Phase 2b, Double-Blind, Randomized, Placebo-Controlled Trial to Evaluate the Efficacy and Immunogenicity of the Intramuscular Norovirus GI.1/GII.4 Bivalent Virus-like Particle Vaccine in Healthy Adults Aged 18 - 49 Years
Phase: PHASE2
Conditions: Healthy Volunteers
Sponsor: Takeda




Title: Phase 2b, Double-Blind, Randomized, Placebo-Controlled Trial to Evaluate the Efficacy and 
Immunogenicity of the Intramuscular Norovirus GI.1/GII.4 Bivalent Virus-like Particle Vaccine 
in Healthy Adults Aged 18 - 49 Years 
NCT Number: NCT02669121
Protocol Approve Date: 15 November 2017 
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.

1.0 TITLE PAGE 
TITLE PAGE 
PROTOCOL 
Phase 2b, Double-Blind, Randomized, Placebo-Controlled Trial to Evaluate the Efficacy 
and Immunogenicity of the Intramuscular Norovirus GI.1/GII.4 Bivalent Virus-like Particle 
Vaccine in Healthy Adults Aged 18 - 49 Years 
Efficacy and Immunogenicity of Norovirus GI.1/GII.4 Bivalent Virus-like Particle Vaccine in 
adults 
Sponsor: 
Takeda Vaccines, Inc. 
40 Landsdowne Street 
Cambridge, MA 02139 USA 
Study Identifier: 
NOR-211 
IND Number: 
014421 
EudraCT Number: 
Not Applicable 
Vaccine Name: 
Norovirus GI.1/GII.4 Bivalent Virus-Like Particle Vaccine 
Date: 
15 November 2017 
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-211 
Page 4 of 103 
Protocol Version 3.0 
15 November 2017 
 
 
INVESTIGATOR AGREEMENT 
I confirm that I have read and that I understand this protocol, the Investigator’s Brochure, 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 [1]. 
 
ICH-GCP Consolidated Guideline [2]. 
 
All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations. 
 
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 B 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-211 
Page 5 of 103 
Protocol Version 3.0 
15 November 2017 
 
 
1.3 
Protocol Amendment 
This document describes the changes in reference to the protocol incorporating Amendment N° 
2.0. The purpose of this amendment is to: 
 
Prevent potential lost-to-follow up (LTFU) of subjects for safety collection at the end of study 
(EOS) visit on Day 45 by increasing the visit window. 
 
Increase flexibility for the timing of trial vaccine administration. 
 
Adapt the exclusion criteria for birth control measures to the study population. 
1.3.1 Amendment History 
Date 
Amendment Number 
Protocol Version 
Amendment Type 
Region 
27 July 2015 
Not applicable 
1.0 
Not applicable 
Global 
9 February 2016 
1.0 
2.0 
Non-substantial 
Global 
15 November 2017 
2.0 
3.0 
Non-substantial 
Global 
0006
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-211 
Page 6 of 103 
Protocol Version 3.0 
15 November 2017 
 
 
1.3.2 
Summary of Changes 
Summary of Protocol Amendment 2.0 dated 15 November 2017 to Protocol Version 2.0 dated 9 February 2016 
Rationale for the amendment: 
 
Prevent potential lost-to-follow up (LTFU) of subjects for safety collection at the end of study (EOS) visit on Day 
45 by increasing the visit window. 
 
Increase flexibility for the timing of trial vaccine administration. 
 
Adapt the exclusion criteria for birth control measures to the study population. 
 
Trial Summary 
Adapted to reflect the changes in the body of the protocol. 
Section 2.1 
 
Table 2-a footnote a: 
Trial personnel will follow U.S. Navy subjects through Day 45, U.S. Air Force subjects through Day 53, 
and U.S. Marine subjects through Day 72. If a subject early terminates (ET), Day 45, Day 53 or Day 72 
procedures, as applicable, should be performed. 
Table 2-a footnote d: 
After written informed consent is obtained within 7 days prior to vaccination or on Day 1, subsequent 
study procedures including blood draw and randomization may be done. Subjects will be randomized 1:1 
to receive NoV GI.1/GII.4 bivalent VLP vaccine or placebo (saline). On Day 1, the subject will receive 
the study dose he/she was randomized to receive. The study dose will be administered IM in the middle 
1/3 of the deltoid muscle. After vaccination, the subject will be observed for at least 15 minutes. If the 
investigational trial dose is delayed beyond the day the routine immunizations required by the US 
military are given, the trial dose may be administered later during the training period. For subjects in 
Subset A, . Tthose concomitant required vaccines administered on Day 1 (the same day as the NoV 
GI.1/GII.4 bivalent VLP vaccine or placebo) will be recorded on the subject’s source documents (by 
manufacturer, lot number, expiry date) and subsequently recorded in the electronic case report form 
(eCRF). For all subjects enrolled after Subset A, this information will be filed at the site as source 
documentation but not recorded in the eCRF. 
Table 2-a footnote f: 
Blood will be collected on all subjects once within 7 days prior to vaccination or on Day 1, and once 
post-vaccination on each of Days 8 and 29 and at the end of the AGE active surveillance period (EOS) in 
order to explore a level of protection. The EOS sera will also provide information on asymptomatic NoV 
illness for those subjects who develop a 4-fold or greater rise in anti-NoV antibodies between Day 29 and 
EOS. 
Table 2-b footnote a: 
During the AGE surveillance period (Day 1 through Day 45 for U.S. Navy, Day 53 for U.S. Air Force, and 
Day 72 for U.S. Marines), those subjects, who present with AGE, will be instructed to record their AGE 
symptoms on the logs and report to the medical clinic for assessment at the next trial visit. Initial AGE 
symptom logs will be given at trial entry to record AGE symptoms. Subjects will be instructed to return 
any subsequent logs and the latest AGE symptom log to the medical clinic at the next trial visit. 
Table 2-b footnote b: 
For those subjects who present with AGE, a stool specimen and a vomitus specimen (vomitus if available) 
will be collected as soon as possible after the onset of each new episode of AGE for processing and 
subsequent RT-PCR testing. If no samples are provided at AGE onset, samples should be obtained as 
soon as possible thereafter. If samples at AGE onset are inadequate ie too small for both RT-PCR to 
NoV and co-infection tests, the sample should be prioritized for RT-PCR to NoV and a subsequent 
sample should be obtained for co-infection testing as soon as possible thereafter. If samples become 
lost, destroyed, damaged or otherwise unavailable for use, AGE onset samples should be repeated as 
soon as possible. After the initial stool specimen is obtained at the onset of AGE; up to three additional 
stool specimens as available (optional), will be obtained once between 7 and 14 days, once between 21 
and 29 days and once at EOS. The onset of AGE is defined as the date the subject initially presents with 
vomiting and diarrhea. 
0007
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-211 
Page 7 of 103 
Protocol Version 3.0 
15 November 2017 
 
 
Trial Summary 
Adapted to reflect the changes in the body of the protocol. 
Table 2-c footnote a: 
Trial personnel will follow U.S. Navy subjects through Day 45, U.S. Air Force subjects through 
Day 53, and U.S. Marine subjects through Day 72. If a subject early terminates (ET), Day 45, 
Day 53 or Day 72 procedures, as applicable, should be performed. 
Section 6.1 
This is a Phase 2b, double blind, randomized, multi-site, placebo-controlled, efficacy trial of a 
single dose of the IM NoV vaccine combined with Al(OH)3 adjuvant compared to a single dose 
of placebo (saline) control. Based on prior incidence rates of AGE over multiple seasons in the 
US Military training installations, the estimated sample size for the trial is 2800-8700 healthy 
subjects aged 18 to 49 years who will be recruited from US military training installations. This 
trial has a case-driven design, with the primary analysis planned after ~ 30 cases of moderate or 
severe AGE due to infection with genotype-specific (GI.1 or GII.4) NoV strains represented in 
the vaccine have been confirmed (excluding co-infection with any of three bacterial pathogens, 
Salmonella, Shigella or Campylobacter). If there are < 30 cases (as defined above) at the end of 
the first season (September through May), the trial may be continued beyond the end of May 
the first season, may be stopped, or may be continued for a second season (September through 
May). If the accrual of cases (as defined above) is slower than expected, an interim analysis 
may be performed when approximately 30 cases of moderate or severe AGE due to any NoV 
strain have been accrued. For all enrolled subjects, accrual of additional AGE cases due to NoV 
will continue for all enrolled subjects until the end of each respective active AGE surveillance 
period (45 days). Thereafter, further enrollment of new subjects will be stopped. 
Section 6.3 
Trial participation is expected to be from enrollment through EOS (trial Day 45 for U.S. Navy 
subjects, trial Day 53 for U.S. Air Force subjects, and trial Day 72 for U.S. Marine subjects) 
Section 7.2 
Criterion #15v: 
Abstinence, defined as refraining from heterosexual intercourse, ie sexual intercourse with 
risk of conception, during the entire study period. 
Criterion #17: 
If male and sexually active, the subject must be advised not to donate sperm from Day 1 
through 6 months after the last dose of trial vaccine. 
Section 7.3 
Bullet 2: 
If the investigational trial dose is delayed beyond the day the routine immunizations required 
by the US military are given, the trial dose may be administered later during the training 
period. 
Section 7.4 
Number 3: 
Lost to follow-up: The subject did not return to the clinic and attempts to contact the subject 
were unsuccessful and/or the subject graduated and left the base. Attempts to contact the 
subject must be documented. 
Section 9.1.3 
Paragraph 1: 
If the subject is interested to participate, trial staff will review the informed consent form and 
will highlight the key aspects of the trial. The consenting procedure may occur in small groups 
of up to three subjects at once. Notably, this procedure will be handled by non-uniformed trial 
staff not involved in the training of the subjects to avoid any feeling of coercion, and also 
include an Ombudsman [28]. 
Section 9.1.4 
Individuals who receivedReceipt of any vaccines within 14 days (for inactivated vaccines) or 
28 days (for live vaccines) prior to enrollment in this trial with the exception of routine 
immunizations as per Military Procedures (see Appendix D). If the investigational trial dose is 
delayed beyond the day the licensed vaccines are given, the trial dose may be subsequently 
administered later during the training period. 
0008
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-211 
Page 8 of 103 
Protocol Version 3.0 
15 November 2017 
 
 
Trial Summary 
Adapted to reflect the changes in the body of the protocol. 
Section 9.1.8 
Paragraph 1: 
All subjects will have surveillance for AGE disease performed from Day 1 until the end of the 
active AGE disease surveillance period (Day 45 for U.S. Navy subjects, Day 53 for U.S. Air 
Force subjects, or Day 72 for U.S. Marine subjects). 
Paragraph 2: 
Subjects will receive standard of care treatment for AGE disease, and a new AGE disease 
symptom log will be given to record AGE disease symptoms until they resolve. Subjects will be 
instructed to return any subsequent and the latest AGE and any subsequent disease symptom 
log to the medical clinictrial site at the next trial visit. A convalescent blood specimen for 
serology will be obtained once between 7 and 14 days after the onset of the AGE disease. After 
the initial stool specimen obtained at the onset of AGE disease: as available, three additional 
stool specimens will be obtained once between 7 and 14 days, once between 21 and 29 days and 
once at end of the acute AGE surveillance periodEOS. These follow-on stool specimens will be 
analyzed for NoV by RT-PCR. If an AGE event occurs within 7 days prior to the EOS visit 
(Day 45), a convalescent serum sample and a single optional stool sample should be collected 
at the EOS visit. There is no further follow-up for AGE after graduation from recruit 
training at Day 45. 
Section 9.1.13 
For female subjects of child bearing potential, pregnancy testing using urine or serum will be 
performed within 72 hours prior to vaccination. Subjects will be provided with information on 
acceptable methods of contraception as part of the subject informed consent process and will be 
asked to sign a consent form stating that they understand the requirements for avoidance of 
pregnancy as well as donation of ova (or sperm in the case of male participants). 
Section 9.3.6 
Heading: 
Procedures at end of Active AGE Disease Surveillance Period (+/-4 - 7 days) 
Section 10.4.3 
Paragraph 1: 
Collection of SAEs will be collected by close monitoring from the time that the subject is 
administered the trial vaccine (Day 1) up to the end of the active AGE disease surveillance 
period (at Day 45 for U.S. Navy subjects, at Day 53 for U.S. Air Force subjects, and at Day 72 
for U.S. Marine subjects). 
Section 16.0 
Additional references. 
Appendix D 
Deletion of table with immunizations for U.S. Marine Corps recruits. 
General 
Minor grammatical and editorial changes. Replacement of IWRS with IRT. Removal of rectal 
swabs 
 
0009
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use

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Only 

Norovirus GI.1/GII.4 Bivalent VLP Vaccine 
 
Trial No. NOR-211 
Page 12 of 103 
Protocol Version 3.0 
15 November 2017 
 
 
Trial Summary 
Adapted to reflect the changes in the body of the protocol. 
Section 9.1.4 
3rd paragraph: 
All medications, vaccines and blood products including specific history of antibiotic use and 
the duration thereof, taken or received by the subjects within 3 months prior to the start of the 
trial are to be recorded on the source document and entered onto the Prior and Concomitant 
Medications eCRF. The use of antipyretics and/or analgesic medications within 24 hours prior 
to vaccination must be identified and the reason for their use (prophylaxis versus treatment) 
must be described in the source documents or the eCRF. 
Section 9.1.7 
A saliva specimen will be collected once during the trial (at any time pre- or post-vaccination) 
either on Day 1 or from subjects in Subset A for assessment of HBGA secretor status or at any 
time (pre- or post-vaccination) during the trial. 
Section 9.1.8 
1st paragraph: 
All subjects will have surveillance for AGE disease performed from Day 1 until the end of the 
active AGE disease surveillance period (Day 45 for U.S. Navy subjects, Day 53 for U.S. Air 
Force subjects, or Day 72 for U.S. Marine subjects). All participants will be given an AGE 
disease symptom log and a thermometer at trial entry within 7 days prior to vaccination or on 
(Day 1) and instructed to record their AGE disease symptoms and report to the medical clinic as 
soon as possible. The subjects will record in the AGE disease symptom log the onset time of 
vomiting and/or diarrhea, their temperature, the number of episodes of vomiting and/or 
diarrhea, and the stop time of vomiting and/or diarrhea to calculate duration of AGE. The 
subjects will also document whether the symptom(s) have had impact on their ability to train. 
The subjects will be given instructed to use the provided thermometers to measure and record 
their temperature on the AGE disease symptom log. The subjects will be informed that the 
recommended route to take their temperature is oral and instructed to use this route. At the 
medical clinic, the subject will be assessed to determine if they have an AGE disease that meets 
the work-up definition (see Section 6.1). Subjects who meet the work-up definition will be 
assessed for disease severity and provide a stool specimen (not rectal swabs) and/or vomitus 
specimen for processing and later detection of NoV by RT-PCR. Subjects will only provide 
vomitus specimen if actively vomiting. All initial stool samples for each new onset episode of 
AGE will be analyzed for the following three enteric pathogens: Salmonella, Shigella, and 
Campylobacter. 
2nd paragraph: 
Subjects will receive standard of care treatment for AGE disease, and a new AGE disease 
symptom log will be given to record AGE disease symptoms until they resolve. Subjects will be 
instructed to return any subsequent and the latest AGE disease symptom log to the medical 
clinic at the next trial visit. A convalescent blood specimen for serology will be obtained once 
between 7 and 14 days after the onset of the AGE disease. After the initial stool specimen 
obtained at the onset of AGE disease: as available, three additional stool specimens will be 
obtained once between 7 and 14 days, once between 21 and 28 29 days and once at end of the 
acute AGE surveillance period. These follow-on stool specimens will be analyzed for NoV by 
RT-PCR. 
Section 9.1.10 
2nd paragraph: 
All enrolled subjects will have blood drawn once within 7 days prior to vaccination or on Day 
1 and once on each of Days 1, 8, 29 and at the EOS (end of the active AGE surveillance 
period). For those subjects who develop AGE during the surveillance period, a single 
convalescent serum specimen will also be obtained once between 7 to 14 days after each new 
onset AGE episode. 
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-211 
Page 14 of 103 
Protocol Version 3.0 
15 November 2017 
 
 
Trial Summary 
Adapted to reflect the changes in the body of the protocol. 
4th bullet (level 1): 
 
Starting on the day of vaccination, the subject will check for specific types of events at the 
injection site (solicited local AEs), any specific generalized symptoms (solicited systemic 
AEs), body temperature (by any method with oral route recommended), any other 
symptoms or change in the subject’s health status, and any medications taken. The subjects 
will be informed that the recommended route to take their temperature is oral and will be 
instructed to use this route. These solicited AEs and body temperature will be recorded in 
the diary daily for 7 days. Assessments should preferably take place in the evening at day’s 
end. 
Section 9.3.5 
3rd bullet: 
 
Instruct subjects to come back to the medical clinic once between 7 and 14 days after the 
onset of the AGE disease for the collection of a convalescent blood specimen. Refer to 
Section 9.1.8. After the initial stool specimen obtained at the onset of AGE disease: as 
available, three additional stool specimens will be obtained once between 7 and 14 days, 
once between 21 and 28 29 days and once at end of the acute AGE surveillance period. 
Refer to Section 9.1.8. 
Section 9.3.6 
Section title: 
9.3.6 
Procedures at end of Active AGE Disease Surveillance Period (+/- 2 4 days) 
Section 9.3.7 
Collect data on AEs. 
Section 10.1 
Table 10-a, Table 10-b footnotes: clarified body temperature is recommended to be taken by 
the oral route and to record the actual method taken on the CRF. 
Section 13.1.5 
2nd paragraph 
For subjects in Subsets A and B, safety will be assessed daily for 7 days after vaccination 
(including the day of vaccination) via collection of solicited AEs, including local AEs 
(injection site: pain, erythema, induration and swelling) and systemic AEs (headache, fatigue, 
myalgia, arthralgia, vomiting, and diarrhea). In addition, other indicators of safety will be 
collected (e.g., body temperature). Body temperature will be summarized by actual route 
taken with no adjustment or conversion for route of measurement. 
Section 13.2 
1st paragraph: 
An interim analysis will be performed on after the first 200 subjects (Subset A) have completed 
the EOS visit, andwhen the assay results are completed. The anti-NoV GI.1 and GII.4 VLP 
antibody responses at baseline (prior to or on Day 1) and on Days 1, 8, 29 and EOS, and the 
antibody responses at baseline (prior to or on Day 1) and on Days 1 and 29 to adenovirus type 
4, to meningococcal vaccine serogroup A, and to the seasonal influenza vaccine H3 strain, will 
be summarized by treatment group and provided to the sponsor and DMC for review. In 
addition, all available safety data for these subjects, including solicited AEs and unsolicited 
AEs, will be summarized and provided to the DMC for review. Specifically, the interim safety 
and immunogenicity for this subset may be summarized separately as the results become 
available. 
0015
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-211 
Page 15 of 103 
Protocol Version 3.0 
15 November 2017 
 
 
Trial Summary 
Adapted to reflect the changes in the body of the protocol. 
Section 13.3 
2nd paragraph: 
The average weekly incidence (as percentage of recruits on the base) over the winter NoV high 
seasons (October-May) and summer low seasons (June-September) of consultation at the 
medical stations for symptoms of AGE were evaluated for the full trial period from September 
2011 to September 2014. The expected background rate of NoV GI.1/GII.4 was calculated 
using two three assumptions. The incidence of NoV over the winter high season is the excess of 
AGE in the winter (first panel in Table 13-a) compared to the summer (second panel in Table 
13-a) and can thus be calculated as the average weekly AGE incidence during the winter season 
minus the average weekly AGE incidence during the preceding corresponding summer season. 
This has been calculated in the last panel in Table 13-a. The second assumption is that 50% of 
the NoV cases are due to GI.1/GII.4 which that is compatible with the overall breakdown of the 
NHRC genotype analysis and the NoV genotypes identified by the CDC as the cause of NoV 
outbreaks reported to CDC over the same 2011-2014 time period. The weekly incidence rates 
are then multiplied by 7.6 (average length of training) to obtain the incidence rate over training 
and thus during the trial. There is a further assumption that all subjects reporting to the medical 
station are all moderate or severe AGE cases are reported to the medical station. 
3rd paragraph: 
The background incidence rate of moderate or severe NoV AGE due to genotype-specific (GI.1 
and GII.4) NoV strains represented in the vaccine (excluding co-infection with Salmonella, 
Shigella, or Campylobacter) is assumed to be 0.535-1.687% per subject-training period of 
observation based on NHRC AGE NoV surveillance data at the planned trial sites (Table 13-a). 
Under such attack rate assumptions, approximately 2800-8700 subjects, randomized in 1:1 
ratio to NoV vaccine and saline placebo, would be needed to reach 30 cases of moderate or 
severe AGE due to NoV infection by genotype-specific (GI.1 or GII.4) NoV strains. As this is a 
case-driven trial, subjects will continue to be enrolled and followed through the entire active 
AGE surveillance period until ~ 30 cases of moderate or severe AGE due to genotype-specific 
(GI.1or GII.4) NoV strains, excluding co-infection are confirmed. Thereafter, the trial will be 
closed to further enrollment. 
Appendix C 
Bullet 25: 
Female subjects of childbearing potential (e.g., non-sterilized, premenopausal female subjects) 
who are sexually active must use adequate contraception (as defined in the informed consent) 
from enrollment Day 1 and throughout the duration of the trial. Regular pPregnancy tests will 
be performed throughout the trial for all female subjects of childbearing potential as defined in 
the protocol and in the informed consent. If a subject is found to be pregnant during trial, the 
investigator will offer the subject the choice to receive unblinded treatment information. 
General 
Minor grammatical and editorial changes. 
 
0016
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-211 
Page 18 of 103 
Protocol Version 3.0 
15 November 2017 
 
 
9.3.2 
Vaccination Procedures (within 7 days prior to vaccination or on Day 1) .......67 
9.3.3 
Post-Vaccination procedures (Day 8 [+7 days] and Day 29 [+7 days]) ...........69 
9.3.4 
Clinic Visits after Vaccination (Day 8, Day 29, End of Active Surveillance)
...........................................................................................................................69 
9.3.5 
Procedures at AGE Disease Visit .....................................................................70 
9.3.6 
Procedures at End of Active AGE Disease Surveillance Period (- 7 days) ......71 
9.3.7 
Safety Follow-up ...............................................................................................71 
9.3.8 
Post-Trial Care ..................................................................................................71 
9.4 
Schedule of Additional Observations and Procedures for Subjects in Subsets A and 
B ...................................................................................................................................71 
9.5 
Biological Sample Retention and Destruction .............................................................71 
10.0 
ADVERSE EVENTS .........................................................................................................72 
10.1 
Definitions....................................................................................................................72 
10.1.1 
Adverse Events (AEs) .......................................................................................72 
10.1.2 
Solicited Adverse Events ..................................................................................72 
10.1.3 
Serious Adverse Events (SAEs)........................................................................75 
10.2 
Causality of AEs ..........................................................................................................75 
10.2.1 
Relationship to Trial Procedures .......................................................................75 
10.2.2 
Outcome of AEs ................................................................................................76 
10.3 
Additional Points to Consider for AEs ........................................................................76 
10.4 
Procedures ....................................................................................................................77 
10.4.1 
Collection and Reporting of AEs ......................................................................77 
10.4.2 
Collection and Reporting of Solicited AEs .......................................................78 
10.4.3 
Collection and Reporting of SAEs ....................................................................78 
10.5 
Follow-up Procedures ..................................................................................................79 
10.5.1 
AEs ....................................................................................................................79 
10.5.2 
SAEs .................................................................................................................79 
10.5.3 
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities
...........................................................................................................................79 
10.5.4 
Post-Trial Events ...............................................................................................79 
11.0 
TRIAL-SPECIFIC REQUIREMENTS .............................................................................80 
12.0 
DATA HANDLING AND RECORDKEEPING ..............................................................81 
12.1 
Electronic CRFs (eCRF) ..............................................................................................81 
12.2 
Record Retention .........................................................................................................81 
13.0 
STATISTICAL METHODS ..............................................................................................83 
0019
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use

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0020
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Norovirus GI.1/GII.4 Bivalent VLP Vaccine 
 
Trial No. NOR-211 
Page 20 of 103 
Protocol Version 3.0 
15 November 2017 
 
 
LIST OF IN-TEXT TABLES 
Table 1.a 
Contact Information .................................................................................................2 
Table 2.a 
Schedule of Trial Procedures for all Subjects (2800-8700 subjects) .....................33 
Table 2.b 
Schedule of Additional Trial Procedures and Analyses for the Subjects Meeting 
Work-up and AGE Case Definitions .....................................................................35 
Table 2.c 
Schedule of Additional Trial Procedures and Analyses for Subsets A and B 
(200 subjects in each subset for a total of 400) ......................................................36 
Table 10.a 
Local and Systemic AEs ........................................................................................73 
Table 10.b 
Intensity Assessment for Solicited safety parameters ............................................74 
Table 13.a 
NHRC AGE NoV Surveillance Data at Planned Trial Sites ..................................87 
Table 16.a 
Routine Immunizations for Newly Arriving U.S. Navy Subjects (NRTC‐Great 
Lakes) ...................................................................................................................102 
 
LIST OF IN-TEXT FIGURES 
Figure 6.a 
Schematic of Trial Design .....................................................................................49 
 
LIST OF APPENDICES 
Appendix A 
Responsibilities of the Investigator ........................................................................96 
Appendix B 
Investigator Consent to Use of Personal Information ............................................98 
Appendix C 
Elements of the Subject Informed Consent ...........................................................99 
Appendix D 
Routine Immunizations ........................................................................................102 
Appendix E 
Five Point Scale Stool Chart ................................................................................103 
 
0021
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-211 
Page 21 of 103 
Protocol Version 3.0 
15 November 2017 
 
 
2.0 
TRIAL SUMMARY 
Name of Sponsor(s): 
40 Landsdowne Street, 
Cambridge, MA 02139, 
USA 
Product Name: 
Norovirus GI.1/GII.4 Bivalent Virus-Like Particle Vaccine 
Trial Title: Phase 2b, Double-Blind, Randomized, Placebo-Controlled Trial to Evaluate the Efficacy and 
Immunogenicity of the Intramuscular Norovirus GI.1/GII.4 Bivalent Virus-like Particle Vaccine in Healthy Adults 
Aged 18 - 49 Years 
IND No.: 014421 
EudraCT No.: Not applicable 
Study Identifier: NOR-211 
Phase: 2b 
Trial Blinding Schema: Double blind 
Background and Rationale: 
Noroviruses (NoVs) cause an acute debilitating illness characterized by vomiting and diarrhea. According to the 
Centers for Disease Control and Prevention (CDC), 21 million cases of acute gastroenteritis (AGE) are due to NoV 
each year in the United States (US). NoVs have emerged as an important cause of outbreaks of viral gastroenteritis 
worldwide. These outbreaks can occur in all age groups, wherever people gather, and commonly result in significant 
morbidity and mortality, particularly in the very old and very young. In addition, NoV illnesses and outbreaks exact a 
significant socioeconomic toll on businesses, hospitals, schools and other closed settings, such as dormitories and 
military barracks. 
AGE is commonly reported within training and deployed US military populations. Viral-associated AGE is easily 
transmitted from human-to-human and can rapidly spread throughout an entire military unit causing widespread 
incapacitation often leading to disruption and reduction in operational readiness. NoV was found to be a major cause 
of AGE outbreaks and sporadic AGE cases among US military personnel deployed during the Persian Gulf War in 
1991 as well as coalition forces in Gulf War II, Iraq and Afghanistan beginning in 2003. Similar outbreaks have been 
described in European military units deployed to these areas. 
AGE surveillance data collected over multiple seasons (2011 through 2014) from the Naval Health Research Center’s 
(NHRC) Enteric Disease Surveillance Program (EDSP) support that NoV was the predominant pathogen identified in 
cases of AGE among US military subjects at the Marine Corps Recruit Depot (MCRD-SD) in San Diego, California, 
at the MCRD in Parris Island (MCRD-PI), South Carolina, and at the Naval Recruit Training Center in Great Lakes 
(NRTC‐GL), Illinois. AGE due to NoV was originally known as “winter vomiting disease”, and as expected, the 
highest detection rate of AGE due to NoV was during the months of September to May for both Marine and Navy 
subjects. The estimated population-based incidence of NoV illness at these training centers is 10 to 35 cases per 1000 
subjects during training (an average of 7.6 weeks) in this high season (September-May). 
Currently, no vaccine exists for protection against AGE due to NoV. Given the disruptive effect of AGE due to NoV 
upon military training, readiness and performance, it is important to develop an effective vaccine. Takeda has 
conducted two proof of concept NoV vaccine and live oral challenge studies; a monovalent GI.1 VLP vaccine 
delivered as intranasal dry powder followed by live NoV genotype GI.1 oral challenge and a bivalent GI.1/GII.4 
bivalent VLP vaccine delivered by intramuscular (IM) injection followed by live NoV genotype GII.4 oral challenge. 
Both trials showed that the VLP based vaccines reduced severity of AGE due to the challenge viruses. The more 
robust immunogenicity drove the decision to pursue the IM route of administration. 
The NoV GI.1/GII.4 bivalent VLP vaccine for IM injection to be evaluated in this trial contains both NoV GI.1 and 
NoV GII.4 VLPs as the antigens formulated with aluminum as aluminum hydroxide (Al(OH)3) adjuvant. Aluminum 
salt-based adjuvants have a demonstrated safety profile of over six decades. The GI.1 VLP represents a single GI.1 
strain and the GII.4 VLP consists of a consensus sequence of three GII.4 strains (cVLP). NoV VLPs are non-infectious 
because they do not contain viral ribonucleic acid (RNA). 
Prior safety and immunogenicity data for the NoV vaccine given by the IM route are available from approximately 
1000 adult subjects, evaluated in five Takeda clinical trials (LV03-104, LV03-105, NOR-107, NOR-201, and 
NOR-210). The NoV vaccine evaluated in these trials either contained both Al(OH)3 plus monophosphoryl lipid A 
0022
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-211 
Page 23 of 103 
Protocol Version 3.0 
15 November 2017 
 
 
trial withdrawal throughout the active AGE surveillance period. 
The 200 subjects in Subset A and 200 subjects in Subset B will be evaluated for solicited local and solicited systemic 
AEs for 7 days after dosing using diary cards returned on or after Day 8 and for unsolicited AEs for 28 days after 
dosing by interview on or after Day 29. 
Surveillance for AGE: 
Each enrolled subject will have surveillance for AGE performed from Day 1 until the end of the active AGE 
surveillance period (Day 45). Each enrolled participant will be given an AGE symptom log at trial entry (Day 1) and 
instructed to record any AGE symptoms and report to the medical clinic as soon as possible after onset of AGE 
symptoms. The subjects will record on the AGE symptom log the onset time of vomiting and/or diarrhea, number of 
episodes of each, and the stop time of vomiting and/or diarrhea to calculate duration of AGE. Other symptoms 
associated with the AGE episode will also be recorded. 
Work-up AGE in ill subjects: 
At the medical clinic, the subject will be assessed to determine if they have an AGE that meets the work-up definition: 
 
1 or more episodes of vomiting within 24 hours judged by the investigator as not related to the training AND/OR; 
 
Any diarrhea episode of 3 or greater severity on a 5-point scale* within 24 hours. 
* Grade 1: fully formed (normal); Grade 2: soft (normal); Grade 3: thick liquid (diarrheal); Grade 4: opaque watery 
(diarrheal); or Grade 5: Rice-water (diarrheal). 
Subjects who meet the work-up definition will provide a fresh stool specimen and vomitus specimen (if available) for 
processing and later detection of NoV by RT-PCR and be assessed for disease severity. Subjects will receive standard 
of care treatment for AGE disease from the site clinic and additional AGE disease symptom logs will be given to 
record further AGE symptoms until resolution. Subjects will be instructed to return all subsequent AGE symptom logs 
to the trial staff at the next trial visit. 
NoV AGE case definition in ill subjects: 
A case of NoV AGE is defined as one occurring > 7 days after immunization until the end of the active AGE 
surveillance period. 
A NoV AGE case is defined as meeting the work-up definition plus a NoV positive stool sample or vomitus sample 
confirmed by RT-PCR. In circumstances where both stool and vomitus samples are obtained, the subject will be 
considered NoV positive if either specimen is confirmed NoV positive by RT-PCR. 
Severity of AGE is defined as follows: 
 
Mild 
 
1 to 2 episodes of vomiting* within 24 hours AND/OR. 
 
3 unformed stools** within 24 hours 
 
 
Moderate 
 
3 to 5 episodes of vomiting* within 24 hours AND/OR 
 
4 to 5 unformed stools** within 24 hours 
 
 
Severe 
 
6 or more episodes of vomiting* within 24 hours AND/OR 
 
6 or more unformed stools** within 24 hours AND/OR 
 
Hospital admission and/or intravenous rehydration for mild or greater AGE 
 
*Judged by the investigator as not due to the training; uses the Common Terminology Criteria for AEs (CTCAE) for vomiting 
episodes. 
**For definition purposes, unformed stools are those meeting a 3 or greater severity of diarrhea on a 5-point scale (*noted above). 
Notes: 
 
“Within 24 hours” refers to a rolling time period. That is, the criteria will be considered to have been met if occurring during 
any 24-hour period between the onset and end of AGE symptoms. 
 
A new episode of vomiting is defined as one that occurs at least 5 minutes after the previous one. 
 
A new episode of diarrhea is defined as ‘a trip to the toilet’. 
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available, a 2nd and 3rd stool specimen will be obtained once 7-14 days, and once 21-28 days thereafter and at the end of active AGE 
surveillance period (Day 45). 
b. Routine immunizations administered as required by the US military.
c. Blood draw for serology (all subjects). Diary card collection and review (subjects in subsets A and B).
d. Blood draw for serology (all subjects). Safety assessment by interview (subjects in subsets A and B).
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Norovirus GI.1/GII.4 Bivalent VLP Vaccine 
 
Trial No. NOR-211 
Page 32 of 103 
Protocol Version 3.0 
15 November 2017 
 
 
AGE were evaluated for the period from September 2011 to September 2014. The expected background rate of NoV 
GI.1/GII.4 was calculated using three assumptions. The incidence of NoV over the winter high season is the excess of 
AGE in the winter compared to the summer and can thus be calculated as the average weekly AGE incidence during 
the winter season minus the average weekly AGE incidence during the corresponding summer season. The second 
assumption is that 50% of the NoV cases are due to GI.1/GII.4 that is compatible with the overall breakdown of the 
NHRC genotype analysis and the NoV genotypes identified by the CDC as the cause of NoV outbreaks reported to 
CDC over the same 2011-2014 time period. The weekly incidence rates are then multiplied by 7.6 (average length of 
training) to obtain the incidence rate over training and thus during the trial. There is a further assumption that all 
subjects reporting to the medical station are moderate or severe AGE cases. 
The background incidence rate of moderate or severe NoV AGE due to genotype-specific (GI.1 and GII.4) NoV 
strains represented in the vaccine (excluding co-infection with Salmonella, Shigella or Campylobacter) is assumed to 
be 0.5-1.7% per subject-training period of observation based on NHRC AGE NoV surveillance data at the planned 
trial sites. Under such attack rate assumptions, approximately 2800-8700 subjects, randomized in 1:1 ratio to NoV 
vaccine and saline placebo, would be needed to reach 30 cases of moderate or severe AGE due to NoV infection by 
genotype-specific (GI.1 or GII.4) NoV strains. As this is a case-driven trial, subjects will continue to be enrolled and 
followed through the entire active AGE surveillance period until ~ 30 cases of moderate or severe AGE due to 
genotype-specific (GI.1or GII.4) NoV strains, excluding co-infection are confirmed. Thereafter, the trial will be 
closed to further enrollment. 
Data Monitoring Committee: 
An overall DMC is established to evaluate overall safety of the NoV program on an ongoing basis. The DMC will 
review the safety and immunogenicity results to the NoV vaccine (Subset A) and the results to the selected 
co-administered vaccines (Subset A). The overall program DMC charter is a separate document. 
NOR-211 Version 3.0 (15 November 2017) 
0033
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Norovirus GI.1/GII.4 Bivalent VLP Vaccine 
 
Trial No. NOR-211 
Page 33 of 103 
Protocol Version 3.0 
15 November 2017 
1.0 TITLE PAGE 
CONFIDENTIAL 
2.1 
Schedule of Trial Procedures 
Table 2.a 
Schedule of Trial Procedures for all Subjects (2800-8700 subjects) 
Procedure 
Screening 
Day 1 
Day 8 
Day 29 
End of active AGE 
Surveillance period 
(a) (Day 45/ET 
Visit window 
-7 days 
 
+ 7 days 
+ 7 days 
- 7 days 
Visits 
X 
X 
X 
X 
X 
Screening interview 
X 
 
 
 
 
Signed informed consent 
X 
 
 
 
 
Assessment of eligibility criteria (b) 
X 
X 
 
 
 
Demographics 
X 
 
 
 
 
Medical history 
X 
 
 
 
 
Prior medications 
X 
 
 
 
 
Concomitant medications & vaccinations 
 
X 
 
 
 
Pregnancy screening (c) 
 
X 
 
 
 
Randomization (d) 
 
X 
 
 
 
Trial treatment (d) 
 
X 
 
 
 
SAEs (e) 
 
X 
X 
X 
X 
Blood draw (10-15 mL) (f) 
X 
X 
X 
X 
(a) 
Trial personnel will follow subjects through Day 45. If a subject early terminates (ET), Day 45 procedures, as applicable, should be performed. 
(b) 
Eligibility by review of inclusion/exclusion criteria will be documented before randomization and before vaccination. Eligibility criteria can be assessed initially within 7 days 
prior to Day 1 procedures and/or on Day 1. 
(c) 
Pregnancy testing by serum or urine must be done within 72 hours prior to vaccination. Results must be confirmed and documented as negative prior to trial dose administration. 
If more than 72 hours have elapsed since pregnancy test was performed, the serum or urine pregnancy test must be repeated within 72 hours prior to trial dose administration by 
either method. 
(d) 
After written informed consent is obtained within 7 days prior to vaccination or on Day 1, subsequent study procedures including blood draw and randomization may be done. 
Subjects will be randomized 1:1 to receive NoV GI.1/GII.4 bivalent VLP vaccine or placebo (saline). On Day 1, the subject will receive the study dose he/she was randomized 
to receive. The study dose will be administered IM in the middle 1/3 of the deltoid muscle. After vaccination, the subject will be observed for at least 15 minutes. If the 
investigational trial dose is delayed beyond the day the routine immunizations required by the US military are given, the trial dose may be administered later during the training 
period. For subjects in Subset A, those concomitant required vaccines administered on Day 1 (the same day as the NoV GI.1/GII.4 bivalent VLP vaccine or placebo) will be 
0034
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-211 
Page 34 of 103 
Protocol Version 3.0 
15 November 2017 
 
CONFIDENTIAL 
recorded on the subject’s source documents (by manufacturer, lot number, expiry date) and subsequently recorded in the electronic case report form (eCRF). For all subjects 
enrolled after Subset A, this information will be filed at the site as source documentation but not recorded in the eCRF. 
(e) 
SAEs and AEs leading to trial withdrawal will be collected and recorded in the eCRF for all subjects by actively monitoring at each visit from Day 1 through to the end of the 
active AGE surveillance period. SAEs will be reported to the sponsor within 24 hours of the investigator becoming aware of the event. 
(f) 
Blood will be collected on all subjects once within 7 days prior to vaccination or on Day 1, and once post-vaccination on each of Days 8 and 29 and at the end of the active 
surveillance period (EOS) in order to explore a level of protection. The EOS sera will also provide information on asymptomatic NoV illness for those subjects who develop a 
4-fold or greater rise in anti-NoV antibodies between Day 29 and EOS. 
Note: ET: early termination visit 
 
0035
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-211 
Page 35 of 103 
Protocol Version 3.0 
15 November 2017 
 
CONFIDENTIAL 
Table 2.b 
Schedule of Additional Trial Procedures and Analyses for the Subjects Meeting Work-up and AGE Case 
Definitions 
Procedure 
AGE onset 
Once Day 7 – 14 
after each AGE 
onset 
Once Day 21 – 29 
after each AGE 
onset 
End of active AGE 
Surveillance period a 
(Day 45/ET 
Visit window 
 
+ 7 days 
+ 7 days 
- 7 days 
AGE symptom log (a) 
X 
 
 
 
Stool sample collection (b)  
X 
X 
X 
X 
Vomitus sample collection (b) 
X 
 
 
 
Convalescent blood draw (5 -10 mL) (c)  
 
X 
 
 
In case of AGE: 
(a) 
During the AGE surveillance period (Day 1 through Day 45), those subjects, who present with AGE, will be instructed to record their AGE symptoms on the logs and report for 
assessment at the next trial visit. Initial AGE symptom logs will be given at trial entry to record AGE symptoms. Subjects will be instructed to return any subsequent logs and the 
latest AGE symptom log at the next trial visit. 
(b) 
For those subjects who present with AGE, a stool specimen and a vomitus specimen (vomitus if available) will be collected as soon as possible after the onset of each new 
episode of AGE for processing and subsequent RT-PCR testing. If no samples are provided at AGE onset, samples should be obtained as soon as possible thereafter. If samples 
at AGE onset are inadequate ie too small for both RT-PCR to NoV and co-infection tests, the sample should be prioritized for RT-PCR to NoV and a subsequent sample should 
be obtained for co-infection testing as soon as possible thereafter. If samples become lost, destroyed, damaged or otherwise unavailable for use, AGE onset samples should be 
repeated as soon as possible. After the initial stool specimen is obtained at the onset of AGE; up to three additional stool specimens (optional), will be obtained once between 7 
and 14 days, once between 21 and 29 days and once at EOS. The onset of AGE is defined as the date the subject initially presents with vomiting and diarrhea. 
(c) 
For those subjects who present with AGE, a convalescent blood sample of 5 – 10 mL of blood will be collected once between 7 and 14 days after the onset of each new episode 
of AGE, defined as the date the subject initially presents with vomiting or diarrhea. 
0036
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-211 
Page 36 of 103 
Protocol Version 3.0 
15 November 2017 
 
CONFIDENTIAL 
Table 2.c 
Schedule of Additional Trial Procedures and Analyses for Subsets A and B (200 subjects in each subset for a total 
of 400) 
Procedure 
Screening 
Day 1 
Day 8 a 
Day 29 
End of active AGE 
Surveillance period 
(a) (Day 45/ET 
Visit window 
- 7 days 
 
+ 7 days 
+ 7 days 
- 7 days 
Subsets A and B subjects only - 
Concomitant medications  
 
 
X 
X 
 
Subset A and B subjects only - Diary 
cardb 
 
 
 
 
 
Distribution 
 
X 
 
 
 
Review/collection  
 
 
X 
 
 
Subset A and B subjects only – 
solicited and unsolicited AEs (b) 
 
X 
X 
X 
 
Subset A subjects only - Saliva 
specimen (c) 
 
X 
 
 
 
Subset A subjects only – Additional 
Blood volume (5 – 10 mL) (d) 
 
X 
 
X 
 
(a) 
Trial personnel will follow subjects through Day 45. If a subject early terminates (ET), Day 45 procedures, as applicable, should be performed. 
(b) 
For Subset A and B subjects only, a diary card for daily collection of solicited AEs for 7 days following vaccination (including the day of vaccination) will be recorded by the 
subject, reviewed with the subject, and entered into the eCRF. For Subset A and B subjects only, Unsolicited AEs for 28 days following vaccination (including the day of 
vaccination) will be collected by interview with the subjects on Day 29 and categorized by the investigator by severity (mild, moderate or severe) and causality (related or not 
related to trial vaccine). 
(c) 
For Subset A only, saliva will be collected and assayed for secretor status (positive or negative for FUT-2 gene expression, respectively), to analyze the serum anti-NoV antibody 
immune responses by secretor status. A single saliva specimen will be collected from these subset A subjects once anytime during the trial (within 7 days prior to or after 
vaccination). 
(d) 
An additional volume of 5 – 10 mL of blood will be collected at the same two time points, once within 7 days prior to vaccination or on Day 1 and once on Day 29 from the first 
200 subjects enrolled (Subset A only) to assess immunogenicity to selected co-administered vaccines. These sera will be tested for antibody responses to adenovirus vaccine type 
4, to meningococcal vaccine serogroup A, and to the seasonal influenza vaccine strain type A/H3. 
Note: ET: early termination
0037
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use

1.0 TITLE PAGE 
Norovirus GI.1/GII.4 Bivalent VLP Vaccine 
 
Trial No. NOR-211 
Page 37 of 103 
Protocol Version 3.0 
15 November 2017 
 
CONFIDENTIAL 
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, 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 and by doing so agrees that it accurately describes the results of the trial. 
0038
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-211 
Page 39 of 103 
Protocol Version 3.0 
15 November 2017 
 
 
SAP 
Statistical Analysis Plan 
SBA 
Serum Bactericidal Assay 
SOC 
System Organ Class 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
US 
United States 
VE 
Vaccine Efficacy 
VLP 
Virus-like Particles 
VPDI 
Vaccine Preventable Disease Incidence 
 
0040
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-211 
Page 40 of 103 
Protocol Version 3.0 
15 November 2017 
 
 
3.4 
Corporate Identification 
TV 
Takeda Vaccines, Inc. 
VBU 
Vaccines Business Unit 
 
0041
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Norovirus GI.1/GII.4 Bivalent VLP Vaccine 
 
Trial No. NOR-211 
Page 41 of 103 
Protocol Version 3.0 
15 November 2017 
 
 
4.0 
INTRODUCTION 
4.1 
Background 
Noroviruses (NoVs) cause an acute debilitating illness characterized by vomiting and diarrhea [3]. 
According to the Centers for Disease Control and Prevention (CDC), 21 million cases of acute 
gastroenteritis (AGE) are due to NoV each year in the United States (US) [4, 5]. NoVs have 
emerged as an important cause of outbreaks of viral gastroenteritis worldwide. These outbreaks 
can occur in all age groups, wherever people gather, and commonly result in significant morbidity 
and mortality, particularly in the very old and very young [6, 7]. In addition, NoV illnesses and 
outbreaks exact a significant socioeconomic toll on businesses, hospitals, schools and other closed 
settings, such as dormitories and military barracks. 
AGE is commonly reported within training and deployed US military populations [8-13]. 
Viral-associated AGE is easily transmitted from human-to-human and can rapidly spread 
throughout an entire military unit causing widespread incapacitation often leading to disruption 
and reduction in operational readiness. NoV was found to be a major cause of AGE outbreaks and 
sporadic AGE cases among US military personnel deployed during the Persian Gulf War in 1991 
[13] as well as coalition forces in Gulf War II, Iraq and Afghanistan beginning in 2003. Similar 
outbreaks have been described in European military units deployed to these areas. 
AGE surveillance data collected over multiple seasons (2011 through 2014) from the Naval Health 
Research Center’s (NHRC) Enteric Disease Surveillance Program (EDSP) support that NoV was 
the predominant pathogen identified in cases of AGE among US military subjects at the Marine 
Corps Recruit Depot (MCRD-SD) in San Diego, California, at the MCRD in Parris Island 
(MCRD-PI), South Carolina, and at the Naval Recruit Training Center in Great Lakes 
(NRTC‐GL), Illinois. AGE due to NoV was originally known as “winter vomiting disease”, and as 
expected, the highest detection rate of AGE due to NoV was during the months of September to 
May for both Marine and Navy subjects. The estimated population-based incidence of NoV illness 
at these training centers is 10 to 35 cases per 1000 subjects during training (an average of 7.6 
weeks) in this high season (September-May) [communication from NHRC-EDSP]. 
Currently, no vaccine exists for protection against AGE due to NoV. Given the disruptive effect of 
AGE due to NoV upon military training, readiness and performance, it is important to develop an 
effective vaccine. Takeda has conducted two proof of concept NoV vaccine and live oral challenge 
studies; a monovalent GI.1 VLP vaccine delivered as intranasal dry powder followed by live NoV 
genotype GI.1 oral challenge [14-18] and a bivalent GI.1/GII.4 bivalent VLP vaccine delivered by 
intramuscular (IM) injection followed by live NoV genotype GII.4 oral challenge [19, 20]. Both 
trials showed that the VLP based vaccines reduced severity of AGE due to the challenge viruses. 
The more robust immunogenicity drove the decision to pursue the IM route of administration. 
The NoV GI.1/GII.4 bivalent VLP vaccine for IM injection to be evaluated in this trial contains 
both NoV GI.1 and NoV GII.4 VLPs as the antigens formulated with aluminum as aluminum 
hydroxide (Al(OH)3) adjuvant. Aluminum salt-based adjuvants have a demonstrated safety profile 
of over six decades [21]. The GI.1 VLP represents a single GI.1 strain and the GII.4 VLP consists 
0042
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-211 
Page 42 of 103 
Protocol Version 3.0 
15 November 2017 
 
 
of a consensus sequence of three GII.4 strains (cVLP). NoV VLPs are non-infectious because they 
do not contain viral ribonucleic acid (RNA). 
Prior safety and immunogenicity data for the NoV vaccine given by the IM route are available 
from approximately 1000 adult subjects, evaluated in five Takeda clinical trials (LV03-104 [20], 
LV03-105 [19], NOR-107, NOR-201, and NOR-210). The NoV vaccine evaluated in these trials 
either contained both Al(OH)3 plus monophosphoryl lipid A (MPL) adjuvants combined or the 
Al(OH)3 adjuvant alone. In clinical trials with the NoV vaccine, a single suspected unexpected 
serious adverse reaction (SUSAR) was reported, and to date, no other serious adverse events 
(SAEs) related to the vaccine were reported in these trials. Trial NOR-107 conducted in adults 
aged 18-64 years, a Phase II dosage, adjuvant justification, safety, and immunogenicity trial, 
evaluated 11 vaccine formulations, and showed that the NoV VLP vaccine adjuvanted with 
aluminum as Al(OH)3 adjuvant was as immunogenic as the NoV VLP vaccine adjuvanted with 
Al(OH)3 and MPL combined. 
Refer to the current Investigator Brochure of Takeda’s NoV GI.1/GII.4 bivalent VLP vaccine for 
additional product information and a more detailed review of pre-clinical and clinical studies [22]. 
4.2 
Rationale for the Proposed Trial 
NoV outbreaks seriously impact military and civilian adult populations. Surveillance studies 
conducted over multiple years have demonstrated a consistently high incidence of NoV-related 
illness among US military subjects. Moreover, the success of a recent adenovirus vaccine efficacy 
(VE) trial in military subjects further supports the selection of the population for this trial [23]. The 
primary goal of this Phase 2b clinical trial is to evaluate the efficacy of the NoV vaccine against 
moderate or severe acute gastroenteritis (AGE) due to genotype-specific (GI.1 and GII.4) NoV 
strains in 2800-8700 healthy US military adult subjects. Specifically, this trial will inform whether 
the NoV vaccine will provide protection against circulating NoV strains. Data from this trial will 
further inform the clinical development plan for Phase 3 of the NoV vaccine. 
The trial will be conducted in accordance with the protocol, the International Conference on 
Harmonization and Good Clinical Practice (ICH-GCP) Guidelines, 21 Code of Federal 
Regulations (CFR) Part 56 & 50, and applicable regulatory requirements. 
0043
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-211 
Page 49 of 103 
Protocol Version 3.0 
15 November 2017 
 
 
All enrolled subjects will be evaluated for serious adverse events (SAEs) and any adverse events 
(AEs) that lead to trial withdrawal throughout the active AGE surveillance period. 
The 200 subjects in Subset A and 200 subjects in Subset B will be evaluated for solicited local and 
solicited systemic AEs for 7 days after dosing using diary cards returned on or after Day 8 and for 
unsolicited AEs for 28 days after dosing by interview on or after Day 29. 
A schematic of the trial design is included as Figure 6.a. A schedule of trial procedures is provided 
in Section 2.1. 
Figure 6.a 
Schematic of Trial Design 
a Fresh stol and/or vomitus specimens for each new onset AGE disease episode and a convalescent serum once 7-14 
days thereafter. As 
available, a 2
nd
and 3
rd
stol specimen wil be obtained once 7-14 
days, and once 
21-28 
days thereafter and at the end of active AGE 
surveilance period (Day 45). 
b. Routine imunizations administered as required by the US military.
c. Blod draw for serology (al subjects). Diary card colection and review (subjects in subsets A and B).
d. Blod draw for serology (al subjects). Safety asesment by interview (subjects in subsets A and B).
e. Blod draw for serology (al subjects) at the end of active AGE surveilance period (Day 45). 
Day 1
28
0
 to 
870 
s ub
j ec
ts
Randomization: 
1 :1
B l o
d Draw
Arm A (Day 1)
14
0
 to 
4350 
s ub
j ec
ts
NoV
 v ac
c i ne
 ( b)
Day 8 ( c)
B l o
d Draw
End of active AGE 
surveillance period ( e)
B l o
d d
r aw
ACUTE GASTROENTERITIS (AGE) SURVEILLANCE (a)
Arm B (Day 1) 
14
0
 to 
4350 
s ub
j ec
ts
Pl a c e b o  Co
n trol
 ( b)
Day 8 ( c)
B l o o d  Draw
End of active AGE 
surveillance period ( e)
B l o
d d
r aw
Day 29 ( d)
B l o
d Draw
Day 29 ( d)
B l o o d  Draw
 
Work-up for AGE in ill subjects: 
At the medical clinic, the subject will be assessed to determine if they have an AGE that meets the 
work-up definition: 
 
1 or more episodes of vomiting within 24 hours judged by the investigator as not related to the 
training AND/OR; 
 
Any diarrhea episode of 3 or greater severity of diarrhea on a 5-point scale* within 24 hours. 
* Grade 1: fully formed (normal); Grade 2: soft (normal); Grade 3: thick liquid (diarrheal); 
Grade 4: opaque watery (diarrheal); or Grade 5: Rice-water (diarrheal) (Appendix E]. 
Subjects who meet the work-up definition will provide a fresh stool specimen, and vomitus 
specimen (if available) for processing and later detection of NoV by RT-PCR and be assessed for 
disease severity. Subjects will receive standard of care treatment for AGE disease from the site 
clinic and additional AGE disease symptom logs will be given to record further AGE symptoms 
until resolution. Subjects will be instructed to return all subsequent AGE symptom logs to the trial 
staff at the next trial visit. 
0050
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-211 
Page 50 of 103 
Protocol Version 3.0 
15 November 2017 
 
 
NoV AGE case definition in ill subjects: 
 
A case of NoV AGE is defined as one occurring > 7 days after immunization until the end 
of the active AGE surveillance period. 
 
A NoV AGE case is defined as meeting the work-up definition plus a NoV positive stool 
sample or vomitus sample confirmed by RT-PCR. In circumstances where both stool and 
vomitus samples are obtained, the subject will be considered NoV positive if either 
specimen is confirmed NoV positive by RT-PCR. 
Severity of AGE is defined as follows: 
Mild 
 
1 to 2 episodes of vomitinga within 24 hours AND/OR. 
 
3 unformed stoolsb within 24 hours 
Moderate 
 
3 to 5 episodes of vomitinga within 24 hours AND/OR 
 
4 to 5 unformed stoolsb within 24 hours 
Severe 
 
6 or more episodes of vomitinga within 24 hours AND/OR 
 
6 or more unformed stoolsb within 24 hours AND/OR 
 
Hospital admission and/or intravenous rehydration for mild or greater AGE 
(a) 
Judged by the investigator as not due to the training; uses the Common Terminology Criteria for AEs (CTCAE) for vomiting 
episodes. 
(b) 
For definition purposes, unformed stools are those meeting a 3 or greater severity of diarrhea on a 5-point scale (*noted 
above). 
Notes: “Within 24 hours” refers to a rolling time period. That is, the criteria will be considered to have been met if occurring during 
any 24-hour period between the onset and end of AGE symptoms. 
A new episode of vomiting is defined as one that occurs at least 5 minutes after the previous one. 
A new episode of diarrhea is defined as ‘a trip to the toilet’. 
6.2 
Justification for Trial Design, Dose, and Endpoints 
NoV outbreaks seriously impact military adult populations; this justifies the selection of this 
population for the trial. 
Data generated to date with Takeda’s NoV GI.1/GII.4 bivalent VLP vaccine administered by IM 
injection from several Phase I or II studies (LV03-104, NOR-107 and NOR-201) with various 
dosages of antigen (see IB), show that peak immune responses were observed 8 days after the first 
dose, with a second dose given 28 days later having only a limited effect. Thus, a single dose 
regimen will be evaluated in the present trial. The aluminum concentration per dose was selected 
empirically from data that demonstrated that this amount of aluminum enhanced the 
immunogenicity of the vaccine [21]. Aluminum salt-based adjuvants have a demonstrated safety 
profile of over six decades [21]. Each dose (0.5 mL) delivers 15 μg of GI.1 NoV VLP, 50 μg of 
GII.4 NoV VLP (consensus of 3 strains), and 500 μg of aluminum as Al(OH)3). Approximately 
1000 subjects have received the NoV bivalent vaccine by IM injection and all doses contained the 
Al(OH)3 adjuvant. 
0051
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-211 
Page 51 of 103 
Protocol Version 3.0 
15 November 2017 
 
 
The U.S. Military administers multiple licensed vaccines to protect enlisted recruits in basic 
training (Appendix D). The immunogenicity of the co-administration of those vaccines on the 
same day with the NoV vaccine has not previously been assessed. The collection of solicited and 
unsolicited symptoms following these vaccinations is consistent with other vaccine evaluation 
studies. These data will be provided to the DMC for their review. (Refer to Section 13.2. Interim 
Analysis) 
Enrollment will begin prior to or during the NoV high season (between September and May). If the 
number of AGE cases due to NoV has not been reached by the end of the first season (end of May), 
enrollment may be continued if more AGE cases are actively accruing later in the current season, 
may be stopped due to the lower incidence of NoV infection, and/or may be continued the 
following September (second season). This duration corresponds to the window of time during 
which ~ 30 AGE cases due to NoV (GI.1/GII.4 or any NoV genogroup GI or GII strain) will occur. 
The AGE disease severity definitions are based on the proceedings of the External Clinical Expert 
meeting: NoV vaccine Phase 3 efficacy trial designs working session (internal document) and 
CTCAE Version 4.0 [26]. Unformed stools are those meeting a 3 or greater severity of diarrhea on 
a 5-point scale [25] (Appendix E). Detection of NoV by RT-PCR in vomitus in addition to stool, 
has been described [27] and vomitus specimens will also be evaluated when collected in addition to 
the stool specimens. 
6.3 
Duration of Subject’s Expected Participation in the Entire Trial 
Trial participation is expected to be from enrollment through EOS (trial Day 45). 
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 one or more of the following criteria are satisfied that 
require temporary suspension or early termination of the trial. 
 
New information or other evaluation regarding the safety or efficacy of the investigational 
vaccine that indicates a change in the known risk/benefit profile, such that the risk/benefit is no 
longer acceptable for subjects participating in the trial. 
 
Significant deviation from Good Clinical Practice (GCP) that compromises the ability to 
achieve the primary trial objectives or compromises subject safety. 
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. 
0052
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-211 
Page 52 of 103 
Protocol Version 3.0 
15 November 2017 
 
 
6.4.3 Procedures for Premature Termination or Suspension of the Trial or the 
Participation of Investigational Site(s) 
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 or their designee; the procedure will be followed by applicable investigational sites 
during the course of termination or trial suspension. 
0053
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-211 
Page 53 of 103 
Protocol Version 3.0 
15 November 2017 
 
 
7.0 
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS 
All entry criteria, including test results, need to be confirmed prior to randomization. 
7.1 
Inclusion Criteria 
Subject eligibility is determined according to the following criteria: [Criteria 1-4 are required for 
all trials] 
1. The subject signs and dates a written, informed consent form 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. 
2. Male or female subjects, 18 to 49 years of age. 
3. Individuals who are in good health at the time of entry into the trial as determined by medical 
history and the clinical judgment of the investigator. 
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. Pregnancy. 
2. Known hypersensitivity to any of the NoV GI.1/GII.4 bivalent VLP vaccine components 
(including excipients). 
3. Subjects with known hypersensitivity or allergy to any of the licensed required concomitant 
vaccine components to be administered (including excipients of these vaccines). 
4. Any condition or circumstance that the investigator determines would interfere with trial 
evaluation or interpretation. 
5. Subjects with known or suspected impairment or alteration of immune function. 
6. Subjects with a history of AGE within 14 days of enrollment. 
7. Subjects with a history of body temperature of 38.0°C (100.4°F) or higher within 3 days of 
intended trial vaccination. 
8. Subjects who have received blood, blood products, and/or plasma derivatives or any parenteral 
immunoglobulin antibody preparation in the past 3 months. 
9. Immunosuppressive therapy within 3 months or systemic (eg, oral or parenteral) corticosteroid 
treatment within 60 days prior to investigational trial dose administration. 
10. Subjects participating in any clinical trial with another investigational product 30 days prior to 
the first trial visit or intending to participate in another clinical trial at any time during the 
conduct of this trial. 
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11. Subjects who are first-degree relatives of individuals involved in the conduct of the trial. 
12. Individuals with any history of progressive or severe neurologic disorder, seizure disorder or 
neuro-inflammatory disease (eg Guillain-Barré syndrome). 
13. Individuals with history or any illness that, in the opinion of the investigator, might interfere 
with the results of the trial or pose additional risk to the subjects due to participation in the trial. 
14. Individuals who received any other vaccines within 14 days (for inactivated vaccines) or 28 
days (for live vaccines) prior to enrollment in this trial with the exception of routine 
immunizations as per Military Procedures (see Appendix D). 
15. If female of childbearing potential, sexually active, and has not used any of the “acceptable 
contraceptive methods” for at least 2 months prior to trial entry: 
a. 
Of childbearing potential is defined as status post onset of menarche and not 
meeting any of the following conditions: menopausal for at least 2 years, status 
after bilateral tubal ligation for at least 1 year, status after bilateral oophorectomy, 
or status after hysterectomy. 
b. Acceptable birth control methods are defined as one or more of the following: 
i. Hormonal contraceptive (such as oral, injection, transdermal patch, 
implant, cervical ring). 
ii. Barrier (condom with spermicide or diaphragm with spermicide) each and 
every time during intercourse. 
iii. Intrauterine device (IUD). 
iv. Monogamous relationship with vasectomized partner. Partner must have 
been vasectomized for at least six months prior to the subjects’ trial entry. 
v. Abstinence, defined as refraining from heterosexual intercourse, ie sexual 
intercourse with risk of conception, during the entire study period. 
16. If female of childbearing potential and sexually active, refusal to use an “acceptable 
contraceptive method” from Day 1 through 6 months after the last dose of trial vaccine. In 
addition, they must be advised not to donate ova during this period (Section 9.1.13). 
17. If male and sexually active, the subject must be advised not to donate sperm from Day 1 
through 6 months after the last dose of trial vaccine. 
18. Any positive or indeterminate pregnancy test. 
There may be instances when individuals meet all entry criteria except one that relates to transient 
clinical circumstances (eg, temperature elevation or recent use of excluded medication or 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. 
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7.3 
Criteria for Delay of Vaccination and/or Blood Sampling 
After enrollment, subjects may encounter clinical circumstances that warrant a delay in the 
administration of trial vaccination. These situations are listed below. In the event that a subject 
meets a criterion for delay of vaccination, the subject may receive trial vaccination once the 
window for delay has passed as long as the subject is otherwise eligible for trial participation. 
 
Subjects who have received antipyretics/analgesic medications within 24 hours prior to the 
intended vaccine administration. 
 
If the investigational trial dose is delayed beyond the day the routine immunizations required 
by the US military are given, the trial dose may be administered later during the training 
period. 
7.4 
Criteria for Discontinuation or Withdrawal of a Subject 
The primary reason for discontinuation or withdrawal of the subject from the trial should be 
recorded in the [electronic] case report form (eCRF) using the following categories. For screen 
failure subjects, refer to Section 9.1.14. 
1. Protocol deviation: The subject may remain in the trial unless continuation in the trial 
jeopardizes the subject’s health, safety or rights. 
2. Adverse Event: The subject has experienced an AE that requires early termination because 
continued participation imposes an unacceptable risk to the subject’s health or the subject is 
unwilling to continue because of the AE. 
3. Lost to follow-up: The subject did not return to the clinic and attempts to contact the subject 
were unsuccessful and/or the subject graduated and left the base. Attempts to contact the 
subject must be documented. 
4. Withdrawal by subject: The subject wishes to withdraw from the trial. The reason for 
withdrawal, if provided, should be recorded in the 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 (ie, withdrawal due 
to an AE should not be recorded in the “voluntary withdrawal” category). 
5. Trial terminated by sponsor. 
6. Pregnancy: Any subject who, despite the requirement for adequate contraception, becomes 
pregnant during the trial will not receive further trial vaccines. The site should maintain contact 
with the pregnant subject and complete a “Clinical Trial Pregnancy Form” as soon as possible. 
In addition, the subject should be followed-up until the birth of the child, or spontaneous or 
voluntary termination; when pregnancy outcome information becomes available, the 
information should be captured using the same form. The subject should be reported as a 
withdrawal from trial and the reason for withdrawal (eg pregnancy) recorded in detail on the 
Trial Termination” eCRF and subject’ medical records. 
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7. Other. 
Note: The specific reasons should be recorded in the “specify” field of the eCRF. 
7.5 
Procedures for Discontinuation or Withdrawal of a Subject 
The investigator may discontinue or withdraw a subject’s trial participation at any time during the 
trial when the subject meets the trial termination criteria described in Section 7.4. In addition, a 
subject may discontinue his or her participation without giving a reason at any time during the 
trial. Should a subject’s participation be discontinued, the primary criterion for termination must 
be recorded, if possible. Subjects who withdraw from the trial or whose participation is 
discontinued should be followed-up for safety. Discontinued or withdrawn subjects will not be 
replaced. 
0057
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$

Norovirus GI.1/GII.4 Bivalent VLP Vaccine 
 
Trial No. NOR-211 
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day. Temperature excursions must be reported to the sponsor as soon as possible and use of these 
vaccines requires sponsor approval. 
8.1.3 Dose and Regimen 
Subjects will receive on Day 1 either one dose of the NoV GI.1/GII.4 bivalent VLP vaccine or 
saline placebo according to their random assignment. 
Routine vaccinations will be sourced and administered by and per US military procedures. (Refer 
to Appendix D. 
8.2 
Trial Vaccine Assignment and Dispensing Procedures 
The investigator or investigator’s designee will access the IRT within 7 days prior to or on Day 1 to 
obtain the subject number. Details of randomization and the IRT will be covered in the IRT user 
manual. 
The investigator or investigator’s designee will utilize the IRT to randomize the subject into the 
trial, including assignment into the subsets. During this contact, the investigator or designee will 
provide the necessary subject identifying information. 
The trial dose identification number to be administered will be assigned by the IRT. 
The vaccination will be administered by the unblinded designee according to the instructions in the 
Pharmacy Manual. 
Each subject will receive either 1 trial dose of NoV GI.1/GII.4 bivalent VLP vaccine or saline 
placebo on Day 1. The NoV GI.1/GII.4 bivalent VLP vaccine or saline placebo will be 
administered by IM injection into the middle third of the deltoid muscle. 
If sponsor-supplied vaccine is lost or damaged, the site can request a replacement from the IRT. 
Expired vaccines must not be administered. 
The investigator or designee will be responsible for overseeing the administration of trial doses to 
subjects enrolled in the trial according to the procedures stipulated in this trial protocol. All trial 
doses will be administered only by unblinded personnel who are qualified to perform that function 
under applicable laws and regulations for that specific trial. 
PRECAUTIONS TO BE OBSERVED IN ADMINISTERING THE TRIAL VACCINE: 
Prior to vaccination, a subject must be determined to be eligible for trial vaccination and it must be 
clinically appropriate in the judgment of the investigator to vaccinate. Eligibility for vaccination 
prior to administration is determined by evaluating the entry criteria outlined in this protocol 
(Sections 7.1 and 7.2). 
Eligibility for subsequent trial procedures is determined by following the criteria outlined in 
Section 7.0. 
Trial vaccines should not be administered to individuals with known hypersensitivity to any 
component of the vaccines. 
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Standard immunization practices are to be observed and care should be taken to administer the 
injection intramuscularly into the middle third of the deltoid muscle. Before administering the 
vaccine, the vaccination site is to be disinfected with a skin disinfectant (eg, 70% alcohol). Allow 
the skin to dry. DO NOT inject intravascularly. 
As with all injectable vaccines, trained medical personnel and appropriate medical treatment 
should be readily available in case of anaphylactic reactions following vaccination. For example, 
epinephrine 1:1000, diphenhydramine, and/or other medications for treating anaphylaxis should 
be available. 
8.3 
Randomization Code Creation and Storage 
Randomization personnel of the sponsor or designee will generate the randomization schedule(s). 
Randomization information will be stored in a secured area, accessible only by authorized 
personnel. 
8.4 
Trial Vaccine Blind Maintenance 
The trial vaccine blind will be maintained by the unblinded designee. 
8.5 
Unblinding Procedure 
The trial vaccine blind shall not be broken by the investigator unless information concerning the 
trial vaccine is necessary for the medical treatment of the subject. In the event of a medical 
emergency, if possible, the medical monitor should be contacted before the trial vaccine blind is 
broken to discuss the need for unblinding. 
For unblinding a subject, the trial vaccine blind can be obtained by the investigator, by accessing 
the IRT. 
The sponsor’s Pharmacovigilance Department must be notified as soon as possible if the trial 
vaccine blind is broken by the investigator. Notably, the completed unblinding form must be sent 
within 24 hours. The date, time, and reason the blind is broken must be recorded in the source 
document and the same information (except the time) must be recorded on the eCRF. 
If a subject is unblinded, the subject must be withdrawn from the trial. Subjects withdrawn from 
the trial due to unblinding should be followed for safety to the end of trial. Further details for 
dealing with safety follow-up for subjects withdrawn from the trial will be provided. 
8.6 
Accountability and Destruction of Sponsor-Supplied Vaccine(s) 
Vaccine supplies will be counted and reconciled at the site before being returned to the sponsor or 
designee as noted below. Sites will maintain source documents in addition to entering data in the 
IRT. 
The investigator or designee must ensure that the sponsor-supplied vaccine is used in accordance 
with the approved protocol and is administered only to subjects enrolled in the trial. To document 
appropriate use of sponsor-supplied vaccine(s) (NoV GI.1/GII.4 bivalent VLP vaccine and saline 
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placebo), the investigator must maintain records of all sponsor-supplied vaccine delivery to the 
site, site inventory, administration and use by each subject, and return to the sponsor or designee. 
Upon receipt of sponsor-supplied vaccine(s), the investigator or designee must verify the contents 
of the shipments against the packing list. The verifier should ensure that the quantity is correct, the 
trial vaccine is received within the labeled storage conditions (ie no cold chain break has occurred 
during transit), and is in good condition. If quantity and conditions are acceptable, investigator or 
designee will acknowledge receipt of the shipment by recording in IRT. 
If there are any discrepancies between the packing list and the actual product received, the sponsor 
or designee must be contacted to resolve the issue. The packing list should be filed in the 
investigator’s essential document file. 
The investigator must maintain 100% accountability for all sponsor-supplied vaccines (including 
placebo) received and administered during his or her entire participation in the trial. Proper 
vaccine accountability includes, but is not limited to: 
 
Verifying that actual inventory matches documented inventory. 
 
Verifying that the log is completed for the vaccine dose identification number used to prepare 
each dose. 
 
Verifying that all containers used are documented accurately on the log. 
 
Verifying that required fields are completed accurately and legibly. 
If any dispensing errors or discrepancies are discovered, the sponsor must be notified immediately. 
The investigator must record the current inventory of all sponsor-supplied vaccines [(NoV 
GI.1/GII.4 bivalent VLP vaccine and saline placebo) in a sponsor-approved vaccine accountability 
log. The following information will be recorded as a minimum: protocol number and title, name of 
investigator, site identifier and number, description of sponsor-supplied vaccine(s), expiry date 
and amount. The IRT will include all required information as a separate entry for each subject to 
whom sponsor-supplied vaccine is administered. 
The investigator will be notified of any expiry date or retest date extension of clinical trial material 
during the trial conduct if applicable. On expiry date notification from the sponsor or designee, the 
site must complete all instructions outlined in the notification, including segregation of expired 
clinical trial material for return to the sponsor or its designee for destruction. 
Prior to site closure or at appropriate intervals throughout the trial, before any clinical trial 
materials are returned to the sponsor or its designee for destruction, a representative from the 
sponsor or its designee will perform clinical trial material accountability and reconciliation. The 
investigator will retain a copy of the documentation regarding clinical trial material accountability, 
return, and/or destruction, and originals will be sent to the sponsor or designee. 
The pharmacist (or designated individual) at each site will be responsible for vaccine 
accountability and will document receipt, use, return, or destruction. Vaccine accountability 
documentation will be reviewed by the monitor during clinical monitoring visits. 
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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 Screening Interview 
Within the first few days after entry into the recruit training facilities, subject groups will be given 
a brief description of the trial. The trial will be introduced and explained by a trial staff member. A 
visual aid/video may be used. Subjects will be asked if they are interested to participate in the trial. 
If so, the subjects will undergo a screening interview. Notably, the screening interview will be 
performed by non-uniformed trial staff not involved in the training of the subjects to avoid any 
feeling of coercion [28]. Subjects may receive the routine immunizations required by the US 
military, before or after the screening interview. No flyers, emails or posters are planned to recruit 
potential trial subjects. 
9.1.2 Review Inclusion/Exclusion Criteria 
Eligibility by review of inclusion/exclusion criteria will be documented after informed consent 
(see Section 9.1.3) and before randomization (Refer to Sections 7.1 and 7.2). 
9.1.3 Informed Consent 
If the subject is interested to participate, trial staff will review the informed consent form and will 
highlight the key aspects of the trial. The consenting procedure may occur in small groups of up to 
three subjects at once. Notably, this procedure will be handled by non-uniformed trial staff not 
involved in the training of the subjects to avoid any feeling of coercion, and also include an 
Ombudsman [28]. 
The requirements of the informed consent are described in Section 15.2 and Appendix C. 
Informed consent must be obtained prior to the subject entering into the trial, and before any 
protocol-directed procedures are performed. The informed consent may be obtained within 7 days 
prior to vaccination or on Day 1. 
A unique subject number (screening number) will be assigned to each subject after informed 
consent is obtained from the IRT. If all eligibility criteria are fulfilled, this subject number will 
become the definitive subject number and will be used throughout the trial. Subject numbers 
assigned to subjects who fail screening should not be reused (Section 9.1.14). 
9.1.4 Demographics, Medical History and Prior Medications 
Demographic information to be obtained will include date of birth, gender, ethnicity, race as 
described by the subject. 
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Medical History will also be collected, 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. 
Adverse medical occurrences that occur after the subject signs the informed consent form but 
before administration of the trial dose, are to be documented in the Medical History. 
All medications, vaccines and blood products including the duration thereof, taken or received by 
the subjects within 3 months prior to the start of the trial are to be recorded on the source document 
and entered onto the Prior and Concomitant Medications eCRF. The use of antipyretics and/or 
analgesic medications within 24 hours prior to vaccination must be identified and the reason for 
their use (prophylaxis versus treatment) must be described in the source documents or the eCRF. 
Medications taken for prophylaxis are those intended to prevent the onset of AEs following 
vaccination. Medications taken for treatment are intended to reduce or eliminate the presence of 
symptoms that are present. 
These data must be written in the source documents. 
Prohibited Therapies (and see also Sections 7.2 and 7.3): 
 
Parenteral Ig preparation, blood products, and/or plasma derivatives within 3 months of trial 
vaccination; 
 
Immunosuppressive therapy within 3 months or systemic (eg, oral or parenteral) corticosteroid 
treatment within 60 days prior to trial dose administration; 
Receipt of any vaccine within 14 days (for inactivated vaccines) or 28 days (for live vaccines) 
prior to enrollment in this trial with the exception of routine immunizations as per Military 
Procedures (see Appendix D). If the investigational trial dose is delayed beyond the day the 
licensed vaccines are given, the trial dose may be subsequently administered later during the 
training period. 
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 informed consent. 
9.1.5 Documentation of Trial Entrance/Randomization 
Only subjects who have signed the informed consent form, meet all of the inclusion criteria and 
none of the exclusion criteria are eligible for entrance/randomization into the vaccination phase. 
The list of randomization assignments is produced by the unblinded statistician and processed by 
IRT. 
If the subject is found to be not eligible for randomization/trial phase, the investigator should 
record the primary reason for failure on the subject enrollment log. 
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9.1.6 Physical Examination 
Subjects have already undergone physical examination per Military Entrance Processing. Entry 
criteria will be based on investigator judgment and by review of the subject’s medical history. 
9.1.7 Assessment of HBGA Secretor Status 
A saliva specimen will be collected once during the trial (at any time pre- or post-vaccination) 
from subjects in Subset A for assessment of HBGA secretor status. 
9.1.8 AGE Disease Surveillance 
All subjects will have surveillance for AGE disease performed from Day 1 until the end of the 
active AGE disease surveillance period (Day 45). All participants will be given an AGE disease 
symptom log and a thermometer at trial entry within 7 days prior to vaccination or on Day 1 and 
instructed to record their AGE disease symptoms and report to the medical clinic as soon as 
possible. The subjects will record in the AGE disease symptom log the onset time of vomiting 
and/or diarrhea, their temperature, the number of episodes of vomiting and/or diarrhea, and the 
stop time of vomiting and/or diarrhea to calculate duration of AGE. The subjects will also 
document whether the symptom(s) have had impact on their ability to train. The subjects will be 
instructed to use the provided thermometers to measure and record their temperature on the AGE 
disease symptom log. The subjects will be informed that the recommended route to take their 
temperature is oral and instructed to use this route. At the medical clinic, the subject will be 
assessed to determine if they have an AGE disease that meets the work-up definition (see 
Section 6.1). Subjects who meet the work-up definition will be assessed for disease severity and 
provide a stool specimen and vomitus specimen for processing and later detection of NoV by 
RT-PCR. Subjects will only provide vomitus specimen if actively vomiting. All initial stool 
samples for each new onset episode of AGE will be analyzed for the following three enteric 
pathogens: Salmonella, Shigella, and Campylobacter. 
Subjects will receive standard of care treatment for AGE disease, and a new AGE disease 
symptom log will be given to record AGE disease symptoms until they resolve. Subjects will be 
instructed to return the latest AGE and any subsequent disease symptom log to the trial site at the 
next trial visit. A convalescent blood specimen for serology will be obtained once between 7 and 
14 days after the onset of the AGE disease. After the initial stool specimen obtained at the onset of 
AGE disease: as available, three additional stool specimens will be obtained once between 7 and 
14 days, once between 21 and 29 days and once at EOS. These follow-on stool specimens will be 
analyzed for NoV by RT-PCR. If an AGE event occurs within 7 days prior to the EOS visit 
(Day 45), a convalescent serum sample and a single optional stool sample should be collected at 
the EOS visit. There is no further follow-up for AGE after graduation from recruit training at Day 
45. 
9.1.9 Identification of Co-pathogens in Stool of Each Subject with New Onset AGE 
The initial stool specimen obtained from each subject with new onset of AGE will be evaluated for 
the following enteric pathogens: Salmonella, Shigella, and Campylobacter. Because the true cause 
0064
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0066
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ct to the Applicable Terms of Us

Norovirus GI.1/GII.4 Bivalent VLP Vaccine 
 
Trial No. NOR-211 
Page 66 of 103 
Protocol Version 3.0 
15 November 2017 
 
 
abnormalities, or maternal and/or newborn complications. This follow-up should occur even if the 
intended duration of safety follow-up for the trial has ended. 
Any pregnancy occurring following trial vaccine administration should be reported immediately, 
using a pregnancy notification form, to the contact listed in the Investigator Site File. 
Should the pregnancy occur after administration of a blinded trial vaccine, the investigator must 
inform the subject of their right to receive treatment information. If the subject chooses to receive 
unblinded treatment information, the individual blind should be broken by the investigator and 
procedures must be followed as described in Section 8.5. 
9.1.14 Documentation of Subjects who are not Randomized 
Investigators must account for all subjects who sign an informed consent. If the subject is found to 
be not eligible at this visit, the investigator should complete the eCRF. The IRT should be 
contacted as a notification of non-randomization. 
The primary reason for non-randomization is recorded in the eCRF using the following categories: 
 
Screen failure (did not meet one or more inclusion criteria or did meet one or more exclusion 
criteria), 
 
Withdrawal by subject, 
 
Trial terminated by sponsor. 
Subject numbers assigned to subjects who fail screening should not be reused. 
9.2 
Monitoring Subject Treatment Compliance 
The investigator will record all injections of trial vaccine given to the subject in the eCRF. 
9.3 
Schedule of Observations and Procedures 
The schedule for all trial-related procedures for all evaluations is shown in Section 2.1. 
Assessments should be completed at the designated visit/time point(s). 
9.3.1 Screening Procedures (Within 7 Days Prior to Vaccination or On Day 1) 
1. Informed consent (Section 9.1.3; Appendix C). 
2. Demographics. 
a. 
Concomitant medications and vaccinations. 
b. Medical history. 
3. Review of systems: Review of systems is a structured interview that queries the subject as to 
any complaints the subject has experienced across each organ system. 
4. Assessment of eligibility criteria. 
0067
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Norovirus GI.1/GII.4 Bivalent VLP Vaccine 
 
Trial No. NOR-211 
Page 67 of 103 
Protocol Version 3.0 
15 November 2017 
 
 
5. The site should schedule the next trial activity; 
6. The subject will receive a written reminder of the next planned trial activity. 
9.3.2 Vaccination Procedures (Within 7 Days Prior to Vaccination or On Day 1) 
 
Prior to vaccination: 
 
Confirm eligibility. Refer to Sections 7.1 and 7.2; 
 Perform a urine or serum pregnancy test for female subjects of child-bearing potential. Refer to 
Section 9.1.13. The pregnancy test must be done within 72 hours prior to vaccination. If more 
than 72 hours have elapsed prior to vaccination, the pregnancy test must be repeated by either 
method. 
 
If the subject meets all eligibility criteria: 
 
Randomize subject. Refer to Section 9.1.5; 
 
Collect data on concomitant medications and vaccinations. Refer to Section 9.1.4; 
 
Collect blood specimen once within 7 days prior to vaccination or on Day 1. Refer to 
Sections 9.1.10 and 9.1.11. Blood should be taken from the subject using an aseptic 
venipuncture technique. Refer to the detailed collection and handling procedures outlined 
in the Manual of Study Procedures. 
 
Collect saliva specimen once at any time during the trial from subjects in Subset A. 
 
Provide diary cards for subjects in Subsets A and B. 
 
Careful training of the subject on how to measure local AEs and body temperature, how to 
complete the diary card and how often to complete the diary card. Training of the subject 
on how to measure an injection site AE should be performed while the subject is under 
observation after vaccination. 
Diary card instructions must include the following: 
 
The subject must understand that timely completion of the diary card on a daily basis is a 
critical component of trial participation. The subject should also be instructed to write 
clearly and to complete the diary card in pen. Any corrections to the diary card should 
include a single strikethrough line with a brief explanation for any change and be initialed 
and dated. 
Please note: 
Diary cards will be the only source document allowed for remote collection of solicited local and 
systemic AEs (including body temperature measurements). The following additional rules apply 
to the documentation of safety information collected by diary card: 
 
The Diary Card should be reviewed with the subject. 
0068
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Norovirus GI.1/GII.4 Bivalent VLP Vaccine 
 
Trial No. NOR-211 
Page 68 of 103 
Protocol Version 3.0 
15 November 2017 
 
 
 
No corrections or additions to the diary card will be allowed after it is reviewed with the 
investigator/designee. 
 
Any data that is identified as implausible or incorrect, and confirmed by the subject to be a 
transcription error should be corrected by the subject on the diary card (the correction 
should include a single strikethrough line and should be initialed and dated by the subject). 
 
Any blank or illegible fields on the diary card not otherwise corrected as above will be 
missing in the eCRF. 
 
The site must enter all readable entries on the diary card into the eCRF. 
 
Any newly described solicited safety information should be added to the diary card by the 
subject and initialed and dated. Any new unsolicited safety information would be recorded 
in the subject source document as a verbally reported event and therefore captured as an 
AE and recorded in the AE eCRF. 
 
Starting on the day of vaccination, the subject will check for specific types of events at the 
injection site (solicited local AEs), any specific generalized symptoms (solicited systemic 
AEs), body temperature (by any method with oral route recommended), any other symptoms 
or change in the subject’s health status, and any medications taken. The subjects will be 
informed that the recommended route to take their temperature is oral and will be instructed to 
use this route. These solicited AEs and body temperature will be recorded in the diary daily for 
7 days. Assessments should preferably take place in the evening at day’s end. 
 
Temperature measurement is to be performed using the thermometer provided by the site. 
If the subject feels unusually hot or cold during the day, the subject should check their 
temperature. If the subject has fever, the highest body temperature observed that day 
should be recorded on the diary card. 
 
The measurement of solicited local AEs (erythema, swelling, and induration) is to be 
performed using the ruler provided by the site. 
 
The collection on the diary card of body temperature, solicited local AEs, and solicited 
systemic AEs will continue for a total of 7 days following vaccine administration. The 
diary cards will be collected and maintained in the trial records. The collection of 
unsolicited AEs and medications will continue for 28 days following vaccine 
administration and be collected by interview.  
After vaccination, the subject will be observed for at least 15 minutes. Information should be 
recorded in the electronic data capture (EDC) system. The investigator or delegate will take the 
opportunity to remind the subject how to measure solicited AEs and body temperature as part of 
this observation period. All safety data will be collected in the subject’s source documents. 
 
The subject will receive a written reminder of the next planned trial activity. The subject 
will be reminded to complete the Diary card daily and to contact the site if there are any 
questions and to contact the site immediately (or as soon as the subject is medically stable) 
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Norovirus GI.1/GII.4 Bivalent VLP Vaccine 
 
Trial No. NOR-211 
Page 69 of 103 
Protocol Version 3.0 
15 November 2017 
 
 
if the subject has a medical condition that leads to a hospitalization or an emergency room 
visit. All contact details will be provided to the subject. 
 
Vaccinate subject according to the assigned investigational trial dose. Refer to Section 8.1.3; 
 
Following vaccination: 
 
Observe subjects for at least 15 minutes after vaccination; 
 
Provide AGE disease symptom log. Refer to Section 9.1.8. 
 
The site should schedule the next trial activity; 
 
The subject will receive a written reminder of the next planned trial activity. 
 
Subjects will be instructed to complete the AGE disease symptom log and to come to the 
medical clinic if they experience vomiting, diarrhea or other symptoms of AGE disease. Refer 
to Section 9.1.8. 
The subject will be reminded to contact the site if there are any questions and to contact the site 
immediately (or as soon as the subject is medically stable) if the subject has a medical condition 
that leads to hospitalization or an emergency room visit. All contact details will be given to the 
subject. 
9.3.3 Post-Vaccination Procedures (Day 8 [+7 Days] and Day 29 [+7 Days]) 
The following post-vaccination procedures will be performed on Day 8 and Day 29: 
 
Collect blood specimen. Refer to Sections 9.1.10 and 9.1.11: 
Blood should be taken from the subject using an aseptic venipuncture technique. Refer to the 
detailed collection and handling procedures outlined in the Manual of Study Procedures. 
 
The site should schedule the next trial activity; 
 
The subject will receive a written reminder of the next planned trial activity. 
Subjects will be instructed to complete the AGE disease symptom log and to come to the medical 
clinic if they experience vomiting, diarrhea or other symptoms of AGE disease. Refer to 
Section 9.1.8. 
The subject will be reminded to contact the site if there are any questions and to contact the site 
immediately (or as soon as the subject is medically stable) if the subject has a medical condition 
that leads to a hospitalization or an emergency room visit. All contact details will be given to the 
subject. 
9.3.4 Clinic Visits after Vaccination (Day 8, Day 29, End of Active Surveillance) 
For all enrolled subjects, clinic visits that do NOT include a study investigational vaccination will 
be performed on Day 8, Day 29, and the EOS. 
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Norovirus GI.1/GII.4 Bivalent VLP Vaccine 
 
Trial No. NOR-211 
Page 70 of 103 
Protocol Version 3.0 
15 November 2017 
 
 
Blood should be taken from all subjects at these time points using an aseptic venipuncture 
technique for later serological testing. 
For all enrolled subjects, at the Day 8, 29 and EOS clinic visits, any SAEs or AEs leading to trial 
withdrawal will be collected by interview and recorded by the trial staff. The healthcare 
professional reviewing these data will discuss the AEs (if any) reported by the subject and will 
determine if any additional diagnoses and/or AEs are present and/or concomitant medications 
have been used. 
For the 400 subjects in Subsets A and B, the Diary Card will be reviewed on or after the Day 8 
clinic visit. At the Day 29 clinic visit, the unsolicited AEs that occurred within the prior 28 days 
will be collected by interview for these 400 subjects.  
The site should schedule the next trial activity clinic visit with the subject. 
The subject will receive a written reminder of the next planned trial activity. The subject will be 
reminded to contact the site if there are any questions and to contact the site immediately (or as 
soon as the subject is medically stable) if the subject has a medical condition that leads to a 
hospitalization or an emergency room visit. 
9.3.5 Procedures at AGE Disease Visit 
 
AGE disease surveillance: Refer to Section 9.1.8 and Table 2.b. 
 
Provide new AGE disease symptom log and instruct subjects to return any subsequent and the 
latest AGE disease symptom log to the medical clinic at the next trial visit; 
 
Instruct subjects to come back to the medical clinic once between 7 and 14 days after the onset 
of the AGE disease for the collection of a convalescent blood specimen. Refer to Section 9.1.8. 
After the initial stool specimen obtained at the onset of AGE disease: as available, three 
additional stool specimens will be obtained once between 7 and 14 days, once between 21 and 
29 days and once at end of the acute AGE surveillance period. Refer to Section 9.1.8. 
The subject will be reminded to contact the site if there are any questions and to contact the site 
immediately (or as soon as the subject is medically stable) if the subject has a medical condition 
that leads to a hospitalization or an emergency room visit. All contact details will be provided to 
the subject. 
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Norovirus GI.1/GII.4 Bivalent VLP Vaccine 
 
Trial No. NOR-211 
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Protocol Version 3.0 
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9.3.6 Procedures at End of Active AGE Disease Surveillance Period (- 7 days) 
 
Collect blood specimen. Refer to Sections 9.1.10 and 9.1.11: 
 
Blood should be taken from the subject using an aseptic venipuncture technique. Refer to the 
detailed collection and handling procedures outlined in the Manual of Study Procedures. 
 
Confirm that a saliva specimen was previously collected from subjects in Subset A. If not 
done, please collect at this visit. 
9.3.7 Safety Follow-up 
 
Collect data on AEs. Refer to Section 10.4. 
9.3.8 Post-Trial Care 
No post-trial care will be provided. 
9.4 
Schedule of Additional Observations and Procedures for Subjects in Subsets A and B 
Observations and procedures in addition to those described in Section 9.3 will be performed for 
subjects in Subsets A and B as detailed in Table 2.c. 
9.5 
Biological Sample Retention and Destruction 
As per the Manual of Study Procedures, collected specimens (blood, stool, vomitus, and saliva) 
will be processed, stored and frozen at each of the clinical sites until shipment to the central 
laboratory for analysis. The sponsor has put into place a system to protect subjects’ personal 
information to ensure optimal confidentiality and defined standard processes for sample and data 
collection, storage, analysis, and destruction. The NHRC shall receive an aliquot of biologic 
specimens (ie stool, serum, and saliva, or nucleic acid extracted from saliva) where adequate 
specimens remain after all testing in support of regulatory approval for commercial sale of trial 
drug has been completed. Any further testing of excess biological specimens will only be done 
after all testing in support of regulatory approval for commercial sale is completed, an appropriate 
IRB has reviewed and approved further testing proposed and both parties, Takeda and NHRC 
agree in writing to such testing. 
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Norovirus GI.1/GII.4 Bivalent VLP Vaccine 
 
Trial No. NOR-211 
Page 72 of 103 
Protocol Version 3.0 
15 November 2017 
 
 
10.0 
ADVERSE EVENTS 
10.1 
Definitions 
10.1.1 Adverse Events (AEs) 
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 
The occurrence of selected indicators of safety (Table 10.a) will be measured/collected for 
subjects included in Subset A. These will be summarized in the final report under the category 
“solicited adverse events” to differentiate them from other AEs which were not solicited. Any 
solicited local or systemic AE observed as continuing on Trial Day 8 will be recorded as an AE on 
the Adverse Event eCRF. 
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Norovirus GI.1/GII.4 Bivalent VLP Vaccine 
 
Trial No. NOR-211 
Page 73 of 103 
Protocol Version 3.0 
15 November 2017 
 
 
Table 10.a 
Local and Systemic AEs 
Local AEs (injection site): 
Pain 
Erythema 
Induration 
Swelling 
Systemic AEs (adult/child ≥ 6 years): 
Headache 
Fatigue 
Myalgia 
Arthralgia 
Vomiting 
Diarrhea 
Fever 
Note: Body temperature will be collected and recorded. The site staff will record the actual route taken on the CRF. 
Fever is defined as greater than or equal to 38°C (100.4°F) regardless of method used [29]. The subjects will be 
informed that the recommended route to take their temperature is oral and will be instructed to use this route. 
The intensity of solicited safety parameters will be assessed as described in Table 10.b. 
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Trial No. NOR-211 
Page 74 of 103 
Protocol Version 3.0 
15 November 2017 
 
 
Table 10.b 
Intensity Assessment for Solicited Safety Parameters  
Adverse Event 
Intensity grade 
Severity/Intensity 
Pain at injection 
site 
0 
None 
1 
Mild: No interference with daily activity 
2 
Moderate: Interference with daily activity with or without treatment 
3 
Severe: Prevents daily activity with or without treatment 
Erythema at 
injection site (a) 
0 
<25 mm 
1 
Mild: >25 – ≤ 50 mm 
2 
Moderate: > 50 – ≤ 100 mm 
3 
Severe: > 100 mm 
Induration at 
injection site (a) 
0 
<25 mm 
1 
Mild: >25 – ≤ 50 mm 
2 
Moderate: > 50 – ≤ 100 mm 
3 
Severe: > 100 mm 
Swelling at 
injection site (a) 
0 
<25 mm 
1 
Mild: >25 – ≤ 50 mm  
2 
Moderate: > 50 – ≤ 100 mm 
3 
Severe: > 100 mm 
Headache 
0 
None 
1 
Mild: No interference with daily activity 
2 
Moderate: Interference with daily activity with or without treatment 
3 
Severe: Prevents daily activity with or without treatment 
Fatigue 
0 
None 
1 
Mild: No interference with daily activity 
2 
Moderate: Interference with daily activity 
3 
Severe: Prevents daily activity 
Myalgia  
0 
None 
1 
Mild: No interference with daily activity 
2 
Moderate: Interference with daily activity 
3 
Severe: Prevents daily activity 
Arthralgia 
0 
None 
1 
Mild: No interference with daily activity 
2 
Moderate: Interference with daily activity 
3 
Severe Prevents daily activity 
Vomiting 
0 
None 
1 
Mild: No interference with daily activity  
2 
Moderate: Interference with daily activity 
3 
Severe: Prevents daily activity 
Diarrhea 
0 
None 
1 
Mild: No interference with daily activity  
2 
Moderate: Interference with daily activity 
3 
Severe: Prevents daily activity  
Fever(b) 
Record body temperature in °C/°F 
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Protocol Version 3.0 
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(a) Subjects are to record greatest surface diameter in mm in the Diary; 
(b) Fever is defined as greater than or equal to 38°C (100.4°F) regardless of method used. Body temperature will be 
collected and recorded. The site staff will record the actual route taken on the CRF. The subjects will be informed 
that the recommended route to take their temperature is oral and will be instructed to use this route. 
10.1.3 Serious Adverse Events (SAEs) 
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. 
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, including solicited systemic AEs (solicited local AEs are considered as related) to trial 
vaccine(s) 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/SAEs. 
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”. 
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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. 
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. 
 
Require vaccine discontinuation or a change in concomitant medication. 
 
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. 
Worsening of AEs: 
 
If the subject experiences a worsening or complication of an AE after starting administration of 
the trial vaccine, the worsening or complication should be recorded as a new AE. Investigators 
should ensure that the AE term recorded captures the change in the condition (eg, “worsening 
of…”). 
 
If the subject experiences a worsening or complication of an AE after any change in trial 
vaccine, the worsening or complication should be recorded as a new AE. Investigators should 
ensure that the AE term recorded captures the change in the condition (eg, “worsening of…”). 
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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 
informed consent 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 
Any unsolicited AEs (see Sections 9.1.12 and 10.1.1) for 28 days after the vaccination (including 
the day of vaccination) will be collected on or after Day 29 by interview of subjects in Subsets A 
and B. All findings for subjects in Subsets A and B experiencing AEs must also be reported in the 
subject's medical records. 
All AEs, whether considered related with the use of the trial vaccine or not, 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. All findings must be reported on an AE eCRF 
or SAE form, as necessary. Reporting of SAEs and AEs that led to trial withdrawal from Day 29 
onwards will be spontaneous or retrospectively collected at the end of the active AGE disease 
surveillance period. 
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(s) (“related” or “not related”). 
 
Investigator’s opinion of the causality (relationship) to trial procedure(s), including the details 
of the suspected procedure. 
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 
[If multiple doses] Action taken with the trial treatment (trial vaccine). 
 
Outcome of event. 
10.4.2 Collection and Reporting of Solicited AEs 
The occurrence of selected indicators of safety will be recorded on diary cards by the subjects 
included in Subsets A and B for 7 days after the vaccination (including the day of vaccination) and 
will be recorded on the “Local and Systemic Reactions” eCRF, as appropriate. Any solicited local 
or systemic AE observed as continuing on trial Day 8 will be recorded as an unsolicited AE on the 
AE eCRF. Any solicited local or systemic AE that resolved before Day 8 but recurred at a later 
time (ie, is discontinuous), will be recorded as an unsolicited AE on the AE eCRF. 
Any solicited AE that meets any of the following criteria must be entered as an AE on the AE 
eCRF: 
 
Solicited local or systemic AEs that lead the subject to withdraw from the trial. 
 
Solicited local or systemic AEs that lead to the subject being withdrawn from the trial by the 
investigator. 
 
Solicited local and systemic AEs that otherwise meet the definition of an SAE (see 
Section 10.1.3) 
10.4.3 Collection and Reporting of SAEs 
Collection of SAEs will be collected by close monitoring from the time that the subject is 
administered the trial vaccine (Day 1) up to the end of the active AGE disease surveillance period 
(at Day 45). 
For all subjects, SAE reporting will be collected at the clinic visits on Days 8, 29, and EOS. Any 
ongoing SAEs at the end of the active AGE disease surveillance period will be followed in the 
electronic health databases and personnel medical records of those subjects who remain active in 
the military. 
SAEs should be reported according to the following procedure: 
A sponsor SAE form that is part of the Investigator Site File 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(s) – if no unblinding is necessary, in a blinded way. 
 
Causality assessment. 
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During the active AGE disease surveillance period, the SAE form should be transmitted within 24 
hours to the attention of the contact(s) in the list provided to each site. All findings in subjects 
experiencing SAEs must also be reported in the subject's medical records. In case of death, a full 
pathologist’s report should be supplied, if possible 
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. AEs will not be monitored after the training has ended, unless deemed necessary by 
the sponsor. 
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 until 
otherwise explained. The timelines and procedure for follow-up reports are the same as those for 
the initial report. Ongoing SAEs at the end of trial visit will be followed by the Principal 
Investigator by review of the subject’s electronic health databases and personnel medical records. 
10.5.3 Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities 
The sponsor or designee will be responsible for reporting to regulatory authorities, including 
investigators and IRBs or IECs, as applicable, all suspected unexpected serious adverse reactions 
(SUSARs) and any other applicable SAEs reported up to the end of the active AGE disease 
surveillance period, 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 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 
An overall DMC is established to evaluate safety of the NoV program on an ongoing basis. The 
DMC will review the safety and immunogenicity results to the NoV vaccine (Subset A) and the 
results to the selected co-administered vaccines (Subset A). The program DMC charter is a 
separate document. 
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Trial No. NOR-211 
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12.0 
DATA HANDLING AND RECORDKEEPING 
The full details of procedures for data handling will be documented in the Data Management Plan. 
AEs, SAEs, medical history, and concurrent conditions will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA) (system organ class (SOC), High Level Group 
Term (HLGT), High Level Term (HLT), Low Level Term (LLT), Preferred Term (PT), and their 
corresponding descriptive terms). Drugs will be coded using the World Health Organization 
(WHO) Drug Dictionary. 
12.1 
Electronic CRFs (eCRF) 
Completed eCRFs are required for each subject who signs an informed consent. 
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 eCRFs 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 a 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 informed consent forms, 
subject authorization forms regarding the use of personal health information (if separate from the 
informed consent forms), copies 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, the International Conference on Harmonization (ICH) E6 Section 4.9.5 
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Norovirus GI.1/GII.4 Bivalent VLP Vaccine 
 
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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 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 for 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. 
0083
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Norovirus GI.1/GII.4 Bivalent VLP Vaccine 
 
Trial No. NOR-211 
Page 87 of 103 
Protocol Version 3.0 
15 November 2017 
 
 
compatible with the overall breakdown of the NHRC genotype analysis and the NoV genotypes 
identified by the CDC as the cause of NoV outbreaks reported to CDC over the same 2011-2014 
time period. The weekly incidence rates are then multiplied by 7.6 (average length of training) to 
obtain the incidence rate over training and thus during the trial. There is a further assumption that 
all subjects reporting to the medical station are moderate or severe AGE cases. 
The background incidence rate of moderate or severe NoV AGE due to genotype-specific (GI.1 
and GII.4) NoV strains represented in the vaccine (excluding co-infection with Salmonella, 
Shigella or Campylobacter) is assumed to be 0.5-1.7% per subject-training period of observation 
based on NHRC AGE NoV surveillance data at the planned trial sites. Under such attack rate 
assumptions, approximately 2800-8700 subjects, randomized in 1:1 ratio to NoV vaccine and 
saline placebo, would be needed to reach 30 cases of moderate or severe AGE due to NoV 
infection by genotype-specific (GI.1 or GII.4) NoV strains. As this is a case-driven trial, subjects 
will continue to be enrolled and followed through the entire active AGE surveillance period until ~ 
30 cases of moderate or severe AGE due to genotype-specific (GI.1or GII.4) NoV strains, 
excluding co-infection are confirmed. Thereafter, the trial will be closed to further enrollment. 
Table 13.a 
NHRC AGE NoV Surveillance Data at Planned Trial Sites 
AGE Incidence Rate (Oct-May) 
  
2011-2012 
2012-2013 
2013-2014 
All Years 
MCRD PI 
0.24% 
0.41% 
0.16% 
0.24% 
MCRD SD 
0.52% 
0.64% 
0.36% 
0.37% 
Great Lakes 
0.37% 
1.41% 
0.83% 
0.80% 
Total 
0.32% 
0.74% 
0.39% 
0.44% 
AGE Incidence Rate (Jun-Sep) 
  
2011-2012 
2012-2013 
2013-2014 
All Years 
MCRD PI 
0.20% 
0.06% 
0.09% 
0.11% 
MCRD SD 
0.20% 
0.17% 
0.12% 
0.17% 
Great Lakes 
0.29% 
0.71% 
0.39% 
0.46% 
Total 
0.19% 
0.28% 
0.19% 
0.23% 
AGE Winter Rates - AGE Summer Rates 
2011-2012 
2012-2013 
2013-2014 
 
Total 
0.13% 
0.46% 
0.20% 
 
50%=GI.1/GII.4 
0.07% 
0.23% 
0.10% 
 
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Norovirus GI.1/GII.4 Bivalent VLP Vaccine 
 
Trial No. NOR-211 
Page 88 of 103 
Protocol Version 3.0 
15 November 2017 
 
 
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 
(CRO) and by the IRB or IEC. 
All aspects of the trial and its documentation will be subject to review by the sponsor or designee 
(as long as blinding is not jeopardized), including but not limited to the Investigator’s Binder, 
investigational trial dose, subject medical records, informed consent documentation, 
documentation of subject authorization to use personal health information (if separate from the 
informed consent forms), 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 Responsible 
Medical Officer (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 trial doses are 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 US Food and Drug Administration [FDA], the United 
Kingdom Medicines and Healthcare Products Regulatory Agency, the Pharmaceuticals and 
Medical Devices Agency 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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Norovirus GI.1/GII.4 Bivalent VLP Vaccine 
 
Trial No. NOR-211 
Page 89 of 103 
Protocol Version 3.0 
15 November 2017 
 
 
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 Harmonized Tripartite Guideline for GCP. 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 or regional 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 Investigator’s Brochure, a copy of 
the informed consent form, and, if applicable, subject recruitment materials and/or advertisements 
and other documents required by all applicable laws and regulations, must be submitted to a 
central or local IRB or IEC for approval. The IRB’s or IEC’s written approval of the protocol and 
subject informed consent must be obtained and submitted to the sponsor or designee before 
commencement of the trial (ie, before shipment of the sponsor-supplied Vaccine or 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, informed consent form) 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 informed consent 
form, 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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Trial No. NOR-211 
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Protocol Version 3.0 
15 November 2017 
 
 
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 Guidelines for GCP and will be in accordance with all 
applicable laws and regulations. The informed consent form, 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 informed consent form 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 are given. The informed consent form will detail the requirements of the 
participant 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 
informed consent form and if applicable, the subject authorization form. The informed consent 
form, 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 informed consent form, 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 informed consent 
form, 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. In the event the subject is not capable of rendering 
adequate written informed consent, then the subject’s legally acceptable representative may 
provide such consent for the subject in accordance with applicable laws and regulations. 
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 form 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 informed consent form and subject 
authorization (if applicable) at the time of consent and prior to the 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 informed consent form, subject authorization form (if applicable), and 
subject information sheet (if applicable) will be stored in the investigator’s site file. The 
investigator must document the date the subject signs the informed consent in the subject’s 
medical record and eCRF. Copies of the signed informed consent form, the signed subject 
authorization form (if applicable), and subject information sheet (if applicable) shall be given to 
the subject. 
All revised informed consent forms must be reviewed and signed by relevant subject in the same 
manner as the original informed consent. The date the revised consent was obtained should be 
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Norovirus GI.1/GII.4 Bivalent VLP Vaccine 
 
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Protocol Version 3.0 
15 November 2017 
 
 
recorded in the subject’s medical record and eCRF, and the subject should receive a copy of the 
revised informed consent form. 
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 Guidelines for GCP and to verify compliance with this protocol, the sponsor 
requires the investigator to permit its monitor or designee’s monitor, representatives from any 
regulatory authority (eg, FDA, Medicines and Healthcare Products Regulatory Agency, 
Pharmaceuticals and Medical Devices Agency), the sponsor’s designated auditors, and the 
appropriate IRBs and IECs to review the subject’s original medical records (source data or 
documents), including, but not limited to, laboratory test result reports, ECG reports, admission 
and discharge summaries for hospital admissions occurring during a subject’s trial participation, 
and autopsy reports. Access to a subject’s original medical records requires the specific 
authorization of the subject as part of the informed consent process (see Section 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 determined by the PIs and the sponsor. 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, as 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. 
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Norovirus GI.1/GII.4 Bivalent VLP Vaccine 
 
Trial No. NOR-211 
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Protocol Version 3.0 
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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. 
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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Norovirus GI.1/GII.4 Bivalent VLP Vaccine 
 
Trial No. NOR-211 
Page 93 of 103 
Protocol Version 3.0 
15 November 2017 
 
 
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 13 November 2017. 
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 31 May 2017. 
3. Atmar RL, Estes MK. The epidemiologic and clinical importance of norovirus infection. 
Gastroenterol Clin North Am. 2006;35:275-90. 
4. Hall AJ, Lopman BA, Payne DC, Patel MM, Gastañaduy PA, Vinjé J, Parashar UD. Norovirus 
disease in the United States. Emerg Infect Dis. 2013;19:1198-205. 
5. Mead PS, Slutsker L, Dietz V, McCaig LF, Bresee JS, Shapiro C, Griffin PM, Tauxe RV. 
Food-related illness and death in the United States. Emerg Infect Dis. 1999;5:607-25. 
6. Trivedi TK, DeSalvo T, Lee L, Palumbo A, Moll M, Curns A, Hall AJ, Patel M, Parashar UD, 
Lopman BA. Hospitalizations and mortality associated with norovirus outbreaks in nursing 
homes, 2009-2010. JAMA. 2012;308:1668-75. 
7. Payne DC, Vinjé J, Szilagyi PG, Edwards KM, Staat MA, Weinberg GA, Hall CB, Chappell J, 
Bernstein DI, Curns AT, Wikswo M, Shirley SH, Hall AJ, Lopman B, Parashar UD. Norovirus 
and medically attended gastroenteritis in U.S. children. N Engl J Med. 2013;368:1121-30. 
8. Porter CK, Faix DJ, Shiau D, Espiritu J, Espinosa BJ, Riddle MS. Postinfectious 
gastrointestinal disorders following norovirus outbreaks. Clin Infect Dis. 2012;55:915-22. 
9. St Clair KJ, Patel S. Initial descriptive and analytical data on an outbreak of norovirus infection 
at marine corps recruit depot Parris Island, South Carolina. J Infect Dis. 2008;198:941-2. 
10. Enteric Disease Surveillance Program. AGE surveillance summary report for study weeks 
22-25 (June 2013). Department of Operational Infectious Diseases, Naval Health Research 
Center, San Diego, CA. 
11. McCarthy M, Estes MK, Hyams KC. Norwalk-like virus infection in military forces: epidemic 
potential, sporadic disease, and the future direction of prevention and control efforts. J Infect 
Dis. 2000;181 Suppl 2:S387-91. 
12. Sharp TW, Hyams KC, Watts D, Trofa AF, Martin GJ, Kapikian AZ, Green KY, Jiang X, 
Estes MK, Waack M, et al. Epidemiology of Norwalk virus during an outbreak of acute 
gastroenteritis aboard a US aircraft carrier. J Med Virol. 1995;45:61-7. 
13. Hyams KC, Malone JD, Kapikian AZ, Estes MK, Xi J, Bourgeois AL, Paparello S, Hawkins 
RE, Green KY. Norwalk virus infection among Desert Storm troops. J Infect Dis. 
1993;167:986-7. 
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14. Ball JM, Graham DY, Opekun AR, Gilger MA, Guerrero RA, Estes MK. Recombinant 
Norwalk virus-like particles given orally to volunteers: phase I study. Gastroenterology. 
1999;117:40-8. 
15. Tacket CO, Mason HS, Losonsky G, Estes MK, Levine MM, Arntzen CJ. Human immune 
responses to a novel norwalk virus vaccine delivered in transgenic potatoes. J Infect Dis. 
2000;18:302-5. 
16. Tacket CO, Sztein MB, Losonsky GA, Wasserman SS, Estes MK. Humoral, mucosal, and 
cellular immune responses to oral Norwalk virus-like particles in volunteers. Clin Immunol. 
2003;108:241-7. 
17. El-Kamary SS, Paetti MF, Mendelman PM, Frey SE, Bernstein DI, Treanor JJ, Ferreira J, 
Chen W, Sublett R, Richardson C, Bargatze RF, Sztein MB, and Tacket CO. 2010. Adjuvanted 
intranasal Norwalk virus-like particle vaccine elicits antibodies and antibody secreting cells 
that express homing receptors in mucosal and peripheral lymphoid tissues. J. Infect. Dis. 202: 
1649-58 (see Erratum J. Infect. Dis. 2011:203:1036. 
18. Atmar RL, Bernstein DI, Harro CD, Al-Ibrahim MS, Chen WH, Ferreira J, Estes MK, Graham 
DY, Opekun AR, Richardson C, Mendelman PM. Norovirus vaccine against experimental 
human Norwalk Virus illness. N Engl J Med. 2011;365:2178-87. 
19. Bernstein DI, Atmar RL, Lyon GM, Treanor JJ, Chen WH, Jiang Xi, Vinjé J, Gregoricus N, 
Frenck RW, Moe CL, AL-Ibrahim MS, Barrett J, Ferreira J, Estes MK, Graham DY, Goodwin 
R, Borkowski A, Clemens R, Mendelman PM. Norovirus vaccine against experimental human 
GII.4 virus illness: a challenge study in healthy adults. J Infect Dis. In press. 
20. Treanor JJ, Atmar RL, Frey SE, Gormley R, Chen WH, Ferreira J, Goodwin R, Borkowski A, 
Clemens R, Mendelman PM. 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 Jun 20. pii: jiu337. 
21. Baylor NW, Egan W, Richman P. Aluminum salts in vaccines-US perspective. Vaccine. 2002 
May 31;20 Suppl 3:S18-23. Review. Erratum in: Vaccine. 2002;20:3428. 
22. Investigator Brochure (Edition 5.0; 29 November 2016). "Intramuscular norovirus GI.1/GII.4 
bivalent virus-like particle (VLP) vaccine adjuvanted with monophosphoryl lipid A (MPL) 
and aluminum hydroxide [Al(OH)3]. 
23. Kuschner RA, Russell KL, Abuja M, Bauer KM, Faix DJ, Hait H, Henrick J, Jacobs M, Liss A, 
Lynch JA, Liu Q, Lyons AG, Malik M, Moon JE, Stubbs J, Sun W, Tang D, Towle AC, Walsh 
DS, Wilkerson D. A phase 3, randomized, double-blind, placebo-controlled study of the safety 
and efficacy of the live, oral adenovirus type 4 and type 7 vaccine, in U.S. military recruits. 
Vaccine. 2013;31:2963-71. 
24. Reeck A, Kavanagh O, Estes MK, Opekun AR, Gilger MA, Graham DY, Atmar RL. 
Serological correlate of protection against norovirus-induced gastroenteritis. J Infect Dis. 
2010;202:1212-8. 
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25. Levine MM, Bergquist EJ, Nalin DR, Waterman DH, Hornick RB, Young CR, Sotman S. 
Escherichia Coli strains that cause diarrhea but do not produce heat-labile or heat-stable 
enterotoxins and are non-invasive. Lancet. 1978;1(8074):1119-22. 
26. U.S. Department of Health and Human Services, National Institutes of Health, National 
Cancer Institute (2009). Common Terminology Criteria for Adverse Events (CTCAE) Version 
4.0. http://evs.nci.nih.gov/ftp1/CTCAE/Archive/CTCAE_4.0_2009-05. 
27. Atmar RL, Opekun AR, Gilger MA, Estes MK, Crawford SE, Neill FH, Ramani S, Hill H, 
Ferreira J, Graham DY. Determination of the 50% human infectious dose for norwalk virus. 
J Infect Dis. 2014;209:1016-22. 
28. DoD_Directive_3216.02 (2011). "Protection of Human Subjects and Adherence to Ethical 
Standards in DoD-Supported Research." 
29. Marcy SM, Kohl KS, Dagan R, Nalin D, Blum M, Jones MC, Hansen J, Labadie J, Lee L, 
Martin BL, O'Brien K, Rothstein E, Vermeer P. Brighton Collaboration Fever Working Group. 
Fever as an adverse event following immunization: case definition and guidelines of data 
collection, analysis, and presentation. Vaccine. 2004;22:551-6. 
30. Breslow NE, Day NE. Statistical methods in cancer research. Volume II--the design and 
analysis of cohort studies. Lyon, France: International Agency for Research on Cancer, 1987. 
31. Prentice RL. Surrogate endpoints in clinical trials: definition and operational criteria. Stat 
Med. 1989;8:431– 40. 
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Appendix A Responsibilities of the Investigator 
Clinical research studies sponsored by the sponsor are subject to ICH GCP 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 with 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 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 56 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 informed consent is the most current 
version approved by the IRB/IEC. Each informed consent form 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 informed consent form 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 clinical study report. 
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Appendix B Investigator Consent to Use of Personal Information 
Takeda will collect and retain personal information of investigator, including his or her name, 
address, and other personally identifiable information. In addition, 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. 
 
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 investigator’s own 
country. 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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Appendix C 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 statement describing the vaccination(s) and the probability for random assignment to each 
treatment. 
10. A description of the possible side effects following vaccine administration that the subject may 
receive. 
11. A description of any reasonably foreseeable risks or discomforts to the subject and, when 
applicable, to an embryo, fetus, or nursing infant. 
12. 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. 
13. Disclosures of appropriate alternative procedures or courses of treatment, if any, that might be 
advantageous to the subject and their important potential risks and benefits. 
14. 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 informed consent form, the 
subject is authorizing such access. 
15. 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. 
16. The anticipated prorated payment(s), if any, to the subject for participating in the trial. 
17. The anticipated expenses, if any, to the subject for participating in the trial. 
18. 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. 
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19. 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. 
20. The consequences of a subject’s decision to withdraw from the research and procedures for 
orderly termination of participation by the subject. 
21. 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. 
22. A statement that results of pharmacogenomic analysis will not be disclosed to an individual, 
unless prevailing laws require the sponsor to do so. 
23. The foreseeable circumstances or reasons under which the subject’s participation in the trial 
may be terminated. 
24. A written subject authorization (either contained within the informed consent form 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. 
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25. Female subjects of childbearing potential (eg, non-sterilized, premenopausal female subjects) 
who are sexually active must use adequate contraception (as defined in the informed consent) 
from enrollment through the duration of the trial. Pregnancy tests will be performed for all 
female subjects of childbearing potential as defined in the protocol and in the informed 
consent. If a subject is found to be pregnant during trial, the investigator will offer the subject 
the choice to receive unblinded treatment information. 
26. 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 D Routine Immunizations 
Table 16.a 
Routine Immunizations for Newly Arriving U.S. Navy Subjects (NRTC‐Great 
Lakes) 
Vaccine 
Number of Doses 
Trial 
Day 1(a) 
Trial 
Day 32 
TWINRIX (Hepatitis A + Hepatitis B) (b) 
2 
X 
X 
VARICELLA (c) 
2 
X 
X 
MMR (c) 
2 
X 
X 
POLIO (inactivated) 
1 
- 
X 
TYPHOID FEVER 
1 
- 
X 
YELLOW FEVER 
1 
- 
X 
GARDASIL (human papillomavirus) 
1 
- 
X 
MENACTRA (d) 
1 
X 
- 
INFLUENZA (seasonal; live nasal or inactivated injectable) 
1 
X 
- 
ADENOVIRUS (live, Types 4&7) (e) 
1 
X 
- 
Tdap (f) 
1 
X 
- 
(a) Licensed concomitant vaccines that may be administered the same day as the NoV GI.1/GII.4 bivalent VLP vaccine or 
placebo. 
(b) Hepatitis A Inactivated and hepatitis B (Recombinant) vaccine. Subjects will receive these vaccines based on their low titers. 
(c) Varicella and Measles, Mumps and Rubella (MMR) vaccines. Varivax and/or MMR are given as noted (15 to 25% of subjects 
have received these vaccines based on their low titers). 
(d) Menactra‐ meningococcal Groups A, C, Y, and W-135 meningitis vaccine. 
(e) Adenovirus live vaccine consists of a single administration of an oral enteric-coated dose of type 4 plus a separate 
enteric-coated dose of type 7 at the same time. 
(f) 
Combined tetanus-diphtheria-acellular pertussis vaccine. 
Note: due to availability, recalls, shortages, and updates, moving between brands may be required 
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Appendix E Five Point Scale Stool Chart 
Five Point Scale Stool Chart [25]: 
 
Grade 1: 
Fully formed (normal) 
 
Grade 2: 
Soft (normal) 
 
Grade 3: 
Thick liquid (diarrheal) 
 
Grade 4 
Opaque watery (diarrheal) 
 
Grade 5: 
Rice-water (diarrheal) 
 
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