Clinical trial NCT02153112
Conditions: Norovirus
Keywords: Drug therapy
Sponsor: Takeda
Start date: 2015-06-23; Completion date: 2018-06-20
Enrollment: 840 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to select the optimal formulation of the norovirus vaccine from different concentrations of virus-like particles (VLP) combined with aluminum hydroxide for further development in children.

Detailed description:
The vaccine being tested in this study is called norovirus GI.1/GII.4 bivalent virus-like particle (VLP) vaccine with aluminum hydroxide. The norovirus vaccine is being tested to assess different formulations of the vaccine that will then be further developed. This study will look at the number of antibodies to norovirus formed in children, toddlers and infants who are administered different formulations of the norovirus vaccine.

The study enrolled 840 patients. Participants will be randomly assigned (by chance) to one of ten treatment groups-which will remain undisclosed to the participant and study doctor during the study (unless there is an urgent medical need).

All participants in Cohort 1 will be vaccinated on Day 1 and Day 29 of the study, and all participants in Cohort 2 will be vaccinated on Day 1, Day 56, and Day 112. All treatment groups in Cohort 1 will receive either one dose of the norovirus vaccine, or two doses. One treatment group in Cohort 2 will receive 2 doses of the norovirus vaccine, and the other group will receive 3. In order to keep the treatment undisclosed to the participant and the doctor in Cohort 1, those randomized to the one-dose groups will receive the norovirus vaccine on Day 1, followed by a dose of placebo vaccine on Day 29. In order to keep the treatment arms undisclosed to the participant and the doctor in Cohort 2, those randomized to the two-dose groups will receive the norovirus vaccine on Day 1 and Day 56, followed by a dose of placebo vaccine on Day 112. Placebo vaccine is saline solution. Participants will be asked to record any symptoms that may be related to the vaccine or the injection site in a diary card for 7 days after each vaccination.

This multi-center trial will be conducted in Finland, Panama, and Colombia. The overall time to participate in this study is up to 210 days for participants in Cohort 1 and up to 293 Days for participants in Cohort 2. Participants in Cohort 1 will make 6 visits to the clinic, and participants in Cohort 2 will make 10 visits to the clinic.

Arms: arm 1: Children 4 to \<9 years of age received one dose of either of the 4 formulations (15 µg of GI.1 norovirus VLP and 15 µg GII.4/GI.1/GII.4 (15 μg/50 μg)/GI.1/GII.4 (50 μg/50 μg) or GI.1/GII.4 (50 μg/150 μg) of the norovirus bivalent virus-like particle (VLP) vaccine, intramuscularly (IM) and 500 µg aluminum hydroxide on Day 1, followed by placebo matching norovirus bivalent VLP vaccine IM on Day 29. arm 2: Children 4 to \<9 years of age received 2 doses of either of the 4 formulations (15 µg of GI.1 norovirus VLP and 15 µg GII.4/GI.1/GII.4 (15 μg/50 μg)/GI.1/GII.4 (50 μg/50 μg) or GI.1/GII.4 (50 μg/150 μg) of the norovirus bivalent VLP vaccine and 500 µg aluminum hydroxide IM on Days 1 and 29. arm 3: Children 1 to \<4 years of age received one dose of either of the 4 formulations (15 µg of GI.1 norovirus VLP and 15 µg GII.4/GI.1/GII.4 (15 μg/50 μg)/GI.1/GII.4 (50 μg/50 μg) or GI.1/GII.4 (50 μg/150 μg) of the norovirus bivalent VLP vaccine and 500 µg aluminum hydroxide, IM on Day 1, followed by placebo-matching norovirus bivalent VLP vaccine, IM on Day 29. arm 4: Children 1 to \<4 years of age received 2 doses of either of the 4 formulations (15 µg of GI.1 norovirus VLP and 15 µg GII.4/GI.1/GII.4 (15 μg/50 μg)/GI.1/GII.4 (50 μg/50 μg) or GI.1/GII.4 (50 μg/150 μg) of the norovirus bivalent VLP vaccine and 500 µg aluminum hydroxide, IM on Days 1 and 29. arm 5: Children 1 to \<4 years of age received one dose of either of the 4 formulations (15 µg of GI.1 norovirus VLP and 15 µg GII.4/GI.1/GII.4 (15 μg/50 μg)/GI.1/GII.4 (50 μg/50 μg) or GI.1/GII.4 (50 μg/150 μg) of the norovirus bivalent VLP vaccine and 500 µg aluminum hydroxide, IM on Day 1, followed by placebo matching norovirus bivalent VLP vaccine, IM on Day 29. arm 6: Children 1 to \<4 years of age received 2 doses of either of the 4 formulations (15 µg of GI.1 norovirus VLP and 15 µg GII.4/GI.1/GII.4 (15 μg/50 μg)/GI.1/GII.4 (50 μg/50 μg) or GI.1/GII.4 (50 μg/150 μg) of the norovirus bivalent VLP vaccine and 500 µg aluminum hydroxide, IM on Days 1 and 29. arm 7: Toddlers 6 months to \<1 year of age received one dose of either of the 4 formulations (15 µg of GI.1 norovirus VLP and 15 µg GII.4/GI.1/GII.4 (15 μg/50 μg)/GI.1/GII.4 (50 μg/50 μg) or GI.1/GII.4 (50 μg/150 μg) of the norovirus bivalent VLP vaccine and 500 µg aluminum hydroxide, IM on Day 1, followed by placebo matching norovirus bivalent VLP vaccine, IM on Day 29. arm 8: Toddlers 6 months to \<1 year of age will receive 2 doses either of the 4 formulations (15 µg of GI.1 norovirus VLP and 15 µg GII.4/GI.1/GII.4 (15 μg/50 μg)/GI.1/GII.4 (50 μg/50 μg) or GI.1/GII.4 (50 μg/150 μg) of the norovirus bivalent VLP vaccine and 500 µg aluminum hydroxide, IM on Days 1 and 29. arm 9: Infants 6 weeks to \<6 months of age received 2 doses of either of the 4 formulations (15 µg of GI.1 norovirus VLP and 15 µg GII.4/GI.1/GII.4 (15 μg/50 μg)/GI.1/GII.4 (50 μg/50 μg) or GI.1/GII.4 (50 μg/150 μg) formulations of the norovirus bivalent VLP vaccine and 500 µg aluminum hydroxide, IM on Days 1 and 56, followed by placebo-matching norovirus bivalent VLP vaccine, IM on Day 112. arm 10: Infants 6 weeks to \<6 months of age received 3 doses of either of the 4 formulations (15 µg of GI.1 norovirus VLP and 15 µg GII.4/GI.1/GII.4 (15 μg/50 μg)/GI.1/GII.4 (50 μg/50 μg) or GI.1/GII.4 (50 μg/150 μg) of the norovirus bivalent VLP vaccine and 500 µg aluminum hydroxide, IM on Days 1, 56 and 112.
Interventions: intervention 1: GI.1/GII.4 (15/15) intervention 2: GI.1/GII.4 (15/50) intervention 3: GI.1/GII.4 (50/50) intervention 4: GI.1/GII.4 (50/150) intervention 5: Placebo
Intervention descriptions: intervention 1: Norovirus GI.1/GII.4 (15 μg/15 μg) bivalent VLP vaccine combined with 500 μg aluminum hydroxide for IM injection intervention 2: Norovirus GI.1/GII.4 (15 μg/50 μg) bivalent VLP vaccine combined with 500 μg aluminum hydroxide for IM injection intervention 3: Norovirus GI.1/GII.4 (50 μg/50 μg) bivalent VLP vaccine combined with 500 μg aluminum hydroxide for IM injection intervention 4: Norovirus GI.1/GII.4 (50 μg/150 μg) bivalent VLP vaccine combined with 500 μg aluminum hydroxide for IM injection intervention 5: Placebo saline solution

Protocol documents:
Prot_000.pdf: 
CONFIDENTIAL 
 
 
PROTOCOL 
A Phase II, Randomized, Double-Blind, Dosage, Safety and Immunogenicity Trial of 
Intramuscular Norovirus GI.1/GII.4 Bivalent Virus-Like Particle Vaccine combined with 
Aluminum Hydroxide adjuvant in Children, Toddlers, and Infants 
NOR-202 Safety and Immunogenicity of Norovirus GI.1/GII.4 Bivalent VLP Vaccine 
in Children 
Sponsor: 
Takeda Vaccines, Inc. 
One Takeda Parkway 
Deerfield, IL 60015 
USA 
Study Identifier: 
NOR-202 
IND Number: 
014421 
EudraCT Number: 
2014-000778-20 
Vaccine Name: 
 
Norovirus GI.1/GII.4 Bivalent Virus-Like Particle Vaccine combined 
with Aluminum Hydroxide 
Date: 
1 March 2016 
Version: 
4.0 
CONFIDENTIAL PROPERTY OF TAKEDA 
This document is a confidential communication of Takeda. Acceptance of this document constitutes the agreement by 
the recipient that no information contained herein will be published or disclosed without written authorization from 
Takeda except to the extent necessary to obtain informed consent from those persons to whom the vaccine may be 
administered. Furthermore, the information is only meant for review and compliance by the recipient, his or her staff, 
and applicable institutional review committee and regulatory agencies to enable conduct of the trial. 


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Norovirus GI.1/GII.4 Bivalent VLP Vaccine 
 
Trial No. NOR-202 
Page 4 of 107 
Protocol Version 4.0 
1 March 2016 
 
CONFIDENTIAL 
1.3 
Protocol Amendment N° 3.0 
This document describes the changes in reference to the Protocol incorporating Amendment N° 
3.0. 
The primary purposes of this amendment are: 1) to enroll an additional 120 children (1 to < 4 
years; designated Group 2a), to assess the safety and immunogenicity of the recently manufactured 
NoV vaccine in a similar age group to Group 2; and 2) to perform the Day 57 IA for Groups 1 and 
2 of Cohort 1, who will complete Day 57 substantially earlier than Groups 2a and 3. The Day 57 IA 
for Groups 2a and 3 combined will be performed at a later time. The Day 140 IA for Group 4 does 
not change. 
The trial vaccine, originally manufactured for trial NOR-202, was not available for clinical use 
after 30 November 2015, due to expiration at 36 months after manufacture. Several factors 
affected the enrolment timeline in trial NOR-202: (1) Takeda’s decision to not initiate enrollment 
until after agreement from the Pediatric Committee of the EMA on the Pediatric Investigational 
Plan (PIP) of the NoV vaccine; (2) and the regulatory, logistical, and operational study 
requirements for implementation of the two prior protocol amendments. 
Per protocol, all children in Groups 1 (4 to < 9 years) and 2 (1 to < 4 years) were enrolled, 
randomized and received one of the four NoV vaccine formulations as a one or two dose trial 
vaccine regimen within the vaccine expiry dating period. Notably, children in Groups 3 (1 or 2 
doses) and 4 (2 or 3 doses) were not enrolled due to expiration of the trial vaccine. Takeda has 
paused this study until additional trial vaccine is manufactured and released for clinical use. 
Takeda has recently produced VLPs at a different manufacturer with increased capacity for 
manufacturing on a larger scale. To date, the NoV vaccine with these recently produced VLPs has 
been manufactured and released for clinical use in two studies in adults; trial NOR-204 in 350 
adults aged 18 to > 85 years and trial NOR-211 in ~ 2800 adults aged 18 to 49 years. 
To understand the safety and immunogenicity of the recently manufactured vaccine in a similar 
age group to Group 2, an additional 120 children designated Group 2a, will be enrolled in trial 
NOR-202, prior to enrolling children in Groups 3 and 4. Specifically, the safety data from Group 
2a will be provided to the Data Monitoring Committee (DMC) for review prior to enrollment of 
the children in Groups 3 and 4. 
Although the VLP manufacturer has changed, the vaccine dosages and regimens with the four 
vaccine formulations evaluated in Groups 1 and 2 will also be evaluated in children in Groups 2a, 
3, and 4. However, only children in Groups 2a, 3, and 4, will receive the recently manufactured 
vaccine. 
Enrollment in Group 2a will be initiated after all four vaccine formulations of the recently 
manufactured vaccine are released for clinical use. 
Full details of changes to the text are given below. The following is a list of the sections modified 
in the amendment: 


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Norovirus GI.1/GII.4 Bivalent VLP Vaccine 
 
Trial No. NOR-202 
Page 7 of 107 
Protocol Version 4.0 
1 March 2016 
 
CONFIDENTIAL 
9.1.5 
Physical examination re-defined. 
9.1.6 
Blood volumes corrected in light of the Day 208 blood draw in Cohort 1 and 
Days 112 and 292 blood draws in Cohort 2 being removed. 
9.1.7 
Editing in and to label of Tables 9a. and 9b. 
9.1.8 
Updated text for CMI testing. 
9.1.9 
Editing. 
9.3.1 
Diary card text moved to section 9.3.3. 
9.3.3 
Diary card use explanation clarified. Minor editing. 
9.3.7 
Benefit Vaccine text added 
13.1.1 
Subject number updated. 
13.1.3 
Number of formulation arms updated. 
13.1.4 
Subject age updated. 
13.3 
Sample size calculation modified. 
Other 
Minor formatting. 
 
Amendment N° 2.0 dated 26 March 2015 to Protocol Version 2.0 dated 7 November 2014 
Rationale for the Amendment: 
This amendment describes the changes in reference to the protocol Amendment N° 2.0. The 
primary purpose of this amendment is to change the trial design with regard to the down-selection 
of formulations based on additional data from the adult trial NOR-107. Specifically, the new 
antibody data from trial NOR-107 resulted in similar immunogenicity and safety in adults 
administered the NoV vaccine both with and without the MPL adjuvant when combined with 
Al(OH)3 adjuvant. Therefore, the decision was made to evaluate the NoV vaccine with the 
Al(OH)3 adjuvant alone in subjects enrolled in trial NOR-202. Therefore, the number of 
formulation arms in this study has been further reduced from eight to four. 
Section 
Description of change 
Title 
Removal of MPL from the title. 
Trial Summary 
Adapted to reflect the changes in the body of the protocol. 
Section 2.1 
Updated trial procedures table. 
Sections 4.1 and 
4.2 
Update of the rationale to reflect the non-inclusion of MPL in the NoV vaccine. 
Section 5.1.2 
Update of the secondary objectives. 
Section 5.1.3 
Update of the exploratory objectives. 
Section 5.2.1 
Update of the primary endpoints. 
Section 5.2.2 
Update of the secondary endpoints. 
Section 5.2.3 
Update of the exploratory endpoints. 
Section 6.1 
Figure 6a updated to reflect the new sample size and subject distribution in the 
two cohorts. 
Section 6.2 
Update to the rationale for the number of treatment arms. 
Section 6.3 
Update on the expected duration of participation. 


Norovirus GI.1/GII.4 Bivalent VLP Vaccine 
 
Trial No. NOR-202 
Page 8 of 107 
Protocol Version 4.0 
1 March 2016 
 
CONFIDENTIAL 
Section 7.3 
Definition of the window for delay of vaccination. 
Section 8.1.1 
Deletion of MPL text from the description of the investigational vaccine. 
Section 8.4 
Deletion of MPL text. 
Section 8.5 
Update of timing of safety follow-up. 
Section 9.1.6 
Update of timings for the final immunogenicity assessments. 
Section 9.1.7 
Deleted text referring to AESIs and updated the duration of the safety 
assessments. Text updated to correspond to Table 9a. 
Section 9.3.1 
Specified blood for CMI testing will be provided by a subset of children. 
Section 9.3.3 
Update of diary card instructions. 
Section 9.3.4 
Update of clinic visits. 
Section 9.3.5 
Update of phone contacts and deletion of reference to AESIs. 
Sections 9.3.7, 
10.1.4, 10.2.1.1, 
10.2.2 
Update to timing of the final visit. 
Sections 10.1.1, 
10.2.1.2, 10.3.2, 
12.0 
Deletion of text referring to AESIs. 
Section 13.1 
Update to timing of the final visit. 
Section 13.1.1 
Update of the statistical analyses. 
Section 13.1.3 
Update to immunogenicity analyses. 
Section 13.1.4 
Update to safety analyses. 
Section 13.2 
Update to the timing of the final analysis. 
Section 13.3 
Update to the sample size justification. 
Section 16.0 
New reference added. 
Appendix D 
Deleted appendix (AESIs). 
 
Amendment N° 2.1 dated 1 April 2015 to Protocol Version 3.0 dated 26 March 2015 
Rationale for the Amendment: 
This amendment corrects inconsistencies identified in V3.0 and is purely administrative.  
Section 
Description of change. 
Trial Summary 
Title aligned with first page (inclusion of ‘adjuvant’). 
Section 2.1 
Table 2a: Optional physical examination added on Day 210. 
Section 2.1 
Table 2b: diary card dispensing added on Days 1 and 56. 
Section 6.1 
Inclusion of ‘safety’ in the first sentence. 
Section 7.3 
Formatting. 
Section 9.3.7 
Benefit vaccine provision is optional. 
Section 13.1.4 
Correction for AEs: collection is daily through day 7. 
 


Norovirus GI.1/GII.4 Bivalent VLP Vaccine 
 
Trial No. NOR-202 
Page 9 of 107 
Protocol Version 4.0 
1 March 2016 
 
CONFIDENTIAL 
Amendment N° 3.0 dated 1 March 2016 to Protocol Version 3.1 dated 1 April 2015 
Rationale for Amendment N° 3.0: 
The primary purposes of this amendment are: 1) to enroll an additional 120 children (1 to < 4 
years; designated Group 2a), to assess the safety and immunogenicity of the recently manufactured 
NoV vaccine in a similar age group to Group 2; and 2) to perform the Day 57 interim analysis (IA) 
for Groups 1 and 2 of Cohort 1, who will complete Day 57 substantially earlier than Groups 2a and 
3. The Day 57 IA for Groups 2a and 3 combined will be performed at a later time. The Day 140 IA 
for Group 4 does not change 
Section 
Description of change. 
Trial Summary Adapted to reflect the changes in the body of the protocol. 
Section 2.1 
Added Table of procedures for Cohort 1 Group 2a as Table 2.b and retitled 
former Table 2.b for Cohort 2 (Group 4) to Table 2.c for Cohort 2. 
Section 4.1 
The safety of the NoV GI.1/GII.4 bivalent VLP vaccine adjuvanted with MPL 
and Al(OH)3 has been evaluated in 2 studies conducted by Takeda (formerly 
LigoCyte): Studies LV03-104 (1 year follow-up is complete) and LV03-105 (1 
year follow-up is complete). Preliminary results of healthy adults enrolled in 
Trial LV03-104 show that no allergic reactions, neurologic adverse events 
(AEs), or serious adverse events (SAEs) related to investigational vaccine were 
reported. In Cohort A, a dosage escalation cohort (5/5, 15/15, 50/50, and 
150/150 µg of NoV GI.1/GII.4 antigens), the observed rates of solicited AEs 
were comparable across the formulation arms. No increase in severity or 
frequency of events was observed with the increased VLP concentration. The 
observed rates were similar following Dose 1 and Dose 2 of investigational 
vaccine. In Trial LV03-105, the 50/50 µg NoV adjuvanted vaccine dosage was 
evaluated and the preliminary results showed similar rates of solicited AEs as 
were seen in Trial LV03-104 and no SAEs related to investigational vaccine 
have been reported. In both studies, an adjuvanted formulation was 
investigated: VLPs were adjuvanted with both Al(OH)3 and MPL and delivered 
by the intramuscular (IM) route of administration. The combination of Al(OH)3 
and MPL corresponds to GlaxoSmithKline’s Adjuvant System 04 [31]. The 
selection of MPL in the investigational vaccine was to emulate the high and 
sustained antigen-specific neutralizing antibody responses that have been 
observed with GlaxoSmithKline’s Cervarix vaccine [32]. Published data 
concerning the use of this form of adjuvant (Al(OH)3 and MPL) supports an 
acceptable safety profile observed in clinical studies [13]. The Al(OH)3 
component is used as an adjuvant in many licensed vaccines at dosages ranging 
from 0.17 mg to 0.85 mg aluminum, and clinical studies have demonstrated 
that aluminum enhances the antigenicity of vaccines such as diphtheria and 
tetanus toxoids together with a demonstrated safety profile of over 6 decades 
[12]. 


Norovirus GI.1/GII.4 Bivalent VLP Vaccine 
 
Trial No. NOR-202 
Page 10 of 107 
Protocol Version 4.0 
1 March 2016 
 
CONFIDENTIAL 
 
Additional text: 
Prior safety and immunogenicity data for the NoV vaccine given by the IM 
route are available from approximately 1000 adult subjects, evaluated in five 
Takeda clinical trials (LV03-104, LV03-105, NOR-107, NOR-201, and 
NOR-210). The NoV vaccine evaluated in these trials either contained both 
Al(OH)3 plus monophosphoryl lipid A (MPL) adjuvants combined or the 
Al(OH)3 adjuvant alone. Trial NOR-107 conducted in adults aged 18-64 
years, a Phase II dosage, adjuvant justification, safety, and immunogenicity 
trial, evaluated 11 vaccine formulations, and showed that the NoV VLP 
vaccine adjuvanted with aluminum as Al(OH)3 adjuvant was as 
immunogenic as the NoV VLP vaccine adjuvanted with Al(OH)3 and MPL 
combined. 
Refer to the current Investigator Brochure of Takeda’s NoV GI.1/GII.4 
bivalent VLP vaccine for additional product information and a more detailed 
review of pre-clinical and clinical studies [31]. 
Section 4.2 
Rationale for the Proposed Trial 
Additional text to paragraph 4: 
Norovirus strains drift from year to year and both GI and GII genogroups cause 
disease in all age groups. Although numerous types are reported, the GII.4 type 
remains dominant and is currently responsible for the majority of outbreaks 
worldwide. The rationale for developing a bivalent vaccine is based on NoV 
epidemiology and the lack of natural protection between genogroups. In trial 
LV03-104, the first NoV bivalent VLP vaccine was given IM, and compared 
equally balanced (1:1) dosages of the GI.1 and GII.4 VLPs in adults. For each 
of the 4 vaccine dosages evaluated (5/5, 15/15, 50/50, and 150/150 µg of NoV 
VLPs), the seroresponse rates (percent of subjects with at least a 4-fold rise in 
antibody levels) and geometric mean fold rises (GMFRs) were lower for the 
GII.4 VLP than for the GI.1 VLP at equivalent antigen dosages. Likewise, 
similar post-vaccination immunogenicity data were observed in adults in trial 
LV03-105, the GII.4 challenge trial that evaluated a 50/50 µg balanced 1:1 
VLP dosage of vaccine. Separately the factorial design trial NOR-107 was 
initiated in subjects ages 18 to 64, to evaluate multiple vaccine formulations 
containing different (balanced and unbalanced) ratios of the antigenic VLP 
components of the bivalent vaccine (GI.1/GII.4) with Al(OH)3 adjuvant both 
with and without MPL adjuvant. Prior safety and immunogenicity data for the 
NoV vaccine given by the IM route are available from approximately 1000 
adult subjects, evaluated in five Takeda clinical trials (LV03-104, LV03-105, 
NOR-107, NOR-201, and NOR-210). The NoV vaccine evaluated in these 
trials either contained both Al(OH)3 plus monophosphoryl lipid A (MPL) 
adjuvants combined or the Al(OH)3 adjuvant alone. Trial NOR-107 
conducted in adults aged 18-64 years, a Phase II dosage, adjuvant 
justification, safety, and immunogenicity trial, evaluated 11 vaccine 


Norovirus GI.1/GII.4 Bivalent VLP Vaccine 
 
Trial No. NOR-202 
Page 11 of 107 
Protocol Version 4.0 
1 March 2016 
 
CONFIDENTIAL 
formulations, and showed that the NoV VLP vaccine adjuvanted with 
aluminum as Al(OH)3 adjuvant was as immunogenic as the NoV VLP 
vaccine adjuvanted with Al(OH)3 and MPL combined. Refer to the current 
Investigator Brochure of Takeda’s NoV GI.1/GII.4 bivalent VLP vaccine for 
additional product information and a more detailed review of pre-clinical 
and clinical studies [31]. 
 
Additional text: 
Rationale for the Amendment N° 3.0: 
The primary purposes of this amendment are: 1) to enroll an additional 120 
children (1 to < 4 years; designated Group 2a), to assess the safety and 
immunogenicity of the recently manufactured NoV vaccine in a similar age 
group to Group 2; and 2) to perform the Day 57 interim analysis (IA) for 
Groups 1 and 2 of Cohort 1, who will complete Day 57 substantially earlier 
than Groups 2a and 3. The Day 57 IA for Groups 2a and 3 combined will be 
performed at a later time. The Day 140 IA for Group 4 does not change. 
The trial vaccine, originally manufactured for trial NOR-202, was not 
available for clinical use after 30 November 2015, due to expiration at 36 
months after manufacture. Several factors affected the enrolment timeline in 
trial NOR-202: (1) Takeda’s decision to not initiate enrollment until after 
agreement from the Pediatric Committee of the EMA on the Pediatric 
Investigational Plan (PIP) of the NoV vaccine; (2) and the regulatory, 
logistical, and operational study requirements for implementation of the two 
prior protocol amendments. 
Per protocol, all children in Groups 1 (4 to < 9 years) and 2 (1 to < 4 years) 
were enrolled, randomized and received one of the four NoV vaccine 
formulations as a one or two dose trial vaccine regimen within the vaccine 
expiry dating period. Notably, children in Groups 3 (1 or 2 doses) and 4 (2 or 
3 doses) were not enrolled due to expiration of the trial vaccine. Takeda has 
paused this study until additional trial vaccine is manufactured and released 
for clinical use. 
Takeda has recently produced VLPs at a different manufacturer with 
increased capacity for manufacturing on a larger scale. To date, the NoV 
vaccine with these recently produced VLPs has been manufactured and 
released for clinical use in two studies in adults; trial NOR-204 in 350 adults 
aged 18 to > 85 years and trial NOR-211 in ~ 2800 adults aged 18 to 49 years. 
To understand the safety and immunogenicity of the recently manufactured 
vaccine in a similar age group to Group 2, an additional 120 children 
designated Group 2a, will be enrolled in trial NOR-202, prior to enrolling 
children in Groups 3 and 4. Specifically, the safety data from Group 2a will 
be provided to the Data Monitoring Committee (DMC) for review prior to 


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Norovirus GI.1/GII.4 Bivalent VLP Vaccine 
 
Trial No. NOR-202 
Page 14 of 107 
Protocol Version 4.0 
1 March 2016 
 
CONFIDENTIAL 
 
Primary evaluation of the trial objectives is planned at 28 days after the final 
(second) vaccination in subjects aged 6 months to less than 9 years (Cohort 1) 
and 28 days after the final (third) vaccination in subjects aged 6 weeks to less 
than 6 months (Cohort 2). In order to maintain the blind and to have the same 
trial time points and dosing regimens, subjects in Cohort 1 (Groups 1, 2, 2a and 
3) who are randomized to the 1 dose group will receive a dose of the NoV 
bivalent VLP vaccine on Day 1 followed by a placebo injection of saline 28 
days later (Day 29) and subjects in the 2 dose group will receive 2 doses of 
NoV VLP vaccine approximately 28 days apart (Days 1 and 29). Likewise, 
subjects in Cohort 2 (Group 4) who are randomized to the 2 dose group will 
receive 2 doses of NoV bivalent VLP vaccine on Days 1 and 56, followed by a 
placebo injection of saline approximately 56 days later (Day 112), and subjects 
in the 3 dose group will receive 3 doses of NoV VLP vaccine approximately 56 
days apart (Days 1, 56, and 112), independent of the infant routine vaccinations 
by approximately 28 days. This is a double-blind trial; investigators, subjects, 
data collectors, and data evaluators are blinded to the specific formulation arms 
and the dosing groups. 
 
Subjects 6 months to less than 9 years of age (inclusive, Cohort 1) will receive 
either 1 or 2 doses by IM injection, at least 28 days apart (Days 1 and 29), in 3 4 
age groups in 3 age ranges (Group 1: aged 4 to less than 9 years; Group 2 and 
Group 2a: aged 1 to less than 4 years; and Group 3: aged 6 months to less than 
1 year). Infants 6 weeks to less than 6 months of age (Group 4/Cohort 2) will 
receive 2 or 3 doses by IM injection given approximately 56 days apart (Days 1, 
56, and 112). Routine child and infant vaccinations will be given on schedule 
per the national guidelines approximately 28 days apart from the 
investigational vaccine in each age group. 
 
Two iInterim analyses (IA) will be performed after the primary safety and 
immunogenicity data are available (ie, Day 57 for Cohort 1 and Day 140 for 
Cohort 2) (primary analysis time point). Day 57 IA for Cohort 1 will be 
provided initially for Groups 1 and 2, who will complete Day 57 substantially 
earlier than Groups 2a and 3. The Day 57 IA for Groups 2a and 3 combined 
will be provided at a later time. Thus, the Day 57 IA will be conducted in two 
parts to be followed by the Day 140 IA in Group 4. The All interim analyses 
will be performed by a separate set of unblinded statisticians and programmers 
at the contract research organization (CRO), Quintiles, who will have access to 
individual treatment assignments but will not otherwise be involved in 
subsequent study conduct. The rest of the personnel involved in the conduct of 
the study, including those at Takeda, Quintiles, and the study sites, will remain 
blinded to the individual subject data (including treatment assignments) until 
unblinding after database lock (Day 210 for Cohort 1 and Day 293 for Cohort 
2). More details on the analyses will be provided in the statistical analysis plan 


Norovirus GI.1/GII.4 Bivalent VLP Vaccine 
 
Trial No. NOR-202 
Page 15 of 107 
Protocol Version 4.0 
1 March 2016 
 
CONFIDENTIAL 
(SAP). 
 
Placebo Control: 
Saline will be administered as a single control injection (as the final dose) in 
order to maintain the trial blind for the 1 dose groups in Groups 1, 2, 2a and 3 
(Cohort 1) and for the 2 dose group in Group 4 (Cohort 2). Subjects in the 1 
dose groups in Cohort 1 receive NoV vaccine on Day 1 and a saline placebo 
injection on Day 29. Subjects in the 2 dose group in Cohort 2 receive NoV 
vaccine on Days 1 and 56 and a saline placebo injection on Day 112. 
 
Visit Schedule 
Clinical trial visits will be performed on Days 1, 8, 29, 36, 57, and 210 for 
Cohort 1 and Days 1, 8, 29, 56, 63, 84, 112, 119, 140, and 293 for Cohort 2. 
Telephone contacts will be performed on Days 3, 32, and 134 for Cohort 1 and 
Days 3, 59, 115, 200 and 260 for Cohort 2. 
Section 6.2 
The trial design is consistent with the evaluation of dose finding studies for 
vaccines. The formulations for NOR-202 are selected based on the initial and 
additional results obtained from the factorial design study NOR-107 in adults. 
Based on additional NOR-107 results, the number of formulation arms has been 
further reduced from 8 in Amendment 1 of the protocol to 4 in this amended 
protocol. The descriptive design of trial NOR-202 in early childhood is justified 
to initially define the dose and dosing regimen for young children at high risk of 
norovirus disease. An additional group designated Group 2a of 120 children 
aged 1 to less than 4 years, has been added within Cohort 1, to allow 
evaluation of the recently manufactured vaccine prior to dosing younger 
children in Groups 3 and 4. Safety in Group 2a will be reviewed by the DMC, 
prior to enrolling in Groups 3 and 4. Immunogenicity will be reviewed as 
available. 
 
A single saline placebo injection will be administered as a placebo control (as a 
final dose on Day 29) in order to maintain the trial blind in subjects in the 
1 dose groups in Groups 1, 2, 2a and 3, (Cohort 1) and in the 2 dose group in 
Group 4 (as a final dose on Day 112 in Cohort 2). 
Section 7.2 
Abbreviation corrected and edited throughout: 
Bullet 3: 
The subject’s legally acceptable authorized representative (LAR) signs and 
dates a written, informed consent form (ICF) and any required privacy 
authorization prior to the initiation of any trial procedures, after the nature of 
the trial has been explained according to local regulatory requirements 
(Appendix C). An assent will also be obtained according to age appropriate 
country-specific regulations. 


Norovirus GI.1/GII.4 Bivalent VLP Vaccine 
 
Trial No. NOR-202 
Page 16 of 107 
Protocol Version 4.0 
1 March 2016 
 
CONFIDENTIAL 
Section 8.2 
Paragraph 4 
The vaccines will be administered IM in the anterolateral thigh for children 
aged ≤12 months; for children aged >12 months, the vaccines will be 
administered in the anterolateral thigh or the deltoid muscle of the subject’s arm 
per national guidelines. Expired vaccines must not be administered. The 
vaccine and placebo are visually distinguishable and the blind must be 
maintained. The vaccination will be prepared and administered by the 
unblinded designee according to the instructions in the Pharmacy Manual. 
Cohort 1 will receive either 1 or 2 doses at least 28 days apart and Cohort 2 will 
receive 2 or 3 doses approximately 56 days apart. In order to maintain the blind 
and to have the same trial time points and dosing regimens, subjects in Cohort 1 
(Groups 1, 2, 2a, and 3) who are randomized to the 1 dose group will receive a 
dose of the NoV bivalent VLP vaccine on Day 1 followed by a placebo 
injection of saline 28 days later (Day 29). Subjects in the 2 dose group will 
receive 2 doses of NoV VLP vaccine approximately 28 days apart (Days 1 and 
29). Likewise, subjects in Cohort 2 (Group 4) who are randomized to the 2 dose 
group will receive 2 doses of NoV bivalent VLP vaccine on Days 1 and 56, 
followed by a placebo injection of saline 56 days later (Day 112), and subjects 
in the 3 dose group will receive 3 doses of NoV VLP vaccine approximately 56 
days apart (Days 1, 56, and 112), independent of the infant routine vaccinations 
by at least 28 days. 
Section 8.3 
Randomization will be stratified by country and age group: Group 1 (age 4 to 
less than 9 years); Groups 2 and 2a (age 1 to less than 4 years); Group 3 (age 6 
months to less than 12 months); and Group 4 (age 6 weeks to less than 
6 months). On Day 1, qualified subjects will be randomized using the IWRS to 
a formulation arm and number of doses depending on their age at the time of 
enrollment. 
Section 9.1.6 
Subjects in Cohort 1 in all vaccine arms will undergo blood sampling for 
serological immunogenicity testing on Day 1 (prior to the first vaccination), 
Day 29 (prior to the second vaccination), Day 57 (28 days after the second 
vaccination), and Day 210; Subjects in Cohort 2 will undergo blood sampling 
for serological testing on Day 1 (prior to the first vaccination), Day 56 (prior to 
the second vaccination), Day 84 (28 days after the second and 28 days prior to 
the third vaccination), Day 140 (28 days after the third vaccination), and Day 
293. To alleviate the pain associated with blood sampling in this pediatric 
population, blood collection will be performed by experienced, trained 
personnel who routinely obtain blood from infants and children, under the 
supervision of the Principal Investigator after optional application of EMLA 
cream/patch and using pediatric size needles. All blood samples will be 
collected in accordance with acceptable laboratory procedures. For serology in 
all subjects, the volume of blood taken at any single visit is approximately 2 


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Norovirus GI.1/GII.4 Bivalent VLP Vaccine 
 
Trial No. NOR-202 
Page 18 of 107 
Protocol Version 4.0 
1 March 2016 
 
CONFIDENTIAL 
A blinded data review will be conducted by the blinded trial team prior to the 
interim analyses and the analysis at study completion (Day 210 in Cohort 1 and 
Day 293 in Cohort 2). Limited blinded data review (of protocol deviations and 
subject evaluability) will also be done prior to the interim analyses. These 
reviews will assess the accuracy and completeness of the trial database and 
subject evaluability. 
Section 13.1.1 
The trial, within each age stratum in both cohorts, is to will evaluate the 
immunogenicity and safety of four formulations (A – D), under twodifferent 
dosing regimens in 4 pediatric age ranges. Two cohorts of subjects will be 
enrolled into the trial. Cohort 1will consist of 4 groups (4 to <9 years, 1 to <4 
years [2 groups] and 6 months to <1 year), enrolled in age-step down fashion 
as described in Section 6.1. The youngest age group (Cohort 2, 6 weeks to <6 
months) will be the last to complete enrollment  (ie, 1 or 2 doses in Cohort 1 
and 2 or 3 doses in Cohort 2). The age groups are used as a stratification factor 
during randomization. The trial factors under investigation, overall, and for 
each group include: formulation (4 formulation arms within each group); 
and number of doses (2 levels for each formulation within each group). For 
groups 1, 2, 2a, and 3 (in Cohort 1) the number of active doses will be 1 or 2 
doses. For group 4 (Cohort 2), the number of active doses will be 2 or 3. 
Within each cohort, subjects are randomized to 1 of 8 trial arms (2 dose levels 
for 4 formulations), with group as a stratification factor. formulation arms 
(4), number of doses (2 levels within each group), and age groups (4 age groups 
with Groups 2 and 2a in the same age range). For summary purposes, there are 
8 arms in the trial within each age group, which are defined by the combination 
of formulation arm and number of doses. The purpose of Group 2a is to 
evaluate the safety and selected immunogenicity endpoints in subjects in the 
same age range as Group 2, but who receive the recently manufactured NoV 
bivalent VLP vaccine. Statistical methods described in the following sections 
will be essentially the same, but will be done only for the endpoints indicated in 
Section 5.2. 
In general, the results (both safety and immunogenicity) from the trial will be 
summarized separately for each agegroup, by formulation/dose arm. For 
immunogenicity results, additional summaries and/analyses by treatment group 
for Cohort 1 will be provided, by pooling subjects in Aage groups 1-3. Other 
summaries based on different groups may be provided, with details provided in 
the SAP. 
Section 13.1.3 
The trial will evaluate the immunogenicity and safety of four formulations 
under different dosing regimens in 4 pediatric age ranges. Two cohorts of 
subjects will be enrolled into the trial. Cohort 1 will consist of 4 groups (4 to 
<9 years, 1 to <4 years [2 groups] and 6 months to <1 year), enrolled in 
age-step down fashion as described in Section 6.1. The youngest age group 


Norovirus GI.1/GII.4 Bivalent VLP Vaccine 
 
Trial No. NOR-202 
Page 19 of 107 
Protocol Version 4.0 
1 March 2016 
 
CONFIDENTIAL 
(Cohort 2, 6 weeks to <6 months) will be the last to complete enrollment. The 
factors under investigation, overall, and for each group include: formulation 
(4 formulation arms within each group); and number of doses (2 levels for 
each formulation within each group). For groups 1, 2, 2a, and 3 (in Cohort 1) 
the number of active doses will be 1 or 2 doses. For group 4 (Cohort 2), the 
number of active doses will be 2 or 3. Within each cohort, subjects are 
randomized to 1 of 8 trial arms (2 dose levels for 4 formulations), with group 
as a stratification factor. 
 
Descriptive statistics for the primary, secondary and exploratory endpoints 
including estimates of seroresponse (≥4-fold rises), and 95% confidence 
intervals (CI) will be provided. Summaries will be provided by formulation arm 
(ie. combination of formulation arms and number of doses) and age group (4 
age ranges with Groups 2 and 2a in the same age range). Additional 
summaries will be provided at the cohort level, by pooling subjects across the 
relevant age groups in Cohort 1, if as applicable. 
 
Furthermore, aAdditional analyses will also be provided at the cohort level 
(pooling groups in Cohort 1). Statistical analyses of the primary endpoint will 
be performed for each cohort using the CMH method [36] stratified by age 
group (in Cohort 1) to assess the effects of formulation/dose combination 
arms. Risk differences and corresponding 95% CIs will be provided for all 
pairwise comparisons of interest, without adjustments for multiplicity. The 
primary analyses will be based on the PPS. 
 
Continuous secondary endpoints, such as GMT and GMFR, will be 
summarized descriptively by group for each of the 8 formulation arms (ie. for 
each of the formulation/dose combinations arm , separately for the 1 and 2 (or 2 
and 3) dose groups), by age groups. 
 
Statistical analyses of selected continuous variables will be performed using 
analysis of covariance (ANCOVA) to assess the effects of formulation arms. 
For example, to assess the effect of formulation on GMT, an ANCOVA model 
of log-transformed GMT will be used with a fixed effect for formulation arm 
(ie. combination of formulation arms and number of doses), and, age stratum as 
a factors, and baseline (pre-vaccination) value as a covariate. Analysis of 
covariance (ANCOVA) will be conducted for selected continuous endpoints 
(such as GMT and GMFR), examining the effect of formulation/dose 
combination using the log-transformed value as the dependent variable and 
the corresponding log-transformed baseline value as a covariate. Cohorts 
will be analyzed separately due to different number of doses (1 or 2 in Cohort 
1; 2 or 3 in Cohort 2). For Cohort 1, the model will include estimates for 
treatment effect (formulation/dose combination) within each group, and at 
the cohort level across groups. The ANCOVA models will include group as a 
factor for analyses of Cohort 1 with a group by formulation/dose 
combination interaction term if appropriate. The pre-specified rule for 


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CCI


Norovirus GI.1/GII.4 Bivalent VLP Vaccine 
 
Trial No. NOR-202 
Page 21 of 107 
Protocol Version 4.0 
1 March 2016 
 
CONFIDENTIAL 
INVESTIGATOR AGREEMENT 
I confirm that I have read and that I understand this protocol, the Investigator’s Brochure, and any 
other product information provided by the sponsor. I agree to conduct this trial in accordance with 
the requirements of this protocol and also protect the rights, safety, privacy, and well-being of trial 
subjects in accordance with the following: 
• The ethical principles that have their origin in the Declaration of Helsinki. 
• International Conference on Harmonization, E6 Good Clinical Practice: Consolidated 
Guideline. 
• All applicable laws and regulations, including, without limitation, data privacy laws, and 
regulations. 
• Regulatory requirements for reporting serious adverse events defined in Section 10.2 of this 
protocol. 
• Terms outlined in the Clinical Study Site Agreement. 
• Appendix A – Responsibilities of the Investigator. 
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix B of this protocol. 
 
Signature of Investigator 
Date 
Investigator Name (print or type) 
Investigator’s Title 
Location of Facility (City, State) 
Location of Facility (Country) 


Norovirus GI.1/GII.4 Bivalent VLP Vaccine 
 
Trial No. NOR-202 
Page 22 of 107 
Protocol Version 4.0 
1 March 2016 
 
CONFIDENTIAL 
TABLE OF CONTENTS 
1.0 
ADMINISTRATIVE INFORMATION ..............................................................................2 
1.1 
Contacts..........................................................................................................................2 
1.2 
Approval ........................................................................................................................3 
1.3 
Protocol Amendment N° 3.0 ..........................................................................................4 
1.3.1 
Amendment History ............................................................................................6 
1.3.2 
Summary of Changes ..........................................................................................6 
2.0 
TRIAL SUMMARY ..........................................................................................................27 
2.1 
Schedule of Trial Procedures .......................................................................................37 
3.0 
TRIAL REFERENCE INFORMATION ...........................................................................42 
3.1 
Trial-Related Responsibilities ......................................................................................42 
3.2 
Principal Investigator/Coordinating Investigator .........................................................42 
3.3 
List of Abbreviations ...................................................................................................43 
3.4 
Corporate Identification ...............................................................................................45 
4.0 
INTRODUCTION .............................................................................................................46 
4.1 
Background ..................................................................................................................46 
4.2 
Rationale for the Proposed Trial ..................................................................................47 
5.0 
TRIAL OBJECTIVES AND ENDPOINTS ......................................................................50 
5.1 
Objectives ....................................................................................................................50 
5.1.1 
Primary Objectives............................................................................................50 
5.1.2 
Secondary Objectives........................................................................................50 
5.1.3 
Exploratory Objectives .....................................................................................50 
5.2 
Endpoints .....................................................................................................................51 
5.2.1 
Primary Endpoints ............................................................................................51 
5.2.2 
Secondary Endpoints ........................................................................................52 
5.2.3 
Exploratory Endpoints ......................................................................................53 
6.0 
TRIAL DESIGN AND DESCRIPTION ...........................................................................55 
6.1 
Trial Design .................................................................................................................55 
6.2 
Justification for Trial Design, Dose, and Endpoints ....................................................57 
6.3 
Duration of Subject’s Expected Participation in the Entire Trial ................................58 
6.4 
Premature Termination or Suspension of Trial or Investigational Site .......................58 
6.4.1 
Criteria for Premature Termination or Suspension of the Trial ........................58 
6.4.2 
Criteria for Premature Termination or Suspension of Investigational Sites .....59 


Norovirus GI.1/GII.4 Bivalent VLP Vaccine 
 
Trial No. NOR-202 
Page 23 of 107 
Protocol Version 4.0 
1 March 2016 
 
CONFIDENTIAL 
6.4.3 
Procedures for Premature Termination or Suspension of the Trial or the 
Participation of Investigational Site(s)..............................................................59 
7.0 
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS ...............60 
7.1 
Inclusion Criteria .........................................................................................................60 
7.2 
Exclusion Criteria ........................................................................................................60 
7.3 
Criteria for Delay of Vaccination and Blood Sampling...............................................61 
7.4 
Criteria for Discontinuation or Withdrawal of a Subject .............................................62 
7.5 
Procedures for Discontinuation or Withdrawal of a Subject .......................................63 
8.0 
CLINICAL TRIAL MATERIAL MANAGEMENT .........................................................64 
8.1 
Investigational Vaccine(s) and Materials .....................................................................64 
8.1.1 
Dosage Form, Manufacturing, Packaging, and Labeling .................................64 
8.1.2 
Storage ..............................................................................................................65 
8.1.3 
Dose and Regimen ............................................................................................65 
8.2 
Investigational Vaccine Assignment and Dispensing Procedures ...............................65 
8.2.1 
Precautions to be Observed in Administering the Investigational Vaccine ......66 
8.3 
Randomization Code Creation and Storage .................................................................66 
8.4 
Investigational Vaccine Blind Maintenance ................................................................67 
8.5 
Unblinding Procedure ..................................................................................................67 
8.6 
Accountability and Destruction of Sponsor-Supplied Vaccine(s) ...............................67 
9.0 
TRIAL PLAN ....................................................................................................................69 
9.1 
Trial Procedures ...........................................................................................................69 
9.1.1 
Informed Consent Procedure ............................................................................69 
9.1.2 
Demographics, Medical History and Medication History Procedure ...............69 
9.1.3 
Documentation of Trial Entrance/Randomization ............................................70 
9.1.4 
Physical Examination Procedure ......................................................................70 
9.1.5 
Vital Signs .........................................................................................................70 
9.1.6 
Immunogenicity Assessments ...........................................................................71 
9.1.7 
Safety Assessments ...........................................................................................71 
9.1.8 
Processing, Labeling and Storage of Peripheral Blood Mononuclear Cell 
Samples .............................................................................................................75 
9.1.9 
Documentation of Subjects who are not Randomized ......................................75 
9.2 
Monitoring Subject Treatment Compliance.................................................................75 
9.3 
Schedule of Observations and Procedures ...................................................................75 
9.3.1 
Pre-vaccination Procedures (Day 1 and Day 29 [Cohort 1] and Day 1, Day 
56, and Day 112 [Cohort 2]) .............................................................................75 


Norovirus GI.1/GII.4 Bivalent VLP Vaccine 
 
Trial No. NOR-202 
Page 24 of 107 
Protocol Version 4.0 
1 March 2016 
 
CONFIDENTIAL 
9.3.2 
Vaccination Procedures (Day 1 and Day 29 [Cohort 1] and Day 1, Day 56, 
and Day 112 [Cohort 2]) ...................................................................................76 
9.3.3 
Post-vaccination Procedures (Day 1 and Day 29 [Cohort 1] and Day 1, Day 
56, and Day 112 [Cohort 2]) .............................................................................76 
9.3.4 
Clinic Visits after Vaccination ..........................................................................78 
9.3.5 
Phone Contacts – Safety Data Collection (Day 134 [Cohort 1] and Days 200 
and 260 [Cohort 2]) ...........................................................................................78 
9.3.6 
Phone Contacts - Reminder Calls (Day 3 and Day 32 [Cohort 1] and Day 3, 
Day 59, and Day 115 [Cohort 2]) .....................................................................79 
9.3.7 
Final Visit..........................................................................................................79 
9.3.8 
Post-Trial Care ..................................................................................................79 
9.4 
Biological Sample Retention and Destruction .............................................................79 
10.0 
AEs .....................................................................................................................................80 
10.1 
Definitions....................................................................................................................80 
10.1.1 
AEs ....................................................................................................................80 
10.1.2 
Causality of AEs ...............................................................................................81 
10.1.3 
Relationship to Trial Procedures .......................................................................81 
10.1.4 
Additional Points to Consider for AEs .............................................................81 
10.1.5 
SAEs .................................................................................................................82 
10.2 
Procedures ....................................................................................................................82 
10.2.1 
Collection and Reporting of AEs ......................................................................82 
10.2.2 
Collection and Reporting of SAEs ....................................................................83 
10.3 
Follow-up of SAEs ......................................................................................................84 
10.3.1 
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities
...........................................................................................................................84 
10.3.2 
Post-Trial Events ...............................................................................................84 
11.0 
TRIAL-SPECIFIC REQUIREMENT(S) ...........................................................................86 
11.1 
Trial-Specific Committees ...........................................................................................86 
11.1.1 
Independent DMC .............................................................................................86 
12.0 
DATA HANDLING AND RECORDKEEPING ..............................................................87 
12.1 
eCRFs ...........................................................................................................................87 
12.2 
Record Retention .........................................................................................................87 
13.0 
STATISTICAL METHODS ..............................................................................................89 
13.1 
Statistical and Analytical Plans ....................................................................................89 
13.1.1 
Analysis Sets .....................................................................................................89 
13.1.2 
Analysis of Demographics and Other Baseline Characteristics .......................90 


Norovirus GI.1/GII.4 Bivalent VLP Vaccine 
 
Trial No. NOR-202 
Page 25 of 107 
Protocol Version 4.0 
1 March 2016 
 
CONFIDENTIAL 
13.1.3 
Immunogenicity Analysis .................................................................................90 
13.1.4 
Safety Analysis .................................................................................................91 
13.2 
Interim Analysis and Criteria for Early Termination ...................................................92 
13.3 
Determination of Sample Size .....................................................................................92 
14.0 
QUALITY CONTROL AND QUALITY ASSURANCE .................................................94 
14.1 
Trial-Site Monitoring Visits .........................................................................................94 
14.2 
Protocol Deviations ......................................................................................................94 
14.3 
Quality Assurance Audits and Regulatory Agency Inspections ..................................94 
15.0 
ETHICAL ASPECTS OF THE TRIAL .............................................................................95 
15.1 
IRB and/or IEC Approval ............................................................................................95 
15.2 
Subject Information, Informed Consent, and Subject Authorization ..........................96 
15.3 
Subject Confidentiality ................................................................................................97 
15.4 
Publication, Disclosure, and Clinical Trial Registration Policy ..................................97 
15.4.1 
Publication and Disclosure ...............................................................................97 
15.4.2 
Clinical Trial Registration.................................................................................97 
15.4.3 
Clinical Trial Results Disclosure ......................................................................98 
15.5 
Insurance and Compensation for Injury .......................................................................98 
16.0 
REFERENCES ..................................................................................................................99 
 
LIST OF IN-TEXT TABLES 
Table 1-a 
Contact Information .................................................................................................2 
Table 2-a 
Schedule of Trial Procedures for Subjects Aged 6 Months to Less Than 9 Years 
(Cohort 1 for Groups 1, 2 and 3; N=360) ..............................................................37 
Table 2-b 
Schedule of Trial Procedures for Subjects Aged 1 to Less Than 4 Years (Cohort 
1 for Group 2a; N=120) .........................................................................................39 
Table 2-c 
Schedule of Trial Procedures For Subjects Aged 6 Weeks to Less Than 6 
Months (Cohort 2; N=360) ....................................................................................40 
Table 8-a 
Sponsor-Supplied Investigational Vaccine ............................................................65 
Table 9-a 
Solicited Safety Parameters in Children Aged 4 to <9 Years ................................73 
Table 9-b 
Solicited Safety Parameters in Children Aged 6 Weeks to <4 Years) ...................74 
Table 13-a 
Probability of Observing 1 or More Events for Assumed “True” Event Rate and 
Given Samples .......................................................................................................93 
 


Norovirus GI.1/GII.4 Bivalent VLP Vaccine 
 
Trial No. NOR-202 
Page 26 of 107 
Protocol Version 4.0 
1 March 2016 
 
CONFIDENTIAL 
LIST OF IN-TEXT FIGURES 
Figure 6-a 
Schematic of Trial Design .....................................................................................55 
 
LIST OF APPENDICES 
Appendix A 
Responsibilities of the Investigator ......................................................................102 
Appendix B 
Investigator Consent to Use of Personal Information ..........................................104 
Appendix C 
Elements of the Subject Informed Consent .........................................................105 
 


Norovirus GI.1/GII.4 Bivalent VLP Vaccine 
 
Trial No. NOR-202 
Page 27 of 107 
Protocol Version 4.0 
1 March 2016 
 
CONFIDENTIAL 
2.0 
TRIAL SUMMARY 
Name of Sponsor(s): 
Takeda Vaccines, Inc. 
One Takeda Parkway 
Deerfield, IL 60015 
USA 
Product Name: 
Norovirus Bivalent GI.1/GII.4 VLP Vaccine 
Trial Title: 
A Phase II, Randomized, Double-Blind, Dosage, Safety and Immunogenicity Trial of Intramuscular Norovirus 
GI.1/GII.4 Bivalent Virus-Like Particle Vaccine combined with Aluminum Hydroxide Adjuvant in Children, 
Toddlers, and Infants 
IND No.: 014421 
EudraCT No.: 2014-000778-20 
Study Identifier: NOR-202 
Phase: II 
Trial Blinding Scheme: Double Blind 
Background and Rationale: 
Noroviruses (NoV) have emerged as the single most significant cause of epidemic outbreaks of non-bacterial 
gastroenteritis worldwide. These outbreaks commonly result in significant morbidity and mortality in almost all age 
groups. Those most at risk are the elderly, the very young, and immunocompromized individuals. Noroviruses cause 
acute debilitating illness characterized by vomiting, diarrhea, and abdominal pain. There are no substantial differences 
in clinical presentation between adults and children, although children less than 1 year of age present more frequently 
with diarrhea and less frequently with vomiting than other age groups. The duration of the diarrhea is also longer in 
this age group with a median duration of 6 days compared to 1 to 3 days in other age groups [1]. In the European Union 
(EU), for children under 5 years of age, it is estimated that each year there are 5,600,000 cases of NoV gastroenteritis 
[2], resulting in 380,000 outpatient and 147,000 emergency room visits (population adjusted from Hall, 2011[3]), 
30,000 to 47,000 hospitalizations (population adjusted from Phillips, 2010 [2]) and as many as 200 deaths (assumes 
ratio of deaths to hospitalizations is the same as rotavirus in the pre-vaccine era). For children below the age of 5 years 
in high income countries, an estimated figure of 64,000 episodes of NoV disease occur requiring hospitalization [4]. 
Whereas mortality due to NoV disease in the pediatric population is rare in industrialized countries, it is frequent in 
developing countries. In developing countries, mortality from NoV disease in children below the age of 5 years is 
approximately 200,000 deaths per year [4, 5]. Although potentially a cause for hospitalization in infants, there are 
fewer deaths than expected possibly due to the protection offered by maternal antibodies during the first 6 months of 
life. A study in Finland found that 68% of infants less than 6 months old had immunoglobin G (IgG) antibodies against 
GII.4 NoV with high avidity, which likely reflects acquired maternal IgG antibodies (from transplacental transfer), 
compared to the antibodies found in infants aged 7 to 12 months. However, the presence of immunoglobin A (IgA) 
antibodies in 20% of these children suggests that maternal antibodies do not offer full protection [6]. Vaccination of 
young infants with a NoV vaccine during the first 6 months of life may provide protection thereafter, when infants and 
young children are at highest risk of acquiring NoV disease. 
In addition to the inherent morbidity and mortality problem, NoV infections exact a significant socioeconomic toll on 
businesses, hospitals, schools, and other closed settings dealing with outbreaks [7]. As the burden of rotavirus in 
children decreases through the childhood rotavirus vaccination programs, NoV infections and disease are likely to 
increase with consequences extending beyond this population [8]. A prophylactic approach could counter this. 
The vaccine in this trial is based on NoV virus-like particles (VLPs) as the antigens. Norovirus VLPs are 
non-infectious because they do not contain viral genomic ribonucleic acid (RNA) and are immunogenic because they 
preserve particulate antigen conformation and structure that mimic functional interactions of the virus with cellular 
receptors. The vaccine also contains the single Al(OH)3 adjuvant. 
Aluminum hydroxide [Al(OH)3] has been shown to enhance the antigenicity and immunogenicity of vaccines. The 
rationale for an Al(OH)3 adjuvanted intramuscular (IM) NoV VLP vaccine is based on the low immune responses 
previously observed in healthy adults after oral administration of Norwalk Virus VLP vaccine [9, 10, 11]. Aluminum 
adjuvant has a demonstrated safety profile of over 6 decades [12]). The aluminum concentration per dose was selected 


Norovirus GI.1/GII.4 Bivalent VLP Vaccine 
 
Trial No. NOR-202 
Page 28 of 107 
Protocol Version 4.0 
1 March 2016 
 
CONFIDENTIAL 
empirically from data that demonstrated that this amount of aluminum enhanced the antigenicity and immunogenicity 
of the vaccine. 
Norovirus strains drift from year to year and both GI and GII genogroups cause disease in all age groups. Although 
numerous types are reported, the GII.4 type remains dominant and is currently responsible for the majority of 
outbreaks worldwide. The rationale for developing a bivalent vaccine is based on NoV epidemiology and the lack of 
natural protection between genogroups. In trial LV03-104, the first NoV bivalent VLP vaccine was given IM, and 
compared equally balanced (1:1) dosages of the GI.1 and GII.4 VLPs in adults. For each of the 4 vaccine dosages 
evaluated (5/5, 15/15, 50/50, and 150/150 µg of NoV VLPs), the seroresponse rates (percent of subjects with at least a 
4-fold rise in antibody levels) and geometric mean fold rises (GMFRs) were lower for the GII.4 VLP than for the GI.1 
VLP at equivalent antigen dosages. Likewise, similar post-vaccination immunogenicity data were observed in adults 
in trial LV03-105, the GII.4 challenge trial that evaluated a 50/50 µg balanced 1:1 VLP dosage of vaccine. Separately 
the factorial design trial NOR-107 was initiated in subjects ages 18 to 64, to evaluate multiple vaccine formulations 
containing different (balanced and unbalanced) ratios of the antigenic VLP components of the bivalent vaccine 
(GI.1/GII.4) with Al(OH)3 adjuvant both with and without MPL adjuvant. Prior safety and immunogenicity data for 
the NoV vaccine given by the IM route are available from approximately 1000 adult subjects, evaluated in five Takeda 
clinical trials (LV03-104, LV03-105, NOR-107, NOR-201, and NOR-210). The NoV vaccine evaluated in these trials 
either contained both Al(OH)3 plus monophosphoryl lipid A (MPL) adjuvants combined or the Al(OH)3 adjuvant 
alone. Trial NOR-107 conducted in adults aged 18-64 years, a Phase II dosage, adjuvant justification, safety, and 
immunogenicity trial, evaluated 11 vaccine formulations, and showed that the NoV VLP vaccine adjuvanted with 
aluminum as Al(OH)3 adjuvant was as immunogenic as the NoV VLP vaccine adjuvanted with Al(OH)3 and MPL 
combined. 
This trial NOR-202 in children aged 6 weeks to less than 9 years will evaluate the safety and immunogenicity of 
multiple formulations with different ratios of the antigenic VLP components of the bivalent vaccine. The formulations 
for NOR-202 are selected based on the initial and additional results obtained from the factorial design study NOR-107 
in adults. Based on the additional NOR-107 results, the number of formulation arms is reduced from 8 in amendment 
N° 1.0 of the original protocol to 4 in this amended protocol. 
The upper age cut-off for the NOR-202 trial was selected based on the assumption that the immune response in older 
children and adolescents aged 9 to <18 years is similar to the immune response observed in those aged ≥18 years. 
Therefore subjects aged 9 to <18 years are not included in trial NOR-202. 
The primary goals of this clinical trial are therefore to evaluate the immunogenicity and safety of 1 to 2 doses in 
children 6 months to less than 9 years of age and 2 to 3 doses in infants 6 weeks to less than 6 months of age with the 
IM NoV bivalent VLP vaccine using different dosages of the VLPs to obtain confirmation of dosage and schedule, in 
these age groups. In order to maintain the trial blind, a single injection of saline placebo will be administered as the 
final dose for the 1 dose group in Cohort 1 and for the 2 dose group in Cohort 2. 
Background and Rationale for Amendment Number 3.0: 
The primary purposes of this amendment are: 1) to enroll an additional 120 children (1 to < 4 years; designated Group 
2a), to assess the safety and immunogenicity of the recently manufactured NoV vaccine in a similar age group to 
Group 2; and 2) to perform the Day 57 interim analysis (IA) for Groups 1 and 2 of Cohort 1, who will complete Day 57 
substantially earlier than Groups 2a and 3. The Day 57 IA for Groups 2a and 3 combined will be performed at a later 
time. The Day 140 IA for Group 4 does not change. 
The trial vaccine, originally manufactured for trial NOR-202, was not available for clinical use after 30 November 
2015, due to expiration at 36 months after manufacture. Several factors affected the enrolment timeline in trial 
NOR-202: (1) Takeda’s decision to not initiate enrollment until after agreement from the Pediatric Committee of the 
EMA on the Pediatric Investigational Plan (PIP) of the NoV vaccine; (2) and the regulatory, logistical, and operational 
study requirements for implementation of the two prior protocol amendments. 
Per protocol, all children in Groups 1 (4 to < 9 years) and 2 (1 to < 4 years) were enrolled, randomized and received 
one of the four NoV vaccine formulations as a one or two dose trial vaccine regimen within the vaccine expiry dating 
period. Notably, children in Groups 3 (1 or 2 doses) and 4 (2 or 3 doses) were not enrolled due to expiration of the trial 


Norovirus GI.1/GII.4 Bivalent VLP Vaccine 
 
Trial No. NOR-202 
Page 29 of 107 
Protocol Version 4.0 
1 March 2016 
 
CONFIDENTIAL 
vaccine. Takeda has paused this study until additional trial vaccine is manufactured and released for clinical use. 
Takeda has recently produced VLPs at a different manufacturer with increased capacity for manufacturing on a larger 
scale. To date, the NoV vaccine with these recently produced VLPs has been manufactured and released for clinical 
use in two studies in adults; trial NOR-204 in 350 adults aged 18 to > 85 years and trial NOR-211 in ~ 2800 adults aged 
18 to 49 years. 
To understand the safety and immunogenicity of the recently manufactured vaccine in a similar age group to Group 2, 
an additional 120 children designated Group 2a, will be enrolled in trial NOR-202, prior to enrolling children in 
Groups 3 and 4. Specifically, the safety data from Group 2a will be provided to the Data Monitoring Committee 
(DMC) for review prior to enrollment of the children in Groups 3 and 4. 
Although the VLP manufacturer has changed, the vaccine dosages and regimens with the four vaccine formulations 
evaluated in Groups 1 and 2 will also be evaluated in children in Groups 2a, 3, and 4. However, only children in 
Groups 2a, 3, and 4, will receive the recently manufactured vaccine. 
Enrollment in Group 2a will be initiated after all four vaccine formulations of the recently manufactured vaccine are 
released for clinical use. 
The trial will be conducted in accordance with the protocol, International Conference on Harmonization-Good 
Clinical Practice (ICH-GCP) Guidelines, and applicable regulatory requirements. 
Trial Design: 
This is a Phase II, randomized, double-blind, multi-site, dosage, safety, and immunogenicity trial of the IM NoV 
bivalent VLP vaccine combined with Al(OH)3,. Subjects randomized in the trial will be placed into 1 of 2 cohorts 
based on age (shown below). 
 
840 subjects 
aged  
6 weeks to < 9 years
Cohort 1
Subjects aged 
6 months to < 9 
years
N= 480
Group 1
4 to <9 years
120  subjects
One Dose
Two Doses
Group 2
1 to < 4 years
120 subjects
One Dose
Two Doses
Group 2a*
1 to < 4 years
120 subjects
One Dose
Two Doses
Cohort 2*
(Group 4)
Subjects aged
6 weeks to <6 
months
N= 360
Two Doses
Three Doses
Group 3*
6 months to < 1 
year
120 subjects
One Dose
Two Doses
* Recently manufactured clinical trial material lots


Norovirus GI.1/GII.4 Bivalent VLP Vaccine 
 
Trial No. NOR-202 
Page 30 of 107 
Protocol Version 4.0 
1 March 2016 
 
CONFIDENTIAL 
Subjects 6 months to less than 9 years of age (inclusive, Cohort 1) will receive either 1 or 2 doses by IM injection, at 
least 28 days apart (Days 1 and 29), in ), in 4 groups in 3 age ranges (Group 1: aged 4 to less than 9 years; Group 2 and 
Group 2a: aged 1 to less than 4 years; and Group 3: aged 6 months to less than 1 year). Infants 6 weeks to less than 
6 months of age (Group 4/Cohort 2) will receive 2 or 3 doses by IM injection, approximately 56 days apart (Days 1, 
56, and 112). Routine child and infant vaccinations will be given on schedule per the national guidelines 
approximately 28 days apart from the investigational vaccine in each age group. 
Primary evaluation of the trial objectives is planned at 28 days after the final (second) vaccination in subjects aged 
6 months to less than 9 years (Cohort 1) and 28 days after the final (third) vaccination in subjects aged 6 weeks to less 
than 6 months (Cohort 2). In order to maintain the blind and to have the same trial time points and dosing regimens, 
subjects in Cohort 1 (Groups 1, 2, 2a and 3) who are randomized to the 1 dose group will receive a dose of the NoV 
bivalent VLP vaccine on Day 1 followed by a placebo injection of saline 28 days later (Day 29) and subjects in the 
2 dose group will receive 2 doses of NoV VLP vaccine approximately 28 days apart (Days 1 and 29). Likewise, 
subjects in Cohort 2 (Group 4) who are randomized to the 2 dose group will receive 2 doses of NoV bivalent VLP 
vaccine on Days 1 and 56, followed by a placebo injection of saline approximately 56 days later (Day 112), and 
subjects in the 3 dose group will receive 3 doses of NoV VLP vaccine approximately 56 days apart (Days 1, 56, and 
112), independent of the infant routine vaccinations by approximately 28 days. This is a double-blind trial; 
investigators, subjects, data collectors, and data evaluators are blinded to the specific formulation and the dosing 
groups. 
This study plans to assess the immunogenicity and safety of the NoV bivalent VLP vaccine in children when given 
independently of the routine pediatric vaccines but, importantly, never to interfere with routine vaccine administration 
of children in each of the countries planned for evaluation. National pediatric vaccine regimens in children 6 weeks to 
less than 6 months of age vary by country (eg, routine pediatric vaccines may be given at 2, 3, and 4 months of age; at 
2, 4, and 6 months of age; or at 3, 5, and 12 months). 
An independent program level Data Monitoring Committee (DMC) has been established to assess safety data on an 
ongoing basis. The DMC will also have study level responsibilities to review data and make recommendations about 
the sequential enrollment of various groups and formulation arms in this study (see Section 11.1.1). 
A licensed benefit vaccine may be offered to all subjects after trial exit. 
Interim analyses (IA) will be performed after the primary safety and immunogenicity data are available (ie, Day 57 for 
Cohort 1 and Day 140 for Cohort 2) (primary analysis time point). The Day 57 IA for Cohort 1 will be provided 
initially for Groups 1 and 2, who will complete Day 57 substantially earlier than Groups 2a and 3. The Day 57 interim 
analyses for Groups 2a and 3 combined will be provided at a later time. Thus, the Day 57 IA will be conducted in two 
parts to be followed by the Day 140 IA in Group 4. All interim analyses will be performed by a separate set of 
unblinded statisticians and programmers at the contract research organization (CRO), Quintiles, who will have access 
to individual treatment assignments but will not otherwise be involved in study conduct. The rest of the personnel 
involved in the conduct of the study, including those at Takeda, Quintiles, and the study sites, will remain blinded to 
the individual subject data (including treatment assignments) until unblinding after database lock (Day 210 for 
Cohort 1 and Day 293 for Cohort 2). 
More details on the analyses will be provided in the statistical analysis plan (SAP). 
Primary Objectives: 
To select the optimal formulation of the NoV bivalent VLP vaccine from different dosages of VLP for further 
development: 
• 
By assessing the seroresponse rate (percentage of subjects with ≥4-fold rises) in serum anti-NoV GI.1 VLP and 
GII.4 VLP antibody titers by Pan immunoglobin (Pan-Ig) enzyme-linked immunosorbent assay (ELISA). 
• 
By assessing the safety profile of different formulations of the NoV bivalent VLP vaccine as measured by 
solicited local and systemic adverse events (AEs) for the period of 7 days after each vaccination and as measured 
by the occurrence of unsolicited AEs 28 days after each vaccination, and serious adverse events (SAEs) 
throughout the trial. 


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CCI


Norovirus GI.1/GII.4 Bivalent VLP Vaccine 
 
Trial No. NOR-202 
Page 32 of 107 
Protocol Version 4.0 
1 March 2016 
 
CONFIDENTIAL 
of approximately 45 subjects. 
Planned Number of Formulation Arms: 4 
Investigational vaccine: Doses of the antigen component of each investigational vaccine are outlined below. 
Investigational vaccines (Arms A, B, C, and D) are manufactured by Althea Technologies, San Diego (CA), United 
States. Presented formulations are an approximation (within a defined specification) of the respective antigen/adjuvant 
concentrations. 
• 
Arm A: GI.1/GII.4 (15 µg/15 µg) 
• 
Arm B: GI.1/GII.4 (15 µg/50 µg) 
• 
Arm C: GI.1/GII.4 (50 µg/50 µg) 
• 
Arm D: GI.1/GII.4 (50 µg/150 µg) 
The investigational vaccine for each arm contains 500 µg alum.  
Subjects aged 6 months to less than 9 years will receive either 1 dose of investigational vaccine on Day 1 and 1 dose of 
saline placebo on Day 29 or 2 doses of investigational vaccine at least 28 days apart (on Day 1 and Day 29). Infants 
aged 6 weeks to less than 6 months will receive 2 doses of investigational vaccine, approximately 56 days apart (on 
Day 1 and Day 56) and 1 dose of saline placebo on Day 112 or 3 doses of investigational vaccine, approximately 
56 days apart (on Days 1, 56, and 112). 
Placebo Control: Saline will be administered as a control injection in order to maintain the trial blind for the 1 dose 
groups in Groups 1, 2, 2a and 3, (Cohort 1) and for the 2 dose group in Group 4 (Cohort 2). Subjects in the 1 dose 
groups in Cohort 1 receive NoV vaccine on Day 1 and a saline placebo injection on Day 29. Subjects in the 2 dose 
group in Cohort 2 receive NoV vaccine on Days 1 and 56 and a saline placebo injection on Day 112. 
Route of Administration: IM (anterolateral thigh for children aged ≤12 months; anterolateral thigh or deltoid muscle 
of the arm for children aged >12 months [per national guidelines]). 
Main Criteria for Inclusion: 
• 
Male and female subjects aged between 6 weeks and less than 9 years at the time of enrollment. 
• 
Subjects who are in good health at the time of entry into the trial as determined by medical history, physical 
examination (including vital signs) and clinical judgment of the investigator. 
• 
The subject’s legally authorized representative (LAR) signs and dates a written, informed consent form (ICF) and 
any required privacy authorization prior to the initiation of any trial procedures, after the nature of the trial has 
been explained according to local regulatory requirements. An assent will also be obtained according to age 
appropriate country-specific regulations. 
• 
Individuals who can comply with trial procedures and are available for the duration of the trial. 
Main Criteria for Exclusion: 
• 
Known hypersensitivity to any of the vaccine components. 
• 
Subjects with known or suspected impairment/alteration of immune function. 
Duration of the Trial: 
Six months after last administration of investigational vaccine. 
Period of Evaluation: 
210 or 293 days. 
Main Criteria for Evaluation and Analyses: 
Endpoints apply to Cohorts 1 and 2 unless otherwise stated. For subjects in Group 2a, the serologic assays to the 
vaccine VLPs for the Pan-Ig ELISA and for the HBGA binding assays will each be performed. Notably, the following 
endpoints will not be performed for Group 2a: Avidity, IgA ELISA, CMI for those aged ≥ 3 years, and HBGA binding 
assay to a panel of GI.1 and GII.4 not represented in the vaccine. 
The primary endpoints for this trial are: 
Immunogenicity 
• 
Seroresponse rate (defined as 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 Pan-Ig ELISA at Day 57 (Cohort 1) and Day 140 


Norovirus GI.1/GII.4 Bivalent VLP Vaccine 
 
Trial No. NOR-202 
Page 33 of 107 
Protocol Version 4.0 
1 March 2016 
 
CONFIDENTIAL 
(Cohort 2). 
Safety 
• 
Percentage of subjects with solicited local AEs of injection site: pain, erythema, induration, and swelling on the 
day of vaccination and then daily through Day 7 after each vaccination. 
• 
Percentage of subjects with solicited systemic AEs of headache, fatigue, myalgia, arthralgia, vomiting (number 
per day/intensity), and diarrhea (number per day/consistency) for children aged 4 to <9 years; and 
irritability/fussiness, drowsiness, loss of appetite, vomiting (number per day/intensity), and diarrhea (number per 
day/consistency) for children aged 6 weeks to <4 years on the day of vaccination and daily through Day 7 after 
each vaccination. 
• 
Body temperature on the day of vaccination (approximately 30 minutes and 6 hours later); then daily through 
Day 7 after each vaccination. 
• 
Percentage of subjects with unsolicited AEs for 28 days after each vaccination. 
• 
Percentage of subjects with SAEs throughout the trial. 
The secondary endpoints for this trial are:  
Immunogenicity 
Pan-Ig ELISA 
• 
Seroresponse rate in serum anti-NoV GI.1 VLP antibody titers as measured by Pan-Ig ELISA on Day 57 
(Cohort 1) and Day 140 (Cohort 2). 
• 
Seroresponse rate in serum anti-NoV GII.4 VLP antibody titers as measured by Pan-Ig ELISA on Day 57 
(Cohort 1) and Day 140 (Cohort 2). 
• 
GMT of anti-NoV GI.1 VLP antibody titers as measured by Pan-Ig ELISA on Day 57 (Cohort 1) and Day 140 
(Cohort 2). 
• 
GMT of anti-NoV GII.4 VLP antibody titers as measured by Pan-Ig ELISA on Day 57 (Cohort 1) and Day 140 
(Cohort 2). 
• 
GMFR of anti-NoV GI.1 VLP antibody titers as measured by Pan-Ig ELISA on Day 57 (Cohort 1) and Day 140 
(Cohort 2). 
• 
GMFR of anti-NoV GII.4 VLP antibody titers as measured by Pan-Ig ELISA on Day 57 (Cohort 1) and Day 140 
(Cohort 2). 
HBGA Binding Assay 
• 
Seroresponse rate in serum anti-NoV GI.1 VLP and GII.4 VLP antibody titers as measured by HBGA binding 
assay on Day 57 (Cohort 1) and Day 140 (Cohort 2). 
• 
Seroresponse rate in serum anti-NoV GI.1 VLP antibody titers as measured by HBGA binding assay on Day 57 
(Cohort 1) and Day 140 (Cohort 2). 
• 
Seroresponse rate in serum anti-NoV GII.4 VLP antibody titers as measured by HBGA binding assay on Day 57 
(Cohort 1) and Day 140 (Cohort 2). 
• 
BT50 of anti-NoV GI.1 VLP antibody titers as measured by HBGA binding assay on Day 57 (Cohort 1) and 
Day 140 (Cohort 2). 
• 
BT50 of anti-NoV GII.4 VLP antibody titers as measured by HBGA binding assay on Day 57 (Cohort 1) and 
Day 140 (Cohort 2). 
• 
GMFR of anti-NoV GI.1 VLP antibody titers as measured by HBGA binding assay on Day 57 (Cohort 1) and 
Day 140 (Cohort 2). 
• 
GMFR of anti-NoV GII.4 VLP antibody titers as measured by HBGA binding assay on Day 57 (Cohort 1) and 
Day 140 (Cohort 2). 
Safety 
• 
Percentage of subjects with any AE leading to subject’s withdrawal from the trial - from the day of vaccination 


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Norovirus GI.1/GII.4 Bivalent VLP Vaccine 
 
Trial No. NOR-202 
Page 36 of 107 
Protocol Version 4.0 
1 March 2016 
 
CONFIDENTIAL 
Interim Analysis: 
Interim analyses will be performed after the primary safety and immunogenicity data (28 days after last dose) are 
available (ie, Day 57 for Cohort 1 and Day 140 for Cohort 2) (primary analysis time point). Day 57 IA for Cohort 1 
will be provided initially for Groups 1 and 2, who will complete Day 57 substantially earlier than Groups 2a and 3. The 
Day 57 IA for Groups 2a and 3 combined will be provided at a later time. Thus, the Day 57 IA will be conducted in two 
parts to be followed by the Day 140 IA in Group 4. All interim analyses will be performed by a separate set of 
unblinded statisticians and programmers at the CRO, Quintiles, who will have access to individual treatment 
assignments but will not otherwise be involved in study conduct. The rest of the personnel involved in the conduct of 
the study, including those at Takeda, Quintiles, and the study sites, will remain blinded to the individual subject data 
(including treatment assignments) until unblinding after database lock (Day 210 for Cohort 1 and Day 293 for Cohort 
2). 
More details on the analyses will be provided in the SAP. 
Data Monitoring Committee: 
An independent program level DMC will assess safety data on an ongoing basis. The DMC will also have study level 
responsibilities to review data and make recommendations about the sequential enrollment of various groups and 
formulation arms in this study. 
Enrollment in this study will be initiated sequentially based on age groups and formulation arms, with ongoing DMC 
review. 
NOR-202 Version 4.0 (1 March 2016) 


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Norovirus GI.1/GII.4 Bivalent VLP Vaccine 
 
Trial No. NOR-202 
Page 40 of 107 
Protocol Version 4.0 
1 March 2016 
 
CONFIDENTIAL 
Table 2-c 
Schedule of Trial Procedures For Subjects Aged 6 Weeks to Less Than 6 Months (Cohort 2; N=360) 
 
 
Timing 
Day 1  
Day 3 
Day 8 
Day 29 
Day 56 
Day 59 
Day 63 
Day 84 
Day 112 
Day 115 
Day 119 
Day 140 
Day 200 
Day 260 
Day 293a 
Procedure 
 
Visits 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
 
 
X 
Phone Contactsb 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
X 
 
Visit Window (days) 
- 
-1/+2 
+3 
+3 
+3 
-1/+2 
+3 
+3 
+3 
-1/+2 
+3 
+7 
+7 
+7 
+7 
Signed Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examinationc 
X 
 
(X) 
(X) 
X 
 
(X) 
(X) 
X 
 
(X) 
(X) 
 
 
(X) 
Trial Vaccine 
Administration 
Xd 
 
 
 
Xd 
 
 
 
Xd 
 
 
 
 
 
 
Diary Card Dispensing 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
Diary Card Delivery 
 
 
X 
X 
 
 
X 
X 
 
 
X 
X 
 
 
 
AEse 
Day 
1-28 
 
 
 
Day 
56-84 
 
 
 
Day 
112-140 
 
 
 
 
 
 
SAEsf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood Draw for Serology 
(2 mL)g 
X 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
X 


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1.0 TITLE PAGE 
Norovirus GI.1/GII.4 Bivalent VLP Vaccine 
 
Trial No. NOR-202 
Page 42 of 107 
Protocol Version 4.0 
1 March 2016 
 
 
CONFIDENTIAL 
 
3.0 
TRIAL REFERENCE INFORMATION 
3.1 
Trial-Related Responsibilities 
The sponsor or their designee will perform all trial-related activities with the exception of those 
identified in the Trial-Related Responsibilities template. The identified vendors in the template for 
specific trial-related activities will perform these activities in full or in partnership with the 
sponsor. 
3.2 
Principal Investigator/Coordinating Investigator 
The sponsor will select a Signatory 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 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. 


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Norovirus GI.1/GII.4 Bivalent VLP Vaccine 
 
Trial No. NOR-202 
Page 45 of 107 
Protocol Version 4.0 
1 March 2016 
 
CONFIDENTIAL 
3.4 
Corporate Identification 
TV 
Takeda Vaccines, Inc. 
 


Norovirus GI.1/GII.4 Bivalent VLP Vaccine 
 
Trial No. NOR-202 
Page 46 of 107 
Protocol Version 4.0 
1 March 2016 
 
CONFIDENTIAL 
4.0 
INTRODUCTION 
4.1 
Background 
Noroviruses (NoV) are non-cultivatable human caliciviruses that have emerged as the single most 
significant cause of epidemic outbreaks of nonbacterial gastroenteritis worldwide [14]. These 
outbreaks commonly result in significant morbidity and mortality. Norovirus outbreaks are 
common in all countries in Europe; however, the number of epidemics being reported in recent 
years has been increasing in England, Wales, Germany, the Netherlands, and other countries [15]. 
The reason for this increase is unclear, but this may be due to the improved recognition of NoV as 
an infectious agent responsible for acute gastroenteritis [16, 17, 18, 19]. In addition, 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 [20, 21]. 
Although NoVs affect people of all ages, those most at risk are elderly, very young, and 
immunocompromized individuals [15]. Following an incubation period of 1 to 2 days, gastric 
symptoms including nausea, diarrhea, vomiting, and abdominal pain appear [22]. These symptoms 
may be accompanied by mild fever, muscle, and joint pain [23]. Illness is generally mild and lasts 
a few days on average. Although usually self-limiting, the disease may become chronic, 
particularly in immunocompromized individuals [17]. Norovirus-infected people may continue to 
shed virus for several weeks following the resolution of the symptoms [14], and some cases may 
be asymptomatic [24]. Norovirus is highly infectious, with 18 to 1000 viral particles estimated to 
be sufficient for infection [25]. More than 50 million cases of illness per year are thought to occur 
in Europe and the United States; many of these cases require medical attention or admission to 
hospitals. There is also a substantial burden of illness in developing countries, where over 
200,000 deaths per year of children under 5 years of age are attributed to NoV [4]. In addition to 
the inherent morbidity and mortality problem, NoV infections exact significant socioeconomic toll 
on businesses, hospitals, schools, and other settings [26]. 
The clinical significance of NoVs was underappreciated prior to the development of molecular 
diagnostic assays that could detect these enteric viruses. The cloning of the prototype genogroup I 
Norwalk virus genome and the production of virus-like particles (VLPs) from a recombinant 
Baculovirus expression system led to the development of sensitive assays that revealed that 
infections due to NoVs are widespread [27, 28, 29]. The investigational vaccine in this trial (ie, 
NoV GI.1/GII.4 bivalent VLP vaccine adjuvanted with aluminum hydroxide [Al(OH)3] [NoV 
GI.1/GII.4 bivalent VLP vaccine]) contains NoV VLPs as the antigens. Norovirus VLPs are 
noninfectious because they do not contain viral genomic ribonucleic acid (RNA) and are 
immunogenic because they preserve particulate antigen conformation and structure that mimic 
functional interactions of the virus with cellular receptors. 
Human NoV cannot be grown in cell culture, and no small animal model of human infection is 
available. Consequently, knowledge of the pathogenesis of NoV, as well as demonstration of 
proof-of-concept for candidate vaccines, has been derived primarily from studies in human 
volunteers who have been experimentally infected with stool filtrates obtained from naturally 
infected human donors or from epidemiologic studies of natural infection [30]. 


Norovirus GI.1/GII.4 Bivalent VLP Vaccine 
 
Trial No. NOR-202 
Page 47 of 107 
Protocol Version 4.0 
1 March 2016 
 
CONFIDENTIAL 
Prior safety and immunogenicity data for the NoV vaccine given by the IM route are available 
from approximately 1000 adult subjects, evaluated in five Takeda clinical trials (LV03-104, 
LV03-105, NOR-107, NOR-201, and NOR-210). The NoV vaccine evaluated in these trials either 
contained both Al(OH)3 plus monophosphoryl lipid A (MPL) adjuvants combined or the Al(OH)3 
adjuvant alone. Trial NOR-107 conducted in adults aged 18-64 years, a Phase II dosage, adjuvant 
justification, safety, and immunogenicity trial, evaluated 11 vaccine formulations, and showed that 
the NoV VLP vaccine adjuvanted with aluminum as Al(OH)3 adjuvant was as immunogenic as the 
NoV VLP vaccine adjuvanted with Al(OH)3 and MPL combined. 
Refer to the current Investigator Brochure of Takeda’s NoV GI.1/GII.4 bivalent VLP vaccine for 
additional product information and a more detailed review of pre-clinical and clinical studies [31]. 
4.2 
Rationale for the Proposed Trial 
Noroviruses have emerged as the single most significant cause of epidemic outbreaks of 
nonbacterial gastroenteritis worldwide. These outbreaks commonly result in significant morbidity 
and mortality in almost all age groups, though elderly, very young, and immunocompromized 
individuals are most at risk. 
The vaccine in this trial is based on NoV VLPs as the antigens. Norovirus VLPs are non-infectious 
because they do not contain viral genomic RNA and are immunogenic because they preserve 
particulate antigen conformation and structure that mimic functional interactions of the virus with 
cellular receptors. The vaccine also contains the single Al(OH)3 adjuvant. 
Al(OH)3 has been shown to enhance the antigenicity and immunogenicity of vaccines. The 
rationale for an Al(OH)3 adjuvanted IM NoV VLP vaccine is based on the low immune responses 
previously observed in healthy adults after oral administration of Norwalk Virus VLP vaccine [9, 
10, 11]. Aluminum adjuvant has a demonstrated safety profile of over 6 decades [12]. The 
aluminum concentration per dose was selected empirically from data that demonstrated that this 
amount of aluminum enhanced the antigenicity and immunogenicity of the NoV GI.1/GII.4 
bivalent VLP vaccine. 
Norovirus strains drift from year to year and both GI and GII genogroups cause disease in all age 
groups. Although numerous types are reported, the GII.4 type remains dominant and is currently 
responsible for the majority of outbreaks worldwide. The rationale for developing a bivalent 
vaccine is based on NoV epidemiology and the lack of natural protection between genogroups. In 
trial LV03-104, the first NoV bivalent VLP vaccine was given IM, and compared equally balanced 
(1:1) dosages of the GI.1 and GII.4 VLPs in adults. For each of the 4 vaccine dosages evaluated 
(5/5, 15/15, 50/50, and 150/150 µg of NoV VLPs), the seroresponse rates (percent of subjects with 
at least a 4-fold rise in antibody levels) and geometric mean fold rises (GMFRs) were lower for the 
GII.4 VLP than for the GI.1 VLP at equivalent antigen dosages. Likewise, similar post-vaccination 
immunogenicity data were observed in adults in trial LV03-105, the GII.4 challenge trial that 
evaluated a 50/50 µg balanced 1:1 VLP dosage of vaccine. Separately the factorial design trial 
NOR-107 was initiated in subjects ages 18 to 64, to evaluate multiple vaccine formulations 
containing different (balanced and unbalanced) ratios of the antigenic VLP components of the 


Norovirus GI.1/GII.4 Bivalent VLP Vaccine 
 
Trial No. NOR-202 
Page 48 of 107 
Protocol Version 4.0 
1 March 2016 
 
CONFIDENTIAL 
bivalent vaccine (GI.1/GII.4) with Al(OH)3 adjuvant both with and without MPL adjuvant. Prior 
safety and immunogenicity data for the NoV vaccine given by the IM route are available from 
approximately 1000 adult subjects, evaluated in five Takeda clinical trials (LV03-104, LV03-105, 
NOR-107, NOR-201, and NOR-210). The NoV vaccine evaluated in these trials either contained 
both Al(OH)3 plus monophosphoryl lipid A (MPL) adjuvants combined or the Al(OH)3 adjuvant 
alone. Trial NOR-107 conducted in adults aged 18-64 years, a Phase II dosage, adjuvant 
justification, safety, and immunogenicity trial, evaluated 11 vaccine formulations, and showed that 
the NoV VLP vaccine adjuvanted with aluminum as Al(OH)3 adjuvant was as immunogenic as the 
NoV VLP vaccine adjuvanted with Al(OH)3 and MPL combined. 
This trial NOR-202 in children aged 6 weeks to less than 9 years will evaluate the safety and 
immunogenicity of multiple formulations with different ratios of the antigenic VLP components of 
the bivalent vaccine. The formulations for NOR-202 are selected based on the initial and 
additional results obtained from the factorial design study NOR-107 in adults. Based on the 
additional NOR-107 results, the number of formulation arms is reduced from 8 in amendment N° 
1.0 of the original protocol to 4 in this amended protocol. 
The upper age cut-off for the NOR-202 trial was selected based on the assumption that the immune 
response in older children and adolescents aged 9 to <18 years is similar to the immune response 
observed in those aged 18 years and over. Therefore subjects aged 9 to ≥18 years, are not included 
in trial NOR-202. 
The primary goals of this clinical trial are therefore to evaluate the immunogenicity and safety of 
1 to 2 doses in children 6 months to less than 9 years of age and 2 to 3 doses in infants 6 weeks to 
less than 6 months of age with the IM NoV bivalent VLP vaccine using different dosages of the 
VLPs to obtain confirmation of dosage, and schedule in these age groups. In order to maintain the 
trial blind, a single injection of saline placebo will be administered as the final dose for the 1 dose 
group in Cohort 1 and for the 2 dose group in Cohort 2. 
Rationale for the Amendment N° 3: 
The primary purposes of this amendment are: 1) to enroll an additional 120 children (1 to < 4 
years; designated Group 2a), to assess the safety and immunogenicity of the recently manufactured 
NoV vaccine in a similar age group to Group 2; and 2) to perform the Day 57 interim analysis (IA) 
for Groups 1 and 2 of Cohort 1, who will complete Day 57 substantially earlier than Groups 2a and 
3. The Day 57 IA for Groups 2a and 3 combined will be performed at a later time. The Day 140 IA 
for Group 4 does not change. 
The trial vaccine, originally manufactured for trial NOR-202, was not available for clinical use 
after 30 November 2015, due to expiration at 36 months after manufacture. Several factors 
affected the enrolment timeline in trial NOR-202: (1) Takeda’s decision to not initiate enrollment 
until after agreement from the Pediatric Committee of the EMA on the Pediatric Investigational 
Plan (PIP) of the NoV vaccine; (2) and the regulatory, logistical, and operational study 
requirements for implementation of the two prior protocol amendments. 


Norovirus GI.1/GII.4 Bivalent VLP Vaccine 
 
Trial No. NOR-202 
Page 49 of 107 
Protocol Version 4.0 
1 March 2016 
 
CONFIDENTIAL 
Per protocol, all children in Groups 1 (4 to < 9 years) and 2 (1 to < 4 years) were enrolled, 
randomized and received one of the four NoV vaccine formulations as a one or two dose trial 
vaccine regimen within the vaccine expiry dating period. Notably, children in Groups 3 (1 or 2 
doses) and 4 (2 or 3 doses) were not enrolled due to expiration of the trial vaccine. Takeda has 
paused this study until additional trial vaccine is manufactured and released for clinical use. 
Takeda has recently produced VLPs at a different manufacturer with increased capacity for 
manufacturing on a larger scale. To date, the NoV vaccine with these recently produced VLPs has 
been manufactured and released for clinical use in two studies in adults; trial NOR-204 in 350 
adults aged 18 to > 85 years and trial NOR-211 in ~ 2800 adults aged 18 to 49 years. 
To understand the safety and immunogenicity of the recently manufactured vaccine in a similar 
age group to Group 2, an additional 120 children designated Group 2a, will be enrolled in trial 
NOR-202, prior to enrolling children in Groups 3 and 4. Specifically, the safety data from Group 
2a will be provided to the Data Monitoring Committee (DMC) for review prior to enrollment of 
the children in Groups 3 and 4. 
Although the VLP manufacturer has changed, the vaccine dosages and regimens with the four 
vaccine formulations evaluated in Groups 1 and 2 will also be evaluated in children in Groups 2a, 
3, and 4. However, only children in Groups 2a, 3, and 4, will receive the recently manufactured 
vaccine. 
Enrollment in Group 2a will be initiated after all four vaccine formulations of the recently 
manufactured vaccine are released for clinical use. 


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Norovirus GI.1/GII.4 Bivalent VLP Vaccine 
 
Trial No. NOR-202 
Page 52 of 107 
Protocol Version 4.0 
1 March 2016 
 
CONFIDENTIAL 
• Body temperature on the day of vaccination (approximately 30 minutes and 6 hours later); then 
daily through Day 7 after each vaccination. 
• Percentage of subjects with unsolicited AEs for 28 days after each vaccination. 
• Percentage of subjects with SAEs throughout the trial. 
5.2.2 
Secondary Endpoints 
Immunogenicity 
Pan-Ig ELISA 
• Seroresponse rate in serum anti-NoV GI.1 VLP antibody titers as measured by Pan-Ig ELISA 
on Day 57 (Cohort 1) and Day 140 (Cohort 2). 
• Seroresponse rate in serum anti-NoV GII.4 VLP antibody titers as measured by Pan-Ig ELISA 
on Day 57 (Cohort 1) and Day 140 (Cohort 2). 
• GMT of anti-NoV GI.1 VLP antibody titers as measured by Pan-Ig ELISA on Day 57 
(Cohort 1) and Day 140 (Cohort 2). 
• GMT of anti-NoV GII.4 VLP antibody titers as measured by Pan-Ig ELISA on Day 57 
(Cohort 1) and Day 140 (Cohort 2). 
• GMFR of anti-NoV GI.1 VLP antibody titers as measured by Pan-Ig ELISA on Day 57 
(Cohort 1) and Day 140 (Cohort 2). 
• GMFR of anti-NoV GII.4 VLP antibody titers as measured by Pan-Ig ELISA on Day 57 
(Cohort 1) and Day 140 (Cohort 2). 
HBGA Binding Assay 
• Seroresponse rate in serum anti-NoV GI.1 VLP and GII.4 VLP antibody titers as measured by 
HBGA binding assay on Day 57 (Cohort 1) and Day 140 (Cohort 2). 
• Seroresponse rate in serum anti-NoV GI.1 VLP antibody titers as measured by HBGA binding 
assay on Day 57 (Cohort 1) and Day 140 (Cohort 2). 
• Seroresponse rate in serum anti-NoV GII.4 VLP antibody titers as measured by HBGA 
binding assay on Day 57 (Cohort 1) and Day 140 (Cohort 2). 
• BT50 of anti-NoV GI.1 VLP antibody titers as measured by HBGA binding assay on Day 57 
(Cohort 1) and Day 140 (Cohort 2). 
• BT50 of anti-NoV GII.4 VLP antibody titers as measured by HBGA binding assay on Day 57 
(Cohort 1) and Day 140 (Cohort 2). 
• GMFR of anti-NoV GI.1 VLP antibody titers as measured by HBGA binding assay on Day 57 
(Cohort 1) and Day 140 (Cohort 2). 


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Norovirus GI.1/GII.4 Bivalent VLP Vaccine 
 
Trial No. NOR-202 
Page 55 of 107 
Protocol Version 4.0 
1 March 2016 
 
CONFIDENTIAL 
6.0 
TRIAL DESIGN AND DESCRIPTION 
6.1 
Trial Design 
This is a Phase II, randomized, double-blind, multi-site, dosage, safety and immunogenicity trial 
of the IM NoV bivalent VLP vaccine combined with Al(OH)3 adjuvant. Subjects randomized into 
the trial will be placed into 1 of 2 cohorts based on age. A schematic of the trial design is included 
as Figure 6-a. 
Figure 6-a 
Schematic of Trial Design 
 
A total of 840 healthy subjects will be enrolled within two cohorts and randomized to vaccine 
regimen as follows: 
• Cohort 1, N= 480, consisting of Group 1: aged 4 to less than 9 years; Group 2: aged 1 to less 
than 4 years; Group 2a: aged 1 to less than 4 years; Group 3: aged 6 months to less than 1 year 
(N= 120 each): subjects will be randomized with equal probabilities to 1 of the 8 unique 
combinations of formulation arms and dose groups (ie, 4 formulation arms and 1 or 2 doses). 
The additional 120 children, designated as Group 2a, are being included to evaluate the 
840 subjects 
aged  
6 weeks to < 9 years
Cohort 1
Subjects aged 
6 months to < 9 
years
N= 480
Group 1
4 to <9 years
120  subjects
One Dose
Two Doses
Group 2
1 to < 4 years
120 subjects
One Dose
Two Doses
Group 2a*
1 to < 4 years
120 subjects
One Dose
Two Doses
Cohort 2*
(Group 4)
Subjects aged
6 weeks to <6 
months
N= 360
Two Doses
Three Doses
Group 3*
6 months to < 1 
year
120 subjects
One Dose
Two Doses
* Recently manufactured clinical trial material lots


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recently manufactured NoV bivalent VLP vaccine formulations prior to enrolling children in 
Groups 3 and 4. Each of the combinations in Groups 1, 2, 2a, and 3 will consist of 
approximately 15 subjects per group. Thus Cohort 1 consists of 480 subjects in Groups 1, 2, 2a, 
and 3 combined. 
• Cohort 2 (Group 4: aged 6 weeks to less than 6 months): 360 subjects will be randomized to 
receive the recently manufactured NoV bivalent VLP vaccine with equal probabilities to 1 of 
the 8 unique combinations of formulation arms and dose groups (ie, 4 formulation arms and 2 
or 3 doses). Each of the combinations will consist of approximately 45 subjects. 
Primary evaluation of the trial objectives is planned at 28 days after the final (second) vaccination 
in subjects aged 6 months to less than 9 years (Cohort 1) and 28 days after the final (third) 
vaccination in subjects aged 6 weeks to less than 6 months (Cohort 2). In order to maintain the 
blind and to have the same trial time points and dosing regimens, subjects in Cohort 1 (Groups 1, 2, 
2a and 3) who are randomized to the 1 dose group will receive a dose of the NoV bivalent VLP 
vaccine on Day 1 followed by a placebo injection of saline 28 days later (Day 29) and subjects in 
the 2 dose group will receive 2 doses of NoV VLP vaccine approximately 28 days apart (Days 1 
and 29). Likewise, subjects in Cohort 2 (Group 4) who are randomized to the 2 dose group will 
receive 2 doses of NoV bivalent VLP vaccine on Days 1 and 56, followed by a placebo injection of 
saline approximately 56 days later (Day 112), and subjects in the 3 dose group will receive 3 doses 
of NoV VLP vaccine approximately 56 days apart (Days 1, 56, and 112), independent of the infant 
routine vaccinations by approximately 28 days. This is a double-blind trial; investigators, subjects, 
data collectors, and data evaluators are blinded to the specific formulation arms and the dosing 
groups. 
This study plans to assess the immunogenicity and safety of the NoV bivalent VLP vaccine in 
children when given independently of the routine pediatric vaccines but, importantly, never to 
interfere with routine vaccine administration of children in each of the countries planned for 
evaluation. National pediatric vaccine regimens in children 6 weeks to 6 months of age vary by 
country (eg, routine pediatric vaccines may be given at 2, 3, and 4 months of age; 2, 4, and 
6 months of age; or at 3, 5, and 12 months of age). 
Subjects 6 months to less than 9 years of age (inclusive, Cohort 1) will receive either 1 or 2 doses 
by IM injection, at least 28 days apart (Days 1 and 29), ), in 4 groups in 3 age ranges (Group 1: 
aged 4 to less than 9 years; Group 2 and Group 2a: aged 1 to less than 4 years; and Group 3: aged 6 
months to less than 1 year). Infants 6 weeks to less than 6 months of age (Group 4/Cohort 2) will 
receive 2 or 3 doses by IM injection given approximately 56 days apart (Days 1, 56, and 112). 
Routine child and infant vaccinations will be given on schedule per the national guidelines 
approximately 28 days apart from the investigational vaccine in each age group. 
An independent program level Data Monitoring Committee (DMC) has been established to assess 
safety data on an ongoing basis. The DMC will also have study level responsibilities to review data 
and make recommendations about the sequential enrollment of various groups and formulation 
arms in this study (see Section 11.1.1). 
Interim analyses will be performed after the primary safety and immunogenicity data are available 


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(ie, Day 57 for Cohort 1 and Day 140 for Cohort 2) (primary analysis time point). The Day 57 IA 
for Cohort 1 will be provided initially for Groups 1 and 2, who will complete Day 57 substantially 
earlier than Groups 2a and 3. The Day 57 IA for Groups 2a and 3 combined will be provided at a 
later time. Thus, the Day 57 IA will be conducted in two parts to be followed by the Day 140 IA in 
Group 4. All interim analyses will be performed by a separate set of unblinded statisticians and 
programmers at the contract research organization (CRO), Quintiles, who will have access to 
individual treatment assignments but will not otherwise be involved in study conduct. The rest of 
the personnel involved in the conduct of the study, including those at Takeda, Quintiles, and the 
study sites, will remain blinded to the individual subject data (including treatment assignments) 
until unblinding after database lock (Day 210 for Cohort 1 and Day 293 for Cohort 2). More details 
on the analyses will be provided in the statistical analysis plan (SAP). 
Investigational Vaccine: 
The investigational vaccine for each arm contains 500 µg alum. 
• Arm A: GI.1/GII.4 (15 µg/15 µg) 
• Arm B: GI.1/GII.4 (15 µg/50 µg) 
• Arm C: GI.1/GII.4 (50 µg/50 µg) 
• Arm D: GI.1/GII.4 (50 µg/150 µg) 
Placebo Control: 
Saline will be administered as a single control injection (as the final dose) in order to maintain the 
trial blind for the 1 dose groups in Groups 1, 2, 2a and 3 (Cohort 1) and for the 2 dose group in 
Group 4 (Cohort 2). Subjects in the 1 dose groups in Cohort 1 receive NoV vaccine on Day 1 and a 
saline placebo injection on Day 29. Subjects in the 2 dose group in Cohort 2 receive NoV vaccine 
on Days 1 and 56 and a saline placebo injection on Day 112. 
Visit Schedule 
Clinical trial visits will be performed on Days 1, 8, 29, 36, 57, and 210 for Cohort 1 and Days 1, 8, 
29, 56, 63, 84, 112, 119, 140, and 293 for Cohort 2. Telephone contacts will be performed on 
Days 3, 32, and 134 for Cohort 1 and Days 3, 59, 115, 200 and 260 for Cohort 2. 
Duration of the Trial 
Subjects will be followed for SAEs for 180 days after the last trial dose. Safety follow-up for other 
unsolicited AEs, and concomitant medications will be for 28 days following each trial dose. 
Schedules of procedures by cohort are listed in Table 2-a and Table 2-c. 
6.2 
Justification for Trial Design, Dose, and Endpoints 
The trial design is consistent with the evaluation of dose finding studies for vaccines. The 
formulations for NOR-202 are selected based on the initial and additional results obtained from the 
factorial design study NOR-107 in adults. Based on additional NOR-107 results, the number of 


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formulation arms has been further reduced from 8 in Amendment 1 of the protocol to 4 in this 
amended protocol. The descriptive design of trial NOR-202 in early childhood is justified to 
initially define the dose and dosing regimen for young children at high risk of norovirus disease. 
An additional group designated Group 2a of 120 children aged 1 to less than 4 years, has been 
added within Cohort 1, to allow evaluation of the recently manufactured vaccine prior to dosing 
younger children in Groups 3 and 4. Safety in Group 2a will be reviewed by the DMC, prior to 
enrolling in Groups 3 and 4. Immunogenicity will be reviewed as available. 
The collection of solicited symptoms and AEs following vaccination are consistent with vaccine 
evaluation studies. 
For this trial, the collection of blood at the given time points, the selection of assays for the 
assessment of antibody response to vaccination and the selected formulations are based on 
experience from previous studies with the investigational vaccine and will assist in the 
determination of the antigen dosage, the need for multiple doses of investigational vaccine in the 
non-adjuvanted arms, and dosage of adjuvant if needed. 
Please refer to the Investigator’s Brochure [31] for further details. 
A single saline placebo injection will be administered as a placebo control (as a final dose on 
Day 29) in order to maintain the trial blind in subjects in the 1 dose groups in Groups 1, 2, 2a and 3, 
(Cohort 1) and in the 2 dose group in Group 4 (as a final dose on Day 112 in Cohort 2). 
6.3 
Duration of Subject’s Expected Participation in the Entire Trial 
Expected duration of trial participation for each subject is up to 210 days (Cohort 1) and 293 days 
(Cohort 2). 
6.4 
Premature Termination or Suspension of Trial or Investigational Site 
6.4.1 
Criteria for Premature Termination or Suspension of the Trial 
The trial will be completed as planned unless 1 or more of the following criteria are satisfied that 
require temporary suspension or early termination of the trial. 
• New information or other evaluation regarding the safety or efficacy of the investigational 
vaccine that indicates a change in the known risk/benefit profile, such that the risk/benefit is no 
longer acceptable for subjects participating in the trial. 
• The DMC recommends that the trial should be suspended or terminated. 
• Significant violation of Good Clinical Practice (GCP) that compromises the ability to achieve 
the primary trial objectives or compromises subject safety. 


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6.4.2 
Criteria for Premature Termination or Suspension of Investigational Sites 
A trial site may be terminated prematurely or suspended if the site (including the investigator) is 
found in significant violation of GCP, protocol, or contractual agreement, is unable to ensure 
adequate performance of the trial, or as otherwise permitted by the contractual agreement. 
6.4.3 
Procedures for Premature Termination or Suspension of the Trial or the 
Participation of Investigational Site(s) 
In the event that the sponsor, an institutional review board (IRB)/independent ethics committee 
(IEC) or regulatory authority elects to terminate or suspend the trial or the participation of an 
investigational site, a trial-specific procedure for early termination or suspension will be provided 
by the sponsor; the procedure will be followed by applicable investigational sites during the course 
of termination or trial suspension. 


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7.0 
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS 
All entry criteria, including test results, need to be confirmed prior to randomization. 
7.1 
Inclusion Criteria 
Subject eligibility is determined according to the following criteria: 
1. Male and female subjects aged between 6 weeks and less than 9 years at the time of 
enrollment. 
2. Subjects who are in good health at the time of entry into the trial as determined by medical 
history, physical examination (including vital signs) and clinical judgment of the 
investigator.  
3. The subject’s legally authorized representative (LAR) signs and dates a written, informed 
consent form (ICF) and any required privacy authorization prior to the initiation of any trial 
procedures, after the nature of the trial has been explained according to local regulatory 
requirements (Appendix C). An assent will also be obtained according to age appropriate 
country-specific regulations. 
4. Individuals who can comply with trial procedures and are available for the duration of the 
trial. 
7.2 
Exclusion Criteria 
Any subject who meets any of the following criteria will not qualify for entry into the trial: 
1. Subjects with a clinically significant active infection (as assessed by the investigator) or 
body temperature 38.0°C (100.4°F) or higher within 3 days of the intended date of 
vaccination. 
2. Subjects who have received antipyretic/analgesic medications within 24 hours prior to the 
intended vaccine administration. 
3. Known hypersensitivity or allergy to investigational vaccine (including excipients of the 
investigational vaccines as summarized in protocol Section 8.1). 
4. Subjects with behavioral or cognitive impairment or psychiatric disease that, in the opinion 
of the investigator, may interfere with the subject's ability to participate in the trial. 
5. Subjects with a history of any progressive or severe neurologic disorder, seizure disorder, 
or neuroinflammatory disease (eg, Guillain-Barré syndrome). 
6. Known or suspected impairment/alteration of immune function, including the following: 
a. Children <18 months of age with history of repeated episodes of acute otitis media 
(AOM) [32] in the first 6 months of life (AOM defined as a bulging tympanic 
membrane) and not to be confused with otitis media with effusion (OME). 


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b. Chronic use of oral steroids (equivalent to 20 mg/day prednisone for ≥12 
weeks/≥2 mg/kg body weight/day for ≥2 weeks) within 60 days prior to Day 1 (use 
of inhaled, intranasal, or topical corticosteroids is allowed). 
c. Receipt of parenteral steroids (equivalent to 20 mg/day prednisone ≥12 
weeks/≥2 mg/kg body weight/day for ≥2 weeks) within 60 days 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. Receipt of immunosuppressive therapy within 6 months prior to Day 1. 
g. Human immunodeficiency virus (HIV) infection or HIV-related disease. 
h. Chronic Hepatitis B or C infection. 
i. Heritable immunodeficiency. 
7. Abnormalities of splenic or thymic function. 
8. Subjects with a known bleeding diathesis or any condition that may be associated with a 
prolonged bleeding time. 
9. Subjects with any serious chronic or progressive disease according to judgment of the 
investigator (eg, neoplasm, insulin dependent diabetes, cardiac, renal, or hepatic disease). 
10. Subjects participating in any clinical trial with another investigational product 30 days 
prior to first trial visit or intent to participate in another clinical trial at any time during the 
conduct of this trial. 
11. Subjects who received any other vaccines within 14 days (for inactivated vaccines) or 
28 days (for live vaccines) prior to enrollment in this trial. 
12. Subjects who are first degree relatives of individuals involved in trial conduct. 
13. Subjects with a history of autoimmune disease. 
14. There may be instances when individuals meet all entry criteria except one that relates to 
transient clinical circumstances (eg, body temperature elevation or recent use of excluded 
medication or vaccine). Under these circumstances, a subject may be considered eligible 
for trial enrollment if the appropriate window for delay has passed, inclusion/exclusion 
criteria have been rechecked, and if the subject is confirmed to be eligible. 
7.3 
Criteria for Delay of Vaccination and Blood Sampling 
After enrollment, subjects may encounter clinical circumstances that warrant a delay in subsequent 
trial vaccination. These situations are listed below: 


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• Subjects with a body temperature 38.0°C (100.4°F) or higher within 3 days of intended trial 
vaccination. 
• Subjects who have received antipyretics/analgesic medications within 24 hours prior to the 
intended vaccine administration. 
• Subjects who have received blood, blood products, and/or plasma derivatives or any parenteral 
immunoglobulin preparation in the past 3 months (prior to initial vaccination). 
If the subject cannot be randomized and vaccinated on Day 1 due to a temporary contraindication 
and must return at a later time, the same identification number (screening number) should be kept. 
If the subject randomization visit is re-scheduled for more than 15 days after the screening, then a 
new ICF should be obtained. 
For subsequent vaccination visits, it is strongly recommended to schedule them as early in the visit 
window as possible, in case these visits need to be re-scheduled due to a vaccination and/or blood 
sampling temporary contraindication. 
There are also circumstances under which receipt of further vaccines is a contraindication in this 
trial. These circumstances include anaphylaxis or severe hypersensitivity reactions following the 
initial vaccination. If these reactions occur, the subject must not receive additional vaccinations, 
but is encouraged to continue in trial participation for safety reasons. 
7.4 
Criteria for Discontinuation or Withdrawal of a Subject 
The primary reason for discontinuation or withdrawal of the subject from the trial should be 
recorded in the electronic case report form (eCRF) using the following categories. For screen 
failure subjects, refer to Section 9.1.9. 
1. Protocol violation: The subject may remain in the trial unless continuation in the trial 
jeopardizes the subject’s health, safety, or rights. 
2. Adverse event: The subject has experienced an AE that requires early termination because 
continued participation imposes an unacceptable risk to the subject’s health or the subject (or 
subject’s LAR) is unwilling to continue because of the AE. For safety reasons, the subject 
should be followed-up after withdrawal. 
3. Lost to follow-up: The subject did not return to the clinic and attempts to contact the subject’s 
LAR were unsuccessful. 
4. Withdrawal by subject: The subject (or subject’s LAR) wishes to withdraw from the trial. The 
reason for withdrawal, if provided, should be recorded in the eCRF. 
Note: All attempts should be made to determine the underlying reason for the withdrawal 
and, where possible, the primary underlying reason should be recorded (ie, withdrawal due 
to an AE should not be recorded in the “voluntary withdrawal” category). 
5. Study terminated by sponsor. 
6. Other. 


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Note: The specific reasons should be recorded in the “specify” field of the eCRF. 
7.5 
Procedures for Discontinuation or Withdrawal of a Subject 
The investigator may 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 (or 
subject’s LAR) 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 scheduled for the 
final visit. Discontinued or withdrawn subjects will not be replaced. 


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8.0 
CLINICAL TRIAL MATERIAL MANAGEMENT 
This section contains information regarding all vaccines and materials provided directly by the 
sponsor, and/or sourced by other means, that are required by the trial protocol, including important 
sections describing the management of clinical trial material. 
8.1 
Investigational Vaccine(s) and Materials 
8.1.1 
Dosage Form, Manufacturing, Packaging, and Labeling 
This trial will involve the use of the following vaccines for IM administration. Althea 
Technologies, San Diego (CA), United States, manufactures the investigational vaccine. 
8.1.1.1 
Sponsor-Supplied Vaccines 
All vaccines described in this protocol will be supplied by the sponsor. The prefilled vials will be 
supplied in tamper-evident, single dose cartons. Some kits may also contain diluent vial(s). Each 
vial and carton will contain a label that includes pertinent trial information and caution statements. 
The label text will either be in English or the specific country language, depending on local 
requirements. The vaccine to be used will be identifiable by a unique identification number and 
managed by the interactive web response system (IWRS). 
• Investigational Vaccines 
The investigational vaccine is presented in a labeled, single-use, 2 mL glass vial with a 
FluroTec-coated butyl rubber stopper and flip-top aluminum overseal that contains a single 
0.5 mL liquid dose for IM injection. Each vial contains additional volume (fill specification, 
0.9±0.05 mL) to facilitate withdrawal of 0.5 mL. Each 0.5 mL dose delivers either 15 or 50 μg of 
GI.1 NV-VLP; 15, 50, or 150 μg of GII.4 C-VLP; all of which are adsorbed to Al(OH)3 adjuvant. 
The doses should be prepared at the time of administration by the unblinded administrator (or 
pharmacist). Before mixing, the vial contents may appear biphasic with a clear upper layer and a 
white precipitate on the bottom of the vial. After the vial contents have been mixed, a uniformly 
turbid suspension should be observed. 
The investigational vaccine also contains the following excipients (per 0.5 mL dose): 
approximately 4.38 mg sodium chloride (150 mM), approximately 1.55 mg L-histidine (20 mM), 
HCl to adjust pH, 1.83 mg sucrose and water for injection. The investigational vaccine does not 
contain a preservative. Investigational vaccine for each of the trial arms (A, B, C and D) contains 
500 µg Al(OH)3 adjuvant. 
• Investigational vaccine for Arm A: GI.1/GII.4 (15 µg/15 µg) 
• Investigational vaccine for Arm B: GI.1/GII.4 (15 µg/50 µg) 
• Investigational vaccine for Arm C: GI.1/GII.4 (50 µg/50 µg) 
• Investigational vaccine for Arm D GI.1/GII.4 (50 µg/150 µg) 
• Placebo Control: Saline (0.9% sodium chloride for injection, USP); 0.5 mL dose; 
administered in same manner as investigational vaccine (Section 8.2). 


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8.1.2 
Storage 
Vaccines will be shipped in refrigerated containers. From receipt and prior to use, vaccines must 
be protected from light and stored at 2°C to 8°C in a refrigerator with controlled access available 
only to authorized trial personnel. The vaccines must not be frozen. Vaccines are single use only. 
All clinical trial material must be kept in an appropriate, limited-access, secure place until it is used 
or returned to the sponsor or designee for destruction. All sponsor-supplied vaccines must be 
stored under the conditions specified on the label, and remain in the original container until 
administered. A daily temperature log of the vaccine storage area must be maintained every 
working day. 
Temperature deviations must be reported to the sponsor; see the Pharmacy Manual for 
instructions. 
8.1.3 
Dose and Regimen 
The formulations for the sponsor-supplied investigational vaccine are presented in Table 8-a. 
Presented formulations are an approximation (within a defined specification) of the respective 
antigen/adjuvant concentrations. The number of subjects in each dose group will be equally 
distributed across the formulation arms. 
Table 8-a 
Sponsor-Supplied Investigational Vaccine 
 
VLP 
15 µg/15 µg 
VLP 
15 µg/50 µg 
VLP 
50 µg/50 µg 
VLP 
50 µg/150 µg 
GI.1/GII.4 [and 500 µg of Al(OH)3] 
Arm A 
Arm B 
Arm C 
Arm D 
8.2 
Investigational Vaccine Assignment and Dispensing Procedures 
The investigator or investigator’s designee will access the IWRS on Day 1 to obtain the subject 
number. 
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 vaccine identification number of the kit to be administered will be assigned by the IWRS. 
The vaccines will be administered IM in the anterolateral thigh for children aged ≤12 months; for 
children aged >12 months, the vaccines will be administered in the anterolateral thigh or the 
deltoid muscle of the subject’s arm per national guidelines. Expired vaccines must not be 
administered. The vaccine and placebo are visually distinguishable and the blind must be 
maintained. The vaccination will be prepared and administered by the unblinded designee 
according to the instructions in the Pharmacy Manual. Cohort 1 will receive either 1 or 2 doses at 
least 28 days apart and Cohort 2 will receive 2 or 3 doses approximately 56 days apart. In order to 


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maintain the blind and to have the same trial time points and dosing regimens, subjects in Cohort 1 
(Groups 1, 2, 2a and 3) who are randomized to the 1 dose group will receive a dose of the NoV 
bivalent VLP vaccine on Day 1 followed by a placebo injection of saline 28 days later (Day 29). 
Subjects in the 2 dose group will receive 2 doses of NoV VLP vaccine approximately 28 days 
apart (Days 1 and 29). Likewise, subjects in Cohort 2 (Group 4) who are randomized to the 2 dose 
group will receive 2 doses of NoV bivalent VLP vaccine on Days 1 and 56, followed by a placebo 
injection of saline 56 days later (Day 112), and subjects in the 3 dose group will receive 3 doses of 
NoV VLP vaccine approximately 56 days apart (Days 1, 56, and 112), independent of the infant 
routine vaccinations by at least 28 days. 
The investigator or designee will be responsible for overseeing the administration of vaccine to 
subjects enrolled in the trial according to the procedures stipulated in this trial protocol. All 
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 sponsor-supplied vaccine is lost or damaged, the site can request a replacement from the IWRS 
(refer to IWRS manual supplied separately). At subsequent vaccine-dispensing visits, the 
investigator or designee will again contact the IWRS to request additional investigational vaccine 
for a subject. 
8.2.1 
Precautions to be Observed in Administering the Investigational Vaccine 
Prior to vaccination, subjects must be determined to be eligible for trial vaccination, and it must be 
clinically appropriate in the judgment of the investigator to vaccinate. Eligibility for vaccination 
prior to first vaccine administration is determined by evaluating the entry criteria outlined in this 
protocol (Sections 7.1 and 7.2). 
Eligibility for subsequent trial vaccination is determined by following the criteria outlined in 
Sections 7.1, 7.2, and 7.3. 
Investigational vaccines should not be administered to subjects with known hypersensitivity to any 
component of the vaccines. 
Standard immunization practices are to be observed, and care should be taken to administer the 
injection IM. Before administering the vaccine, the vaccination site is to be disinfected with a skin 
disinfectant (eg, 70% alcohol). Allow the skin to dry. DO NOT inject intravascularly. 
As with all injectable vaccines, trained medical personnel and appropriate medical treatment 
should be readily available in case of anaphylactic reactions following vaccination. For example, 
epinephrine 1:1000, diphenhydramine, and/or other medications for treating anaphylaxis should 
be available. 
8.3 
Randomization Code Creation and Storage 
Randomization personnel of the sponsor or designee will generate the randomization schedule. 
Randomization information will be stored in a secured area, accessible only by authorized 
personnel. 


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Randomization will be stratified by country and group: Group 1 (age 4 to less than 9 years); 
Groups 2 and 2a (age 1 to less than 4 years); Group 3 (age 6 months to less than 12 months); and 
Group 4 (age 6 weeks to less than 6 months). On Day 1, qualified subjects will be randomized 
using the IWRS to a formulation arm and number of doses depending on their age at the time of 
enrollment. 
Randomization into groups and formulation arms will be restricted during various stages of the 
study as described previously in the protocol (section 6.1) based on DMC review of data from 
certain groups/arms prior to opening enrollment to other groups (see Section 11.1.1). 
8.4 
Investigational Vaccine Blind Maintenance 
This is a double-blind trial; investigators, subjects, data collectors (eg, investigator), and data 
evaluators (eg, trial statisticians) are blinded to the specific formulation arm (ie, GI.1/GII.4 VLP). 
The investigational vaccine blind will be maintained by the unblinded designee. 
8.5 
Unblinding Procedure 
The investigational vaccine blind shall not be broken by the investigator unless information 
concerning the investigational vaccine is necessary for the medical treatment of the subject. In the 
event of a medical emergency, if possible, the medical monitor should be contacted before the 
investigational vaccine blind is broken to discuss the need for unblinding. 
For unblinding a subject, the investigational vaccine blind can be obtained by the investigator by 
accessing the IWRS. 
The sponsor’s Pharmacovigilance Department and their designee must be notified as soon as 
possible if the investigational vaccine blind is broken by the investigator for the purposes of a 
medical emergency, and if appropriate a completed SAE form must be sent within 24 hours. The 
date, time, and reason the blind was broken must be recorded in the source document and the same 
information (except the time) must be recorded on the eCRF. 
In the event of accidental unblinding of the investigational vaccine, the sponsor shall be 
immediately contacted for further decision about the subject’s eligibility to continue in the trial. 
Regardless of the sponsor’s decision, the subject should be followed for safety through Day 210 
(Cohort 1) or Day 293 (Cohort 2). 
8.6 
Accountability and Destruction of Sponsor-Supplied Vaccine(s) 
Vaccine supplies will be counted and reconciled at the site before being returned to the sponsor or 
designee as noted below. Sites will maintain source documents in addition to entering data in the 
IWRS. 
The investigator or designee must ensure that the sponsor-supplied vaccine is used in accordance 
with the approved protocol and is administered only to subjects randomized into the trial. To 
document appropriate use of sponsor-supplied vaccine, the investigator must maintain records of 


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all sponsor-supplied vaccine delivery to the site, site inventory, dispensation, and use by each 
subject, and return to the sponsor or designee as noted below. 
Upon receipt of sponsor-supplied vaccine, the investigator or designee must verify the contents of 
the shipments against the packing list. The verifier should ensure that the quantity is correct, the 
medication is received within the labeled storage conditions, and the medication is in good 
condition. If the quantity and conditions are acceptable, the investigator or designee will 
acknowledge receipt of the shipment by recording it in the IWRS. 
If there are any discrepancies between the packing list and the actual product received, the sponsor 
must be contacted to resolve the issue. The packing list should be filed in the investigator’s 
essential document file. 
The investigator must maintain 100% accountability for all sponsor-supplied vaccines received 
and administered during his or her entire participation in the trial. Proper vaccine accountability 
includes, but is not limited to the following: 
• Verifying that actual inventory matches documented inventory. 
• Verifying that the log is completed for the vaccine ID number used to prepare each dose. 
• Verifying that all containers used are documented accurately on the log. 
• Verifying that required fields are completed accurately and legibly. 
If any dispensing errors or discrepancies are discovered, the sponsor must be notified immediately. 
The investigator must record the current inventory of all sponsor-supplied vaccines on a 
sponsor-approved vaccine accountability log. The following information will be recorded at a 
minimum: protocol number and title, name of investigator, site identifier and number, description 
of sponsor-supplied vaccines, expiry date, and amount. The IWRS will include all required 
information as a separate entry for each subject who is administered sponsor-supplied vaccine.  
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 of investigational vaccine. 
Vaccine accountability documentation will be reviewed by the unblinded monitor during clinical 
monitoring visits. 


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9.0 
TRIAL PLAN  
9.1 
Trial Procedures 
The following sections describe the trial procedures and data to be collected. For each procedure, 
subjects are to be assessed by the same investigator or site personnel whenever possible. The 
Schedule of Trial Procedures is located in Section 2.1. 
9.1.1 
Informed Consent Procedure 
The requirements of the informed consent are described in Section 15.2. 
Informed consent must be obtained prior to the subject entering into the trial, and before any 
protocol-directed procedures are performed. An assent will also be obtained according to age 
appropriate country-specific regulations. 
After informed consent is obtained, a unique identification number (screening number) will be 
assigned to each subject by the IWRS. If all eligibility criteria are fulfilled, this will become the 
definitive subject number to be used throughout the trial. Subject numbers assigned to subjects 
who fail screening should not be reused (Section 9.1.9). 
9.1.2 
Demographics, Medical History and Medication History Procedure 
Demographic information to be obtained will include age, sex, race as described by the subject or 
subject’s legal guardian. 
Medical history will also be collected, including but not limited to any medical history that may be 
relevant to subject eligibility for trial participation such as prior vaccinations, concomitant 
medications, and previous and ongoing illnesses or injuries. Relevant medical history can also 
include any medical history that contributes to the understanding of an AE that occurs during trial 
participation, if it represents an exacerbation of an underlying disease/pre-existing problem. 
Adverse medical occurrences that occur after the ICF and assent form (where applicable) have 
been signed, but before administration of the vaccine, will be documented in the Medical History 
eCRF. 
All prescription medications, vaccines and blood products taken or received by the subjects within 
3 months prior to the start of the trial are to be recorded on the Prior and Concomitant Medications 
eCRF. The use of antipyretics and/or analgesic medications within 24 hours prior to vaccination 
must be identified and the reason for their use (prophylaxis versus treatment) must be described in 
the source documents or the eCRF. Trial vaccination should be delayed if subjects have used 
antipyretics/analgesic medications within 24 hours prior to vaccine administration. 
Medications taken for prophylaxis are those intended to prevent the onset of AEs following 
vaccination. Medications taken for treatment are intended to reduce or eliminate the presence of 
symptoms that are present. 
Assess and record concomitant therapy (prescription medications ONLY) and vaccine history 
from 3 months prior to Day 1 in the subject’s source document. 


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Prohibited Therapies (see also Section 7.2): 
• Parenteral immunoglobulin preparation, blood products, and/or plasma derivatives 
administered within 3 months of the first vaccination. 
• Immunosuppressive therapy within 6 months or systemic (eg, oral or parenteral) corticosteroid 
treatment within 60 days prior to vaccine administration or planned during the trial period. 
• Administration of other vaccines within 14 days (for inactivated vaccines) or 28 days (for live 
vaccines) prior to enrollment in this trial. 
These data must be written in the source documents. 
Medical history (including corresponding medication) to be obtained will include any significant 
conditions or diseases that have disappeared or resolved at or prior to signing of informed consent. 
9.1.3 
Documentation of Trial Entrance/Randomization 
Only subjects whose legal representative(s) have signed the ICF and, where required, have signed 
assent, meet all of the inclusion criteria and none of the exclusion criteria are eligible for 
enrollment/randomization into the vaccination phase. The list of randomization assignments is 
produced by IWRS. 
If the subject is found to be not eligible for randomization/trial phase, the investigator should 
record the primary reason for failure on the screening log. 
9.1.4 
Physical Examination Procedure 
Physical examinations must be performed by a qualified health professional in accordance with 
local regulations and licensing requirements designated within the Site Responsibility Delegation 
Log. A complete physical exam will be performed on Day 1. A detailed physical examination 
includes, but is not limited to: auscultation of heart and lungs, palpation of the abdomen, 
inspection of extremities (including skin over intended vaccination sites), and a check of general 
appearance. Additional physical examination procedures may be performed if indicated by review 
of the subject’s medical history. The findings will be documented in the subject’s source 
document. 
Physical examinations (type) will be performed at clinic visits on Day 1 (complete) and Day 29 
(brief) for Cohort 1 and Day 1 (complete), Day 56 (brief), and Day 112 (brief) for Cohort 2. 
Subjects may undergo a brief symptom-directed physical examination at any other clinic visit. 
9.1.5 
Vital Signs 
During the physical examination, a subject should have their vital signs measured. These may 
include heart rate, body temperature, height, and weight. Refer to the Procedures Manual. 


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CONFIDENTIAL 
9.1.6 
Immunogenicity Assessments 
Subjects in Cohort 1 in all vaccine arms will undergo blood sampling for serological 
immunogenicity testing on Day 1 (prior to the first vaccination), Day 29 (prior to the second 
vaccination), Day 57 (28 days after the second vaccination), and Day 210; Subjects in Cohort 2 
will undergo blood sampling for serological testing on Day 1 (prior to the first vaccination), Day 
56 (prior to the second vaccination), Day 84 (28 days after the second and 28 days prior to the third 
vaccination), Day 140 (28 days after the third vaccination), and Day 293. To alleviate the pain 
associated with blood sampling in this pediatric population, blood collection will be performed by 
experienced, trained personnel who routinely obtain blood from infants and children, under the 
supervision of the Principal Investigator after optional application of EMLA cream/patch and 
using pediatric size needles. All blood samples will be collected in accordance with acceptable 
laboratory procedures. For serology in all subjects, the volume of blood taken at any single visit is 
approximately 2 mL. For subjects (without CMI testing), the approximate total volume of blood in 
the trial is 8 mL for Cohort 1 subjects in Groups 1, 2, 2a, and 3 (4 blood draws) and 10 mL for 
Cohort 2 subjects in Group 4 (5 blood draws). For those subjects with CMI, a subset of the subjects 
aged ≥ 3 years at selected sites in Groups 1 and 2 only, an additional volume of 3 mL of blood at 
each of three time points will be drawn immediately prior to and approximately 28 days after each 
vaccination (Days 1, 29, and 57) for a subtotal of approximately 9 mL. To clarify, for those 
children aged 3 years and older selected to be in the CMI subset in Groups 1 and 2 only, a total of 
17 mL per subject will be obtained for the entire study period. Because subjects in Group 2a will 
not participate in CMI testing, the total volume of blood for Group 2a subjects is 8 mL. Likewise, 
the total volume of blood for Group 3 subjects remains at 8 mL. To clarify, for the youngest 
infants, those in Cohort 2 (Group 4), a total of 10 mL per subject will be obtained for the entire 
study period. All blood samples will be processed and stored at the trial site according to the 
Laboratory Guidelines as provided in the Procedures Manual. 
9.1.7 
Safety Assessments 
The occurrence of selected indicators of reactogenicity (listed below), which by definition can 
occur only up to 7 days after vaccination (including the day of vaccination), will be collected 
during site visits or remotely via diary cards and will be recorded on the “Local and Systemic 
Reactions” eCRF as applicable. These will be summarized in the final report under the category 
“solicited AEs” to differentiate them from other AEs that were unsolicited. Any solicited local or 
systemic AE observed as continuing on the 8th day after the last administered vaccination 
(including day of vaccination) will be recorded as an AE on the Adverse Event eCRF.  
Local AEs (injection site):  
• Pain. 
• Erythema. 
• Induration. 
• Swelling. 


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• Erythema, induration, and swelling will measured with a millimeter ruler provided to each 
parent at screening visit. 
Systemic AEs (children aged 4 to <9 years): 
• Headache. 
• Fatigue. 
• Myalgia. 
• Arthralgia. 
• Vomiting. 
• Diarrhea. 
Systemic AEs (children aged 6 weeks to <4 years): 
• Irritability/fussiness. 
• Drowsiness. 
• Loss of appetite. 
• Vomiting. 
• Diarrhea (number of loose/liquid stools per day and consistency). 
Other indicators of reactogenicity: 
• Body temperature. 
SAEs will be collected through Day 210 (Cohort 1) or Day 293 (Cohort 2). Any unsolicited AEs 
will be collected for 28 days following each study dose. AEs leading to subject’s withdrawal will 
be collected from Day 1 through Day 210 (Cohort 1) or Day 293 (Cohort 2). 
Solicited Safety Parameters 
Safety parameters will be collected during site visits or remotely via diary cards. The grading scale 
for children 4 to < 9 years of age and older is shown in Table 9-a; the grading scale for children 
younger than 6 weeks to < 4 years is shown in Table 9-b. 


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Table 9-a 
Solicited Safety Parameters in Children Aged 4 to <9 Years 
Adverse Event  
Intensity grade  
Severity/Intensity 
Pain at injection 
site 
0 
None  
1 
Mild: Does not interfere with play and daily activities 
2 
Moderate: Interferes with play and daily activities with or without treatment 
3 
Severe: Prevents daily activities with or without treatment 
Erythema at 
injection site(a) 
0 
<25 mm 
1 
Mild: 25 – ≤50 mm 
2 
Moderate: >50 – ≤100 mm 
3 
Severe: >100 mm 
Swelling at 
injection site(a) 
0 
<25 mm 
1 
Mild: 25 – ≤50 mm 
2 
Moderate: >50 – ≤100 mm 
3 
Severe: >100 mm 
Induration at 
injection site(a) 
0 
<25 mm 
1 
Mild: 25 – ≤50 mm 
2 
Moderate: >50 – ≤100 mm 
3 
Severe: >100 mm 
Body 
temperature*  
Record temperature in °C/°F 
Headache  
0 
No headache 
1 
Mild: No interference with activity 
2 
Moderate: Some interference with activity with or without treatment 
3 
Severe: Prevents daily activity with or without treatment 
Fatigue 
0 
None 
1 
Mild: No interference with activity 
2 
Moderate: Some interference with activity 
3 
Severe: Significant; prevents daily activity 
Muscle aches/ 
Myalgia 
0 
None 
1 
Mild: No interference with activity 
2 
Moderate: Some interference with activity 
3 
Severe: Significant; prevents daily activity 
Joint aches/ 
Arthralgia 
0 
None 
1 
Mild: No interference with activity 
2 
Moderate: Some interference with activity 
3 
Severe: Significant; prevents daily activity 
Vomiting 
0 
None 
1 
Mild: No interference with activity 
2 
Moderate: Some interference with activity 
3 
Severe: Prevents daily activity 
Diarrhea 
0 
None 
1 
Mild: No interference with activity 
2 
Moderate: Some interference with activity 
3 
Severe: Prevents daily activity  
* = Fever is defined as greater than or equal to 38°C (100.4°F) regardless of method used [33]. Body temperature will 
be collected and recorded, preferably using the same method throughout the trial for a subject. The site staff will 
record the actual temperature route taken on the CRF. Note that identification of fever, as a solicited AE will be 
accomplished in the study database, based on actual temperature measurements. (a) Record greatest surface diameter 
in mm in the Diary. 


Norovirus GI.1/GII.4 Bivalent VLP Vaccine 
 
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CONFIDENTIAL 
Table 9-b 
Solicited Safety Parameters in Children Aged 6 Weeks to <4 Years) 
Adverse Event  
Intensity grade  
Severity/Intensity 
Pain at injection site  
0 
None  
1 
Mild: Minor reaction to touch  
2 
Moderate: Cries/protests on touch  
3 
Severe: Cries when limb is moved/spontaneously painful  
Erythema at injection 
site (a) 
0 
<10 mm 
1 
Mild: >10 – ≤ 20 mm 
2 
Moderate: > 20 – ≤ 40 mm 
3 
Severe: > 40 mm 
Swelling at injection 
site (a) 
0 
<10 mm 
1 
Mild: >10 – ≤ 20 mm 
2 
Moderate: > 20 – ≤ 40 mm 
3 
Severe: > 40 mm 
Induration at 
injection site (a) 
0 
<10 mm 
1 
Mild: >10 – ≤ 20 mm 
2 
Moderate: > 20 – ≤ 40 mm 
3 
Severe: > 40 mm 
Body temperature*  
Record temperature in °C/°F 
Irritability/Fussiness 
0 
Behaviour as usual  
1 
Mild: Crying more than usual/no effect on normal activity  
2 
Moderate: Crying more than usual/interferes with normal activity  
3 
Severe: Crying that cannot be comforted/prevents normal activity  
Drowsiness  
0 
Behaviour as usual  
1 
Mild: Drowsiness easily tolerated  
2 
Moderate: Drowsiness that interferes with normal activity  
3 
Severe: Drowsiness that prevents normal activity  
Loss of appetite  
0 
Appetite as usual  
1 
Mild: Eating less than usual/no effect on normal activity  
2 
Moderate: Eating less than usual/interferes with normal activity  
3 
Severe: Not eating at all  
Vomiting 
0 
None 
1 
Mild: No interference with activity or 1 – 2 episodes/24 hours 
2 
Moderate: Some interference with activity or >2 episodes/24 hours 
3 
Severe: Prevents daily activity, requires outpatient intravenous 
(IV) hydration 
Diarrhea 
0 
None 
1 
Mild: 2 – 3 loose stools/24 hours 
2 
Moderate: 4 – 5 loose stools/24 hours 
3 
Severe: ≥6 watery stools/24 hours or requires outpatient 
IV hydration 
* = Fever is defined as greater than or equal to 38.0°C (100.4°F) regardless of method taken [33]. Body 
temperature will be collected and recorded, preferably using the same method throughout the trial for a subject. 
The site staff will record the actual temperature route taken on the CRF. Note that identification of fever, as a 
solicited AE will be accomplished in the study database, based on actual temperature measurements. (a) Record 
greatest surface diameter in mm in the Diary. 


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Norovirus GI.1/GII.4 Bivalent VLP Vaccine 
 
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CONFIDENTIAL 
Review of organ systems: Review of organ systems is a structured interview that queries the 
subject or the subject’s LAR as to any complaints the subject has experienced across each organ 
system. 
“General” physical examination and body temperature: refer to Section 9.1.4 for details. 
Vital signs: refer to Section 9.1.5 for details. 
Review of eligibility criteria: refer to Sections 7.1 and 7.2 for details. 
Enrollment: refer to Section 9.1.1 – Day 1 only. 
Randomization: refer to Section 9.1.3 – Day 1 only 
Blood sampling: Prior to administering the trial vaccination, blood will be drawn from all subjects 
for serologic immunogenicity testing and from the subset of subjects selected for the CMI testing 
(children aged ≥ 3 years at selected sites). Details regarding the volume of blood and testing to be 
performed are specified in Sections 9.1.6 and 9.1.8. 
9.3.2 
Vaccination Procedures (Day 1 and Day 29 [Cohort 1] and Day 1, Day 56, and 
Day 112 [Cohort 2]) 
After confirming eligibility (and enrolling the subject on Day 1), vaccination will be performed 
according to the assigned investigational vaccine and according to the procedures described in 
Section 8.2. At later clinic visits that involve vaccination (Day 29 [Cohort 1] and Day 56 and 
Day 112 [Cohort 2]), it will be confirmed that the subject does not meet any criteria for delaying or 
cancelling additional trial vaccination, as described in Section 7.3. 
9.3.3 
Post-vaccination Procedures (Day 1 and Day 29 [Cohort 1] and Day 1, Day 56, 
and Day 112 [Cohort 2]) 
The following post-vaccination procedures will be performed on Day 1 and Day 29 (Cohort 1), 
and Day 1, Day 56, and Day 112 (Cohort 2). 
• Careful training of the subject’s LAR on how to measure local AEs and body temperature, how 
to complete the diary card, and how often to complete the diary card. Training should be 
directed at the individual(s) who will perform the measurements of local AEs and those who 
will enter the information into the diary card. This individual may or may not be the subject’s 
LAR, but if a person other than the subject’s LAR enters information into the diary card, this 
person’s identity must be documented in the trial file and this person must receive training on 
the diary card. Training of the subject’s LAR on how to measure an injection site reaction 
should be performed while the subject is under observation after vaccination. 
Diary card instructions must include the following: 
• The subject’s LAR must understand that timely completion of the diary card on a daily basis is 
a critical component of trial participation. The subject’s LAR should also be instructed to write 
clearly and to complete the diary card in pen. Any corrections to the diary card that are 


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CONFIDENTIAL 
performed by the person completing the diary card should include a single strikethrough line 
with a brief explanation for any change and be initialed and dated. 
Please note: 
Diary cards will be the only source document allowed for remote collection of solicited local and 
systemic AEs (including body temperature measurements). The following additional rules apply 
to the documentation of safety information collected by diary card: 
• The Diary Card should be reviewed with the subject’s LAR. 
• No corrections or additions to the diary card will be allowed after it is reviewed with the 
investigator/designee. 
• Any data that is identified as implausible or incorrect, and confirmed by the subject’s LAR to 
be a transcription error should be corrected by the subject’s LAR on the diary card (the 
correction should include a single strikethrough line and should be initialed and dated by the 
subject’s LAR). 
• Any blank or illegible fields on the diary card not otherwise corrected as above will be missing 
in the eCRF. 
• The site must enter all readable entries on the diary card into the eCRF. 
• Any newly described solicited safety information should be added to the diary card by the 
subject’s LAR or by the person who is authorized by the subject’s LAR to complete the diary, 
then initialed and dated. Any new unsolicited safety information such as a verbally reported 
event, should also be recorded in the subject medical chart (as recorded on the diary 
card/source document) and captured as an AE and recorded in the AE eCRF. 
• Starting on the day of vaccination, the subject’s LAR will check for specific types of events at 
the injection site (solicited local AEs), any specific generalized symptoms (solicited systemic 
AEs), body temperature (any method), any other symptoms or change in the subject’s health 
status, and any medications taken (excluding vitamins and minerals). These solicited AEs and 
body temperature will be recorded in the diary. Assessments should preferably take place in 
the evening at day’s end. 
• Temperature measurement is to be performed using the thermometer provided by the site. If 
the subject feels unusually hot or cold during the day, the subject’s LAR should check their 
temperature. If the subject has fever, the highest body temperature observed that day should be 
recorded on the diary card. 
• The measurement of solicited local AEs (erythema, swelling, and induration) is to be 
performed using the ruler provided by the site. 
• The collection on the diary card of body temperature, solicited local AEs, and solicited 
systemic AEs will continue for a total of 7 days following vaccine administration. The 
collection on the diary card of unsolicited AEs and medications will continue for 28 days 
following vaccine administration. 


Norovirus GI.1/GII.4 Bivalent VLP Vaccine 
 
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After vaccination, the subject will be observed for at least 30 minutes, including observation for 
unsolicited AEs, solicited AEs, and body temperature measurement. The investigator or delegate 
will take the opportunity to remind the subject’s LAR how to measure solicited reactions and body 
temperature as part of this observation period. All safety data will be collected in the subject’s 
source documents. 
The site should schedule the post-vaccination reminder calls (Days 3, and 32 for Cohort 1, and 
Days 3, 59, and 115 for Cohort 2). 
The subject’s LAR will receive a written reminder of the next planned trial activity. The subject’s 
LAR will be reminded to complete the diary card daily, to contact the site if there are any 
questions, and to contact the site immediately (or as soon as the subject is medically stable) if the 
subject has a medical condition that leads to a hospitalization or an emergency room visit. All 
contact details will be provided to the subject’s LAR by the responsible site staff. 
9.3.4 
Clinic Visits after Vaccination 
Clinic visits that do NOT include a vaccination will be performed on Day 8, Day 36, Day 57, and 
Day 210 (Cohort 1) and Day 8, Day 29, Day 63, Day 84, Day 119, Day 140, and Day 293 (Cohort 
2). 
At each visit a brief symptom-directed physical assessment may be performed, including (but not 
limited to) the measurement of vital signs. Corresponding information will be documented in the 
source documents and eCRFs. 
Blood should be taken from the subject using an aseptic venipuncture technique for serological 
immunogenicity testing as described in Sections 9.1.6 and 9.1.8. Refer to the detailed collection 
and handling procedures outlined in the Procedures Manual. 
The site should schedule the next trial activity clinic visit with the subject’s LAR. 
The subject or the subject’s LAR will receive a written reminder of the next planned trial activity. 
The subject or the subject’s LAR will be reminded to contact the site if there are any questions and 
to contact the site immediately (or as soon as the subject is medically stable) if the subject has a 
medical condition that leads to a hospitalization or an emergency room visit. 
9.3.5 
Phone Contacts – Safety Data Collection (Day 134 [Cohort 1] and Days 200 
and 260 [Cohort 2]) 
Safety calls will be performed on Day 134 for subjects in Cohort 1 and on Days 200 and 260 for 
subjects in Cohort 2. Safety calls are calls made to the subject by a trained healthcare provider. 
These calls will follow a script which will facilitate the collection of relevant safety information. 
The subject’s LAR will be interviewed according to the script, and information relating to SAEs, 
and concomitant medications or vaccinations associated with those events must be written down. 
All safety information described by the subject must be written down in a designated location 
within the source documents and not written on the script used for the telephone call. The site 
should schedule the next safety call or clinic visit with the subject’s LAR. The subject or the 


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subject’s LAR will be reminded to contact the site if there are any questions and to contact the site 
immediately (or as soon as the subject is medically stable) if the subject has a medical condition 
that leads to a hospitalization or an emergency room visit. 
9.3.6 
Phone Contacts - Reminder Calls (Day 3 and Day 32 [Cohort 1] and Day 3, 
Day 59, and Day 115 [Cohort 2]) 
Post-vaccination reminder phone calls will be performed on Day 3 and Day 32 (Cohort 1) and on 
Day 3, Day 59, and Day 115 (Cohort 2). The purpose is to remind the subject or the subject’s LAR 
about completion of the diary card. It is a conversation that follows the reminder telephone call 
script provided to the site (refer to the Procedures Manual), and it is not intended to be a call for 
collection of safety data. If the subject or the subject’s LAR wishes to describe safety information, 
this information should only be collected by a trained healthcare professional at the site, and the 
safety data described must be written down in source documents. The subject or the subject’s LAR 
should be reminded to write the information down in the diary card and to contact the site via the 
telephone number provided in the informed consent to discuss medical questions. 
9.3.7 
Final Visit 
The final visit will be performed on Day 210 for Cohort 1, and Day 293 for Cohort 2. If a subject 
terminates earlier, standard visit procedures should be performed if possible (ie, Day 210 
procedures for Cohort 1, and Day 293 for Cohort 2). For all subjects receiving an investigational 
vaccine, the investigator must complete the End-of-Trial eCRF page. 
After trial exit and outside the context of this trial, a licensed benefit vaccine may be offered to all 
enrolled subjects. The choice of this vaccine will be discussed between the sponsor and the 
investigator, and will need to be approved by the appropriate ethics committee. This licensed 
benefit vaccine would only be administered according to the labelling approved in the country. 
9.3.8 
Post-Trial Care 
No post-trial care will be provided. 
9.4 
Biological Sample Retention and Destruction 
In this trial, specimens for immune response testing will be collected as described in Sections 9.1.6 
and 9.1.8. After blood draw and serum processing, the serum samples will be preserved and 
retained at a central laboratory that was contracted by the sponsor for this purpose for up to but not 
longer than 20 years or as required by applicable law. The sponsor has put into place a system to 
protect the subjects’ personal information to ensure optimal confidentiality and defined standard 
processes for sample and data collection, storage, analysis, and destruction. 


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10.0 AEs 
10.1 Definitions 
10.1.1 
AEs 
An AE is defined as any untoward medical occurrence in a clinical investigation subject 
administered a vaccine. Adverse medical occurrences that occur after the ICF and assent form 
(where applicable) have been signed but before administration of the vaccine are documented in 
the Medical History. An AE does not necessarily have a causal relationship with investigational 
vaccine administration. 
An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal 
laboratory finding), symptom, or disease whether or not it is considered related to the 
investigational vaccine. 
AEs will be graded by the investigator using the following categorical descriptors: 
Mild (Grade 1) 
Awareness of symptoms that are easily tolerated, cause minimal 
discomfort, and do not interfere with everyday activities.  
Moderate (Grade 2) 
Sufficient discomfort is present to cause interference with normal 
activity.  
Severe (Grade 3) 
Extreme distress, causing significant impairment of functioning or 
incapacitation. Prevents normal everyday activities.  
Relatedness to vaccine will also be assessed by the investigator. SAEs will be reported to the 
sponsor within 24 hours of the investigator becoming aware of the event. 
Please note: any solicited AE that meets any of the following criteria must also be entered as an AE 
on the Adverse Event eCRF. 
• Solicited local or systemic AEs that lead the subject to withdraw from the trial. 
• Solicited local or systemic AEs lasting beyond 7 days after vaccination (including day of 
vaccination). 
• Solicited local and systemic AEs that lead to the subject being withdrawn from the trial by the 
investigator. 
• Solicited local and systemic AEs that otherwise meet the definition of an SAE (see 
Section 10.1.5). 


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10.1.2 
Causality of AEs 
Relatedness to vaccine will also be assessed by the investigator. The relationship of each AE to 
investigational vaccine(s) will be assessed using the following categories: 
Related: 
An AE that follows a reasonable temporal sequence from administration of an 
investigational vaccine, and for which reasonable possible involvement of the 
investigational vaccine can be argued, although factors other than the 
investigational vaccine, such as underlying diseases, complications and 
concomitant drugs, may also be responsible. 
Not Related: 
An AE that does not follow a reasonable temporal sequence from administration 
of an investigational vaccine and/or that can reasonably be explained by other 
factors, such as underlying diseases, complications, and concomitant drugs. 
10.1.3 
Relationship to Trial Procedures 
Relationship (causality) to trial procedures should be determined for all AEs. 
The relationship should be assessed as “Yes” if the investigator considers that there is reasonable 
possibility that an event is due to a trial procedure. Otherwise, the relationship should be assessed 
as “No.” 
10.1.4 
Additional Points to Consider for AEs 
An untoward occurrence generally may: 
• Indicate a new diagnosis or unexpected worsening of a pre-existing condition. Intermittent 
events for pre-existing conditions or underlying disease should not be considered as AEs. 
• Necessitate therapeutic intervention. 
• Require an invasive diagnostic procedure. 
• Require investigational vaccine delay or discontinuation or a change in concomitant 
medication. 
• Be considered unfavorable by the investigator for any reason. 
Diagnoses versus signs and symptoms: 
• Each event should be recorded to represent a single diagnosis. Accompanying signs (including 
abnormal laboratory values) or symptoms should NOT be recorded as additional AEs. If a 
diagnosis is unknown, sign(s) or symptom(s) should be recorded appropriately as an AE(s). 
Worsening of AEs: 
• If the subject experiences a worsening or complication of an AE after any administration of the 
investigational vaccine, the worsening or complication should be recorded as a new AE. 
Investigators should ensure that the AE term recorded captures the change in the condition (eg, 
“worsening of…”). 


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Changes in severity of AEs: 
• If the subject experiences changes in severity of an AE, the event should be captured once with 
the maximum severity recorded. 
Preplanned surgeries or procedures: 
• Preplanned procedures (surgeries or therapies) that were scheduled prior to signing of 
informed consent are not considered AEs (but will be recorded in the subject’s medical 
history). Complications resulting from any planned surgery should be reported as AEs. 
Elective surgeries or procedures: 
• Elective procedures performed where there is no change in the subject’s medical condition 
should not be recorded as AEs, but should be documented in the subject’s source documents. 
Complications resulting from an elective surgery should be reported as AEs. 
Follow Up: 
• All AEs will be monitored until resolution or a stable status is reached or until a formal 
diagnosis can be made. AEs will not be monitored beyond Day 210(Cohort 1) or Day 293 
(Cohort 2), unless deemed necessary by the sponsor. 
10.1.5 
SAEs 
An SAE is defined as any untoward medical occurrence that at any dose: 
a. Results in DEATH. 
Is LIFE THREATENING. 
• The term “life threatening” refers to an event in which the subject was at risk of death at the 
time of the event; it does not refer to an event that hypothetically might have caused death 
if it were more severe. 
Requires inpatient HOSPITALIZATION or prolongation of existing hospitalization. 
Results in persistent or significant DISABILITY/INCAPACITY. 
Is an IMPORTANT MEDICAL EVENT that satisfies any of the following: 
• May require intervention to prevent items 1 through 4 above. 
• May expose the subject to danger, even though the event is not immediately life 
threatening or fatal or does not result in hospitalization. 
10.2 Procedures 
10.2.1 
Collection and Reporting of AEs 
Please refer to Section 10.2.2 for Collection and Reporting of SAEs. 


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10.2.1.1 
AE Reporting 
All subjects experiencing AEs within 28 days of each study dose, whether considered causally 
related with the use of the investigational vaccine or not, must be monitored until symptoms 
subside and any abnormal laboratory values have returned to baseline, or until there is a 
satisfactory explanation for the changes observed, or until death, in which case a full pathologist’s 
report should be supplied, if possible. All findings must be reported on an Adverse Event eCRF 
and on the SAE form, if applicable (see Section 10.2.2), which is part of the Investigator Site File. 
All findings in subjects experiencing AEs must also be reported in the subject’s medical records. 
AE reporting beyond Day 57 (Cohort 1) or Day 140 (Cohort 2) will be spontaneous, at safety calls, 
or retrospectively at Day 210 (Cohort 1) or Day 293 (Cohort 2). 
The following information will be documented for each event: 
• Reported term for the AE. 
• Start and end date. 
• Serious (Y/N)? 
• Severity. 
• Investigator’s opinion of the causality (relationship) between the event and administration of 
investigational vaccine(s) (“related” or “not related”). 
• Investigator’s opinion of the causality (relationship) to trial procedure(s), including the details 
of the suspected procedure. 
• Action taken with study treatment (investigational vaccine). 
• Outcome of event. 
10.2.2 
Collection and Reporting of SAEs 
Collection of SAEs will commence from the time that the subject is administered the first study 
dose (Day 1). Routine collection of SAEs will continue until the end of the trial (All subjects 
experiencing AEs within 28 days of each study dose, whether considered causally related with the 
use of the investigational vaccine or not, must be monitored until symptoms subside and any 
abnormal laboratory values have returned to baseline, or until there is a satisfactory explanation for 
the changes observed, or until death, in which case a full pathologist’s report should be supplied, if 
possible. All findings must be reported on an Adverse Event eCRF and on the SAE form, if 
applicable, which is part of the Investigator Site File. All findings in subjects experiencing AEs 
must also be reported in the subject’s medical records. AE reporting beyond Day 57 (Cohort 1) or 
Day 140 (Cohort 2) will be spontaneous, at safety calls, or retrospectively at Day 210 (Cohort 1) 
and Day 293 (Cohort 2). 
SAEs should be reported according to the following procedure: 


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A sponsor SAE form must be completed, in English, and signed by the investigator immediately or 
within 24 hours of first onset or notification of the event. The information should be completed as 
fully as possible but contain, at a minimum: 
• A short description of the event and the reason why the event is categorized as serious. 
• Subject identification number. 
• Investigator’s name. 
• Name of the investigational vaccine(s) –in a blinded way in blinded trials. 
• Causality assessment. 
The SAE form should be transmitted within 24 hours to the attention of the contact(s) in the list 
provided to each site. 
10.3 Follow-up of 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, and postmortem results) should be sent to the sponsor. 
All SAEs should be followed up until resolution or permanent outcome of the event or is otherwise 
explained. The timelines and procedure for follow-up reports are the same as those for the initial 
report. 
10.3.1 
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities 
The sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
(SUSARs) and any other applicable SAEs to regulatory authorities, including the European 
Medicines Agency (EMA), the Food and Drug Administration (FDA), 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 investigational 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. 
10.3.2 
Post-Trial Events 
Any related SAEs that occur outside of the protocol-specified observation period or after the end 
of the trial must be reported to the sponsor. These AEs will be processed by the sponsor’s 


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Pharmacovigilance Department. Instructions for how to submit these AEs will be provided in a 
handout in the Investigator Site File.  


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11.0 TRIAL-SPECIFIC REQUIREMENT(S) 
11.1 Trial-Specific Committees 
An independent DMC will be used for this trial as described in Section 11.1.1.  
11.1.1 
Independent DMC 
An independent program level DMC will assess safety data on an ongoing basis. The DMC will 
also have study level responsibilities to review data and make recommendations about the 
sequential enrollment of various groups and formulation arms in this study. 
Enrollment in this study will be initiated sequentially based on age groups and formulation arms, 
with ongoing DMC review. 
The DMC will be composed at a minimum of 2 members with pediatric infectious disease and/or 
vaccine expertise, and a clinician and statistician. The DMC will monitor safety during the study 
and can meet ad hoc, as necessary. The roles and responsibilities of the DMC will be described in 
the DMC charter. 
In the event that safety monitoring uncovers an issue that needs to be addressed by unblinding at 
the group level, only members of the DMC can conduct additional analyses of the safety data. 


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12.0 DATA HANDLING AND RECORDKEEPING 
The full details of procedures for data handling will be documented in the Data Management Plan. 
Unsolicited and solicited AEs, SAEs, and medical history will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA) codes (system organ class [SOC], High-level 
Group Terms, High-level Terms, Lower-level Terms, preferred terms [PTs]) and their 
corresponding descriptive terms. Drugs will be coded using the World Health Organization 
(WHO) Drug Dictionary. 
12.1 eCRFs  
Completed eCRFs are required for each subject whose LAR consented to the subject’s 
participation and signed an ICF for the minor child. 
The sponsor or its designee will supply investigative sites with access to eCRFs. The sponsor will 
make arrangements to train appropriate site staff in the use of the eCRF. These forms are used to 
transmit the information collected in the performance of this trial to the sponsor and regulatory 
authorities. eCRFs must be completed in English. 
After completion of the entry process, computer logic checks will be run to identify items, such as 
inconsistent dates, missing data, and questionable values. Queries may be issued by sponsor 
personnel (or designees) and will be answered by the site. 
Corrections to eCRFs are recorded in an audit trail that captures the old information, the new 
information, identification of the person making the correction, the date the correction was made, 
and the reason for change. Reasons for significant corrections should additionally be included. 
The investigator or designee must review the eCRFs for completeness and accuracy and must sign 
and date the appropriate eCRFs as indicated. Furthermore, the investigator must retain full 
responsibility for the accuracy and authenticity of all data entered on the eCRFs. 
eCRFs will be reviewed for completeness and acceptability at the trial site during periodic visits by 
trial monitors. The sponsor or its designee will be permitted to review the subject’s medical and 
hospital records pertinent to the trial to ensure accuracy of the eCRFs. The completed eCRFs are 
the sole property of the sponsor and should not be made available in any form to third parties, 
except for authorized representatives of appropriate governmental health or regulatory authorities, 
without written permission of the sponsor. 
12.2 Record Retention 
The investigator agrees to keep the records stipulated in Section 12.1 and those documents that 
include (but are not limited to) the trial-specific documents, the identification log of all 
participating subjects, medical records, temporary media such as thermal-sensitive paper (which 
should be copied and certified), source worksheets, all original signed and dated ICFs and assent 
forms (where applicable), 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, 


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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 an application is not approved, until at least 2 years 
after the investigation is discontinued and regulatory authorities are notified. In addition, ICH E6 
Section 4.9.5 states that the trial records should be retained until an amount of time specified by 
applicable regulatory requirements or for a time specified in the Clinical Study Site Agreement 
between the investigator and sponsor. 
Refer to the Clinical Study Site Agreement for the sponsor’s requirements on record retention. The 
investigator should contact and receive written approval from the sponsor before disposing of any 
such documents. 


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13.0 STATISTICAL METHODS 
13.1 Statistical and Analytical Plans 
A SAP will be prepared and finalized prior to the interim analyses (Day 57 in Cohort 1 and Day 
140 in Cohort 2). This document will provide further details regarding the definition of analysis 
variables and analysis methodology to address all trial objectives. Unless otherwise stated, the 
statistical methods described in the following subsections apply to all groups. 
A blinded data review will be conducted by the blinded trial team prior to the analysis at study 
completion (Day 210 in Cohort 1 and Day 293 in Cohort 2). Limited blinded data review (of 
protocol deviations and subject evaluability) will also be done prior to the interim analyses. These 
reviews will assess the accuracy and completeness of the trial database and subject evaluability. 
13.1.1 
Analysis Sets 
The analyses sets are defined as follows: 
Safety Analysis Set: all subjects who receive at least 1 dose of vaccine (NoV GI.1/GII.4 bivalent 
VLP vaccine or control vaccine). 
Full Analysis Set (FAS): all subjects who are randomized and have at least 1 NoV GI.1/GII.4 
bivalent VLP vaccine injection. 
Per-Protocol Analysis Set (PPS): all subjects who receive the planned vaccination and do not have 
major protocol violations will be included in the PPS. The major protocol violation criteria will be 
finalized as part of the blinded data review prior to the IA (Day 57 for Cohort 1 and Day 140 in 
Cohort 2). 
The safety analysis will be based on the Safety Analysis Set. The primary immunogenicity 
analyses will be based on the PPS, and secondary immunogenicity analyses will be based on the 
FAS. 
The trial will evaluate the immunogenicity and safety of four formulations under different dosing 
regimens in 4 pediatric age ranges. Two cohorts of subjects will be enrolled into the trial. Cohort 
1will consist of 4 groups (4 to <9 years, 1 to <4 years [2 groups] and 6 months to <1 year), enrolled 
in age-step down fashion as described in Section 6.1. The youngest age group (Cohort 2, 6 weeks 
to <6 months) will be the last to complete enrollment. The factors under investigation, overall, and 
for each group include: formulation (4 formulation arms within each group); and number of doses 
(2 levels for each formulation within each group). For groups 1, 2, 2a, and 3 (in Cohort 1) the 
number of active doses will be 1 or 2 doses. For group 4 (Cohort 2), the number of active doses 
will be 2 or 3. Within each cohort, subjects are randomized to 1 of 8 trial arms (2 dose levels for 4 
formulations), with group as a stratification factor. The purpose of Group 2a is to evaluate the 
safety and selected immunogenicity endpoints in subjects in the same age range as Group 2, but 
who receive the recently manufactured NoV bivalent VLP vaccine. Statistical methods described 
in the following sections will be essentially the same, but will be done only for the endpoints 
indicated in Section 5.2. 


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In general, the results (both safety and immunogenicity) from the trial will be summarized 
separately for each group, by formulation/dose arm. For immunogenicity results, additional 
summaries and/analyses by treatment group for Cohort 1 will be provided, by pooling subjects in 
age groups. Other summaries based on different groups may be provided, with details provided in 
the SAP. 
Unless otherwise specified, descriptive summary statistics include mean, SD, median, minimum, 
and maximum values for continuous variables, and the number and percentage of subjects in 
specified categories for categorical variables. 
13.1.2 
Analysis of Demographics and Other Baseline Characteristics 
Age, gender, race, and other baseline characteristics will be summarized descriptively by 
formulation arm, separately for each of the age groups in the cohorts. 
13.1.3 
Immunogenicity Analysis  
The trial will evaluate the immunogenicity and safety of four formulations under different dosing 
regimens in 4 pediatric age ranges. Two cohorts of subjects will be enrolled into the trial. Cohort 1 
will consist of 4 groups (4 to <9 years, 1 to <4 years [2 groups] and 6 months to <1 year), enrolled 
in age-step down fashion as described in Section 6.1. The youngest age group (Cohort 2, 6 weeks 
to <6 months) will be the last to complete enrollment. The factors under investigation, overall, and 
for each group include: formulation (4 formulation arms within each group); and number of doses 
(2 levels for each formulation within each group). For groups 1, 2, 2a, and 3 (in Cohort 1) the 
number of active doses will be 1 or 2 doses. For group 4 (Cohort 2), the number of active doses 
will be 2 or 3. Within each cohort, subjects are randomized to 1 of 8 trial arms (2 dose levels for 4 
formulations), with group as a stratification factor. 
Descriptive statistics for the primary, secondary and exploratory endpoints including estimates of 
seroresponse (≥4-fold rises), and 95% confidence intervals (CI) will be provided. Summaries will 
be provided by formulation arm (ie. combination of formulation arms and number of doses) and 
group (4 age ranges with Groups 2 and 2a in the same age range). Additional summaries will be 
provided at the cohort level, by pooling subjects across the relevant age groups in Cohort 1, as 
applicable. 
Additional analyses will also be provided at the cohort level (pooling groups in Cohort 1). 
Statistical analyses of the primary endpoint will be performed for each cohort using the CMH 
method [36] stratified by group (in Cohort 1) to assess the effects of formulation/dose 
combination. Risk differences and corresponding 95% CIs will be provided for all pairwise 
comparisons of interest, without adjustments for multiplicity. The primary analyses will be based 
on the PPS. 
Continuous secondary endpoints, such as GMT and GMFR, will be summarized descriptively by 
group for each of the 8 formulation/dose combinations. 
Analysis of covariance (ANCOVA) will be conducted for selected continuous endpoints (such as 
GMT and GMFR), examining the effect of formulation/dose combination using the 


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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. 
Unsolicited AEs 
Unsolicited AEs, and SAEs, will be MedDRA coded and summarized by system organ class 
(SOC) and preferred term (PT) for each formulation arm in each cohort. AEs leading to subject’s 
withdrawal from the trial will also be summarized. 
All unsolicited AEs up to 28 days after each study vaccination will be included in the analyses of 
all AEs. SAEs, and AEs leading to subject withdrawal from the trial collected during the trial will 
be included. 
In general, unsolicited AEs will be tabulated at each of the following levels: overall summary 
(subjects 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 by SOC and PT, including events with frequency greater than 5% (and as above 
for subjects with at least 1 AE); by SOC, PT, and severity; and by SOC, PT, and relationship to the 
investigational vaccine. Unless otherwise specified, unsolicited AEs will be summarized in the 
following 3 ways: 1) overall up to 28 days after each vaccination, 2) with onset between 1 and 7 
days after each vaccination, and 3) with onset between 8 and 28 days after each vaccination. 
13.2 Interim Analysis and Criteria for Early Termination 
Interim analyses will be performed after the primary safety and immunogenicity data are available 
(ie, Day 57 for Cohort 1 and Day 140 for Cohort 2) (primary analysis time point). Day 57 interim 
analyses (IA) for Cohort 1 will be provided initially for Groups 1 and 2, which will complete Day 
57 substantially earlier than Group2a and 3. The Day 57 IA for Groups 2a and 3 combined will be 
provided at a later time. Thus, the Day 57 IA will be conducted in two parts to be followed by the 
Day 140 IA. All interim analyses will be performed by a separate set of unblinded statisticians and 
programmers at the contract research organization (CRO), Quintiles, who will have access to 
individual treatment assignments but will not otherwise be involved in study conduct. The rest of 
the personnel involved in the conduct of the study, including those at Takeda, Quintiles, and the 
study sites, will remain blinded to the individual subject data (including treatment assignments) 
until unblinding after database lock (Day 210 for Cohort 1 and Day 293 for Cohort 2). More details 
on the analyses will be provided in the statistical analysis plan (SAP). 
13.3 Determination of Sample Size 
This trial is designed to be descriptive and is not based on testing formal null hypotheses, and 
therefore the sample size was not determined based on formal statistical power calculations. 
However, for illustrative purposes, the probabilities of detecting 1 or more AEs in this design for 
various scenarios are provided. 
Safety: Including all randomized subjects, Table 13-a illustrates the probability of observing 1 or 
more events (eg, any specific type of AE related to study vaccine) for a range of assumed true but 


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unknown event rates in the range of 0.33% to 5.00% (without considering the background 
incidence). 
Table 13-a 
Probability of Observing 1 or More Events for Assumed “True” Event Rate 
and Given Samples 
“True” Unknown Event Rate 
Sample Size 
N=480 
N=360 
N=240 
N=120 
0.33% 
79.5% 
69.6% 
54.8% 
32.7% 
0.50% 
91.0% 
83.5% 
70.0% 
45.2% 
1.00% 
99.2% 
97.3% 
91.0% 
70.1% 
2.00% 
>99.9% 
99.9% 
99.2% 
91.1% 
3.00% 
>99.9% 
>99.9% 
99.9% 
97.4% 
4.00% 
>99.9% 
>99.9% 
>99.9% 
99.2% 
5.00% 
>99.9% 
>99.9% 
>99.9% 
99.8% 
Therefore, even with an event rate as low as 0.33%, there is a 80% chance that at least 1 such event 
will be observed in Cohort 1 of the trial. Restricting to one age group in Cohort 1 (N=120) there is 
still a 91% chance of observing 1 or more events when the true rate is 2.00%. 


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14.0 QUALITY CONTROL AND QUALITY ASSURANCE 
14.1 Trial-Site Monitoring Visits 
Monitoring visits to the trial site will be made periodically during the trial to ensure that all aspects 
of the protocol are followed. Source documents will be reviewed for verification of data recorded 
on the eCRFs. Source documents are defined as original documents, data, and records. The 
investigator and institution guarantee access to source documents by the sponsor or its designee 
(CRO) and by the IRB or IEC. 
All aspects of the trial and its documentation will be subject to review by the sponsor or designee 
(as long as blinding is not jeopardized), including but not limited to the Investigator’s Binder, 
investigational 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 FDA, the United Kingdom Medicines and Healthcare products 
Regulatory Agency, the Pharmaceuticals and Medical Devices Agency of Japan). If the trial site is 
contacted for an inspection by a regulatory body, the sponsor should be notified immediately. The 
investigator and institution guarantee access for quality assurance auditors to all trial documents as 
described in Section 14.1. 


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15.0 ETHICAL ASPECTS OF THE TRIAL 
This trial will be conducted with the highest respect for the individual participants (ie, subjects) 
according to the protocol, the ethical principles that have their origin in the Declaration of 
Helsinki, and the ICH Harmonized Tripartite Guideline for GCP. Each investigator will conduct 
the trial according to applicable local or regional regulatory requirements and align his or her 
conduct in accordance with the “Responsibilities of the Investigator” that are listed in Appendix A. 
The principles of Helsinki are addressed through the protocol and through appendices containing 
requirements for informed consent and investigator responsibilities. 
15.1 IRB and/or IEC Approval 
IRBs and IECs must be constituted according to the applicable local 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.  
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 [31], 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 
competent authority to begin the trial. Until the site receives notification, no protocol activities, 
including screening, may occur. 
Sites must adhere to all requirements stipulated by their respective IRB or IEC. This may include 
notification to the IRB or IEC regarding protocol amendments, updates to the ICF, recruitment 
materials intended for viewing by subjects, local safety reporting requirements, reports and 
updates regarding the ongoing review of the trial at intervals specified by the respective IRB or 
IEC, and submission of the investigator’s final status report to IRB or IEC. All IRB and IEC 
approvals and relevant documentation for these items must be provided to the sponsor or its 
designee. 
Subject incentives should not exert undue influence for participation. Payments to subjects must 
be approved by the IRB or IEC and sponsor.  


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15.2 Subject Information, Informed Consent, and Subject Authorization 
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
applicable laws and regulations. The ICF, assent form (where applicable), 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. In the event the subject is not capable of rendering adequate written 
informed consent, then the subject’s LAR may provide such consent for the subject in accordance 
with applicable laws and regulations. 
The subject or the subject’s LAR 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 or the subject’s LAR 
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, or the subject’s LAR, at the time of consent 
and prior to the subject entering into the trial. The subject or the subject’s LAR 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. 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 or the relevant subject’s LAR in 
the same manner as the original informed consent. The date the revised consent was obtained 


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should be recorded in the subject’s medical record, 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 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, electrocardiogram 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 investigators 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 patients that it sponsors anywhere in the world on ClinicalTrials.gov or 
other publicly accessible websites before trial initiation. The sponsor contact information, along 
with investigator’s city, country, and recruiting status will be registered and available for public 
viewing. 


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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. 
In line with European Community (EC) Regulation N° 1901/2006, the sponsor will submit the 
pediatric studies within 6 months of their completion and irrespective of whether it is part of a 
Pediatric Investigation Plan (completed or not yet completed) or not, or whether it is intended for 
submission later on as part of a variation, extension or new stand-alone marketing-authorization 
application or not [35]. 
15.5 Insurance and Compensation for Injury 
Each subject in the trial must be insured in accordance with the regulations applicable to the site 
where the subject is participating. If a local underwriter is required, then the sponsor or sponsor’s 
designee will obtain clinical trial insurance against the risk of injury to clinical trial subjects. Refer 
to the Clinical Study Site Agreement regarding the sponsor’s policy on subject compensation and 
treatment for injury. If the investigator has questions regarding this policy, he or she should contact 
the sponsor or sponsor’s designee. 


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16.0 REFERENCES 
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history of human calicivirus infection: a prospective cohort study. Clin Infect 
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2. Phillips G, et al. Community incidence of norovirus-associated infectious intestinal disease 
in England: improved estimates using viral load for norovirus diagnosis. Am. J. Epidemiol. 
2010;171:1014-22. 
3. Hall AJ, et al. Incidence of acute gastroenteritis and role of norovirus, Georgia, USA, 
2004-2005. Emerg. Infect. Dis. 2011;17:1381-8. 
4. Patel MM, et al. Systematic literature review of role of noroviruses in sporadic 
gastroenteritis. Emerg. Infect. Dis. 2008;14:1224-31. 
5. Hoa Tran TN, Trainor E, Nakagomi T, Cunliffe NA, Nakagomi O. Molecular 
epidemiology of noroviruses associated with acute sporadic gastroenteritis in children: 
Global distribution of genogroups, genotypes and GII.4 variants, J Clin Virol. 2013 
Mar;56(3):269-77. 
6. Nurminen K, Blazevic V, Huhti L, Räsänen S, Koho T, Hytönen VP, Vesikari T. 
Prevalence of norovirus GII-4 antibodies in Finnish children. J Med Virol. 2011 
Mar;83(3):525-31. doi: 10.1002/jmv.21990. PMID: 21264875. 
7. Menon VK, George S, Aladin F, Nawaz S, Sarkar R, Lopman B, Gray JJ, Gomara 
MI, Kang G. Comparison of age-stratified seroprevalence of antibodies 
against norovirus GII in India and the United Kingdom. PLoS One. 2013;8(2):e56239. doi: 
10.1371/journal.pone.0056239. Epub 2013 Feb 21. 
8. Tan M and Jiang X. Association of histo-blood group antigens with susceptibility to 
norovirus infection may be strain-specific rather than genogroup dependent. J Infect Dis. 
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9. Ball JM, et al. Recombinant Norwalk virus-like particles given orally to volunteers: phase I 
study. Gastroenterology 1999;117:40-8. 
10. Tacket CO, et al. Human immune responses to a novel Norwalk virus vaccine delivered in 
transgenic potatoes. J. Infect. Dis. 2000;182:302-5. 
11. Tacket CO, et al. Humoral, mucosal, and cellular immune responses to oral Norwalk 
virus-like particles in volunteers. Clin. Immunol. 2003;108:241-7. 
12. Baylor NW, Egan W, Richman P. Aluminium salts in vaccines—US perspective. Vaccine 
2002;20:S18–23. Corrigendum in Vaccine 2002;20:3428. 
13. Garçon N, et al. The safety evaluation of adjuvants during vaccine development: the AS04 
experience. Vaccine 2011;29:4453-9. 
 


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14. Atmar RL and Estes MK. The epidemiologic and clinical importance of norovirus 
infection. Gastroenterol Clin North Am. 2006;35:275-90, viii. 
15. Lopman BA, Reacher MH, Vipond IB, Hill D, Perry C, Halladay T, et al. Epidemiology 
and cost of nosocomial gastroenteritis, Avon, England, 2002-2003. Emerg Infect Dis. 
2004;10:1827-34. 
16. Papaventsis DC, Dove W, Cunliffe NA, Nakagomi O, Combe P, Grosjean P, et al. 
Norovirus infection in children with acute gastroenteritis, Madagascar, 2004-2005. Emerg 
Infect Dis. 2007;13:908-11. 
17. Lee BE, Pang XL, Robinson JL, Bigam D, Monroe SS, Preiksaitis JK. Chronic norovirus 
and adenovirus infection in a solid organ transplant recipient. Pediatr Infect Dis J. 
2008;27:360-2. 
18. Soares CC, Santos N, Beard RS, Alburquerque MC, Maranhão AG, Rocha LN, et al. 
Norovirus detection and genotyping for children with gastroenteritis, Brazil Emerg Infect 
Dis. 2007;13:1244-6. 
19. Nakagomi T, Correia JB, Nakagomi O, Montenegro FM, Cuevas LE, Cunliffe NA, et al. 
Norovirus infection among children with acute gastroenteritis in Recife, Brazil: disease 
severity is comparable to rotavirus gastroenteritis. Arch Virol. 2008;153:957-60. 
20. van Beek J, Ambert-Balay K, Botteldoorn N, Eden JS, Fonager J, Hewitt J, et al. 
Indications for worldwide increased norovirus activity associated with emergence of a new 
variant of genotype II.4, late 2012. Euro Surveill. 2013;18,8-9. 
21. Kroneman A, Vennema H, Harris J, Reuter G, von Bonsdorff CH, Hedlund KO, et al. 
Increase in norovirus activity reported in Europe. Euro Surveill. 2006; 11, E061214. 
22. Estes MK, Prasad BV, Atmar RL. Noroviruses everywhere: has something changed? Curr 
Opin Infect Dis. 2006;19:467-74. 
23. Donaldson EF, Lindsmith LC, Lobue AD, Baric RS. Norovirus pathogenesis: mechanisms 
of persistence and immune evasion in human populations. Immunol Rev. 
2008;225:190-211. 
24. Gallimore CI, Cubitt D, du Plessis N, Gray JJ. Asymptomatic and symptomatic excretion 
of noroviruses during a hospital outbreak of gastroenteritis. J Clin Microbiol. 
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25. Teunis PF, Moe CL, Liu P, Miller SE, Lindesmith L, Baric RS. Norwalk virus: how 
infectious is it? J Med Virol. 2008;80:1468-76. 
26. Lopman B, Vennema H, Kohli E, Pothier P, Sanchez A, Negredo A, et al. Increase in viral 
gastroenteritis outbreaks in Europe and epidemic spread of new norovirus variant. Lancet 
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27. Kitamoto N, Tanaka T, Natori K, Takeda N, Nakata S, Jiang X, et al. Cross-reactivity 
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antibodies obtained from mice immunized orally with one type of VLP. J Clin Microbiol. 
2002;40:2459-65. 
28. Okame M, Shiota T, Hansman G, Takagi M, Yagyu F, Takanashi S, et al. Anti-norovirus 
polyclonal antibody and its potential for development of an antigen-ELISA. J Med Virol. 
2007;79(8):1180-6. 
29. de Rougemont A, Ruvoen-Clouet N, Simon B, Estienney M, Elie-Caille C, Aho S, et al. 
Qualitative and quantitative analysis of the binding of GII.4 norovirus variants onto human 
blood group antigens. J Virol. 2011;85(9):4057-70. doi: 10.1128/JVI.02077-10. Epub 
2011 Feb 23. 
30. Atmar RL, Opekun AR, Gilger MA, Estes MK, Crawford SE, Neill FH, et al. Norwalk 
virus shedding after experimental human infection. Emerg Infect Dis. 2008;14(Oct 
10):1553-7. doi: 10.3201/eid1410.080117. 
31. Investigator’s Brochure. Intramuscular Norovirus GI.1/GII.4 bivalent virus-like particle 
(VLP) vaccine adjuvanted with monophosphoryl lipid A (MPL) and aluminum hydroxide 
[Al(OH)3]. Date 03 October 2013. Edition 3. 
32. Pichichero ME, Casey JR, Almudevar A. Nonprotective Responses to Pediatric Vaccine 
Occur in Children who are Otitis Prone. Pediatr Infect Dis J. 2013;32(11):1163-9.  
33. Marcy SM, Kohl KS, Dagan R, Nalin D, Blum M, Connell Jones M, Hansen J, Labadie J, 
Lee L, Martin BL, O'Brien K, Rothstein E, Vermeer P and The Brighton Collaboration 
Fever Working Group. Fever as an adverse event following immunization: case definition 
and guidelines of data collection, analysis, and presentation. Vaccine 2004;22:551-6. 
34. Ge M, Durham LK, Meyer RD, Xie W, and Thomas N. Covariate-Adjusted Difference in 
Proportions from Clinical Trials Using Logistic Regression and Weighted Risk 
Differences, Therapeutic Innovation & Regulatory Science July 2011 vol. 45 no. 4 
481-493 
35. EC Regulation N° 1901/2006 OF THE EUROPEAN PARLIAMENT AND OF THE 
COUNCIL of 12 December 2006 on medicinal products for paediatric use and amending 
Regulation (EEC) No 1768/92, Directive 2001/20/EC, Directive 2001/83/EC and 
Regulation (EC) No 726/2004. 


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Appendix A Responsibilities of the Investigator 
Clinical research studies sponsored by the sponsor are subject to ICH GCP and all the applicable 
local laws and regulations. 
The investigator agrees to assume the following responsibilities: 
1. Conduct the trial in accordance with the protocol. 
2. Personally conduct or supervise the staff that will assist in the protocol. 
3. Ensure that trial-related procedures, including trial specific (non routine/non standard panel) 
screening assessments are NOT performed on potential subjects, prior to the receipt of written 
approval from relevant governing bodies/authorities. 
4. Ensure that all colleagues and employees assisting in the conduct of the trial are informed of 
these obligations. 
5. Secure prior approval of the trial and any changes by an appropriate IRB/IEC that conform to 
ICH, and local regulatory requirements. 
6. Ensure that the IRB/IEC will be responsible for initial review, continuing review, and approval 
of the protocol. Promptly report to the IRB/IEC all changes in research activity and all 
anticipated risks to subjects. Make at least yearly reports on the progress of the trial to the 
IRB/IEC, and issue a final report within 3 months of trial completion. 
7. Ensure that requirements for informed consent, as outlined in ICH and local regulations, are 
met. 
8. Obtain valid informed consent from each subject who participates in the trial, and document 
the date of consent in the subject’s medical chart. Valid informed consent is the most current 
version approved by the IRB/IEC. Each ICF should contain a subject authorization section that 
describes the uses and disclosures of a subject’s personal information (including personal 
health information) that will take place in connection with the trial. If an ICF does not include 
such a subject authorization, then the investigator must obtain a separate subject authorization 
form from each subject or the subject’s LAR. 
9. Prepare and maintain adequate case histories of all persons entered into the trial, including 
eCRFs, hospital records, laboratory results, etc, and maintain these data for a minimum of 
2 years following notification by the sponsor that all investigations have been discontinued or 
that the regulatory authority has approved the marketing application. The investigator should 
contact and receive written approval from the sponsor before disposing of any such 
documents. 
10. Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents. 
11. Maintain current records of the receipt, administration, and disposition of sponsor-supplied 
vaccines, and return all unused sponsor-supplied vaccines to the sponsor. 


Norovirus GI.1/GII.4 Bivalent VLP Vaccine 
 
Trial No. NOR-202 
Page 103 of 107 
Protocol Version 4.0 
1 March 2016 
 
CONFIDENTIAL 
12. Report AEs to the sponsor promptly. In the event of an SAE, notify the sponsor within 24 
hours. 


Norovirus GI.1/GII.4 Bivalent VLP Vaccine 
 
Trial No. NOR-202 
Page 104 of 107 
Protocol Version 4.0 
1 March 2016 
 
CONFIDENTIAL 
Appendix B Investigator Consent to Use of Personal Information 
The sponsor will collect and retain personal information of investigator, including his or her name, 
address, and other personally identifiable information. In addition, investigator’s personal 
information may be transferred to other parties located in countries throughout the world (eg, the 
United Kingdom, United States, and Japan), including the following: 
• The sponsor, its affiliates, and licensing partners. 
• Business partners assisting Takeda, its affiliates, and licensing partners. 
• Regulatory agencies and other health authorities. 
• IRBs and IECs. 
Investigator’s personal information may be retained, processed, and transferred by the sponsor and 
these other parties for research purposes including the following: 
• Assessment of the suitability of investigator for the trial and/or other clinical studies. 
• Management, monitoring, inspection, and audit of the trial. 
• Analysis, review, and verification of the trial results. 
• Safety reporting and pharmacovigilance relating to the trial. 
• Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to the trial. 
• Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to other vaccines used in other clinical studies that may contain the 
same chemical compound present in the investigational vaccine. 
• Inspections and investigations by regulatory authorities relating to the trial. 
• Self-inspection and internal audit within the sponsor, its affiliates, and licensing partners. 
• Archiving and audit of trial records. 
• Posting investigator site contact information, trial details, and results on publicly accessible 
clinical trial registries, databases, and websites. 
Investigator’s personal information may be transferred to other countries that do not have data 
protection laws that offer the same level of protection as data protection laws in investigator’s own 
country. Investigator acknowledges and consents to the use of his or her personal information by 
the sponsor and other parties for the purposes described above.


1.0 TITLE PAGE 
Norovirus GI.1/GII.4 Bivalent VLP Vaccine 
 
Trial No. NOR-202 
Page 105 of 107 
Protocol Version 4.0 
1 March 2016 
 
 
CONFIDENTIAL 
 
Appendix C Elements of the Subject Informed Consent 
In seeking informed consent, the following information shall be provided to each subject: 
1 A statement that the trial involves research. 
2 An explanation of the purposes of the research. 
3 The expected duration of the subject’s participation. 
4 A description of the procedures to be followed, including invasive procedures. 
5 The identification of any procedures that are experimental. 
6 The estimated number of subjects involved in the trial. 
7 A description of the subject’s responsibilities. 
8 A description of the conduct of the trial. 
9 A statement describing the vaccination(s) and the probability for random assignment to 
each treatment. 
10 A description of the possible side effects following vaccine administration that the subject 
may receive. 
11 A description of any reasonably foreseeable risks or discomforts to the subject. 
12 A description of any benefits to the subject or to others that reasonably may be expected 
from the research. When there is no intended clinical benefit to the subject, the subject 
should be made aware of this. 
13 Disclosures of appropriate alternative procedures or courses of treatment, if any, that might 
be advantageous to the subject and their important potential risks and benefits. 
14 A statement describing the extent to which confidentiality of records identifying the 
subject will be maintained, and a note of the possibility that regulatory agencies, auditor(s), 
IRB/IEC, and the monitor may inspect the records. By signing a written ICF, the subject or 
the subject’s LAR is authorizing such access. 
15 For research involving more than minimal risk, an explanation as to whether any 
compensation and an explanation as to whether any medical treatments are available if 
injury occurs and, if so, what they consist of or where further information may be obtained. 
16 The anticipated prorated payment(s), if any, to the subject for participating in the trial. 
17 The anticipated expenses, if any, to the subject for participating in the trial. 


Norovirus GI.1/GII.4 Bivalent VLP Vaccine 
 
Trial No. NOR-202 
Page 106 of 107 
Protocol Version 4.0 
1 March 2016 
 
CONFIDENTIAL 
18 An explanation of whom to contact for answers to pertinent questions about the research 
(investigator), subject’s rights, and IRB/IEC and whom to contact in the event of a 
research-related injury to the subject. 
19 A statement that participation is voluntary, that refusal to participate will involve no 
penalty or loss of benefits to which the subject otherwise is entitled, and that the subject 
may discontinue participation at any time without penalty or loss of benefits to which the 
subject is otherwise entitled. 
20 The consequences of a subject’s decision to withdraw from the research and procedures for 
orderly termination of participation by the subject. 
21 A statement that the subject or the subject’s LAR will be informed in a timely manner if 
information becomes available that may be relevant to the subject’s willingness to continue 
participation in the trial. 
22 A statement that results of pharmacogenomic analysis will not be disclosed to an 
individual, unless prevailing laws require the sponsor to do so. 
23 The foreseeable circumstances or reasons under which the subject’s participation in the 
trial may be terminated. 
24 A written subject authorization (either contained within the ICF or provided as a separate 
document) describing to the subject the contemplated and permissible uses and disclosures 
of the subject’s personal information (including personal health information) for purposes 
of conducting the trial. The subject authorization must contain the following statements 
regarding the uses and disclosures of the subject’s personal information: 
a. that personal information (including personal health information) may be 
processed by or transferred to other parties in other countries for clinical research 
and safety reporting purposes, including, without limitation, to the following: 
(1) the sponsor, its affiliates, and licensing partners; (2) business partners assisting 
the sponsor, its affiliates, and licensing partners; (3) regulatory agencies and other 
health authorities; and (4) IRBs/IECs; 
b. it is possible that personal information (including personal health information) may 
be processed and transferred to countries that do not have data protection laws that 
offer subjects the same level of protection as the data protection laws within this 
country; however, the sponsor will make every effort to keep your personal 
information confidential, and your name will not be disclosed outside the clinic 
unless required by law; 
c. that personal information (including personal health information) may be added to 
the sponsor’s research databases for purposes of developing a better understanding 
of the safety and effectiveness of the investigational vaccine(s), studying other 
therapies for patients, developing a better understanding of disease, and improving 
the efficiency of future clinical studies; 


Norovirus GI.1/GII.4 Bivalent VLP Vaccine 
 
Trial No. NOR-202 
Page 107 of 107 
Protocol Version 4.0 
1 March 2016 
 
CONFIDENTIAL 
d. that subjects agree not to restrict the use and disclosure of their personal 
information (including personal health information) upon withdrawal from the trial 
to the extent that the restricted use or disclosure of such information may impact the 
scientific integrity of the research; and 
e. that the subject’s identity will remain confidential in the event that trial results are 
published. 
25 A statement that clinical trial information from this trial will be publicly disclosed in a 
publicly accessible website, such as ClinicalTrials.gov. 

SAP_001.pdf: 
TITLE PAGE 
TAKEDA VACCINES, INC. 
STATISTICAL ANALYSIS PLAN 
AMENDMENT 1 
 
STUDY NUMBER: NOR-202 
 
A Phase II, Randomized, Double-Blind, Dosage, Safety and Immunogenicity Trial of 
Intramuscular Norovirus GI.1/GII.4 Bivalent Virus-Like Particle Vaccine combined with 
Aluminum Hydroxide Adjuvant in Children, Toddlers, and Infants 
NOR-202 Safety and Immunogenicity of Norovirus GI.1/GII.4 Bivalent VLP Vaccine in 
Children 
PHASE II 
 
Version: Final 
Date: 17 February 2017 
 
 
 
 
CONFIDENTIAL PROPERTY OF TAKEDA 
This document is a confidential communication of Takeda. Acceptance of this document 
constitutes the agreement by the recipient that no information contained herein will be published 
or disclosed without written authorization from Takeda. 


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NOR-202 
Page 3 of 49 
Statistical Analysis Plan Amendment 1 Final 
17 February 2017 
 
CONFIDENTIAL 
2.0 
TABLE OF CONTENTS 
1.0 
APPROVAL SIGNATURES...............................................................................................2 
2.0 
TABLE OF CONTENTS .....................................................................................................3 
3.0 
LIST OF ABBREVIATIONS ..............................................................................................5 
4.0 
OBJECTIVES ......................................................................................................................6 
4.1 
Primary Objectives.........................................................................................................6 
4.2 
Secondary Objectives.....................................................................................................6 
4.3 
Exploratory Objectives ..................................................................................................6 
4.4 
Study Design ..................................................................................................................7 
5.0 
ANALYSIS ENDPOINTS ................................................................................................13 
5.1 
Primary Endpoints .......................................................................................................13 
5.2 
Secondary Endpoints ...................................................................................................13 
5.3 
Exploratory Endpoints .................................................................................................14 
6.0 
DETERMINATION OF SAMPLE SIZE ..........................................................................17 
7.0 
METHODS OF ANALYSIS AND PRESENTATION .....................................................18 
7.1 
General Considerations ................................................................................................18 
7.2 
Analysis Sets ................................................................................................................22 
7.3 
Disposition of Subjects ................................................................................................23 
7.4 
Demographic and Baseline Characteristics .................................................................24 
7.5 
Medical History and Concurrent Medical Conditions .................................................24 
7.6 
Medication History and Concomitant Medications .....................................................24 
7.7 
Duration of Follow up and Vaccine Regimen Compliance .........................................25 
7.8 
Immunogenicity Analysis ............................................................................................25 
7.8.1 Primary Immunogenicity Endpoint(s) ...................................................................26 
7.8.2 Secondary and Exploratory Immunogenicity Endpoint(s) ....................................27 
7.8.3 Additional Immunogenicity Endpoint(s) ...............................................................29 
7.9 
Pharmacokinetic/Pharmacodynamic Analysis .............................................................29 
7.10 
Other Outcomes ...........................................................................................................29 
7.11 
Safety Analysis ............................................................................................................29 
7.11.1 Adverse Events ......................................................................................................30 
7.11.2 Clinical Laboratory Evaluations ............................................................................32 
7.11.3 Vital Signs ..............................................................................................................32 
7.11.4 12-Lead ECGs ........................................................................................................32 
7.11.5 Other Observations Related to Safety ....................................................................32 
7.12 
Interim Analysis ...........................................................................................................32 
7.13 
Changes in the Statistical Analysis Plan ......................................................................33 


NOR-202 
Page 4 of 49 
Statistical Analysis Plan Amendment 1 Final 
17 February 2017 
 
CONFIDENTIAL 
8.0 
REFERENCES ..................................................................................................................47 
 
LIST OF IN-TEXT TABLES 
Table 4.a 
Schedule of Trial Procedures for Subjects Aged 6 Months to Less Than 
9 Years (Cohort 1 for Groups 1, 2 and 3; N=360) .................................................10 
Table 4.b 
Schedule of Trial Procedures for Subjects Aged 1 to Less Than 4 Years 
(Cohort 1 for Group 2a; N=120) ............................................................................11 
Table 4.c 
Schedule of Trial Procedures for Subjects Aged 6 Weeks to Less Than 
6 Months (Cohort 2; N=360) .................................................................................12 
Table 7.a 
Visit Windows for Immunogenicity by Visit.........................................................21 
Table 7.b 
Visit Windows for Vital Signs by Visit .................................................................21 
 
LIST OF IN-TEXT FIGURES 
Figure 4.a 
Schematic of Trial Design .......................................................................................7 
 
LIST OF APPENDICES 
Appendix A 
Severity Grading Scale for Solicited Local AEs in Children Aged 4 
to  <9 Years ............................................................................................................48 
Appendix B 
Severity Grading Scale for Solicited Local AEs in Children Aged Weeks 
to <4 Years .............................................................................................................49 
 


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NOR-202 
Page 8 of 49 
Statistical Analysis Plan Amendment 1 Final 
17 February 2017 
 
CONFIDENTIAL 
A total of 840 healthy subjects will be randomized to the following cohorts, with stratification by 
country and group: 
 Cohort 1, N=480 (Group 1: aged 4 to less than 9 years; Group 2: aged 1 to less than 4 years; 
Group 2a: aged 1 to less than 4 years; Group 3: aged 6 months to less than 1 year [N=120 
each]: subjects will be randomized with equal probabilities to 1 of the 8 unique combinations 
of formulation arms and dose groups (ie, 4 formulation arms and 1 or 2 doses). The 
additional 120 children, designated as Group 2a, are being included to evaluate the recently 
manufactured NoV bivalent VLP vaccine formulations prior to enrolling children in Groups 
3 and 4. Each of the combinations will consist of approximately 15 subjects per group. Thus 
Cohort 1 consists of 480 subjects in Groups 1, 2, 2a, and 3 combined. 
 Cohort 2 (Group 4: aged 6 weeks to less than 6 months): 360 subjects will be randomized to 
receive the recently manufactured NoV bivalent VLP vaccine with equal probabilities to 1 of 
the 8 unique combinations of formulation arms and dose groups (ie, 4 formulation arms and 2 
or 3 doses). Each of the combinations will consist of approximately 45 subjects. 
 This study plans to assess the immunogenicity and safety of the NoV bivalent VLP vaccine 
in children when given independently of the routine pediatric vaccines but, importantly, 
never to interfere with routine vaccine administration of children in each of the countries 
planned for evaluation. National pediatric vaccine regimens in children 6 weeks to 6 months 
of age vary by country (eg, routine pediatric vaccines may be given at 2, 3, and 4 months of 
age; 2, 4, and 6 months of age; or at 3, 5, and 12 months of age). 
Subjects 6 months to less than 9 years of age (inclusive, Cohort 1) will receive either 1 or 2 doses 
by IM injection, at least 28 days apart (Days 1 and 29), in 4 groups comprising 3 age ranges 
(Group 1: aged 4 to less than 9 years; Group 2 and Group 2a: both groups aged 1 to less than 
4 years; and Group 3: aged 6 months to less than 1 year). Infants 6 weeks to less than 6 months 
of age (Group 4/Cohort 2) will receive 2 or 3 doses by IM injection given approximately 56 days 
apart (Days 1, 56, and 112). Routine child and infant vaccinations will be given on schedule per 
the national guidelines approximately 28 days apart from the investigational vaccine in each age 
group. 
An independent program level Data Monitoring Committee (DMC) has been established to 
assess safety data on an ongoing basis. The DMC will also have study level responsibilities to 
review data and make recommendations about the sequential enrollment of various groups and 
formulation arms in this study (see Protocol Section 11.1.1).  
Interim analyses will be performed after the primary safety and immunogenicity data are 
available (ie, Day 57 for Cohort 1 and Day 140 for Cohort 2, primary analysis time point). The 
Day 57 IA for Cohort 1 will be provided initially for Groups 1 and 2, who will complete Day 57 
substantially earlier than Groups 2a and 3. The Day 57 IA for Groups 2a and 3 combined will be 
provided at a later time. Thus, the Day 57 IA will be conducted in two parts to be followed by 
the Day 140 IA in Group 4. All interim analyses will be performed by a separate set of unblinded 
statisticians and programmers at Quintiles who will have access to individual treatment 
assignments but will not otherwise be involved in subsequent study conduct. The rest of the 


NOR-202 
Page 9 of 49 
Statistical Analysis Plan Amendment 1 Final 
17 February 2017 
 
CONFIDENTIAL 
personnel involved in the conduct of the study, including those at Takeda, Quintiles, and the 
study sites, will remain blinded to the individual subject data (including treatment assignments) 
until unblinding after database lock (Day 210 for Cohort 1 and Day 293 for Cohort 2). 
Investigational Vaccine: 
The investigational vaccine for each formulation arm contains 500 µg aluminum as Al(OH)3.  
 Arm A: GI.1/GII.4 (15 µg/15 µg)  
 Arm B: GI.1/GII.4 (15 µg/50 µg)  
 Arm C: GI.1/GII.4 (50 µg/50 µg)  
 Arm D: GI.1/GII.4 (50 µg/150 µg)  
Placebo Control: 
Saline will be administered as a single control injection (as the final dose) in order to maintain 
the trial blind for the 1 dose groups in Groups 1, 2, 2a and 3 (Cohort 1) and for the 2 dose group 
in Group 4 (Cohort 2). Subjects in the 1 dose groups in Cohort 1 receive NoV vaccine on Day 1 
and a saline placebo injection on Day 29. Subjects in the 2 dose group in Cohort 2 receive NoV 
vaccine on Days 1 and 56 and a saline placebo injection on Day 112. 
Visit Schedule 
Clinical trial visits will be performed on Days 1, 8, 29, 36, 57, and 210 for Cohort 1 and Days 1, 
8, 29, 56, 63, 84, 112, 119, 140, and 293 for Cohort 2. Telephone contacts will be performed on 
Days 3, 32, and 134 for Cohort 1 and Days 3, 59, 115, 200 and 260 for Cohort 2. 
Duration of the Trial 
Expected duration of trial participation for each subject is up to 210 days (Cohort 1) and 
293 days (Cohort 2). Subjects will be followed for SAEs for 180 days after the last trial dose. 
Safety follow-up for other unsolicited AEs, and concomitant medications will be for 28 days 
following each trial dose.  
 Schedules of procedures by cohort are listed in Table 4.a and Table 4.b. 


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NOR-202 
Page 13 of 49 
Statistical Analysis Plan Amendment 1 Final 
17 February 2017 
 
CONFIDENTIAL 
5.0 
ANALYSIS ENDPOINTS 
Endpoints apply to Cohorts 1 and 2 unless otherwise stated. For subjects in Group 2a, the 
serologic assays to the vaccine VLPs for the Pan-Ig ELISA and for the HBGA binding assays 
will each be performed. Notably, the following endpoints will not be performed for Group 2a: 
Avidity, IgA ELISA, CMI for those aged ≥ 3 years, and HBGA binding assay to a panel of GI.1 
and GII.4 not represented in the vaccine. 
5.1 
Primary Endpoints 
Immunogenicity 
 Seroresponse rate (defined as 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 Pan-Ig ELISA at 
Day 57 (Cohort 1) and Day 140 (Cohort 2). 
Safety 
 Percentage of subjects with solicited local AEs of injection site pain, erythema, induration, 
and swelling on the day of vaccination and then daily through Day 7 after each vaccination 
(including the day of vaccination). 
 Percentage of subjects with solicited systemic AEs of headache, fatigue, myalgia, arthralgia, 
vomiting (number per day/intensity), and diarrhea (number per day/consistency) for children 
aged 4 to <9 years; and irritability/fussiness, drowsiness, loss of appetite, vomiting (number 
per day/intensity), and diarrhea (number per day/consistency) for children aged 6 weeks to 
<4 years on the day of vaccination and daily through Day 7 after each vaccination. 
 Body temperature on the day of vaccination (approximately 30 minutes and 6 hours later); 
then daily through Day 7 after each vaccination. 
 Percentage of subjects with unsolicited AEs for 28 days after each vaccination. 
 Percentage of subjects with SAEs throughout the trial. 
5.2 
Secondary Endpoints 
Immunogenicity 
Pan-Ig ELISA 
 Seroresponse rate in serum anti-NoV GI.1 VLP antibody titers as measured by Pan-Ig ELISA 
on Day 57 (Cohort 1) and Day 140 (Cohort 2). 
 Seroresponse rate in serum anti-NoV GII.4 VLP antibody titers as measured by Pan-Ig 
ELISA on Day 57 (Cohort 1) and Day 140 (Cohort 2). 
 GMT of anti-NoV GI.1 VLP antibody titers as measured by Pan-Ig ELISA on Day 57 
(Cohort 1) and Day 140 (Cohort 2). 
 GMT of anti-NoV GII.4 VLP antibody titers as measured by Pan-Ig ELISA on Day 57 
(Cohort 1) and Day 140 (Cohort 2). 


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6.0 
DETERMINATION OF SAMPLE SIZE 
This trial is designed to be descriptive and is not based on testing formal null hypotheses, and 
therefore the sample size was not determined based on formal statistical power calculations. 
However, for illustrative purposes, the probabilities of detecting 1 or more AEs in this design for 
various scenarios are provided in Protocol Section 13.3 
 


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7.0 
METHODS OF ANALYSIS AND PRESENTATION 
7.1 
General Considerations  
This statistical analysis plan (SAP) is based on protocol Amendment 3, Version 4.0, dated 
01 March 2016.  
The purpose of this trial is to evaluate the immunogenicity and safety profile of 4 formulations 
under different dosing regimens in 4 pediatric age ranges. Two cohorts of subjects will be 
enrolled into the trial (Figure 4.a). Cohort 1 will consist of 4 age groups (4 to <9 years, 1 to 
<4 years [2 groups] and 6 months to <1 year), enrolled in age-step-down fashion as described in 
Section 4.4. The youngest age group (Cohort 2, 6 weeks to <6 months) will be the last to 
complete enrollment. Enrollment into each successive age group is initiated based on DMC 
recommendation. Hereafter the age groups (5 groups covering 4 age ranges) will be designated 
as ‘group’. The factors under investigation for each group within each cohort include: 
formulation (4 formulation arms within each group); and number of doses (2 levels for each 
formulation within each group). For groups 1, 2, 2a, and 3 (in Cohort 1), the number of active 
doses will be 1 or 2 doses. For group 4 (Cohort 2), the number of active doses will be 2 or 3. 
Within each cohort, subjects are randomized to 1 of 8 trial arms (2 dose levels for 4 
formulations), with group as a stratification factor. The purpose of Group 2a is to evaluate the 
safety and selected immunogenicity endpoints in subjects in the same age range as Group 2, but 
who receive the recently manufactured NoV bivalent VLP vaccine. Statistical methods described 
in the following sections will be essentially the same, but will be done only for the endpoints 
indicated in Section 5.2. 
Immunogenicity and safety endpoints will be summarized descriptively (frequency and percent 
for categorical data; and number of subjects with non-missing observations, mean [or geometric 
mean], standard deviation [SD] [or geometric standard deviation {GSD}], median, minimum, 
and maximum for continuous data, unless specified otherwise) at all relevant study visits, as 
appropriate. In summary tables for categorical data for which categories are defined on the 
electronic case report form (eCRF), all categories will be presented as specified, even if the 
subject count within that category is zero. For other categorical data (eg, AEs and medications), 
only categories with at least 1 subject will be presented. Unless otherwise specified, for each 
group summarized, category percentages will be based on the number of subjects in the group 
with non-missing data and the non-missing ‘n’ will be displayed for each count/percentage. 
Minimum and maximum values will be presented using the same number of decimal places as 
the recorded data. Means, geometric means, least squares means (LS Means), and medians will 
be presented to 1 more decimal place than the recorded data. SD and GSD will be presented to 
2 more decimal places than the recorded data. The confidence interval (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 (eg, 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”. 


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In general, summaries and analyses will be provided by formulation/dose combination (the 
8 available combinations of the 4 formulations and 2 dose groups), by age group and by cohort. 
For the by-cohort summaries and analyses, those for Cohort 1 are pooled over the 3 age groups 
(ie, groups 1 – 3). 
Unless otherwise specified, all data collected during the trial will be presented in the subject 
listings. For all listings where information on screen failure is collected, the screen failures data 
will be presented at the end of the listing. 
All statistical analyses will be generated using SAS Version 9.2 or higher. 
Handling of Missing Values 
There will be no imputation of missing data with the exception of (1) missing or partial dates (ie, 
start dates of AEs), and (2) titer values measured as below the lower limit of quantification 
(LloQ) for the particular antigen and assay.  
Missing or Partial Dates 
Partial dates will be presented as recorded in the listings. Missing and partial AE start dates will 
be imputed to determine the relationship between the start date of the event and the dose dates of 
the double-blind vaccinations. 
An adverse event should be temporally associated with the correct vaccination dose as far as 
possible. If an event has a missing or incomplete onset 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 of the vaccination dates will be used for imputation. For 
example, if Vaccination 1 is on 01 January 2015 and Vaccination 2 is on 02 March 2015 and the 
event has an incomplete onset date of February 2015, then the event would have an imputed date 
of 01 February 2015. If the available start date information is insufficient to distinguish between 
1 or more vaccination dates, then the event end date will be used to determine the earliest 
possible imputed date relative to the latest vaccination. In the above example if an event is 
known to start in 2015 (day and month missing) and the end date is known as 20 March 2015, 
then an imputed onset date of 02 March (date of Vaccination 2) will be used. If an event is 
missing both onset and end date then the last vaccination date will be used as the imputed onset 
date. Similar logic will be used for partial dates of subjects in age group 4, who receive 3 doses.  
The imputation of partial end dates for AEs will consider information such whether the AEs are 
ongoing by the end of study. 
Titers measured below the LloQ 
If a titer value, for either of the 2 vaccine VLPs or for exploratory endpoint non-vaccine 
antigens, is measured as below LloQ, it will be imputed as the half of the LloQ in summaries and 
analyses, but will be listed as reported in the raw serology data. For example, a serologic assay 
with LloQ = 30 generally reports values below LloQ as “<30”. The data listings will present the 
values as “<30”, while values of 15 (30/2) are to be used in the summaries and analyses.  
Since the missing data resulting from dropouts in vaccine trials are typically classified as missing 
completely at random (MCAR) [1], a simple way of handling the missing data is to use a 


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“complete case analysis”. That is, the subjects with missing data are to be excluded. Complete 
case analysis is essentially being done since the per-protocol analysis set (PPS) excludes subjects 
not receiving the full vaccine regimen or not having data at the primary endpoint times of Day 57 
(Cohort 1) or Day 140 (Cohort 2). If more than 20% of the subjects have missing data for the 
primary immunogenicity endpoint, multiple imputation methods may be explored as a sensitivity 
analysis. 
Handling of Temperature Measurements 
If temperature data (whether collected by subject via memory aid, 30-minute in-clinic 
assessment, or as part of vitals collection at exam) contain a mixture of Fahrenheit and 
centigrade measurements, a temperature value in centigrade will be derived from the collected 
measurement as follows. If the original value was recorded in centigrade, the derived 
temperature value will be set equal to the recorded value; if the recorded value is in Fahrenheit, 
the derived temperature value will be the conversion to degrees Fahrenheit.  
All summaries and analyses of temperature will be presented in centigrade. However, the 
‘temperature as recorded’ will be retained in the analysis dataset. The ‘temperature as recorded’ 
and ‘temperature in degrees centigrade’ will both be presented in the relevant data listing. 
Baseline Definition and Windowing Conventions  
Study Day 1 is defined as the date of the first vaccination, as recorded on the eCRF vaccination 
page. Other study days are defined relative to Study Day 1, with Day -1 being the day prior to 
Day 1. In addition, day relative to vaccination will be derived for each vaccination dose. For 
example, day relative to the first dose will be equal to the Study Day. Day relative to the second 
dose will start with a value of 1 on the day of the second dose and so on for each vaccination 
given. Day relative to dose is of use for tables presenting summaries of events relative to dose.  
For listings presenting observations or events by day, both the Study Day and Day Relative to 
Dose will be presented. 
Baseline is defined as the last non-missing measurement taken before the first dose of 
vaccination (Day 1), unless otherwise defined for a particular endpoint parameter. 
A windowing convention will be used to determine the analysis value for a given study visit for 
observed data analyses. The window definitions as outlined below in Table 7.a and Table 7.b 
will be used for the immunogenicity (serology and CMI) and vital signs, respectively. The 
window conventions are:  
1. A window of +/- 7 days from the target day is applied to the following visits:  
Study Days 29 and 57 for cohort 1 and Study Days 56, 84, 112, and 140 for cohort 2;  
2. A window of +/- 28 days from the target day is applied to the following visits: Study Day 
210 for cohort 1 and Study Day 293 for cohort 2.  
The windows for immunogenicity are constructed by dosing period relative to actual dosing day. 
Windows for vital signs are constructed relative to the actual study day. 


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One or more results for a particular immunogenicity or vital sign variable may be obtained in the 
same visit window (see study window definitions in Table 7.a and Table 7.b). In such an event, 
the result with the date closest to the expected visit date will be used. In the event that 2 
observations are equidistant from the expected visit date, the later observation will be used. 
Table 7.a 
Visit Windows for Immunogenicity by Visit  
 
 
 
 
Visit Window (Study Day) 
Cohort 
Period 
Visit 
Day Relative to Dose 
within the Period(b) 
Serology 
CMI and 
Avidity(c) 
1 
Period 1 
(Relative to Dose 1) 
Baseline(a) 
≤1 
≤1 
≤1 
Day 29 
29 
22 – 36 
22 – 36 
Period 2 
(Relative to Dose 2) 
Day 57 
29 
22 – 36 
22 – 36 
Day 210 
182 
154 – 210 
--- 
2 
Period 1 
(Relative to Dose 1) 
Baseline(a) 
≤1 
≤1 
≤1 
Day 56 
56 
49 – 63 
49 – 63 
Period 2 
(Relative to Dose 2) 
Day 84 
29 
22 – 36 
22 – 36 
Period 3 
(Relative to Dose 3) 
Day 140 
29 
22 – 36 
22 – 36 
Day 293 
182 
154 – 210 
--- 
(a) Where time is available, the time of the collection must be prior to the first dose of study drug. Day 1 
observations taken after the first dose are considered post-baseline values.  
(b) For each period, the administration of the study drug is designated as Study Day 1. For analyses within a 
period, the study day value is incremented by 1 for each date following the vaccine administration. Dates 
prior to the vaccine administration are decremented by 1, with the date preceding the vaccine 
administration designated as Study Day -1 (there is no Study Day 0). 
(c) CMI is measured only for Cohort 1. 
Table 7.b 
Visit Windows for Vital Signs by Visit  
Cohort 
Visit 
Visit Window (Study Day) 
Vital Signs 
1 
Baseline(a) 
≤1 
Day 29 
22 – 36 
2 
Baseline(a) 
≤1 
Day 56 
49 – 63 
Day 112 
105 - 119 
(a) Where time is available, the time of the collection must be prior to the first dose of study drug. Day 1 
observations taken after the first dose are considered post-baseline values. 
 
In-Clinic Reactogenicity Assessments and Diary Data 
On vaccination days, at 30 minutes following the dose, in-clinic assessments of reactogenicity 
(solicited local and systemic AEs) and temperatures are collected onto the eCRF. These data are 
only collected on vaccination days so visit window rules do not apply. 


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In addition, solicited local and systemic Aes and body temperature are recorded daily (by diary) 
by the subject’s legal guardian for 7 days following each dose (day of dose plus 6 additional 
days). These data are collected at the study visit following the dose and contain entries by day 
within that interval. Visit window rules will not be applied to the diary data; they will be 
summarized by diary day (and within specified diary day intervals, eg, 1-7, 1-3, 4-7) following 
vaccination. 
7.2 
Analysis Sets 
The analyses sets are defined as follows: 
Safety Analysis Set: all subjects who receive at least 1 dose of vaccine (NoV GI.1/GII.4 bivalent 
VLP vaccine or control vaccine). 
Full Analysis Set (FAS): all subjects who are randomized and have at least 1 NoV GI.1/GII.4 
bivalent VLP vaccine injection. 
Per-Protocol Analysis Set (PPS): all subjects who receive the planned vaccination and do not 
have major protocol violations will be included in the PPS. 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 major protocol violations will be identified prior to unblinding from 
review of study monitoring deviation logs and through programmatic review of blinded data, 
based on pre-specified criteria. Clinical judgment from Takeda will be necessary to classify each 
deviation as a “major” violation or not. The major protocol violation criteria will be finalized as 
part of the blind data review prior to the interim analysis (Day 57 for Cohort 1 and Day 140 in 
Cohort 2) and may include: 
1) Not meeting entry criteria, based on selected inclusion/exclusion criteria (exclusion criteria 
#6 and #7) defined in protocol sections 7.1 and 7.2;  
Exclusion criterion #6: Known or suspected impairment/alteration of immune function, 
including the following:  
a) Children <18 months of age with history of repeated episodes of acute otitis media 
(AOM) in the first 6 months of life (AOM defined as a bulging tympanic membrane) 
and not to be confused with otitis media with effusion (OME). 
b) Chronic use of oral steroids (equivalent to 20 mg/day prednisone for ≥12 weeks / ≥2 
mg/kg body weight /day for ≥2 weeks) within 60 days prior to Day 1 (use of inhaled, 
intranasal, or topical corticosteroids is allowed).  
c) Receipt of parenteral steroids (equivalent to 20 mg/day prednisone ≥12 weeks / ≥2 
mg/kg body weight /day for ≥2 weeks) within 60 days 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.  


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f) Receipt of immunosuppressive therapy within 6 months prior to Day 1.  
g) Human immunodeficiency virus (HIV) infection or HIV-related disease.  
h) Chronic Hepatitis B or C infection. 
i) Heritable immunodeficiency.  
Exclusion criterion #7: Abnormalities of splenic or thymic function. 
2) Receiving wrong treatment. 
3) Receiving prohibited therapies in the following categories (also specified in protocol 
Section 9.1.2): 
 Parenteral immunoglobulin preparation, blood products, and/or plasma 
derivatives within 3 months of the first vaccination. 
 Immunosuppressive therapy within 6 months or systemic (eg, oral or parenteral) 
corticosteroid treatment within 60 days prior to vaccine administration or planned 
during the trial period. 
4) Significant deviation from protocol-specified dosing and/or sample collection regimen as 
subject to pre-lock blinded medical review. 
5) Not receiving all planned doses of the investigational vaccine. 
6) Did not have evaluable blood sample at Baseline and Day 57 (for subjects from Cohort 1) 
and Baseline and Day 140 (for subjects from Cohort 2). 
7) Other major violations, which may be identified during blinded data review prior to the 
interim analysis (Day 57 for Cohort 1 and Day 140 in Cohort 2) and study completion 
(Day 210 in Cohort 1 and Day 293 in Cohort 2).  
The primary population for immunogenicity analyses will be based on the PPS. Supportive 
immunogenicity analyses on the primary and key secondary endpoints will also be performed 
using FAS. All safety analyses will be based on the Safety Analysis Set. Subjects excluded from 
any of the analysis datasets will be listed with the reason for exclusion in the final clinical study 
report. Major violations resulting in exclusion from the PPS will also be summarized by reason 
for exclusion. 
7.3 
Disposition of Subjects 
Disposition of all screened subjects will be summarized descriptively, including a summary of 
the number of screened subjects and the number of randomized subjects by group. The primary 
reasons for ineligibility for randomization will be summarized by group. The number of 
randomized patients by treatment arm and center, and analysis populations by group and 
formulation/dose combination will also be presented. 
Disposition for all randomized subjects will be summarized by the 8 formulation/dose 
combinations within each group and cohort. Disposition categories include: 


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 Number of randomized subjects and number of randomized subjects but not dosed; 
 Number of subjects completing the vaccine regimen/study visits; 
 Number of subjects who prematurely discontinued the vaccine regimen/study visits; 
 Primary reason for premature discontinuation of the vaccine regimen/study visits. 
Primary reason for premature discontinuation of the vaccine regimen/study visits will be 
summarized. For interim analysis, a subject is to be assumed ongoing unless he/she completed 
the end of study eCRF page for Day 210 (cohort 1) or Day 293 (cohort 2), indicating either 
completion or early termination. 
Protocol deviations pertaining to study conduct are routinely collected and reviewed as part of 
study monitoring. These deviation logs are maintained by study management. Non-minor 
deviations will be transferred to the clinical data base and presented in the subject data listings. 
As described in Section 7.2 (under PPS), deviations will also reviewed as part of blinded data 
review prior to interim and final data locks to determine if any deviation constitutes a major 
protocol violation. 
7.4 
Demographic and Baseline Characteristics 
Age, gender, race, and other baseline characteristics will be summarized descriptively by 
formulation arm and dose group, overall and separately for each of the groups in the cohorts, for 
randomized subjects and subjects in the PPS. Baseline characteristics will include the numbers 
and percentages of subjects with Baseline (pre-vaccination) values of antibody titers below the 
LLoQ for each assay (Pan-Ig, HBGA, and IgA) for each VLP antigen (GI.1 and GII.4). In 
addition the number and percentage of subjects with values below the LLoQ for all assays and 
antigens will be provided.  
7.5 
Medical History and Concurrent Medical Conditions 
Medical history and concurrent medical conditions will be coded using the Medical Dictionary 
for Drug Regulatory Activities (MedDRA, Version 17.0 or later) coding system. 
Frequencies and percentages of subjects by medical history and concurrent medical conditions 
will be summarized by system organ class (SOC) and preferred term (PT) for the safety 
population and by age group, dose group and formulation arm. Multiple entries for an individual 
patient under the same SOC/PT will only be counted once 
7.6 
Medication History and Concomitant Medications 
Medication history and concomitant medications will be coded using the World Health 
Organization DRUG dictionary (WHODrug, 01MAR2014 version or later). 
Medication history includes all medication that was taken but ended at informed consent or 
within 3 months prior to the time of informed consent. Concomitant medications include 
medications taken from informed consent through post-study follow-up. 


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Statistical Analysis Plan Amendment 1 Final 
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CONFIDENTIAL 
Frequencies and percentages of subjects by medication history and concomitant medications will 
be summarized by preferred medication name for the safety population and by group, dose group 
and formulation arm. Subjects with multiple uses of a medication history or concomitant 
medication will be counted once for a given preferred medication name.  
A glossary of medication history and concurrent medications by preferred medication name will 
be presented. 
7.7 
Duration of Follow up and Vaccine Regimen Compliance 
Compliance rate will be summarized by the 8 formulation/dose combinations for each group, by 
presenting the number and percentage of subjects receiving each vaccine dose. The vaccination 
date/time information will be listed for each subject. The duration of follow-up will be 
summarized as a continuous variable, and also as a frequency and percentage of subjects in the 
following categories: (1.1) 1 – 29 days, (1.2) 30 - 57 days, (1.3) > 57 days for cohort 1 and (2.1) 
1 - 56 days, (2.2) 57 - 112 days, (2.3) 113 - 140 days, (2.4) >140 days for cohort 2. The duration 
of follow-up is defined as the number of days from the first vaccination to the date of last contact 
specified on the End of Study Visits form. This will generally be the date of the last clinic visit 
but could be a phone contact. For interim analyses, if the End of Study Visits form is not 
available, the date of data cutoff will be used for calculation 
7.8 
Immunogenicity Analysis 
General Methodology 
The primary population for immunogenicity analyses will be the PPS. Supportive 
immunogenicity analyses on primary and key secondary endpoints will also be performed using 
FAS. 
Descriptive statistics for the primary, secondary, and exploratory endpoints will be computed for 
all available assays at all relevant time points and include the following: 
- 
Titer values (eg, GMT, BT50, GMFR): geometric mean, GSD, 95% CIs, minimum, and 
maximum; 
- 
Other continuous endpoints: mean, SD, median, minimum, and maximum;  
- 
Categorical variable (eg, seroresponse rate): number and percentage of subjects, and 95% 
CIs in specified categories. The 95% CI of seroresponse rate will be calculated using 
exact (Clopper-Pearson) method.  
Cohorts will be analyzed separately due to different number of doses (1 or 2 in Cohort 1; 2 or 3 
in Cohort 2).  
Analysis of covariance (ANCOVA) will be conducted for continuous outcome parameters 
(eg, GMT, GMFR), examining the effect of formulation/dose combination using log-transformed 
values of the endpoint as the dependent variable and the corresponding log-transformed baseline 
(pre-vaccination) value as a continuous covariate. The ANCOVA models will include group as a 
factor for analyses of Cohort 1 with a group by formulation/dose combination interaction term if 


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CONFIDENTIAL 
appropriate as follows. If the interaction term p-value is <= 0.05, the term will remain in the 
model. If the p-value is >0.05 it will be removed. For Cohort 1, the model will include estimates 
for treatment (formulation/dose combination) effect within each group, and at the cohort level 
across groups. A factor for country will be included in all models. 
For binomial outcomes the Cochran-Mantel-Haenszel (CMH) method [2] for difference in 
proportions will be conducted, stratified by group (Cohort 1).  
All pairwise comparisons (with the lower level as a reference group) will be presented, without 
adjustments for multiplicity.  
Pre-specified comparisons of interest will be tested. The pre-specified comparisons of interest 
are the following: 
- 
“A: 15/15, 1 Dose”   vs. “A: 15/15, 2 Dose” 
- 
“A: 15/15, 1 Dose”   vs. “B: 15/50, 2 Dose” 
- 
“B: 15/50, 1 Dose”   vs. “C: 50/50, 1 Dose” 
- 
“B: 15/50, 1 Dose”   vs. “B: 15/50, 2 Dose”  
- 
“C: 50/50, 1 Dose”   vs. “B: 15/50, 2 Dose” 
- 
“C: 50/50, 1 Dose”   vs. “C: 50/50, 2 Dose” 
- 
“C: 50/50, 1 Dose”   vs. “D: 50/150, 2 Dose” 
- 
“D: 50/150, 1 Dose” vs. “D: 50/150, 2 Dose” 
- 
“A: 15/15, 2 Dose”   vs. “B: 15/50, 2 Dose” 
- 
“A: 15/15, 2 Dose”   vs. “C: 50/50, 2 Dose” 
- 
“A: 15/15, 2 Dose”   vs. “D: 50/150, 2 Dose” 
- 
“B: 15/50, 2 Dose”   vs. “C: 50/50, 2 Dose” 
- 
“B: 15/50, 2 Dose”   vs. “D: 50/150, 2 Dose” 
- 
“C: 50/50, 2 Dose”   vs. “D: 50/150, 2 Dose”. 
Subjects with baseline values below the LLoQ for all assays (Pan-Ig, HGBA, and IgA) and VLP 
antigens (GI.1 and GII.4) will be identified. If warranted, selected immunogenicity summaries 
may be prepared for subsets of interest. 
7.8.1 Primary Immunogenicity Endpoint(s) 
The primary immunogenicity endpoint for this trial is seroresponse rate, defined as the 
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 Pan-Ig ELISA at Day 57 (Cohort 1) and Day 140 
(Cohort 2). The primary analyses will be based on the PPS data but will also be provided using 
the FAS. 
The seroresponse rates and 95% CIs will be summarized (as described in the General 
Methodology of Section 7.9) for each of the 8 formulation/dose combinations (4 formulation 
arms; 1 and 2 [or 2 and 3] doses), by group. These summaries will also be provided at the cohort 
level (pooling subjects across groups in Cohort 1). The 95% CI of seroresponse rate will be 


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CONFIDENTIAL 
(ie, according to the formulation arms, separately for the 1 and 2 (or 2 and 3) dose groups), for 
each age stratum, and overall within each cohort. 
7.11.1 Adverse Events 
In-Clinic Assessments of Reactogenicity 
In-clinic 30-minutes post-vaccination assessments of reactogenicity AEs include local events 
(injection site pain, erythema/redness, induration, and swelling) and systemic events (headache, 
fatigue, myalgia, arthralgia, vomiting [number per day/intensity] and diarrhea [number per day/ 
consistency] for children aged 4 to <9 years; and irritability/fussiness, drowsiness, loss of 
appetite, vomiting [number per day/intensity], and diarrhea [number per day/consistency] for 
children aged 6 weeks to < 4 years). Severity of injection site pain and of the systemic events is 
assessed in-clinic as mild, moderate or severe according to Protocol Tables 9a (age 4 – 9 years) 
and 9b (age 6 weeks to <4 years). Measurements of the largest diameter for injection site 
erythema/redness, swelling, and induration are collected. These measurements will be used to 
derive severity grades based on the criteria included in Appendix A and Appendix B. 
Temperature measurements are also collected and a systemic event of ‘fever’ will be derived as 
Yes/No based on temperatures >= 38 degrees centigrade [3]. Temperature levels will also be 
categorized in 0.5 degree intervals (centigrade). Number and percent of subjects with 
reactogenicity events 30-minutes post vaccination will be summarized for each vaccine 
administered, for each local and systemic event, and by severity. 
Subjects’ Legal Guardian Assessments of Reactogenicity via Subject’s Diary 
Reactogenicity is also assessed by the subject’s legal guardian for 7 days following each 
vaccination (day of vaccination and the following 6 days) via diary collection of solicited AEs. 
These include local events (injection site pain, erythema/redness, induration, and swelling) and 
systemic events of headache, fatigue, myalgia, arthralgia, vomiting (number per day/intensity), 
and diarrhea (number per day/consistency) for children aged 4 to <9 years; and 
irritability/fussiness, drowsiness, loss of appetite, vomiting (number per day/intensity), and 
diarrhea (number per day/consistency) for children aged 6 weeks to < 4 years. Measurements of 
the largest diameter for injection site erythema/redness, swelling, and induration are collected. 
These measurements will be used to derive severity grades based on the criteria presented in 
Appendix A and Appendix B. Temperature measurements are also collected and a systemic 
event of ‘fever’ will be derived as Yes/No based on temperature >= 38 degrees centigrade. 
Temperature levels will also be categorized in 0.5 degree intervals (centigrade). Severity 
categories for each solicited AE are defined in Protocol Section 9.1.7. In addition, the 
relationship of solicited systemic symptoms occurring within 7 days after each vaccination is 
assessed by the investigator during diary review.  
For each solicited AE, the percentage of subjects will be summarized by event severity for each 
day for the 7 days following vaccination (including the day of vaccination) and overall within the 
7 days following vaccination. 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 


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CONFIDENTIAL 
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.  
The relationship of solicited systemic symptoms occurring within 7 days after each vaccination 
will also be tabulated. If a subject reported more than one episode of the same event, then the 
strongest relationship will be included in the summaries. 
A summary of the day of first onset of each event with intensity grade mild or higher and the 
number of days subjects reported experiencing each event with intensity grade mild or higher 
will also be provided for each vaccination. The number of days a subject reported experiencing a 
symptom is calculated as the total of all days the subject reported the symptom, regardless of 
whether the symptom was reported on consecutive days (eg, a headache reported on Day 1, Day 
3, and Day 4 would be included with a duration of 3 days).  
For all summaries by each vaccination, summaries after any vaccination will also be included. 
Unsolicited AEs 
Unsolicited AEs will be coded using the MedDRA, Version 17.0 or later.  
All unsolicited AEs will be collected for 28 days following each vaccination. To attain 28 full 
days, all AEs with onset on the day of vaccination (day 1 relative to the given vaccination day) 
through day 29 relative to the given vaccination day will be included. SAEs and AEs leading to 
subject withdrawal from the trial will be collected throughout the trial. 
Unsolicited AEs will be assigned to vaccine dose (1st, 2nd or 3rd, if applicable). All summaries 
described in this Section will be generated by vaccine dose number. Summaries by each 
vaccination will also include summaries after any vaccination 
The incidence of AEs will be summarized by SOC and PT by presenting the number and 
percentage of subjects with an AE. A subject will be counted only once within each SOC and 
within each PT, or the overall category. Separate summaries will be provided for AEs by 
maximum severity (mild, moderate, severe) and relationship (not related, related) to study 
vaccine. If a subject reported more than one AE within a SOC or PT, then the AE with the 
highest known severity or strongest relationship within each SOC and each PT will be included 
in the summaries by severity or relationship, respectively. These summaries will generally be 
presented in the following 3 ways: 1) overall up to 28 days after each vaccination, 2) with onset 
between 1 and 7 days after each vaccination, and 3) with onset between 8 and 28 days after each 
vaccination. 
In addition, the incidence of AEs will be summarized by SOC and by PT separately. Vaccine-
related AEs and vaccine-related AEs by maximum intensity will be summarized by SOC and PT. 
These summaries will be provided for events occurring up to 28 days after each vaccination.  
In addition, for each group, most frequent unsolicited AEs (with frequency of preferred term 
greater than 5% and with a minimum of two subjects in any of the 8 formulation/dose 
combination groups) will be summarized (number/percent of subjects with the event) up to 28 
days after either vaccination by SOC and PT. This summary will also be done for most frequent 
non-serious events (presenting both number of events and number/percent of subjects with the 


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CONFIDENTIAL 
event). The number of most frequent non-serious events will also be presented. Note that the 
summaries of most frequent non-serious events are being prepared only for trial results 
disclosure requirements and will not necessarily be addressed in the clinical study report (CSR). 
The incidence of AEs leading to investigational vaccine withdrawal will be summarized by SOC 
and PT after each vaccination and for the entire study duration (including all events leading to 
withdrawal with onset after the first vaccination dose through the end of the study).  
The number of SAEs and number/percent of subjects experiencing SAEs will be summarized by 
SOC and PT after each vaccination and for the entire study duration (including all reported SAEs 
with onset after the first vaccination dose).  
In addition to the overall AE listing, separate listings for SAEs, AEs leading to subject 
withdrawal from the trial, AEs resulting in death will be provided 
7.11.2 Clinical Laboratory Evaluations 
{Not applicable. Not a routine procedure in the protocol}. 
7.11.3 Vital Signs 
Vital signs are collected during the scheduled physical examinations. Heart rate, body 
temperature, height, and weight will be summarized descriptively at each scheduled visit. The 
change from baseline to each scheduled post-baseline visit will also be presented. Measurement 
parameters will be sorted alphabetically 
7.11.4 12-Lead ECGs 
{Not Applicable. Not a routine procedure in the protocol} 
7.11.5 Other Observations Related to Safety 
{Not applicable}  
7.12 
Interim Analysis 
Interim analyses are planned in this study: Day 57 for Cohort 1 and Day 140 for Cohort 2 
(primary analysis time point). The Day 57 interim for Cohort 1 will be provided initially for 
Groups 1 and 2, which will complete Day 57 substantially earlier than Groups 2a and 3. The Day 
57 IA for Groups 2a and 3 combined will be provided at a later time. Thus, the Day 57 IA will be 
conducted in two parts to be followed by the Day 140 IA in Group 4. Interim analyses will be 
finalized after the primary safety and immunogenicity data for the group are available, ie, after 
all subjects from Cohort 1 have completed Day 57 or terminated early and after all subjects from 
Cohort 2 have completed Day 140 or terminated early.  
The interim analyses will be performed by a separate group of unblinded statisticians and 
programmers at Quintiles who will have access to individual treatment assignments, but will not 
be involved in subsequent study conduct. The rest of the personnel involved in the conduct of the 
study, including those at Takeda, Quintiles, and the study sites, will remain blinded to the 


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CONFIDENTIAL 
individual subject data (including treatment assignments) until unblinding after database lock 
(Day 210 for Cohort 1 and Day 293 for Cohort 2).  
The interim results will be shared with limited personnel at Takeda and will include only 
aggregate group unblinded reports. Individual results will not be shared with any Takeda 
personnel or the Quintiles blinded team. The list of team members from the study who are given 
access to the group results will be documented in an unblinding plan. Statistical Methodology for 
interim analyses will be the same as for final study analysis, described in previous sections, but 
may be a subset of the analyses to be performed at the end of the study.  
Data listings containing subject-level unblinding information will not be generated for either the 
Day 57 or Day 140 analyses for Cohort 1 and Cohort 2, respectively.  
Complete clinical database subject listings will be provided only at final analysis (ie, Day 210 for 
Cohort 1 and Day 393 for Cohort 2) after the database is locked  
7.13 
Changes in the Statistical Analysis Plan  
Changes from the Analyses Planned in Protocol Version 3.0, 1 March 2016 
Section 13.1.4 of the Protocol (Version 3.1) referred to exclusion of biologically implausible 
measurements. Large or implausible outlying values may be identified by medical reviewers 
during blind data review and queried before database lock. However, no criteria to identify 
implausible measurements will be defined in this SAP. Due to the age range of the subjects and 
the multi-regional settings in this trial, a reliable and consistent cut-off for implausible 
measurements cannot be developed. Hence all values in the database at time of database lock 
will be included in the analyses.  
Section 6.1 in the study protocol indicated that two interim analyses are to be performed after the 
primary safety and immunogenicity data are available (ie, Day 57 for Cohort 1 and Day 140 for 
Cohort 2). Cohort 1 consists of 3 age groups enrolled in age step-down fashion. However due to 
delay in availability of investigational product, enrollment of Group 3 has been delayed. 
Therefore, the Day 57 interim analysis of Cohort 1 will proceed on schedule but will initially 
include only age groups 1 and 2. After study enrollment resumes, Day 57 interim analyses of 
Group 3 will be provided at a later time. 
Description of the Amendment 1 changes to the initial Statistical Analysis Plan  
The initial NOR-202 SAP (11 February 2016) has been amended to address changes to the  
NOR-202 study design effected in Protocol Version 4.0, (Amendment 3) 01 March 2016 [4]. A 
description of those changes follows. Unless otherwise stated, the reason for each of the changes 
is to align with Protocol Version 4.0 by updating statistical methodology text to reflect the 
addition of Group 2a to the study. 


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CONFIDENTIAL 
Section 4.4, Figure 4.a 
Prior Text: 
Figure 1 
Schematic of Trial Design 
 
 


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CONFIDENTIAL 
Amended Text: 
Figure 4.a 
Schematic of Trial Design 
 
 
Reason for Change: 
Reflect the addition of Group 2a to the study. 
 
Section 4.4, Figure 4.a description 
Prior Text: 
A total of 720 healthy subjects will be randomized to the following cohorts, with stratification by 
country and group: 
 Cohort 1, N=360 (Group 1: aged 4 to less than 9 years; Group 2: aged 1 to less than 4 years; 
Group 3: aged 6 months to less than 1 year [N=120 each]: subjects will be randomized with 
equal probabilities to 1 of the 8 unique combinations of formulation arms and dose groups 
(ie, 4 formulation arms and 1 or 2 doses). Each of the combinations will consist of 
approximately 15 subjects per age group. 
 Cohort 2 (Group 4: aged 6 weeks to less than 6 months): 360 subjects will be randomized 
with equal probabilities to 1 of the 8 unique combinations of formulation arms and dose 
840 subjects 
aged  
6 weeks to < 9 years
Cohort 1
Subjects aged 
6 months to < 9 
years
N= 480
Group 1
4 to <9 years
120  subjects
One Dose
Two Doses
Group 2
1 to < 4 years
120 subjects
One Dose
Two Doses
Group 2a*
1 to < 4 years
120 subjects
One Dose
Two Doses
Cohort 2*
(Group 4)
Subjects aged
6 weeks to <6 
months
N= 360
Two Doses
Three Doses
Group 3*
6 months to < 1 
year
120 subjects
One Dose
Two Doses
* Recently manufactured clinical trial material lots


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Statistical Analysis Plan Amendment 1 Final 
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CONFIDENTIAL 
groups (ie, 4 formulation arms and 2 or 3 doses). Each of the combinations will consist of 
approximately 45 subjects. 
Amended Text: 
A total of 840 healthy subjects will be randomized to the following cohorts, with stratification by 
country and group: 
 Cohort 1, N=480 (Group 1: aged 4 to less than 9 years; Group 2: aged 1 to less than 4 years; 
Group 2a: aged 1 to less than 4 years; Group 3: aged 6 months to less than 1 year [N=120 
each]: subjects will be randomized with equal probabilities to 1 of the 8 unique combinations 
of formulation arms and dose groups (ie, 4 formulation arms and 1 or 2 doses). The 
additional 120 children, designated as Group 2a, are being included to evaluate the 
recently manufactured NoV bivalent VLP vaccine formulations prior to enrolling 
children in Groups 3 and 4. Each of the combinations will consist of 15 subjects per group. 
Thus Cohort 1 consists of 480 subjects in Groups 1, 2, 2a, and 3 combined. 
 Cohort 2 (Group 4: aged 6 weeks to less than 6 months): 360 subjects will be randomized to 
receive the recently manufactured NoV bivalent VLP vaccine with equal probabilities to 1 of 
the 8 unique combinations of formulation arms and dose groups (ie, 4 formulation arms and 2 
or 3 doses). Each of the combinations will consist of 45 subjects. 
Reason for Change: 
Reflect the addition of Group 2a to the study. 
 
Section 4.4, second paragraph following figure description bullets 
Prior Text: 
Subjects 6 months to less than 9 years of age (inclusive, Cohort 1) will receive either 1 or 2 doses 
by IM injection, at least 28 days apart (Days 1 and 29), in 3 age groups (Group 1: aged 4 to less 
than 9 years; Group 2: aged 1 to less than 4 years; Group 3: aged 6 months to less than 1 year). 
Infants 6 weeks to less than 6 months of age (Group 4/Cohort 2) will receive 2 or 3 doses by IM 
injection given approximately 56 days apart (Days 1, 56, and 112). Routine child and infant 
vaccinations will be given on schedule per the national guidelines approximately 28 days apart 
from the investigational vaccine in each age group. 
Amended Text: 
Subjects 6 months to less than 9 years of age (inclusive, Cohort 1) will receive either 1 or 2 doses 
by IM injection, at least 28 days apart (Days 1 and 29), in 4 groups comprising 3 age ranges 
(Group 1: aged 4 to less than 9 years; Group 2 and Group 2a: each group aged 1 to less than 
4 years; and Group 3: aged 6 months to less than 1 year). Infants 6 weeks to less than 6 months 
of age (Group 4/Cohort 2) will receive 2 or 3 doses by IM injection given approximately 56 days 
apart (Days 1, 56, and 112). Routine child and infant vaccinations will be given on schedule per 
the national guidelines approximately 28 days apart from the investigational vaccine in each age 
group. 


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CONFIDENTIAL 
Reason for Change: 
Reflect the addition of Group 2a to the study and make it clear that the additional group (2a) is 
enrolled in the dame age range as group 2. 
 
Section 4.4, fourth paragraph following figure description bullets 
Prior Text: 
Two interim analyses will be performed after the primary safety and immunogenicity data are 
available (ie, Day 57 for Cohort 1 and Day 140 for Cohort 2, primary analysis time point). The 
interim analyses will be performed by a separate group of unblinded statisticians and 
programmers at Quintiles who will have access to individual treatment assignments but will not 
be involved in subsequent study conduct.  
Amended Text: 
Interim analyses will be performed after the primary safety and immunogenicity data are 
available (ie, Day 57 for Cohort 1 and Day 140 for Cohort 2, primary analysis time point). The 
Day 57 IA for Cohort 1 will be provided initially for Groups 1 and 2, who will complete 
Day 57 substantially earlier than Groups 2a and 3. The Day 57 IA for Groups 2a and 3 
combined will be provided at a later time. Thus, the Day 57 IA will be conducted in two 
parts to be followed by the Day 140 IA in Group 4. All interim analyses will be performed by 
a separate set of unblinded statisticians and programmers at Quintiles who will have access to 
individual treatment assignments but will not be otherwise involved in subsequent study 
conduct. 
Reason for Change:  
Update the description of interim analysis strategy to align with the protocol description, 
amended to accommodate the addition of Group 2a and the delayed enrolment of Group 3. 
 
Section 4.4, Investigational Vaccine: 
Prior text: 
Placebo Control: 
Saline will be administered as a single control injection (as the final dose) in order to maintain 
the trial blind for the 1 dose groups in Groups 1, 2, and 3 (Cohort 1) and for the 2 dose group in 
Group 4 (Cohort 2).  
Visit Schedule 
Clinical trial visits will be performed on Days 1, 8, 29, 36, 57, and 210 for Cohort 1 and Days 1, 
8, 29, 56, 63, 84, 112, 119, 140, and 293 for Cohort 2. Telephone contacts will be performed on 
Days 3, 32, and 134 for Cohort 1 and Days 3, 59, 115, and 260 for Cohort 2. 
 


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CONFIDENTIAL 
Revised Text: 
Placebo Control: 
Saline will be administered as a single control injection (as the final dose) in order to maintain 
the trial blind for the 1 dose groups in Groups 1, 2, 2a and 3 (Cohort 1) and for the 2 dose group 
in Group 4 (Cohort 2).  
Visit Schedule 
Clinical trial visits will be performed on Days 1, 8, 29, 36, 57, and 210 for Cohort 1 and Days 1, 
8, 29, 56, 63, 84, 112, 119, 140, and 293 for Cohort 2. Telephone contacts will be performed on 
Days 3, 32, and 134 for Cohort 1 and Days 3, 59, 115, 200 and 260 for Cohort 2. 
Reason for Change: 
Reflect the addition of Group 2a and make a correction to the telephone contact schedule for 
Cohort 2. 
 
Section 4.4, Duration of Trial: 
Prior Text: 
Subjects will be followed for SAEs for 180 days after the last trial dose. Safety follow-up for 
other unsolicited AEs, and concomitant medications will be for 28 days following each trial 
dose.  
Amended Text: 
Expected duration of trial participation for each subject is up to 210 days (Cohort 1) and 
293 days (Cohort 2). Subjects will be followed for SAEs for 180 days after the last trial dose. 
Safety follow-up for other unsolicited AEs, and concomitant medications will be for 28 days 
following each trial dose. 
Reason for Change: 
Clarify the total expected study duration for each subject. 
Section 4.4, Schedules of Protocol Procedures in Table 4.a, Table 4.b and Table 4.c. 
Prior Text: 
Table 1 
Schedule of Trial Procedures for Subjects Aged 6 Months to Less Than 9 Years 
(Cohort 1) 
{Table body and footnotes a-g} 
h. CMI will be analyzed in children aged ≥ 3 years at selected sites. For these subjects, 3 mL of whole blood will 
be obtained for whole blood method assays immediately prior to and approximately 28 days after each dose (eg, 
Days 1, 29, and 57) for a subtotal of 9 mL. Thus, for those children in the CMI subset, a total of 17 mL/subject 
will be obtained for the entire study period. 


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Statistical Analysis Plan Amendment 1 Final 
17 February 2017 
 
CONFIDENTIAL 
Amended Text: 
Table 4.a 
Schedule of Trial Procedures for Subjects Aged 6 Months to Less Than 9 Years 
(Cohort 1 for Groups 1, 2 and 3; N=360) 
{Table body and footnotes a-g} 
h. CMI will be analyzed in a subset of children aged ≥ 3 years at selected sites. For these subjects, 3 mL of whole 
blood will be obtained for whole blood method assays immediately prior to and approximately 28 days after 
each dose (eg, Days 1, 29, and 57) for a subtotal of 9 mL. Thus, for those children in the CMI subset, a total of 
17 mL/subject will be obtained for the entire study period 
 
Table 4.b 
Schedule of Trial Procedures for Subjects Aged 1 to Less Than 4 Years 
(Cohort 1 for Group 2a; N=120) 
Timing 
 
 
Procedure 
Day 1 
Day 3 
Day 8 
Day 29 
Day 32 
Day 36 
Day 57 
Day 134 
Day 210(a) 
Visits 
X 
 
X 
X 
 
X 
X 
 
X 
Phone Contacts(b) 
 
X 
 
 
X 
 
 
X 
 
Visit Window (days) 
- 
-
1/+2 
+3 
+3 
-
1/+2 
+3 
+3 
±7 
+7 
Signed Informed Consent 
X 
 
 
 
 
 
 
 
 
Physical Examination(c) 
X 
 
(X) 
X 
 
(X) 
(X) 
 
(X) 
Trial Vaccine Administration 
X(d) 
 
 
X(d) 
 
 
 
 
 
Diary Card Dispensing 
X 
 
 
X 
 
 
 
 
 
Diary Card Delivery 
 
 
X 
X 
 
X 
X 
 
 
Aes(e) 
Day 1-
28 
 
 
Day 28-
56 
 
 
 
 
 
SAEs(f) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood Draw for Serology (2 mL)(g) 
X 
 
 
X 
 
 
X 
 
X 
Use of (X) indicates that samples or procedures that generally will not be performed but may be performed to investigate 
an AE, previous laboratory abnormality, or at the time of premature discontinuation.  
Footnotes: 
(a) Day 210 is the 6-month end of study visit. 
(b) Phone contacts are only reminder calls on Days 3 and 32; phone contact on Day 134 is for safety data collection 
(Protocol Sections 9.35 and 9.36). 
(c) Complete at the first visit (Day 1), brief physical exam at each vaccination, and symptom-directed thereafter. If 
a subject early terminates (ET), Day 210 procedures should be performed. 
(d) All subjects receive NoV vaccine at Day 1; subjects in the 1 dose groups in Cohort 1 Group 2a receive a saline 
placebo injection at Day 29 whereas subjects in the 2 dose groups in Cohort 1 Group 2a receive NoV vaccine at 
Day 1 and Day 29. 
(e) AEs will be categorized by the investigator by severity (mild, moderate, or severe) and causality (related or not 
related to vaccine). 


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Statistical Analysis Plan Amendment 1 Final 
17 February 2017 
 
CONFIDENTIAL 
(f) SAEs will be reported to the sponsor within 24 hours of the investigator becoming aware of the event. 
(g) Blood draw for serology at 4 visits (all subjects); 2 mL per time point for a total of 8 mL. Anti-NoV specific 
GI.1 and GII.4 VLP antibodies by Pan-Ig ELISA and HBGA antibody assays; GMT, GMFR, and seroresponse 
rate (≥4-fold rise from baseline) will be determined for all available subjects in each formulation group. Serum 
for IgA, Avidity, and HBGA for a panel of GI.1 and GII.4 strains not represented in the vaccine will not be 
evaluated for Group 2a subjects. CMI will not be evaluated for Group 2a subjects. 
 
Reason for Change: 
Separate the schedule of study procedures for Cohort 1 (formerly Table 1) into 2 tables 
(Table 4.a and Table 4.b) to reflect the differences in study procedures for Group 2a and those 
for Groups 1 and 2, and to clarify that samples for CMI are only collected in a subset of groups 1 
and 2. 
 
Prior Text: 
Table 2 
Schedule of Trial Procedures for Subjects Aged 6 Weeks to Less Than 6 Months 
(Cohort 2; N=360) 
 
Amended Text: 
Table 4.c 
Schedule of Trial Procedures for Subjects Aged 6 Weeks to Less Than 6 Months 
(Cohort 2; N=360) 
 
Reason for Change: 
Renumber former Table 2 to Table 4.c. to follow current tables 4.a and 4.b. 
 
Section 5.0, Analysis endpoints, first paragraph: 
Prior Text: 
Endpoints apply to Cohorts 1 and 2 unless otherwise stated.  
Amended Text: 
Endpoints apply to Cohorts 1 and 2 unless otherwise stated. For subjects in Group 2a, the 
serologic assays to the vaccine VLPs for the Pan-Ig ELISA and for the HBGA binding 
assays will each be performed. Notably, the following endpoints will not be performed for 
Group 2a: Avidity, IgA ELISA, CMI for those aged ≥ 3 years, and HBGA binding assay to 
a panel of GI.1 and GII.4 not represented in the vaccine 
Reason for Change: 
Include a general summary of the differences in endpoints between groups 1, 2 and 2a. 
 


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NOR-202 
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Statistical Analysis Plan Amendment 1 Final 
17 February 2017 
 
CONFIDENTIAL 
enrolled into the trial Figure 4.a). Cohort 1 will enroll 3 age groups, oldest group to youngest 
group, in a step-down fashion. The youngest age group (Cohort 2) will be enrolled last. 
Enrollment into each successive age group (oldest to youngest) is initiated based on DMC 
recommendation. The factors under investigation for each age group within each cohort include: 
formulation (4 formulation arms within each age group); and number of doses (2 levels for each 
formulation within each age group). For age groups1-3 (in Cohort 1), the number of active doses 
will be 1 or 2 doses. For age group 4 (Cohort 2), the number of active doses will be 2 or 3. 
Within each cohort, subjects are randomized to 1 of 8 trial arms (2 dose levels for 4 
formulations), with age group as a stratification factor.  
Amended Text: 
This statistical analysis plan (SAP) is based on protocol Amendment 3, Version 4.0, dated 
01 March 2016.  
The purpose of this trial is to evaluate the immunogenicity and safety profile of 4 formulations 
under different dosing regimens in 4 pediatric age ranges. Two cohorts of subjects will be 
enrolled into the trial (Figure 4.a). Cohort 1 will consist of 4 groups (4 to <9 years, 1 to <4 
years [2 groups] and 6 months to <1 year), enrolled in age-step-down fashion as described in 
Section 4.4. The youngest age group (Cohort 2, 6 weeks to <6 months) will be the last to 
complete enrollment. Enrollment into each successive group is initiated based on DMC 
recommendation. Hereafter the age groups (5 groups covering 4 age ranges) will be 
designated as ‘group’. The factors under investigation for each group within each cohort 
include: formulation (4 formulation arms within each group); and number of doses (2 levels for 
each formulation within each group). For groups 1, 2, 2a, and 3 (in Cohort 1), the number of 
active doses will be 1 or 2 doses. For group 4 (Cohort 2), the number of active doses will be 
2 or 3. Within each cohort, subjects are randomized to 1 of 8 trial arms (2 dose levels for 4 
formulations), with group as a stratification factor. The purpose of Group 2a is to evaluate the 
safety and selected immunogenicity endpoints in subjects in the same age range as Group 2, 
but who receive the recently manufactured NoV bivalent VLP vaccine. Statistical methods 
described in the following sections will be essentially the same, but will be done only for the 
endpoints indicated in Section 5.2. 
Reason for Change: 
Reflect the addition of Group 2a to the study.  
 
Section 7.1 Methods of Analysis and Presentation, Handling of Missing Values, Titers 
measured below the LLoQ 
Prior Text: 
If a titer value is measured as below LLoQ, it will be imputed as the half of the LLoQ in 
summaries and analyses, but will be listed as reported in the raw serology data.  
Amended Text: 


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Statistical Analysis Plan Amendment 1 Final 
17 February 2017 
 
CONFIDENTIAL 
If a titer value, for either of the 2 vaccine VLPs or for exploratory endpoint non-vaccine 
antigens, is measured as below LLoQ, it will be imputed as the half of the LLoQ in summaries 
and analyses, but will be listed as reported in the raw serology data.  
Reason for Change: 
Clarify handling of assay titer values below the LLoQ. 
 
Section 7.4 Demographic and Baseline Characteristics 
Prior Text: 
Age, gender, race, and other baseline characteristics will be summarized descriptively by 
formulation arm and dose group, separately for each of the groups in the cohorts, for randomized 
subjects and subjects in the PPS. 
Amended Text: 
Age, gender, race, and other baseline characteristics will be summarized descriptively by 
formulation arm and dose group, overall and separately for each of the groups in the cohorts, 
for randomized subjects and subjects in the PPS. 
Reason for Change: 
Correct omission. 
Section 7.7, Study Drug Exposure and Compliance, section header 
Prior Text: 
7.7 Study Drug Exposure and Compliance 
Amended Text: 
7.7 Duration of Follow-up and Vaccine Regimen Compliance 
Reason for Change: 
In vaccine studies there is no continuous dosing. Therefore study duration is summarized along 
with vaccination regimen compliance. 
 
Section 7.8, Immunogenicity Analysis, General Methodology 
Prior Text: 
Analysis of covariance (ANCOVA) will be conducted for continuous outcome parameters, 
examining the effect of formulation/dose combination using log-transformed values of the 
endpoint as the dependent variable and the corresponding log-transformed baseline (pre-
vaccination) value as a continuous covariate. The ANCOVA models will also include age group 
as a factor for analyses of Cohort 1 with an age group by formulation/dose combination 
interaction term as follows. If the interaction term p-value is <= 0.05, the term will remain in the 


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Statistical Analysis Plan Amendment 1 Final 
17 February 2017 
 
CONFIDENTIAL 
model. If the p-value is >0.05 it will be removed. For Cohort 1, the model will include estimates 
for treatment (formulation/dose combination) effect within each age group, and at the cohort 
level across age groups. A factor for country will be included. 
Amended Text: 
Analysis of covariance (ANCOVA) will be conducted for continuous outcome parameters (eg, 
GMT, GMFR), examining the effect of formulation/dose combination using log-transformed 
values of the endpoint as the dependent variable and the corresponding log-transformed baseline 
(pre-vaccination) value as a continuous covariate. The ANCOVA models will include group as 
a factor for analyses of Cohort 1 with a group by formulation/dose combination interaction term 
if appropriate as follows. If the interaction term p-value is <= 0.05, the term will remain in the 
model. If the p-value is >0.05 it will be removed. For Cohort 1, the model will include estimates 
for treatment (formulation/dose combination) effect within each group, and at the cohort level 
across groups. A factor for country will be included in all models. 
Reason for Change: 
(1) clarify that country will be included as a factor in all models (2) change text to refer to group 
rather than age group, to clarify that group (4 groups [groups 2 and 2a with same age range]), not 
age range per se, is the factor of interest in the statistical model for Cohort 1 and (3) provide 
examples of continuous parameters 
 
Section 7.8, Immunogenicity Analysis, comparisons of interest 
Prior Text: 
Subjects with baseline values below the LLoQ for all assays (Pan-Ig, HGBA, and IgA) and VLP 
antigens (GI.1 and GII.4) will be identified. If warranted, selected immunogenicity summaries 
may be prepared by for this subset. 
Amended Text: 
Subjects with baseline values below the LLoQ for all assays (Pan-Ig, HGBA, and IgA) and VLP 
antigens (GI.1 and GII.4) will be identified. If warranted, selected immunogenicity summaries 
may be prepared for subsets of interest. 
Reason for Change: 
Correction of typo and clarification of phrase. 
 
Section 7.8.1 Immunogenicity Analysis, Secondary and Exploratory Continuous 
Immunogenicity Endpoints 
Prior Text: 
GMT, BT50 and GMFR will be analyzed with an ANCOVA model examining the effect of 
formulation/dose combination using the log-transformed value as the dependent variable and the 
corresponding log-transformed baseline value as a covariate. The ANCOVA models will include 


NOR-202 
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Statistical Analysis Plan Amendment 1 Final 
17 February 2017 
 
CONFIDENTIAL 
age group as a factor for analyses of Cohort 1 with an age group by formulation/dose 
combination interaction term included as follows. If the interaction term p-value is <= 0.05, the 
term will remain in the model. If the p-value is >0.05 it will be removed. For Cohort 1, the model 
will include estimates for treatment (formulation/dose combination) effect within each age 
group, and at the cohort level across age groups. A factor for country will be included. All the 
applicable pairwise comparisons will be provided with lower levels as the reference groups, with 
no adjustments for multiplicity. The 14 comparisons of interest listed in the General 
Methodology of section 7.8 will be tested. The analyses will be based on the PPS. 
Box plots and/or reverse cumulative distribution (RCD) curves will be provided for comparisons 
of interest. 
Amended Text: 
GMT, BT50 and GMFR will be analyzed with an ANCOVA model examining the effect of 
formulation/dose combination using the log-transformed value as the dependent variable and the 
corresponding log-transformed baseline value as a covariate. The ANCOVA models will include 
group as a factor for analyses of Cohort 1 with a group by formulation/dose combination 
interaction term included if appropriate, as follows. If the interaction term p-value is <= 0.05, 
the term will remain in the model. If the p-value is >0.05 it will be removed. For Cohort 1, the 
model will include estimates for treatment (formulation/dose combination) effect within each 
group, and at the cohort level across groups. A factor for country will be included. All the 
applicable pairwise comparisons will be provided with lower levels as the reference groups, with 
no adjustments for multiplicity. The 14 comparisons of interest listed in the General 
Methodology of section 7.8 will be tested. The analyses will be based on the PPS. 
Box plots and/or reverse cumulative distribution (RCD) curves will be provided for comparisons 
of interest. Other graph formats may be included for illustration purpose 
Reason for Change: 
Change text to (1) refer to group rather than age group, to clarify that group (4 groups [groups 2 
and 2a with same age range]), not age range per se, is the factor of interest in the statistical 
model for Cohort 1; (2) clarify method for inclusion of interaction term in final model. 
 
Section 7.12, Interim Analysis 
Prior Text: 
Interim analyses are planned in this study: Day 57 for Cohort 1 and Day 140 for Cohort 2 
(primary analysis time point). The Day 57 interim for Cohort 1 will be provided initially for 
Groups 1 and 2, which will complete Day 57 substantially earlier than Group 3. Group 3 Day 57 
interim analyses will be provided at a later time. Interim analyses will be performed after the 
primary safety and immunogenicity data are available, ie, after all subjects from Cohort 1 have 
completed Day 57 or terminated early and after all subjects from Cohort 2 have completed Day 
140 or terminated early. 
Amended Text: 


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Statistical Analysis Plan Amendment 1 Final 
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CONFIDENTIAL 
Interim analyses are planned in this study: Day 57 for Cohort 1 and Day 140 for Cohort 2 
(primary analysis time point). The Day 57 interim for Cohort 1 will be provided initially for 
Groups 1 and 2, which will complete Day 57 substantially earlier than Groups 2a and 3. The 
Day 57 IA for Groups 2a and 3 combined will be provided at a later time. Thus, the Day 57 
IA will be conducted in two parts to be followed by the Day 140 IA in Group 4. Interim 
analyses will be finalized after the primary safety and immunogenicity data for the group are 
available, ie, after all subjects from Cohort 1 have completed Day 57 or terminated early and 
after all subjects from Cohort 2 have completed Day 140 or terminated early. 
Reason for Change:  
Update the description of interim analysis strategy to align with the protocol description, 
amended to accommodate the addition of Group 2a and the delayed enrolment of Group 3. 
 
Section 7.13, Changes in the Statistical Analysis Plan 
Updated to provide a change history in this document (SAP Amendment 1) relative to the 
NOR-202 SAP (11 February 2016). 


NOR-202 
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Statistical Analysis Plan Amendment 1 Final 
17 February 2017 
 
CONFIDENTIAL 
8.0 
REFERENCES 
1. 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.  
2. Ge M, Durham LK, Meyer RD, Xie W, and Thomas N. Covariate-Adjusted Difference in 
Proportions from Clinical Trials Using Logistic Regression and Weighted Risk Differences, 
Therapeutic Innovation & Regulatory Science, July 2011, vol. 45 no. 4, 481-493. 
3. Marcy SM, Kohl KS, Dagan R, Nalin D, Bum M, Connell Jones M, Hansen J, Labadie J, Lee 
L, Martin BL, O’Brien K, Rothstein E, Vermeer P and The Brighton Collaboration Fever 
Working Group. Fever as an adverse event following immunization: case definition and 
guidelines of data collection, analysis, and presentation. Vaccine 2004;22:551-6. 
4. A Phase II, Randomized, Double-Blind, Dosage and Adjuvant Justification, Safety and 
Immunogenicity Trial of Intramuscular Norovirus GI.1/GII.4 Bivalent Virus-Like Particle 
Vaccine combined with Aluminum Hydroxide, with and without Monophosphoryl Lipid A 
Adjuvant in Children, Toddlers, and Infants, Takeda Vaccines, Inc., Protocol No. NOR-202, 
Version 4.0 (Amendment 3) dated 01 March, 2016. 


NOR-202 
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Statistical Analysis Plan Amendment 1 Final 
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CONFIDENTIAL 
Appendix A Severity Grading Scale for Solicited Local AEs in Children Aged 4 
to  <9 Years 
Adverse Event 
Intensity 
Grade 
Severity/Intensity 
Pain at injection 
site 
0 
None 
1 
Mild: Does not interfere with play and daily activities 
2 
Moderate: Interferes with play and daily activities with or without treatment 
3 
Severe: Prevents daily activities with or without treatment 
Erythema at 
injection site 
0 
<25 mm 
1 
Mild: ≥25 – ≤50 mm 
2 
Moderate: >50 – ≤100 mm 
3 
Severe: >100 mm 
Swelling at 
injection site 
0 
<25 mm 
1 
Mild: ≥25 – ≤50 mm 
2 
Moderate: >50 – ≤100 mm 
3 
Severe: >100 mm 
Induration at 
injection site 
0 
<25 mm 
1 
Mild: ≥25 – ≤50 mm 
2 
Moderate: >50 – ≤100 mm 
3 
Severe: >100 mm 
Source: Protocol Version 4.0, Table 9.a. 
 


NOR-202 
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Statistical Analysis Plan Amendment 1 Final 
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CONFIDENTIAL 
Appendix B Severity Grading Scale for Solicited Local AEs in Children Aged Weeks 
to <4 Years 
Adverse Event 
Intensity 
Grade 
Severity/Intensity 
Pain at injection 
site 
0 
None 
1 
Mild: Minor reaction to touch 
2 
Moderate: Cries/protests on touch 
3 
Severe: Cries when limb is moved/spontaneously painful 
Erythema at 
injection site 
0 
<10 mm 
1 
Mild: ≥10 – ≤20 mm 
2 
Moderate: >20 – ≤40 mm 
3 
Severe: >40 mm 
Swelling at 
injection site 
0 
<10 mm 
1 
Mild: ≥10 – ≤20 mm 
2 
Moderate: >20 – ≤40 mm 
3 
Severe: >40 mm 
Induration at 
injection site 
0 
<10 mm 
1 
Mild: ≥10 – ≤20 mm 
2 
Moderate: >20 – ≤40 mm 
3 
Severe: >40 mm 
Source: Takeda Vaccines Pharmacovigilance. 


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