A Phase III, Observer-blind, Randomized, Multi-country Study to Assess the Reactogenicity and Safety of the Porcine Circovirus (PCV) Free Liquid Formulation of GSK's Oral Live Attenuated Human Rotavirus (HRV) Vaccine as Compared to the Lyophilized Formulation of the GSK's HRV Vaccine, When Administered as a 2-dose Vaccination in Infants Starting at Age 6-12 Weeks
Phase: PHASE3
Conditions: Infections, Rotavirus
Sponsor: GlaxoSmithKline

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Clinical Study Protocol 
Sponsor: 
GlaxoSmithKline Biologicals SA 
Rue de l'Institut 89 
1330 Rixensart, Belgium 
Primary study vaccine and 
number 
Porcine circovirus (PCV)-free liquid formulation of 
GSK’s oral live attenuated human rotavirus (HRV) 
vaccine (444563) 
Other study vaccine 
Lyophilized formulation of GSK’s oral live attenuated 
HRV vaccine (ROTARIX) 
eTrack study number and 
abbreviated title 
208236 (ROTA-096)  
Investigational New Drug 
(IND) number 
BB-IND 16992 
EudraCT number 
2018-001986-18 
Date of protocol 
Final Version 2: 09 November 2018 
Date of protocol 
amendment/administrative 
change 
Amendment 1 Final: 23 September 2019 
Administrative change 1 Final: 24 February 2020 
Amendment 2: 30 March 2020 
Short title  
Safety study of 2 formulations of GSK’s human 
rotavirus (HRV) vaccine (444563), in healthy infants 
starting at age 6-12 weeks. 
Title  
A phase III, observer-blind, randomized, multi-country 
study to assess the reactogenicity and safety of the 
Porcine circovirus (PCV) free liquid formulation of 
GSK’s oral live attenuated human rotavirus (HRV) 
vaccine as compared to the lyophilized formulation of 
the GSK’s HRV vaccine, when administered as a 2-
dose vaccination in infants starting at age 6-12 weeks. 
Co-ordinating authors 
, Scientific Writer 
, Scientific Writer 
(Amended 30 March 2020) 
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208236 (ROTA-096) 
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eTrack study number and 
abbreviated title 
208236 (ROTA-096) 
IND number 
BB-IND 16992 
EudraCT number 
2018-001986-18 
Title  
A phase III, observer-blind, randomized, multi-country 
study to assess the reactogenicity and safety of the 
Porcine circovirus (PCV) free liquid formulation of 
GSK’s oral live attenuated human rotavirus (HRV) 
vaccine as compared to the lyophilized formulation of 
the GSK’s HRV vaccine, when administered as a 2-
dose vaccination in infants starting at age 6-12 weeks. 
Contributing authors 
 
, Clinical & Epidemiology Project 
Lead (CEPL) 
 
, Clinical & Epidemiology Project 
Lead (CEPL) 
 
, Clinical Research and Development Leads 
(CRDL) 
 
, Clinical Research and 
Development Leads (CRDL) 
 
, Lead Statistician 
 
 Statistician 
 
, Study Delivery Lead 
 
, Study 
Delivery Lead 
 
, Clinical Safety 
Representative 
 
, Oversight Data Manager 
 
, Study Data Manager 
 
, Study Data Manager 
 
, Global Regulatory Affairs 
Representative 
 
, Global Patents Representative 
 
, Clinical Trial Supply Manager 
 
, Clinical Trial Supply Manager 
GSK Biologicals’ Protocol DS v 16.0 
© 2018 GSK group of companies or its licensor. 
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208236 (ROTA-096) 
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Protocol Amendment 2 Sponsor Signatory Approval 
eTrack study number and 
abbreviated title 
208236 (ROTA-096) 
IND number 
BB-IND 16992 
EudraCT number 
2018-001986-18 
Date of protocol amendment 
Amendment 2: 30 March 2020 
Title  
A phase III, observer-blind, randomized, multi-
country study to assess the reactogenicity and safety 
of the Porcine circovirus (PCV) free liquid 
formulation of GSK’s oral live attenuated human 
rotavirus (HRV) vaccine as compared to the 
lyophilized formulation of the GSK’s HRV vaccine, 
when administered as a 2-dose vaccination in infants 
starting at age 6-12 weeks. 
Sponsor signatory 
Paul Gillard, MD 
Clinical & Epidemiology Project Lead, 
Live Viral Vaccines, RDC Belgium, 
GlaxoSmithKline Biologicals, SA. 
 
 
Signature 
 
 
 
Date 
 
 
 
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Protocol Amendment 2 Investigator Agreement 
I agree: 
 
To conduct the study in compliance with this protocol, any future protocol 
amendments or protocol administrative changes, with the terms of the clinical trial 
agreement and with any other study conduct procedures and/or study conduct 
documents provided by GlaxoSmithKline Biologicals SA (GSK). 
 
To assume responsibility for the proper conduct of the study at this site. 
 
That I am aware of, and will comply with, ‘Good Clinical Practice’ (GCP) and all 
applicable regulatory requirements. 
 
To ensure that all persons assisting me with the study are adequately informed about 
the GSK’s study vaccine and other study-related duties and functions as described in 
the protocol. 
 
To supervise any individual or party to whom I have delegated trial-related duties 
and functions conducted at the trial site. 
 
To ensure that any individual or party to whom I have delegated trial-related duties 
and functions conducted at the trial site are qualified to perform those trial-related 
duties and functions. 
 
To acquire the reference ranges for laboratory tests performed locally and, if required 
by local regulations, obtain the laboratory’s current certification or Quality 
Assurance procedure manual. 
 
To co-operate with a representative of GSK in the monitoring process of the study 
and in resolution of queries about the data. 
 
To have control of all essential documents and records generated under my 
responsibility before, during, and after the trial. 
 
That I have been informed that certain regulatory authorities require the sponsor to 
obtain and supply, as necessary, details about the investigator’s ownership interest in 
the sponsor or the investigational vaccine, and more generally about his/her financial 
ties with the sponsor. GSK will use and disclose the information solely for the 
purpose of complying with regulatory requirements. 
Hence, I: 
 
Agree to supply GSK with any necessary information regarding ownership interest 
and financial ties (including those of my spouse and dependent children). 
 
Agree to promptly update this information if any relevant changes occur during the 
course of the study and for 1 year following completion of the study. 
 
Agree that GSK may disclose any information about such ownership interests and 
financial ties to regulatory authorities. 
 
Agree to provide GSK with an updated Curriculum Vitae and other documents 
required by regulatory agencies for this study. 
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eTrack study number and 
abbreviated title 
208236 (ROTA-096) 
IND number 
BB-IND 16992 
EudraCT number 
2018-001986-18 
Date of protocol amendment 
Amendment 2: 30 March 2020 
Title  
A phase III, observer-blind, randomized, multi-
country study to assess the reactogenicity and safety 
of the Porcine circovirus (PCV) free liquid 
formulation of GSK’s oral live attenuated human 
rotavirus (HRV) vaccine as compared to the 
lyophilized formulation of the GSK’s HRV vaccine, 
when administered as a 2-dose vaccination in infants 
starting at age 6-12 weeks. 
Investigator name 
 
 
 
Signature 
 
 
 
Date 
 
 
 
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Sponsor Information 
1. Sponsor 
GlaxoSmithKline Biologicals SA 
Rue de l’Institut 89 
B-1330 Rixensart, Belgium 
2. Sponsor Medical Expert for the Study 
Refer to the local study contact information document. 
3. Sponsor Study Monitor 
Refer to the local study contact information document. 
4. Sponsor Study Contact for Reporting of a Serious Adverse Event 
GSK Central Back-up Study Contact for Reporting SAEs: refer to protocol Section 
12.3.7.3  
Study Contact for Reporting SAEs: refer to the local study contact information 
document. 
5. GSK’s Central Safety Physician On-Call Contact information for Emergency 
Unblinding  
GSK Central Safety Physician and Back-up Phone contact: refer to protocol Section 
8.3.4.1. 
 
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PROTOCOL AMENDMENT/ADMINISTRATIVE CHANGE 
SUMMARY OF CHANGES TABLE 
Table 1 
Document history 
Document 
Date 
Amendment 2 
30-MAR-2020 
Administrative Change 1 
24-FEB-2020 
Amendment 1 
23-SEP-2019 
Original Protocol 
09-NOV-2018 
Amendment 2 30-MAR-2020 
Overall Rationale for the Amendment 2 
This protocol amendment 2 outlines measures that may be applicable during special 
circumstances (e.g., COVID-19 pandemic). The purpose of the amendment is to protect 
participant’s welfare and safety, and as far as possible ensure the potential benefit to 
the participant and promote data integrity. 
Table 2 
List of main changes in the protocol and their rationale 
Section # and Name 
Description of Change 
Brief Rationale 
Section 1. Synopsis 
Added footnote to study design figure, 
Figure 1 and Table 1 on study 
procedures specifically around Visit 3, 
with cross-reference to new section 
(Section 8.4) on study procedures 
during special circumstances, such as 
COVID-19 pandemic. Added footnote 
to Table 2 about study interval around 
Visit 2 during special circumstances, 
such as COVID-19 pandemic 
To provide flexibility to certain study procedures 
in response to disease outbreak situation, as 
exemplified by the COVID-19 pandemic, to 
protect participant’s welfare and safety, and as 
far as possible ensure the potential benefit to 
the participant and promote data integrity 
Section 2. Schedule of 
activities 
Section 5.2. Overall design 
Section 8. Study 
assessments and 
procedures 
Added cross-reference to new section 
(Section 8.4) on study procedures 
during special circumstances, such as 
COVID-19 pandemic 
Section 8.4 
Added new section to provide guidance 
on adapting study procedures during 
special circumstances, such as COVID-
19 pandemic 
All changes are tracked in Section 12.4 (Appendix 4). Deleted text is in strikethrough 
and newly added text is in bold italics. 
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TABLE OF CONTENTS 
PAGE 
SPONSOR INFORMATION ............................................................................................ 6 
1. 
SYNOPSIS ............................................................................................................. 13 
2. 
SCHEDULE OF ACTIVITIES (SOA) ....................................................................... 15 
3. 
INTRODUCTION .................................................................................................... 18 
3.1. 
Study rationale ............................................................................................ 18 
3.2. 
Background ................................................................................................ 19 
3.3. 
Benefit/Risk assessment ............................................................................. 20 
3.3.1. 
Risk assessment .......................................................................... 20 
3.3.2. 
Benefit assessment ..................................................................... 21 
3.3.3. 
Overall Benefit: Risk conclusion ................................................... 21 
4. 
OBJECTIVES AND ENDPOINTS ........................................................................... 21 
5. 
STUDY DESIGN .................................................................................................... 22 
5.1. 
Scientific rationale for study design ............................................................. 22 
5.2. 
Overall design ............................................................................................. 22 
5.3. 
Number of subjects ..................................................................................... 24 
5.4. 
Subject and study completion ..................................................................... 24 
6. 
STUDY POPULATION ........................................................................................... 24 
6.1. 
Inclusion criteria for enrollment ................................................................... 24 
6.2. 
Exclusion criteria for enrollment .................................................................. 25 
6.2.1. 
Medical conditions ....................................................................... 25 
6.2.2. 
Prior/Concomitant therapy ........................................................... 25 
6.2.3. 
Prior/Concurrent clinical study experience ................................... 26 
6.2.4. 
Other exclusions .......................................................................... 26 
6.3. 
Criteria for temporary delay for enrollment and vaccination......................... 26 
7. 
TREATMENTS ....................................................................................................... 26 
7.1. 
Treatments administered ............................................................................ 27 
7.2. 
Method of treatment assignment ................................................................. 28 
7.2.1. 
Subject identification .................................................................... 28 
7.2.2. 
Randomization of treatment ......................................................... 28 
7.2.2.1. 
Randomization of supplies .......................................... 28 
7.2.2.2. 
Treatment allocation to the subject ............................. 28 
7.2.2.2.1. 
Study group and treatment 
number allocation ................................... 28 
7.2.2.2.2. 
Treatment number allocation for 
subsequent doses .................................. 29 
7.3. 
Blinding ....................................................................................................... 29 
7.3.1. 
Emergency unblinding ................................................................. 29 
7.4. 
Handling, storage and replacement of study vaccines ................................ 30 
7.4.1. 
Storage and handling of study vaccines ....................................... 30 
7.4.2. 
Replacement of unusable vaccines doses ................................... 31 
7.5. 
Concomitant medications/products and concomitant vaccinations .............. 31 
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7.5.1. 
Recording of concomitant medications/products and 
concomitant vaccinations ............................................................. 31 
7.6. 
Contraindications to subsequent vaccine administration ............................. 32 
7.7. 
Warnings and precautions .......................................................................... 32 
8. 
STUDY ASSESSMENTS AND PROCEDURES ..................................................... 33 
8.1. 
General study aspects ................................................................................ 34 
8.2. 
Pre-vaccination procedures ........................................................................ 34 
8.2.1. 
Collection of demographic data .................................................... 34 
8.2.2. 
Medical and vaccination history ................................................... 34 
8.2.3. 
Physical examination ................................................................... 34 
8.2.4. 
Pre-vaccination body temperature ............................................... 35 
8.3. 
Safety Assessments ................................................................................... 35 
8.3.1. 
Safety definitions ......................................................................... 35 
8.3.2. 
Time period and frequency for collecting adverse event 
and serious adverse event information ........................................ 35 
8.3.3. 
Method of detecting AEs and SAEs ............................................. 36 
8.3.4. 
Reporting of serious adverse events ............................................ 36 
8.3.4.1. 
Contact information for reporting of serious 
adverse events ........................................................... 37 
8.3.4.2. 
Regulatory reporting requirements for serious 
adverse events ........................................................... 37 
8.3.5. 
Follow-up of adverse events and serious adverse events ............ 37 
8.3.6. 
Treatment of adverse events ....................................................... 38 
8.3.7. 
Subject card ................................................................................. 38 
8.4. 
Study procedures during special circumstances (Amended 30 
March 2020) ............................................................................................... 38 
9. 
DISCONTINUATION CRITERIA ............................................................................. 39 
9.1. 
Discontinuation from the study .................................................................... 39 
9.2. 
Discontinuation of study vaccines ............................................................... 40 
9.3. 
Lost to follow-up .......................................................................................... 40 
10. STATISTICAL CONSIDERATIONS ........................................................................ 41 
10.1. 
Sample size determination .......................................................................... 41 
10.2. 
Populations for analyses ............................................................................. 41 
10.3. 
Statistical analyses ..................................................................................... 41 
10.3.1. 
Subjects disposition ..................................................................... 41 
10.3.2. 
Demography and baseline characteristics analyses ..................... 41 
10.3.3. 
Safety analyses ........................................................................... 42 
10.3.4. 
Interim analyses ........................................................................... 42 
10.4. 
Sequence of analyses ................................................................................. 42 
11. REFERENCES ....................................................................................................... 43 
12. APPENDICES ........................................................................................................ 45 
12.1. 
Appendix 1: Abbreviations, glossary of terms and trademarks .................... 45 
12.1.1. 
List of abbreviations ..................................................................... 45 
12.1.2. 
Glossary of terms ......................................................................... 47 
12.1.3. 
Trademarks ................................................................................. 50 
12.2. 
Appendix 2: Study governance considerations............................................ 51 
12.2.1. 
Regulatory and ethical considerations ......................................... 51 
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12.2.2. 
Financial disclosure ..................................................................... 51 
12.2.3. 
Informed consent process ............................................................ 52 
12.2.4. 
Data protection ............................................................................ 52 
12.2.5. 
Publication policy ......................................................................... 52 
12.2.6. 
Dissemination of clinical study data ............................................. 53 
12.2.7. 
Data quality assurance ................................................................ 53 
12.2.8. 
Source documents ....................................................................... 54 
12.2.9. 
Study and site closure .................................................................. 54 
12.3. 
Appendix 3: Adverse events: definitions and procedures for 
recording, evaluating, follow-up, and reporting ............................................ 55 
12.3.1. 
Definition of adverse event........................................................... 55 
12.3.1.1. Adverse event definition ............................................. 55 
12.3.1.2. Events meeting the adverse event definition............... 55 
12.3.1.3. Events NOT meeting the adverse event 
definition ..................................................................... 56 
12.3.2. 
Definition of SAE .......................................................................... 56 
12.3.3. 
Solicited adverse events .............................................................. 57 
12.3.4. 
Unsolicited adverse events .......................................................... 57 
12.3.5. 
Clinical laboratory parameters and other abnormal 
assessments qualifying as adverse events or serious 
adverse events ............................................................................ 58 
12.3.6. 
Detecting and recording adverse events and serious 
adverse events ............................................................................ 58 
12.3.6.1. Time period for detecting and recording 
adverse events and serious adverse events ............... 59 
12.3.6.2. Evaluation of adverse events and serious 
adverse events ........................................................... 59 
12.3.6.2.1. Active questioning to detect 
adverse events and serious 
adverse events ....................................... 59 
12.3.6.2.2. Assessment of adverse events ............... 60 
12.3.6.2.3. Medically attended visits ......................... 62 
12.3.7. 
Reporting of serious adverse events ............................................ 63 
12.3.7.1. Prompt reporting of serious adverse events to 
GSK ........................................................................... 63 
12.3.7.2. SAEs requiring expedited reporting to GSK ................ 63 
12.3.7.3. Back-up system in case the electronic reporting 
system does not work ................................................. 63 
12.3.8. 
Updating of SAE information after removal of write access 
to the subject’s eCRF ................................................................... 63 
12.3.9. 
Follow-up of adverse events and serious adverse events ............ 64 
12.3.9.1. Follow-up during the study .......................................... 64 
12.3.9.2. Follow-up after the subject is discharged from 
the study ..................................................................... 64 
12.4. 
Appendix 4: Protocol Amendment/Administrative change History ............... 65 
 
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LIST OF TABLES 
PAGE 
Table 1 
Schedule of activities.............................................................................. 15 
Table 2 
Intervals between study visits ................................................................. 18 
Table 3 
Study objectives and endpoints .............................................................. 21 
Table 4 
Study groups, treatments and epoch foreseen in the study .................... 23 
Table 5 
Treatments administered ........................................................................ 27 
Table 6 
Contact information for emergency unblinding ....................................... 29 
Table 7 
Reporting periods for collecting safety information ................................. 35 
Table 8 
Timeframes for submitting serious adverse event reports to GSK .......... 36 
Table 9 
Contact information for reporting of serious adverse events ................... 37 
Table 10 
Two-sided 95% exact confidence intervals for the true adverse 
event rate at different possible observed adverse event rates 
(675 subjects per group) ........................................................................ 41 
Table 11 
Solicited general adverse events ............................................................ 57 
Table 12 
Intensity scales to be used by the parent(s)/LAR(s) for solicited 
adverse events during the solicited follow-up period .............................. 60 
Table 13 
Intensity scales for diarrhea, vomiting and fever occurring during 
the solicited period ................................................................................. 60 
 
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LIST OF FIGURES 
PAGE 
Figure 1 
Study design overview ........................................................................... 22 
 
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1. 
SYNOPSIS 
Indication: 
Active immunization of infants against gastroenteritis (GE) due to rotavirus (RV). 
Rationale: 
Study rationale 
Using advanced technology in 2010, researchers from the University of California, San 
Francisco identified deoxyribonucleic acid (DNA) fragments of Porcine circovirus type 1 
(PCV-1) in GlaxoSmithKline Biologicals SA’s (GSK’s) human rotavirus (HRV) vaccine 
(ROTARIX). Further investigations conducted by GSK and the United States (US) Food 
and Drug Administration (FDA) confirmed the presence of PCV-1 DNA fragments in 
ROTARIX and in its starting materials as well as low levels of PCV-1 viral particles 
during production process and in the final container. PCV-1 is not known to cause disease 
in either animals or humans [Hattermann, 2004b; Hattermann, 2004a] and there is no 
evidence that the presence of PCV-1 in ROTARIX poses a safety risk to vaccinated 
subjects. Laboratory investigations showed that the anti-PCV-1 antibody seropositivity 
rate in vaccinated subjects was below that observed during assay qualification in samples 
from unvaccinated subjects [Han, 2017]. The presence of PCV-1 in ROTARIX is, 
therefore, a manufacturing quality issue [Dubin, 2013; Han, 2017]. 
GSK has replaced the cell bank and virus seeds used as the base production material for 
its HRV vaccine and in accordance with regulators, the company continues to 
manufacture ROTARIX to the existing approved standards of production and quality, to 
meet public health needs worldwide. 
The viral potency of the PCV-free HRV vaccine (no detection of PCV-1 and PCV-2 
according to the limit of detection of the tests used) lot selected for this study (target 
potency of 6.8 log10 cell culture infective dose (CCID50) per dose up to 7.0 log10 CCID50 
per dose) is in the upper range of the usual potencies of the commercial production 
batches, routinely released for worldwide distribution. In order to keep the titer stable 
until administration during the study, the PCV-free study vaccine will be stored frozen. 
Only in 2 countries, i.e. Canada and the US, an upper limit for the potency titer at release 
was required by the Regulatory Authorities and implemented for ROTARIX (lyophilized 
formulation in the US and liquid formulation in Canada). The upper limit was set at 6.5 
log10 CCID50 per dose. Following discussions with the FDA, it is being considered to 
increase the upper limit of the potency for the liquid formulation allowing acceptable 
range of potencies at release of the vaccine. 
As part of the phase III studies, GSK plans to conduct study Rota-096, to evaluate the 
reactogenicity and safety of a PCV-free HRV liquid vaccine lot with a potency titer at 
release above 6.5 log10 CCID50 per dose. The sample size of the study ensures completion 
of the total safety database size across the PCV-free development, as agreed with FDA. 
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A recent in-house pharmacovigilance analysis of the risk of intussusception (IS) after 
administration of the ROTARIX liquid vaccine (data lock point 15 January 2018) suggests 
no evidence of any association between the ROTARIX potency at release and the risk of 
IS. As no clear trend was observed in these data, FDA agreed that Rota-096 may proceed. 
Objectives and Endpoints:  
Objectives 
Endpoints 
Primary 
To evaluate the reactogenicity of the liquid HRV vaccine 
and lyophilized HRV vaccine in terms of solicited 
adverse events (AEs) during the 8-day (Day 1-Day 8) 
follow-up period after each vaccination. 
 
Occurrence of each solicited general AE within 8 
days (Day 1–Day 8) after each vaccination. 
To assess the safety of the liquid HRV vaccine and 
lyophilized HRV vaccine in terms of unsolicited AEs 
during the 31-day (Day 1-Day 31) follow-up period after 
each vaccination and serious adverse events (SAEs) 
during the entire study period. 
 
Occurrence of unsolicited AEs within 31 days 
(Day 1–Day 31) after any vaccination, according 
to the medical dictionary for regulatory activities 
(MedDRA) classification. 
 
Occurrence of SAEs throughout the study period 
(i.e. from Dose 1 of the HRV vaccine to study 
conclusion at the end of the follow-up period). 
Overall Design:  
 
The Extended safety follow-up (ESFU) contact (by telephone call or any other convenient procedure) will take place 6 
months after the last dose of the study vaccines. 
N=Target number of subjects, n=Target number of subjects in each study group. 
*Two doses of the study vaccines will be administered to subjects at 1-month or 2-months interval. 
#For authorized sites in Canada only, with approved site level standard operating procedures (SOP): Safety 
assessments scheduled at Visit 3 (Month 2-4) may take place at the subject’s home or at the investigator’s clinical 
facility as appropriate to the circumstances in the judgment of the investigator. 
**Refer to Section 8.4 for study procedures to be considered during special circumstances (Amended 30 
March 2020). 
An Independent Data Monitoring Committee (IDMC) consisting of clinical experts and a 
biostatistician will review the safety data on a regular basis to evaluate if there is any 
safety concern with the PCV-free liquid HRV vaccine. 
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2. 
SCHEDULE OF ACTIVITIES (SOA) 
Table 1 
Schedule of activities  
Age 
6-12 
weeks 
3-5 
months 
4-7 
months 
9-11 
months 
Notes 
Epoch 
Epoch 001 
 
Type of contact 
Visit 1 
Visit 2 
Visit 3*/** 
ESFU 
Refer to Section 8.4 for study procedures to be considered during 
special circumstances (Amended 30 March 2020) 
Timepoints 
Day 1 Month 1-2  Month 2-4  Month 7-8  
Informed consent 
● 
 
 
 
(See Section 12.2.3 for details)  
Check inclusion/exclusion criteria 
● 
 
 
 
Recheck clinical status before randomization and/or first dose of study 
treatment (See Section 6.1 and 6.2 for inclusion and exclusion criteria) 
Collect demographic data 
● 
 
 
 
(See Section 8.2.1 for more information) 
Record gestational age at birth 
● 
 
 
 
 
Medical history 
● 
 
 
 
(See Section 8.2.2 for more information) 
Physical examination 
● 
 
 
 
Physical examination at each study visit subsequent to the first vaccination 
visit, will be performed only if the subjects’ parent(s)/LAR(s) indicates 
during questioning that there might be some underlying pathology(ies) or if 
deemed necessary by the investigator or delegate. Physical examination 
information will not be captured in the eCRF for study visits subsequent to 
the first vaccination visit. (See Section 8.2.3 for more information) 
History of previous vaccination history from birth 
● 
 
 
 
(See Section 8.2.2 for more information)  
Pre-vaccination body temperature 
● 
● 
 
 
(See Section 8.2.4 for more information) 
Measure/record length and weight 
● 
 
 
 
 
Vaccines 
Check criteria for temporary delay for enrollment and 
vaccination 
O 
O 
 
 
(See Section 6.3 for more information) 
Randomization 
● 
 
 
 
(See Section 7.2.2.2.1 for more information) 
Treatment number allocation for subsequent doses  
 
● 
 
 
(See Section 7.2.2.2.2 for more information) 
Check contraindications and warnings and precautions 
● 
● 
 
 
(See Section 7.6 and 7.7 for more information) 
Recording of administered treatment number 
● 
● 
 
 
 
Vaccine administration 
● 
● 
 
 
Two oral doses of the study vaccines will be administered at 1-month to 2-
months interval to subjects. (See Section 7.1 for more information) 
Record regurgitation/vomiting 
● 
● 
 
 
Any regurgitation or vomiting by the subjects after study vaccine 
administration should be recorded in the eCRF. 
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Age 
6-12 
weeks 
3-5 
months 
4-7 
months 
9-11 
months 
Notes 
Epoch 
Epoch 001 
 
Type of contact 
Visit 1 
Visit 2 
Visit 3*/** 
ESFU 
Refer to Section 8.4 for study procedures to be considered during 
special circumstances (Amended 30 March 2020) 
Timepoints 
Day 1 Month 1-2  Month 2-4  Month 7-8  
Vaccine replacement dose administration in case of 
regurgitation/vomiting 
● 
● 
 
 
If regurgitation or vomiting, which may have impaired vaccine take, occurs 
within 30 minutes after vaccination, a single replacement dose may be 
given at the same vaccination visit at the discretion of the investigator. 
This information should be recorded in the eCRF. The subject should 
continue to participate in the study. 
Safety assessments 
Record any concomitant medications/vaccinations 
● 
● 
● 
 
Concomitant administration of routine pediatric vaccines will be allowed 
according to the local immunization practices in each participating country. 
All concomitant vaccinations given during the study period will be recorded 
in the eCRF (See Section 7.5 for more information) 
Distribution of diary cards 
O 
O 
 
 
 
Recording of solicited AEs within 8 days after each 
vaccination (Day 1-Day 8) by subjects’ parent(s)/LAR(s) in 
diary card 
● 
● 
 
 
(See Section 12.3.6 for more information) 
Recording of non-serious unsolicited AEs within 31 days 
after each vaccination (Day 1-Day 31) by subjects’ 
parent(s)/LAR(s) in diary card. 
● 
● 
 
 
(See Section 12.3.6 for more information) 
Return of diary cards 
 
O 
O 
 
 
Diary card transcription by the investigator or designee 
 
● 
● 
 
 
Recording of AEs/SAEs leading to withdrawal from study 
● 
● 
● 
● 
 
Recording of SAEs 
● 
● 
● 
● 
(See Section 12.3.6 for more information) 
Recording of SAEs related to study participation, or to a 
concurrent GSK medication/vaccine 
● 
● 
● 
● 
(See Section 12.3.6 for more information) 
Safety contact 
 
 
 
● 
A safety follow-up contact will be done by a telephone call or any other 
convenient procedure to collect information on SAEs and medication taken 
for treatment of SAEs. 
Study conclusion 
 
 
 
● 
(See Section 5.4 for more information) 
ESFU=Extended safety follow-up; AE=Adverse event; SAE=Serious adverse event; LAR=Legally acceptable representative; eCRF=electronic case report form 
● is used to indicate a study procedure that requires documentation in the individual eCRF 
○ is used to indicate a study procedure that does not require documentation in the individual eCRF 
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*For authorized sites in Canada only, with approved site level standard operating procedures (SOP): Safety assessments scheduled at Visit 3 (Month 2-4) may take place at the 
subject’s home or at the investigator’s clinical facility as appropriate to the circumstances in the judgment of the investigator.  
**Refer to Section 8.4 for study procedures to be considered during special circumstances (Amended 30 March 2020). 
 
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Whenever possible, the investigator should arrange study visits within the interval 
described in Table 2. 
Table 2 
Intervals between study visits 
Interval 
Optimal length of interval 1 
Allowed interval 
Visit 1  Visit 2* 
1–2 months  
28 days-83 days after Dose 1 of HRV vaccines  
Visit 2  Visit 3 
1–2 months  
31 days-83 days after Dose 2 of HRV vaccines 
Visit 2  ESFU contact 2 
6 months 
180 days- 210 days after Dose 2 of HRV vaccines  
1 Whenever possible the investigator should arrange study visits within this interval. 
2 A safety follow-up contact (by telephone call or any other convenient procedure) to collect information on SAEs and 
medication taken for treatment of SAEs. 
*If despite best efforts it is not possible to administer the 2nd dose of study vaccine within the allowed interval, 
a maximum age of 24 weeks may be used (Amended 30 March 2020). 
3. 
INTRODUCTION 
3.1. 
Study rationale 
Using advanced technology in 2010, researchers from the University of California, San 
Francisco identified deoxyribonucleic acid (DNA) fragments of Porcine circovirus type 1 
(PCV-1) in GlaxoSmithKline Biologicals SA’s (GSK’s) human rotavirus (HRV) vaccine 
(ROTARIX). Further investigations conducted by GSK and the United States (US) Food 
and Drug Administration (FDA) confirmed the presence of PCV-1 DNA fragments in 
ROTARIX and in its starting materials as well as low levels of PCV-1 viral particles 
during production process and in the final container. An initial retrospective laboratory 
investigation conducted by GSK on 40 ROTARIX recipients found no immunologic 
response against PCV-1 [Dubin, 2013]. A subsequent investigation showed an 
anti-PCV-1 antibody seropositivity rate of 1% (90% confidence interval [CI]: 0.3, 2.6) in 
recipients of ROTARIX (3/299 samples) and 0.3% (90% CI: 0.0, 1.6) in the placebo group 
(1/296 samples). The difference in post-vaccination seropositivity rates between the 2 
study groups was -0.66% (90% CI: -2.16, 0.60). One subject in the vaccinated group was 
also seropositive before vaccination. The seropositivity rate observed in vaccinated 
subjects was below that observed during assay qualification in samples from 
unvaccinated subjects [Han, 2017]. PCV-1 is not known to cause disease in either 
animals or humans [Hattermann, 2004a; Hattermann, 2004b] and there is no evidence 
that the presence of PCV-1 in ROTARIX poses a safety risk to vaccinated subjects. The 
presence of PCV-1 in ROTARIX is, therefore, a manufacturing quality issue [Dubin, 
2013; Han, 2017]. 
GSK has replaced the cell bank and virus seeds used as the base production material for 
its HRV vaccine and, in accordance with regulators, the company continues to 
manufacture ROTARIX to the existing approved standards of production and quality, to 
meet public health needs worldwide. 
The viral potency of the PCV-free HRV (No detection of PCV-1 and PCV-2 according to 
the limit of detection of the tests used) vaccine lot selected for this study (target potency 
of 6.8 log10 cell culture infective dose (CCID50) per dose up to 7.0 log10 CCID50 per dose) 
is in the upper range of the usual potencies of the commercial production batches, 
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routinely released for worldwide distribution. In order to keep the titer stable until 
administration during the study, the PCV-free study vaccine will be stored frozen. 
Only in 2 countries, i.e. Canada and the US, an upper limit for the potency titer at release 
was required by the Regulatory Authorities and implemented for ROTARIX (lyophilized 
formulation in the US and liquid formulation in Canada). The upper limit was set at 
6.5 log10 CCID50 per dose. Following discussions with the FDA, it is being considered to 
increase the upper limit of the potency for the liquid formulation allowing acceptable 
range of potencies at release of the vaccine. 
As part of the phase III studies, GSK plans to conduct study Rota-096, to evaluate the 
reactogenicity and safety of a PCV-free HRV liquid vaccine lot with a potency titer at 
release above 6.5 log10 CCID50 per dose. The sample size of the study ensures completion 
of the total safety database size across the PCV-free development, as agreed with FDA. 
A recent in-house pharmacovigilance analysis of the risk of intussusception (IS) after 
administration of the ROTARIX liquid vaccine (data lock point 15 January 2018) suggests 
no evidence of any association between the ROTARIX potency at release and the risk of 
IS. As no clear trend was observed in these data, FDA agreed that Rota-096 may proceed. 
3.2. 
Background 
Rotavirus (RV) infection is the leading cause of acute gastroenteritis (GE) and severe 
diarrhea in infants and young children <5 years of age [Atherly, 2009]. It has been 
estimated that in 2013, approximately 215 000 deaths (95% CI: 197 000, 233 000) were 
caused due to RV. India, Nigeria, Pakistan, and Democratic Republic of Congo 
accounted for approximately half (49%) of all the estimated RV deaths in 2013 [Tate, 
2016]. 
Although RV infection rarely causes death in Europe, North America and Australia, it 
remains the most common cause of hospitalization for GE in children 
[Desselberger, 2012]. In developed countries, in addition to hospitalization for GE, RV 
infection also leads to major medical and societal costs. Over the last many years, the 
development of vaccines has been beneficial in the prevention of considerable morbidity 
and mortality due to RV. Two live oral RV vaccines have been licensed in many 
countries: one is derived from an attenuated human strain of RV and the other combines 
5 bovine-human reassortant strains [Glass, 2006]. Each of these vaccines has been proven 
highly effective in preventing severe RV diarrhea. These vaccines could reduce deaths 
from diarrhea and improve child survival through programs such as childhood 
immunizations and diarrheal disease control in developing countries. The World Health 
Organization (WHO) recognizes RV vaccination as an effective measure to prevent RV 
infection and to reduce disease burden, and recommends its inclusion into all national 
infant immunization programs, particularly in countries where RV GE associated fatality 
rates are high among children aged <5 years (e.g. south and south-eastern Asia and 
sub-Saharan Africa) [WHO position paper, 2013]. 
GSK’s HRV vaccine (ROTARIX) is a vaccine for oral use, containing the live attenuated 
HRV RIX4414 strain (referred as HRV in the document). Infants aged younger than 3 
months who received the vaccine did not develop diarrhea, vomiting or fever during the 
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trial [Vesikari, 2004a]. The initial studies conducted by GSK in Finland showed safety, 
immunogenicity and efficacy of the ROTARIX vaccine [Vesikari, 2004b]. In Latin 
American and European studies, vaccine efficacy of ROTARIX vaccine was high, ranging 
from 80.5% to 90.4% against severe RV GE, and 83.0% to 96.0% against hospitalization 
due to RV GE during the first 2 years of life [Vesikari, 2007; Linhares, 2008]. 
Furthermore, results from a phase III clinical study undertaken in Singapore, Hong Kong, 
and Taiwan showed that during the first 2 years of life, 2 doses of ROTARIX vaccine 
provided a high level of protection against severe RV GE (vaccine efficacy: 96.1%), and 
had a safety profile similar to the placebo [Phua, 2012]. Such safety and efficacy studies 
in Europe, Latin America and Asia have confirmed that the vaccine is well-tolerated and 
efficacious (range: 80-96%) in preventing severe RV GE in the first 2 years of life 
[Cunliffe, 2014]. 
ROTARIX is registered in at least 130 countries and more than 400 million doses of the 
vaccine (lyophilized and liquid formulations) are estimated to have been distributed 
worldwide from its launch until July 2017. 
Please refer to the current investigator’s brochure (IB) for information regarding the 
pre-clinical and clinical studies and the epidemiological information of ROTARIX 
vaccine. 
3.3. 
Benefit/Risk assessment 
Please refer to the current IB and the prescribing information for the summary of 
potential risks and benefits of the ROTARIX vaccine. 
The following section outlines the risk assessment and mitigation strategy for this study 
protocol: 
3.3.1. 
Risk assessment 
Important 
potential/identified risk of 
clinical significance 
Summary of data/rationale 
for risk 
Mitigation strategy 
GSK’s HRV vaccine 
IS 
Spontaneous data 
 
Subjects will be followed up to 6 months 
after receipt of the vaccine to check for 
any safety signal. 
 
Parent(s)/legally acceptable 
representative (LAR)(s) should report any 
untoward symptoms their child 
experiences after receiving the vaccine 
immediately to the investigator. 
 
Parent(s)/LAR(s) will be instructed to call 
the doctor right away or go to the 
emergency department if the baby has 
any sign or symptom of IS after getting the 
vaccine, even if it has been several weeks 
since the last vaccine dose. 
Hematochezia 
Spontaneous data 
Gastroenteritis with vaccine 
viral shedding in infants with 
severe combined 
immunodeficiency (SCID) 
Spontaneous data 
Kawasaki disease 
Based on signal observed for 
RotaTeq vaccine 
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Important 
potential/identified risk of 
clinical significance 
Summary of data/rationale 
for risk 
Mitigation strategy 
 
All serious adverse events (SAEs) should 
be reported by the investigator 
immediately to GSK. 
 
Subjects with SCID will be excluded from 
participating in this study (Refer to Section 
6.2 for more details). 
Study procedures 
Allergic reaction to the 
vaccines 
Spontaneous data 
Subjects will be observed for at least 30 minutes 
after vaccine administration, with medical 
attention available in case of anaphylaxis. 
3.3.2. 
Benefit assessment 
By receiving the HRV vaccines the subject may have the benefit of being protected 
against RV disease. 
In addition, the subjects will undergo a physical examination at the first study visit. In 
case the study doctor discovers any medical condition, the subject will be referred to the 
local healthcare system. 
3.3.3. 
Overall Benefit: Risk conclusion 
Considering the measures taken to minimize the risk to subjects participating in this 
study, the potential or identified risks in association with the HRV vaccines and study 
procedures are justified by the potential benefits (prevention/treatment) that may be 
afforded to subjects receiving the vaccines for immunization against RV. 
4. 
OBJECTIVES AND ENDPOINTS  
Table 3 
Study objectives and endpoints 
Objectives 
Endpoints 
Primary 
To evaluate the reactogenicity of the liquid HRV vaccine 
and lyophilized HRV vaccine in terms of solicited 
adverse events (AEs) during the 8-day (Day 1-Day 8) 
follow-up period after each vaccination. 
 
Occurrence of each solicited general AE within 8 
days (Day 1–Day 8) after each vaccination. 
To assess the safety of the liquid HRV vaccine and 
lyophilized HRV vaccine in terms of unsolicited AEs 
during the 31-day (Day 1-Day 31) follow-up period after 
each vaccination and serious adverse events (SAEs) 
during the entire study period.  
 
Occurrence of unsolicited AEs within 31 days 
(Day 1–Day 31) after any vaccination, according 
to the medical dictionary for regulatory activities 
(MedDRA) classification. 
 
Occurrence of SAEs throughout the study period 
(i.e. from Dose 1 of the HRV vaccine to study 
conclusion at the end of the follow-up period). 
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5. 
STUDY DESIGN  
5.1. 
Scientific rationale for study design 
Two oral doses of the study vaccines will be administered at 1-month or 2-months 
interval to subjects, according to the immunization schedule for RV vaccine 
administration in participating countries. 
As the liquid formulation of ROTARIX is not licensed in the US, the lyophilized 
formulation of the vaccine will be used as control in all phase III studies as part of the 
PCV-free development plan. 
Due to the difference in the appearance and volume between lyophilized HRV vaccine 
and PCV-free liquid HRV vaccine, the study will be observer-blinded. 
An Independent Data Monitoring Committee (IDMC) consisting of clinical experts and a 
biostatistician will review the safety data on a regular basis to evaluate if there is any 
safety concern with the PCV-free liquid HRV vaccine. 
5.2. 
Overall design 
Figure 1 
Study design overview  
 
The Extended safety follow-up (ESFU) contact (by telephone call or any other convenient procedure) will take place 6 
months after the last dose of the study vaccines. 
N=Target number of subjects, n=Target number of subjects in each study group. 
*Two doses of the study vaccines will be administered to subjects at 1-month or 2-months interval. 
#For authorized sites in Canada only, with approved site level standard operating procedures (SOP): Safety 
assessments scheduled at Visit 3 (Month 2-4) may take place at the subject’s home or at the investigator’s clinical 
facility as appropriate to the circumstances in the judgment of the investigator. 
**Refer to Section 8.4 for study procedures to be considered during special circumstances (Amended 30 
March 2020). 
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Protocol waivers or exemptions are not allowed unless necessary for the management of 
immediate safety concerns. Therefore, adherence to the study design requirements, 
including those specified in the schedule of activities (SoA) (Section 2), are essential and 
required for study conduct. 
 
Type of study: self-contained 
 
Experimental design: Phase III, observer-blind, randomized (1:1), controlled, multi-
country study with 2 parallel groups 
 
Duration of the study: The total duration of the study, per subject, will be 
approximately 7-8 months including the 6 months of extended safety follow-up 
(ESFU) period after the last dose of HRV vaccine 
 
Epoch 001: Primary starting at Visit 1 (Day 1) and ending at the ESFU contact 
(Month 7-8) 
 
Primary completion date (PCD): ESFU contact (Month 7-8) 
Refer to Section 12.1.2 for the definition of PCD. 
 End of study (EoS): Last subject last contact (Month 7-8) 
Refer to Section 12.1.2 for the definition of EoS. 
 
Study groups: 
Table 4 
Study groups, treatments and epoch foreseen in the study  
Study groups 
Number of 
subjects 
Age at Dose 1 
(Min-Max) 
Treatment name 
Vaccine/Product 
names 
Epoch 
Epoch 001 
(observer-blind) 
Liq 
675 
6-12 weeks  
HRV Liquid (oral 
administration) 
HRV PCV-free* 
x 
Lyo  
675  
6-12 weeks  
HRV Lyophilized 
(oral 
administration) 
HRV Lyo  
x 
HRV Diluent 
*HRV PCV-free: no detection of PCV-1 and PCV-2 according to the limit of detection of the tests used. 
 
Control: active control, GSK’s lyophilized HRV vaccine. 
 
Vaccination schedule: 
 
Two doses of HRV vaccines to be administered according to 0, 1-2-month 
schedule. 
 
Concomitant administration of routine childhood vaccines will be allowed 
according to the local immunization practices in each participating country. 
 
Treatment allocation: Randomized with balanced allocation (1:1) using GSK’s 
central internet randomization system (SBIR). Refer to Section 7.2.2 for detailed 
description of the randomization method. 
 
Blinding: observer-blind. 
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Refer to Section 7.3 for details on blinding procedures. 
 
Data collection: Standardized electronic case report form (eCRF). Solicited AEs will 
be collected using a diary card. 
 
Safety monitoring: An IDMC consisting of clinical experts and a biostatistician will 
review the safety data on a regular basis to evaluate if there is any safety concern 
with the PCV-free liquid HRV vaccine. 
5.3. 
Number of subjects  
The target sample size is 1350 subjects, 675 subjects per group. 
Withdrawals will not be replaced. 
Overview of the recruitment plan: 
 
All subjects will be enrolled at multiple sites in different countries. 
 
Enrollment will be terminated when approximately 1350 eligible subjects will be 
enrolled. 
 
The recruitment and randomization will be monitored by SBIR. 
5.4. 
Subject and study completion 
A subject is considered to have completed the study if he/she is available for the 
concluding contact (ESFU contact) as described in the protocol. 
Global completion of the study is required in order to provide sufficient subjects as 
defined in Section 10.1 Sample Size Determination. 
6. 
STUDY POPULATION 
6.1. 
Inclusion criteria for enrollment 
Deviations from inclusion criteria are not allowed because they can potentially jeopardize 
the scientific integrity, regulatory acceptability of the study or subject safety. Therefore, 
adherence to the criteria as specified in the protocol is essential. 
All subjects must satisfy ALL the following criteria at study entry: 
 
Subjects’ parent(s)/LAR(s) who, in the opinion of the investigator, can and will 
comply, with the requirements of the protocol (e.g. completion of the diary cards, 
return for follow-up visits). 
 
Written or witnessed/thumb printed informed consent obtained from the 
parent(s)/LAR(s) of the subject prior to performance of any study specific procedure.  
 
Healthy subjects as established by medical history and clinical examination before 
entering into the study. 
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 
A male or female between, and including, 6 and 12 weeks (42-90 days) of age at the 
time of the first vaccination. 
6.2. 
Exclusion criteria for enrollment 
6.2.1. 
Medical conditions 
 
Uncorrected congenital malformation (such as Meckel’s diverticulum) of the 
gastrointestinal tract that would predispose for IS. 
 
Very prematurely born infants (born ≤28 weeks of gestation). 
 
History of IS. 
 
Family history of congenital or hereditary immunodeficiency. 
 
Any confirmed or suspected immunosuppressive or immunodeficient condition, 
based on medical history and physical examination (no laboratory testing required). 
 
Hypersensitivity to latex. 
 
Major congenital defects or serious chronic illness, as assessed by the investigator. 
 
Previous confirmed occurrence of RV GE. 
 
History of any reaction or hypersensitivity likely to be exacerbated by any 
component of the vaccines. 
 
History of SCID. 
6.2.2. 
Prior/Concomitant therapy 
 
Use of any investigational or non-registered product (drug, vaccine or medical 
device) other than the study vaccines during the period starting 30 days before the 
first dose of study vaccines (Day -29 to Day 1), or planned use during the study 
period. 
 
Planned administration/administration of a vaccine not foreseen by the study 
protocol in the period starting 30 days before the first dose and ending 30 days after 
the last dose of study vaccine administration, with the exception of the inactivated 
influenza vaccine, which is allowed at any time during the study, and other licensed 
routine childhood vaccinations.  
 
Administration of long-acting immune-modifying drugs at any time during the study 
period (e.g. infliximab). 
 
Administration of immunoglobulins and/or any blood products from birth or planned 
administration during the study period. 
 
Chronic administration (defined as more than 14 days in total) of 
immunosuppressants or other immune-modifying drugs since birth. For 
corticosteroids, this will mean prednisone 0.5 mg/kg/day, or equivalent. Inhaled 
and topical steroids are allowed. 
 
Previous vaccination against RV. 
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6.2.3. 
Prior/Concurrent clinical study experience 
 
Concurrently participating in another clinical study, at any time during the study 
period, in which the subject has been or will be exposed to an investigational or a 
non-investigational vaccine/product (drug or medical device). 
6.2.4. 
Other exclusions 
 
Child in care 
Please refer to Section 12.1.2 for the definition of child in care. 
6.3. 
Criteria for temporary delay for enrollment and vaccination  
Vaccination may be postponed within the allowed time interval until transient 
circumstances cited below have been resolved: 
 
Acute disease and/or fever at the time of enrollment/or subsequent vaccination. 
Fever is defined as temperature 38.0°C/100.4°F. The preferred location for 
measuring temperature in this study will be the oral, the axillary or the rectal. 
Subjects with a minor illness (such as mild diarrhea, mild upper respiratory 
infection) without fever may be enrolled at the discretion of the investigator. 
 
GE within 7 days preceding the HRV vaccine administration. 
7. 
TREATMENTS 
Study treatment is defined as a set of investigational product(s) or marketed product(s) or 
placebo intended to be administered to a subject. 
The treatments administered in this study are presented in Table 5. 
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7.1. 
Treatments administered 
Table 5 
Treatments administered  
Study treatment name 
HRV Liquid 
HRV Lyophilized 
Vaccine/Product name 
HRV PCV-free* 
HRV Lyo 
HRV Diluent 
Presentation 
Liquid vaccine in a 
pre-filled oral 
applicator 
Lyophilized vaccine in a 
monodose glass vial 
Diluent for lyophilized vaccine 
(calcium carbonate liquid antacid) 
supplied separately in a pre-filled 
oral applicator. 
Vaccine/Product 
formulation 
PCV-free HRV 
RIX4414 live 
attenuated  
=106.8-7.0CCID50 
HRV RIX4414 live 
attenuated  
>=106.0CCID50 
CaCO3=60mg 
Storage condition 
-20°C or -4°F 
+2 to +8°C or +36 to 
+46°F 
+2 to +8°C or +36 to +46°F 
Route of Administration  
oral 
oral 
 
Location 
Not applicable 
Not applicable 
 
Directionality 
Not applicable 
Not applicable 
 
Laterality 
Not applicable 
Not applicable 
Number of doses to be 
administered 
2 
2 
Volume to be 
administered#  
1.5 ml 
1 ml 
Packaging and labeling 
Refer to SPM for 
more details 
Refer to SPM for more details 
Manufacturer 
GSK 
GSK 
*HRV PCV-free: No detection of PCV-1 and PCV-2 according to the limit of detection of the tests used. 
#Refer to the study procedure manual (SPM) for storage, handling and preparation methods. 
Refer to Section 2 for schedule of treatment administration. 
After completing all prerequisite procedures prior to vaccination (refer to Section 7.6 
regarding the contraindications to subsequent vaccination), 1 dose of study vaccine will 
be given orally (refer to Table 5 for details regarding the treatment administered).  
In order to allow the swallowing of the entire volume of the single oral dose (of liquid or 
lyophilized formulation), the administration should occur in a quiet environment. The 
subject should be seated in a reclining position. Administer orally (i.e. into the subject’s 
mouth toward the inner cheek) the entire content of oral applicator. Sufficient time should 
be allowed for the baby to swallow the vaccine solution, to avoid regurgitation or 
vomiting. If regurgitation or vomiting, which may have impaired vaccine take, occurs 
within 30 minutes after study vaccine administration, a single replacement dose may be 
given at the same vaccination visit at the discretion of the investigator. This information 
should be recorded in the eCRF. The subject should continue to participate in the study. 
If the investigator or delegate determines that the subject’s health on the day of 
administration temporarily precludes vaccine administration, the visit will be rescheduled 
within the allowed interval for this visit (refer to Table 2). 
The subjects will be observed closely for at least 30 minutes following the administration 
of the vaccines, with appropriate medical treatment readily available in case of 
anaphylaxis and syncope. 
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7.2. 
Method of treatment assignment 
7.2.1. 
Subject identification 
Subject identification numbers will be assigned sequentially to the subjects who have 
consented to participate in the study, according to the range of subject identification 
numbers allocated to each study center. 
7.2.2. 
Randomization of treatment 
7.2.2.1. 
Randomization of supplies 
The numbering of HRV vaccine supplies will be performed at GSK, using a block 
scheme randomization in MATerial EXcellence (MATEX), a program developed for use 
in Statistical Analysis System (SAS®) (Cary, NC, US) by GSK. Entire blocks will be 
shipped to the study centers/warehouse(s). 
To allow GSK to take advantage of greater rates of recruitment than anticipated at 
individual centers in this multi-center study and to thus reduce the overall study 
recruitment period, an over-randomization of supplies will be prepared. 
7.2.2.2. 
Treatment allocation to the subject 
The treatment numbers will be allocated by dose. 
7.2.2.2.1. Study group and treatment number allocation 
Allocation of the subject to a study group/a treatment number at the investigator site will 
be performed using SBIR. The randomization algorithm will use a minimization 
procedure accounting for center and the country as minimization factors. Minimization 
factors will have equal weight in the minimization algorithm. 
After obtaining the signed and dated informed consent form (ICF) from the subject’s 
parent(s)/LAR(s) and having checked the eligibility of the subject, the site staff in charge 
of the vaccine administration will access SBIR. Upon providing the subject identification 
number, the randomization system will determine the study group and will provide the 
treatment number to be used for the first dose. 
The number of each administered treatment must be recorded in the eCRF on the Vaccine 
Administration screen. 
When SBIR is not available, please refer to the SBIR user guide or the SPM for specific 
instructions. 
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7.2.2.2.2. Treatment number allocation for subsequent doses  
For each dose subsequent to the first dose, the study staff in charge of the vaccine 
administration will access SBIR, provide the subject identification number, and the 
system will provide a treatment number consistent with the allocated study group. 
The number of each administered treatment must be recorded in the eCRF on the Vaccine 
Administration screen. 
7.3. 
Blinding  
Data will be collected in an observer-blind manner. By observer-blind, it is meant that 
during the course of the study, the vaccine(s) recipient and those responsible for the 
evaluation of any study endpoint (e.g. safety and reactogenicity) will all be unaware of 
which vaccine was administered. To do so, vaccine preparation and administration will 
be done by authorized medical personnel who will not participate in any of the study 
clinical evaluation assays. 
7.3.1. 
Emergency unblinding 
Unblinding of a subject’s individual treatment code should occur only in the case of a 
medical emergency when knowledge of the treatment is essential for the clinical 
management or welfare of the subject. 
The emergency unblinding process consists of the automated Internet-based system 
(SBIR) that allows the investigator to have unrestricted, immediate and direct access to 
the subject’s individual study treatment. 
As back-up process, the investigator has the option of contacting a GSK Helpdesk (refer 
to Table 6) if he/she needs support to perform the unblinding (i.e. he/she cannot access 
the automated Internet-based system). 
Non-investigator physician (e.g. physician from emergency room) or subject’s parent or 
LAR/care giver/family member can also request emergency unblinding either via the 
investigator (preferred option) or via the GSK Helpdesk (back-up process). Contact 
details of investigator and GSK Helpdesk are reported in the subject card. 
Table 6 
Contact information for emergency unblinding  
GSK Helpdesk 
24/24 hour and 7/7-day availability 
The Helpdesk is available by phone, fax and email 
Phone: 
 
For Canada, US and Puerto Rico 
Toll-free number: 
 
Fax: 
 
email: 
 
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GSK Vaccines Clinical Safety and Pharmacovigilance (VCSP) staff may unblind the 
treatment assignment for any subject in case of Suspected Unexpected Serious Adverse 
Reaction (SUSAR) as well as in case of fatal or life-threatening cases. If the SAE 
requires that an expedited regulatory report be sent to 1 or more regulatory agencies, a 
copy of the report, identifying the subject’s treatment assignment, may be sent to 
investigators in accordance with local regulations and/or GSK policy. 
7.4. 
Handling, storage and replacement of study vaccines 
7.4.1. 
Storage and handling of study vaccines 
Liquid formulation of PCV-free HRV vaccine  
As the PCV-free liquid HRV vaccine must be stored at -20°C, the vaccine must be 
thawed before being administered. Refer to the Module on Clinical Trial Supplies in the 
SPM for detailed instructions on the storage, handling, thawing, preparation and 
administration of the frozen PCV-free HRV vaccine. 
The pre-filled oral applicator is shaken well before use. The vaccine (approximately 1.5 
ml) should then be administered orally as a single dose. 
Lyophilized formulation of HRV vaccine 
To prepare lyophilized HRV vaccine for administration, the entire content of the supplied 
diluent (calcium carbonate buffer) should be transferred from the oral applicator into the 
vial of the lyophilized product via the intermediate device. The vial should be shaken 
well to re-suspend the vaccine. The entire volume of the re-suspended product 
(approximately 1 ml) should be withdrawn into the same oral applicator and the 
re-suspended product should then be administered promptly as a single oral dose. 
The study vaccines must be stored at the respective label storage temperature conditions 
in a safe and locked place. Access to the storage space should be limited to authorized 
study personnel. The storage conditions will be assessed during pre-study activities under 
the responsibility of the sponsor study contact. The storage temperature should be 
continuously monitored with calibrated (if not validated) temperature monitoring 
device(s) and recorded. Refer to the Module on Clinical Trial Supplies in the SPM for 
more details on storage of the study vaccines. 
A temperature excursion is any temperature that is not in range of the label storage 
temperature conditions. Temperatures outside the range of label storage temperature 
conditions must be reported and/or documented. Temperature excursion impacting study 
vaccines must be reported and/or documented. 
In the frame of the reporting, the lack/absence of temperature monitoring documentation 
from a device meeting GSK requirement has to be considered as a temperature excursion. 
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Study vaccines that are impacted by a temperature excursion may not be used and must 
be quarantined at label storage conditions until usage approval has been obtained 
from/via the local study contact (e.g. Site monitor). 
Refer to the Module on Clinical Trial Supplies in the SPM for details and instructions on 
the temperature excursion reporting and usage decision process, packaging and 
accountability of the study vaccines. 
7.4.2. 
Replacement of unusable vaccines doses 
In addition to the vaccine doses provided for the planned number of subjects (including 
over-randomization when applicable), at least 30% additional vaccine doses will be 
supplied to replace those that are unusable.  
7.5. 
Concomitant medications/products and concomitant 
vaccinations 
7.5.1. 
Recording of concomitant medications/products and 
concomitant vaccinations 
At each study visit, the investigator or delegate should question the subject’s 
parent(s)/LAR(s) about any medications/products taken and vaccinations received by the 
subject. 
The following concomitant medication(s)/product(s)/vaccine(s) must be recorded in the 
eCRF. 
 
All concomitant medications/products, except vitamins and dietary supplements, 
administered during the period starting 30 days before and ending 30 days after each 
dose of study vaccines. 
 
Any concomitant vaccination administered in the period from first study vaccination 
(Visit 1) and ending at the last study visit (Visit 3). 
 
Prophylactic medication (i.e. medication administered in the absence of ANY 
symptom and in anticipation of a reaction to the vaccination). 
An anti-pyretic is considered to be prophylactic when it is given in the absence of fever 
and any other symptom, to prevent fever from occurring (fever is defined as temperature 
38.0°C/100.4°F regardless the location of measurement). The preferred location for 
measuring temperature in this study will be the oral, the axillary or the rectal. 
 
Any concomitant medications/products/vaccines relevant to an SAE to be reported as 
per protocol or administered at any time during the study period for the treatment of 
an SAE. In addition, concomitant medications relevant to SAEs need to be recorded 
on the expedited Adverse Event report. 
 
Any investigational or non-registered product (drug or vaccine) other than the study 
vaccines used during the study period between Visit 1 to Visit 3. 
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 
Immunosuppressants or other immune-modifying drugs administered chronically 
(i.e. more than 14 days in total) during the study period between Visit 1 to Visit 3. 
For corticosteroids, this will mean prednisone 0.5 mg/kg/day, or equivalent. Inhaled 
and topical steroids are allowed. 
 
Immunoglobulins and/or any blood products administered during the study period 
between Visit 1 to Visit 3. 
 
Long-acting immune-modifying drugs administered at any time during the study 
period between Visit 1 to Visit 3 (e.g. infliximab). 
 
The Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy. 
7.6. 
Contraindications to subsequent vaccine administration 
Prior to receipt of additional study vaccination, subjects must be evaluated to confirm that 
they are eligible for subsequent vaccination. If subjects meet any of the original exclusion 
criteria or the criteria listed below, they should not receive additional vaccinations. 
However, these subjects should be encouraged to continue study participation. 
 
Subjects who experience any SAE judged to be possibly or probably related to study 
vaccine or non-study vaccines, including hypersensitivity reactions 
 
Subjects who develop any new condition which, in the opinion of the investigator, 
may pose additional risk to the subject if he/she continues to participate in the study 
 
Anaphylaxis following the administration of vaccines 
 
Hypersensitivity reaction following the administration of the vaccines 
 
Any uncorrected congenital malformation of the gastrointestinal tract (such as 
Meckel’s diverticulum) that would predispose for IS 
 
Any history of IS 
 
SCID 
7.7. 
Warnings and precautions 
Warnings and precautions to vaccination must be checked at the beginning of each 
vaccination visit.  
The HRV vaccine (both lyophilized and liquid formulations) should under no 
circumstances be injected. 
There are no data on the safety and efficacy of ROTARIX in infants with gastrointestinal 
illnesses. Administration of ROTARIX vaccine may be considered with caution in such 
infants when, in the opinion of the physician, withholding the vaccine entails a greater 
risk. 
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Post-marketing safety data indicate a transient increased risk of IS after vaccination, 
mostly within 7 days following the administration of the first dose of ROTARIX vaccine 
and, to a lesser extent, the second dose. The overall incidence of IS remains rare. 
Whether ROTARIX vaccine affects the overall risk of IS has not been established. 
Therefore, parent(s)/LAR(s) should be advised to promptly report any symptoms 
indicative of IS (severe abdominal pain, persistent vomiting, bloody stools, abdominal 
bloating and/or high fever). 
Excretion of the vaccine virus in the stools is known to occur after vaccination and lasts 
for 10 days on average with peak excretion around the seventh day. In clinical studies, 
cases of transmission of excreted vaccine virus to seronegative contacts of vaccines have 
been observed without causing any clinical symptoms. ROTARIX vaccine should be 
administered with caution to individuals with immunodeficient close contacts, such as 
individuals with malignancies, or who are otherwise immunocompromised or receiving 
immunosuppressive therapy. Contacts of recent vaccines should be advised to observe 
careful hygiene (including washing their hands) when changing children’s diapers. 
The tip caps of the pre-filled oral applicators of diluent may contain natural rubber latex 
which may cause allergic reactions in individuals who are sensitive to latex. 
Refer to the most recent version of the IB or label/package insert for more details on 
warnings and precautions. 
8. 
STUDY ASSESSMENTS AND PROCEDURES 
Study procedures and their timing are summarized in the SoA (Section 2). 
Protocol waivers or exemptions are not allowed unless necessary for the management of 
immediate safety concerns. 
Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the subject(s) should discontinue study 
treatment. 
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct. 
All screening evaluations must be completed and reviewed to confirm that potential 
subjects meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all subjects screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
Procedures conducted as part of the subject’s routine clinical management (e.g. blood 
count) and obtained before signing of ICF may be utilized for screening or baseline 
purposes provided the procedure met the protocol-specified criteria and was performed 
within the time-frame defined in the SoA. 
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During special circumstances (e.g., COVID-19 pandemic), the specific guidance from 
local public health and other competent authorities regarding the protection of 
individuals’ welfare must be applied. For the duration of such special circumstances, 
the measures detailed in Section 8.4 may be implemented for enrolled participants. 
(Amended 30 March 2020)  
8.1. 
General study aspects 
Supplementary study conduct information not mandated to be present in this protocol is 
provided in the accompanying SPM. The SPM provides the investigator and the site 
personnel with administrative and detailed technical information that does not impact the 
safety of the subjects. 
8.2. 
Pre-vaccination procedures 
8.2.1. 
Collection of demographic data 
Record demographic data such as gestational age at birth, sex and race in the subject’s 
eCRF. 
8.2.2. 
Medical and vaccination history  
Obtain the subject’s medical/vaccination history by interview and/or review of the 
subject’s medical records and record any pre-existing conditions or signs and/or 
symptoms present in a subject prior to the first study vaccination in the eCRF. 
8.2.3. 
Physical examination 
 
Perform a physical examination of the subject, including assessment of oral or 
axillary or rectal body temperature, length and weight. 
 
Collected information needs to be recorded in the eCRF. 
 
Physical examination at each study visit subsequent to the first vaccination visit, will 
be performed only if the subjects’ parent(s)/LAR(s) indicates during questioning that 
there might be some underlying pathology(ies) or if deemed necessary by the 
investigator or delegate. 
 
If the investigator determines that the subject’s health on the day of vaccination 
temporarily precludes vaccination, the visit will be rescheduled. 
 
Treatment of any abnormality observed during this examination has to be performed 
according to local medical practice outside this study or by referral to an appropriate 
health care provider. 
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8.2.4. 
Pre-vaccination body temperature 
The oral or axillary or rectal body temperature of each subject needs to be measured prior 
to any study vaccine administration. If the subject has fever (fever is defined as 
temperature 38.0°C/100.4°F regardless of the location of measurement) on the day of 
vaccination, the vaccination visit will be rescheduled within the allowed interval for this 
visit (see Section 6.3). 
8.3. 
Safety Assessments 
The investigator and any designees are responsible for detecting, documenting, and 
reporting events that meet the definition of an AE or SAE. The investigator and any 
designees remain responsible for following up AEs that are serious, considered related to 
the study treatment or the study, or that caused the subject to discontinue the study. 
8.3.1. 
Safety definitions 
Please refer to Section 12.3 for safety definitions. 
8.3.2. 
Time period and frequency for collecting adverse event and 
serious adverse event information 
An overview of the protocol-required reporting periods for AEs and SAEs is given in 
Table 7. Refer to the Section 12.3.6.1 for details on the time period for recording safety 
information. 
Table 7 
Reporting periods for collecting safety information 
Study activity 
Pre-V*  
V1 
Dose 1 
7 days 
Post-
V1 
30 
days  
Post-
V1 
 
V2 
Dose 2 
7 days 
Post-
V2 
30 
days  
Post-
V2 
 
V3 (30 
days after 
the last 
dose) 
 ESFU (Study 
conclusion) 
Day 1 
 
 
Month 1-2
 
 
Month 2-4  
Month 7-8 
Solicited general 
AEs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Unsolicited AEs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AEs/SAEs 
leading to 
withdrawal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SAEs  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SAEs related to 
study participation or 
GSK concurrent 
medication/vaccine 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
* Consent obtained. Pre-V: pre-vaccination; V = Visit. 
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All SAEs will be recorded and reported via Expedited Adverse Event Reporting Form to 
the sponsor or designee immediately and under no circumstance should this exceed 24 
hours after the investigator became aware of it, as indicated in section 12.3 (Appendix 3). 
The investigator will submit any updated SAE data to the sponsor within 24 hours of it 
being available. 
A post-study AE/SAE is defined as any event that occurs outside of the AE/SAE 
reporting period defined in Table 7. Investigators are not obligated to actively seek AEs 
or SAEs in former study subjects. However, if the investigator learns of any SAE, 
including a death, at any time after a subject has been discharged from the study, and 
he/she considers the event to be reasonably related to the study vaccines, the investigator 
will promptly notify the study contact for reporting SAEs. 
8.3.3. 
Method of detecting AEs and SAEs 
The method of recording, evaluating, and assessing intensity, causality and outcome of 
AEs and SAEs and the procedures for completing and transmitting SAE reports are 
provided in Section 12.3.6. 
Refer to Section 8.4 for measures for safety follow-up that may be implemented during 
special circumstances (Amended 30 March 2020). 
Care will be taken not to introduce bias when detecting AE and/or SAE. Open-ended and 
non-leading verbal questioning of the subject’s parent(s)/LAR(s) is the preferred method 
to inquire about AE occurrence. 
8.3.4. 
Reporting of serious adverse events 
Table 8 
Timeframes for submitting serious adverse event reports to GSK  
Type of event 
Initial reports 
Follow-up of relevant information on a 
previous report 
Time-frame 
Documents 
Time-frame 
Documents 
SAEs 
24 hours* ‡ 
electronic Expedited 
Adverse Events Report 
24 hours* 
electronic Expedited Adverse 
Events Report 
* Time-frame allowed after receipt or awareness of the information. 
‡ The investigator will be required to confirm review of the SAE causality by ticking the ‘reviewed’ box in the electronic 
Expedited Adverse Events Report within 72 hours of submission of the SAE. 
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8.3.4.1. 
Contact information for reporting of serious adverse events  
Table 9 
Contact information for reporting of serious adverse events  
Study contact for questions regarding SAEs 
Refer to the local study contact information document 
Back-up study contact for reporting SAEs 
24/24 hour and 7/7-day availability: 
GSK Clinical Safety & Pharmacovigilance 
Outside US & Canada sites: 
Fax: 
 or 
 
Email address: 
 
US sites only: 
Fax: 
 
Canada sites only: 
Fax: 
 
8.3.4.2. 
Regulatory reporting requirements for serious adverse events 
Prompt notification of an SAE by the investigator to the sponsor is essential for meeting 
legal obligations and ethical responsibilities for the safety of subjects and the safety of a 
study treatment under clinical investigation.  
The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study treatment under clinical 
investigation. The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRB)/Independent Ethics Committees (IEC), and investigators. 
Investigator safety reports must be prepared for SUSAR according to local regulatory 
requirements and sponsor policy and forwarded to investigators as necessary. 
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (e.g. summary or listing of SAEs) from the sponsor will 
review and then file it along with the IB and will notify the IRB/IEC, if appropriate 
according to local requirements. 
8.3.5. 
Follow-up of adverse events and serious adverse events 
After the initial AE/SAE report, the investigator is required to proactively follow each 
subject at subsequent visits/contact. All SAEs, will be followed until the event is 
resolved, stabilized, otherwise explained, or the subject is lost to follow-up. Further 
information on follow-up procedures is given in Section 12.3.9. 
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8.3.6. 
Treatment of adverse events 
Treatment of any AE is at the sole discretion of the investigator and according to current 
good medical practice. Any medication administered for the treatment of an SAE should 
be recorded in Expedited Adverse Event Report of the subject’s eCRF (refer to Section 
7.5). 
8.3.7. 
Subject card 
Study subjects’ parent(s)/LAR(s) must be provided with the address and telephone 
number of the main contact for information about the clinical study. 
The investigator (or designate) must, therefore, provide a “subject card” to each subject’s 
parent(s)/LAR(s). In an emergency situation, this card serves to inform the responsible 
attending physician that the subject is in a clinical study and that relevant information 
may be obtained by contacting the investigator. 
Subjects’ parent(s)/LAR(s) must be instructed to keep subject cards in their possession at 
all times during the study duration. 
8.4. 
Study procedures during special circumstances (Amended 
30 March 2020) 
During special circumstances (e.g., COVID-19 pandemic), the specific guidance from 
local public health and other competent authorities regarding the protection of 
individuals’ welfare must be applied.  
For the duration of such special circumstances, the following measures may be 
implemented for enrolled participants: 
 
Safety follow-up may be made by a telephone call, other means of virtual contact 
or home visit, if appropriate. 
 
Diary cards may be transmitted from and to the site by electronic means and/or 
conventional mail. 
 
If despite best efforts it is not possible to send diary cards to the site within the visit 
window as defined in the protocol (see Table 2), the diary cards should be returned 
to site before study end (the last ESFU contact). 
 
If despite best efforts it is not possible to administer the 2nd dose of study vaccine as 
defined in the protocol (see Table 2), a maximum age of 24 weeks may be used. 
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9. 
DISCONTINUATION CRITERIA 
9.1. 
Discontinuation from the study 
From an analysis perspective, a ‘withdrawal’ from the study refers to any subject who 
was not available for the concluding contact foreseen in the protocol.  
All data collected until the date of withdrawal/last contact of the subject will be used for 
the analysis. 
A subject is considered a ‘withdrawal’ from the study when no study procedure has 
occurred, no follow-up has been performed and no further information has been collected 
for this subject from the date of withdrawal/last contact. 
Investigators will make an attempt to contact those subjects who do not return for 
scheduled visits or follow-up. 
Primary reason for study withdrawal will be documented in the eCRF. The investigator 
will document whether the decision to withdraw a subject from the study was made by 
the by the subject’s parent(s)/LAR(s), or by the investigator, as well as which of the 
following possible reasons was responsible for withdrawal: 
 
AEs requiring expedited reporting 
 
Unsolicited non-serious AE 
 
Solicited AE 
 
Protocol deviation  
 
Withdrawal by subject, not due to an AE* 
 
Migrated/Moved from the study area 
 
Lost to follow-up 
 
Sponsor study termination 
 
Other (specify) 
*In case a subject is withdrawn from the study because the subject’s parent(s)/LAR(s) 
has withdrawn consent, the investigator will document the reason for withdrawal of 
consent, if specified by the subject’s parent(s)/LAR(s), in the eCRF. 
Subjects who are withdrawn from the study because of SAEs/AEs must be clearly 
distinguished from subjects who are withdrawn for other reasons. Investigators will 
follow subjects who are withdrawn from the study as result of an SAE/AE until 
resolution of the event (see Section 12.3.9). 
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9.2. 
Discontinuation of study vaccines 
A ‘withdrawal’ from the study vaccines refers to any subject who does not receive the 
complete treatment, i.e. when no further planned dose is administered from the date of 
withdrawal. A subject withdrawn from the study vaccines may continue further study 
procedures (safety or immunogenicity) if planned in the study protocol, as deemed 
appropriate by the investigator.  
Primary reason relative to premature discontinuation of the study vaccines will be 
documented on the Vaccine Administration screen of the eCRF. The investigator will 
document whether the decision to discontinue further vaccination/treatment was made by 
the subject’s parent(s)/LAR(s), or by the investigator, as well as which of the following 
possible reasons was responsible for withdrawal: 
 
AEs requiring expedited reporting 
 
Unsolicited non-serious AE 
 
Solicited AE 
 
Not willing to be vaccinated 
 
Other (specify). 
9.3. 
Lost to follow-up 
A subject will be considered lost to follow-up if subject’s parent(s)/LAR(s) repeatedly 
fails to return for scheduled visits and is unable to be contacted by the study site.  
The following actions must be taken if a subject’s parent(s)/LAR(s) fails to return to the 
clinic for a required study visit: 
 
The site must attempt to contact the subject’s parent(s)/LAR(s) and reschedule the 
missed visit as soon as possible and counsel them on the importance of maintaining 
the assigned visit schedule and ascertain whether or not the subject’s 
parent(s)/LAR(s) wishes the subject to and/or should continue in the study. 
 
Before a subject is deemed lost to follow-up, the investigator or designee must make 
every effort to regain contact with the subject’s parent(s)/LAR(s) (where possible, 3 
telephone calls and, if necessary, a certified letter to the parent’s/LAR’s last known 
mailing address or local equivalent methods). These contact attempts should be 
documented in the subject’s medical record. 
 
Should the subject’s parent(s)/LAR(s) continue to be unreachable, the subject will be 
considered to have withdrawn from the study with a primary reason of lost to follow-
up. 
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10. 
STATISTICAL CONSIDERATIONS 
10.1. 
Sample size determination 
The target sample size is 1350 subjects (675 subjects per group). 
Table 10 provides the 95% exact CI for different possible observed number of subjects 
with AEs for the study (675 subjects per group). 
Table 10 
Two-sided 95% exact confidence intervals for the true adverse event 
rate at different possible observed adverse event rates (675 subjects 
per group) 
Subjects 
vaccinated 
Observed number 
subjects reporting 
the adverse events 
Observed 
percentage of 
subjects with the 
adverse events  
95% exact confidence interval 
Lower limit 
Upper limit 
675 
0 
0.0 
0.0% 
0.5% 
1 
0.1 
0.0% 
0.7% 
10 
1.5 
0.7% 
2.7% 
30 
4.4 
3.0% 
6.2% 
50 
7.4 
5.5% 
9.6% 
100 
14.8 
12.2% 
17.7% 
10.2. 
Populations for analyses 
For purposes of analysis, the following analysis sets are defined: 
Analysis set 
Description 
Enrolled  
All subjects who were randomized or vaccinated  
Exposed  
All subjects who received at least 1 dose of the study treatment. For the sake of 
analysis, the study group is defined by the treatment administered at Dose 1. 
10.3. 
Statistical analyses 
10.3.1. 
Subjects disposition 
Number of enrolled, vaccinated (at least 1 vaccination, full vaccination course) subjects 
and reason for withdrawal, included in each study group or in total will be described. 
10.3.2. 
Demography and baseline characteristics analyses 
The median, mean, range and standard deviation of age (in weeks) at each study vaccine 
dose and of the gestational age at birth will be computed by study group. The median, 
mean and standard deviation of length (in centimeters) and weight (in kilograms) at 
Visit 1 will be computed by study group. The distribution of racial and sex composition 
of the study population will be presented. 
The distribution of subjects enrolled in each country/site will be tabulated across and per 
study group. 
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Important protocol deviations including ineligibility, unblinding, mis-administration of 
treatment, use of prohibited medication/vaccination and deviations from intervals 
between vaccination Visit 1 and Visit 2 (see Table 2) will be tabulated by study group. 
10.3.3. 
Safety analyses 
The primary safety analysis will be performed on the Exposed set. 
Endpoint 
Statistical analysis methods 
Primary  
Within groups assessment 
The percentage of doses and of subjects reporting at least 1 AE (solicited or unsolicited) during 
the 8-day (Day 1-Day 8) solicited follow-up period post-vaccination will be computed, along with 
exact 95% CI. The same calculations will be done for AEs (solicited or unsolicited) rated as 
grade 3 in intensity, those assessed as causally related to vaccination, those rated as grade 3 
in intensity with causal relationship to vaccination and those that resulted in a medically 
attended visit. 
The percentage of doses and of subjects reporting each individual solicited general AE will be 
computed, over the 8-day (Day 1-Day 8) solicited follow-up period post-vaccination, along with 
exact 95% CI. The same calculations will be done for each individual general solicited AE rated 
as grade 3 in intensity, those assessed as causally related to vaccination, those rated as grade 
3 in intensity with causal relationship to vaccination and those that resulted in a medically 
attended visit. For fever, additional analyses will be performed by 0.5C increments. These 
calculations will also be performed by country, sex and frequent race. 
The verbatim reports of unsolicited AEs will be reviewed by a physician and the signs and 
symptoms will be coded according to MedDRA. Every verbatim term will be matched with the 
appropriate preferred term. The percentage of subjects with unsolicited AEs occurring within 
31-day (Day 1-Day 31) follow-up period after any dose with its exact 95% CI will be tabulated 
by group, and by preferred term. Similar tabulation will be done for unsolicited AEs rated as 
grade 3, for unsolicited AEs with causal relationship to vaccination, for unsolicited AEs rated as 
grade 3 with causal relationship to vaccination and those that resulted in a medically attended 
visit. These calculations will also be performed by country. 
For each study group, the percentage of subjects who started taking at least 1 concomitant 
medication, antipyretic medication and prophylactic antipyretic medication during the 8-day 
(Day 1-Day 8) and 31-day (Day 1-Day 31) follow-up periods post-vaccination will be tabulated 
by dose, by subject for each dose and across the 2 doses. 
Subjects who experienced at least 1 SAE during the entire study period (from Dose 1 till ESFU 
contact at Month 7-8) will be summarized by study group and all SAEs will be tabulated. 
10.3.4. 
Interim analyses 
No interim analysis has been planned for this study. 
10.4. 
Sequence of analyses 
The final study report will contain the final analyses of all primary endpoints.  
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11. 
REFERENCES 
Atherly D, Dreibelbis R, Parashar U D, et al. Rotavirus Vaccination: Cost-Effectiveness 
and Impact on Child Mortality in Developing Countries The Journal of Infectious 
Diseases 2009; 200: S28–38. 
Cunliffe N, Zaman K, Rodrigo C, et al. Early exposure of infants to natural rotavirus 
infection: a review of studies with human rotavirus vaccine RIX441, BMC Pediatrics 2014; 
14: 295. 
Desselberger U. Updating prevaccination rotavirus-associated mortality Lancet Infect Dis 
2012; 12: 94-96. 
Dubin G, Toussaint J F, Cassart J P, et al. Investigation of a regulatory agency enquiry 
into potential porcine circovirus type 1 contamination of the human rotavirus vaccine, 
Rotarix™: Approach and outcome. 2013; 9: 2398-2408. 
Glass R I, Parashar U D, Bresee J S, et al. Rotavirus vaccines: current prospects and 
future challenges, Lancet 2006; 368: 323–32. 
Han HH, Karkada N, Jayadeva G, Dubin G. Serologic response to porcine circovirus type 
1 (PCV-1) in infants vaccinated with the human rotavirus vaccine, Rotarix: A 
retrospective laboratory analysis. Human Vaccines and Immunotherapeutics. 
2017;13(1):237-244. 
Hattermann K, Roedner C, Schmitt C, et al. Infection studies on human cell lines with 
porcine circovirus type 1 and porcine circovirus type 2. Xenotransplantation. 2004a; 
11(3): 284-94. 
Hattermann K, Maerz A, Slanina H, et al. Assessing the risk potential of porcine 
circoviruses for xenotransplantation: consensus primer-PCR-based search for a human 
circovirus. Xenotransplantation. 2004b; 11(6): 547-50. 
Linhares A C, Velázquez F R, Pérez-Schael I, et al. Efficacy and safety of an oral live 
attenuated human rotavirus vaccine against rotavirus gastroenteritis during the first 2 
years of life in Latin American infants: a randomised, double-blind, placebo-controlled 
phase III study. Lancet. 2008; 371(9619): 1181-9. 
Phua K B, Lim FS, Lau Y L et al. Rotavirus vaccine RIX4414 efficacy sustained during 
the third year of life: A randomised clinical trial in an Asian population, Vaccine 2012; 
30: 4552-7. 
Tate J E, Burton A H, Boschi-Pinto C. Global, Regional, and National Estimates of 
Rotavirus Mortality in Children <5 Years of Age, 2000-2013. Clin Infect Dis. 2016: S96-
S105. 
Vesikari T, Karvonen A, Korhonen T, et al. Safety and immunogenicity of RIX4414 live 
attenuated human rotavirus vaccine in adults, toddlers and previously uninfected infants. 
Vaccine 2004a; 22: 2836–42. 
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Vesikari T, Karvonen A, Puustinen L, et al. Efficacy of RIX4414 live attenuated human 
rotavirus vaccine in Finnish infants. Pediatr Infect Dis J 2004b; 23: 937–43. 
Vesikari T, Karvonen A, Prymula R, et al. Efficacy of human rotavirus vaccine against 
rotavirus gastroenteritis during the first 2 years of life in European infants: randomised, 
double-blind controlled study. Lancet 2007; 370: 1757–63. 
WHO position paper. Weekly epidemiological record. Rotavirus vaccines WHO position 
paper - 2013; 88: 49–64. 
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12. 
APPENDICES 
12.1. 
Appendix 1: Abbreviations, glossary of terms and 
trademarks 
12.1.1. 
List of abbreviations  
AE: 
Adverse event 
CCID50: 
Median cell culture infective dose (quantity of virus 
causing infection in 50% of exposed cells) 
CI:  
Confidence interval 
COVID-19 
Corona Virus Disease-2019 
DNA: 
Deoxyribonucleic acid 
eCRF: 
electronic case report form 
EoS: 
End of study 
ESFU: 
Extended safety follow-up 
EU: 
European Union 
FDA: 
Food and Drug Administration 
GCP: 
Good Clinical Practice 
GE: 
Gastroenteritis 
GSK: 
GlaxoSmithKline Biologicals SA 
HRV: 
Human rotavirus 
IB: 
Investigator’s brochure 
ICF: 
Informed consent form 
ICH: 
International Conference on Harmonization 
IDMC: 
Independent Data Monitoring Committee 
IEC: 
Independent Ethics Committee 
IND: 
Investigational new drug 
IRB: 
Institutional Review Board 
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IS: 
Intussusception 
LAR: 
Legally acceptable representative 
LSLV: 
Last subject last visit 
MedDRA: 
Medical dictionary for regulatory activities 
PCD: 
Primary completion date 
PCV-1: 
Porcine circovirus type 1 
RV: 
Rotavirus 
SAE: 
Serious adverse event 
SBIR: 
Central internet randomization system 
SCID: 
Severe combined immunodeficiency 
SoA:  
Schedule of activities 
SOP: 
Standard Operating Procedure 
SPM:  
Study procedures manual 
SUSAR: 
Suspected unexpected serious adverse reaction 
US: 
United States 
WHO: 
World Health Organization 
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12.1.2. 
Glossary of terms  
Adverse event: 
Any untoward medical occurrence in a patient or clinical 
investigation subject, temporally associated with the use of a 
medicinal product, whether or not considered related to the 
medicinal product. 
An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or 
disease (new or exacerbated) temporally associated with the 
use of a medicinal product. For marketed medicinal products, 
this also includes failure to produce expected benefits (i.e. 
lack of efficacy), abuse or misuse. 
Blinding: 
A procedure in which 1 or more parties to the trial are kept 
unaware of the treatment assignment in order to reduce the 
risk of biased study outcomes. The level of blinding is 
maintained throughout the conduct of the trial, and only when 
the data are cleaned to an acceptable level of quality will 
appropriate personnel be unblinded or when required in case 
of a serious adverse event. In an observer-blind study, the 
subject and the site and sponsor personnel involved in the 
clinical evaluation of the subjects are blinded while other 
study personnel may be aware of the treatment assignment 
(see Section 7.3 for details on observer-blinded studies). 
Child in care: 
A child who has been placed under the control or protection 
of an agency, organization, institution or entity by the courts, 
the government or a government body, acting in accordance 
with powers conferred on them by law or regulation. The 
definition of a child in care can include a child cared for by 
foster parents or living in a care home or institution, provided 
that the arrangement falls within the definition above. The 
definition of a child in care does not include a child who is 
adopted or has an appointed legal guardian. 
Diarrhea: 
Passage of 3 or more looser than normal stools within a day. 
Eligible: 
Qualified for enrollment into the study based upon strict 
adherence to inclusion/exclusion criteria. 
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End of Study (EoS): 
(Synonym of End of 
Trial) 
For studies with collection of human biological samples 
and/or imaging data, the EoS is defined as follows: Last 
subject last visit (LSLV) (Visit X) or Last testing results 
released of samples collected at Visit X*  
For studies that involve imaging techniques for data 
collection: Last reading results released for all subjects from 
Visit X* if it occurs after LSLV.  
* In this case EoS must be achieved no later than 8 months 
after LSLV.  
For studies without collection of human biological samples or 
imaging data: Last subject last visit (Visit X). 
For studies with re-use human biological samples or imaging 
data: Last testing results released or Last reading results. In 
this case EoS must be achieved no later than 8 months after 
the start of the testing. 
Epoch: 
Interval of time in the planned conduct of a study. An epoch 
is associated with a purpose (e.g. screening, randomization, 
treatment, follow-up), which applies across all arms of a 
study. NOTE: Epoch is intended as a standardized term to 
replace: period, cycle, phase, stage. 
Essential documents: 
Documents which individually and collectively permit 
evaluation of the conduct of a study and the quality of the 
data produced 
eTrack: 
GSK’s tracking tool for clinical trials. 
Investigational 
vaccine: 
(Synonym of 
Investigational 
Medicinal Product) 
A pharmaceutical form of an active ingredient being tested in 
a clinical trial, including a product with a marketing 
authorization when used in a way different from the approved 
form, or when used for an unapproved indication, or when 
used to gain further information about an approved use. 
Investigator: 
A person responsible for the conduct of the clinical trial at a 
trial site. If a trial is conducted by a team of individuals at a 
trial site, the investigator is the responsible leader of the team 
and may be called the principal investigator. 
The investigator can delegate trial-related duties and 
functions conducted at the trial site to qualified individual or 
party to perform those trial-related duties and functions 
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Legally acceptable 
representative 
(LAR): 
(The terms legal 
representative or 
legally authorized 
representative are 
used in some 
settings.) 
An individual or juridical or other body authorized under 
applicable law to consent, on behalf of a prospective subject, 
to the subject's participation in the clinical trial. 
Primary completion 
date (PCD): 
The date that the final subject was examined or received an 
intervention for the purpose of final collection of data for all 
primary outcomes, whether the clinical trial was concluded 
according to the pre-specified protocol or was terminated. 
HRV PCV-free 
No detection of PCV-1 and PCV-2 according to the limit of 
detection of the tests used. 
Randomization: 
Process of random attribution of treatment to subjects in order 
to reduce bias of selection. 
Self-contained study: 
Study with objectives not linked to the data of another study. 
Site monitor: 
An individual assigned by the sponsor who is responsible for 
assuring proper conduct of clinical studies at 1 or more 
investigational sites. 
Solicited adverse 
event: 
AEs to be recorded as endpoints in the clinical study. The 
presence/occurrence/intensity of these events is actively 
solicited from the subject or an observer during a specified 
post-vaccination follow-up period. 
Source data: 
All information in original records and certified copies of 
original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction 
and evaluation of the trial. Source data are contained in 
source documents (original records or certified copies). 
Source documents: 
Original documents, data, and records (e.g. hospital records, 
clinical and office charts, laboratory notes, memoranda, 
subjects' diaries or evaluation checklists, pharmacy 
dispensing records, recorded data from automated 
instruments, copies or transcriptions certified after 
verification as being accurate copies, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, 
subject files, and records kept at the pharmacy, at the 
laboratories and at medico-technical departments involved in 
the clinical trial). 
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Study vaccine: 
Any investigational vaccine/product being tested and/or any 
authorized use of a vaccine/product/placebo as a reference or 
administered concomitantly, in a clinical trial that evaluates 
the use of an investigational vaccine/product. 
Subject: 
Term used throughout the protocol to denote an individual 
who has been contacted in order to participate or participates 
in the clinical study, either as a recipient of the vaccines or as 
a control. 
Subject number: 
A unique number identifying a subject, assigned to each 
subject consenting to participate in the study. 
Treatment: 
Term used throughout the clinical study to denote a set of 
investigational product(s) or marketed product(s) or placebo 
intended to be administered to a subject. 
Treatment number: 
A number identifying a treatment to a subject, according to 
treatment allocation. 
Unsolicited adverse 
event: 
Any AE reported in addition to those solicited during the 
clinical study. Also, any ‘solicited’ symptom with onset 
outside the specified period of follow-up for solicited 
symptoms will be reported as an unsolicited adverse event. 
Vomiting: 
One or more episodes of forceful emptying of partially 
digested stomach contents ≥1 hour after feeding within a day. 
12.1.3. 
Trademarks 
Trademark Information 
Trademarks of the GSK group of 
companies 
 
Generic description 
ROTARIX 
 
Human rotavirus vaccine 
 
Trademarks not owned by the GSK group 
of companies 
 
Generic description 
RotaTeq (Merck & CO., Inc.) 
 
Rotavirus vaccine, live, oral, pentavalent 
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12.2. 
Appendix 2: Study governance considerations 
12.2.1. 
Regulatory and ethical considerations 
 
This study will be conducted in accordance with the protocol and with: 
 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines 
 
Applicable International Conference on Harmonization (ICH) Good Clinical 
Practice (GCP) Guidelines 
 
Applicable laws and regulations 
 
The protocol, protocol amendments, ICF or informed assent form, IB, and other 
relevant documents (e.g. advertisements) must be submitted, to an IRB/IEC by the 
investigator for review and approval. These documents will be signed and dated by 
the investigator before the study is initiated. 
 
Any amendments to the protocol will require IEC/IRB approval before 
implementation of changes made to the study design, except for changes necessary to 
eliminate an immediate hazard to study subjects. 
 
GSK will provide full details of the above procedures to the investigator, either 
verbally, in writing, or both. 
 
The investigator will be responsible for the following: 
 
Providing written summaries of the status of the study to the IRB/IEC annually 
or more frequently in accordance with the requirements, policies, and 
procedures established by the IRB/IEC. 
 
Notifying the IRB/IEC of SAE(s) or other significant safety findings as required 
by IRB/IEC procedures. 
 
Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 
536/2014 for clinical studies (if applicable), and all other applicable local 
regulations. 
12.2.2. 
Financial disclosure 
Investigators and sub-investigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interest prior 
initiation of the center and at the end of the study. Investigators are responsible for 
providing an update of Financial Disclosure if their financial interest changes at any point 
during their participation in a study and for 1 year after completion of the study. 
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12.2.3. 
Informed consent process 
The investigator or his/her representative will explain the nature of the study to the 
subject’s legally authorized representative and answer all questions regarding the study. 
Subject’s parent(s)/LAR(s) must be informed that the participation is voluntary. 
Freely given and written or witnessed/thumb printed informed consent must be obtained 
from each subject’s parent(s)/LAR(s), as appropriate, prior to participation in the study. 
The content of informed consent form must meet the requirements of 21 CFR 50, local 
regulations, ICH guidelines, Health Insurance Portability and Accountability Act 
(HIPAA) requirements, where applicable, and the IRB/IEC or study center. 
The medical record must include a statement that written informed consent was obtained 
before the subject was enrolled in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF. 
Subject’s parent(s)/LAR(s) must re-consent to the most current version of the ICF(s) or 
an ICF addendum during their participation in the study. 
A copy of the ICF(s) must be provided to the subject’s parent(s)/LAR(s). 
12.2.4. 
Data protection 
Subjects will be assigned a unique identifier by the sponsor. Any subject records or 
datasets that are transferred to the sponsor will contain the identifier only; subject names 
or any information which would make the subject identifiable will not be transferred.  
The parent(s)/LAR(s) must be informed that subject’s personal study-related data will be 
used by the sponsor in accordance with local data protection law. The level of disclosure 
must also be explained to the subject’s parent(s)/LAR(s). 
The parent(s)/LAR(s) must be informed that subject’s medical records may be examined 
by Clinical Quality Assurance auditors or other authorized personnel appointed by the 
sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
12.2.5. 
Publication policy 
GSK aims to publish the results of this study in searchable, peer reviewed scientific 
literature. GSK will target to submit within 18 months from last subject last visit (LSLV) 
for interventional studies and the completion of the analysis for non-interventional 
studies and will follow the guidance from the International Committee of Medical Journal 
Editors. 
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12.2.6. 
Dissemination of clinical study data 
The key design elements of this protocol will be posted on the GSK Clinical Study 
Register and on publicly accessible registers including ClinicalTrials.gov. Where 
required, protocol summaries will also be posted on national or regional clinical trial 
registers or databases (e.g. EudraCT database) in compliance with the applicable 
regulations. 
GSK also assures that results will be submitted to ClinicalTrials.gov within the required 
time-frame, in compliance with the current regulations. 
At the time of study results posting, the full study protocol and statistical analysis plan 
will also be posted on ClinicalTrials.gov. 
For studies that are in scope of the European Union (EU) Clinical Trial Regulation, 
summaries of the results of GSK interventional studies (phase I-IV) in pediatric 
population will also be posted within defined timelines on the publicly available EU 
Clinical Trial Register. If it is not possible to submit a summary of the results within the 
required timelines, the summary of results shall be submitted as soon as it is available. In 
this case, the protocol shall specify when the results are going to be submitted, together 
with a justification. 
Under the framework of the SHARE initiative, anonymized patient-level data from GSK 
sponsored interventional studies that evaluate products will be made available within 6 
months of this publication to independent researchers whose research proposals have 
been approved by an independent panel. Requests for access may be made through 
www.clinicalstudydatarequest.com. 
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the study report, provided reasonable access to statistical 
tables, figures, and relevant reports. GSK will also provide the investigator with the full 
summary of the study results. The investigator is encouraged to share the summary 
results with the study subjects, as appropriate. 
12.2.7. 
Data quality assurance 
The investigator should maintain a record of the location(s) of their respective essential 
documents including source documents. The storage system used during the trial and for 
archiving (irrespective of the type of media used) should provide for document 
identification, version history, search, and retrieval. 
Essential documents for the trial may be added or reduced where justified (in advance of 
trial initiation) based on the importance and relevance to the trial. When a copy is used to 
replace an original document (e.g. source documents, CRF), the copy should fulfill the 
requirements for certified copies. 
All subject data relating to the study will be recorded on electronic CRF unless 
transmitted to the sponsor or designee electronically (e.g. laboratory data). The 
investigator is responsible for verifying that data entries are accurate and correct by 
electronically signing the CRF. 
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The investigator must maintain adequate and accurate source documents and trial records 
that include all pertinent observations on each of the site’s trial subjects that support the 
information entered in the eCRF. 
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source documents or certified 
copies. 
The sponsor or designee is responsible for the data management of this study including 
quality checking of the source data. 
Study monitors will perform ongoing source data verification to confirm that data entered 
into the eCRF by authorized site personnel are attributable, legible, contemporaneous, 
original, accurate, and complete. Changes to source data should be traceable, should not 
obscure the original entry, and should be explained if necessary (e.g. via an audit trail). 
Safety and rights of subjects must be protected and study be conducted in accordance 
with the currently approved protocol and any other study agreements, ICH GCP, and all 
applicable regulatory requirements. 
Trial records and source documents, including signed ICF, pertaining to the conduct of 
this study must be retained by the investigator for 25 years from the issue of the final 
Clinical Study Report (CSR)/equivalent summary unless local regulations or institutional 
policies require a longer retention period. No records may be destroyed during the 
retention period without the written approval of the sponsor. No records may be 
transferred to another location or party without written notification to the sponsor. 
12.2.8. 
Source documents 
Source documents provide evidence for the existence of the subject and substantiate the 
integrity of the data collected. Investigator should maintain a record of the location(s) of 
their source documents. 
Data entered in the eCRF that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained. The investigator may 
need to request previous medical records or transfer records, depending on the study. 
Also, current medical records must be available. 
Definition of what constitutes source data and source documents can be found in the 
Section 12.1.2. 
12.2.9. 
Study and site closure 
GSK or its designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of GSK, provided there is sufficient notice given 
to account for patient’s safe exit from study participation. Study sites regular closure will 
be upon study completion. A study site is considered closed when all required 
data/documents and study supplies have been collected and a study site closure visit has 
been performed. 
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The investigator may initiate study site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to: 
 
Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines 
 
Inadequate recruitment of subjects by the investigator 
 
Discontinuation of further study treatment development 
At the end of last study contact, the investigator will: 
 
Review data collected to ensure accuracy and completeness 
 
Complete the Study Conclusion screen in the eCRF. 
12.3. 
Appendix 3: Adverse events: definitions and procedures for 
recording, evaluating, follow-up, and reporting 
12.3.1. 
Definition of adverse event 
12.3.1.1. 
Adverse event definition 
An AE is any untoward medical occurrence in a clinical study subject, temporally 
associated with the use of a study treatment, whether or not considered related to the 
study treatment. 
NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study treatment. 
12.3.1.2. 
Events meeting the adverse event definition  
Significant or unexpected worsening or exacerbation of the condition/indication under 
study. 
 
New conditions detected or diagnosed after study vaccines administration even 
though they may have been present prior to the start of the study. 
 
Signs, symptoms, or the clinical sequelae of a suspected interaction. 
 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
vaccines or a concurrent medication (overdose per se should not be reported as an 
AE/SAE). 
 
Signs, symptoms temporally associated with study vaccines administration. 
 
Significant failure of expected pharmacological or biological action.  
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 
Pre- or post-treatment events that occur as a result of protocol-mandated procedures 
(i.e. invasive procedures, modification of subject’s previous therapeutic regimen). 
 
Medically attended visits related to AEs (e.g. Hospital stays, physician visits and 
emergency room visits). 
AEs to be recorded as endpoints (solicited AEs) are described in Section 12.3.3. All other 
AEs will be recorded as UNSOLICITED AEs. 
The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be 
reported as AE or SAE if they fulfill the definition of an AE or SAE. 
12.3.1.3. 
Events NOT meeting the adverse event definition  
 
Situations where an untoward medical occurrence did not occur (e.g. social and/or 
convenience admission to a hospital, admission for routine examination). 
 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.  
 
Pre-existing conditions or signs and/or symptoms present in a subject prior to the 
first study vaccination. These events will be recorded in the medical history section 
of the eCRF. 
12.3.2. 
Definition of SAE 
An SAE is any untoward medical occurrence that: 
a. 
Results in death, 
b. Is life-threatening, 
Note: The term ‘life-threatening’ in the definition of ‘serious’ 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, which hypothetically might have caused death, had it been more severe. 
c. 
Requires hospitalization or prolongation of existing hospitalization, 
Note: In general, hospitalization signifies that the subject has been admitted at the 
hospital or emergency ward for observation and/or treatment that would not have 
been appropriate in the physician’s office or in an out-patient setting. Complications 
that occur during hospitalization are also considered AEs. If a complication prolongs 
hospitalization or fulfills any other serious criteria, the event will also be considered 
serious. When in doubt as to whether ‘hospitalization’ occurred, or was necessary, 
the AE should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition (known or 
diagnosed prior to informed consent signature) that did not worsen from baseline is 
NOT considered an AE. 
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d. Results in disability/incapacity 
Note: The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions. This definition is not intended to include experiences 
of relatively minor medical significance such as uncomplicated headache, nausea, 
vomiting, diarrhea, influenza like illness, and accidental trauma (e.g. sprained ankle) 
which may interfere or prevent everyday life functions but do not constitute a 
substantial disruption. 
Medical or scientific judgment should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
subject or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition. These should also be considered serious. 
Examples of such events are invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions 
that do not result in hospitalization. 
12.3.3. 
Solicited adverse events 
Solicited general adverse events 
The following general AEs will be solicited (Table 11): 
Table 11 
Solicited general adverse events 
Infants 
Fever 
Irritability/Fussiness 
Diarrhea 
Vomiting 
Loss of appetite 
Cough/runny nose 
Note: Parent(s)/LAR(s) will be instructed to measure and record the oral, axillary or 
rectal body temperature in the evening. Should additional temperature measurements be 
performed at other times of day, parent(s)/LAR(s) will be instructed to record the highest 
temperature in the diary card. 
12.3.4. 
Unsolicited adverse events 
An unsolicited AE is an AE that was not solicited using a subject diary* and that was 
spontaneously communicated by a parent(s)/LAR(s) who has signed the informed 
consent. 
*In this section and in Section 12.3.6, subject diary refers to diary card. 
Potential unsolicited AEs may be medically attended (defined as symptoms or illnesses 
requiring hospitalization, or emergency room visit, or visit to/by a health care provider), 
or were of concern to the parent(s)/LAR(s). In case of such events, parent(s)/LAR(s) will 
be instructed to contact the site as soon as possible to report the event(s). The detailed 
information about the reported unsolicited AEs will be collected by the qualified site 
personnel during the interview and will be documented in the subject’s records. 
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Unsolicited AEs that are not medically attended nor perceived as a concern by 
parent(s)/LAR(s) will be collected during interview with the parent(s)/LAR(s) and by 
review of available medical records at the next visit. 
12.3.5. 
Clinical laboratory parameters and other abnormal assessments 
qualifying as adverse events or serious adverse events  
In absence of diagnosis, abnormal laboratory findings (e.g. clinical chemistry, 
hematology, urinalysis) or other abnormal assessments (e.g. vital signs etc.) that are 
judged by the investigator to be clinically significant will be recorded as AE or SAE if 
they meet the definition of an AE or SAE (refer to Sections 12.3.1 and 12.3.2). Clinically 
significant abnormal laboratory findings or other abnormal assessments that are present at 
baseline and significantly worsen following the start of the study will also be reported as 
AEs or SAEs. However, clinically significant abnormal laboratory findings or other 
abnormal assessments that are associated with the disease being studied, unless judged by 
the investigator as more severe than expected for the subject’s condition, or that are 
present or detected at the start of the study and do not worsen, will not be reported as AEs 
or SAEs. 
The investigator will exercise his or her medical and scientific judgment in deciding 
whether an abnormal laboratory finding or other abnormal assessment is clinically 
significant. 
12.3.6. 
Detecting and recording adverse events and serious adverse 
events 
A paper diary, hereafter referred to as subject diary will be used in this study to capture 
solicited and unsolicited AEs. The subject’s parent(s)/LAR(s) should be trained on how 
and when to complete each field of the subject diary. 
The subjects’ parent(s)/LAR(s) will be instructed to contact the investigator immediately 
should the subjects manifest any signs or symptoms they perceive as serious. 
Subject diary training should be directed at the individual(s) who will perform the 
measurements of AEs and who will enter the information into the subject diary. This 
individual may not be the subject’s parent(s)/LAR(s), but if a person other than the 
subject’s parent(s)/LAR(s) enters information into the subject diary, this person’s identity 
must be documented in the subject diary/subject’s source record. Any individual that 
makes entries into the subject diary must receive training on completion of the subject 
diary at the time of the visit when subject diary is dispensed. This training must be 
documented in the subject’s source record. 
At each vaccination visit, subject diaries will be provided to the subject’s 
parent(s)/LAR(s). The subject’s parent(s)/LAR(s) will be instructed to measure and 
record the oral or axillary or rectal body temperature, and any solicited general AEs (i.e. 
on the day of vaccination and during the next 7 days) or any unsolicited AEs (i.e. on the 
day of vaccination and during the next 30 days) occurring after vaccination. The subject’s 
parent(s)/LAR(s) will be instructed to return the completed subject diaries to the 
investigator at the next study visit. 
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 
Collect and verify completed subject diaries during discussion with the subject’s 
parent(s)/LAR(s) on Visit 2 and Visit 3. 
 
Any unreturned subject diaries will be sought from the subject’s parent(s)/LAR(s) 
through telephone call(s) or any other convenient procedure. 
The investigator will transcribe the collected information into the eCRF in English. 
12.3.6.1. 
Time period for detecting and recording adverse events and serious 
adverse events 
All AEs within 31 days following administration of each dose of study vaccines (Day 1 
to Day 31) must be recorded onto the appropriate section of the eCRF, irrespective of 
intensity or whether or not they are considered vaccination-related. 
The time period for collecting and recording SAEs will begin at the first receipt of study 
vaccines and will end 6 months following administration of the last dose of study 
vaccines for each subject. See Section 12.3.7 for instructions on reporting of SAEs. 
All AEs/SAEs leading to withdrawal from the study will be collected and recorded from 
the time of the first receipt of study vaccine. 
In addition to the above-mentioned reporting requirements and in order to fulfill 
international reporting obligations, SAEs that are related to study participation (i.e. 
protocol-mandated procedures, invasive tests, a change from existing therapy) or are 
related to a concurrent GSK medication/vaccine will be collected and recorded from the 
time the subject’s parent(s)/LAR(s) consents to participate in the study until she/he is 
discharged from the study. 
12.3.6.2. 
Evaluation of adverse events and serious adverse events 
12.3.6.2.1. Active questioning to detect adverse events and serious adverse 
events 
As a consistent method of collecting AEs, the subject’s parent(s)/LAR(s) should be asked 
a non-leading question such as: 
‘Has your child acted differently or felt different in any way since receiving the vaccines 
or r since the last visit?’ 
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g. hospital progress notes, laboratory and diagnostics reports) relative 
to the event. The investigator will then record all relevant information regarding an 
AE/SAE in the eCRF. The investigator is not allowed to send photocopies of the 
subject’s medical records to GSK instead of appropriately completing the eCRF. 
However, there may be instances when copies of medical records for certain cases are 
requested by GSK. In this instance, all subject identifiers will be blinded on the copies of 
the medical records prior to submission to GSK. 
The investigator will attempt to establish a diagnosis pertaining to the event based on 
signs, symptoms, and/or other clinical information. In such cases, the diagnosis should be 
documented as the AE/SAE and not the individual signs/symptoms. 
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12.3.6.2.2. Assessment of adverse events 
1. Assessment of intensity 
The intensity of the following solicited AEs will be assessed as described in Table 12 and 
Table 13: 
Table 12 
Intensity scales to be used by the parent(s)/LAR(s) for solicited 
adverse events during the solicited follow-up period 
Adverse Event 
Intensity grade 
Parameter 
Fever* 
 
Record temperature in °C/°F using any age-appropriate route. 
Irritability/Fussiness 
0 
Behavior as usual 
1 
Crying more than usual/no effect on normal activity 
2 
Crying more than usual/interferes with normal activity 
3 
Crying that cannot be comforted/prevents normal activity 
Diarrhea $ 
 
Record the number of looser than normal stools /day 
Vomiting § 
 
Record the number of vomiting episodes/day 
Loss of appetite 
0 
Appetite as usual 
1 
Eating less than usual/no effect on normal activity 
2 
Eating less than usual/interferes with normal activity 
3 
Not eating at all 
Cough/runny nose 
0 
Normal 
1 
Cough/runny nose which is easily tolerated 
2 
Cough/runny nose which interferes with daily activity 
3 
Cough/runny nose which prevents daily activity 
* Fever is defined as temperature 38.0°C/100.4°F. The preferred location for measuring temperature in this study will 
be the oral, the axillary and the rectal. 
$ Diarrhea is defined as passage of 3 or more looser than normal stools within a day. 
§ Vomiting is defined as 1 or more episodes of forceful emptying of partially digested stomach contents ≥1 hour after 
feeding within a day. 
Table 13 
Intensity scales for diarrhea, vomiting and fever occurring during 
the solicited period 
Adverse Event 
Intensity grade 
Parameter 
Diarrhea $ 
0 
Normal (0-2 looser than normal stools/day) 
1 
3 looser than normal stools/day 
2 
4-5 looser than normal stools/day 
3 
 6 looser than normal stools/day 
Vomiting § 
0 
Normal (no emesis) 
1 
1 episode of vomiting/day 
2 
2 episodes of vomiting/day 
3 
3 episodes of vomiting/day 
Fever 
0 
temperature <38.0°C/100.4° F 
1 
temperature 38.0°C/100.4° F – 38.5°C/101.3 F  
2 
temperature >38.5°C/101.3 F – 39.5°C/103.1 F 
3 
temperature >39.5°C/103.1 F 
$ Diarrhea is defined as passage of 3 or more looser than normal stools within a day. 
§ Vomiting is defined as 1 or more episodes of forceful emptying of partially digested stomach contents ≥1 hour after 
feeding within a day. 
The intensity grade for diarrhea, vomiting and fever as shown in this table will be scored at GSK. 
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The investigator will assess the maximum intensity that occurred over the duration of the 
event for all unsolicited AEs (including SAEs) recorded during the study. The assessment 
will be based on the investigator’s clinical judgment. 
The intensity should be assigned to one of the following categories: 
1 (mild) 
= 
An AE which is easily tolerated by the subject, causing minimal 
discomfort and not interfering with everyday activities. 
2 (moderate) 
= 
An AE which is sufficiently discomforting to interfere with 
normal everyday activities. 
3 (severe) 
= 
An AE which prevents normal, everyday activities  
(in a young child, such an AE would, for example, prevent 
attendance at a day-care center and would cause the 
parent(s)/LAR(s) to seek medical advice). 
An AE that is assessed as Grade 3 (severe) should not be confused with an SAE. Grade 
3 is a category used for rating the intensity of an event; and both AEs and SAEs can be 
assessed as Grade 3. An event is defined as ‘serious’ when it meets one of the pre-
defined outcomes as described in Section 12.3.2. 
2. Assessment of causality 
The investigator is obligated to assess the relationship between study vaccines and the 
occurrence of each AE/SAE using clinical judgment. In case of concomitant 
administration of multiple vaccines/products, if possible, the investigator should specify 
if the AE could be causally related to a specific vaccine/product administered (i.e. 
investigational, control/placebo or co-administered vaccine). When causal relationship to 
a specific vaccine cannot be determined, the investigator should indicate the AE to be 
related to all products. 
Alternative plausible causes, such as natural history of the underlying diseases, 
concomitant therapy, other risk factors, and the temporal relationship of the event to the 
study vaccines will be considered and investigated. The investigator will also consult the 
IB and/or Prescribing Information for marketed products to determine his/her assessment. 
There may be situations when an SAE has occurred and the investigator has minimal 
information to include in the initial report to GSK. However, it is very important that the 
investigator always makes an assessment of causality for every event prior to submission 
of the Expedited Adverse Events Report to GSK. The investigator may change his/her 
opinion of causality in light of follow-up information and update the SAE information 
accordingly. The causality assessment is one of the criteria used when determining 
regulatory reporting requirements. 
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Causality of all AEs should be assessed by the investigator using the following question: 
Is there a reasonable possibility that the AE may have been caused by the study vaccine? 
YES 
: 
There is a reasonable possibility that the study vaccines contributed to 
the AE.  
NO 
: 
There is no reasonable possibility that the AE is causally related to the 
administration of the study vaccines. There are other, more likely 
causes and administration of the study vaccines is not suspected to have 
contributed to the AE. 
If an event meets the criteria to be determined as ‘serious’ (see Section 12.3.2), additional 
examinations/tests will be performed by the investigator in order to determine ALL 
possible contributing factors for each SAE. 
Possible contributing factors include: 
 
Medical history. 
 
Other medication. 
 
Protocol-required procedure. 
 
Other procedure not required by the protocol. 
 
Lack of efficacy of the vaccines, if applicable. 
 
Erroneous administration. 
 
Other cause (specify). 
3. Assessment of outcomes 
The investigator will assess the outcome of all unsolicited AEs (including SAEs) 
recorded during the study as: 
 
Recovered/resolved. 
 
Recovering/resolving. 
 
Not recovered/not resolved. 
 
Recovered with sequelae/resolved with sequelae. 
 
Fatal (SAEs only). 
12.3.6.2.3. Medically attended visits 
For each solicited and unsolicited symptom the subject experiences, the subject’s 
parent(s)/LAR(s) will be asked if the subject received medical attention defined as 
hospitalization, or an otherwise unscheduled visit to or from medical personnel for any 
reason, including emergency room visits. This information will be recorded in the eCRF.  
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12.3.7. 
Reporting of serious adverse events 
12.3.7.1. 
Prompt reporting of serious adverse events to GSK  
SAEs that occur in the time period defined in Section 12.3.6 will be reported promptly to 
GSK within the timeframes described in Table 8, once the investigator determines that 
the event meets the protocol definition of an SAE. 
12.3.7.2. 
SAEs requiring expedited reporting to GSK  
Once an investigator becomes aware that an SAE has occurred in a study subject, the 
investigator (or designate) must complete the information in the electronic Expedited 
Adverse Events Report WITHIN 24 HOURS. The report will always be completed as 
thoroughly as possible with all available details of the event. Even if the investigator does 
not have all information regarding an SAE, the report should still be completed within 24 
hours. Once additional relevant information is received, the report should be updated 
WITHIN 24 HOURS. 
The investigator will always provide an assessment of causality at the time of the initial 
report. The investigator will be required to confirm the review of the SAE causality by 
ticking the ‘reviewed’ box in the electronic Expedited Adverse Events Report within 72 
hours of submission of the SAE. 
12.3.7.3. 
Back-up system in case the electronic reporting system does not work 
If the electronic reporting system does not work, the investigator (or designate) must 
complete, then date and sign a paper Expedited Adverse Events Report and fax it to the 
study contact for reporting SAEs (refer to the Sponsor Information) or to GSK Clinical 
Safety and Pharmacovigilance department within 24 hours.  
This back-up system should only be used if the electronic reporting system is not working 
and NOT if the system is slow. As soon as the electronic reporting system is working 
again, the investigator (or designate) must complete the electronic Expedited Adverse 
Events Report within 24 hours. The final valid information for regulatory reporting will 
be the information reported through the electronic SAE reporting system.  
12.3.8. 
Updating of SAE information after removal of write access to the 
subject’s eCRF 
When additional SAE information is received after removal of the write access to the 
subject’s eCRF, new or updated information should be recorded on the appropriate paper 
report, with all changes signed and dated by the investigator. The updated report should 
be faxed to the study contact for reporting SAEs (refer to the Sponsor Information) or to 
GSK Clinical Safety and Pharmacovigilance department within the designated reporting 
time frames specified in Table 8. 
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12.3.9. 
Follow-up of adverse events and serious adverse events 
12.3.9.1. 
Follow-up during the study 
After the initial AE/SAE report, the investigator is required to proactively follow each 
subject and provide additional relevant information on the subject’s condition to GSK 
(within 24 hours for SAEs; refer to Table 8). 
All SAEs documented at a previous visit/contact and designated as not recovered/not 
resolved or recovering/resolving will be reviewed at subsequent visits/contacts until the 
last visit of the subject. 
All AEs documented at a previous visit/contact and designated as not recovered/not 
resolved or recovering/resolving will be reviewed at subsequent visits/contacts until 30 
days after the last vaccination. 
12.3.9.2. 
Follow-up after the subject is discharged from the study 
The investigator will follow subjects: 
 
with SAEs, or subjects withdrawn from the study as a result of an AE, until the event 
has resolved, subsided, stabilized, disappeared, or until the event is otherwise 
explained, or the subject is lost to follow-up. 
If the investigator receives additional relevant information on a previously reported SAE, 
he/she will provide this information to GSK using a paper/electronic Expedited Adverse 
Events Report and/or pregnancy report as applicable. 
GSK may request that the investigator performs or arranges the conduct of additional 
clinical examinations/tests and/or evaluations to elucidate as fully as possible the nature 
and/or causality of the AE or SAE. The investigator is obliged to assist. If a subject dies 
during participation in the study or during a recognized follow-up period, GSK will be 
provided with any available post-mortem findings, including histopathology. 
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12.4. 
Appendix 4: Protocol Amendment/Administrative change 
History 
The Protocol Amendment Summary of Changes Table for the current amendment 
is located directly before the Table of Contents (TOC). 
DOCUMENT HISTORY 
Document 
Date of Issue 
Amendment 2 
30-MAR-2020 
Administrative Change 1 
24-FEB-2020 
Amendment 1 
23-SEP-2019 
Original Protocol 
09-NOV-2018 
Overall Rationale for the Amendment 2 
This protocol amendment 2 outlines measures that may be applicable during special 
circumstances (e.g., COVID-19 pandemic). The purpose of the amendment is to protect 
participant’s welfare and safety, and as far as possible ensure the potential benefit to 
the participant and promote data integrity. 
List of main changes in the protocol and their rationale 
Section # and Name 
Description of Change 
Brief Rationale 
Section 1. Synopsis 
Added footnote to study design figure, 
Figure 1 and Table 1 on study 
procedures specifically around Visit 3, 
with cross-reference to new section 
(Section 8.4) on study procedures 
during special circumstances, such as 
COVID-19 pandemic. Added footnote 
to Table 2 about study interval around 
Visit 2 during special circumstances, 
such as COVID-19 pandemic 
To provide flexibility to certain study procedures 
in response to disease outbreak situation, as 
exemplified by the COVID-19 pandemic, to 
protect participant’s welfare and safety, and as 
far as possible ensure the potential benefit to 
the participant and promote data integrity 
Section 2. Schedule of 
activities 
Section 5.2. Overall design 
Section 8. Study 
assessments and 
procedures 
Added cross-reference to new section 
(Section 8.4) on study procedures 
during special circumstances, such as 
COVID-19 pandemic 
Section 8.4 
Added new section to provide guidance 
on adapting study procedures during 
special circumstances, such as COVID-
19 pandemic 
Detailed description of Amendment 2: 
A footnote to study design figure in Section 1 (Synopsis) and Table 1 in Section 2 
(Schedule of activities) and Figure 1 in Section 5.2 (Overall study design) was added, 
with cross-reference to the new section, Section 8.4, on guidance for study procedures 
during special circumstances such as COVID-19 pandemic: Refer to Section 8.4 for 
study procedures to be considered during special circumstances.  
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A footnote to Table 2 was added, about study interval around Visit 2 during special 
circumstances, such as COVID-19 pandemic: If despite best efforts it is not possible to 
administer the 2nd dose of study vaccine within the allowed interval, a maximum age of 
24 weeks may be used. 
In the following sections, amended text is indicated in bold italics: 
Cover page 
Co-ordinating author  
, Scientific Writer 
Section 8 
Study assessments and procedures 
During special circumstances (e.g., COVID-19 pandemic), the specific guidance from 
local public health and other competent authorities regarding the protection of 
individuals’ welfare must be applied. For the duration of such special circumstances, 
the measures detailed in Section 8.4 may be implemented for enrolled participants. 
Section 8.4 
Study procedures during special circumstances  
During special circumstances (e.g., COVID-19 pandemic), the specific guidance from 
local public health and other competent authorities regarding the protection of 
individuals’ welfare must be applied.  
For the duration of such special circumstances, the following measures may be 
implemented for enrolled participants: 
 
Safety follow-up may be made by a telephone call, other means of virtual contact 
or home visit, if appropriate. 
 
Diary cards may be transmitted from and to the site by electronic means and/or 
conventional mail. 
 
If despite best efforts it is not possible to send diary cards to the site within the visit 
window as defined in the protocol (see Table 2), the diary cards should be returned 
to site before study end (the last ESFU contact). 
 
If despite best efforts it is not possible to administer the 2nd dose of study vaccine as 
defined in the protocol (see Table 2), a maximum age of 24 weeks may be used. 
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Detailed description of Protocol Administrative Change 1: 
Title page: Changes in the name of co-ordinating author and list of contributing authors. 
 
Co-ordinating author: 
 Scientific Writer (SW), 
 
, Study Data Manager (SDM), 
 
, Clinical Trial Supply Manager (CTSM). 
Title pages, Sponsor signatory page, Investigator agreement page: The administrative 
change was made to correct the category of the study title (short title versus title). No 
changes were made to the study title itself. 
Title Short title  
Safety study of 2 formulations of GSK’s human 
rotavirus (HRV) vaccine (444563), in healthy 
infants starting at age 6-12 weeks. 
Short title Title  
A phase III, observer-blind, randomized, multi-
country study to assess the reactogenicity and safety 
of the Porcine circovirus (PCV) free liquid 
formulation of GSK’s oral live attenuated human 
rotavirus (HRV) vaccine as compared to the 
lyophilized formulation of the GSK’s HRV vaccine, 
when administered as a 2-dose vaccination in infants 
starting at age 6-12 weeks. 
Overall rationale for Protocol Amendment 1 (23-Sep-2019) 
The protocol was amended primarily to include the possibility of home visit at Visit 3 
(Month 2-4) safety assessments for authorized Canadian sites only. In addition, other 
administrative and editorial changes required in the protocol were also updated. The main 
changes are captured in the table below. The rationale for all the changes is presented 
thereafter. 
List of main changes in Protocol Amendment 1 (23-Sep-2019) and their rationale 
Section # and Name 
Description of Change 
Brief Rationale 
Footnote for Section 1 
Overall design, Table 1: 
Schedule of Activities and 
Figure 1 Study design 
overview 
Possibility of home visit at Visit 3 
(Month 2-4) safety assessment, for 
authorized Canadian sites only. 
Home visits will be allowed only in Canada as 
permitted by local regulations. This provision is 
allowed only for sites with an approved site level 
Standard Operating Procedure (SOP). Sites 
without an appropriate approved SOP will not 
be permitted to perform home visits. This 
possibility should reduce the subject withdrawal 
rate from the study and reduce logistical burden 
of subjects’ parent(s)/legally acceptable 
representatives (LARs). 
Sites from other participating countries are not 
permitted for home visits. 
Table 6: Contact 
information for emergency 
unblinding 
Deletion of a decommissioned fax 
number (for North America and Puerto 
Rico) from contact information for 
emergency unblinding. 
To ensure the appropriate contact information is 
presented in the protocol and non-functional 
emergency contact number is deleted. 
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Detailed description of Protocol Amendment 1: 
Title page: Changes in the name of co-ordinating author and list of contributing authors. 
 
Co-ordinating author: 
, Scientific Writer (SW), 
 
, Clinical & Epidemiology Project Lead (CEPL), 
 
, Clinical Research and Development Lead (CRDL),  
 
, Study Delivery Lead (SDL). 
Section 1 Overall design, Table 1 Schedule of activities and Figure 1 Study design 
overview: a footnote was added, as home visits will be allowed only in Canada as 
permitted per local regulations. The provision is allowed specifically for sites in Canada 
with an approved site level Standard Operating Procedure (SOP). Sites without an 
appropriate approved SOP will not be permitted to perform home visits. This possibility 
should reduce the subject withdrawal rate from the study and reduce logistical burden of 
subjects’ parent/LAR. 
 
For authorized sites in Canada only, with approved site level standard operating 
procedures (SOP): Safety assessments scheduled at Visit 3 (Month 2-4) may take 
place at the subject’s home or at the investigator’s clinical facility as appropriate to 
the circumstances in the judgment of the investigator. 
Section 1 Synopsis (Study rationale), Section 3 Introduction, Table 4 Study groups, 
treatments and epoch foreseen in the study, Table 5 Treatments administered and 
Section 12.1.2 Glossary of terms: the definition of HRV PCV-free was added. 
 
HRV PCV-free: No detection of PCV-1 and PCV-2 according to the limit of 
detection of the tests used. 
Section 6.3 Criteria for temporary delay for enrollment and vaccination: the word 
subsequent vaccination has been added. 
Vaccination may be postponed within the allowed time interval until transient 
circumstances cited below have been resolved: 
Acute disease and/or fever at the time of enrollment/subsequent vaccination. Fever is 
defined as temperature 38.0°C/100.4°F. The preferred location for measuring 
temperature in this study will be the oral, the axillary or the rectal. Subjects with a minor 
illness (such as mild diarrhea, mild upper respiratory infection) without fever may be 
enrolled at the discretion of the investigator. 
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Table 6 Contact information for emergency unblinding: Deletion of decommissioned 
fax number (for North America and Puerto Rico) from contact information for emergency 
unblinding: 
GSK Helpdesk 
24/24 hour and 7/7-day availability 
The Helpdesk is available by phone, fax and email 
Phone: 
 
For Canada, US and Puerto Rico 
Toll-free number: 
 
Fax: 
 
Fax (North America and Puerto Rico): 
 
email: 
 
Section 7.4.1: Storage and handling of study vaccines and Table 5: Treatments 
administered: text was updated to clarify that details about storage and handling of 
vaccines can also be found in the SPM. 
Rationale: 
 
In Table 5: Treatments administered, the words “storage, handling and” were added 
in the footnote referring to the study procedure manual. The sentence will be read as 
“#Refer to the study procedure manual (SPM) for storage, handling and preparation 
methods”. 
 
In Section 7.4.1 Storage and handling of study vaccines, in the description section 
for Liquid formulation of PCV-free HRV vaccine, the words storage, handling, 
were missing. To provide better clarity the same have been added. The sentence will 
be read as “Refer to the Module on Clinical Trial Supplies in the SPM for detailed 
instructions on the storage, handling, thawing, preparation and administration of the 
frozen PCV-free HRV vaccine”. 
Table 9 Contact information for reporting of serious adverse events: for uniformity, 
the word Canadian has been replaced by Canada. 
Study contact for questions regarding SAEs 
Refer to the local study contact information document 
Back-up study contact for reporting SAEs 
24/24 hour and 7/7-day availability: 
GSK Clinical Safety & Pharmacovigilance 
Outside US & Canada sites: 
Fax: 
 or 
 
Email address: 
 
US sites only: 
Fax: 
 
Canadaian sites only: 
Fax: 
 
Section 12.1.1: List of abbreviations: The term SOP and the expansion Standard 
Operating Procedure was added. 
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