A Phase 2, Long-Term Immunogenicity Follow-up Trial of Adult and Elderly Subjects Who Have Previously Received an Intramuscular Injection of Norovirus GI.1/GII.4 Bivalent Virus-Like Particle Vaccine
Phase: PHASE2
Conditions: Healthy Volunteers, Norovirus
Sponsor: Takeda




Title: A Phase 2, Long-Term Immunogenicity Follow-up Trial of Adult and Elderly Subjects who 
have Previously Received an Intramuscular Injection of Norovirus GI.1/GII.4 Bivalent Virus-Like 
Particle Vaccine 
NCT Number: NCT03039790
Protocol Approve Date: 27 March 2018
Certain information within this protocol has been redacted (ie, specific content is masked irreversibly from 
view with a black/blue bar) to protect either personally identifiable information (PPD) or company 
confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.
Other information as needed to protect confidentiality of Takeda or partners, personal information, or 
to otherwise protect the integrity of the clinical study.

PAGE 
 
TITLE PAGE 
 
A Phase 2, Long-Term Immunogenicity Follow-up Trial of Adult and Elderly Subjects who 
have Previously Received an Intramuscular Injection of Norovirus GI.1/GII.4 Bivalent 
Virus-Like Particle Vaccine 
Long-Term Immunogenicity of the Norovirus GI.1/GII.4 Bivalent VLP Vaccine in Adults 
Sponsor: 
Takeda Vaccines, Inc. 
40 Landsdowne Street, 
Cambridge, MA 02139, 
USA 
Study Identifier: 
NOR-213 
IND Number: 
014421 
EudraCT Number: 
2016-004288-37 
Vaccine Name: 
Not Applicable 
Date: 
27 March 2018 
Version: 
3.0 
0002
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use

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Norovirus GI.1/GII.4 Bivalent VLP Vaccine 
 
Trial No. NOR-213 
Page 4 of 60 
Protocol Version 3.0 
27 March 2018 
 
 
INVESTIGATOR AGREEMENT 
I confirm that I have read and that I understand this protocol, the Investigator’s Brochure IB), and 
any other product information provided by the sponsor. I agree to conduct this trial in accordance 
with the requirements of this protocol and also protect the rights, safety, privacy, and well-being of 
trial subjects in accordance with the following: 
 The ethical principles that have their origin in the Declaration of Helsinki. 
 International Council for Harmonization, E6 Good Clinical Practice: Consolidated Guideline 
[2]. 
 All applicable laws and regulations, including, but not limited to those related to data privacy 
and clinical trial disclosure. 
 Regulatory requirements for reporting serious adverse events defined in Section 10.4 of this 
protocol. 
 Terms outlined in the Clinical Study Site Agreement. 
 Appendix A – Responsibilities of the Investigator. 
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix C of this protocol. 
 
Signature of Investigator 
Date 
Investigator Name (print or type) 
Investigator’s Title 
Location of Facility (City, State) 
Location of Facility (Country) 
 
0005
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use

Norovirus GI.1/GII.4 Bivalent VLP Vaccine 
 
Trial No. NOR-213 
Page 5 of 60 
Protocol Version 3.0 
27 March 2018 
 
 
1.3 
Protocol Amendment Summary of Changes 
This document describes the changes in reference to the protocol incorporating Amendment N° 
2.0. 
The purpose of this amendment is to update the protocol to remove reference to trial NOR-222. 
This trial will no longer be included in the vaccine development plan. Full details on changes of 
text are given in Section 1.3.2. 
1.3.1 Amendment History 
Date 
Amendment Number 
Protocol Version 
Amendment Type 
Region 
05 December 2016 
Not applicable 
1.0 
Not applicable 
Global 
02 October 2017 
1.0 
2.0 
Non-substantial 
Global 
27 March 2018 
2.0 
3.0 
Non-substantial 
Global 
1.3.2 Summary of Changes 
Amendment to Protocol Version 2.0 02 October 2017 
Rationale for the Amendment: 
The reason for this amendment is to remove NOR-222 from the long-term follow-up due to it being cancelled. 
Accordingly, sample size has been reduced and interim analysis (IA) language has been modified to state that the IA 
will be performed when all participants have provided one blood sample corresponding to at least their first year of 
participation in NOR-213. 
 
Section 
Description of change 
2.0 Trial summary 
Adapted to reflect the changes in the body of the protocol. 
2.1 Schedule of 
Trial Procedures 
Removal of text pertaining to NOR-222 from the table. 
3.3 List of 
Abbreviations 
Geometric mean blocking titer (50%) 
4.2 Rationale for 
the Proposed Trial 
Completed or ongoing trials have included a safety and immunogenicity follow-up of 
maximum 1 year. NOR-213 is designed to capture data from adults and older adults previously 
vaccinated with NoV vaccine, providing the opportunity to evaluate long-term 
immunogenicity data up to 5 years following the first dose of NoV vaccine. Four Three trials 
have been selected for this purpose: NOR-107 (adults aged 18 to 64 years, 1 or 2 doses 11 
compositions of GI.1/GII.4/MPL, 167 or 500 µg aluminum as Al(OH)3), NOR-210 (adults 
aged 18 to 49 years, 1 dose 15/50/0 µg GI.1/GII.4, 500 µg aluminum as Al(OH)3) and, 
NOR-204 (adults aged 18 to 49 and ≥60 years, 1 or 2 doses 15/50/0 or 15/50/15 µg 
GI.1/GII.4/MPL, 500 µg aluminum as Al(OH)3) and NOR-222 (adults aged 18 to 49 years, 1 
dose 15/50/0 µg GI.1/GII.4, 500 µg aluminum as Al(OH)3). Subjects who participated in trials 
NOR-107 and NOR-210 will enter NOR-213 during the 3rd and 2nd year post-vaccination, 
respectively. NOR-204 is ongoing, and subjects participating in NOR-213 will enter the trial 
during the 2nd year post-vaccination. NOR-222 has not yet started and subjects participating in 
NOR-213 will enter the trial during the 1st year post-vaccination. The rationale for the 
selection of these trials is based on the opportunity to obtain long-term follow-up data for 
immunogenicity of the NoV vaccine in adult and elderly populations. 
0006
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use

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Norovirus GI.1/GII.4 Bivalent VLP Vaccine 
 
Trial No. NOR-213 
Page 7 of 60 
Protocol Version 3.0 
27 March 2018 
 
 
Section 
Description of change 
13.2 Interim 
Analysis and 
Criteria for Early 
Termination 
An IA will be performed after all subjects have provided one blood sample corresponding to at 
least their first year of participation in NOR-213 completed at least the 1-year follow-up visit 
and the data for that trial segment have been sufficiently reviewed for accuracy and correctness. 
An interim report will be developed based on these data. The final CSR will include the 
description of the immunogenicity results for the duration of the trial (corresponding to up to 5 
years post-primary vaccination) as well as safety data. The sponsor may consider terminating 
or amending the trial after review of the IA. 
16.0 References 
Global Investigator’s Brochure. Norovirus Bivalent VLP Vaccine. Edition 64.0, 224 December 
November 20176. 
 
0008
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use

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Non

Norovirus GI.1/GII.4 Bivalent VLP Vaccine 
 
Trial No. NOR-213 
Page 11 of 60 
Protocol Version 3.0 
27 March 2018 
 
 
6.4.3 
Procedures for Premature Termination or Suspension of the Trial or the 
Participation of Investigational Sites ................................................................30 
7.0 
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS ...............31 
7.1 
Inclusion Criteria .........................................................................................................31 
7.2 
Exclusion Criteria ........................................................................................................31 
7.3 
Criteria for Delay of Blood Sampling ..........................................................................31 
7.4 
Criteria for Early Trial Termination of a Subject’s Trial Participation .......................32 
8.0 
CLINICAL TRIAL MATERIAL MANAGEMENT .........................................................33 
8.1 
Dosages Administered During the Primary Vaccination Trials ..................................33 
8.1.1 
NOR-107 [NCT 02038907] ..............................................................................33 
8.1.2 
NOR-210 [NCT 02475278] ..............................................................................34 
8.1.3 
NOR-204 [NCT 02661490] ..............................................................................34 
9.0 
TRIAL PLAN ....................................................................................................................35 
9.1 
Trial Procedures ...........................................................................................................35 
9.1.1 
Informed Consent..............................................................................................35 
9.1.2 
Documentation of Trial Entrance ......................................................................35 
9.1.3 
Demographics, Medical History and Prior Medications ...................................35 
9.1.4 
Physical Examination........................................................................................35 
9.1.5 
Vital Signs .........................................................................................................36 
9.1.6 
Immunogenicity Assessments ...........................................................................36 
9.1.7 
Processing, Labeling and Storage of Biological Samples ................................36 
9.1.8 
Safety Assessments ...........................................................................................36 
9.1.9 
Contraception and Pregnancy Avoidance Procedure ........................................36 
9.1.10 
Pregnancy ..........................................................................................................36 
9.1.11 
Documentation of Subjects who are not Randomized ......................................36 
9.2 
Monitoring Subject Treatment Compliance.................................................................36 
9.3 
Schedule of Observations and Procedures ...................................................................37 
9.3.1 
Screening Visit (Day 1) ....................................................................................37 
9.3.2 
Annual Visits ....................................................................................................37 
9.3.3 
Final (End of Trial) Visit ..................................................................................37 
9.3.4 
Post-Trial Care ..................................................................................................37 
9.4 
Biological Sample Retention and Destruction .............................................................38 
10.0 
ADVERSE EVENTS .........................................................................................................39 
10.1 
Definitions....................................................................................................................39 
10.1.1 
Adverse Events .................................................................................................39 
0012
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use

Norovirus GI.1/GII.4 Bivalent VLP Vaccine 
 
Trial No. NOR-213 
Page 12 of 60 
Protocol Version 3.0 
27 March 2018 
 
 
10.1.2 
Solicited Adverse Events ..................................................................................39 
10.1.3 
Adverse Events of Special Interest ...................................................................39 
10.1.4 
Serious Adverse Events ....................................................................................39 
10.2 
Causality of AEs ..........................................................................................................40 
10.2.1 
Relationship to Trial Procedures .......................................................................40 
10.2.2 
Outcome of AEs ................................................................................................40 
10.3 
Additional Points to Consider for AEs ........................................................................41 
10.4 
Procedures ....................................................................................................................41 
10.4.1 
Collection and Reporting of AEs ......................................................................41 
10.4.2 
Collection and Reporting of Solicited AEs .......................................................42 
10.4.3 
Collection and Reporting of AESI ....................................................................42 
10.4.4 
Collection and Reporting of SAEs ....................................................................42 
10.5 
Follow-up Procedures ..................................................................................................43 
10.5.1 
AEs ....................................................................................................................43 
10.5.2 
SAEs .................................................................................................................43 
10.5.3 
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities
...........................................................................................................................43 
10.5.4 
Post-Trial Events ...............................................................................................43 
11.0 
TRIAL-SPECIFIC REQUIREMENTS .............................................................................44 
11.1 
Data Monitoring Committee ........................................................................................44 
12.0 
DATA HANDLING AND RECORD KEEPING .............................................................45 
12.1 
Electronic CRFs ...........................................................................................................45 
12.2 
Record Retention .........................................................................................................45 
13.0 
STATISTICAL METHODS ..............................................................................................47 
13.1 
Statistical and Analytical Plans ....................................................................................47 
13.1.1 
Analysis Sets .....................................................................................................47 
13.1.2 
Analysis of Demographics and Other Baseline Characteristics .......................47 
13.1.3 
Efficacy Analysis ..............................................................................................47 
13.1.4 
Immunogenicity Analysis .................................................................................47 
13.1.5 
Safety Analysis .................................................................................................48 
13.1.6 
Other Analyses ..................................................................................................48 
13.2 
Interim Analysis and Criteria for Early Termination ...................................................48 
13.3 
Determination of Sample Size .....................................................................................48 
14.0 
QUALITY CONTROL AND QUALITY ASSURANCE .................................................49 
14.1 
Trial-Site Monitoring Visits .........................................................................................49 
0013
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use

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Norovirus GI.1/GII.4 Bivalent VLP Vaccine 
 
Trial No. NOR-213 
Page 14 of 60 
Protocol Version 3.0 
27 March 2018 
 
 
2.0 
TRIAL SUMMARY 
Name of Sponsor: 
Takeda Vaccines, Inc. 
40 Landsdowne Street, 
Cambridge, MA 02139, 
USA 
Product Name: 
Norovirus GI.1/GII.4 Bivalent Virus-Like Particle (VLP) 
Vaccine 
Trial Title: A Phase 2, Long-Term Immunogenicity Follow-up Trial of Adult and Elderly Subjects who have 
Previously Received an Intramuscular Injection of Norovirus GI.1/GII.4 Bivalent Virus-Like Particle Vaccine. 
IND No.: 014421 
EudraCT No: 2016-004288-37 
Trial Identifier: NOR-213 
Phase: 2 
Trial Blinding Scheme: Not applicable 
Background and Rationale: 
Noroviruses have emerged as the single most significant cause of epidemic outbreaks of non-bacterial gastroenteritis 
worldwide. These outbreaks commonly result in significant morbidity and mortality in almost all age groups. Those 
most at risk are the elderly, the very young and immunocompromised individuals. 
Currently, no vaccine exists for protection against acute gastroenteritis (AGE) due to norovirus and treatment remains 
symptomatic. Human noroviruses are difficult to cultivate and so far, it has not been possible to develop a live 
attenuated or an inactivated norovirus vaccine. The investigational vaccine being developed by Takeda, norovirus 
genotypes GI.1/GII.4 bivalent virus-like particle (VLP) vaccine (NoV vaccine), contains GI.1 Norwalk Virus VLP 
and norovirus GII.4 consensus VLP which represents a consensus sequence of 3 GII.4 strains, as antigens. Norovirus 
VLPs are non-infectious because they do not contain viral ribonucleic acid but are immunogenic because they 
preserve particulate antigen conformation and structure that mimic the functional interactions of the virus with cellular 
receptors. The rationale for developing a bivalent vaccine is based on known epidemiology that both GI.1 and GII.4 
genotypes circulate and do not cross-protect in nature. The intramuscular (IM) NoV vaccine has been evaluated as 
different compositions of GI.1/GII.4 VLP adjuvanted with aluminum as aluminum hydroxide ([Al(OH)3]; adults and 
children) or Al(OH)3 combined with monophosphoryl lipid A (MPL) (adults). 
Safety and immunogenicity data are available from several Takeda trials in which subjects received at least 1 dose of 
a NoV vaccine composition under development. Data related to the primary objective of NOR-107 showed the 
optimal NoV vaccine composition among those evaluated, contains 15 µg GI.1 VLP, 50 µg GII.4 VLP, 500 µg 
aluminum as Al(OH)3 in adults. No clear benefit on vaccine immunogenicity was suggested from including 50 µg or 
15 µg MPL in the NoV vaccine formulation or from administering 2 doses 28 days apart. A single dose of 15 µg GI.1 
VLP, 50 µg GII.4 VLP, 500 µg aluminum as Al(OH)3 was tested in trial NOR-210, confirming a robust immune 
response up to 28 days after vaccination. The different compositions of the NoV vaccine have been well-tolerated, and 
have an acceptable safety profile. 
Completed or ongoing trials have included a safety and immunogenicity follow-up of maximum 1 year. NOR-213 is 
designed to capture data from adults and older adults previously vaccinated with NoV vaccine, providing the 
opportunity to evaluate long-term immunogenicity data up to 5 years following the first dose of NoV vaccine. Three 
trials have been selected for this purpose: NOR-107 (adults aged 18 to 64 years, 1 or 2 doses 11 compositions of 
GI.1/GII.4/MPL, 167 or 500 µg aluminum as Al(OH)3), NOR-210 (adults aged 18 to 49 years, 1 dose 15/50/0 µg 
GI.1/GII.4, 500 µg aluminum as Al(OH)3) and NOR-204 (adults aged 18 to 49 and ≥60 years, 1 or 2 doses 15/50/0 or 
15/50/15 µg GI.1/GII.4/MPL, 500 µg aluminum as Al(OH)3). Subjects who participated in trials NOR-107 and 
NOR-210 will enter NOR-213 during the 3rd and 2nd year post-vaccination, respectively. NOR-204 is ongoing, and 
subjects participating in NOR-213 will enter the trial during the 2nd year post-vaccination. The rationale for the 
selection of these trials is based on the opportunity to obtain long-term follow-up data for immunogenicity of the NoV 
vaccine in adult and elderly populations. 
0015
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Norovirus GI.1/GII.4 Bivalent VLP Vaccine 
 
Trial No. NOR-213 
Page 18 of 60 
Protocol Version 3.0 
27 March 2018 
 
 
Interim Analysis 
An IA will be performed after all subjects have provided one blood sample corresponding to at least their first year of 
participation in NOR-213 and the data for that trial segment have been sufficiently reviewed for accuracy and 
correctness. An interim report will be developed based on these data. 
The final clinical study report (CSR) will include the description of the immunogenicity results corresponding to up to 
5 years post-primary vaccination as well as safety data. The sponsor may consider terminating or amending the trial 
after review of the IA. 
Data Monitoring Committee: 
No trial-specific committee is planned for this trial. An overall data monitoring committee is established to evaluate 
overall safety of the Takeda NoV vaccine program on an ongoing basis. 
NOR-213 Version 3.0 (27 March 2018) 
 
0019
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use

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Norovirus GI.1/GII.4 Bivalent VLP Vaccine 
 
Trial No. NOR-213 
Page 20 of 60 
Protocol Version 3.0 
27 March 2018 
 
 
3.0 
TRIAL REFERENCE INFORMATION 
3.1 
Trial-Related Responsibilities 
The sponsor will perform all trial-related activities with the exception of those identified in the 
Trial-Related Responsibilities template. The identified vendors in the template for specific 
trial-related activities will perform these activities in full or in partnership with the sponsor. 
3.2 
Principal Investigator/Coordinating Investigator 
The sponsor will select a Signatory Principal Investigator/Coordinating Investigator from the 
investigators who participate in the trial. Selection criteria for this investigator will include 
significant knowledge of the trial protocol, the investigational vaccine used in the primary 
vaccination trials, their expertise in the therapeutic area and the conduct of clinical research as well 
as trial participation. The Signatory Principal Investigator/Coordinating Investigator will be 
required to review and sign the clinical study report (CSR) and by doing so agrees that it accurately 
describes the results of the trial. 
0021
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use

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Norovirus GI.1/GII.4 Bivalent VLP Vaccine 
 
Trial No. NOR-213 
Page 22 of 60 
Protocol Version 3.0 
27 March 2018 
 
 
SAP 
Statistical analysis plan 
SOC 
System organ class 
SUSAR 
Suspected unexpected serious adverse reaction 
VLP 
Virus-like particle 
0023
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use

Norovirus GI.1/GII.4 Bivalent VLP Vaccine 
 
Trial No. NOR-213 
Page 23 of 60 
Protocol Version 3.0 
27 March 2018 
 
 
3.4 
Corporate Identification 
TV 
Takeda Vaccines, Inc 
VBU 
Vaccine Business Unit 
 
0024
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use

Norovirus GI.1/GII.4 Bivalent VLP Vaccine 
 
Trial No. NOR-213 
Page 24 of 60 
Protocol Version 3.0 
27 March 2018 
 
 
4.0 
INTRODUCTION 
4.1 
Background 
Noroviruses have emerged as the single most significant cause of epidemic outbreaks of 
non-bacterial gastroenteritis worldwide [3, 4]. These outbreaks commonly result in significant 
morbidity and mortality in almost all age groups. Those most at risk are the elderly, the very young 
and immunocompromised individuals [5]. 
Currently, no vaccine exists for protection against acute gastroenteritis (AGE) due to norovirus 
and treatment remains symptomatic. Human noroviruses are difficult to cultivate and so far, it has 
not been possible to develop a live attenuated or an inactivated norovirus vaccine. The 
investigational vaccine being developed by Takeda, norovirus genotypes GI.1/GII.4 bivalent 
virus-like particle (VLP) vaccine (NoV vaccine), contains GI.1 Norwalk Virus VLP and norovirus 
GII.4 consensus VLP which represents a consensus sequence of 3 GII.4 strains, as antigens. 
Norovirus VLPs are non-infectious because they do not contain viral ribonucleic acid but are 
immunogenic because they preserve particulate antigen conformation and structure that mimic the 
functional interactions of the virus with cellular receptors. The rationale for developing a bivalent 
vaccine is based on known epidemiology that both GI.1 and GII.4 genotypes circulate and do not 
cross-protect in nature. The intramuscular (IM) NoV vaccine has been evaluated as different 
compositions of GI.1/GII.4 VLP adjuvanted with aluminum as aluminum hydroxide [Al(OH)3] 
(adults and children) or Al(OH)3 combined with monophosphoryl lipid A (MPL) (adults). 
Safety and immunogenicity data are available from several Takeda trials in which subjects 
received at least 1 dose of a NoV vaccine composition under development [6-8]. Data related to the 
primary objective of NOR-107 showed the optimal NoV vaccine composition among those 
evaluated, contains 15 µg GI.1 VLP, 50 µg GII.4 VLP, 500 µg aluminum as Al(OH)3 in adults. No 
clear benefit on vaccine immunogenicity was suggested from including 50 µg or 15 µg MPL in the 
NoV vaccine formulation or from administering 2 doses 28 days apart. A single dose of 15 µg 
GI.1 VLP, 50 µg GII.4 VLP, 500 µg aluminum as Al(OH)3 was tested in trial NOR-210, 
confirming a robust immune response up to 28 days after vaccination. 
The different compositions of the NoV vaccine have been well-tolerated, and have an acceptable 
safety profile. 
Refer to the current IB for further information [9]. 
The trial will be conducted in accordance with the protocol, ICH-GCP Guidelines, and applicable 
regulatory requirements. 
4.2 
Rationale for the Proposed Trial 
Completed or ongoing trials have included a safety and immunogenicity follow-up of maximum 
1 year. NOR-213 is designed to capture data from adults and older adults previously vaccinated 
with NoV vaccine, providing the opportunity to evaluate long-term immunogenicity data up to 
5 years following the first dose of NoV vaccine. Three trials have been selected for this purpose: 
NOR-107 (adults aged 18 to 64 years, 1 or 2 doses 11 compositions of GI.1/GII.4/MPL, 167 or 
0025
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use

Norovirus GI.1/GII.4 Bivalent VLP Vaccine 
 
Trial No. NOR-213 
Page 25 of 60 
Protocol Version 3.0 
27 March 2018 
 
 
500 µg aluminum as Al(OH)3), NOR-210 (adults aged 18 to 49 years, 1 dose 15/50/0 µg 
GI.1/GII.4, 500 µg aluminum as Al(OH)3) and NOR-204 (adults aged 18 to 49 and ≥60 years, 1 or 
2 doses 15/50/0 or 15/50/15 µg GI.1/GII.4/MPL, 500 µg aluminum as Al(OH)3). Subjects who 
participated in trials NOR-107 and NOR-210 will enter NOR-213 during the 3rd and 2nd year 
post-vaccination, respectively. NOR-204 is ongoing, and subjects participating in NOR-213 will 
enter the trial during the 2nd year post-vaccination. The rationale for the selection of these trials is 
based on the opportunity to obtain long-term follow-up data for immunogenicity of the NoV 
vaccine in adult and elderly populations. 
This trial will be conducted in accordance with the protocol, ICH-GCP Guidelines and applicable 
regulatory requirements. 
0026
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use

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and 

Norovirus GI.1/GII.4 Bivalent VLP Vaccine 
 
Trial No. NOR-213 
Page 29 of 60 
Protocol Version 3.0 
27 March 2018 
 
 
Figure 6.a 
Schematic of Trial Design 
 
6.2 
Justification for Trial Design, Dose, and Endpoints 
Subjects who participated in trials NOR-107, NOR-210 and NOR-204 will have already reached 
1 year or more post-primary vaccination with NoV vaccine at the time of trial NOR-213 start. 
The endpoints defined for this trial aim to provide data on persistence of the immune response for 
up to 5 years following the administration of NoV vaccine. 
Please refer to the IB [9]. 
6.3 
Planned Duration of Subject’s Expected Participation in the Entire Trial 
The total estimated duration of trial participation is approximately 2 years for subjects who 
previously participated in NOR-107. 
The total estimated duration of trial participation is approximately 3 years for subjects who 
previously participated in NOR-210 and NOR-204. 
6.4 
Premature Termination or Suspension of Trial or Investigational Site 
6.4.1 Criteria for Premature Termination or Suspension of the Trial 
The trial will be completed as planned unless 1 or more of the following criteria are satisfied that 
require temporary suspension or early termination of the trial: 
 Significant deviation from GCP that compromises the ability to achieve the primary 
vaccination trial objectives or compromises subject safety. 
0030
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Norovirus GI.1/GII.4 Bivalent VLP Vaccine 
 
Trial No. NOR-213 
Page 30 of 60 
Protocol Version 3.0 
27 March 2018 
 
 
6.4.2 Criteria for Premature Termination or Suspension of Investigational Sites 
A trial site may be terminated prematurely or suspended if the site (including the investigator) is 
found in significant deviation from GCP, protocol, or contractual agreement, is unable to ensure 
adequate performance of the trial, or as otherwise permitted by the contractual agreement. 
6.4.3 Procedures for Premature Termination or Suspension of the Trial or the 
Participation of Investigational Sites 
In the event that the sponsor, an institutional review board (IRB)/independent ethics committee 
(IEC) or regulatory authority elects to terminate or suspend the trial or the participation of an 
investigational site, a trial-specific procedure for early termination or suspension will be provided 
by the sponsor; the procedure will be followed by applicable investigational sites during the course 
of termination or trial suspension. 
0031
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Norovirus GI.1/GII.4 Bivalent VLP Vaccine 
 
Trial No. NOR-213 
Page 31 of 60 
Protocol Version 3.0 
27 March 2018 
 
 
7.0 
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS 
All entry criteria need to be confirmed prior to performing any trial procedure. 
7.1 
Inclusion Criteria 
Subject eligibility is determined according to the following criteria: 
1. The subject is aged over 18 years. 
2. Male and female subjects who previously received at least 1 dose of NoV vaccine in trials 
NOR-107, NOR-210 and NOR-204, have baseline and post-vaccination data, and completed 
the primary vaccination trial protocol as initially described. 
3. The subject signs and dates a written, informed consent form (ICF) and any required privacy 
authorization prior to the initiation of any trial procedures, after the nature of the trial has been 
explained according to local regulatory requirements (Appendix B). 
4. Individuals who can comply with trial procedures and are available for the duration of 
follow-up. 
7.2 
Exclusion Criteria 
Any subject who meets any of the following criteria will not qualify for entry into the trial: 
1. Participation in any clinical trial is allowed, on condition that no investigational product is 
administered within 30 days prior to blood sampling. 
2. In the opinion of the investigator, the subject is not medically eligible to provide blood 
specimens. 
3. Individuals with behavioral or cognitive impairment or psychiatric disease that, in the opinion 
of the investigator, may interfere with the subject’s ability to participate in the trial. 
There may be instances when individuals meet all entry criteria except one that relates to transient 
clinical circumstances (eg, temperature elevation or recent vaccine). Under these circumstances, 
eligibility for trial enrollment may be considered if the appropriate window for delay has passed, 
inclusion/exclusion criteria have been rechecked, and if the subject is confirmed to be eligible. 
7.3 
Criteria for Delay of Blood Sampling 
After enrollment, subjects may encounter clinical circumstances that warrant a delay in blood 
sampling. 
1. Individuals who received any other vaccines within 14 days (for inactivated vaccines) or 
28 days (for live vaccines) prior to blood sampling. 
2. In the event that a subject meets a criterion for delay of blood sampling, the subject may 
undergo this procedure once the window for delay has passed as long as the subject is 
otherwise eligible for trial participation. 
0032
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Norovirus GI.1/GII.4 Bivalent VLP Vaccine 
 
Trial No. NOR-213 
Page 32 of 60 
Protocol Version 3.0 
27 March 2018 
 
 
7.4 
Criteria for Early Trial Termination of a Subject’s Trial Participation 
Under some circumstances, a subject’s trial participation may be terminated early. This means that 
no further trial procedures (including data collection) will be performed on that subject beyond the 
specific date of early termination. The primary reason for early termination of the subject from the 
trial should be recorded in the subject’s electronic case report form (eCRF “end of study visit” 
page) using the following categories. For screen failure subjects, refer to Section 9.1.11. 
1. Adverse Event (AE): The subject has experienced an AE (irrespective of being 
related/unrelated to the Trial Vaccine administered during the primary vaccination trial or 
trial-related procedures during NOR-213) that requires early termination because continued 
participation imposes an unacceptable risk to the subject’s health and/or the subject is 
unwilling to continue participation because of the AE. If the subject is unwilling to continue 
because of the AE, the primary reason for early termination in this case will be ‘withdrawal due 
to AE’ and not ‘withdrawal of consent’, see below. Any ongoing AEs leading to early 
termination should be followed by the investigator until resolution or stabilization. 
2. Lost to follow-up: The subject did not return to the clinic and at least 3 attempts to contact the 
subject were unsuccessful. Attempts to contact the subject must be documented. 
3. Withdrawal of consent: The subject wishes to withdraw from the trial. The primary reason for 
early termination will be ‘withdrawal of consent” if the subject withdraws from participation 
due to a non-medical reason (ie, reason other than AE). The reason for withdrawal, if provided, 
should be recorded in the subject’s eCRF. 
Note: All attempts should be made to determine the underlying reason for the withdrawal and, 
where possible, the primary underlying reason should be recorded. 
4. Premature trial termination by the sponsor, a regulatory agency, the IRB/IEC, or any other 
authority. 
If the clinical trial is prematurely terminated by the sponsor, the investigator is to promptly 
inform the trial subjects and local IRB/IEC and should assure appropriate follow-up for the 
subjects according to Section 10.5.4. The primary reason for early termination in this case will 
be ‘trial termination”. 
5. Subject’s death during trial participation. 
6. Other. 
Note: The specific reasons should be recorded in the “specify” field of the subject’s eCRF. 
0033
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Norovirus GI.1/GII.4 Bivalent VLP Vaccine 
 
Trial No. NOR-213 
Page 33 of 60 
Protocol Version 3.0 
27 March 2018 
 
 
8.0 
CLINICAL TRIAL MATERIAL MANAGEMENT 
No trial vaccine will be administered during this trial. 
8.1 
Dosages Administered During the Primary Vaccination Trials 
The NoV vaccine dosages administered during the selected primary vaccination trials are listed in 
the following sections. Details on manufacturing, packaging, labeling and storage are provided in 
the individual protocols. 
8.1.1 NOR-107 [NCT 02038907] 
Trial title: A phase 2, randomized, controlled, double-blind, dosage and adjuvant justification, 
safety and immunogenicity trial of IM NoV vaccine adjuvanted with aluminum as Al(OH)3 and 
with or without MPL in adults. 
Subjects aged 18 to 64 years inclusive (stratified as 18 to 49 years and 50 to 64 years) received 
either 1 dose of NoV vaccine or 2 doses of NoV vaccine by IM injection, 28 days apart. In order to 
remain blinded and to have the same trial time points with both dosing regimens, subjects 
randomized to the one-dose treatment arms received a dose of hepatitis A vaccine (Havrix®, 
manufactured by GSK) followed by a dose of NoV vaccine 28 days later (Table 8.a). 
Table 8.a 
Identity of Trial Vaccines – NOR-107 
Trial Vaccine/Arm 
Vaccine Dose 
MPL 
Route of Administration 
Route 
Timing 
GI.1-VLP (µg) 
GII.4 VLP (µg) 
NoV vaccine(a)/ Arm 1 
15 
15 
50 
IM 
Day 28 
NoV vaccine(a)/ Arm 2 
15 
50 
50 
IM 
Day 28 
NoV vaccine(a)/ Arm 3 
50 
50 
50 
IM 
Day 28 
NoV vaccine(a)/ Arm 4 
15 
15 
15 
IM 
Day 28 
NoV vaccine(a)/ Arm 5 
15 
50 
15 
IM 
Day 28 
NoV vaccine(a)/ Arm 6 
50 
50 
15 
IM 
Day 28 
NoV vaccine(a)/ Arm 7 
15 
15 
0 
IM 
Day28 
NoV vaccine(a)/ Arm 8 
15 
50 
0 
IM 
Days 1, Day 28 
NoV vaccine(a)/ Arm 9 
50 
50 
0 
IM 
Day 28 
NoV vaccine(a)/ Arm 10 
50 
150 
0 
IM 
Days 1, Day 28 
NoV vaccine(a)/ Arm 11 
15 
50 
0 
IM 
Days 1, Day 28 
One-dose groups 
Havrix® 
- 
IM 
Day 1 (1-dose arms) 
(a) Investigational vaccine for formulation arms 1 to 10 contained 500 µg aluminum as Al(OH)3. For formulation arm 
11, the investigational vaccine contained approximately 1/3 the aluminum content of the other arms (167 µg). 
Havrix® was administered as the first dose for the 1-dose arms in order to maintain the blind. 
0034
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Norovirus GI.1/GII.4 Bivalent VLP Vaccine 
 
Trial No. NOR-213 
Page 34 of 60 
Protocol Version 3.0 
27 March 2018 
 
 
8.1.2 NOR-210 [NCT 02475278] 
Trial title: Phase 2, single arm, open-label trial for serologic assay validation, proficiency testing, 
safety and immunogenicity of the IM NoV vaccine. 
Subjects aged 18 to 49 years provided a pre-vaccination blood sample (to evaluate baseline 
norovirus antibody titers) and were vaccinated with a single dose of the NoV vaccine occurred on 
Day 1 (Table 8.b). 
Table 8.b 
Identity of Trial Vaccines – NOR-210 
Trial Vaccine 
Vaccine Dose  
Route of Administration 
GI.1 NoV VLP 
GII.4 NoV VLP 
Aluminum as Al(OH)3 
NoV Vaccine 
15 μg 
50 μg 
500 μg 
IM 
NoV Vaccine = Norovirus vaccine. 
8.1.3 NOR-204 [NCT 02661490] 
Trial title: A phase 2, randomized, double-blind, safety and immunogenicity trial of NoV vaccine 
in healthy elderly adults. 
Subjects aged 18 to 49 and ≥60 years received either 1 dose of saline (placebo) control on Day 1 
and 1 dose of NoV vaccine (composition A or composition B) or 2 doses of NoV vaccine 
(composition A or composition B) by IM injection, 28 days apart. In order to remain blinded and to 
have the same trial time points with both dosing regimens, subjects randomized to the one-dose 
treatment arms received a dose of saline (placebo) control followed by a dose of NoV vaccine 28 
days later (Table 8.c). 
Table 8.c 
Identity of Trial Vaccines – NOR-204 
Age groups (years) 
Day 1 
Day 29 
Route of 
Administration 
18–49 
Saline Placebo 
Composition A 
IM 
60–74 
Saline Placebo 
Composition A 
IM 
Composition A 
Composition A 
IM 
Saline Placebo 
Composition B 
IM 
Composition B 
Composition B 
IM 
75–84  
Saline Placebo 
Composition A 
IM 
Composition A 
Composition A 
IM 
Saline Placebo 
Composition B 
IM 
Composition B 
Composition B 
IM 
≥85 
Saline Placebo 
Composition A 
IM 
Composition A  
Composition A 
IM 
Saline Placebo 
Composition B 
IM 
Composition B  
Composition B 
IM 
Composition A: 15 μg of GI.1 norovirus VLP; 50 μg of GII.4 norovirus VLP, 500 µg Al(OH)3. 
Composition B: 15 μg of GI.1 norovirus VLP; 50 μg of GII.4 norovirus VLP, 500 µg Al(OH)3, 15 μg of MPL. 
0035
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Norovirus GI.1/GII.4 Bivalent VLP Vaccine 
 
Trial No. NOR-213 
Page 35 of 60 
Protocol Version 3.0 
27 March 2018 
 
 
9.0 
TRIAL PLAN 
9.1 
Trial Procedures 
The following sections describe the trial procedures and data to be collected. For each procedure, 
subjects are to be assessed by the same investigator or site personnel whenever possible. The 
Schedule of Trial Procedures is located in Section 2.1. 
9.1.1 Informed Consent 
The requirements of the ICF are described in Section 15.2. 
Informed consent must be obtained prior to the subject entering into the trial, and before any 
protocol-directed procedures are performed. 
9.1.2 Documentation of Trial Entrance 
Only subjects who have a signed ICF, meet all of the inclusion criteria and none of the exclusion 
criteria are eligible for entrance into the trial. 
After informed consent is obtained, each subject will be identified with the same unique subject 
number allocated for the primary vaccination trial. There is no randomization. If all eligibility 
criteria are fulfilled, this subject number will be used throughout the trial. If a subject is found to be 
not eligible for the trial phase, the Investigator should record the primary reason for failure on the 
screening log and the subject number assigned to subjects who fail screening will not be reused, 
and the screen failure eCRF should be completed. 
9.1.3 Demographics, Medical History and Prior Medications 
Demographic information to be obtained includes age, sex and race/ethnicity. 
Medical History will be collected at trial entry, including but not limited to any medical history 
that may be relevant to subject eligibility for trial participation such as prior vaccinations, 
concomitant medications, and previous and ongoing illnesses or injuries. Relevant medical history 
can also include any medical history that contributes to the understanding of an AE that occurs 
during trial participation, if it represents an exacerbation of an underlying disease/preexisting 
problem. 
Assess and record concomitant therapy (prescription medications ONLY) and vaccine history 
from 1 month prior to Day 1 in the subject’s eCRF. 
Medical history (including corresponding medication) to be obtained will include any significant 
conditions or diseases that have disappeared or resolved at, or prior to, signing of the ICF. 
9.1.4 Physical Examination 
Physical examination will not be performed during this trial. 
0036
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ercial Us

Norovirus GI.1/GII.4 Bivalent VLP Vaccine 
 
Trial No. NOR-213 
Page 38 of 60 
Protocol Version 3.0 
27 March 2018 
 
 
9.4 
Biological Sample Retention and Destruction 
In this trial, specimens for immune response testing will be collected as described in Section 9.1.6. 
After blood draw and processing, the serum and PBMC samples will be preserved and retained at a 
central laboratory that was contracted by the sponsor for this purpose for up to but not longer than 
20 years or as required by applicable law. The sponsor has put into place a system to protect the 
subjects’ personal information to ensure optimal confidentiality and defined standard processes for 
sample and data collection, storage, analysis, and destruction. 
Serum and PBMC samples will be used for the analyses defined in this protocol, but can also, with 
permission from the subject, be used to assess, improve or develop tests related to the norovirus 
AGE or the NoV vaccine under trial that will allow more reliable measurement of the response to 
the NoV vaccine. 
0039
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Norovirus GI.1/GII.4 Bivalent VLP Vaccine 
 
Trial No. NOR-213 
Page 39 of 60 
Protocol Version 3.0 
27 March 2018 
 
 
10.0 
ADVERSE EVENTS 
10.1 
Definitions 
10.1.1 Adverse Events 
An AE is defined as any untoward medical occurrence in a clinical investigation subject 
administered a trial vaccine; it does not necessarily have to have a causal relationship with trial 
vaccine administration. 
An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal 
laboratory finding), symptom, or disease temporally associated with the administration of a trial 
vaccine whether or not it is considered related to the trial vaccine. 
AEs will be graded by the investigator in the following manner: 
Mild 
Grade 1 
 Awareness of symptoms that are easily tolerated, causing minimal 
discomfort and not interfering with everyday activities. Relieved with 
or without symptomatic treatment. 
Moderate Grade 2 
 Sufficient discomfort is present to cause interference with normal 
activity. Only partially relieved with symptomatic treatment. 
Severe 
Grade 3 
 Extreme distress, causing significant impairment of functioning or 
incapacitation. Prevents normal everyday activities. Not relieved with 
symptomatic treatment 
10.1.2 Solicited Adverse Events 
Not applicable to this trial – no vaccine administered. 
10.1.3 Adverse Events of Special Interest 
Not collected. 
10.1.4 Serious Adverse Events 
An SAE is defined as any untoward medical occurrence that: 
1. Results in DEATH. 
2. Is LIFE THREATENING. 
 The term “life threatening” refers to an event in which the subject was at risk of death at the 
time of the event; it does not refer to an event that hypothetically might have caused death 
if it were more severe. 
3. Requires inpatient HOSPITALIZATION or prolongation of existing hospitalization. 
4. Results in persistent or significant DISABILITY/INCAPACITY. 
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5. Leads to a CONGENITAL ANOMALY/BIRTH DEFECT in the offspring of a subject. 
6. Is an IMPORTANT MEDICAL EVENT that satisfies any of the following: 
 May require intervention to prevent items 1 through 5 above. 
 May expose the subject to danger, even though the event is not immediately life 
threatening or fatal or does not result in hospitalization. 
10.2 
Causality of AEs 
Relatedness (causality) to vaccine will also be assessed by the investigator. The relationship of 
each AE, will be assessed using the following categories: 
Related: 
There is suspicion that there is a relationship between the trial vaccine and the 
AE (without determining the extent of probability); there is a reasonable 
possibility that the trial vaccine contributed to the AE. 
Not Related: 
There is no suspicion that there is a relationship between the trial vaccine and the 
AE; there are other more likely causes and administration of the trial vaccine is 
not suspected to have contributed to the AE. 
10.2.1 Relationship to Trial Procedures 
Relationship (causality) to trial procedures should be determined for all AEs. 
The relationship should be assessed as “Yes” if the investigator considers that there is reasonable 
possibility that an event is due to a trial procedure. Otherwise, the relationship should be assessed 
as “No”. 
10.2.2 Outcome of AEs 
Resolved: 
The subject has fully recovered from the event or the condition has 
returned to the level observed at baseline 
Resolving: 
The event is improving but the subject is still not fully recovered 
Not resolved: 
The event is ongoing at the time of reporting and the subject has still not 
recovered 
Resolved with 
sequelae: 
As a result of the AE, the subject suffered persistent and significant 
disability/incapacity (eg, became blind, deaf or paralysed) 
Fatal: 
The subject died due to the event. If the subject died due to other 
circumstances than the event, the outcome of the event per se should be 
stated otherwise (eg, Not Resolved or Resolving) 
Unknown: 
If outcome is not known or not reported. 
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10.3 
Additional Points to Consider for AEs 
An untoward occurrence generally may: 
 Indicate a new diagnosis or unexpected worsening of a pre-existing condition. Intermittent 
events for pre-existing conditions or underlying disease should not be considered as AEs. 
 Necessitate therapeutic intervention. 
 Require an invasive diagnostic procedure. 
 Be considered unfavorable by the investigator for any reason. 
Diagnoses vs. signs and symptoms: 
 Each event should be recorded to represent a single diagnosis. Accompanying signs (including 
abnormal laboratory values) or symptoms should NOT be recorded as additional AEs. If a 
diagnosis is unknown, signs or symptoms should be recorded appropriately as AEs. 
Changes in severity of AEs: 
 If the subject experiences changes in severity of an AE, the event should be captured once with 
the maximum severity recorded. 
Preplanned surgeries or procedures: 
 Preplanned procedures (surgeries or therapies) that were scheduled prior to signing of ICF are 
not considered AEs. Complications resulting from any planned surgery should be reported as 
AEs. 
Elective surgeries or procedures: 
 Elective procedures performed where there is no change in the subject’s medical condition 
should not be recorded as AEs, but should be documented in the subject’s source documents. 
Complications resulting from an elective surgery should be reported as AEs. 
10.4 
Procedures 
10.4.1 Collection and Reporting of AEs 
All AEs, whether or not considered related to the use of the trial vaccine administered during the 
primary vaccination trial or a trial procedure, must be monitored until symptoms subside and any 
abnormal laboratory values have returned to baseline, or until there is a satisfactory explanation for 
the changes observed, or until death, in which case a full pathologist’s report should be supplied, if 
possible. For this trial, recording of AEs in the subject’s eCRF is limited to fatal and life 
threatening SAEs, NoV vaccine-related SAEs, potential immune–mediated events of medical 
significance and any procedure-related medical occurrences and must be recorded in the subject’s 
source documents. 
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The following information will be documented for each event: 
 Reported term for the AE, 
 Start and end date, 
 Serious (Y/N), 
 Severity, 
 Investigator’s opinion of the causality (relationship) between the event and administration of 
trial vaccine during the primary vaccination trial (“related” or “not related”), 
 Investigator’s opinion of the causality (relationship) to trial procedure(s), including the details 
of the suspected procedure, 
 Outcome of event. 
10.4.2 Collection and Reporting of Solicited AEs 
Not applicable to this trial – no vaccine administered. 
10.4.3 Collection and Reporting of AESI 
Not applicable. 
10.4.4 Collection and Reporting of SAEs 
Collection of SAEs will commence from the time that the subject enters trial NOR-213 (Day 1), 
following signature of the ICF. Routine collection of SAEs will continue until the end of the trial 
(Year 5). 
SAEs should be reported according to the following procedure: 
A sponsor SAE form must be completed, in English, and signed by the investigator immediately or 
within 24 hours of first onset or notification of the event. The information should be completed as 
fully as possible but contain, at a minimum: 
 A short description of the event and the reason why the event is categorized as serious. 
 Subject identification number. 
 Investigator’s name. 
 Name of the trial vaccine administered during the primary vaccination trial. 
 Causality assessment. 
The SAE form should be transmitted within 24 hours to the attention of the contact(s) in the list 
provided to each site. 
Note: (1) For this trial, SAE reporting will be done by eCRF. If the Electronic Data Capture (EDC) 
system is unavailable, a paper Sponsor SAE form/paper CRF should be completed and the event 
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must be entered into the EDC once access is available. (2) For this trial, recording of SAEs in the 
subject’s eCRF is limited to fatal and life threatening SAEs, NoV vaccine-related SAEs, potential 
immune–mediated events of medical significance and any procedure-related medical occurrences 
and must be recorded in the subject’s source documents. 
10.5 
Follow-up Procedures 
10.5.1 AEs 
All AEs will be monitored until resolution or a stable status is reached or until a formal diagnosis 
can be made or until the end of the trial, whichever occurs first. Ongoing SAEs could potentially 
be followed outside of this trial or in a planned extension trial. 
10.5.2 SAEs 
If information not available at the time of the first report becomes available at a later date, the 
investigator should complete a follow-up SAE form or provide other written documentation and 
fax it immediately within 24 hours of receipt. Copies of any relevant data from the hospital notes 
(eg, laboratory tests, discharge summary, postmortem results) should be sent to the sponsor. 
All SAEs should be followed up until resolution or permanent outcome of the event or is otherwise 
explained. The timelines and procedure for follow-up reports are the same as those for the initial 
report. 
10.5.3 Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities 
The sponsor or designee will be responsible for the reporting of all suspected unexpected serious 
adverse reactions (SUSARs) and any other applicable SAEs to regulatory authorities, investigators 
and IRBs or IECs, as applicable, in accordance with national regulations in the countries where the 
trial is conducted. Relative to the first awareness of the event by/or further provision to the sponsor 
or sponsor’s designee, SUSARs will be submitted within 7 days for fatal and life-threatening 
events and 15 days for other SUSARs, unless otherwise required by national regulations. The 
sponsor will also prepare an expedited report for other safety issues where these might materially 
alter the current benefit-risk assessment of an investigational medicinal product or that would be 
sufficient to consider changes in the trial vaccine administration or in the overall conduct of the 
trial. The investigational site also will forward a copy of all expedited reports to their IRB or IEC 
in accordance with national regulations. 
10.5.4 Post-Trial Events 
Any SAE that occurs outside of the protocol-specified observation period or after the end of the 
trial but considered to be caused by the trial vaccine administered during the primary vaccination 
trial must be reported to the sponsor. These SAEs will be processed by the sponsor’s 
Pharmacovigilance Department. Instructions for how to submit these SAEs will be provided in a 
handout in the Investigator Site File. 
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11.0 
TRIAL-SPECIFIC REQUIREMENTS 
There are no trial-specific requirements or committees for this trial. 
11.1 
Data Monitoring Committee 
An overall data monitoring committee is established to evaluate overall safety of the Takeda NoV 
vaccine program on an ongoing basis. 
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12.0 
DATA HANDLING AND RECORD KEEPING 
The full details of procedures for data handling will be documented in the Data Management Plan. 
AEs, medical history, and concurrent conditions will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA system organ class [SOC], high level group term, high level 
term, low level term, preferred term [PT], and their corresponding descriptive terms). Drugs will 
be coded using the World Health Organization Drug Dictionary. 
12.1 
Electronic CRFs 
Completed eCRFs are required for each subject who provides a signed ICF. 
The sponsor or its designee will supply investigative sites with access to eCRFs. The sponsor will 
make arrangements to train appropriate site staff in the use of the eCRF. These forms are used to 
transmit the information collected in the performance of this trial to the sponsor and regulatory 
authorities. eCRFs must be completed in English. 
After completion of the entry process, computer logic checks will be run to identify items, such as 
inconsistent dates, missing data, and questionable values. Queries may be issued by sponsor 
personnel (or designees) and will be answered by the site. 
Corrections to eCRFs are recorded in an audit trail that captures the old information, the new 
information, identification of the person making the correction, the date the correction was made, 
and the reason for change. 
The principal investigator or designee must review the eCRFs for completeness and accuracy and 
must sign and date the appropriate eCRFs as indicated. Furthermore, the investigator must retain 
full responsibility for the accuracy and authenticity of all data entered on the eCRFs. 
eCRFs will be reviewed for completeness and acceptability at the trial site during periodic visits by 
trial monitors. The sponsor or its designee will be permitted to review the subject’s medical and 
hospital records pertinent to the trial to ensure accuracy of the eCRFs. The completed eCRFs are 
the sole property of the sponsor and should not be made available in any form to third parties, 
except for authorized representatives of appropriate governmental health or regulatory authorities, 
without written permission of the sponsor. 
12.2 
Record Retention 
The investigator agrees to keep the records stipulated in Section 12.0 and those documents that 
include (but are not limited to) the trial-specific documents, the identification log of all 
participating subjects, medical records. Temporary media such as thermal sensitive paper should 
be copied and certified, source worksheets, all original signed and dated ICFs, subject 
authorization forms regarding the use of personal health information (if separate from the ICFs), 
electronic copy of eCRFs, including the audit trail, and detailed records of vaccine disposition to 
enable evaluations or audits from regulatory authorities, the sponsor or its designees. Furthermore, 
ICH E6 Section 4.9.5 requires the investigator to retain essential documents specified in ICH E6 
(Section 8) until at least 2 years after the last approval of a marketing application for a specified 
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vaccine indication being investigated or, if an application is not approved, until at least 2 years 
after the investigation is discontinued and regulatory authorities are notified. In addition, ICH E6 
Section 4.9.5 states that the trial records should be retained until an amount of time specified by 
applicable regulatory requirements or for a time specified in the Clinical Study Site Agreement 
between the investigator and sponsor. 
Refer to the Clinical Study Site Agreement for the sponsor’s requirements on record retention. The 
investigator should contact and receive written approval from the sponsor before disposing of any 
such documents. 
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13.1.5 Safety Analysis 
The FAS will be used for all safety analyses. 
Fatal and life threatening SAEs, NoV vaccine-related SAEs, potential immune–mediated events of 
medical significance and any procedure-related medical occurrences will be coded using the 
MedDRA and summarized by SOC and PT by each primary vaccination trial. Details for 
summarizing or listing these events will be provided in the SAP. 
13.1.6 Other Analyses 
Not applicable. 
13.2 
Interim Analysis and Criteria for Early Termination 
An IA will be performed after all subjects have provided one blood sample corresponding to at 
least their first year of participation in NOR-213 and the data for that trial segment have been 
sufficiently reviewed for accuracy and correctness. An interim report will be developed based on 
these data. The final CSR will include the description of the immunogenicity results corresponding 
to up to 5 years post-primary vaccination as well as safety data. The sponsor may consider 
terminating or amending the trial after review of the IA. 
13.3 
Determination of Sample Size 
This trial is descriptive and will only enroll subjects who previously received at least 1 dose of 
NoV vaccine, have baseline and post-vaccination data, and completed the primary vaccination 
trial according to protocol. Sample size will not be determined based on formal statistical power 
calculations. 
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14.0 
QUALITY CONTROL AND QUALITY ASSURANCE 
14.1 
Trial-Site Monitoring Visits 
Monitoring visits to the trial site will be made periodically during the trial to ensure that all aspects 
of the protocol are followed. Source documents will be reviewed for verification of data recorded 
on the eCRFs. Source documents are defined as original documents, data, and records. The 
investigator and institution guarantee access to source documents by the sponsor or its designee 
contract research organization and by the IRB or IEC. 
All aspects of the trial and its documentation will be subject to review by the sponsor or designee, 
including but not limited to the Investigator’s Binder, subject medical records, ICF documentation, 
documentation of subject authorization to use personal health information (if separate from the 
ICFs), and review of eCRFs and associated source documents. It is important that the investigator 
and other trial personnel are available during the monitoring visits and that sufficient time is 
devoted to the process. 
14.2 
Protocol Deviations 
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to trial subjects. Should other unexpected circumstances arise that will require 
deviation from protocol-specified procedures, the investigator should consult with the medical 
monitor (and IRB or IEC, as required) to determine the appropriate course of action. There will be 
no exemptions (a prospective approved deviation) from the inclusion or exclusion criteria. 
14.3 
Quality Assurance Audits and Regulatory Agency Inspections 
The trial site also may be subject to quality assurance audits by the sponsor or designees. In this 
circumstance, the sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the vaccine is stored and prepared, and any other facility used during the trial. In addition, 
there is the possibility that this trial may be inspected by regulatory agencies, including those of 
foreign governments (eg, the Food and Drug Administration [FDA], the United Kingdom 
Medicines and Healthcare products Regulatory Agency [MHRA], the Pharmaceuticals and 
Medical Devices Agency [PMDA] of Japan). If the trial site is contacted for an inspection by a 
regulatory body, the sponsor should be notified immediately. The investigator and institution 
guarantee access for quality assurance auditors to all trial documents as described in Section 14.1. 
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15.0 
ETHICAL ASPECTS OF THE TRIAL 
This trial will be conducted with the highest respect for the individual participants (ie, subjects) 
according to the protocol, the ethical principles that have their origin in the Declaration of 
Helsinki, and the ICH-GCP guidelines. Each investigator will conduct the trial according to 
applicable local or regional regulatory requirements and align his or her conduct in accordance 
with the “Responsibilities of the Investigator” that are listed in Appendix A. The principles of 
Helsinki are addressed through the protocol and through appendices containing requirements for 
informed consent and investigator responsibilities. 
15.1 
IRB and/or IEC Approval 
IRBs and IECs must be constituted according to the applicable local requirements of each 
participating region. The sponsor or designee will require documentation noting all names and 
titles of members who make up the respective IRB or IEC. If any member of the IRB or IEC has 
direct participation in this trial, written notification regarding his or her abstinence from voting 
must also be obtained. Those US sites unwilling to provide names and titles of all members due to 
privacy and conflict of interest concerns should instead provide a Federal Wide Assurance 
Number or comparable number assigned by the Department of Health and Human Services. 
The sponsor or designee will supply relevant documents for submission to the respective IRB or 
IEC for the protocol’s review and approval. This protocol, the IB, a copy of the ICF, and, if 
applicable, subject recruitment materials and/or advertisements and other documents required by 
all applicable laws and regulations, must be submitted to a central or local IRB or IEC for 
approval. The IRB’s or IEC’s written approval of the protocol and subject ICF must be obtained 
and submitted to the sponsor or designee before commencement of the trial (ie, before trial specific 
screening activity). The IRB or IEC approval must refer to the trial by exact protocol title, number, 
and version date; identify versions of other documents (eg, ICF) reviewed; and state the approval 
date. The sponsor will notify the site once the sponsor has confirmed the adequacy of site 
regulatory documentation and, when applicable, the sponsor has received permission from the 
competent authority to begin the trial. Until the site receives notification no protocol activities, 
including screening may occur. 
Sites must adhere to all requirements stipulated by their respective IRB or IEC. This may include 
notification to the IRB or IEC regarding protocol amendments, updates to the ICF, recruitment 
materials intended for viewing by subjects, local safety reporting requirements, reports and 
updates regarding the ongoing review of the trial at intervals specified by the respective IRB or 
IEC, and submission of the investigator’s final status report to IRB or IEC. All IRB and IEC 
approvals and relevant documentation for these items must be provided to the sponsor or its 
designee. 
Subject incentives should not exert undue influence for participation. Payments to subjects must 
be approved by the IRB or IEC and sponsor. 
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15.2 
Subject Information, Informed Consent and Subject Authorization 
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH-GCP Guidelines and will be in accordance with all applicable 
laws and regulations. The ICF, subject authorization form (if applicable), and subject information 
sheet (if applicable) describe the planned and permitted uses, transfers, and disclosures of the 
subject’s personal and personal health information for purposes of conducting the trial. The ICF 
and the subject information sheet (if applicable) further explain the nature of the trial, its 
objectives, and potential risks and benefits, as well as the date informed consent is given. The ICF 
will detail the requirements of the subject and the fact that he or she is free to withdraw at any time 
without giving a reason and without prejudice to his or her further medical care. 
The investigator is responsible for the preparation, content, and IRB or IEC approval of the ICF 
and if applicable, the subject authorization form. The ICF, subject authorization form (if 
applicable), and subject information sheet (if applicable) must be approved by both the IRB or IEC 
and the sponsor prior to use. 
The ICF, subject authorization form (if applicable), and subject information sheet (if applicable) 
must be written in a language fully comprehensible to the prospective subject. It is the 
responsibility of the investigator to explain the detailed elements of the ICF, subject authorization 
form (if applicable), and subject information sheet (if applicable) to the subject. Information 
should be given in both oral and written form whenever possible and in the manner deemed 
appropriate by the IRB or IEC. 
The subject must be given ample opportunity to: (1) inquire about details of the trial and (2) decide 
whether or not to participate in the trial. If the subject determines he or she will participate in the 
trial, then the informed consent and subject authorization form (if applicable) must be signed and 
dated by the subject at the time of consent and prior to the subject entering into the trial. The 
subject should be instructed to sign using their legal names, not nicknames, using blue or black 
ballpoint ink. The investigator must also sign and date the ICF and subject authorization (if 
applicable) at the time of consent and prior to subject entering into the trial; however, the sponsor 
may allow a designee of the investigator to sign to the extent permitted by applicable law. 
Once signed, the original ICF, subject authorization form (if applicable), and subject information 
sheet (if applicable) will be stored in the investigator’s site file. The investigator must document 
the date the subject signs the ICF in the subject’s medical record and eCRF. Copies of the signed 
informed consent, the signed subject authorization form (if applicable), and subject information 
sheet (if applicable) shall be given to the subject. 
All revised ICFs must be reviewed and signed by the relevant subject in the same manner as the 
original ICF. The date the revised consent was obtained should be recorded in the subject’s 
medical record and eCRF, and the subject should receive a copy of the revised informed consent. 
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15.3 
Subject Confidentiality 
The sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this trial, a subject’s source data will only be linked to the 
sponsor’s clinical trial database or documentation via a unique identification number. As permitted 
by all applicable laws and regulations, limited subject attributes, such as sex, age, or date of birth, 
and subject initials may be used to verify the subject and accuracy of the subject’s unique 
identification number. 
To comply with ICH-GCP Guidelines and to verify compliance with this protocol, the sponsor 
requires the investigator to permit its monitor or designee’s monitor, representatives from any 
regulatory authority (eg, FDA, MHRA, PMDA), the sponsor’s designated auditors, and the 
appropriate IRBs and IECs to review the subject’s original medical records (source data or 
documents), including, but not limited to, laboratory test result reports, admission and discharge 
summaries for hospital admissions occurring during a subject’s trial participation, and autopsy 
reports. Access to a subject’s original medical records requires the specific authorization of the 
subject as part of the ICF process (see Section 15.2). 
Copies of any subject source documents that are provided to the sponsor must have certain 
personally identifiable information removed (ie, subject name, address, and other identifier fields 
not collected on the subject’s eCRF). 
15.4 
Publication, Disclosure, and Clinical Trial Registration Policy 
15.4.1 Publication and Disclosure 
The results of this trial are expected to be published in a scientific journal. It is anticipated that 
clinical and laboratory co-investigators will participate in authorship. The order of authorship and 
choice of journal will be proposed by the sponsor to the PIs, to be eventually agreed upon by all 
authors. The data analysis center for this trial will provide the analyses needed for publication. 
Information regarding this trial will be posted on ClinicalTrials.gov. 
15.4.2 Clinical Trial Registration 
In order to ensure that information on clinical trials reaches the public in a timely manner and to 
comply with applicable law, regulation and guidance, the sponsor will, at a minimum register all 
clinical trials conducted in subjects that it sponsors anywhere in the world on ClinicalTrials.gov or 
other publicly accessible websites before trial initiation. The sponsor contact information, along 
with investigator’s city, country, and recruiting status will be registered and available for public 
viewing. 
15.4.3 Clinical Trial Results Disclosure 
The sponsor will post the results of this clinical trial, regardless of outcome, on ClinicalTrials.gov 
or other publicly accessible websites, as required by applicable laws and/or regulations. 
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Trial completion corresponds to the date on which the final subject was examined or received an 
intervention for the purposes of final collection of data for the primary outcome, whether the 
clinical trial concluded according to the pre-specified protocol or was terminated. 
15.5 
Insurance and Compensation for Injury 
Each subject in the trial must be insured in accordance with the regulations applicable to the site 
where the subject is participating. If a local underwriter is required, then the sponsor or sponsor’s 
designee will obtain clinical trial insurance against the risk of injury to clinical trial subjects. Refer 
to the Clinical Study Site Agreement regarding the sponsor’s policy on subject compensation and 
treatment for injury. If the investigator has questions regarding this policy, he or she should contact 
the sponsor or sponsor’s designee. 
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16.0 
REFERENCES 
1. WMA Declaration of Helsinki - Ethical Principles for Medical Research Involving Human 
Subjects. 
https://www.wma.net/policies-post/wma-declaration-of-helsinki-ethical-principles-for-medic
al-research-involving-human-subjects/ Accessed 12 March 2018. 
2. Guideline for good clinical practice. 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R
1_Guideline.pdf Accessed 12 March 2018. 
3. Atmar RL and Estes MK. The epidemiologic and clinical importance of norovirus infection. 
Gastroenterol Clin North Am 2006;35(2):275-90, viii. doi: 0.1016/j.gtc.2006.03.001. 
4. Ramani S, Atmar RL, Estes MK. Epidemiology of human noroviruses and updates on vaccine 
development. Curr Opin in Gastroenterol 2014:30(1):25-33. doi: 
10.1097/MOG.0000000000000022. 
5. Lopman B, Vennema H, Kohli E, Pothier P, Sanchez A, Negredo A et al. Increase in viral 
gastroenteritis outbreaks in Europe and epidemic spread of new norovirus variant. Lancet 
2004;363(9410):682-88. doi: 10.1016/S0140-6736(04)15641-9. 
6. Treanor JJ, Atmar RL, Frey SE, Gormley R, Chen WH, Ferreira J et al. A novel intramuscular 
bivalent norovirus virus-like particle vaccine candidate-reactogenicity, safety, and 
immunogenicity in a phase 1 trial in healthy adults. J Infect Dis 2014;210(11):1763-71. doi: 
10.1093/infdis/jiu337. 
7. Bernstein DI, Atmar RL, Lyon GM, Treanor JJ, Chen WH, Jiang X et al. Norovirus vaccine 
against experimental human GII.4 virus illness: a challenge study in healthy adults. J Infect Dis 
2015;15;211(6):870-78. doi: 10.1093/infdis/jiu497. 
8. Atmar RL, Baehner F, Cramer JP, Song E, Borkowski A and Mendelman PM; on behalf of the 
NOR-201 Study Group. Rapid Responses to 2 Virus-Like Particle Norovirus Vaccine 
Candidate Formulations in Healthy Adults: A Randomized Controlled Trial. J Infect Dis 
2016;214(6):845-53. doi: 10.1093/infdis/jiw259. 
9. Global Investigator’s Brochure. Norovirus Bivalent VLP Vaccine. Edition 6.0, 22 November 
2017. 
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Appendix A Responsibilities of the Investigator 
Clinical research studies sponsored by the sponsor are subject to ICH GCP guidelines and all the 
applicable local laws and regulations. 
The investigator agrees to assume the following responsibilities: 
1. Conduct the trial in accordance with the protocol. 
2. Personally conduct or supervise the staff who will assist in the protocol. 
3. Ensure that trial related procedures, including trial specific (non-routine/non-standard panel) 
screening assessments are NOT performed on potential subjects, prior to the receipt of written 
approval from relevant governing bodies/authorities. 
4. Ensure that all colleagues and employees assisting in the conduct of the trial are informed of 
these obligations. 
5. Secure prior approval of the trial and any changes by an appropriate IRB/IEC that conform to 
21 Code of Federal Regulations (CFR) Part 56, ICH, and local regulatory requirements. 
6. Ensure that the IRB/IEC will be responsible for initial review, continuing review, and approval 
of the protocol. Promptly report to the IRB/IEC all changes in research activity and all 
anticipated risks to subjects. Make at least yearly reports on the progress of the trial to the 
IRB/IEC, and issue a final report within 3 months of trial completion. 
7. Ensure that requirements for informed consent, as outlined in 21 CFR Part 50, ICH and local 
regulations, are met. 
8. Obtain valid informed consent from each subject who participates in the trial, and document 
the date of consent in the subject’s medical chart. Valid ICF is the most current version 
approved by the IRB/IEC. Each ICF should contain a subject authorization section that 
describes the uses and disclosures of a subject’s personal information (including personal 
health information) that will take place in connection with the trial. If an ICF does not include 
such a subject authorization, then the investigator must obtain a separate subject authorization 
form from each subject. 
9. Prepare and maintain adequate case histories of all persons entered into the trial, including 
eCRFs, hospital records, laboratory results, etc, and maintain these data for a minimum of 
2 years following notification by the sponsor that all investigations have been discontinued or 
that the regulatory authority has approved the marketing application. The investigator should 
contact and receive written approval from the sponsor before disposing of any such 
documents. 
10. Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents. 
11. Maintain current records of the receipt, administration, and disposition of sponsor-supplied 
vaccines, and return all unused sponsor-supplied vaccines to the sponsor. 
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12. Report AEs to the sponsor promptly. In the event of an SAE, notify the sponsor within 
24 hours. 
13. Review and provide a signature as approval of the content of the CSR. 
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Appendix B Elements of the Subject Informed Consent 
In seeking informed consent, the following information shall be provided to each subject: 
1. A statement that the trial involves research. 
2. An explanation of the purposes of the research. 
3. The expected duration of the subject’s participation. 
4. A description of the procedures to be followed, including invasive procedures. 
5. The identification of any procedures that are experimental. 
6. The estimated number of subjects involved in the trial. 
7. A description of the subject’s responsibilities. 
8. A description of the conduct of the trial. 
9. A description of any reasonably foreseeable risks or discomforts to the subject and, when 
applicable, to an embryo, fetus, or nursing infant. 
10. A description of any benefits to the subject or to others that reasonably may be expected from 
the research. When there is no intended clinical benefit to the subject, the subject should be 
made aware of this. 
11. A statement describing the extent to which confidentiality of records identifying the subject 
will be maintained, and a note of the possibility that regulatory agencies, auditor(s), IRB/IEC, 
and the monitor may inspect the records. By signing a written ICF, the subject is authorizing 
such access. 
12. For research involving more than minimal risk, an explanation as to whether any compensation 
and an explanation as to whether any medical treatments are available if injury occurs and, if 
so, what they consist of or where further information may be obtained. 
13. The anticipated prorated payment(s), if any, to the subject for participating in the trial. 
14. The anticipated expenses, if any, to the subject for participating in the trial. 
15. An explanation of whom to contact for answers to pertinent questions about the research 
(investigator), subject’s rights, and IRB/IEC and whom to contact in the event of a 
research-related injury to the subject. 
16. A statement that participation is voluntary, that refusal to participate will involve no penalty or 
loss of benefits to which the subject otherwise is entitled, and that the subject may discontinue 
participation at any time without penalty or loss of benefits to which the subject is otherwise 
entitled. 
17. The consequences of a subject’s decision to withdraw from the research and procedures for 
orderly termination of participation by the subject. 
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18. A statement that the subject will be informed in a timely manner if information becomes 
available that may be relevant to the subject’s willingness to continue participation in the trial. 
19. A statement that results of pharmacogenomic analysis will not be disclosed to an individual, 
unless prevailing laws require the sponsor to do so. 
20. The foreseeable circumstances or reasons under which the subject’s participation in the trial 
may be terminated. 
21. A written subject authorization (either contained within the ICF or provided as a separate 
document) describing to the subject the contemplated and permissible uses and disclosures of 
the subject’s personal information (including personal health information) for purposes of 
conducting the trial. The subject authorization must contain the following statements regarding 
the uses and disclosures of the subject’s personal information: 
a) that personal information (including personal health information) may be processed by or 
transferred to other parties in other countries for clinical research and safety reporting 
purposes, including, without limitation, to the following: (1) Takeda, its affiliates, and 
licensing partners; (2) business partners assisting Takeda, its affiliates, and licensing 
partners; (3) regulatory agencies and other health authorities; and (4) IRBs/IECs; 
b) it is possible that personal information (including personal health information) may be 
processed and transferred to countries that do not have data protection laws that offer 
subjects the same level of protection as the data protection laws within this country; 
however, Takeda will make every effort to keep your personal information confidential, 
and your name will not be disclosed outside the clinic unless required by law; 
c) that personal information (including personal health information) may be added to 
Takeda’s research databases for purposes of developing a better understanding of the 
safety and effectiveness of the investigational vaccine(s), studying other therapies for 
patients, developing a better understanding of disease, and improving the efficiency of 
future clinical studies; 
d) that subjects agree not to restrict the use and disclosure of their personal information 
(including personal health information) upon withdrawal from the trial to the extent that 
the restricted use or disclosure of such information may impact the scientific integrity of 
the research; and 
e) that the subject’s identity will remain confidential in the event that trial results are 
published. 
22. A statement that clinical trial information from this trial will be publicly disclosed in a publicly 
accessible website, such as ClinicalTrials.gov. 
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Appendix C Investigator Consent to Use of Personal Information 
Takeda will collect and retain personal information concerning the investigator, including his or 
her name, address, and other personally identifiable information. In addition, the investigator’s 
personal information may be transferred to other parties located in countries throughout the world 
(eg, the United Kingdom, United States, and Japan), including the following: 
 Takeda, its affiliates, and licensing partners. 
 Business partners assisting Takeda, its affiliates, and licensing partners. 
 Regulatory agencies and other health authorities. 
 IRBs and IECs. 
Investigator’s personal information may be retained, processed, and transferred by Takeda and 
these other parties for research purposes including the following: 
 Assessment of the suitability of investigator for the trial and/or other clinical studies. 
 Management, monitoring, inspection, and audit of the trial. 
 Analysis, review, and verification of the trial results. 
 Safety reporting and pharmacovigilance relating to the trial. 
 Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to the trial. 
 Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to other vaccines used in other clinical studies that may contain the 
same chemical compound present in the investigational vaccine administered to subjects 
during the primary vaccination trial. 
 Inspections and investigations by regulatory authorities relating to the trial. 
 Self-inspection and internal audit within Takeda, its affiliates, and licensing partners. 
 Archiving and audit of trial records. 
 Posting investigator site contact information, trial details and results on publicly accessible 
clinical trial registries, databases, and websites. 
Investigator’s personal information may be transferred to other countries that do not have data 
protection laws that offer the same level of protection as data protection laws in the investigator’s 
own country. The investigator acknowledges and consents to the use of his or her personal 
information by Takeda and other parties for the purposes described above. 
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