change: This 
information is pertinent for the safety group to assess and report on SAEs.  
27. 10.3.1 Screening and Baseline Period Description of Change: Dosing interval was increased from 
5 to 7 days. Purpose for Change: To allow for greater flexibility in the scheduling of subject visits. The 
change was not related to any safety or efficacy concerns.  
28. 10.3.3.1 SC Infusion Visits, 10.3.4.2 IV Infusion Visits Description of Change: Clarification was 
added to the window around the telephone follow-up visits. Purpose for Change: To align with the 
table footnotes.  
29. 10.6 Subject Diary and Patient Reported Outcomes Description of Change: Clarification was 
added that the diary will be the source records for patient-reported data. Purpose for Change: To 
add clarification for data management as there may be other sources for infusion data.  
30. 10.6 Subject Diary and Patient Reported Outcomes Description of Change: The following 
sentence was removed “After a reconciliation against eCRF, the data will be imported into the study 
database.” Purpose for Change: The study database will not be reconciled against the diary, 
information will be reviewed by the investigator at various visits.  
31. 10.7 Subject Completion/Discontinuation Description of Change: Death was added as a reason 
for discontinuation. Purpose for Change: To clarify for the data management for field options in the 
eCRF.  
32. 11.2 Rasch-Built Overall Disability Scale (R-ODS) Description of Change: Additional information on 
eDiaries at screening was added. Purpose for Change: To align with table footnotes.  
33. 12.1.1.2 Suspected Unexpected Serious Adverse Reaction (SUSAR) Description of Change: Added 
additional information on the requirements on reporting SUSARs. “The sponsor will ensure that all 
relevant information about suspected unexpected serious adverse reactions (SUSARs) that are fatal 
or lifethreatening, 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/EC). The sponsor will comply with applicable 
laws/requirements for reporting SUSARs and all other SAEs to the ECs and investigators.” 
 
  
For non-commercial use only

34. 12.1.2 Assessment of Adverse Events Description of Change: The qualifier of 30 days was added 
for SAE reporting after study completion using the SAE Report Form. Additional text was added 
regarding the use of CIOMS forms or MedWatch forms after the 30 days from study completion. 
Purpose for Change: Clarification was added to the timing of SAE reporting.  
35. 12.7.1 Hematology and Clinical Chemistry, Table 21-1, Table 21-2, Table 21-3, Table 21-4, Table 
21-5, Table 21-6, Table 21-7, and Table 21-8 Description of Change: A window was added for Hgb 
and hematocrit, and specifications for when a reticulocyte count would be performed was added to 
the body text and removed from the tables (21-1, 21-2, 21-3, 21-3, 21-4, 21-5, 21-6, 21-7) and added 
to table 21-8. Purpose for Change: Text was moved from the tables to the text body for clarity.  
36. 12.7.9.2 Assessment of Abnormal Laboratory Values Description of Change: Specification was 
added that investigators did not need to indicate if hyaluronidase antibody values constituted an AE. 
Purpose for Change: To align with the new text in Section 12.7.12.1, Guidance on Reporting and 
Assessing rHuPH20 (hyaluronidase) antibody test results.  
37. 12.7.10 Trough Serum IgG Description of Change: Removed “within 60 minutes” from the 
sentence regarding when the IgG sample must be collected. Purpose for Change: The sample needs 
collected prior to infusion but does not necessarily need to be collected within 60 minutes.  
38. 12.7.12.1 Guidance on Reporting and Assessing rHuPH20 (hyaluronidase) antibody test results 
Description of Change: Guidance was added to the protocol on reporting and assessing antibody test 
results. Purpose for Change: Text was added to clarify that neutralizing antibodies do not have to be 
reported as AEs.  
39. 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.  
40. 16.6 Laboratory and Reader Standardization Description of Change: R-ODS was removed. 
Purpose for Change: R-ODS is not a PRO so it does not need to be included in this list.  
41. 21.2 Schematics for Study Visits and Assessments Figure 21-1, Figure 21-2 Description of Change: 
Figure 21-1 and Figure 21-2 were removed. References to these figures were removed throughout 
the protocol. Purpose for Change: To avoid redundancy and potential errors from updates.  
42. 21.3 Schedule of Study Procedures and Assessments Table 21-1, Table 21-2, Table 21-3, Table 21-
4 Description of Change: The words “at least” were added to the footnote about when the R-ODS 
assessment will be completed. Purpose for Change: The R-ODS assessment might be completed 
more than once a week.  
43. 21.3 Schedule of Study Procedures and Assessments Table 21-1, Table 21-2, Table 21-3 
Description of Change: Additional information on eDiary dispensation and data collection was added 
to the footnote. Purpose for Change: To add clarity for the protocol.  
44. 21.3 Schedule of Study Procedures and Assessments Table 21-1, Table 21-2, Table 21-3 
Description of Change: The words “after 24 h but within 72 h + 1 business day” and “or after 
completion of the last day of dosing for an infusion that was administered over multiple consecutive 
days” were added to the footnote. Purpose for Change: Clarification was added to the window 
around the telephone follow-up visits. 
45. 21.3 Schedule of Study Procedures and Assessments Table 21-3 Description of Change: The 
footnote “to be performed prior to infusion” was updated to “to be performed prior to the start of 
For non-commercial use only

the infusion (or prior to the first day of dosing for an infusion dose that is to be administered over 
multiple days)”. Purpose for Change: To align with the other assessment tables.  
46. 21.3 Schedule of Study Procedures and Assessments Table 21-3 Description of Change: The 
footnote pertaining to the interim assessment/visits during Week 16 was updated to match the 
footnote in Table 21-7. Purpose for Change: For consistency within the protocol.  
47. 21.3 Schedule of Study Procedures and Assessments Table 21-4 Description of Change: “Prior to 
each infusion rate change” was added to the list of when vital signs need monitored and recorded. 
Purpose for Change: To align with nursing standard of care and to ensure safety of the subjects in 
the study.  
48. 21.3 Schedule of Study Procedures and Assessments Table 21-1, Table 21-2, Table 21-3, Table 21-
5, Table 21-6, Table 21-7 Description of Change: An extra column was added for the +72 h blood 
sample, related to Week 3 (Table 21-1), Week 5 (Table 21-2), and Week 8 (Table 21-3). Purpose for 
Change: To increase visibility of the following footnote and those related to it on other tables “To be 
collected 72 (±24) h (ie, 48 – 96 h) after the Week 3 infusion, the subject’s first full-dose infusion of 
IP (HYQVIA/HyQvia or placebo with rHuPH20).” This was to help call attention to the difference in 
timing for the safety labs at this visit.”  
49. 21.3 Schedule of Study Procedures and Assessments Table 21-1, Table 21-2, Table 21-3, Table 21-
4, Table 21-5, Table 21-6, Table 21-7, 12.7.1 Hematology and Clinical Chemistry Description of 
Change: The following footnote was removed from the tables “In the event that no safety concerns 
are raised, these sampling time points may be waived or modified upon recommendation by the 
DMC and notification by the sponsor/sponsor’s representative.” And the following text was updated 
in Section 12.7.1 instead “In the event that no safety concerns are raised, 2 weeks following the first 
infusion, at the time of the first full dose, approximately 72 h, and 7 and 14 days following the first 
full dose in Epoch 1 and E2W3 in Epoch 2 sampling time points may be waived or modified upon 
recommendation by the DMC and notification by the sponsor/sponsor’s representative.” 
 
  
50. 21.3 Schedule of Study Procedures and Assessments Table 21-1, Table 21-2, Table 21-3 
Description of Change: A footnote was updated to include the following “For the rest of the SC 
period, the reference to calculate the visit is Week 1 and not the Pre-SC BL Visit”. Purpose for 
Change: To add clarity for the Investigators.  
51. 21.3 Schedule of Study Procedures and Assessments Table 21-1, Table 21-2, Table 21-3, Table 21-
5, Table 21-6, Table 21-7 Description of Change: A footnote was updated to include the following: 
“For any deviation from allowable study visit windows (±2 or ±3 day windows), subjects would be 
required to be brought back to the original planned visit date of the next visit in order to ensure 
subject safety. All other assessment or procedure visits, which do not have a visit window or a 
reference note in the protocol, should follow visit windows of ±3 days. There will be no visit window 
allowed in the ramp up period after Visit 1 (Week 1).” Purpose for Change: To add clarity for the 
Investigators.  
52. 21.3 Schedule of Study Procedures and Assessments Table 21-1, Table 21-2, Table 21-3 
Description of Change: A footnote was updated to include the following (parenthesis to show 
variation among tables): “Week 1 should be calculated from the last day of dosing for an infusion 
dose that is to be administered over multiple days. For the rest of the SC period, the reference to 
calculate the visit is Week 1 and not the Pre-SC BL Visit (Exception: Week 3 (Week 5, Week 8) +72 h, 
Week 4 (Week 6, Week 9) (please see note f) and Week 5 (Week 7) that are calculated from Week 3 
For non-commercial use only

(Week 5, Week 10) due to safety assessments in the protocol).” Purpose for Change: To add clarity 
for the Investigators.  
53. 21.3 Schedule of Study Procedures and Assessments Table 21-1, Table 21-2, Table 21-3 
Description of Change: A footnote was updated to include the following: “ie, Week 13, Week 15, or 
Week 17.” Similar footnotes were added on additional tables. Purpose for Change: To add clarity to 
the visit window.  
54. 21.3 Schedule of Study Procedures and Assessments Table 21-1, Table 21-2, Table 21-3 
Description of Change: An extra row and footnote was added for randomization. “Randomization 
can occur between the last day of IGIV and Week 1 assessments (once last IGIV is fully administered 
and eligibility is confirmed).” Purpose for Change: To add clarity for the Investigators.  
55. 21.3 Schedule of Study Procedures and Assessments Table 21-1, 21-2, Table 21-3 Description of 
Change: A footnote was added “A minimum of a 3-day interval is required between E1W4 and E1W5 
(E1W6 and E1W7, E1W9 and E1W10 visits, depending on the Table).” Purpose for Change: To specify 
the timing and procedure when there is an overlap of visits.  
56. 21.3 Schedule of Study Procedures and Assessments Table 21-1, Table 21-2, Table 21-3 
Description of Change: A footnote was added Whenever there is an overlap of a safety visit and an 
infusion visit, the safety laboratory assessments should be performed first prior to the IP infusion”. 
Purpose for Change: To specify the timing and procedure when there is an overlap of visits.  
57. 21.3 Schedule of Study Procedures and Assessments Table 21-4 Description of Change: Vital signs 
were added to all visits in the treatment period in the table. Purpose for Change: To align with the 
footnote as well as ensure the data is obtained.  
58. 21.3 Schedule of Study Procedures and Assessments Table 21-4 Description of Change: The 
following text was added to a footnote “ie, Week 10, Week 13, Week 16”. Purpose for Change: To 
help specify the timing.  
59. 21.3 Schedule of Study Procedures and Assessments Table 21-4 Description of Change: Two new 
footnotes were added and additional information was added to an existing footnote to clarify the 
procedure when INCAT evaluation indicates relapse and to add GAMMAGARD Liquid/KIOVIG 
instructions for rescue medication. Two new footnotes were added: “In case the first INCAT 
evaluation indicating relapse (during Epoch 1) occurs during a study visit and not at an unscheduled 
visit, and the second (confirmatory) INCAT evaluation (Pre-IV BL Epoch 2) is performed on the same 
day, and in addition the Investigator’s preference is to administer the rescue medication (E2W1) also 
on the same day—repetition of same laboratory assessments should be avoided (eg, combining 
E1W15 at 2 weekly dose regimen, E1W14 at 3 weekly dose regimen, or E1W16 at 4 weekly dose 
regimen together with Pre-IV BL Epoch 2 and E2W1 all on the same day. In this case laboratory 
assessments of Epoch 1 study visit are the same as the ones in E2W1 before IP. These laboratory 
assessments should then be performed only once for subject’s safety regarding blood volume 
taken.” “GAMMAGARD Liquid/KIOVIG or GAMUNEX-C (for US sites only), can be given as a rescue 
medication on Epoch 2, after the second INCAT evaluation, as early as the same day and no later 
than 7 days, at the discretion of the Investigator When administration of the rescue medication 
(E2W1) does not occur on same day as second (confirmatory) INCAT evaluation (Pre-IV BL Epoch 2), 
then Table 21-4 all study procedures and assessments should be performed at ‘Pre-IV BL’ Epoch 2 
day and Table 21-8, all clinical laboratory assessments should be performed (before infusion) at 
‘E2W1’ visit day.” Additional information on existing footnote: “If INCAT evaluation indicates relapse 
during the SC treatment, the second confirmatory INCAT evaluation (Pre-IV BL Epoch 2) can be 
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performed as early as the same day of the first INCAT evaluation and no later than 7 days after the 
first INCAT evaluation and by the same rater.” Purpose for Change: To add clarity for the 
Investigators.  
60. 21.3 Schedule of Study Procedures and Assessments Table 21-5 Description of Change: A 
footnote “prior to start of infusion (as applicable)” was added to the row of Serum IgG. Purpose for 
Change: To align with the protocol text.  
61. 21.3 Schedule of Study Procedures and Assessments Table 21-5 Description of Change: A 
footnote was updated from “to be collected prior to the subjects” to “to be collected prior to the 
start of the subjects”. Purpose for Change: To align with the protocol text.  
62. 21.3 Schedule of Study Procedures and Assessments Table 21-6 Description of Change: A 
footnote was moved from E1W7 to E1W8. Purpose for Change: There is no infusion at E1W7.  
63. 21.3 Schedule of Study Procedures and Assessments Table 21-7 Description of Change: E1W26 
was changed to E1W28. Purpose for Change: To align with Table 21-3.  
64. Schedule of Study Procedures and Assessments Table 21-7 Description of Change: A column was 
added for E1W12. Purpose for Change: To align with the other table of assessments.  
65. 21.3 Schedule of Study Procedures and Assessments Table 21-8 Description of Change: 
Additional information was added to a footnote to clarify the procedure when INCAT evaluation 
indicates relapse, and to add GAMMAGARD Liquid/KIOVIG instructions for rescue medication. “In 
case the first INCAT evaluation indicating relapse (during Epoch 1) occurs during a study visit and not 
at an unscheduled visit, and the second (confirmatory) INCAT evaluation (Pre-IV BL Epoch 2) is 
performed on the same day, and in addition the Investigator’s preference is to administer the rescue 
medication (E2W1) also on the same day—repetition of same lab assessments should be avoided 
(eg, combining E1W15 at 2 weekly dose regimen, E1W14 at 3 weekly dose regimen, or E1W16 at 4 
weekly dose regimen together with Pre-IV BL Epoch 2 and E2W1 all on the same day). In this case 
laboratory assessments of Epoch 1 study visit are the same as the ones in E2W1 before IP. These 
laboratory assessments should then be performed only once for subject’s safety regarding blood 
volume taken. When administration of the rescue medication (E2W1) does not occur on same day as 
second (confirmatory) INCAT evaluation (Pre-IV BL Epoch 2), then Table 21-4 all study procedures 
and assessments should be performed at ‘Pre-IV BL’ Epoch 2 day and Table 21-8, all clinical 
laboratory assessments should be performed (before infusion) at ‘E2W1’ visit day.” Purpose for 
Change: To add clarity for the Investigators.  
66. 21.4 Clinical Laboratory Assessments Table 21-5, Table 21-6, Table 21-7, Table 21-8 Description 
of Change: A clause was added indicating that subjects who met the criteria would have to return for 
additional testing: “…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.” Purpose for Change: Updated for to match the 
body of the protocol.  
67. 21.4 Clinical Laboratory Assessments Table 21-5 Description of Change: A footnote was added to 
the serum IgG. Purpose for Change: To align with the protocol body text.  
68. Investigator Acknowledgement Description of Change: A second Investigator acknowledgement 
form was added. Purpose for Change: An EU specific acknowledgement page was added per 
template. 
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Protocol amendment #2: 161403-protocol-amend-2-2016apr22  
Amendment to amendment #1: 161403-protocol-amend-1-2015aug25 (22 items) 
1. Throughout the document Description of Change: Minor editorial/grammatical and/or 
administrative changes that do not substantively affect the study conduct or patient safety have 
been made. Investigator acknowledgement page for coordinating investigator has been updated. 
Purpose for Change: To improve the readability and/or clarity of the protocol.  
2. Throughout the document Description of Change: A secondary outcome measure was added to 
Epoch 1 and 2 with additional tertiary outcome measures added to Epoch 2. Relevant text was 
changed to maintain consistency throughout the document with additional text added to describe 
the biostatistical analysis of the specified outcome measures. Purpose for Change: To gain additional 
relevant information regarding outcome measures of efficacy.  
3. Throughout the document Description of Change: The following sentence was added: “any LDH 
test result of 2X ULN or greater will trigger analysis of the sample for LDH isoenzymes.” Purpose for 
Change: To clarify when LDH isoenzyme testing should be performed.  
4. Synopsis, Section 9.1 Inclusion criteria Description of Change: An additional inclusion criteria was 
added: “Subject is willing and able to sign an informed consent form (ICF)”. Language regarding the 
subjects’ legal representative was deleted from the protocol: “or the subjects’ legally authorized 
representatives”. 
  
5. Section 10.3.1 Screening and Baseline Period Description of Change: The following text was 
added: “The subject’s previous electrodiagnostic records including those obtained at the time of 
diagnosis, if available, can be used for initial screening. If a previous evaluable nerve conduction 
report is available, an additional study at the time of screening is not mandatory but highly 
recommended. This is recommended because according to recent data it would be possible to 
determine whether the subject is going to need IgG for control of his disease or if the subject is in 
remission by reviewing these 2 separate tests.” Purpose for Change: This text was added to clarify 
the use of previous of electrodiagnostic records during Screening.  
6. Section 10.3.4.4 End of IV Treatment Period Description of Change: The following bullet point was 
deleted: “Subjects who responded to IGIV treatment throughout the 6 month treatment period and 
completed the End-of-Epoch 2 visit may opt to participate in an open-label extension study for the 
evaluation of long term safety, tolerability, immunogenicity, and efficacy of HYQVIA/HyQvia in CIDP. 
Subjects who are interested will be asked to provide informed consent for the extension study prior 
to conducting any of the End-of-IV Treatment Period (study completion) procedures.” Purpose for 
Change: Only subjects who complete Epoch 1 may opt to participate in the open-label extension.  
7. 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.  
8. Section 17.5 Description of Ethical Considerations Relating to the Trial Description of Change: This 
is a new section added to the protocol that contains an explanation and discussion of the ethical 
rationale used for design of the trial. Purpose for Change: To clarify the ethical considerations of the 
trial.  
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9. Synopsis, Section 9.1 Inclusion Criteria Description of Change: Males or females of age ≥18 at the
time of screening. Purpose for Change: CIDP is a disease which can be found in subjects >80 years,
this change was made by recommendation by Canadian investigator.
10. Throughout the document Description of Change: Minimal monthly maintenance dose of IGIV
was decreased from 0.5 to 0.4 g/kg. Purpose for Change: After discussing with European Union,
Canada, and US investigators and key opinion leaders, 0.4 g/kg was recommended as the lowest
minimal monthly maintenance dose.
11. Synopsis, Section 9.2 Exclusion Criteria, Section 10.3.1.1 Rescreening, 10.5 Medications and Non-
Drug Therapies Description of Change: Allowance for steroid treatment if administered >3 months
prior to screening and within 3 months of screening allowing for a single steroid dose or
Methylprednisolone Dose Pack for the treatment of AE and non-CIDP indications. Purpose for
Change: A wide consensus from investigators and key opinion leaders agreed that these changes
would be beneficial for the subjects.
12. Section 8.2 Overall Study Design, Section 21.3 Schedule of Study Procedures and Assessments
(Table 21-1) Description of Change: Unscheduled visits in Epoch 2 were added. Purpose for Change:
At any time during treatment period, unscheduled visit(s) for INCAT assessment will be allowed for
patients who experience CIDP worsening, in order to determine whether worsening meets the
definition of relapse.
13. 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. Section 12.1.2.3 was deleted. Section 12.3 was updated
from eCRF reporting to SAE Report Form reporting. Purpose of Change: The EDC system cannot pull
all information on to the form which is required for Baxalta GDS. EDC should be re-programmed.
Section 12.1.2.3 was no longer needed as it describes processes for electronic SAE reporting. Section
12.3 updates were to reflect the changes from eCRF reporting of SAEs to paper reporting.
14. Section 8.7.2 Preparation and Storage of Pooled Products Description of Change: 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. Section 17.4 Data Monitoring Committee Description of Change: The DMC may recommend to
stop the trial if it finds toxicities or if treatment is proven to be not beneficial. Purpose of Change:
Major or critical decisions should be in the hands of the Sponsor/Management. For the purpose of
“reason” “stopping the study” is a very grave decision and should be assess by a larger group
including the program innovation team and other experts.
16. Synopsis, Section 9.1 Inclusion Criteria Description of Change: “Partial or complete resolution of
neurological symptoms and deficits” was added to inclusion criteria 3. Purpose of Change: To clarify
reasons subjects might have received IgG treatment.
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17. Section 9.3 Withdrawal and Discontinuation Description of Change: Language was added to the 
Pregnancy Registry to specify that the participation is based on whether it is available in the 
respective country. Purpose of Change: To add flexibility for countries that might not have the 
Pregnancy Registry.  
18. Section 12.1.1 Definitions Description of Change: A definition of TEAE was added into the 
protocol. Purpose of Change: The Baxalta template was updated.  
19. Section 12.1.1.2 Suspected Unexpected Serious Adverse Reaction (SUSAR) Description of Change: 
A new section on SUSARs were added into the protocol. Purpose of Change: Baxalta protocol 
template text was updated to include this additional language and reporting requirements.  
20. Section 12.7.13 Backup Samples/Biobanking Description of Change: The clause “for no more than 
2 years after the final study report has been completed” was added to the storage of serum samples. 
  
21. Throughout the document Description of Change: Updated template text. Purpose of Change: 
Baxalta protocol template was recently updated. Minor textual changes made throughout the 
document.  
22. Synopsis, Section 8.7.3 Administration, Section 8.7.4 Description of Treatment Description of 
Change: Mode of administration is divided into 2 parts, 1 for bifurcated needle set, and 1 for 
trifurcated needle set. Purpose of Change: To add an option to administer study drug simultaneously 
at 3 body sites using a trifurcated needle set. 
Protocol amendment #1: 161403-protocol-amend-1-2015aug25  
Amendment to Original: 161403-protocol-2015may27 (4 items)   
1. Throughout the document Description of Change: Minor editorial/grammatical and/or 
administrative changes that do not substantively affect the study conduct or patient safety have 
been made. Investigator acknowledgement page for coordinating investigator has been inserted. 
Section 21.3 Schedule of Study Procedures and Assessments and Section 21.4 Clinical Laboratory 
Assessments have been updated to fix a few missing assessments that were inadvertently omitted. 
Purpose for Change: To improve the readability and/or clarity of the protocol.  
2. Section 6.6 Compliance Statement Description of Change: Added the text “the Declaration of 
Helsinki (October 2013)”. Purpose for Change: To explicitly state that this study will be conducted in 
compliance with the latest version of the Declaration of Helsinki. In the original protocol, this was 
implicitly referred to through the cited regulations including ICH GCP E6 and the European Clinical 
Trial Directive 2001/20/EC.  
3. Section 8.5.2 Unblinding Description of Change: The text was revised as follows: “Treatment 
assignment is not to be revealed before the study is completed/terminated, except in emergency 
cases when unblinding is necessary for the clinical management of an SAE. In such events, every 
attempt must be made to contact and consult with the study’s Medical Monitor before breaking the 
blind. Tthe investigator may unblind via the integrated web response system (IWRS) at any time (ie, 
24 hours per day, 7 days per week) to obtain the treatment assignment. However, the medical 
monitor will not be unblinded. Details of unblinding procedures and contact information for the 
study’s medical monitor will be provided to study sitesand will be included in the Medical 
Monitoring Plan. The investigator must keep a log stating the date and time of breaking the code, 
reason for breaking the code, study product administered, subject identification number and 
randomization code, and site personnel who were unblinded.” Purpose for Change: To reflect that 
For non-commercial use only

the responsibility to break the treatment code in emergency situations resides solely with the 
investigator.  
4. Section 12.1.2.3 Safety Reporting Description of Change: The following paragraph has been added: 
“The sponsor will ensure that all relevant information about suspected unexpected serious adverse 
reactions (SUSARs) that are fatal or life-threatening, as well as all other serious unexpected ARs, are 
reported to regulatory authorities within the timeframes mandated by the applicable regulations 
(eg, ICH Guideline E2A and the European Clinical Trial Directive (2001/20/EC). The sponsor will 
comply with applicable laws/requirements for reporting SUSARs and all other SAEs to the ECs and 
investigators.” Purpose for Change: To explicitly stated that the sponsor’s responsibility to inform 
regulatory authorities, ethics committees, and investigators worldwide of any SUSARs and all other 
SAEs in a timely manner in accordance with applicable regulations such as the European Clinical Trial 
Directive (2001/20/EC).  
Original protocol: 161403-protocol-2015may27    
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