Clinical trial NCT02661490
Conditions: Norovirus
Keywords: Norovirus
Sponsor: Takeda
Start date: 2016-02-01; Completion date: 2017-09-29
Enrollment: 320 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to further develop a formulation and dose regimen of the norovirus GI.1/GII.4 bivalent virus-like particle (VLP) vaccine that is immunogenic and safe in an elderly population aged 60 years and above.

Detailed description:
The vaccine being tested in this study is called norovirus GI.1/GII.4 bivalent virus-like particle (VLP) vaccine adjuvanted with aluminum hydroxide (Formulation A) or adjuvanted with monophosphoryl lipid A (MPL) and aluminum hydroxide (Formulation B). Two norovirus vaccine formulations are being tested to select for further development the formulation that will generate an optimal specific antibody response that may provide protection against norovirus and is safe in a population aged 60 years and above. This study will look at side effects and the level of antibodies to norovirus formed in people who will be injected with different formulations of the norovirus vaccine candidate.

The study will enroll approximately 325 patients. Participants will be randomly assigned (by chance) to one of five treatment groups.

* Norovirus GI.1/GII.4 bivalent VLP vaccine (Formulation A) 1-dose, participants ≥ 60 years
* Norovirus GI.1/GII.4 bivalent VLP vaccine (Formulation A) 2-dose, participants ≥ 60 years
* Norovirus GI.1/GII.4 bivalent VLP vaccine (Formulation B) 1-dose, participants ≥ 60 years
* Norovirus GI.1/GII.4 bivalent VLP vaccine (Formulation B) 2-dose, participants ≥ 60 years
* Norovirus GI.1/GII.4 bivalent VLP vaccine (Formulation A) 1-dose, participants 18 to 49 years All participants in the age of 60 years and older will be administered either NoV vaccine (Formulation A or B) or placebo on Day 1 and NoV vaccine (Formulation A or B) on Day 29 of the study. In order to keep the treatment arms undisclosed to the patient and the doctor, those randomized to the one dose groups will receive a dose of placebo (this is a saline solution that has no active ingredient) on Day 1 followed by the NoV vaccine on Day 29. Those randomized to 2 doses with receive the NoV vaccine on Day 1 and Day 29. In case of an urgent medical need a participant can be unblinded.

Adults aged 18 to 49 will receive placebo on Day 1 followed by NoV vaccine Formulation A on Day 29.

Participants will be asked to record any reactions/ symptoms that may be related or not to the vaccine in a diary card for 28 days after each vaccination.

This multi-center trial will be conducted in the United States of America. The overall time to participate in this study is up to 393 days. Participants will make multiple visits to the clinic including a final follow-up visit on Day 393.

Arms: arm 1: Participants ≥ 60 years of age, 1-dose regimen: Norovirus bivalent placebo-matching vaccine, intramuscularly (IM), on Day 1, followed by norovirus (NoV) GI.1 (15 μg)/GII.4 (50 μg) bivalent virus-like particle (VLP) vaccine (Formulation A), IM, on Day 29. arm 2: Participants ≥ 60 years of age, 2-dose regimen: Norovirus GI.1 (15 μg)/GII.4 (50 μg) bivalent VLP vaccine (Formulation A), IM, on Days 1 and 29. arm 3: Participants ≥ 60 years of age, 1-dose regimen: Norovirus bivalent placebo-matching vaccine, IM on Day 1, followed by norovirus GI.1 (15 μg)/GII.4 (50 μg) bivalent VLP vaccine with 15 μg monophosphoryl lipid A (MPL) (Formulation B), IM, on Day 29. arm 4: Participants ≥ 60 years of age, 2-dose regimen: Norovirus GI.1 (15 μg)/GII.4 (50 μg) bivalent VLP vaccine with 15 μg MPL (Formulation B), IM, on Days 1 and 29. arm 5: Participants 18 to 49 years of age, 1-dose regimen: Norovirus bivalent placebo-matching vaccine, IM, on Day 1, followed by norovirus GI.1 (15 μg)/GII.4 (50 μg) bivalent VLP vaccine (Formulation A), IM, on Day 29.
Interventions: intervention 1: Norovirus GI.1/GII.4 Bivalent VLP Vaccine intervention 2: 0.9% sodium chloride (saline) intervention 3: Norovirus GI.1/GII.4 Bivalent VLP Vaccine
Intervention descriptions: intervention 1: Norovirus GI.1/GII.4 bivalent VLP vaccine adjuvanted with aluminum hydroxide, without MPL for IM injection intervention 2: norovirus bivalent placebo-matching vaccine intervention 3: Norovirus GI.1/GII.4 bivalent VLP vaccine adjuvanted with MPL and aluminum hydroxide for IM injection

Protocol documents:
Prot_001.pdf: 



Title: A Phase II, Randomized, Double-blind, Safety and Immunogenicity Trial of Norovirus 
GI.1/GII.4 Bivalent Virus-Like Particle Vaccine in Healthy Elderly Adults 
NCT Number: NCT02661490
Protocol Approve Date: 16 November 2015 
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.


Norovirus GI.1/GII.4 Bivalent VLP Vaccine 
Trial No. NOR-204 
Page 1 of 92 
Protocol Version 2.0 
16 November 2015 
PROTOCOL 
A Phase II, Randomized, Double-blind, Safety and Immunogenicity Trial of Norovirus GI.1/GII.4 
Bivalent Virus-Like Particle Vaccine in Healthy Elderly Adults 
NOR-204 Safety and Immunogenicity of Norovirus GI.1/GII.4 Bivalent VLP Vaccine in an 
Elderly Population 
Sponsor: 
Takeda Vaccines, Inc. 
One Takeda Parkway 
Deerfield, Illinois 60015 USA 
Trial Identifier: 
NOR-204 
IND Number: 
014421  
EudraCT Number: 
Not Applicable 
Vaccine Name 
Norovirus GI.1/GII.4 Bivalent VLP Vaccine 
Date: 
16 November 2015 
Version: 
Version 2.0 
0002
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


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Norovirus Bivalent VLP Vaccine 
 
Trial No. NOR-204 
Page 25 of 92 
Protocol Version 2.0 
16 November 2015 
 
Sample Size Justification: 
This is a phase II trial designed primarily to be descriptive. Therefore the sample size was not determined based on 
formal statistical power calculations but rather to provide a reasonable clinical database to assess safety and 
immunogenicity in an elderly population. 
Interim Analysis: 
A review of safety data will be performed by the Data Monitoring Committee (DMC) as soon as the first 
approximately 100 subjects have completed the Day 36 Visit (8 days post last vaccination) to verify if safety results 
observed in the present trial are consistent with what has been observed in previous trials with the NoV GI.1/GII.4 
Bivalent VLP Vaccine performed by Takeda. In order to have a good representation of the entire trial population, 
efforts will be made in terms of enrollment to have those first approximately 100 subjects equally distributed in each 
permutation. 
An interim analysis on safety and immunogenicity data is planned when all subjects have completed the Day 57 Visit 
(28 days after last vaccination). This analysis will include group results but not individual subject information. This 
analysis will be performed by a separate set of unblinded statisticians and programmers at a selected independent 
Contract Research Organization (CRO) who will have access to individual treatment assignments but will not be 
involved in subsequent trial conduct. Except for the unblinded pharmacist and unblinded administrator, the personnel 
involved in the conduct of the trial including those at the Sponsor site, the CRO, and the trial sites, will remain blinded 
to the individual subject data (including treatment assignment) until unblinding after database lock for data through 
Day 393. 
Data Monitoring Committee: 
An overall DMC is established to evaluate overall safety of the Takeda Norovirus vaccine program on an ongoing 
basis. The composition, role and responsibilities of the DMC are presented in a separate DMC Charter.  
NOR-204 Protocol Version 2.0 (16 November 2015)
0026
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-204 
Page 28 of 92 
Protocol Version 2.0 
16 November 2015 
 
 
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 for specific trial-related 
activities will perform these activities in full or in partnership with the Sponsor. 
3.2 
Principal Investigator 
The Sponsor will select a Principal 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. 
0029
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-204 
Page 30 of 92 
Protocol Version 2.0 
16 November 2015 
 
 
Pan-Ig 
Pan Immunoglobulin 
PBMC 
Peripheral Blood Mononuclear Cell 
PFS 
Prefilled Syringe 
PPS 
Per-Protocol Analysis Set 
PT 
Preferred Term 
PV 
Pharmacovigilance 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SOC 
System Organ Class 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TNF-α 
Tumor Necrosis Factor-alpha 
US 
United States 
USA 
United States of America 
VLP 
Virus Like Particle 
0031
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-204 
Page 31 of 92 
Protocol Version 2.0 
16 November 2015 
 
3.4 
Corporate Identification 
TV 
Takeda Vaccines, Inc. 
VBU 
Vaccine Business Unit 
 
0032
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-204 
Page 32 of 92 
Protocol Version 2.0 
16 November 2015 
 
4.0 
INTRODUCTION 
4.1 
Background 
Noroviruses (NoVs) cause acute debilitating illness characterized by vomiting, diarrhea and 
abdominal pain. NoVs are non-cultivatable human caliciviruses that have emerged as the single 
most significant cause of epidemic outbreaks of viral gastroenteritis worldwide [1, 2]. Endemic 
norovirus (NoV) disease occurs year round but exhibits seasonality, with a pronounced winter 
peak in countries in the northern hemisphere. These outbreaks can occur in all age groups, and 
commonly result in significant morbidity and mortality, particularly in the elderly, the 
immunocompromised subjects, and the very young subjects [3-7]. According to the Centers for 
Disease Control and Prevention (CDC), 21 million cases of acute gastroenteritis are due to 
NoVs each year in the United States (US) [8]. 
NoVs comprises a genetically diverse family consisting of 6 genogroups (GI–GVI), 3 of which 
(genogroup I [GI], genogroup II [GII], and genogroup IV [GIV]) cause human disease. NoV 
strains drift from year to year, and although both GI and GII genogroups and numerous 
genotypes are reported, the GII, genotype 4 (GII.4) type remains dominant causing the majority 
of outbreaks worldwide [9-11]. Recently, surveillance systems have shown an increase in NoV 
activity globally during late 2012 due to the emergence of a new NoV GII.4 variant, termed 
Sydney 2012 [12]. 
Norovirus Vaccine 
The rationale for developing a bivalent vaccine is based on known epidemiology that both GI, 
genotype 1 (GI.1) and GII.4 circulate and do not cross-protect in nature. NoV Virus Like 
Particles (VLPs) are non-infectious particles because they do not contain viral genomic 
ribonucleic acid (RNA); however they are immunogenic because they preserve the particulate 
antigen conformation and structure that mimic functional interactions of the virus with cellular 
receptors. 
The NoV GI.1/GII.4 Bivalent VLP Vaccine under development at Takeda is based on NoV GI.I 
and GII.4 VLPs as the antigens. These 2 genotypes cause the vast majority of NoV outbreaks. 
The GI.1 VLP represents a single GI.1 strain and the GII.4 VLP represents a consensus 
sequence of 3 GII.4 strains. 
The 2 NoV GI.1/GII.4 Bivalent VLP Vaccine formulations tested in trial NOR-204 
(Formulations A and B) contain the adjuvant aluminum hydroxide (Al(OH)3) which has been 
shown to enhance the antigenicity of vaccines [13, 14]. Formulation B also contains 
monophosphoryl lipid A (MPL) as adjuvant. This combination of both, MPL and aluminum salt 
is used in the commercially available vaccines Cervarix®, a human papilloma virus (HPV) 
vaccine, and Fendrix® indicated for hepatitis B prevention for patients with renal insufficiency. 
Aluminum salt-based adjuvants are used in multiple vaccines and have an acceptable safety 
profile [14]. The aluminum concentration per dose was selected empirically from data that 
demonstrated that this amount of aluminum enhanced the antigenicity of the vaccine. 
0033
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-204 
Page 33 of 92 
Protocol Version 2.0 
16 November 2015 
 
Selection of the NoV GI.1/GII.4 Bivalent VLP Vaccine formulations for trial NOR-204 is 
based on safety and immunogenicity data observed in adults 18–64 years of age in trial 
NOR-107 described below. 
Preclinical Safety and Toxicology 
A Good Laboratory Practice (GLP) safety trial was performed in rabbits to evaluate safety and 
toxicology of NoV GI.1/GII.4 Bivalent VLP Vaccine with MPL and Al(OH)3. Five, 0.5 mL 
doses of NoV GI.1/GII.4 Bivalent VLP Vaccine, each containing 300 µg of total VLP (150 µg 
of GI.1 VLP and 150 µg of GII.4 cVLP) with 500 µg of Al(OH)3 and 50 µg of MPL were 
administered by single daily intramuscular (IM) injection on Days 1, 15, 29, 43, and 57. The 
vaccine was well tolerated in rabbits. No mortality and no systemic toxicity were observed. 
Refer to current version of the Investigator Brochure for more details [15]. 
Clinical Safety and Immunogenicity 
The safety of the NoV GI.1/GII.4 Bivalent VLP Vaccine given by the IM route was evaluated 
in 2 completed trials in 234 healthy US adult subjects. Trial LV03-104 included 102 subjects 
(aged 18–49 years, 50–64 years, 65–85 years). Trial LV03-105 included 132 subjects (aged 
18–50 years). Both trials compared the NoV GI.1/GII.4 Bivalent VLP Vaccine with Saline 
Placebo given by IM injection as a 2-dose regimen, 28 days apart. In both trials combined, 133 
adults received at least 1 dose of the NoV GI.1/GII.4 Bivalent VLP Vaccine and 101 adults 
received at least 1 dose of Saline Placebo. No allergic reactions, neurologic adverse events 
(AEs), or serious adverse events (SAEs) related to the vaccine were reported in either trial. No 
increase in severity or frequency of symptoms was observed with increased VLP dosages or 
with increased age or after Dose 2 of vaccine compared with Dose 1. The IM NoV GI.1/GII.4 
Bivalent VLP Vaccine was well tolerated. 
The completed dosage escalation trial, LV03-104, which compared 5/5, 15/15, 50/50 and 
150/150 µg dosages of the GI.1 and GII.4 VLPs in adults showed the percentage of subjects 
with at least a four-fold rise in antibody levels (seroresponse rate) and Geometric Mean Fold 
Rise (GMFR) were lower for the GII.4 VLP than for the GI.1 VLP at equivalent antigen 
dosages. Similar post-vaccination immunogenicity data were obtained in the completed GII.4 
challenge trial LV03-105 that evaluated a candidate vaccine containing 50/50 µg VLP. 
Trial LV03-104 comprised a group of 10 subjects aged 65-85 years who received the NoV 
formulation at 50/50 µg. Response patterns to both VLP components of the vaccine were 
similar but point estimates of titers to the GII.4 component were lower than those to the GI.1 
component. Pan-Immunoglobulin (Pan-Ig) and immunoglobulin A (IgA) responses to both 
VLP components were similar in the 3 age groups, but immunoglobulin G (IgG) responses 
showed some age-dependent variation with IgG Geometric Mean Titers (GMT) lower in those 
aged 65-85 years. 
Trial NOR-107 was designed to evaluate various dosages of antigen of the bivalent vaccine 
ranging from 15 to 150 µg, with and without MPL adjuvant (0 µg, 15 µg, and 50 µg) in 420 
healthy adult subjects. There was no trend towards an increased systemic reactogenicity profile 
with increasing antigen content in adjuvanted and unadjuvanted formulations. The majority of 
the reactions observed were mild to moderate in all groups and there were no SAEs related to 
the vaccine reported. The immune responses to both VLP antigens were similar with and 
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-204 
Page 34 of 92 
Protocol Version 2.0 
16 November 2015 
 
without the MPL adjuvant. The ongoing trial NOR-201 was designed to evaluate 2 NoV 
GI.1/GII.4 VLP antigen formulations (15 µg/50 µg and 50 µg/50 µg), adjuvanted with 50 µg of 
MPL and 500 µg Al(OH3) in approximately 450 adults aged 18–49 years. The preliminary 
results of this trial are consistent with the observations of trial NOR-107 trial and confirm that 
15 µg of GI.1 VLP combined with 50 µg of GII.4-VLP, provide a superior immune response to 
the GII.4 component than did the 50 µg of GI.1 VLP combined with 50 µg of GII.4 VLP. 
4.2 
Rationale for the Proposed Trial 
NoV outbreaks can occur in all age groups. There are no substantial differences in clinical 
presentation between adults and children, however elderly are more susceptible to 
complications and are at greater risk of NoV associated deaths. 
The clinical significance of NoVs was underestimated prior to the development of diagnostic 
assays to detect these enteric viruses. NoV-related illnesses and outbreaks exact a significant 
socioeconomic toll on hospitals, schools, businesses and other closed settings such as hospitals 
and long care settings. 
Elderly population will increase dramatically in the next few years reaching approximately 
30% of the total population by year 2030. Aging and more explicitly, the natural decline of the 
immune system increases their susceptibility to infection and compromises responsiveness to 
vaccines [16]. New vaccine strategies might be beneficial to this age group and there might be 
potential for specific vaccine formulations or dose regimens adapted to their age. 
Preliminary data in a population aged ≥65 years are available from trial LV03-104 as 
previously described, however those findings need to be further explored in a larger trial. 
The present phase II trial, NOR-204, is designed to address the safety and immunogenicity of 2 
formulations of the NoV GI.1/GII.4 Bivalent VLP Vaccine (Formulation A and Formulation B) 
in an elderly population when given according to either a 1-dose regimen or 2-dose regimen 28 
days apart. The 2 NoV GI.1/GII.4 Bivalent VLP Vaccine formulations (Formulation A and 
Formulation B) are selected based on safety and immunogenicity data from trial NOR-107.  
The trial population will be stratified into four age groups including: 18–49 years, 60–74 years, 
75–84 years, and 85 years and above. The 18–49 age group is added to the trial to provide a 
head-to-head comparison in order to limit eventual trial bias in results interpretation that may 
occur with historical comparisons. Elderly subjects (age groups 60–74 years, 75–84 years, and 
85 years and above) will be randomized to receive either 1 or 2 doses of the NoV GI.1/GII.4 
Bivalent VLP Vaccine (Formulation A or Formulation B). The 18–49 age group will receive 
only 1 NoV GI.1/GII.4 Bivalent VLP Vaccine dose of Formulation A that is considered the 
formulation for further development in this age group by Takeda. Subjects allocated to the 
1-dose regimen of the NoV GI.1/GII.4 Bivalent VLP Vaccine will receive 1 injection with 
Saline Placebo on Day 1 to respect trial blinding. Twenty-eight days later (Day 29), they will 
receive their vaccination with the Formulation A vaccine. 
Immunogenicity and safety evaluation will be done in each age group at various time points 
throughout the trial. The primary trial objective is the Day 57 immunogenicity assessment 
(28 days after the last vaccination) and safety assessment for the trial period. 
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-204 
Page 35 of 92 
Protocol Version 2.0 
16 November 2015 
 
The trial will be conducted in accordance with the protocol, the International Conference on 
Harmonization-Good Clinical Practice (ICH-GCP) Guidelines and applicable regulatory 
requirements. 
0036
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-204 
Page 49 of 92 
Protocol Version 2.0 
16 November 2015 
 
7.5 
Procedures for Discontinuation or Withdrawal of a Subject 
The Investigator may terminate 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. In addition, efforts should be made to perform all procedures as scheduled for the 
Final Visit.   
Subjects withdrawn or discontinued from the trial should be followed for safety through to the 
End of Trial (Day 393). The safety follow up procedures will be described in the manual of 
study procedures. 
Discontinued or withdrawn subjects will not be replaced. 
0050
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Norovirus GI.1/GII.4 Bivalent VLP Vaccine  
 
Trial No. NOR-204 
Page 52 of 92 
Protocol Version 2.0 
16 November 2015 
 
Table 8-1 
Subject Distribution for Trial NOR-204 
Age groups (years) 
Number of subjects 
Dose regimen (a) 
Day 1 
Day 29 
18–49 
25 
1 
Saline Placebo 
Formulation A 
60–74 
25 
1 
Saline Placebo 
Formulation A 
25 
2 
Formulation A 
Formulation A 
25 
1 
Saline Placebo 
Formulation B 
25 
2 
Formulation B 
Formulation B 
75–84  
25 
1 
Saline Placebo 
Formulation A 
25 
2 
Formulation A 
Formulation A 
25 
1 
Saline Placebo 
Formulation B 
25 
2 
Formulation B 
Formulation B 
≥85 
25 
1 
Saline Placebo 
Formulation A 
25 
2 
Formulation A  
Formulation A 
25 
1 
Saline Placebo 
Formulation B 
25 
2 
Formulation B  
Formulation B 
Total evaluable subjects
325 
 
 
aOne dose versus 2-dose regimen with the NoV GI.1/GII.4 Bivalent VLP Vaccine (Formulations A or B) 
8.2 
Trial Vaccine Assignment and Dispensing Procedures 
The Investigator or Investigator’s designee will access the IWRS on Day 1 to obtain the subject 
number. Details of randomization and the IWRS will be covered in the IWRS User Manual. 
The Investigator or Investigator’s designee will utilize the IWRS to randomize the subject into 
the trial. During this contact, the Investigator or designee will provide the necessary subject 
identifying information. 
The trial vaccine identification numbers to be administered will be assigned by the IWRS. 
The trial vaccine will be prepared and administered by the unblinded designee according to the 
instructions in the Pharmacy Manual. All investigational vaccine preparation will be 
documented. 
All trial vaccines (NoV GI.1/GII.4 Bivalent VLP Vaccines and Saline Placebo) will be 
administered IM into the middle third of the deltoid muscle of the subject’s arm, preferably the 
non-dominant arm. 
The Investigator or designee will be responsible for overseeing the administration of 
investigational vaccine to subjects enrolled in the trial according to the procedures stipulated in 
this trial protocol. All the trial vaccines will be administered only by unblinded personnel who 
are qualified to perform that function under applicable laws and regulations for that specific 
trial. 
If trial vaccines are lost or damaged, the site can request a replacement from the IWRS (refer to 
the IWRS manual supplied separately). 
8.2.1 
Precautions to be Observed in Administering the Investigational 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 
0053
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-204 
Page 55 of 92 
Protocol Version 2.0 
16 November 2015 
 
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. 
0056
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-204 
Page 64 of 92 
Protocol Version 2.0 
16 November 2015 
 
9.4 
Biological Sample Retention and Destruction 
In this trial, specimens for immune response testing will be collected as described in Section 
9.1.6. Biological samples will be processed and stored per the Laboratory Guidelines as 
provided in the Procedures Manual. The samples will be retained at sponsor contracted 
laboratories/facilities for up to but no longer than 20 years, or as required by applicable laws. 
The Sponsor has put into place a system to protect the subjects’ personal information to ensure 
optimal confidentiality and defined standard processes for sample and data collection, storage, 
analysis, and destruction. 
Serum samples, PBMCs, or salivary specimens, will be used for the analyses defined in this 
protocol, but may also be used, with the permission of the subject to assess, improve or develop 
tests related to the disease or the vaccine under trial that will allow more reliable measurement 
of the response to the vaccine. 
0065
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-204 
Page 66 of 92 
Protocol Version 2.0 
16 November 2015 
 
The intensity of solicited safety parameters will be assessed as described in Table 10-2. 
Table 10-2 
Intensity Assessment for Solicited Safety Parameters 
Solicited Event 
Grade 
Assessment  
Pain at injection site: 
0 
No pain 
1 
Mild: No interference with daily activity 
2 
Moderate: Interference with daily activity with or without 
3 
Severe: Prevents daily activity with or without treatment  
Erythemaa at injection site: 
0 
<25 mm 
1 
Mild: ≥25 – ≤50 mm 
2 
Moderate: >50 – ≤100 mm 
3 
Severe: >100 mm 
Indurationa at injection site: 
0 
<25 mm 
1 
Mild: ≥25 – ≤50 mm  
2 
Moderate: >50 – ≤100 mm  
3 
Severe: >100 mm  
Swellinga at injection site: 
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 
3 
Severe: Prevents daily activity with or without treatment  
Fatigue: 
0 
None  
1 
Mild No interference with daily activity 
2 
Moderate: Interference with activity 
3 
Sever Prevents daily activity 
Myalgia: 
0 
None 
1 
Mild: No interference with daily activity 
2 
Moderate: Interference with activity 
3 
Severe: Significant; prevents daily activity 
Arthralgia: 
0 
None 
1 
Mild: No interference with daily activity 
2 
Moderate: Interference with 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  
Feverb: 
Record temperature in °C /°F (preferably oral) 
a Subjects are to record the 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 taken [17]. 
0067
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Norovirus GI.1/GII.4 Bivalent VLP Vaccine  
 
Trial No. NOR-204 
Page 71 of 92 
Protocol Version 2.0 
16 November 2015 
 
The SAE form should be transmitted within 24 hours to the attention of the contact(s) in the list 
provided to each site. 
Note: For this study, SAE reporting will be done by eCRF. If the Electronic Data Capture 
(EDC) system is unavailable, a paper Sponsor SAE form/paper CRF should be completed and 
the event must be entered into the EDC once access is available. 
10.5 Follow-up Procedures 
10.5.1 
AEs 
All AEs will be monitored until resolution or a stable status is reached or until a formal 
diagnosis can be made or until the end of the trial, whichever occurs first.  
10.5.2 
SAEs 
If information not available at the time of the first report becomes available at a later date, the 
Investigator should complete a follow-up SAE form or provide other written documentation 
and fax it immediately within 24 hours of receipt. Copies of any relevant data from the hospital 
notes (eg, laboratory tests, discharge summary, postmortem results) should be sent to the 
Sponsor. 
All SAEs should be followed up until resolution or permanent outcome of the event or is 
otherwise explained. The timelines and procedure for follow-up reports are the same as those 
for the initial report. 
Note: For this trial, SAE reporting will be done by eCRF. If the EDC system is unavailable, a 
paper Sponsor SAE form/paper CRF should be completed and the event must be entered into 
the EDC once access is available. 
10.5.3 
Safety Reporting to Investigators, IRBs or IECs, and Regulatory 
Authorities 
The Sponsor or designee will be responsible for the reporting of all suspected unexpected 
serious adverse reactions (SUSARs) and any other applicable SAEs to regulatory authorities, 
including the European Medicines Agency (EMA), Investigators and IRBs or IECs, as 
applicable, in accordance with national regulations in the countries where the trial is conducted. 
Relative to the first awareness of the event by/or further provision to the Sponsor or Sponsor’s 
designee, SUSARs will be submitted within 7 days for fatal and life-threatening events and 
15 days for other SUSARs, unless otherwise required by national regulations. The Sponsor will 
also prepare an expedited report for other safety issues where these might materially alter the 
current benefit-risk assessment of an investigational medicinal product or that would be 
sufficient to consider changes in the trial vaccine administration or in the overall conduct of the 
trial. The investigational site also will forward a copy of all expedited reports to their IRB or 
IEC in accordance with national regulations. 
10.5.4 
Post-Trial Events 
Any AE 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(s) must be reported to the Sponsor. These 
0072
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-204 
Page 72 of 92 
Protocol Version 2.0 
16 November 2015 
 
AEs will be processed by the Sponsor’s Pharmacovigilance Department. Instructions for how 
to submit these AEs will be provided in a handout in the Investigator Site File. 
0073
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-204 
Page 73 of 92 
Protocol Version 2.0 
16 November 2015 
 
11.0 TRIAL-SPECIFIC REQUIREMENTS 
11.1 Trial-Specific Committees 
No trial-specific committee will be used for this trial. 
11.1.1 
Data Monitoring Committee 
An overall DMC is established to evaluate overall safety of the Takeda Norovirus vaccine 
program on an ongoing basis. The composition, role and responsibilities of the DMC are 
presented in a separate DMC Charter. 
0074
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-204 
Page 74 of 92 
Protocol Version 2.0 
16 November 2015 
 
12.0 DATA HANDLING AND RECORD KEEPING 
The full details of procedures for data handling will be documented in the Data Management 
Plan. AEs, medical history, and concurrent conditions will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA) System Organ Class (SOC), High Level 
Group Term (HLGT), High Level Term (HLT), Low Level Term (LL), 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. Reasons for significant corrections 
should additionally be included. 
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. 
Electronic CRFs will be reviewed for completeness and acceptability at the trial site during 
periodic visits by trial monitors. The Sponsor or its designee will be permitted to review the 
subject’s medical and hospital records pertinent to the trial to ensure accuracy of the eCRFs. 
The completed eCRFs are the sole property of the Sponsor and should not be made available in 
any form to third parties, except for authorized representatives of appropriate governmental 
health or regulatory authorities, without written permission of the Sponsor. 
12.2 Record Retention 
The Investigator agrees to keep records of the eCRF and those documents that include (but are 
not limited to) the trial-specific documents, the identification log of all participating subjects, 
source documents. Temporary media such as thermal sensitive paper should be copied and 
certified, source worksheets, all original signed and dated ICFs, subject authorization forms 
regarding the use of personal health information (if separate from the ICFs), electronic copy of 
eCRFs, including the audit trail, and detailed records of vaccine disposition to enable 
evaluations or audits from regulatory authorities, the Sponsor or its designees. Furthermore, 
International Conference on Harmonization (ICH) E6 Section 4.9.5 requires the Investigator to 
retain essential documents specified in ICH E6 (Section 8) until at least 2 years after the last 
approval of a marketing application for a specified vaccine indication being investigated or, if 
0075
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-204 
Page 75 of 92 
Protocol Version 2.0 
16 November 2015 
 
an application is not approved, until at least 2 years after the investigation is discontinued and 
regulatory authorities are notified. In addition, ICH E6 Section 4.9.5 states that the trial records 
should be retained until an amount of time specified by applicable regulatory requirements or 
for a time specified in the Clinical Trial Site Agreement between the Investigator and Sponsor. 
Refer to the Clinical Trial 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. 
0076
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-204 
Page 77 of 92 
Protocol Version 2.0 
16 November 2015 
 
13.1.3 
Safety Analysis 
All summaries and analyses of safety data are based on subjects in the Safety Analysis Set. 
Unless otherwise specified, the safety data will be summarized according to the treatment arms 
within each age group. Further grouping or sub-grouping may be investigated as appropriate 
(eg, all age classes ≥60 years together). In general, data imputation will not be performed for 
any missing safety data. The criteria for implausible measurements are defined in the statistical 
analysis plan, and any measurements meeting those criteria (eg, body temperature >42°C) will 
be excluded from the summaries and analyses. 
Reactogenicity 
Reactogenicity will be assessed for 7 days following each vaccination (the day of vaccination 
and the following 6 days) 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 reactogenicity will be 
collected (body temperature). The categories for each solicited AE are defined in Section 
10.1.3. Solicited adverse event data (reactogenicity) will be captured daily for 7 days (on the 
day of vaccination and the following 6 days). 
For each solicited AE, the percentage of subjects will be summarized by event severity for each 
day (from Day 1 to Day 7) and overall. In addition, summaries will be provided for the intervals 
of Days 1 to 3 following each vaccination, and Days 4 to 7 following each vaccination. A 
summary of the day of first onset of each event and the number of days subjects reported 
experiencing each event will also be provided. For subjects with more than 1 episode of the 
same event, the maximum severity will be used for tabulations. 
The occurrence of reactogenicity will also be summarized descriptively by the number of days 
subjects reported experiencing the symptom, by treatment group within each age group. 
Unsolicited AEs 
Unsolicited AEs, SAEs and AESI will be coded using the MedDRA and summarized by SOC 
and PT for each trial treatment arm in each age group. AEs leading to subject’s withdrawal from 
the trial will also be summarized. 
All unsolicited AEs up to 28 days after the last vaccination will be included in the analyses of 
all AEs. For SAEs and AEs leading to subject withdrawal from the trial, any AE collected 
during the trial will be included. 
In general, unsolicited AEs will be tabulated at each of the following levels: overall summary 
(subject with at least 1 AE) and by SOC and PT. Subjects reporting more than 1 occurrence for 
the term (level) being summarized will be counted only once. Unsolicited AEs will be 
summarized as follows: by PT including events with frequency greater than 2%; by SOC and 
PT; by SOC, PT, and severity; and by SOC, PT, and relationship to the investigational vaccine. 
Unless otherwise specified, unsolicited AEs in the treatment arm and age groups will be 
summarized in the following 3 ways: 1) overall up to 28 days after the first and second 
vaccination, 2) with onset between 1 and 7 days after the first and second vaccination, and 
3) with onset between 8 and 28 days after the first and second vaccination. 
0078
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


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icab


Norovirus GI.1/GII.4 Bivalent VLP Vaccine  
 
Trial No. NOR-204 
Page 79 of 92 
Protocol Version 2.0 
16 November 2015 
 
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, trial vaccine, subject medical records, informed consent documentation, documentation 
of subject authorization to use personal health information (if separate from the ICFs), and 
review of eCRFs and associated source documents. It is important that the Investigator and 
other trial personnel are available during the monitoring visits and that sufficient time is 
devoted to the process. 
14.2 Protocol Deviations 
The Investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to trial subjects. Should other unexpected circumstances arise that will 
require deviation from protocol-specified procedures, the Investigator should consult with the 
medical monitor (and IRB or IEC, as required) to determine the appropriate course of action. 
There will be no exemptions (a prospective approved deviation) from the inclusion or exclusion 
criteria. 
14.3 Quality Assurance Audits and Regulatory Agency Inspections 
The trial site also may be subject to quality assurance audits by the Sponsor or designees. In this 
circumstance, the Sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the vaccine is stored and prepared, and any other facility used during the trial. In 
addition, there is the possibility that this trial may be inspected by regulatory agencies, 
including those of foreign governments (eg, the Food and Drug Administration [FDA], the 
United Kingdom Medicines and Healthcare products Regulatory Agency, 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. 
0080
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-204 
Page 80 of 92 
Protocol Version 2.0 
16 November 2015 
 
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 state and federal/local 
requirements of each participating region. The Sponsor or designee will require documentation 
noting all names and titles of members who make up the respective IRB or IEC. If any member 
of the IRB or IEC has direct participation in this trial, written notification regarding his or her 
abstinence from voting must also be obtained. Those US sites unwilling to provide names and 
titles of all members due to privacy and conflict of interest concerns should instead provide a 
Federal Wide Assurance Number or comparable number assigned by the Department of Health 
and Human Services. 
The Sponsor or designee will supply relevant documents for submission to the respective IRB 
or IEC for the protocol’s review and approval. This protocol, the Investigator’s Brochure, a 
copy of the ICF, and, if applicable, subject recruitment materials and/or advertisements and 
other documents required by all applicable laws and regulations, must be submitted to a central 
or local IRB or IEC for approval. The IRB’s or IEC’s written approval of the protocol and 
subject 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, ICF) reviewed; and 
state the approval date. The Sponsor will notify the site once the Sponsor has confirmed the 
adequacy of site regulatory documentation and, when applicable, the Sponsor has received 
permission from the competent authority to begin the trial. Until the site receives notification of 
approval, no protocol activities, including screening, may occur. 
Sites must adhere to all requirements stipulated by their respective IRB or IEC. This may 
include notification to the IRB or IEC regarding protocol amendments, updates to the ICF, 
recruitment materials intended for viewing by subjects, local safety reporting requirements, 
reports and updates regarding the ongoing review of the trial at intervals specified by the 
respective IRB or IEC, and submission of the Investigator’s final status report to IRB or IEC. 
All IRB and IEC approvals and relevant documentation for these items must be provided to the 
Sponsor or its designee. 
Subject incentives should not exert undue influence for participation. Payments to subjects 
must be approved by the IRB or IEC and Sponsor. 
0081
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-204 
Page 81 of 92 
Protocol Version 2.0 
16 November 2015 
 
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 ICF, subject authorization form (if applicable), and 
subject information sheet (if applicable) describe the planned and permitted uses, transfers, and 
disclosures of the subject’s personal and personal health information for purposes of 
conducting the trial. The ICF and the subject information sheet (if applicable) further explain 
the nature of the trial, its objectives, and potential risks and benefits, as well as the date 
informed consent is given. The ICF will detail the requirements of the 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 ICF 
and if applicable, the subject authorization form. The ICF, subject authorization form (if 
applicable), and subject information sheet (if applicable) must be approved by both the IRB or 
IEC and the Sponsor prior to use. 
The ICF, subject authorization form (if applicable), and subject information sheet (if 
applicable) must be written in a language fully comprehensible to the prospective subject. It is 
the responsibility of the Investigator to explain the detailed elements of the ICF, subject 
authorization form (if applicable), and subject information sheet (if applicable) to the subject. 
Information should be given in both oral and written form whenever possible and in the manner 
deemed appropriate by the IRB or IEC.  
The subject, must be given ample opportunity to: (1) inquire about details of the trial and (2) 
decide whether or not to participate in the trial. If the subject, determines he or she will 
participate in the trial, then the ICF and subject authorization form (if applicable) must be 
signed and dated by the subject, at the time of consent and prior to the subject entering into the 
trial. The subject should be instructed to sign using their legal names, not nicknames, using blue 
or black ballpoint ink. The Investigator must also sign and date the ICF and subject 
authorization (if applicable) at the time of consent and prior to subject entering into the trial; 
however, the Sponsor may allow a designee of the Investigator to sign to the extent permitted 
by applicable law. 
Once signed, the original ICF, subject authorization form (if applicable), and subject 
information sheet (if applicable) will be stored in the Investigator’s site file. The Investigator 
must document the date the subject signs the informed consent in the subject’s medical record 
and eCRF. Copies of the signed ICF, the signed subject authorization form (if applicable), and 
subject information sheet (if applicable) shall be given to the subject. 
All revised ICFs must be reviewed and signed by relevant subjects in the same manner as the 
original informed consent. The date the revised consent was obtained should be recorded in the 
subject’s medical record and eCRF, and the subject should receive a copy of the revised ICF. 
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 
0082
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-204 
Page 82 of 92 
Protocol Version 2.0 
16 November 2015 
 
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, at a minimum register 
all clinical trials conducted in subjects that it Sponsors anywhere in the world on 
ClinicalTrials.gov or other publicly accessible websites before trial initiation. The Sponsor 
contact information, along with Investigator’s city, country, and recruiting status will be 
registered and available for public viewing. 
15.4.3 
Clinical Trial Results Disclosure 
The Sponsor will post the results of this clinical trial, regardless of outcome, on 
ClinicalTrials.gov or other publicly accessible websites, as required by applicable laws and/or 
regulations. 
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. 
0083
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-204 
Page 83 of 92 
Protocol Version 2.0 
16 November 2015 
 
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 Trial 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. 
0084
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


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SAP_000.pdf: 


Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.
Title: A Phase II, Randomized, Double-blind, Safety and Immunogenicity Trial of Norovirus GI.1/
GII.4 Bivalent Virus-Like Particle Vaccine in Healthy Elderly Adults 
NCT Number: NCT02661490
SAP Approve Date:  02 February 2017 
Certain information within this Statistical Analysis Plan has been redacted (ie, specific content is masked 
irreversibly from view with a black/blue bar) to protect either personally identifiable (PPD) information 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.


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NOR-204 
Page 3 of 41 
Statistical Analysis Plan (Final 1.0) 
02 February 2017 
 
2.0 
TABLE OF CONTENTS 
1.0 
TITLE PAGE .......................................................................................................................1 
1.1 
Approval Signatures.......................................................................................................2 
2.0 
TABLE OF CONTENTS .....................................................................................................3 
List of In-Text Tables ................................................................................................................4 
List of In-Text Figures ...............................................................................................................4 
List of APPENDICES ................................................................................................................4 
3.0 
LIST OF ABBREVIATIONS ..............................................................................................5 
4.0 
OBJECTIVES ......................................................................................................................7 
4.1 
Primary Objectives.........................................................................................................7 
4.2 
Secondary Objectives.....................................................................................................7 
4.3 
Exploratory Objectives ..................................................................................................7 
4.4 
Study Design ..................................................................................................................7 
5.0 
ANALYSIS ENDPOINTS ................................................................................................14 
5.1 
Primary Endpoints .......................................................................................................14 
5.2 
Secondary Endpoints ...................................................................................................14 
5.3 
Exploratory Endpoints .................................................................................................15 
6.0 
DETERMINATION OF SAMPLE SIZE ..........................................................................18 
7.0 
METHODS OF ANALYSIS AND PRESENTATION .....................................................19 
7.1 
General Principles ........................................................................................................19 
7.1.1 Study Day and Analysis Window Definitions .......................................................20 
7.1.2 Conventions for Handling Missing Values ............................................................21 
7.2 
Analysis Sets ................................................................................................................22 
7.3 
Disposition of Subjects ................................................................................................24 
7.3.1 Disposition .............................................................................................................24 
7.3.2 Protocol Violations ................................................................................................24 
7.4 
Demographic and Other Baseline Characteristics .......................................................25 
7.5 
Medical History and Concurrent Medical Conditions .................................................25 
7.6 
Medication History and Concomitant Medications .....................................................25 
7.7 
Study Drug Exposure and Compliance ........................................................................25 
7.8 
Immunogenicity Analysis ............................................................................................26 
7.8.1 Primary Efficacy Endpoint(s) ................................................................................26 
7.8.2 Secondary Efficacy Endpoint(s) ............................................................................27 
7.8.3 Additional Immunogenicity Endpoint(s) ...............................................................30 
7.9 
Pharmacokinetic/Pharmacodynamic Analysis .............................................................32 
7.9.1 Pharmacokinetic Analysis ......................................................................................32 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


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NOR-204 
Page 6 of 41 
Statistical Analysis Plan (Final 1.0) 
02 February 2017 
 
MPL 
Monophosphoryl Lipid A 
NoV 
Norovirus 
NoVs 
Noroviruses 
Pan-Ig 
Pan Immunoglobulin 
PBMC 
Peripheral Blood Mononuclear Cell 
PPS 
Per Protocol Set 
PT 
Preferred Term 
SAE 
Serious Adverse Event 
SAF 
Safety Analysis Set 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SOC 
System Organ Class 
TNF-α 
Tumor Necrosis Factor-alpha 
ULoQ 
Upper Limit of Quantification 
VLP 
Virus-like Particles 
WHODrug 
World Health Organization Drug Dictionary 
 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


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NOR-204 
Page 8 of 41 
Statistical Analysis Plan (Final 1.0) 
02 February 2017 
 
vaccine administrations. The 18–49 year old subjects will receive only one NoV G.1/GII.4 
Bivalent VLP Vaccine dose (Formulation A). 
All age groups will be enrolled in parallel. In order to maintain blinding and to have the same 
trial time point with both dosing regimens relative to the last vaccination, subjects randomized 
into the 1-dose groups will receive 1 dose of Saline Placebo on Day 1 followed by 1 dose of the 
investigational NoV G.1/GII.4 Bivalent VLP Vaccine 28 days later. Subjects who receive the 
Saline Placebo first will undergo exactly the same follow up as the other subjects who receive 
the first dose of NoV G.1/GII.4 Bivalent VLP Vaccine on Day 1. 
Planned number of Arms. 
• Arm 1: NoV GI.1/GII.4 Bivalent VLP Vaccine, Formulation A, 1-dose regimen (subjects 
≥60 years). 
• Arm 2: NoV GI.1/GII.4 Bivalent VLP Vaccine, Formulation A, 2-dose regimen (subjects 
≥60 years). 
• Arm 3: NoV GI.1/GII.4 Bivalent VLP Vaccine, Formulation B, 1-dose regimen (subjects 
≥60 years). 
• Arm 4: NoV GI.1/GII.4 Bivalent VLP Vaccine, Formulation B, 2-dose regimen (subjects 
≥60 years). 
• Arm 5: NoV GI.1/GII.4 Bivalent VLP Vaccine, Formulation A, 1-dose regimen (Subjects 
18–49 years). 
All subjects will receive trial vaccination on Day 1 and Day 29 as shown in Table 1. If Dose 2 is 
not given on Day 29, subsequent visits should be calculated from the actual Day given (e.g., if 
Dose 2 is given on trial Day 31, the next visit should be scheduled for trial Day 38). 
Table 1 Subject Distribution for Trial NOR-204 
Age groups (years) 
Number of subjects 
Dose regimen (a) 
Day 1 
Day 29 
18–49 
25 
1 
Saline Placebo 
Formulation A 
60–74 
25 
1 
Saline Placebo 
Formulation A 
25 
2 
Formulation A 
Formulation A 
25 
1 
Saline Placebo 
Formulation B 
25 
2 
Formulation B 
Formulation B 
75–84  
25 
1 
Saline Placebo 
Formulation A 
25 
2 
Formulation A 
Formulation A 
25 
1 
Saline Placebo 
Formulation B 
25 
2 
Formulation B 
Formulation B 
≥85 
25 
1 
Saline Placebo 
Formulation A 
25 
2 
Formulation A  
Formulation A 
25 
1 
Saline Placebo 
Formulation B 
25 
2 
Formulation B  
Formulation B 
Total evaluable subjects 
325 
 
 
 
aOne dose versus 2-dose regimen with the NoV G.1/GII.4 Bivalent VLP Vaccine (Formulations A or B) 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


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NOR-204 
Page 10 of 41 
Statistical Analysis Plan (Final 1.0) 
02 February 2017 
 
A schematic of the trial design is included as Figure 1. 
Figure 1 Schematic of Trial NOR-204 Design  
 
Trial Vaccines: 
Norovirus GI.1/GII.4 Bivalent VLP Vaccine: two vaccine formulations will be evaluated in this 
trial: 
• Formulation A (per dose): 15 μg of GI.1 NoV VLP; 50 μg of GII.4 NoV VLP (consensus of 
3 strains) without MPL, all of which are adsorbed to Al(OH)3 adjuvant (500 µg aluminum). 
• Formulation B (per dose): 15 μg of GI.1 NoV VLP; 50 μg of GII.4 NoV VLP (consensus of 
3 strains) with 15 μg of MPL, all of which are adsorbed to Al(OH)3 adjuvant (500 µg 
aluminum). 
Control: Placebo (saline) will be 0.9% sodium chloride for injection without preservative. It will 
be used as a control to maintain the trial blinding in subjects who are in the one-dose groups of 
NoV GI.1/GII.4 Bivalent VLP Vaccine. 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


NOR-204 
Page 11 of 41 
Statistical Analysis Plan (Final 1.0) 
02 February 2017 
 
All vaccines will be administered by intramuscular (IM) route into the middle third of the deltoid 
muscle, preferably in the non-dominant arm. 
Visit Schedule 
Clinical trial visits will be performed on Days 1, 8, 29, 36, 57, 211 and 393 for subjects in all 
five treatment arms.  
Duration of Trial 
Subjects will be enrolled for approximately 393 days; that is to capture safety information 365 
days after the last trial dose. Short term follow-up for AEs, SAEs, concomitant medications and 
AESI will be 28 days following each dose (Dose 1: through Day 28, collected on Day 29 and 
Dose 2: through Day 56, collected on Day 57). Final follow-up for SAEs and AESI will be 
performed 365 days following the last vaccination (i.e., on Day 393). 
A schedule of procedures is listed in Table 2.  
 
 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


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NOR-204 
Page 14 of 41 
Statistical Analysis Plan (Final 1.0) 
02 February 2017 
 
5.0 
ANALYSIS ENDPOINTS 
5.1 
Primary Endpoints 
Immunogenicity 
• Percentage of subjects with a 4-fold rise or greater in serum anti-NoV antibody titers for both 
GI.1 VLP and GII.4 VLP as measured by Histoblood Group Antigen (HBGA) blocking assay 
on Day 57 (28 days after the last vaccination). 
Safety 
• Percentage of subjects with solicited local AEs (pain, erythema, induration, and swelling at 
the injection site) for 7 days (the day of vaccination and the following six days) after each 
vaccination; 
• Percentage of subjects with solicited systemic AEs (headache, fatigue, myalgia, arthralgia, 
vomiting, and diarrhea) for 7 days after each vaccination; 
• Percentage of subjects with elevated body temperature ≥38°C (defined as fever) for 7 days 
after each vaccination; 
• Percentage of subjects with any unsolicited AEs from Day 1 through Day 28 (post-
vaccination 1) and from Day 29 through Day 57 (post-vaccination 2), inclusive; 
• Percentage of subjects with SAEs throughout the trial. 
5.2 
Secondary Endpoints 
Immunogenicity 
HBGA blocking assay 
• Percentage of subjects with a 4-fold rise or greater of serum anti-NoV GI.1 VLP and anti-
NoV GII.4 VLP antibody titers as measured by HBGA blocking assay (Day 8, Day 29, Day 
36, Day 211, and Day 393); 
• Percentage of subjects with a 4-fold rise or greater of serum anti-NoV GI.1 VLP antibody 
titers as measured by HBGA blocking assay (Day 8, Day 29, Day 36, Day 57, Day 211, and 
Day 393); 
• Percentage of subjects with a 4-fold rise or greater of serum anti-NoV GII.4 VLP antibody 
titers as measured by HBGA blocking assay (Day 8, Day 29, Day 36, Day 57, Day 211, and 
Day 393); 
• GMT of anti-NoV GI.1 VLP antibody titers as measured by HBGA blocking assay (Day 1, 
Day 8, Day 29, Day 36, Day 57, Day 211, and Day 393); 
• GMT of anti-NoV GII.4 VLP antibody titers as measured by HBGA blocking assay (Day 1, 
Day 8, Day 29, Day 36, Day 57, Day 211, and Day 393); 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


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able Terms of


NOR-204 
Page 18 of 41 
Statistical Analysis Plan (Final 1.0) 
02 February 2017 
 
6.0 
DETERMINATION OF SAMPLE SIZE 
This trial is designed to be primarily descriptive. Therefore the sample size was not determined 
based on formal statistical power calculations but rather to provide a reasonable clinical database 
to assess safety and immunogenicity in an elderly population. 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


NOR-204 
Page 19 of 41 
Statistical Analysis Plan (Final 1.0) 
02 February 2017 
 
7.0 
METHODS OF ANALYSIS AND PRESENTATION 
7.1 
General Principles  
All statistical analyses will be generated using SAS Version 9.2 or higher. 
Immunogenicity and safety endpoints will be summarized descriptively (frequency and percent 
for categorical data; and number of subjects with non-missing observation, mean, standard 
deviation (SD), median, minimum and maximum for continuous data) by all relevant study 
visits, as appropriate. In summary tables for categorical data for which categories are defined on 
the eCRF, all categories will be presented as specified, even if the subject count within that 
category is zero. For other categorical data (e.g. adverse events and medications), only categories 
with at least 1 subject will be presented. 
In general, summaries and analyses are to be provided by treatment arm and by age group. The 
following terminology and conventions will be used as applicable. 
Presentation of results by treatment, and by treatment within each age group (60–74, 75–84, and 
≥85 years), will be provided for: 
• A1: Arm 1: NoV GI.1/GII.4 Bivalent VLP Vaccine, Formulation A, 1-dose regimen (subjects ≥60 years). 
• A2: Arm 2: NoV GI.1/GII.4 Bivalent VLP Vaccine, Formulation A, 2-dose regimen (subjects ≥60 years). 
• 
A3: Arm 3: NoV GI.1/GII.4 Bivalent VLP Vaccine, Formulation B, 1-dose regimen (subjects ≥60 years). 
• A4: Arm 4: NoV GI.1/GII.4 Bivalent VLP Vaccine, Formulation B, 2-dose regimen (subjects ≥60 years). 
• 
A5: Arm 5: NoV GI.1/GII.4 Bivalent VLP Vaccine, Formulation A, 1-dose regimen (Subjects 18–49 
years). 
When applicable, summaries of all subjects (treatment arms A1, A2, A3, A4 and A5 combined), 
and/or summaries of all elderly subjects (treatment arms A1, A2, A3, and A4 combined), will be 
provided. 
Unless otherwise stated the conventions below will be used in reporting results. Minimum and 
maximum values will be presented using the same number of decimal places as the recorded 
data. Means, the least squares means (LS Means), and medians will be presented to 1 more 
decimal place than the recorded data. Standard deviations (SD) will be presented to 2 more 
decimal places than the recorded data. The CI about a parameter estimate will be presented using 
the same number of decimal places as the parameter estimate (ie., 1 more decimal place than the 
recorded data). Percentages will be presented to 1 decimal place (e.g., 80.3%). All p-values will 
be rounded to 3 decimal places. If a p-value is less than 0.001, it will be reported as “<0.001”; if 
a p-value is greater than 0.999, it will be reported as “>0.999”. 
When count data are presented, the percentage will be suppressed when the count is zero in order 
to draw attention to the non-zero counts. 
Baseline is defined as the last non-missing measurement taken before the first dose of 
vaccination including the screening value or a value from an unscheduled visit, if necessary. 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


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NOR-204 
Page 22 of 41 
Statistical Analysis Plan (Final 1.0) 
02 February 2017 
 
An adverse event should be temporally associated with the correct vaccination dose as far as 
possible. If an event has a missing or incomplete start date the date will be imputed using the 
following guidelines. If available date information indicates that the start of an event is between 
two vaccination dates, then the earliest possible date will be used for imputation. For example, if 
Vaccination 1 is on 01 January 2016 and Vaccination 2 is on 02 March 2016 and the event has 
an incomplete start date of February 2016, then the event would have an imputed date of 01 
February 2016. If the available start date information is insufficient to distinguish between 1 or 
more vaccination dates, then the event end date will be assessed to determine the earliest possible 
imputed date relative to the latest vaccination. In the above example if an event is known to start 
in 2016 (day and month missing) and the end date is known as 20 March 2016, then an imputed 
start date of 02 March (date of Vaccination 2) will be used. If an event is missing both start and 
end date then the last vaccination date will be used as the imputed start date. When event end 
dates are missing or partially missing, information such as whether the AEs are ongoing by the 
end of study will be taken into consideration. 
Titer measured below LLoQ or above ULoQ  
For a titer value measured as having a value below LLoQ, it is to be imputed as the half of the 
LLoQ in summaries and analyses, and it will be listed as reported in the raw data. For example, 
if an assay has the level of LLoQ of 120, and a sample is reported to have “<120” as the titer 
level, a value of 60 (half of 120) is to be used for the statistical summaries.  
For a titer value measured as having a value above ULoQ, a value of the level of ULoQ will be 
used for the summaries and analyses, and it will be listed as reported in the raw data. For 
example, if an assay has the level of ULoQ of 120, and a sample is reported to have “>120” as 
the titer level, a value of 120 is to be used for the statistical summaries. 
7.2 
Analysis Sets 
The following analysis sets are defined for this study.  
Randomized Set: all randomized subjects regardless of whether any study vaccine (NoV VLP 
vaccine or placebo) was received. Data will be analyzed according to treatment randomized. 
Note that subjects who were randomized in error (per IWRS) will be excluded from the 
Randomized Set. 
Safety Analysis Set (SAF): all subjects who receive at least 1 dose of vaccine (NoV VLP vaccine 
or placebo). Data will be analyzed according to treatment received. 
Full Analysis Set (FAS): all subjects who are randomized and have at least 1 dose of vaccine 
(NoV VLP vaccine or placebo). Data will be analyzed according to treatment randomized. 
Per Protocol Set (PPS): All subjects in the FAS, who receive the planned vaccination (both 
doses of vaccine, i.e. NoV VLP vaccine or placebo), and do not have major protocol violations 
will be included in the PPS. The categories of major protocol violations include:  
1) Not meeting entry criteria, based on selected inclusion/exclusion criteria (exclusion 
criteria #10 and #11) defined in protocol [1, 2] Sections 7.1 and 7.2; 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


NOR-204 
Page 23 of 41 
Statistical Analysis Plan (Final 1.0) 
02 February 2017 
 
Exclusion criterion #10: Known or suspected impairment/alteration of immune function, 
including the following: 
a. Chronic use of oral steroids (Equivalent to 20 mg/day prednisone ≥ 12 weeks / ≥ 
2 mg/kg body weight / day prednisone ≥ 2 weeks) within 60 days prior to Day 1 
(use of inhaled, intranasal, or topical corticosteroids is allowed). 
b. Receipt of parenteral steroids (Equivalent to 20 mg/day prednisone ≥ 12 weeks / ≥ 
2 mg/kg body weight / day prednisone ≥ 2 weeks) within 60 days prior to Day 1. 
c. Receipt of immunosuppressive therapy within 3 months prior to Day 1. 
d. Receipt of immunostimulants within 60 days prior to Day 1. 
e. Receipt of parenteral, epidural or intra-articular immunoglobulin preparation, 
blood products, and/or plasma derivatives within 3 months prior to Day 1 or 
planned during the full length of the trial. 
f. Human Immunodeficiency Virus (HIV) infection or HIV-related disease. 
g. Genetic immunodeficiency. 
           Exclusion criterion #11: Abnormalities of splenic or thymic function. 
2) Receiving wrong trial treatment; 
3) Not receiving both doses of trial vaccine or receiving the second trial dose inadmissibly 
outside of the visit window; 
4) Receiving prohibited therapies in the following categories (also specified in protocol [1, 
2] Section 9.1.2): 
• Parenteral immunoglobulin preparation, blood products, and/or plasma 
derivatives within 3 months of the first vaccination, or any time during the trial. 
• Immunosuppressive therapy within 6 months or systemic (eg, oral or parenteral) 
corticosteroid treatment within 60 days prior to vaccine administration. 
• Administration of other vaccines within 14 days (for inactivated vaccines) or 28 
days (for live vaccines) prior to administration of study vaccine. 
5) Other major violations that compromise the primary immunogenicity endpoint 
assessment.  
A major protocol violation is defined as a protocol deviation that is considered to have a 
significant impact on the immunogenicity results of the subject. All protocol deviations will be 
identified prior to unblinding and a clinical judgment will be necessary to classify each deviation 
as a "major" violation or not.  These violations and the judgment regarding their use will be 
listed and summarized in the final clinical study report. Refer to Section 7.3.2. The major 
protocol violation criteria will be finalized as part of the blind data review prior to the interim 
analysis planned after all subjects have completed the Day 57 Visit (28 days after last 
vaccination). Refer to Section 7.12. 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


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NOR-204 
Page 26 of 41 
Statistical Analysis Plan (Final 1.0) 
02 February 2017 
 
The analyses described above will be based on SAF. All data will be presented in listings as 
well. 
7.8 
Immunogenicity Analysis 
Immunogenicity analyses will be based primarily on PPS. Supportive immunogenicity analyses 
will be performed using FAS. 
Immunogenicity results from the trial will be summarized by treatment (A1, A2, A3, A4 and 
A5), and by treatment within each age group. Treatment arm A5 will be presented as reference, 
in each age group level analysis. In addition, for primary and secondary immunogenicity 
endpoints only, results will be summarized by dosing regimen (over all age groups and within 
each age group), where ‘1-Dose’ grouping will summarize results over treatments A1 and A3 
(i.e. one dose regimen treatment arms) and ‘2-Dose’ grouping will summarize results over 
treatments A2 and A4 (i.e. two dose regimen treatment arms). Finally, for primary and secondary 
immunogenicity endpoints only, results will be summarized by formulation type (over all age 
groups and within each age group), where ‘MPL-’ grouping will summarize results over 
treatments A1 and A2 (i.e. formulation A treatment arms) and ‘MPL+’ grouping will summarize 
results over treatments A3 and A4 (i.e. formulation B treatment arms). 
Where comparisons between treatment groups are to be performed, the following pre-specified 
pairwise comparisons of interest will be presented: 
a. A2 vs A1; A3 vs A1; A4 vs A1;   
b. A3 vs A2; A4 vs A2; A4 vs A3;  
c. A1 vs A5; A2 vs A5; A3 vs A5; A4 vs A5; 
d. 1-Dose (A1 + A3) vs 2-Dose (A2 + A4). 
e. MPL- (A1 + A2) vs MPL+ (A3 + A4). 
7.8.1 Primary Efficacy Endpoint(s) 
The primary immunogenicity endpoint is defined in Section 5.1. 
The primary endpoint will be presented by treatment arms for all age groups and within each 
elderly age group level, as well as by dosing regimen, as described in Section 7.8, at Day 57 for 
the PPS. 
For each subject (i) the fold rise (fi) in titer value, at a specific post baseline time point is 
calculated as : 
f i = vpost/vpre 
where vpost is the post vaccination value of the titer at that specific time point and vpre is the pre 
vaccination (baseline) value of the titer. Subjects with a 4-fold rise or greater (i.e f i >= 4) in 
serum anti-NoV antibody titers for both GI.1 VLP and GII.4 VLP as measured by HBGA 
blocking assay on Day 57 (28 days after the last vaccination) will be counted within each 
treatment arm at the visit and rates and percentages will be provided based on the number of 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


NOR-204 
Page 27 of 41 
Statistical Analysis Plan (Final 1.0) 
02 February 2017 
 
subjects with a non-missing value within the treatment arm at the visit as well as the 
corresponding 95% CI. The exact (Clopper-Pearson) method will be used to produce the 95% CI, 
i.e. no adjustment related to age stratification will be applied. 
In addition, pairwise comparisons with lower level as a reference group, as defined in Section 
7.8, will be presented for Day 57, without multiplicity adjustment.   
Risk ratios, and corresponding 95% CIs and Fisher’s exact test p-values, will be calculated as 
well as risk differences and associated confidence limits based on the Newcombe score method 
for pairwise comparisons (a, b, c and d) between treatment arms, within each elderly age group 
(60–74, 75–84, and ≥85 years).   
For between treatment arms analyses for all elderly age groups combined (60–74, 75–84, and 
≥85 years), pairwise comparisons (a, b, c and d) will be performed as well. For pairwise 
comparisons ‘a’, ‘b’, ‘d’ and ‘e’ only, a Cochran Mantel Haenzel (CMH) method stratified by 
age, will be used to provide the age adjusted risk ratios, the corresponding 95% CIs and p-values. 
In addition age adjusted risk differences and corresponding 95% Wald-type CIs will be provided 
(due to computational simplicity) using a CMH weighting strategy. For pairwise comparisons 
‘c’, a simple non stratified approach will be followed similar to the one described in the previous 
paragraph. Since elderly population treatment arms A1, A2, A3 and A4 do not share the same 
age stratification as the younger adults treatment arm A5, crude estimates for rates and 
proportions for treatment arms A1, A2, A3 and A4 will be utilized when comparing these with 
treatment arm A5. 
Since the missing data resulting from dropouts in vaccine trials are typically missing completely 
at random (MCAR) [4], a simple way of handling missing data is to use a “complete case 
analysis”, i.e., to exclude subjects with missing data at baseline or at the endpoint visit.  In the 
case when more than 20% of the subjects have missing data in primary immunogenicity 
endpoint, multiple imputation methods may be explored as a sensitivity analysis. 
7.8.2 Secondary Efficacy Endpoint(s) 
Secondary immunogenicity endpoints are listed in Section 5.2.  
Endpoints listed below, corresponding to percentages of subjects with a 4-fold rise or greater of 
serum anti-NoV antibody titers for GI.1 VLP and GII.4 VLP separately or both GI.1 VLP and 
GII.4 VLP simultaneously as measured by HBGA blocking assay or Pan-Ig Enzyme-linked 
Immunosorbent Assay (ELISA), will be summarized for study visits Day 8, Day 29, Day 36, 
Day 57, Day 211, and Day 393, following a similar approach to that described in Section 7.8.1 
for the primary endpoint. Any pairwise comparisons, with lower level as a reference group, as 
defined in Section 7.8, are to be presented for Day 36, Day 57, Day 211, and Day 393 only. 
In addition, percentages of subjects with a 4-fold rise or greater and corresponding 95% CI will 
be graphically summarized using bar charts, by treatment arms for all age groups and within each 
elderly age group level for Day 8, Day 29, Day 36, Day 57, Day 211 and Day 393. 
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HBGA blocking assay 
• Percentage of subjects with a 4-fold rise or greater of serum anti-NoV GI.1 VLP and 
GII.4 VLP antibody titers as measured by HBGA blocking assay (Day 8, Day 29, Day 
36, Day 211, and Day 393); 
• Percentage of subjects with a 4-fold rise or greater of serum anti-NoV GI.1 VLP antibody 
titers as measured by HBGA blocking assay (Day 8, Day 29, Day 36, Day 57, Day 211, 
and Day 393); 
• Percentage of subjects with a 4-fold rise or greater of serum anti-NoV GII.4 VLP 
antibody titers as measured by HBGA blocking assay (Day 8, Day 29, Day 36, Day 57, 
Day 211, and Day 393); 
Pan-Ig Enzyme-linked Immunosorbent Assay (ELISA) 
• Percentage of subjects with a 4-fold rise or greater of serum anti-NoV GI.1 VLP and 
GII.4 VLP antibody titers as measured by Pan-Ig ELISA (Day 8, Day 29, Day 36, Day 
57, Day 211, and Day 393); 
• Percentage of subjects with a 4-fold rise or greater of serum anti-NoV GI.1 VLP antibody 
titers as measured by Pan-Ig ELISA (Day 8, Day 29, Day 36, Day 57, Day 211, and 
Day 393); 
• Percentage of subjects with a 4-fold rise or greater of serum anti-NoV GII.4 VLP 
antibody titers as measured by Pan-Ig ELISA (Day 8, Day 29, Day 36, Day 57, Day 211, 
and Day 393); 
Continuous endpoints listed below, corresponding to values of serum anti-NOV antibody titers 
for GI.1 VLP or GII.4 VLP separately as measured by HBGA blocking assay or Pan-Ig Enzyme-
linked Immunosorbent Assay (ELISA), will be summarized and provided in the following way. 
Geometric mean titers (GMT) and the corresponding geometric standard deviation (GSD), and 
95% CIs for the GMT as well as the minimum and maximum titer value, will be presented at 
first instance by treatment, and by treatment within each elderly age group, as well as by dosing 
regimen. Treatment arm A5 will be presented as reference, in each age group level analysis. 
Similarly estimates of Geometric Mean Fold Rise (GMFR) and the corresponding geometric 
standard deviation (GSD), and 95% CIs for the GMFR as well as the minimum and maximum 
fold rise value, will be presented following the same approach as the GMT results. 
In addition, Geometric Mean Anti-NoV Antibody Titers and Geometric Mean Fold Rise in Anti-
Nov Antibody Titers will be graphically summarized using bar charts, by treatment arms for all 
age groups and within each elderly age group level for Day 1, Day 8, Day 29, Day 36, Day 57, 
Day 211 and Day 393 respectively. 
HBGA blocking assay 
• GMT of anti-NoV GI.1 VLP antibody titers as measured by HBGA blocking assay 
(Day 1, Day 8, Day 29, Day 36, Day 57, Day 211, and Day 393); 
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• GMT of anti-NoV GII.4 VLP antibody titers as measured by HBGA blocking assay 
(Day 1, Day 8, Day 29, Day 36, Day 57, Day 211, and Day 393); 
• GMFR of anti-NoV GI.1 VLP antibody titers as measured by HBGA blocking assay 
(Day 8, Day 29, Day 36, Day 57, Day 211, and Day 393); 
• GMFR of anti-NoV GII.4 VLP antibody titers as measured by HBGA blocking assay 
(Day 8, Day 29, Day 36, Day 57, Day 211, and Day 393). 
Pan-Ig Enzyme-linked Immunosorbent Assay (ELISA) 
• GMT of anti-NoV GI.1 VLP antibody titers as measured by Pan-Ig ELISA (Day 1, 
Day 8, Day 29, Day 36, Day 57, Day 211, and Day 393); 
• GMT of anti-NoV GII.4 VLP antibody titers as measured by Pan-Ig ELISA (Day 1, 
Day 8, Day 29, Day 36, Day 57, Day 211, and Day 393); 
• GMFR of anti-NoV GI.1 VLP antibody titers as measured by Pan-Ig ELISA (Day 8, 
Day 29, Day 36, Day 57, Day 211, and Day 393); 
• GMFR of anti-NoV GII.4 VLP antibody titers as measured by Pan-Ig ELISA (Day 8, 
Day 29, Day 36, Day 57, Day 211, and Day 393). 
The GMT will be calculated as the anti-logarithm of the mean of the log-transformed titer values 
vi, i.e., anti-logarithm of ∑(log transformed titer/n), where n is the number of subjects with non 
missing titer information. Similarly the GSD for GMT will be calculated as the anti-logarithm 
transformation of the standard deviation of the log-transformed titer. The 95% CI will be 
calculated as the anti-logarithm transformation of the upper and lower limits for a two-sided CI 
for the mean of the log-transformed titers.  
GMFR will be calculated as anti-logarithm of the mean of the log-transformed fold rise (fi) in 
titer values, at a specific post baseline time point defined as : 
f i = vpost/vpre 
where vpost is the post vaccination value of the titer at that specific post baseline time point and 
vpre is the pre vaccination baseline value of the titer, i.e., anti-logarithm of ∑ (log transformed 
(post-vaccination titer/ pre-vaccination titer)/n), where n is the number of subjects with non 
missing titer information at both pre and post baseline visits. The GSD and 95% CIs for GMFR 
will be calculated similarly to those for GMT.  
In addition, statistical analyses utilizing an ANCOVA model will be performed for the 
continuous endpoints listed above. An ANCOVA model will be run separately at each study visit 
corresponding to Day 36, Day 57, Day 211, and Day 393 only, within each elderly age group, 
and overall. The model will be used to perform pre-specified pairwise comparisons (a, b, c, d, e), 
including treatment arm as a fixed factor and baseline values as a covariate. Treatment arm A5 
will be included in the analysis model in order to serve as reference. 
More formally the following model: 
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Statistical Analysis Plan (Final 1.0) 
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7.9 
Pharmacokinetic/Pharmacodynamic Analysis 
Not applicable.   
7.9.1 Pharmacokinetic Analysis 
Not applicable.   
7.9.2 Pharmacodynamic Analysis 
Not applicable. 
7.10 
Other Outcomes 
Not applicable.  
7.11 
Safety Analysis 
All summaries and analyses of safety data are based on subjects in the Safety Analysis Set. 
Unless otherwise specified, the safety data will be summarized by treatment arm, all elderly 
subjects, for all age groups at first instance and by treatment arm and all elderly subjects within 
age groups as appropriate. 
In general, data imputation will not be performed for any missing safety data. The biologically 
implausible measurements for body temperature and solicited local symptoms are provided in 
Table 4. Any measurements meeting those criteria will be excluded from the summaries and 
analyses, but included in the data listings. 
Table 4 Definitions of implausible measurements 
Parameters 
Criteria 
Body temperature (collected in diary data) 
< 35°C or > 42°C 
Erythema 
>50.0 cm 
Induration  
>50.0 cm 
Swelling 
>50.0 cm 
7.11.1 Adverse Events 
Reactogenicity 
After vaccination on Day 1 and Day 29, the subject will be assessed for reactogenicity by 
investigator/staff for at least 30 minutes including observation for solicited AEs, including local 
AEs (injection site: pain, erythema, induration and swelling) and systemic AEs (headache, 
fatigue, myalgia, arthralgia, vomiting, and diarrhea), as well as body temperature measurement. 
Furthermore reactogenicity will be assessed for 7 days following each vaccination (the day of 
vaccination and the following 6 days) via diary card completion and collection of solicited AEs, 
including local AEs (injection site: pain, erythema, induration and swelling) and systemic AEs 
(headache, fatigue, myalgia, arthralgia, vomiting, diarrhea, body temperature).  
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Statistical Analysis Plan (Final 1.0) 
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The categories for each solicited AE are defined in Section 10.1.3 of the protocol [1, 2]. Pain is 
summarized as either none or any: where "any" will be broken down into the following 
categories: mild, moderate, and severe. Erythema, swelling and induration are recorded as yes or 
no, where the definition of "yes" is any area >= 25 mm; and "yes" will be further broken down 
into the following categories: >= 25 mm - <= 50 mm, > 50 mm - <= 100 mm, and > 100 mm. 
Severity categories for erythema, induration and swelling will be displayed in summary tables as: 
Mild: >=25-<=50 mm, Moderate: >50-<=100 mm, Severe: >100 mm, Any: >=25 mm, None: 
<25 mm.                                                                                                   
Body temperature will be categorized as fever present (>= 100.4ºF, >=38oC) or fever absent (< 
100.4ºF, < 38oC). For those subjects with fever present this will be further categorized as 
provided in Table 5. 
Unless otherwise specified, the categories based on the Celsius (with 0.5 oC increment) will be 
provided in the summary table.  Conversion from Fahrenheit to Celsius as follows: 
• Body Temperature in Celsius = (Body Temperature in Fahrenheit – 32) x (5/9) 
Table 5 Fever Categorization[3] 
Fever Present? 
Body Temperatures oC (oF) 
No 
< 38.0oC                   (< 100.4ºF) 
Yes 
38.0 oC – <38.5 oC       (100.4 oF – <101.2 oF)  
38.5 oC – <39 oC       (101.2 oF – <102.1 oF) 
39.0 oC – <39.5 oC       (102.1 oF – <103.1 oF) 
39.5 oC – <40.0 oC       (103.1 oF – <104.0 oF) 
>= 40.0 oC                     (>= 104.0 ºF) 
For each solicited (local and systemic) AE assessment 30 minutes after each vaccination the 
percentage of subjects reporting an event will be summarized by event severity and by 
vaccination (first dose or second dose) and overall (after any dose). Additionally, the relationship 
of solicited systemic symptoms 30 minutes after each vaccination will be tabulated.  
The number and percentage of subjects without any solicited AE (Local, Systemic or Body 
Temperature) within 7 days following each vaccination (including the day of vaccination) will be 
summarized for each vaccination dose.  
Furthermore, for each solicited AE collected via diary cards, the percentage of subjects will be 
summarized by event severity for each day from Day 1 to Day 7 following each vaccination 
(including the day of vaccination) and overall. In addition, summaries will be provided for the 
intervals of Days 1 to 3 and Days 4 to 7 following each vaccination. For subjects with more than 
1 episode of the same event within an interval (overall within the 7 days following vaccination, 
days 1-3, and days 4-7), the maximum severity will be used for tabulations. 
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Statistical Analysis Plan (Final 1.0) 
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The relationship of solicited systemic symptoms occurring within 7 days after each vaccination 
will be tabulated. If a subject reported more than one episode of the same event, then the 
strongest relationship will be included in the summaries. 
The occurrence of reactogenicity will also be summarized descriptively by the number of days 
subjects reported experiencing the symptom, by treatment group within each age group. The 
number of days a subject reported experiencing the symptom is the total of all days the subject 
reported the symptom within the first 7 days following each dose, regardless of whether the 
symptom was reported on consecutive days (e.g. a headache reported on Day 1 and on Days 3 
and 4 would be included as 3 days). In the case when the event was ongoing at Day 7 post-
vaccination, 1 day will be added to the total number of days, as it assumes the event is observed 
at least 1 day after Day 7 post-vaccination. This convention will not be applied for body 
temperature however, as the CRF does not include a question to establish whether fever was 
ongoing at Day 7 post-vaccination. 
A summary of the day of first onset of each event will also be provided for each vaccination. 
For all summaries by each vaccination, summaries after any vaccination will also be included. 
All tabular summaries of solicited AEs will be presented by treatment arm and by age group. 
Additionally, summaries of solicited adverse events within 7 days after vaccination will include 
summaries by formulation type (overall age groups and within age group), where ‘MPL-‘ 
grouping will summarize results over the formulation A treatment arms (A1 and A2) and 
‘MPL+’ grouping will summarize results over the formulation B treatment arms (A3 and A4). 
Unsolicited AEs 
Unsolicited AEs, SAEs and AESI will be coded using MedDRA dictionary. 
Any unsolicited AEs are collected for 28 days following each vaccination (day of vaccination + 
27 days).  SAEs and AEs leading to subject withdrawal from the trial is collected throughout the 
trial from Day 1 through to Day 393. 
AEs are also evaluated by the Investigator for the co-existence of AESI which are pre-defined 
AEs that are specifically highlighted to the Investigator. The list of AESI is summarized in 
Appendix A. AESI are collected by close monitoring from Day 1 up to Day 393 using the 
relevant AE CRF page. 
Definition of unsolicited AEs, SAEs and AESI are provided in Sections 10.1.1, 10.1.3 and 10.1.4 
of the protocol [1, 2] respectively. 
Whilst the investigator’s identification of AESI are present on the study database, for the purpose 
of reporting, AESI will be identified programmatically  via a reference a list of relevant specific 
PTs provided by Takeda. AESI identified based on this process will be reported in the relevant 
tables and listings. Therefore, the investigator assignment of AESI (identified on the relevant AE 
CRF page file) will not be utilized for reporting purposes. 
In general unsolicited AEs will be tabulated at each of the following levels: overall summary 
(subject with at least 1 AE) and by SOC and PT by presenting the number and percentage of 
subjects with an AE.  Subjects reporting more than 1 occurrence for the term (level) being 
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Statistical Analysis Plan (Final 1.0) 
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summarized will be counted only once. More specifically a subject will be counted only once 
within each SOC and within each PT, or the overall category.  
Unless otherwise specified, unsolicited AEs will be summarized in the following 3 ways as 
needed:  
1) overall up to 28 days after each vaccination (day of vaccination + 27 days),  
2) with onset between 1 and 7 days after each vaccination (day of vaccination + 6 days), 
and  
3) overall up to end of study  
Unsolicited AEs will be summarized as follows:  
• Overview (Unsolicited AEs, AESI, SAEs, Deaths) for 1, 2, 3;   
• by SOC and PT for 1, 2;   
• by SOC for 1;  
• by PT for 1; 
• by PT including events with frequency greater than 2%, of all subjects in each 
treatment arm, up to 28 days after either vaccination (day of vaccination + 27 days); 
• by SOC and PT (Non-serious Unsolicited AEs) including events with frequency 
greater than 2%, of all subjects in each treatment arm, up to 28 days after either 
vaccination (day of vaccination + 27 days); 
• by SOC, PT, and relationship (not related, related) to IMP for 1, 2;  
• by SOC and PT (IMP-related Unsolicited AEs) for 1;  
• by SOC, PT, and maximum severity (mild, moderate, severe) for 1, 2; 
• by SOC, PT, and maximum severity (mild, moderate, severe) including only those 
events considered related to IMP for 1; 
If a subject reported more than one AE within a SOC or PT, then the AE with the highest known 
severity or most closely related occurrence within each SOC and each PT will be included in the 
summaries by severity or relationship, respectively. If an AE with a start date at or after the first 
dose has a missing severity or relationship information, then this will be imputed using a worst 
case approach, i.e. missing severity will be imputed as ‘severe’ and missing relationship will be 
imputed as ‘related’. 
Unsolicited AEs will be assigned to vaccine dose (1st, 2nd). All summaries described in this 
section will be generated by vaccine dose number (except for those summaries reporting events 
with frequency greater than 2%). Summaries by vaccination will also include summaries after 
any vaccination. 
In addition all AEs collected throughout the trial and identified as SAEs, AESI or AEs leading to 
study discontinuation will be summarized by SOC and PT after each vaccination and overall.  
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Statistical Analysis Plan (Final 1.0) 
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All tabular summaries of AEs will be presented by treatment arm and by age group. 
Additionally, the Overview table described above, will include summaries by formulation type 
(overall age groups and within age group), where ‘MPL-‘ grouping will summarize results over 
the formulation A treatment arms (A1 and A2) and ‘MPL+’ grouping will summarize results 
over the formulation B treatment arms (A3 and A4). 
The listings for SAEs, AESI, AEs leading to study discontinuation, and AEs resulting in death 
will be provided. 
7.11.2 Clinical Laboratory Evaluations 
Not applicable (not as a routine procedure in the protocol [1, 2]). 
7.11.3 Vital Signs 
The vital signs collected in the trial include: systolic blood pressure, diastolic blood pressure, 
heart rate and body temperature. Vital signs will be summarized descriptively by treatment arm 
overall and within elderly age groups, at scheduled time points. The change from baseline to 
each scheduled post-baseline time point will also be presented. Measurement parameters will be 
presented alphabetically. All data will be listed as well. 
7.11.4 12-Lead ECGs 
Not applicable. 
7.11.5 Other Observations Related to Safety 
Complete physical examination will be performed on Day 1, the same day as the first vaccine 
administration. A detailed physical examination includes but is not limited to: height and weight, 
auscultation of heart and lungs, palpation of the abdomen, inspection of extremities (including 
skin over intended vaccination site), and a check of general appearance. Additional physical 
examinations may be performed if indicated by review of the subject’s medical history. 
Symptom-directed physical examination may be performed during the trial visits if deemed 
necessary. All data will only be listed. 
7.12 
Interim Analysis 
A review of safety data will be performed by the DMC as soon as the first approximately 100 
subjects have completed the Day 36 Visit (8 days post last vaccination) to verify if safety results 
observed in the present trial are consistent with what has been observed in previous trials with 
the NoV GI.1/GII.4 Bivalent VLP Vaccine performed by Takeda. In order to have a good 
representation of the entire trial population, efforts will be made in terms of enrollment to have 
those first approximately 100 subjects equally distributed in each permutation. DMC Tables, and 
Listings to be presented during the DMC sessions are identified in Appendix B. 
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An interim analysis on safety and immunogenicity data is planned when all subjects have 
completed the Day 57 Visit (28 days after last vaccination). This analysis will include group 
results but not individual subject information.  
Each of the DMC safety review and interim analysis will be performed by a team of unblinded 
statisticians and programmers at PPD who will have access to individual treatment assignments 
but will not be involved in subsequent trial conduct. With exception of the unblinded pharmacist 
and unblinded administrator, the personnel involved in the conduct of the trial including those at 
the Sponsor site, at PPD, and the trial sites, will remain blinded to the individual subject data 
(including treatment assignment) until unblinding after database lock for data through Day 393. 
The list of team members from the study who will gain access to unblinded treatment codes and 
outputs will be documented in an unblinding plan. 
7.13 
Changes in the Statistical Analysis Plan  
Not applicable 
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Statistical Analysis Plan (Final 1.0) 
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8.0 
REFERENCES 
1. A Phase II, Randomized, Controlled, Double-Blind, Safety and Immunogenicity Trial of 
Norovirus GI.1/GII.4 Bivalent Virus-Like Particle Vaccine in Healthy Elderly Adults,  
Takeda Vaccines, Inc., Protocol No. NOR-204, dated 16 July, 2015. 
2. A Phase II, Randomized, Controlled, Double-Blind, Safety and Immunogenicity Trial of 
Norovirus GI.1/GII.4 Bivalent Virus-Like Particle Vaccine in Healthy Elderly Adults,  
Takeda Vaccines, Inc., Protocol No. NOR-204, dated 16 November, 2015. 
3. Guidance for Industry: Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers 
Enrolled in Preventive Vaccine Clinical Trials 
4. Li, X, Wang, W. Liu, G. and Chan, I, Handling Missing Data in Vaccine Clinical Trials for 
Immunogenicity and Safety Evaluation. Journal of Biopharmaceutical Statistics, 2011, 21(2), 
294-310 
 
 
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NOR-204 
Page 39 of 41 
Statistical Analysis Plan (Final 1.0) 
02 February 2017 
 
Appendix A  Adverse Events of Special Interest (AESI) 
Cardiac Disorders 
• 
Endocarditis 
• 
Pericarditis  
• 
Myocarditis 
 
Gastrointestinal Disorders 
• 
Celiac Disease 
• 
Ulcerative Colitis 
• 
Crohn's Disease 
• 
Ulcerative Proctitis 
• 
Inflammatory Bowel Disease (non-specific) 
 
Immune System Disorders 
• 
ANA Increased 
• 
Autoimmune Hemolytic Anemia 
• 
Anti-ds DNA Increased 
• 
Autoimmune Hepatitis 
• 
Anti-Phospholipid Syndrome 
• 
Idiopathic thrombocytopenic purpura (ITP) 
• 
Autoimmune Glomerulonephritis 
• 
Serum Sickness 
Infections and Infestations 
• 
Fever of Unknown Origin 
• 
Sinusitis 
Musculoskeletal and Connective Tissue Diseases 
• 
ANCA-Associated Vasculitis 
• 
Polymyositis 
• 
Arthritis/Bursitis (non-specified) 
• 
Reactive Arthritis 
• 
Behcet’s Syndrome 
• 
Rheumatoid Arthritis 
• 
Cutaneous Lupus 
• 
Sarcoidosis 
• 
Dermatomyositis 
• 
Scleroderma 
• 
Juvenile Rheumatoid Arthritis 
• 
Sjorgen’s Syndrome 
• 
Mixed Connective Tissue Disease 
• 
Systemic Lupus Erythematosis 
• 
Mono-Articular Arthritis 
• 
Temporal Arteritis 
• 
Pauci-Articular Arthritis 
• 
Wegener’s Granulomatosis 
• 
Polymyalgia Rheumatica 
 
Neuroinflammatory Disorders 
• 
Acute disseminated encephalomyelitis (ADEM) 
• 
Myasthenia Gravis 
• 
Bell's Palsy/Facial Palsy 
• 
Myelitis/Transverse Myelitis 
• 
Encephalitis 
• 
Neuritis 
• 
Demyelinating Disease 
• 
Optic Neuritis 
• 
Guillain Barré Syndrome 
• 
Paraesthesia (non-specific) 
• 
Hypoaesthesia (non-specific) 
• 
Uveitis 
• 
Multiple Sclerosis 
 
Renal and Urinary Disorders 
• 
Glomerulonephritis 
• 
Proteinuria 
• 
Hematuria 
• 
Renal failure 
• 
Nephritis 
 
Skin 
• 
Alopecia 
• 
Stevens-Johnson Syndrome 
• 
Dermatomyositis 
• 
Toxic Epidermal Necrolysis (TEN) 
• 
Erythema Nodosum 
• 
Vitiligo 
• 
Psoriasis and Psoriatic Arthropathy 
 
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NOR-204 
Page 40 of 41 
Statistical Analysis Plan (Final 1.0) 
02 February 2017 
 
Thyroid Disorders 
• 
Graves' (Basedow's) Disease 
• 
TSH High 
• 
Goiter (non-specified) 
• 
Thyroid Disorder (non-specific) 
• 
Hyperthyroidism 
• 
Thyroiditis 
• 
Hypothyroidism 
 
Vascular Disorders 
• 
Pulmonary Embolism 
• 
Vasculitis 
• 
Raynaud's Phenomenon 
 
Others 
 
• 
Aphthous Stomatitis 
• 
Insulin-dependent diabetes mellitus (IDDM) 
 
 
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NOR-204 
Page 41 of 41 
Statistical Analysis Plan (Final 1.0) 
02 February 2017 
 
Appendix B  Data Monitoring Committee (DMC) Outputs 
The following Tables and Listings will be provided during the DMC sessions. Treatment 
information for blinded and unblinded reports will be handled accordingly. 
DMC ID 
Full TLF Shell ID 
Title 
Analysis Set 
Tables 
 
 
 
DMC Table 1 
Table 15.1.5 
Disposition of Subjects 
All Randomized Subjects 
DMC Table 2 
Table 15.1.8.1 
Demographics and Baseline Characteristics 
All Randomized Subjects 
DMC Table 3 
Table 15.3.1.2.1 
Summary of Subjects without Solicited Adverse 
Events (Local, Systemic or Body Temperature) 
within 7 Days After each Vaccination 
Safety Analysis Set 
DMC Table 4 
Table 15.3.1.3.1 
Summary of Solicited Local Adverse Events within 7 
Days After each Vaccination 
Safety Analysis Set 
DMC Table 5 
Table 15.3.1.3.2 
Summary of Solicited Systemic Adverse Events 
within 7 Days After each Vaccination 
Safety Analysis Set 
DMC Table 6 
Table 15.3.1.4.1 
Summary (Daily) of Solicited Local Adverse Events 
Within 7 Days After each Vaccination 
Safety Analysis Set 
DMC Table 7 
Table 15.3.1.4.2 
Summary (Daily) of Solicited Systemic Adverse 
Events within 7 Days After each 
Vaccination 
Safety Analysis Set 
DMC Table 8 
Table 15.3.2.2.1 
Unsolicited Adverse Events Up to 28 
Days After Vaccination by System 
Organ Class and Preferred Term 
Safety Analysis Set 
DMC Table 9 
Table 15.3.2.7 
Serious Adverse Events after each 
Vaccination by System Organ Class 
and Preferred Term 
Safety Analysis Set 
DMC Table 10 
Table 15.3.2.8 
Adverse Events of Special Interest 
After each Vaccination by System 
Organ Class and Preferred Term 
Safety Analysis Set 
Listings 
 
 
 
DMC Appendix 1 
Appendix 16.2.1.2 
 
Disposition – Vaccine Regimen 
All Randomized Subjects 
DMC Appendix 2 
Appendix 16.2.1.3 
Disposition – Study Visits 
All Randomized Subjects 
DMC Appendix 3 
Appendix 16.2.4.1 
Demographics and Baseline Characteristics 
All Randomized Subjects 
DMC Appendix 4 
Appendix 16.2.5.1 
Study Treatment Administration 
Safety Analysis Set 
DMC Appendix 5 
Appendix 16.2.7.1 
Solicited Local Adverse Events 
Safety Analysis Set 
DMC Appendix 6 
Appendix 16.2.7.2 
Solicited Systemic Adverse Events 
Safety Analysis Set 
DMC Appendix 7 
Appendix 16.2.7.3 
Diary Body Temperature 
Safety Analysis Set 
DMC Appendix 8 
Appendix 16.2.7.4 
Adverse Events 
Safety Analysis Set 
DMC Appendix 9 
Appendix 16.2.7.6 
Serious Adverse Events 
Safety Analysis Set 
DMC Appendix 10 
Appendix 16.2.7.8 
Adverse Events of Special Interest 
Safety Analysis Set 
 
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