An Open-label, Randomized, Controlled, Single Centre, Phase IIb Study to Assess the Immunogenicity, Reactogenicity and Safety of Three Live Oral Rotavirus Vaccines, ROTAVAC® , ROTAVAC 5CM and Rotarix® in Healthy Zambian Infants
Phase: PHASE2
Conditions: Diarrhea, Diarrhea Rotavirus
Sponsor: Centre for Infectious Disease Research in Zambia

Protocol Number: CVIA 066 
 
An Open-label, Randomized, Controlled, Single Centre, Phase IIb 
Study to Assess the Immunogenicity, Reactogenicity and Safety of 
Three Live Oral Rotavirus Vaccines, ROTAVAC®, ROTAVAC 
5CM and Rotarix® in Healthy Zambian Infants. 
  
Abbreviated Title: Study of BBIL’s ROTAVAC® and ROTAVAC 5CM vaccines in Zambia 
 
Trial Registration: NCT03602053  
 
 
 
Investigator: 
 Centre for Infectious Disease Research in Zambia, Zambia 
Sponsor: Centre for Infectious Disease Research in Zambia, Zambia 
In Collaboration with:  PATH, USA  
Pharmaceutical Support: Bharat Biotech International Ltd, India  
Funder: PATH, USA  
 
 
Protocol Version Number: 01 
Version Date: 11 July, 2018 
 
 
 
 
 
Confidentiality Statement 
 
This document is confidential and is to be distributed for review only to investigators, 
potential investigators, consultants, study staff, and applicable independent ethics 
committees or institutional review boards.  The contents of this document shall not be 
disclosed to others without written authorization from PATH (or others, as applicable), 
unless it is necessary to obtain informed consent from potential study participants. 
 

Protocol Number: CVIA 066 
An Open-label, Randomized, Controlled, Single Centre, Phase IIb 
Study to Assess the Immunogenicity, Reactogenicity and Safety of 
Three Live Oral Rotavirus Vaccines, ROTAVAC®, ROTAVAC 
5CM and Rotarix® in Healthy Zambian Infants. 
Abbreviated Title: Study of BBIL’s ROTAVAC® and ROTAVAC 5CM vaccines in Zambia 
Trial Registration: Submission in Srocess 
Investigator: 
 Centre for Infectious Disease Research in Zambia, Zambia 
Sponsor: Centre for Infectious Disease Research in Zambia, Zambia 
In Collaboration with:  PATH, USA  
Pharmaceutical Support: Bharat Biotech International Ltd, India  
Funder: PATH, USA  
Protocol Version Number: 01 
Version Date: 11 July, 2018 
Confidentiality Statement 
This document is confidential and is to be distributed for review only to investigators, 
potential investigators, consultants, study staff, and applicable independent ethics 
committees or institutional review boards.  The contents of this document shall not be 
disclosed to others without written authorization from PATH (or others, as applicable), 
unless it is necessary to obtain informed consent from potential study participants. 

Protocol Number ± CVIA 066  
Version Number: 01 Version Date: 11 July, 2018 
 
Confidential  
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TA%L( OF CONT(NTS 
 
 
Contents 
ABBR(VIATIONS AND ACRON<MS.......................................................................... 6 
STAT(M(NT O) COMPLIANC( ................................................................................. 8 
PROTOCOL SI*NATUR( PA*( .................................................................................. 9 
.(< ROL(S AND CONTACT IN)ORMATION .......................................................... 10 
PROTOCOL SUMMAR< ............................................................................................ 15 
1 
BAC.*ROUND AND RATIONAL( ................................................................ 19 
11 
Burden of Disease ............................................................................................. 19 
12 
PathoJen .......................................................................................................... 21 
13 
DescriStion of Study Vaccine ............................................................................. 22 
131 Immune ResSonses to Rotavirus Vaccines ........................................................... 24 
132 Potential Safety RisNs of Rotavirus Vaccines ....................................................... 25 
1 
Summary of Nonclinical Studies of Study Vaccine ............................................... 26 
15 
Summary of Clinical Studies of Study Vaccines ................................................... 27 
151 ROTAVAC® 20qC ........................................................................................ 27 
152 ROTAVAC 5C ................................................................................................. 31 
153 ROTAVAC 5CM .............................................................................................. 32 
16 
Potential RisNs andor Benefits of Study Vaccine ................................................. 33 
1 
Overall DeveloSment StrateJy ............................................................................ 34 
18 
Study Rationale ................................................................................................ 34 
2 
H<POTH(S(S, OBJ(CTIV(S AND (NDPOINTS ............................................ 35 
21 
Study HySotheses ............................................................................................. 35 
22 
Study ObMectives ............................................................................................... 35 
221 Primary ObMective ............................................................................................. 35 
222 Secondary ObMectives ........................................................................................ 35 
223 ([Sloratory ObMective........................................................................................ 35 
23 
Study (ndSoints ................................................................................................ 35 
231 Primary (ndSoint .............................................................................................. 35 
232 Secondary (ndSoints ......................................................................................... 36 
233 ([Sloratory (ndSoints: ...................................................................................... 36 
3 
STUD< D(SI*N ............................................................................................. 37 
 
STUD< POPULATION .................................................................................... 39 
1 
DescriStion of Study Site 	 PoSulation ............................................................... 39 
2 
Inclusion Criteria .............................................................................................. 39 
3 
([clusion Criteria ............................................................................................. 40 
 
Continued (liJibility Confirmation for SubseTuent Vaccination ............................ 41 
5 
Reasons for :ithdraZal ..................................................................................... 41 
5 
STUD< PRODUCTS ....................................................................................... 42 
51 
Study Vaccine .................................................................................................. 42 
511 Product DescriStion ........................................................................................... 42 
512 Manufacturer .................................................................................................... 43 
513 Presentation and )ormulation ............................................................................. 43 

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51 Stability and StoraJe ......................................................................................... 46 
515 The Vaccine Vial Monitor2 ................................................................................ 46 
52 
Dose PreSaration and Administration .................................................................. 47 
53 
Accountability and disSosal ............................................................................... 49 
531 Vaccine suSSly ................................................................................................. 49 
532 DisSensinJ ....................................................................................................... 50 
533 Return or destruction ......................................................................................... 51 
6 
STUD< PROC(DUR(S ................................................................................... 51 
61 
Recruitment ...................................................................................................... 51 
62 
Study visits ....................................................................................................... 52 
621 Day 0 ±ScreeninJ(nrolment Visit ...................................................................... 52 
622 Second Visit Day 28 ....................................................................................... 53 
623 Third Visit Day 56 .......................................................................................... 54 
62 )ourth Visit Day 8 ........................................................................................ 55 
625 Interim Contacts and Visits ................................................................................ 56 
626 ManaJement of Serious Adverse (vents includinJ IntussusceStion ........................ 56 
62 Schedule of events ............................................................................................ 56 
63 
Study Termination ............................................................................................ 58 
631 (nd of Trial AccordinJ to the Protocol ................................................................ 58 
632 SusSension andor Premature Termination of the Trial .......................................... 58 
6 
Lost to folloZuS .............................................................................................. 58 
65 
Use of concomitant vaccinesmedication durinJ the study ................................... 59 
66 
UnblindinJ Srocedure ........................................................................................ 59 
6 
Clinical Srocedures ........................................................................................... 59 
68 
Termination of ZithdraZn study SarticiSant ......................................................... 60 
 
LABORATOR< (VALUATIONS R(4UIR(M(NTS ....................................... 60 
1 
SamSle collection, distribution and storaJe .......................................................... 60 
2 
ImmunoloJical laboratory assays ........................................................................ 61 
3 
Assays Tualification, standardi]ation, validation ................................................... 61 
 
)uture use of stored samSles .............................................................................. 62 
5 
Bioha]ard containment ...................................................................................... 62 
8 
SA)(T< ASS(SSM(NT AND R(PORTIN* ..................................................... 62 
81 
Definitions ....................................................................................................... 62 
811 Adverse (vent A( .......................................................................................... 62 
812 Adverse druJ reaction ICH  SusSected Adverse Reaction )DA ........................ 63 
813 Serious Adverse (vent SA( ............................................................................. 63 
81 ReSortinJ Period and Parameter ......................................................................... 64 
82 
Severity of Adverse (vents ................................................................................ 64 
83 
Causality of Adverse (vent ................................................................................ 66 
8 
)olloZuS of Adverse (vent ............................................................................... 67 
85 
*eneral *uidance on RecordinJ Adverse (vents .................................................. 68 
86 
ReSortinJ of SA( .............................................................................................. 69 
861 InvestiJator ReSortinJ to SSonsor ....................................................................... 69 
862 Notification and RevieZ of SA(s ....................................................................... 69 
863 SSonsor ReSortinJ to ReJulatory AJency ............................................................ 70 
 
SA)(T< OV(RSI*HT ..................................................................................... 70 

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1 
Routine RevieZs by PrinciSal InvestiJator ........................................................... 70 
2 
Routine RevieZs by Protocol Safety RevieZ Team PSRT ................................... 70 
3 
Study Pause Rule .............................................................................................. 71 
 
Study Pause Procedure ...................................................................................... 72 
10 
DATA HANDLIN* AND R(CORD.((PIN* .................................................. 72 
101 
Definitions ....................................................................................................... 72 
1011 Source Data ...................................................................................................... 72 
1012 Source Documents ............................................................................................ 73 
102 
Data CaSture Methods Case ReSort )orm DeveloSment and ComSletion .............. 73 
103 
Data ManaJement ............................................................................................. 74 
10 
Retention of Study Records ................................................................................ 74 
11 
STATISTICAL CONSID(RATIONS ................................................................. 74 
111 
OvervieZ and *eneral Considerations ................................................................. 74 
112 
Randomi]ation Procedures ................................................................................. 75 
113 
SamSle Si]e and PoZer...................................................................................... 75 
11 
Analysis PoSulations ......................................................................................... 76 
111 (nrolled PoSulation ........................................................................................... 76 
112 )ull Analysis SoSulation .................................................................................... 76 
113 Per Protocol SoSulation ..................................................................................... 77 
11 Safety SoSulation .............................................................................................. 77 
115 
Analytical MethodoloJy .................................................................................... 77 
1151 Analysis of demoJraShics and other baseline characteristics .................................. 77 
1152 Analysis of Srimary obMective ............................................................................. 78 
1153 Analysis of secondary obMectives ........................................................................ 78 
115 Analysis of e[Sloratory obMective ........................................................................ 80 
1155 MultiSlicity ...................................................................................................... 80 
1156 HandlinJ of DroSouts and MissinJ Data .............................................................. 80 
116 
Analysis SeTuence ............................................................................................ 80 
12 
4UALIT< ASSURANC( AND 4UALIT< CONTROL ...................................... 80 
121 
*eneral Considerations ...................................................................................... 81 
122 
([ternal MonitorinJ .......................................................................................... 81 
123 
IndeSendent AuditinJ ........................................................................................ 81 
12 
ReJulatory AJency InsSection ............................................................................ 82 
13 
(THICAL CONSID(RATIONS AND IN)ORM(D CONS(NT ........................ 82 
131 
(thical Standards .............................................................................................. 82 
132 
(thical RevieZ ................................................................................................. 82 
133 
Informed Consent Process .................................................................................. 83 
13 
ParticiSant Confidentiality ................................................................................. 83 
135 
Reimbursement ................................................................................................. 84 
136 
RisN and Benefits .............................................................................................. 84 
13 
ComSensation for Research Related InMury .......................................................... 85 
1 
PROTOCOL MODI)ICATIONS AND AM(NDM(NTS ..................................... 85 
11 
Administrative Modifications ............................................................................. 86 
12 
Clinical Modifications ....................................................................................... 86 
13 
Protocol Deviations and Violations ..................................................................... 86 
15 
)INANCIN* AND INSURANC( ...................................................................... 87 

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16 
PUBLICATION POLIC< .................................................................................. 87 
1 
LIT(RATUR( CIT(D ...................................................................................... 88 
APPENDIX 1 - DECLARATION OF HELSINKI .......................................................... 1 
APPENDIX 2 – APPLICABLE DEFINITIONS FOR GRADING OF AES .................... 1 
 
 
 
 
 
 
 

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A%%R(VIATIONS AND ACRON<MS 
 
A( 
 
Adverse (vents 
A()I  
Adverse (vents )olloZinJ Immuni]ation 
A*(  
Acute *astroenteritis 
AIIMS  
All India Institute of Medical Sciences 
ART  
AntiRetroviral Treatment 
ANC  
Acid Neutrali]inJ CaSacity 
BBIL  
Bharat Biotech International Limited 
BM*)  
Bill 	 Melinda *ates )oundation  
CCHMC 
Cincinnati Children
s HosSital Medical Center 
CCID  
Cell Culture Infectious Dose 
CDC  
Centers for Disease Control 
CDSCO  
Central DruJs Standard Control OrJani]ation 
C)R 
 
Code of )ederal ReJulations 
CI 
 
Confidence interval 
CIDRZ 
Centre for Infectious Disease Research in Zambia 
CIOMS 
Council for International OrJani]ations of Medical Sciences  
CM 
 
Centimeter 
CMC  
Christian Medical ColleJe 
CR) 
 
Case ReSort )orm 
CRO  
Contract Research OrJani]ation 
DMC  
Data ManaJement Centre 
DBT  
DeSartment of BiotechnoloJy  
DM(M 
Dulbecco’s Modified (aJle Medium 
DMP  
Data ManaJement Plan  
DTZP  
DiShtheria, Tetanus, Pertussis Zhole cell 
(C 
 
(thics Committee 
(DC  
(lectronic Data CaSture 
(LISA  
(n]ymelinNed immunosorbent assay 
(PI 
 
([Sanded ProJram on Immuni]ation 
)A 
 
)ull Analysis 
)DA  
)ood and DruJ Administration 
))U 
 
)ocus )orminJ Units 
*CP  
*ood Clinical Practices 
*MC  
*eometric Mean Concentration 
*M)R  
*eometric Mean )old Rise 
*MT  
*eometric Mean Titer 
*RAS  
*enerally RecoJni]ed as Safe 
*S.  
*la[oSmith.line 
HeSB  
HeSatitis B 
Hib 
 
+DHPRSKLOXV LQIOXHQ]DH W\SH E 
I(C 
 
IndeSendent (thics Committee 
IATA  
International Air TransSort Association  
IJ 
 
ImmunoJlobulin 
IMP 
 
InvestiJational Medicinal Products  

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IRB 
 
Institutional RevieZ Board 
ICH 
International Council for Harmonisation of Technical ReTuirements for 
Pharmaceuticals for Human Use  
IMP 
InvestiJational Medicinal Product 
.* 
 
.iloJram 
LLO4  
LoZer Limit of 4uantification 
MCH  
Maternal and Child Health 
MedDRA  
Medical Dictionary for ReJulatory Activities 
mJ 
 
milliJram 
mL 
 
milliliter 
MOH  
Ministry of Health 
MTA  
Material Transfer AJreement  
NIAID  
National Institute of AllerJy and Infectious Diseases 
NHRA  
National Health Research Authority 
NLT 
 
Not Less Than 
NSP 
 
Non Structural Protein 
OPD  
Out Patient DeSartment 
ORS  
Oral Rehydration Solution 
ORT  
Oral Rehydration TheraSy 
ORV  
Oral Rotavirus Vaccine 
PIDC  
PostImmuni]ation Diary Card 
PP 
 
Per Srotocol 
PSRT  
Protocol Safety RevieZ Team 
RCD  
Reverse Cumulative Distribution  
RV*(  
Rotavirus Jastroenteritis 
SA( 
 
Serious Adverse (vent 
SA*(  
StrateJic Advisory *rouS of ([Serts on Immuni]ation 
SAP 
 
Statistical Analysis Plan 
SAS 
 
Society for ASSlied Studies 
SCID  
Severe Combined Immunodeficiency  
SCR 
 
Seroconversion Rate 
SD 
 
Standard Deviation 
SDMC  
Statistical Data ManaJement Center  
SIIPL  
Serum Institute of India Private Limited 
SOC  
System OrJan Class 
SOP 
 
Standard OSeratinJ Procedure s  
SPC 
 
Summary of Product characteristics  
SST 
 
Serum SeSarator Tubes 
ST 
 
Serum SeSarator tubes 
ULO4  
USSer Limit of 4uantification 
UNZABR(C  University of Zambia Biomedical Research (thics Committee 
VP 
 
Viral Protein 
VVM  
Vaccine Vial Monitor  
:HO  
:orld Health OrJani]ation 
:HO DD  
:HO DruJ Dictionary 
ZAMRA 
Zambia Medicines ReJulatory Authority 

Protocol Number ± CVIA 066  
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STAT(M(NT OF COMPLIANC( 
The study Zill be carried out in accordance Zith *ood Clinical Practice *CP as reTuired by the 
folloZinJ: 
x 
International Conference on Harmonisation ICH *uidance for *CP (6 
x 
:orld Medical Association :MA Declaration of HelsinNi ± (thical PrinciSles for 
Research InvolvinJ Human SubMects Oct 2013 or subseTuent amendments 
x ASSlicable Rules of Zambia 
All Ney Sersonnel all individuals resSonsible for the desiJn and conduct of this study have 
comSleted Human SubMects Protection TraininJ, ResSonsible Conduct of Research RCR traininJ 
and ICH*CP traininJ 
 
 
 

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.(< ROL(S AND CONTACT INFORMATION 
 
PARTICIPATIN* INSTIT8TIONS 
Sponsor 
Centre for Infectious Disease Research in Zambia, 
LusaNa, Zambia, 10101  
Phone: 
(mail:i
  
In Collaboration with 
 
PATH  
2201 :estlaNe Avenue, Suite 200 
Seattle, :A 8121, USA  
Phone: 
  
(mail:
 
Vaccine Manufacturer 
Bharat Biotech International Ltd  
*enome Valley, ShameerSet,  
Hyderabad 50008, TelanJana, India 
Phone: 
(mail: 
 
Clinical Trial Site 
*eorJe Research Clinic,  
Centre for Infectious Disease Research in Zambia, 
LusaNa, Zambia, 10101  
Phone: 
(mail: 
 
Research Laboratories   
The :ellcome Trust Research Laboratory, 
DeSartment of *astrointestinal Sciences, 
Christian Medical ColleJe,  
Vellore 632 00, Tamil Nadu, India 
Phone: 
(mail: 
 
 
Cincinnati Children
s HosSital Medical Center CCHMC 

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Division of Infectious Diseases 
Cincinnati, Ohio, USA 
Phone: 
 
(mail: 
 
Contract 
Research 
Organizations 
 
Clinical Operations 
)amily Health International )HI 360 
35 BlacNZell Street, Suite 200 
Durham, NC 201 USA 
Phone: 
 
Zebsite: ZZZfhi360orJ  
 
Data Management and %iostatistics 
DiaJnoSearch Life Sciences Private Limited 
02, Dosti Pinnacle, (, Road No 22, :aJle (state,  
Thane 0060, India 
Phone: 
(mail: 
(thics Committee 
 
University of Zambia Biomedical Research (thics Committee 
UNZABR(C 
PO Bo[ 50110 
LusaNa 
Phone:  
(mail: 
 
 
:estern IRB  
101 3th Avenue S( Suite 120 
PuyalluS, :A 832115 
Phone: 
 
(mail: 

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ADMINISTRATIV( STR8CT8R( 
Principal Investigator 
 
 
Chief Scientific Officer 
Centre for Infectious Disease Research in Zambia, 
LusaNa, Zambia, 10101  
Phone: 
(mail: 
 
Sponsor Representative 
Head Research OSerations 
Centre for Infectious Disease Research in Zambia, 
LusaNa, Zambia, 10101  
Phone: 
 
(mail: 
  
PATH¶s  Medical Officer 
 
Senior Medical Officer 
PATH  15th )loor, Dr *oSal Das BhaZan,  
28, BaraNhamba Road, ConnauJht Place,  
NeZ Delhi  110001 India 
Phone: 
(mail: 
 
Vaccine 
Manufacturer 
Representative 
 
 
([ecutive Director  
Bharat Biotech International Limited,  
*enome Valley, ShameerSet, Hyderabad,  
TelanJana  
Phone: 
 
(mail: 
  
Protocol Statistician  
 
 
Biostatistician 
PATH ±2201 :estlaNe Avenue, Suite 200 

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Seattle, :A 8121 USA 
Phone: 
(mail: 
Clinical 
Operations 
Specialist 
 
Senior Clinical Research Officer, 
Center for Vaccine Innovation and Access CVIA 
PATH  2201 :estlaNe Avenue, Suite 200,  
Seattle, :A 8121, USA 
Phone: 
(mail: 
Pharmacist of Record   
Head of Pharmacy 
Centre for Infectious Disease Research in Zambia 
LusaNa, Zambia, 10101  
Phone: 
 
(mail: 
Immunology Laboratories 
 
  
The :ellcome Trust Research Laboratory 
DeSartment of *astrointestinal Sciences 
Christian Medical ColleJe 
Vellore 632 00, Tamil Nadu, India 
Tel: 
 
(mail: 
 
 
 
Cincinnati Children
s HosSital Medical Center CCHMC 
Division of Infectious Diseases 
Cincinnati, Ohio 
Phone: 
(mail: 
 

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Contract 
Research 
Organizations 
Clinical Operation 
ProMect ManaJer )HI360 
Valley Rd, Chancery Bld, 
P O Bo[ 38835  00623_ Nairobi, .enya  
Phone: 
 
(mail:
 
Data Management and %iostatistics 
 
ProMect ManaJer DiaJnoSearch Life Sciences Private Limited 
02, Dosti Pinnacle, (, Road No 22, :aJle (state,  
Thane 0060, India 
Phone: 
(mail:

Protocol Number ± CVIA 066  
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PROTOCOL S8MMAR< 
 
Title 
An Open-label, Randomized, Controlled, Single Centre, Phase IIb 
Study to Assess the Immunogenicity, Reactogenicity and Safety of 
Three Live Oral Rotavirus Vaccines, ROTAVAC®, ROTAVAC 
5CM and Rotarix® in Healthy Zambian Infants. 
Short Title 
Study of BBIL’s ROTAVAC® vaccines in Zambia 
Protocol Number 
CVIA 066 
Trial Phase 
Phase IIb 
Investigational 
Products 
ROTAVAC®: Bharat Biotech International Ltd
s licensed and :HO
SreTualified rotavirus vaccine, ROTAVAC® is a live, attenuated 
*P>11@ monovalent vaccine at a dose of 05mL NLT loJ 1050 focus 
forminJ units ))U Ser dose, to be administered orally  The vaccine is 
recommended to be stored at 20C  
ROTAVAC® 5CM: Bharat Biotech International Ltd
s neZ Rotavirus 
vaccine, ROTAVAC 5CM is a live, attenuated *P>11@ monovalent 
vaccine at a dose of 05mL NLT loJ 1050 focus forminJ units ))U Ser 
dose, to be administered orally  The vaccine is recommended to be 
stored at 28qC 
Rotarix®: *S. BioloJicals’ licensed rotavirus vaccine, Rotari[® is a 
live attenuated RI;1 strain of human rotavirus of the *1P>8@ tySe 
containinJ not less than 1060 CCID50 cell culture infectious dose 50 
of the RI; 1 strain of human rotavirus 15 ml of the liTuid vaccine 
administered orally The vaccine is recommended to be stored at 28qC 
Study Hypotheses 
 
Immunogenicity 
ROTAVAC® and ROTAVAC 5CM administered as a 3dose series 
induce comSarable immune resSonse in healthy African infants 
Safety 
ROTAVAC® and ROTAVAC 5CM administered as a 3dose series are 
both safe and Zelltolerated in healthy African infants 
Study ObMectives 
 
 
Primary ObMective:    
Immunogenicity 
To evaluate and comSare the immunoJenicity of ROTAVAC® and 
ROTAVAC® 5CM, 28 days after the last dose of the vaccine, Zhen 
administered to infants in a threedose schedule at 6, 10 and 1 ZeeNs 
of aJe  

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Secondary ObMectives:   
Safety   
 
To assess the reactoJenicity  days after each vaccination and safety  
ZeeNs after the last vaccination of the ROTAVAC® and ROTAVAC® 
5CM, Zhen administered to infants in a threedose schedule at 6, 10 
and 1 ZeeNs of aJe and Rotari[®, Zhen administered to infants in a 
tZodose schedule at 6 and 10 ZeeNs of aJe  
Immunogenicity 
To evaluate the immunoJenicity of Rotari[® 28 days after the last dose 
of the vaccine, Zhen administered to infants in a tZodose schedule at 6 
and 10 ZeeNs of aJe 
(xploratory ObMective: 
To evaluate the immunoJenicity of the three vaccines by (LISA usinJ 
812 *1P8 virus as a substrate in a subset of the samSles collected 
Study (ndpoints 
 
 
Primary (ndpoint:   
Immunogenicity: 
*eometric mean concentrations *MCs of serum antirotavirus IJA 
antibodies, 28 days after the last dose of a study vaccine, as measured by 
en]ymelinNed immunosorbent assay (LISA usinJ :C3 as the viral 
lysate  
Secondary (ndpoints: 
Safety  
The secondary safety endSoints Zill include:  
x Immediate adverse events, Zithin 30 minutes’ Sostvaccination 
x Solicited Sostvaccination reactoJenicity fever, diarrhea, vomitinJ, 
decreased aSSetite, irritability, decreased activity level durinJ the  
day Seriod Day 06 after each vaccination 
x Unsolicited A(s from first vaccination throuJh  ZeeNs after the last 
vaccination 
x SA(s, includinJ intussusceStion from first vaccination throuJh  
ZeeNs after the last vaccination of each study SarticiSant 
Immunogenicity 
The secondary immunoJenicity endSoints antirotavirus IJA usinJ 
:C3 as the Lysate Zill be as folloZs: 
x Seroconversion rate 28 days after last dose of study vaccine Day 8 
for ROTAVAC® and ROTAVAC® 5CM and Day 56 for Rotari[® 
Seroconversion is defined as a Sostvaccination serum antirotavirus 
IJA antibody concentration of at least 20 UmL if a baseline 

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concentration is  20 UmL or a Sostvaccination serum anti
rotavirus IJA antibody concentration of  2fold baseline level if a 
baseline concentration is  20 UmL 
x SeroSositivity rate at baseline and 28 days after last dose of study 
vaccine Day 8 for ROTAVAC® and ROTAVAC 5CM and Day 56 
for Rotari[® SeroSositivity is defined as serum antirotavirus IJA 
antibody concentration  20 UmL  
x SeroresSonse rate 28 days after last dose of study vaccine Day 8 
for ROTAVAC® and ROTAVAC 5CM and Day 56 for Rotari[® 
SeroresSonse Zill be assessed as a fourfold, threefold and tZo fold 
rise in antibody concentration from baseline 
x *eometric Mean )old Rise *M)R that is a ratio of *MCs at 28 
days after last dose of study vaccine Day 8 for ROTAVAC® and 
ROTAVAC 5CM and Day 56 for Rotari[® Zith reference to 
baseline    
(xploratory (ndpoints: 
The e[Sloratory endSoints based on antirotavirus IJA antibodies 
measured by (LISA usinJ 812 as the viral lysate in a subset of 
samSles Zill be as folloZs: 
x *MCs of serum antirotavirus IJA antibodies 28 days after the last 
dose of study vaccine 
x Seroconversion rate 28 days after last dose of study vaccine 
Seroconversion is defined as a Sostvaccination serum antirotavirus 
IJA antibody concentration of at least 20 UmL if a baseline 
concentration is  20 UmL or a Sostvaccination serum anti
rotavirus IJA antibody concentration of  2fold baseline level if a 
baseline concentration is 20 UmL 
x SeroSositivity rate at baseline and 28 days after last dose of study 
vaccine SeroSositivity is defined as serum antirotavirus IJA 
antibody concentration  20 UmL  
x *M)R that is a ratio of *MCs at 28 days after last dose of study 
vaccine Zith reference to baseline    
 
Study Design 
x This study is desiJned as a Phase IIb, sinJle center, randomi]ed, 
controlled, oSen label study Zith 3 JrouSs of infants n 150 Ser 
JrouS receivinJ either three doses of ROTAVAC® three doses of 
ROTAVAC 5CM or tZo doses of Rotari[® 50 SarticiSants Zill be 
randomi]ed 1:1:1 to receive ROTAVAC®, ROTAVAC 5CM or 
Rotari[® The three doses of ROTAVAC® and ROTAVAC 5CM 
Zill be administered at 6, 10 and 1 ZeeNs of aJe Zhereas tZo doses 
of Rotari[® Zill be administered at 6 and 10 ZeeNs of aJe All 
vaccines Zill be administered concomitantly Zith (PI vaccines 
includinJ DiShtheria, Tetanus, Pertussis, +DHPRSKLOXV LQIOXHQ]DH 

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W\SH E and HeSatitis B vaccine DTZPHibHeSB, Pneumococcal 
conMuJate vaccine and OPV at 6, 10 and 1 ZeeNs and IPV at ZeeN 
1 Zhen sZitched to in Zambia The SarticiSants Zill be monitored 
for 30 minutes folloZinJ vaccine administration for immediate 
adverse events 
x A blood samSle Zill be obtained from all the SarticiSatinJ infants 
before first vaccination and four ZeeNs after the last vaccine dose 
This Zould mean that the blood samSle Zill be collected at 
aSSro[imately 1 ZeeNs of aJe for infants in the Rotari[® arm and 
18 ZeeNs for infants in the ROTAVAC® JrouSs    
x (nhanced SassiveActive surveillance for vaccine reactoJenicity 
solicited reactions over the day Seriod after each vaccination Zill 
be conducted on all infants In addition, surveillance for unsolicited 
A(s, SA(s includinJ intussusceStion Zill be carried out over the 
Seriod betZeen first vaccination and four ZeeNs after the last 
vaccination on all infants 
x The study Zill comSare the immunoJenicity of the tZo formulations 
of ROTAVAC® ie ROTAVAC® vs ROTAVAC 5CM and Zill 
descriStively analy]e the immune resSonse to Rotari[® 
Study population 
50 infants 150 Ser arm, 68 ZeeNs of aJe Zill be enrolled in the study 
All enrolments Zill be done in a sinJle centre in Zambia 
Number 
of 
participating sites 
One At the CIDRZ Research Unit at *eorJe Health Centre in LusaNa  
Study Duration 
ASSro[imately 12 months 
Participant 
Duration 
3  5 months Ser SarticiSant includinJ folloZ uS Seriod of 28  days 
after the last vaccination 
 
 
 
 
 

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 
%AC.*RO8ND AND RATIONAL( 
. 
%urden of Disease  
Diarrhea is a maMor cause of death amonJ children under five years of aJe Jlobally1 Rotavirus is 
the leadinJ cause of severe diarrhea, resultinJ in an estimated 215 000 ranJe, 1 000±233 000 
deaths in 2013 Zhich corresSonds to 3 of all deaths in children 5 years of aJe The larJest 
number of rotavirus deaths occurred in subSaharan Africa, Zhere the number is estimated at 121 
000 ranJe, 111 000±131 000 deaths in 2013 Rotavirus deaths decreased at a sloZer rate in sub
Saharan Africa than in the other reJions, resultinJ in an increasinJ SroSortion of all rotavirus 
deaths occurrinJ in this reJion from 3 in 2000 to 563 in 2013 1 More than 0 of rotavirus 
deaths occurred in countries eliJible for *avi suSSort 2  
)iJure 1 Mortality rate due to rotavirus disease amonJ children 5 years of aJe, by country, 2013 
 
Diarrhea is the third leadinJ cause of child death in Zambia US to onethird of diarrhea cases 
resultinJ in hosSitali]ation andor death are caused by vaccineSreventable rotavirus3 In line Zith 
the Zorld averaJes, in 2013, Zambia reSorted a total of 563 diarrhea related deaths of Zhich 
382 diarrheas Zere Sositive for rotavirus This corresSonds to aSSro[imately 3 of allcause 
mortality in children less than 5 years of aJe  
Nearly all children, reJardless of JeoJraShic location or economic status, are infected Zith 
rotavirus before their third birthday, but children in loZincome countries are far more liNely to be 
infected earlier in life and, because access to urJent care can be limited or unavailable in rural, 
imSoverished settinJs, they are more liNely to develoS severe disease and die5 Studies conducted 
in Zambia have reSorted seroSositivity rate in aSSro[imately 25 of the infants Srior to 
vaccination6  

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HiJh rotavirus mortality rates still Srevail in loZincome countries in sSite of the siJnificant imSact 
of oral rehydration theraSy ORT and the Jeneral imSrovement in sanitary conditions Such hiJh 
mortality rates are liNely associated Zith the elevated incidence of malnutrition, other co
morbidities and Zith limited access to aSSroSriate medical care In addition to causinJ loss of lives, 
rotavirus Slaces a heavy burden on health care systems and on families Zith Srohibitive medical 
care costs and loss of Sroductivity for adults taNinJ care of sicN children  
Standard methods of sanitation such as antibacterial soaSs are not 100 effective in NillinJ the 
virus, and because loZ numbers of viruses can cause infection, transmission is common even Zith 
Jood hyJiene Sractices The most effective antiseStics aJainst rotavirus are alcohols, Zhich have 
been found to reduce the number of viruses on the hands by Jreater than  HoZever, taS Zater 
alone, or taS Zater Zith reJular soaS reduces the titer by only 28 Thus, rotavirus vaccination 
is noZ recommended for use in every country in the Zorld and should be a Sart of a comSrehensive 
strateJy to control diarrheal diseases Zith the scalinJ uS of both Srevention Sromotion of early 
and e[clusive breastfeedinJ, handZashinJ Zith soaS, imSroved Zater and sanitation and treatment 
SacNaJes includinJ loZosmolarity ORS and ]inc Rotavirus vaccine imSlementation in settinJs 
of hiJh child mortality in Africa and Asia is Must beJinninJ to occur, and the real lifesavinJ 
Sotential of vaccination has yet to be reali]ed 
The Sublic health imSact of rotavirus vaccination has been demonstrated in several countries )or 
e[amSle, in the USA, a measurable decrease Zas seen in the number of rotavirus Jastroenteritis 
hosSitali]ations accomSanied by a suJJested herd effect SrotectinJ older nonvaccinated children, 
Zhile in Me[ico a decline of uS to 50 in diarrheal deaths in children  5 years of aJe Zas 
attributed directly to the use of the vaccine :HO continues to recommend that the first dose of 
either RotaTeT® or Rotari[® be administered as soon as Sossible after 6 ZeeNs of aJe, alonJ Zith 
DTP vaccination ASart from a loZ risN of intussusceStion 1 to 5 Ser 100 000 infants vaccinated 
the current rotavirus vaccines are considered safe and Zell tolerated In loZ income countries, 
vaccine efficacy can be loZer than in industriali]ed settinJs, similar to other live oral vaccines, 
hoZever, due to the hiJh rates of severe diarrhea, this modest efficacy still translates into hiJh 
Sublic health imSact, thereby maNinJ rotavirus vaccination hiJhly costeffective in hiJhmortality 
settinJs  
Live attenuated oral rotavirus vaccines Zere first develoSed for hiJhincome countries and have 
been shoZn to have modest efficacy in develoSinJ countries in the ranJe of 0 to 60 812 In 
countries in Africa Zhich had introduced rotavirus vaccination, the African rotavirus surveillance 
netZorN has reSorted a siJnificant droS in the SroSortion of hosSitali]ed rotavirus diarrhea amonJ 
children less than five years of aJe The surveillance reSorted a direct correlation of this effect 
Zith the time Zhen rotavirus vaccine Zas introduced In the countries that introduced rotavirus 
vaccine by 2013 RZanda, Tan]ania, Zambia and (thioSia, averaJe rotavirus vaccine coveraJe 
reached uS to 0 in 2015 and rotavirus Sositivity decreased from 35 in 2010 to 1 in year 
2015 Understandably, the coveraJe Zas loZer in year 2015 in countries Zhich imSlemented 
vaccination after year 2013 Zith only 51 in year 2015 but in these countries too, the averaJe 
rotavirus Sositivity decreased from 1 in 2013 to 25 in 2015 hence SrovinJ the advantaJes of 
imSlementinJ rotavirus vaccination in SroJrammatic settinJs Rotari[® Zas introduced in the 
routine Sublic health immuni]ation SroJram in LusaNa, Zambia, in January 2012 and Zas rolled 
out countryZide in November 2013 A study in LusaNa Zambia reSorted that folloZinJ rotavirus 
vaccine introduction, seasonal SeaNs of rotavirus and allcause A*( Zere smaller The study 
observed a siJnificant reduction in A*(associated inhosSital morbidity and mortality folloZinJ 

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rotavirus vaccine introduction The Jreatest reduction Zas seen in infants 1 year Zho accounted 
for 8 of rotavirus hosSitali]ations Srior to vaccine introduction13 Another case control study 
in Zambia reSorted a Vaccine (ffectiveness of around 26 aJainst rotavirus diarrhea of all severity 
and around 56 aJainst hosSitali]ed children concludinJ that rotavirus vaccines are more effective 
aJainst disease of increased severity of illness comSared Zith milder disease3   
Three rotavirus vaccines, Rotari[® *S., RotaTeT® MercN and ROTAVAC® BBIL are 
currently :HO SreTualified Zith Rotari[® and RotaTeT® beinJ Zidely available One other 
vaccine, ROTASIIL® SIIPL, has been licensed in India and may be evaluated for :HO 
SreTualification AlthouJh Rotari[® and RotaTeT® are considered effective in SreventinJ severe 
Jastrointestinal disease and are currently more Zidely available and have been demonstrated to be 
safe and effective in loZincome, hiJhburden SoSulations, they are not affordable in develoSinJ 
countries The recent Jlobal recommendation by the :orld Health OrJani]ation :HO’s 
StrateJic Advisory *rouS of ([Serts on Immuni]ation SA*( for the inclusion of rotavirus 
vaccines in all national immuni]ation SroJrams and considered a Sriority Sarticularly in countries 
in South and Southeast Asia and subSaharan Africa is e[Sected to further increase demand, but 
economic barriers to access remain, and vaccine suSSly continues to be an issue for the countries 
in most need To address this, it is critical that a mature marNet for rotavirus vaccines, includinJ 
manufacturers from develoSinJ countries, develoSs as TuicNly as Sossible At US1 Ser dose, 
initially, ROTAVAC® is substantially less e[Sensive than other available rotavirus vaccines  
. 
Pathogen  
Rotavirus Zas identified in 13 from the small intestine
s eSithelial cells of children Zho are 
affected by diarrhea1 Humans are mainly infected by sSecies A, B, and C amonJ the available 
eiJht sSecies A, B, C, D, (, ), *, and H, but more than 0 of diarrheal infections are caused 
by sSecies A  
The rotavirus Jenome, shelled Zith three Sroteins a core, inner membrane, and outer caSsid, 
contains an 11seJmented doublestranded Jenome Both structural Sroteins VP1±VP, VP6, 
VP and nonstructural Srotein NSP1±NSP are encoded by rotaviral RNA Jene seJment, but 
only Jene seJment 11 codes for NSP5 and NSP6 The outer shell that is used to characteri]e the 
rotavirus strain is formed by VP a JlycoSrotein* Srotein and VP a Sroteasecleaved 
Srotein²P Srotein The combination of * and P Sroteins is mediated by VP and VP structural 
Srotein due to its indeSendent nature of seJreJation and more than 80 of severe rotavirus disease 
is caused by the mostly common four combinations P>8@*1, P>@*2, P>8@*3, P>8@* of * and 
P Sroteins It is susSected that clinical Srotection Srobably involves mucosal intestinal, systemic 
antibody resSonse, and cellmediated immunity, hoZever it is difficult to reali]e the mechanism 
of Srotection, as Zell as duration of Srotection aJainst rotavirus infection15,16 
The e[act mechanism of rotavirus infection Zithin the Sublic health community is relatively 
unNnoZn1,18 Probably, rotavirus diarrhea is multifactorial, Zith malabsorStion and secretion 
comSonents, and may have other comSonents suJJested to be related to villus ischemia and 
intestinal motility The rotavirus mostly Srefer to infect durinJ cool and dry seasons Zith infection 
shoZinJ SeaNs in Zinter to cause diarrhea1,20  
The molecular mechanisms underlyinJ the raSid induction of heterotySic Srotective immunity to 
rotavirus, Zhich Srovides the basis for the efficacy of licensed monovalent rotavirus vaccines, have 

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remained unNnoZn (SidemioloJic and clinical studies demonstrate that heterotySic Srotective 
immunity is Jenerated after a sinJle rotavirus infection21  or immuni]ation22,23  
. 
Description of Study Vaccine  
Several studies have documented that the first rotavirus infection in infants Srotects aJainst severe 
diarrhea durinJ reinfection 21,2 In the mid180s, neonates born at the All India Institute of 
Medical Sciences NeZ Delhi Zere commonly infected Zith a rotavirus strain before hosSital 
discharJe that Zas later encoded 116( These infants remained asymStomatic and e[Serienced 
6 feZer eSisodes of rotavirus diarrhea than did a cohort of babies born at the same institute Zho 
Zere not neonatally infected A Jreater reduction in the severity of diarrhea Zas observed in the 
neonatally infected than the noninfected neonates Because infection Zith strain 116( did not 
cause diarrhea in neZborns and Zas not found in older Satients Zith diarrhea, it aSSeared to be 
naturally attenuated )urthermore, the strain JreZ Zell in the infant Jut, induced rotavirussSecific 
immunoJlobulin IJ A or IJM antibody resSonses, and offered clinical Srotection 25,26 :hile 
rotaviruses do not commonly infect infants in the first feZ months of life, this strain Zas uniTue 
in that it JreZ in the Sresence of transSlacental antibodies from the mother2 Human neonatal 
strains similar to Rotavirus 116( Jiven alone are liNely to Srotect children aJainst a variety of 
rotavirus strains of different serotySes28  
Bharat Biotech International Limited Hyderabad, India develoSed the oral rotavirus vaccine 
ORV 116( to address the need for a safe, effective, and affordable vaccine for India and the 
develoSinJ Zorld as a Sart of the IndoUS Vaccine Action ProJram and Zith technical suSSort 
from the DeSartment of BiotechnoloJy India, the US Centers for Disease Control and Prevention 
CDC, the National Institutes of Health, Stanford University, and PATH2   The vaccine Zas 
successfully develoSed and named as ROTAVAC® )urther, clinical trials in India Sroved the 
efficacy of ROTAVAC® in SreventinJ severe rotavirus Jastroenteritis ROTAVAC® Zas licensed 
by CDSCO National ReJulatory AJency in 201 ROTAVAC® Zas initially aSSroved as a 3
dose reJimen to be Jiven Zith routine childhood vaccines at 6, 10, and 1 ZeeNs of aJe alonJ Zith 
25 mL citratebicarbonate buffer to facilitate SassaJe throuJh the acidic contents of the uSSer 
Jastrointestinal tract 
Several studies have been carried out to e[amine the role of buffer on the Serformance of rotavirus 
vaccines 3032 Some of these studies noted that rotaviruses are moderately acid labile, and the 
acidic environment affects the viability of the virus 33,3  althouJh natural transmission of rotavirus 
occurs via the faecaloral route and occurs in the Sresence of unneutrali]ed Jastric acid It is also 
Sostulated that the human infant stomach Zith hiJher SH levels aSSro[imately 32 comSared to 
adults aSSro[imately 10 may be more Sermissive for the survival of rotavirus In addition, in 
humans, homoloJous rotaviruses human oriJin rotavirus in a human are much more !1000 fold 
infectious than heteroloJous rotavirus nonhuman oriJin rotavirus in a human and only very 
small Tuantities of homoloJous rotavirus 10 infectious doses or less are Jenerally able to cause 
infection, immune resSonse and illness35,36 In Jeneral, the results have been found to be mi[ed in 
nature and all commercial vaccines use bufferinJ comSonents either as Sart of the formulation 
RotaTeT® and Rotari[®, in some marNets or reconstituted at the time of administration Rotasiil® 
in India and Rotari[®  in some marNets Zhich Sose several loJistic and SroJrammatic challenJes 
in terms of either havinJ to seSarately transSort and store the bufferinJ diluent, and administer 
relatively larJe volumes 15 to 216 mL of reconstituted or readytouse vaccine orally to 
infants33 )rom a vaccine administration Soint of vieZ for infants, loZ dose volumes, tySically 

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around 05 mL, are Sreferred Immuni]ation SroJrams Srefer vaccines that are ³readytouse´ and 
do not reTuire reconstitution or administration of seSarate comSonents, such as a diluent or a 
buffer, to minimi]e errors in administration   
ConsiderinJ the human oriJin of 116( strain, Zhich belonJs to the * and P>11@ JenotySes and 
the aJe at immuni]ation, it Zas hySothesi]ed that the strain may reSlicate and the vaccine may 
confer immunity Zithout a buffer administration as it Zas initially recovered from an 
asymStomatic neonate )urther, the hiJh SH stability of the 116( strain also suJJests that the 
challenJe of Sremi[inJ the vaccine Zith the buffer before administration could be avoided, and 
hence bySass any SroJrammatic challenJe Zhen beinJ administered alonJ the other vaccines in 
The ([Sanded ProJram on Immuni]ation (PI  
In vieZ of this, and suSSorted by the results of a clinical study demonstratinJ similar immune 
resSonse achieved by ROTAVAC® Zhen administered Zith and Zithout antacid buffer, 
ROTAVAC® Zithout buffer Zas also aSSroved and the vaccine Zas licensed on 30 ASr 2015 and 
is noZ available for commercial use ROTAVAC® has a dosinJ volume of 05 mldose Zith the 
inherent acid neutrali]inJ caSacity of the vaccine eliminatinJ the need to administer an alNali 
buffer seSarately Srior to the vaccine Hence the cold chain footSrint of these vaccines is marNedly 
reduced Zith the cold chain volume of ROTAVAC® beinJ betZeen 322 cm3dose Zhereas the 
same is betZeen 625  526 for RotaTeT® and 112   1153 cm3dose Ser vial for Rotari[® 
The vaccine Zas still recommended to be stored at 20 C The *overnment of India has rolled out 
rotavirus vaccination as Sart of the (PI in a Shased manner and ROTAVAC® is beinJ used for this 
SurSose in feZ of the states in India Till date, the comSany has suSSlied 35 million doses to the 
(PI SroJram in India It has also initiated suSSly of :HO PreTualified the vaccine to UNIC() 
and other immuni]ation SroJrams ZorldZide0 
BBIL further undertooN the develoSment of a liTuid formulation of the vaccine, ROTAVAC 5C 
that is stable at 28 C for over 2 months thereby maNinJ it amenable for easier storaJe and 
transSort  This formulation contains the same rotavirus strain 116( as in ROTAVAC® These 
formulations also have sufficient Acid Neutrali]inJ CaSacity ANC to neutrali]e the Jastric Muices 
in stomach, thus, suSSortinJ survival of the vaccine virus The formulation Zas chanJed by 
addition of e[ciSients and stabili]ers belonJinJ to the *enerally reJarded as Safe *RAS 
cateJory  
)urther to this and based on the ROTAVAC® clinical trial results Zithout buffer, formulation of 
ROTAVAC 5C 15 mL Zas modified to 05mL volume and the internal buffer comSonents Zere 
removed, Zhich later Zas named as ROTAVAC® 5CM, a liTuid formulation that is stable at 28 
C storaJe temSerature ROTAVAC 5CM is Zithout buffer and has additional e[ciSients and 
stabili]ers same as in ROTAVAC 5C, Zith established safety and immunoJenicity that belonJ 
to *RAS cateJory and additionally any neZ safety concerns are not anticiSated ROTAVAC 5CM 
vaccine formulation also has e[cellent stability at 25C and 3C The advantaJes Zith such liTuid 
formulations include stability at 28C Zhich maNes the vaccine amenable for easier storaJe and 
transSort, and the acid neutrali]inJ caSacity Zhich eliminates the need to administer an alNali 
buffer seSarately Srior to the vaccine  
International Patents have been Jranted in several countries includinJ India, USA, U. and South 
Africa for these ROTAVAC® vaccine formulations  
The diaJram beloZ describes the develoSment of ROTAVAC® formulations 

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.. Immune Responses to Rotavirus Vaccines 
ChallenJe of adult volunteers Zith Zild tySe rotavirus strains and trials of live rotavirus vaccines 
have shoZn a correlation betZeen Sree[istinJ rotavirus antibodies, Sarticularly IJA, and the 
ability of the viruses to infect corresSondinJly, serum resSonses after live virus challenJe resultinJ 
in infection include a siJnificant increase in antibody levels, IJA in Sarticular TestinJ antibodies 
in serum of infants under  months of aJe, before they receive a live vaccine, has demonstrated 
the Sresence of siJnificant amounts of antirotavirus sSecific IJ* of maternal oriJin, the halflife 
of Zhich is such that by the fourth month such antibodies are barely detectable  On the other hand, 
IJA antibodies are NnoZn not to cross the Slacenta and therefore are not Sresent in Sreimmune 
serum unless natural infection has occurred AccordinJly, the induction of an IJA seroresSonse is 
the best available tool to assess the immunoJenicity of any rotavirus vaccines  
An (LISAbased antirotavirus IJA, develoSed and validated by :ard, et al, at the Cincinnati 
Children’s HosSital Medical Center CCHMC and later adaSted to use in multiSle laboratories, 
has become the standard test to evaluate immune resSonses to rotavirus vaccine1  :hen evaluated 
in develoSed countries, all Sreviously licensed vaccines RotaShield®, Rotari[®, and RotaTeT® 
Zere shoZn to induce a 3 or  fold resSonse deSendinJ on the study analysis in 80 or more 

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of the SarticiSants Zith corresSondinJ Jeometric mean concentrations *MCs 100 HoZever, 
Zhen tested in resource Soor countries, and in Sarallel to their diminished efficacy in these 
countries, both the seroresSonse rates as Zell as the *MCs are Jreatly diminished Zith 
seroresSonse rates in some cases beloZ 0 and *MCs as loZ as 30 Note, hoZever, that in sSite 
of this Sarallelism, no correlation has been found betZeen IJA resSonses and efficacy levels  
Conversely, in some studies immunoJenicity rates have been hiJher than the efficacy rates )or 
instance, the seroresSonse rates for Rotari[® in Vietnam study have been aSSro[imately  Zith 
efficacy rates of aSSro[imately 6 A study conducted in Zambia reSorted a baseline 
seropositivity rate of around 25% in the enrolled infants and the overall seroconversion frequency 
to Rotarix® for IgA in the infants was 60.2%. The post vaccination GMCs observed in the study 
were between 63 and 112 and were dependent on the season. It was observed that seropositive 
infants at baseline were less likely to seroconvert compared to their seronegative counterparts (P 
= 0.04); and there was no evidence of an association between maternal HIV status and 
seroconversion (P = 0.25).6  
.. Potential Safety RisNs of Rotavirus Vaccines  
RisN of vaccination Zith live attenuated rotaviruses include develoSment of fever, diarrhea or 
vomitinJ as a conseTuence of the JroZth of the virus in the child’s intestine, hoZever, all the 
animal and animalhuman rotavirus reassortants tested to date at similar or hiJher titers to those 
used Zith ROTAVAC® have seen adverse events liNe fever, diarrhea, couJh, vomitinJ, irritability, 
otitis media, nasoSharynJitis, bronchosSasm, cryinJ and rash beinJ reSorted as common adverse 
events In babies, natural rotavirus infection can cause diarrhea, vomitinJ and fever these 
occurrences have been selfcontained and of easy manaJement3,38  
Shortly after the introduction of RotaShield® in the US, the vaccine Zas associated Zith a very 
small increase in the incidence of intussusceStion after vaccination, Sarticularly folloZinJ the first 
vaccine dose in older infants This led to ZithholdinJ any subseTuent use of this vaccine and Sut 
a siJnificant burden on future rotavirus vaccine develoSers to demonstrate Zith a reasonable 
deJree of certainty that their candidates Zere not associated Zith this outcome Both Rotari[® and 
RotaTeT® underZent larJe safety studies in tens of thousands of children in Zhich the occurrence 
of intussusceStion Zas closely folloZed The hiJh level of efficacy observed in those studies, alonJ 
Zith the vaccine safety Srofile and lacN of association Zith intussusceStion Zere sufficient to 
achieve licensure in many countries Additional SostmarNetinJ studies initially suJJested that 
intussusceStion miJht still be associated Zith the licensed vaccines, but at much loZer rates than 
could have been detected in the clinical trials A recently comSleted study in the US, Zhere Sost
vaccination surveillance Zas conducted in 33 ZeeN old infants after the administration of over 
50,000 doses of the RotaTeT® vaccine, shoZed a lacN of association betZeen vaccination and the 
occurrence of intussusceStion in the Seriods of 1 to  or 1 to 30 days Sostvaccination22  
The :HO Sresently suSSorts seven Rotari[® vaccineusinJ countries includinJ Zambia, and 
another four countries that are usinJ the RotaTeT® vaccine, to systematically collect surveillance 
data on intussusceStion, and other Adverse events folloZinJ immuni]ation A()I Tools for 
systematic collection of data are readily available for enhanced surveillance2  
 

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. 
Summary of Nonclinical Studies of Study Vaccine  
To[icoloJy studies for oral rotavirus 116( vaccine Zere conducted in SZiss Albino Mice, SSraJue 
DaZley Rat, )ischer )3 Rats and rabbits The Sreclinical to[icity studies of Rotavirus 116( 
)ormulations Zere conducted in RCC Laboratories, a *LP certified testinJ facility and CPCS(A 
and AAALAC Accredited animal facility The characteri]ation from these studies identified that 
the vaccine did not damaJe any orJan structurally or functionally in animals The Summary details 
of the studies Serformed for Oral Rotavirus 116( vaccine formulations is tabulated beloZ: 
Study 
%atch numberDose 
Composition 
A 28Day ReSeated Dose 
To[icity 
Study 
of 
TZo 
)ormulations 
of 
Oral 
Rotavirus 116( Vaccine, Live 
Attenuated in SZiss Albino 
Mice 
 
DosinJ: Day 0, 3, 6, , 12, 15 
and day 28 
T)11002  
1060 ))U05mL  
Sucrose 0, Trehalose05, HA 
035, LAH 1, 3mM Ca,  
Citrate ± 0052 M,  
Potassium PhosShate ± 01 M,  
T)11012  
1060 ))U10mL  
Sucrose 30, Lactose 5, HA 
035, LAH 05, 3mM Ca, 
Citrate ± 003 M, Bicarbonate ± 03 
M 
ReSeated Dose 28 Days Oral 
To[icity Study Zith Oral 
Rotavirus 116(e Vaccine, II 
*eneration 
)our 
)ormulations 
In 
SSraJue 
DaZley Rat  
DosinJ: Day 0, day , day 1 
and day 21 
 
ReSeated Dose 28 Days Oral 
To[icity Study Zith Oral 
Rotavirus 116( Vaccine, II 
*eneration 
)our 
)ormulations in Rabbits 
DosinJ: Day 0, day , day 1 
and day 21 
61(Z13001  
10610 ))U15 mL  
 
Sucrose 0, Trehalose 05, 
LAH 05, HA 035, 
11 M Potassium PhosShate  
61(Z13002  
10615 ))U15 mL  
 
Sucrose 50, Trehalose 05, 
LAH 05 , HSA ± 035, 0053 M 
Trisodium 
Citrate, 
01 
M 
Potassium PhosShate  
61(Z13003  
10618 ))U15 mL  
 
Sucrose50, Trehalose05,  
LAH10, 
HSA035, 
015M 
Trisodium Citrate, 03M Potassium 
PhosShate  
61(Z1300  
1053 ))U15 mL  
 
Sucrose 55, Trehalose 08, 
LAH 10, 015 M Trisodium 
Citrate, 03 M Potassium PhosShate  
61DA13001Reference 
10538 ))U05 mL 
28 Day ReSeated Oral Dose 
Proof of ConceSt Study Zith 
Oral Rotavirus 116( Vaccine, 
Ii 
*eneration 
TZo 
)ormulations in )ischer )3 
Rats 
DosinJ: Day 0, day 1 and day 
28 
61(Z13001  
10610 ))U15 mL  
Sucrose 0, Trehalose 05, 
LAH 05, HA 035, 11 M 
Potassium PhosShate  
61(Z1300 
1053 ))U15 mL  
 
Sucrose 55, Trehalose 08, 
LAH 10, 015 M Trisodium 
Citrate, 03 M Potassium PhosShate  
61DA13001Reference 
10538 ))U05 mL 
 
In the above studies all animals in the JrouSs Zere observed and e[amined for clinical siJns, 
oShthalmoscoSy, body ZeiJhts and food consumStion, clinical SatholoJy, orJan ZeiJhts and 
histoSatholoJy of the Sreserved orJans and tissues The studies revealed no adverse findinJs in 

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any of the Oral Rotavirus 116( Vaccine treated animals, and all the formulations Zere comSarable 
Zith reference test item 
In conclusion, under the conditions of these studies, 28day reSeated oral dose Zith Oral Rotavirus 
116( formulations revealed no adverse findinJs in any treated animals, Zhen comSared Zith the 
Slacebo The studies Zere initiated in 05 mL formulations and later on in continuation of develoSinJ 
formulation Zith buffer Zherein the dose volume is 15 mL The SroSosed ROTAVAC 5CM has 
similar e[ciSients as in 61(Z13001 and T)11002 and differ only in the concentration Buffer 
comSosition is similar to 61(Z1300 Zherein the buffer system is citrate ShosShate Dose volume 
and concentration of buffer system and e[ciSients did not affect the results of the studies Hence 
it is Sroved that the e[ciSients and buffer system used for ROTAVAC 5CM Zere tested in animal 
model for to[icity and it is safe Please refer to ROTAVAC 5CM IB version 1 dated 2 December 
201 for additional details 
.5 
Summary of Clinical Studies of Study Vaccines  
.5. ROTAVAC® (-0qC) 
The early clinical develoSment of A*M. Vaccine 116( in adults, children and infants Zere a 
collaborative effort betZeen the Society for ASSlied Studies SAS, AIIMS, NIAID and PATH 
The results of these studies, Zhich Zere conducted amonJ adults, children aJes 2 to 12 years, and 
infants aJes 6 to  ZeeNs, Srovided the basis for BBIL to further develoS the vaccine The 
folloZinJ are the studies that Zere conducted Zith ROTAVAC®  
 
Table . List of clinical trials of ROTAVAC® 
Clinical trial 
Phase 
N 
Formulation 
Location (ndpoint 
Status 
Phase 1: 
adults 
30 
116( or I321 1050))U 
or Placebo 
India 
Safety 
ComSleted 
Phase 1: 
children 
30 
India 
Safety 
ComSleted 
Phase 1: 
infants 
0 
India 
Safety and 
immunoJenicity 
ComSleted 
Phase 1b2a: 
infants 
360 
116(, 100 ffu or 1050 
ffu or Placebo 
India 
Safety and 
immunoJenicity 
ComSleted 
Phase 3: 
infants 
6800 
116( 1050 ffu Zith 
buffer or  
Placebo 
India 
(fficacy 
ComSleted 
Phase 3: 
infants  
1356  
116( 1050 ffu Zith 
buffer or  
Placebo 
India  
Lottolot 
consistency and 
interference Zith 
childhood 
vaccines 
ComSleted 
Phase : 
infants  
00 
ROTAVAC® Zithout 
buffer 
India 
ImmunoJenicity 
and safety 
ComSleted 

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ROTAVAC® Zith 
buffer administered 5 
minutes before 
ROTAVAC® Zith 
buffer administered 
simultaneously  
Phase : 
infants 
6 
ROTAVAC® or 
Rotari[® 
India 
ImmunoJenicity 
and safety 
ComSleted 
Phase 3 
([Sloratory: 
infants 
65 
ROTAVAC® or Rotavac 
5C 15 ml or Rotavac 
5C 20 ml 
India 
ReactoJenicity 
and Safety 
ComSleted 
Phase 3 
Confirmatory: 
infants 
1,302 
ROTAVAC® or Rotavac 
5C  20 ml, Lot 1 	 2 
India 
ImmunoJenicity 
and safety 
ComSleted 
Phase 3: 
infants 
360 
ROTAVAC®  or 
ROTAVAC 5CM 
India 
Safety and 
immunoJenicity 
ComSleted 
In these studies, ROTAVAC® Zithout buffer Zas used 
Phase  Study in Healthy Adults in India 
A Shase 1 randomi]ed, doubleblind, Slacebocontrolled, safety and immunoJenicity study Zas 
conducted in healthy adults A total of 30 volunteers aJed 185 years received a sinJle oral dose 
of either the 116( or I321 1050))U or Placebo accordinJ to a 1:1:1 vaccine: vaccine: Slacebo 
randomi]ation Vaccine or Slacebo Zas administered orally after consuminJ 2J sodium 
bicarbonate dissolved in 120 ml sterile Zater to buffer stomach acidity The study evaluated safety 
and immunoJenicity of the study vaccines and sheddinJ of the vaccine virus No vaccinerelated 
SA( Zas reSorted IntussusceStion Zas not reSorted by any SarticiSant None of the SarticiSants 
shed rotavirus in stools as ascertained throuJh antiJen detection (ny]me LinNed Immunosorbent 
Assay (LISA None of the SarticiSants seroconverted ie had a fold rise in rotavirus sSecific 
IJA Both vaccines reSlicated Soorly in adults and aSSeared to be safe 
Phase  Study in Healthy Children in India 
A Shase 1 study Zith similar study desiJn as the adult study above Zas conducted in healthy 
children aJed 212 years This study also did not reSort any vaccinerelated SA( or case of 
intussusceStion SymStoms such as fever, diarrhea, vomitinJ Zere rare and not differentially 
distributed Mild abdominal Sain Zas more common in the study vaccine JrouSs, but only one 
child reTuired medication Both vaccines reSlicated Soorly in children and aSSeared to be safe 
None of the SarticiSants shed rotavirus in stools as e[amined by antiJen detection (LISA One 
SarticiSant seroconverted ie had a fold rise in rotavirus sSecific IJA in the 116( JrouS the 
baseline concentration in this child Zas loZ 
Phase  Study in Healthy Infants in India 
This study Zas a Shase 1 randomi]ed, double blind, safety and immunoJenicity study of live, 
attenuated neonatal rotavirus vaccine candidate strains 116( or I321 in healthy nonmalnourished 
infants aJed 812 ZeeNs The study enrolled 0 infants Zith 30 infants each receivinJ 116( or 
I321 vaccines 1050 fluorescence focus units, ffu in 1 ml or Slacebo UIP vaccines Zere not 
administered concomitantly The study evaluated safety and immunoJenicity of the study vaccines 

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and sheddinJ of the vaccine virus ([Sected adverse events such as fever, diarrhea associated Zith 
vomitinJ and diarrhea not associated Zith vomitinJ Zere similar in both JrouSs Virus Zas shed 
on day 3 or , by tZo out of 30 infants in the Slacebo JrouS, one out of 2 in I321JrouS and 12 out 
of 30 in 116( JrouS infants In the Ser Srotocol analysis, the SroSortion of infants shoZinJ t fold 
rise in IJA antibody durinJ 28 days Sost administration of vaccineSlacebo Zas five out of 30 
16 in the Slacebo JrouS, nine out of 28 321 in I321 JrouS and 16 out of 30 533 in 
116( JrouS The study concluded that 116( strain is attenuated, clinically safe and hiJhly 
immunoJenic Zith a sinJle dose3 
Phase ba Study in Healthy Infants in India 
A fro]en 0C Rotavirus 116( candidate vaccine Sroduced by BBIL suSSorted by DeSartment 
of BiotechnoloJy DBT and PATH Zas tested in a dose ranJinJ study for safety and 
immunoJenicity in infants 820 ZeeNs of aJe The randomi]ed, double blind Slacebocontrolled 
trial tested tZo doses of the ORV 116(, 100 ffu and 1050 ffu Infants received a dose of either 
vaccine at 8, 12, and 16 ZeeNs, seSarately from routine vaccines There Zere no vaccinerelated 
serious adverse events, and no siJnificant differences in clinical adverse events or laboratory 
to[icity Zere observed betZeen vaccine and Slacebo reciSients The seroconversion rates Zith the 
1050 ffu dose Zere 65 vs 233 Zith a sinJle dose and 8 and 281 after three doses in 
the vaccine and Slacebo JrouSs, resSectively These Zere siJnificantly hiJher than the loZer dose 
These results led to selection of three doses of the vaccine candidate in a dose of 1;105 ))Udose 
for the Shase III efficacy study    
Phase  Study in Infants in India 
The fro]en 20C Rotavirus 116( candidate vaccine Sroduced by BBIL suSSorted by DeSartment 
of BiotechnoloJy DBT and PATH has been tested in an efficacy study in infants The Shase 3 
Sivotal efficacy study Zas a doubleblind Slacebo controlled, multicenter trial enrollinJ 6 
infants The infants Zere randomi]ed to receive three doses of vaccine 116( 1050ffu or Slacebo 
at 6, 10, and 1 ZeeNs of aJe The Srimary outcome Zas severe rotavirus Jastroenteritis Zith 11 
Soints on the VesiNari scale Based on the incidence in the tZo arms, vaccine efficacy aJainst 
severe rotavirus Jastroenteritis in children in the first year of life Zas calculated as 563 5 
CI 36 to 6 Zhereas it Zas only marJinally less at 8 in the second year of life Overall 
efficacy uS to 2 years of aJe Zas 551 S  00001 The study estimated that the number of 
infants needed to be immuni]ed to Srevent one eSisode of severe RV*( in the first 2 years of life 
Zas 0 and for RV*( of any severity, it Zas 21 Seroconversion rates Zere analysed usinJ 2, 3 
and fold resSonse The IJA immune resSonse rates Zere moderate fold 3, 2fold 
563 and 3fold 6 Viral sheddinJ Zas hiJhest on day 3 or  after dose 1 2 The 
The Srotection offered by the vaccine durinJ the first 2 years of life Zas aJainst the array of 
commonly circulatinJ JenotySes includinJ *1P>8@, *2P>@, *12P>6@, *12P>8@ and *P>@, 
althouJh 116( vaccine has an unusual *P>11@ JenotySe that is rarely associated Zith clinical 
disease in India or other countries This suJJests that the vaccine could offer siJnificant Srotection 
in varyinJ JeoJraShical settinJs over time SA(s, deaths and cases of intussusceStion Zere similar 
betZeen vaccine and Slacebo JrouSs 23  
Phase  Lot Consistency and Non-Interference with Childhood Vaccines Study in India  
This is a Slacebocontrolled study desiJned to assess noninterference of ORV 116( to the 
childhood vaccines namely Sentavalent vaccine and oral Solio vaccine, Zhen coadministered at 

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6, 101 and 118 ZeeNs of aJe and clinical consistency in the immune resSonses to the three 
Sroduction lots of ORV 116( This study demonstrated that three doses of ROTAVAC® can be 
safely coadministered Zith three doses of Sentavalent vaccine and oral Solio vaccine Zithout 
diminishinJ an infant’s serum antibody resSonses to each comSonent of these vaccines The three 
ROTAVAC® lots tested Zere Sroven to be not different as statistical clinical eTuivalence across 
them Zas established ROTAVAC® is Jenerally Zell tolerated Zith resSect to solicited adverse 
events of sSecial interest fever, vomitinJ, diarrhea, couJh, listlessness or less active, runny nose, 
irritability, and rash There Zas no case of intussusceStion associated Zith the administration of 
ROTAVAC® 5 
 
Based on SromisinJ results of the Shase 3, safety and efficacy clinical trial of the oral rotavirus 
human 116( strain ORV 116(, ROTAVAC® Zith buffer, manufactured by Bharat Biotech 
International Limited, Hyderabad, India, it Zas licensed in India in 201  
Phase  :ith and :ithout %uffer Study in Infants in India  
This Zas a sinJle blind study to evaluate the immunoJenicity and safety of ROTAVAC® A total 
of 00 SarticiSants Zere enrolled in the study in three different treatment JrouSs Zith 1:1:1 ratio 
ROTAVAC® Zas administered in a 3dose series Zith and Zithout buffer to healthy infants 
ImmunoJenicity Zas tested in terms of *MCs of serum anti rotavirus IJA and seroconversion in 
all three treatment JrouSs Seroconversion Zas defined as achievement of Sostvaccination titer of 
!20 UmL in infants Zith Srevaccination titer of 20 UmL or achievement of a 2fold rise in 
their Sostvaccination titer if Srevaccination titers Zere ! 20 UmL Immune resSonse in three 
treatment JrouSs is comSarable Zith no statistically siJnificant difference detected 
Seroconversion and *MCs achieved in JrouS II ROTAVAC® administered Zithout buffer Zas 
similar to that in the other tZo treatment JrouSs Zhere ROTAVAC® is administered Zith buffer 
Post vaccination antirotavirus IJA *MCs in the JrouS to Zhich ROTAVAC® Zas administered 
Zithout buffer Zas 20 UmL in comSarison to 16 UmL and 12 UmL in the tZo JrouSs 
Zhich received antacid buffer 5 minutes Srior to vaccine and simultaneously mi[ed Zith vaccine, 
resSectively Similarly, the threefold seroconversion observed in the JrouSs that received 
ROTAVAC® Zithout antacid buffer and Zith buffer Zere betZeen 25 and 22  
ROTAVAC® vaccine Zas Zell tolerated in all three treatment JrouSs that received the vaccine 
Zith or Zithout the antacid buffer The reactoJenicity and safety Zith resSect to solicited and 
unsolicited adverse events Zere comSarable across the three JrouSs Zith no statistically siJnificant 
difference6  
Phase  Comparator Study 
ImmunoJenicity and safety of ROTAVAC® Zas comSared Zith a :HO SreTualified rotavirus 
vaccine Rotari[® in a seSarate Shase IV, multicenter, oSenlabelled, randomi]ed clinical trial in 
healthy infants in India )our hundred and si[tyfour infants aJed 68 ZeeNs Zere eTually 
randomi]ed to receive 3doses of ROTAVAC® JrouS I or 2dose Rotari[® JrouS II Infants in 
JrouS 1 Zere vaccinated on day 0, day 28 and day 56 Zith 3 doses of ROTAVAC® and infants in 
JrouS II Zere vaccinated on day 0 and day 28 Zith 2 doses of Rotari[® The tZo JrouSs Zere 
comSared for differences in seroloJical resSonses and safety Seroconversion Zas defined as 
achievement of Sostvaccination titer of !20 UmL in infants Zith Srevaccination titer of 20 
UmL or achievement of a 2fold rise in their Sostvaccination titer if Srevaccination titers Zere 

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! 20 UmL Seroconversion Zas reSorted in 31 SarticiSants and 306 SarticiSants in JrouS I 
and II resSectively Antirotavirus Jeometric mean concentration *MC Zas 20 and 28 for 
JrouS I and II resSectively The SroSortion of infants Zho achieved fourfold rise in antibodies 
from baseline Zas 25 and 21 in JrouS I and II resSectively Adverse (vents Zere caStured 
and analy]ed for the entire study SoSulation A total of 100 and 106 SarticiSants in the treatment 
ROTAVAC® and ROTARI;® JrouSs reSorted at least one adverse event The distribution of 
solicited, unsolicited, and serious adverse events Zas similar across JrouSs The study 
demonstrated immunoloJical noninferiority Zith the comSarator Rotari[® Zith a clinically 
acceStable safety Srofile Data on file CTRI20151200628 
The study results clearly establish that buffer administration is not reTuired to ensure the 
immunoJenicity of the vaccine Not havinJ buffer also addresses the SroJrammatic issues, such 
as incorrect reconstitution of a vaccine, temSorary unavailability of the buffer, and reduction of 
the cold chain footSrint, etc :ith due imSortance to all these findinJs, ROTAVAC® Zithout buffer 
Zas licensed in India in the year 2015 This formulation Zas included in the :HO list of 
SreTualified vaccines on 5th January 2018 The formulation still reTuired storaJe and transSortation 
at 20C 
.5. ROTAVAC 5C 
The currently licensed fro]en ROTAVAC® vaccine needed to be stored and transSorted at 20C 
BBIL has been enJaJed since 200 in the develoSment of a liTuid formulation that is stable at 2
8C storaJe temSerature over 2 months and also has sufficient Acid Neutrali]inJ CaSacity ANC 
to neutrali]e the Jastric Muices in the stomach, thus suSSortinJ survival of the vaccine virus This 
chanJes the formulation by addition of e[ciSients and stabili]ers belonJinJ to the *RAS 
*enerally RecoJni]ed as Safe cateJory The advantaJes Zith this formulation are tZofold: 1 
ROTAVAC 5C is a stable liTuid vaccine that offers many advantaJes as discussed later 2 the 
acid neutrali]inJ caSacity eliminates the need to administer an alNali buffer seSarately Srior to the 
vaccine ROTAVAC 5C contains the same rotavirus strain 116( as in ROTAVAC® 
International Patents have been Jranted in several countries includinJ India, USA, U. and South 
Africa for these rotavirus vaccine formulations 
Phase  (xploratory Study 
In this Shase 3 e[Sloratory study, 68 ZeeNold healthy infants n 65 Zere randomi]ed a 1:1:1 
ratio to receive ROTAVAC 5C 15 mL )1 arm, n 225 or ROTAVAC 5C 2 mL )2 arm, n 225 
or ROTAVAC® 05 mL n 225 There Zere no statistically siJnificant differences in the Sre and 
Sost vaccination IJA concentrations betZeen the ROTAVAC 5C )1 and )2 and ROTAVAC® 
arms mean baseline concentration 20, 223 and 22 UmL resSectively S 08 comSarinJ all 
arms and Sost vaccination concentration 635, 51 and 60 UmL, resSectively S 012 
comSarinJ all arms Seroconversion occurred by day 8 in 288 5 CI: 22, 3 of 
infants in the ROTAVAC 5C )1 arm, 36 5 CI: 311, 2 of the ROTAVAC 5C 
)2 arm, and 13 5 CI: 3, 8 of the ROTAVAC® arm SiJnificantly Jreater 
SroSortions of healthy infants seroconverted in the ROTAVAC® arm comSared to the ROTAVAC 
5C )1 arm S 00085 There Zas no siJnificant difference in seroconversion rates betZeen the 
ROTAVAC® and ROTAVAC 5C )2 formulation S 08 Adverse event rates Zere found to 
be 222 in the ROTAVAC 5C )1 arm, 1 in the ROTAVAC 5C )2 arm, and 206 in 
the ROTAVAC® arm The maMority of these adverse events Zere reSorted Zithin seven days of 

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the study vaccine administration There Zas no statistically siJnificant difference in the SroSortion 
of healthy infants e[SeriencinJ adverse events betZeen those receivinJ either ROTAVAC 5C 
formulation )1 or )2 and those receivinJ ROTAVAC® S 010 The safety Srofile of both 
ROTAVAC 5C formulations )1 and )2 Zas found to be similar to the ROTAVAC® formulation 
)eZer healthy infants e[Serienced Jastrointestinal disturbances Zith the ROTAVAC 5C 2 mL 
)2 formulation comSared to the ROTAVAC 15 mL )1 formulation There Zere no A(s 
leadinJ to discontinuation, no A(s leadinJ to death, and no cases of intussusceStion Thus, it is 
concluded that the ROTAVAC 5C 2 mL )2 formulation is noninferior to the ROTAVAC® 
20C 05 mL formulation Data on )ile CTRI2015020055 
Phase  Confirmatory Study 
In this Shase 3 confirmatory study, 68 ZeeNold healthy infants n 1302 Zere randomi]ed to 
receive ROTAVAC 5C 2 mL Lot 1 n 32, ROTAVAC 5C 2 mL Lot 2 n 32, ROTAVAC 5C 
2 mL Lot 3 n 320, or ROTAVAC® 20C 05 mL n 331 There Zere no statistically siJnificant 
differences in the Sre and Sostvaccination IJA concentrations betZeen the ROTAVAC 5C and 
ROTAVAC® arms mean baseline concentration 20, 236, 215 and 285 for ROTAVAC 5C Lot 
1, 2 and 3 and ROTAVAC®, resSectively S 025 Seroconversion fold or Jreater increase 
in IJA concentration over baseline, occurred by day 8 in 315 5 CI 26 to 32 in the 
ROTAVAC 5C Lot 1 arm, 321 5 CI 26 to 3 in the ROTAVAC 5C Lot 2 arm, 3 
5 CI 23 to 06 in the ROTAVAC 5C Lot 3 arm, and 312 5 CI 260 to 368 in 
the ROTAVAC® arm The differences in seroconversion betZeen arms Zas not statistically 
siJnificant S 08156 There Zere 861 healthy infants Zho e[Serienced 2,8 adverse events Of 
these, 30 infants e[Serienced 33 vaccinerelated adverse events Vaccinerelated adverse events 
occurred in 16 of healthy infants in the ROTAVAC 5C Lot 1 arm, 32 of healthy infants in 
the ROTAVAC 5C Lot 2 arm, 2 of healthy infants in the ROTAVAC 5C Lot 3 arm and 1 
of healthy infants in the ROTAVAC®  arm S 086 The maMority of adverse events occurred 
Zithin  days of vaccine administration There Zere no adverse events leadinJ to discontinuation, 
no deaths and no cases of intussusceStion reSorted durinJ this study Noninferiority aJainst the 
ROTAVAC®  formulation Zas established usinJ tZosided 5 confidence intervals for the 
*MC ratio betZeen ROTAVAC 5C all lots combined to ROTAVAC®, reTuirinJ a loZer limit 
Jreater than 050 Data on )ile CTRI2015020055 
 
.5. ROTAVAC 5CM 
)urther to this and based on the ROTAVAC clinical trial results Zithout buffer, formulation of 
ROTAVAC 5C 15 mL )ormulation 1(Z Zas modified to 05mL volume and the internal buffer 
comSonents Zere removed, Zhich later Zas named as ROTAVAC 5CM, a liTuid formulation that 
is stable at 28C 53C storaJe temSerature ROTAVAC 5CM is Zithout buffer and has 
additional e[ciSients and stabili]ers same as in )ormulation 1(Z, Zith established safety and 
immunoJenicity that belonJ to *RAS *enerally RecoJni]ed as Safe CateJory and neZ safety 
concerns are not anticiSated The ROTAVAC 5CM vaccine has also been filed for international 
Satents  
Phase  Study 
A Shase 3, multicenter, randomi]ed, oSen labeled clinical study Zas conducted to evaluate the 
immunoJenicity, reactoJenicity and safety of ROTAVAC 5CM stored at 28 C, in comSarison 

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Zith ROTAVAC® stored at 20oC in healthy infants aJed 68 ZeeNs The study enrolled 360 
SarticiSants Zhich Zere randomi]ed in the tZo JrouSs in a ratio of 3: 1 Zith 20 SarticiSants in 
the ROTAVAC 5CM arm and 0 in the ROTAVAC® arm Both formulations Zere administered 
in a dose of 05 ml at 6, 10 and 1 ZeeNs of aJe alonJ Zith routine childhood vaccinations Blood 
samSles for immunoJenicity analysis Zere collected before first vaccination and  ZeeNs after last 
vaccination The Sostvaccination *MCs reSorted in the ROTAVAC 5CM and ROTAVAC® 
JrouSs Zere 180 and 155, resSectively The ratio of *MC ROTAVAC 5CM ROTAVAC® 
Zas estimated as 081 and the loZer bound of tZosided 5  CI Zas found to fall in the 2fold 
marJin bounds of 05 to 2 Hence the tZo vaccines Zere assessed to be eTuivalent Also, the tZo 
vaccines Zere found to be similar Zhen assed in terms of seroconversion 32 vs 282, 
fourfold rise 2218 vs 2125, threefold rise 22 vs 3000, tZofold rise 3831vs 
3125 for ROTAVAC 5CM and ROTAVAC® arms, resSectively The adverse events Zere, Pain 
at the site of inMection 322 and 386, Redness at the site of inMection 360 and 325, 
SZellinJ at the site of inMection 320 and 350, cryinJ 183 and 1 and fever 
650 and 605 in ROTAVAC 5CM and ROTAVAC® JrouSs resSectively Many of these 
may be ascribed to routine childhood immuni]ation administered concomitantly No case of 
intussusceStion Zas reSorted amonJ the study SoSulation Zho Zere administrated Zith either of 
tZo vaccines Overall, this study demonstrated that immunoJenicity and safety Srofiles of both 
vaccines ROTAVAC 5CM and ROTAVAC® Zas similar Data on file Data on )ile 
CTRI2016110081 
.6 
Potential RisNs andor %enefits of Study Vaccine  
ROTAVAC 5CM is the ne[t Jeneration formulation of ROTAVAC® and has the same virus strain 
as ROTAVAC® Zith addition of some stabili]ers and e[ciSients of *RAS cateJory ROTAVAC® 
and ROTAVAC 5CM have been e[tensively studied in Sreclinical and clinical studies 
ROTAVAC® has been administered to more than ,000 children in clinical trials in India 
includinJ one study demonstratinJ efficacy of the vaccine and another study demonstratinJ non
inferiority of immune resSonse vs Rotari[ In these studies, ROTAVAC® Zas found to be 
efficacious efficacy of 551 uS to 2 years of aJe and immunoJenic The Sivotal study had active 
surveillance for adverse events and the vaccine Zas found to be safe ROTAVAC 5CM has been 
shoZn to be eTually immunoJenic as ROTAVAC Based on these data ROTAVAC® has been 
licensed in India and Zas recently included in the :HO list of SreTualified vaccines It has already 
been administered to millions of children in India under the national immuni]ation Slan Zithout 
any maMor concern  The Sotential risN for the vaccine include commonly reSorted adverse events 
liNe fever, vomitinJ, diarrhea, couJh, runny nose, irritability and rash In babies, natural rotavirus 
infection can cause diarrhea, vomitinJ and fever It is Sossible that enrolled SarticiSants may have 
a feZ looser than usual stools, cry, or have a sliJhtly hiJher than usual temSerature for a day or 
tZo after vaccination Zith the attenuated rotavirus vaccine These events are similar to those 
reSorted in other rotavirus vaccine clinical trials In the Phase 3 efficacy study, 11 intussusceStion 
cases as defined by BriJhton Jrade 1 have been reSorted 8 of 532 SarticiSants in vaccine JrouS 
and 3 of the 223 in Slacebo JrouS None occurred Zithin 30 days of a vaccine dose and all Zere 
reSorted only after the third dose The intussusceStion events folloZinJ the third dose occurred 
betZeen 112 and 58 days Sostvaccination in the vaccine JrouS and betZeen 36 and 605 days in 
the Slacebo JrouS Ten of the cases Zere rotavirus neJative Zhen tested for Sresence of rotavirus 
antiJen in stools by (LISA None of the four rotavirus Sositive cases had the vaccine virus strain 
 

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Since the earlier studies Zere Serformed in India another develoSinJ country it can be e[Sected 
that the vaccine Zill be similarly beneficial in Zambia, and Zill have similar safety Srofile  
. 
Overall Development Strategy  
ROTAVAC® is indicated for active immuni]ation of infants from the aJe of 6 ZeeNs for the 
Srevention of Jastroenteritis due to rotavirus Zhen administered as a 3dose series ROTAVAC® 
has been licensed in India in 201 and has been included on the :HO list of SreTualified vaccines 
since early 2018 These milestones Zere achieved based on the data Jenerated in India This trial 
Zill Jenerate immunoJenicity and safety data on ROTAVAC® and ROTAVAC 5CM outside of 
India to suSSort :HO SA*( Solicy recommendations and countrylevel decisionmaNinJ  
. 
Study Rationale 
This study has been desiJned to comSare ROTAVAC 5CM Zith the neZly :HO SreTualified 
vaccine ROTAVAC® amonJ infants in Africa  )our hundred and fifty infants, 68 ZeeNs of aJe 
Zill be enrolled and randomi]ed to receive either three doses of ROTAVAC® or ROTAVAC 5CM, 
four ZeeNs aSart, at 6, 10 and 1 ZeeNs of aJe or tZo doses of Rotari[® current standard of care 
in Zambia, four ZeeNs aSart at 6 and 10 ZeeNs of aJe The main SurSose of this study is to assess 
the immunoJenicity of a full course of the tZo formulations of ROTAVAC®, ie, ROTAVAC® 
and ROTAVAC 5CM and to assess the safety and reactoJenicity of the vaccine amonJ African 
infants Rotari[® has been included as the third arm since it is beinJ used for routine immuni]ation 
of children in Zambia and holds the vast maMority of the *AVIeliJible country marNet share This 
arm Zill act as an internal control to validate immune resSonse of ROTAVAC® and ROTAVAC 
5CM Zhich are beinJ tested for the first time in African continent The study Zill also assess the 
safety and reactoJenicity of a full immuni]ation course and of each dose of the study vaccines, 
Zith the aim of describinJ its safety in Zambia  
Because Rotari[® is a tZodose human rotavirus vaccine and ROTAVAC® and ROTAVAC 5CM 
are threedose human rotavirus vaccines, ma[imi]inJ comSarability of immunoJenicity data is a 
critical driver of the desiJn and tests to be used In order to ensure ma[imal comSarability, blood 
samSlinJ time Soints in a threedose arm ie ROTAVAC® and ROTAVAC 5CM are at 18 ZeeNs 
of aJe, and for Rotari[® at 1 ZeeNs of aJe ie  ZeeNs after last dose ROTAVAC® has already 
been studied in a similar study desiJn in studies conducted in Indian SoSulation  
This trial Zill Jenerate immunoJenicity and safety data on ROTAVAC® and ROTAVAC 5CM 
outside of India to suSSort :HO SA*( Solicy recommendations and countrylevel decision
maNinJ At the conclusion of the study, PATH, Sublic health leaders and site investiJators, 
toJether Zith Bill 	 Melinda *ates )oundation BM*) officers Zill suSSort BBIL in 
communication of results to Jlobal and national SolicymaNers and to the Jlobal Sublic health 
community Presentation of data to Zambian Ministry of Health, :HO and in Seer revieZed oSen 
access Sublications Zill be Ney audiences tarJeted for communication of results 
Primary immunoJenicity analysis of all samSles Zill be based on a validated (LISA Zhich uses 
strain :C3 as a substrate The same test Zas also used for clinical trials suSSortinJ licensure of 
the ROTAVAC® Zithout buffer in India and for :HO SreTualification of the vaccine A subset 
of the samSles 50 Sairsarm collected Zill also be tested by a validated (LISA Zhich uses strain 
812 *1P8 virus as a substrate Strain 812 Zas the isolated strain that Zas used to develoS the 
Rotari[® Vaccine Since no correlation betZeen the tZo assays has been established and it is 

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e[Sected that tests emSloyinJ heteroloJous strains as substrate may Jive loZer concentrations, no 
ZithinJrouS or betZeen assay comSarisons Zill be done 
 
H<POTH(S(S, O%-(CTIV(S AND (NDPOINTS 
. 
Study Hypotheses 
Immunogenicity 
x 
ROTAVAC® and ROTAVAC 5CM administered as a 3dose series induce comSarable 
immune resSonse in healthy African infants 
Safety 
x 
ROTAVAC® and ROTAVAC 5CM administered as a 3dose series are both safe and Zell
tolerated in healthy African infants 
. 
Study ObMectives 
.. Primary ObMective 
Immunogenicity 
x To evaluate and comSare the immunoJenicity of ROTAVAC® and ROTAVAC 5CM 28 days 
after the last dose of the vaccine, Zhen administered to infants in a threedose schedule at 6, 
10 and 1 ZeeNs of aJe  
.. Secondary ObMectives 
Safety   
 
x To assess the reactoJenicity  days after each vaccination and safety  ZeeNs after the last 
vaccination of the ROTAVAC® and ROTAVAC 5CM, Zhen administered to infants in a three
dose schedule at 6, 10 and 1 ZeeNs of aJe and Rotari[®, Zhen administered to infants in a 
tZodose schedule at 6 and 10 ZeeNs of aJe  
Immunogenicity 
x 
To evaluate the immunoJenicity of Rotari[® 28 days after the last dose of the vaccine, Zhen 
administered to infants in a tZodose schedule at 6 and 10 ZeeNs of aJe 
.. (xploratory ObMective 
x 
To evaluate the immunoJenicity of the three vaccines by (LISA usinJ 812 *1P8 virus as 
a substrate in a subset of the samSles collected 
. 
Study (ndpoints 
.. Primary (ndpoint 
Immunogenicity: 

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*eometric mean concentrations *MCs of serum antirotavirus IJA antibodies 28 days after 
the last dose of a study vaccine, as measured by en]ymelinNed immunosorbent assay (LISA 
usinJ :C3 as the viral lysate  
.. Secondary (ndpoints 
Safety  
The secondary safety endSoints Zill include: 
x 
Immediate adverse events, Zithin 30 minutes Sostvaccination 
x 
Solicited Sostvaccination reactoJenicity fever, diarrhea, vomitinJ, decreased aSSetite, 
irritability, decreased activity level durinJ the  day Seriod Day 06 after each vaccination 
x 
Unsolicited A(s from first vaccination throuJh  ZeeNs after the last vaccination 
x 
SA(s, includinJ intussusceStion from first vaccination throuJh  ZeeNs after the last 
vaccination of each study SarticiSant 
 Immunogenicity 
The secondary immunoJenicity endSoint antirotavirus IJA usinJ :C3 as the Lysate Zill be as 
folloZs: 
x 
Seroconversion rate 28 days after last dose of study vaccine Day 8 for ROTAVAC® and 
ROTAVAC 5CM and Day 56 for Rotari[® Seroconversion Zill be defined as a Sost
vaccination serum antirotavirus antibody IJA concentration of at least 20 UmL if a baseline 
concentration is  20 UmL or a Sostvaccination serum antirotavirus IJA concentration of  
2fold baseline level if a baseline concentration is  20 UmL 
x 
SeroSositivity rate at baseline and 28 days after last dose of study vaccine Day 8 for 
ROTAVAC® and ROTAVAC 5CM and Day 56 for Rotari[® SeroSositivity is defined as 
serum antirotavirus IJA antibody concentration  20 UmL 
x 
SeroresSonse rate 28 days after last dose of study vaccine Day 8 for ROTAVAC® and 
ROTAVAC 5CM and Day 56 for Rotari[® SeroresSonse Zill be assessed as a fourfold, 
threefold and tZo fold rise in antibody concentration from baseline 
x 
*eometric Mean )old Rise *M)R that is a ratio of *MCs at 28 days after last dose of study 
vaccine Day 8 for ROTAVAC® and ROTAVAC 5CM and Day 56 for Rotari[® Zith 
reference to baseline    
.. (xploratory (ndpoints: 
The e[Sloratory endSoints based on antirotavirus IJA antibodies measured by (LISA usinJ 8
12 as the viral lysate in a subset of samSles Zill be as folloZs: 
x *MCs of serum antirotavirus IJA antibodies 28 days after the last dose of study vaccine 
x Seroconversion rate 28 days after last dose of study vaccine Seroconversion is defined as a 
Sostvaccination serum antirotavirus IJA antibody concentration of at least 20 UmL if a 
baseline concentration is  20 UmL or a Sostvaccination serum antirotavirus IJA antibody 
concentration of  2fold baseline level if a baseline concentration is 20 UmL 

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x SeroSositivity rate at baseline and 28 days after last dose of study vaccine SeroSositivity is 
defined as serum antirotavirus IJA antibody concentration  20 UmL 
x 
*M)R that is a ratio of *MCs at 28 days after last dose of study vaccine Zith reference to 
baseline 
 
ST8D< D(SI*N 
This study is desiJned as a Phase IIb, sinJlecenter, randomi]ed, activecontrolled, oSenlabel 
study enrollinJ a total of 50 healthy infants 68 ZeeNs 256 days of aJe ProsSective 
SarticiSants, Zhose Sarent or leJal Juardian siJn an informed consent form and Sass the test of 
understandinJ, Zill be assessed for eliJibility to SarticiSate in the study ScreeninJ for eliJibility 
Zill include solicitation of medical history, assessment of vital siJns, and Shysical e[amination  
If the SarticiSant is found to be eliJible, the infants Zill be allocated to one of the three JrouSs in 
a ratio of 1:1:1 n 150 Ser JrouS to receive either three doses of ROTAVAC®, three doses of 
ROTAVAC 5CM or tZo doses of Rotari[®  ZeeNs aSart minimum interval of  ZeeNs and 
ma[imum of 5 ZeeNs Allocation of treatment to individual SarticiSants Zill be based on a 
randomi]ation schedule develoSed in coordination Zith the data manaJement orJani]ation for 
unbiased randomi]ation of SarticiSants to the treatments Three doses of ROTAVAC® and 
ROTAVAC 5CM Zill be administered at 6, 10 and 1 ZeeNs of aJe Zhereas tZo doses of Rotari[® 
Zill be administered at 6 and 10 ZeeNs of aJe see table beloZ All vaccines Zill be administered 
concomitantly Zith (PI vaccines includinJ DiShtheria, Tetanus, Pertussis, +DHPRSKLOXV 
LQIOXHQ]DH W\SH % and HeSatitis B vaccine DTZPHibHeSB, Pneumococcal conMuJate vaccine 
and OPV at 6, 10 and 1 ZeeNs and IPV at ZeeN 1 Zhen sZitched to in Zambia Should any 
chanJes to the (PI schedule in the Zambia occur before or durinJ the study the vaccines Jiven 
alonJside the study vaccines Zill be alloZed to reflect the current SroJram Zithout a Srotocol 
amendment unless this is considered to interfere Zith the assessment of the study endSoints in any 
Zay The SarticiSants Zill be monitored for 30 minutes folloZinJ vaccine administration for 
immediate adverse events liNe anaShyla[is, vomitinJ etc  
*roup 
No 
of 
SarticiSants 
Visit 1  
68 ZeeNs 
Visit 2  
V128  days 
Visit 3  
 V228  days 
A 
150 
ROTAVAC® 
ROTAVAC® 
ROTAVAC® 
B 
150 
ROTAVAC 5CM 
ROTAVAC 5CM  
ROTAVAC 5CM  
C 
150 
Rotari[® 
Rotari[® 
NA 
To evaluate the Rotavirus vaccine immunoJenicity, a blood samSle Zill be obtained from all the 
SarticiSatinJ infants before first vaccination and four ZeeNs 1 ZeeN after the last vaccine dose 
This Zould mean that the blood samSle Zill be collected at aSSro[imately 1 ZeeNs of aJe for 
infants in the Rotari[® arm and 18 ZeeNs for infants in the ROTAVAC *rouSs Serum Anti
rotavirus IJA antibodies Zill be analy]ed at :ellcome Trust Research Laboratory, Christian 
Medical ColleJe, Vellore, India usinJ a validated (LISA Zhich uses :C3 virus as a substrate A 
subset of samSles 50 samSle Sairs Ser arm Zill also be analy]ed by another (LISA usinJ the 
Rotari[ sSecific strain 812 as a lysate at Cincinnati Children
s HosSital Medical Center 
CCHMC, Cincinnati, Ohio, USA The study Zill comSare the immunoJenicity of the tZo 

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formulations of ROTAVAC® ie ROTAVAC® vs ROTAVAC 5CM in terms of *MCs and Zill 
describe Zithout comSarinJ the immune resSonse to Rotari[®  
Study Schema 
 
(nhanced SassiveActive surveillance for vaccine reactoJenicity solicited reactions over the 
day Seriod after each vaccination Zill be conducted on all infants In addition, surveillance for 
unsolicited A(s, SA(s includinJ intussusceStion Zill be carried out over the Seriod betZeen first 
vaccination and four ZeeNs after the last vaccination on all infants ParticiSants Zill be evaluated 
for:  
x 
Immediate adverse events Zithin 30 minutes Sostvaccination 
x 
days Sostvaccination reactoJenicity, ie, the occurrence of solicited reactions fever, 
diarrhea, vomitinJ, decreased aSSetite, irritability, decreased activity level after each 
vaccination 
x 
Unsolicited A(s from first vaccination throuJh four ZeeNs after the last vaccination 
x 
Incidence of serious adverse events SA(s includinJ intussusceStion, from first vaccination 
throuJh four ZeeNs after the last vaccination 
)or evaluation of Sostvaccination reactoJenicity, the Sarent Zill be Jiven a diJital thermometer 
and a PostImmuni]ation Diary Card PIDC coverinJ Days 06 Day 0   day of vaccination 
They Zill be instructed to record their child’s a[illary temSerature as Zell as other solicited 
reactions on the PIDC for  days Sostvaccination Study staff Zill maNe a home visit on Days 2 
1 day and Day  1 day to determine health status and to suSSort comSletion of the PIDC as 
Zell as caSture information on the PIDC recorded todate ComSleted PIDC Zill be collected by 

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the field officer on the Day  1 day folloZinJ vaccination The data in the PIDC collected by 
the Sarents Zill be revieZed by the study ShysiciandesiJnee and entered in the CR)  
All SA(s Zill be reSorted folloZinJ established reJulatory reTuirements  
Safety Zill be monitored by onsite clinical staff and routinely by a Protocol Safety RevieZ Team 
PSRT, an internal JrouS of Shysicians Zhich includes the InvestiJator team and PATH Medical 
Officers  The PSRT Zill have Srovision of e[Sedited meetinJ that could be triJJered by reSortinJ 
of Sredefined A(s The PSRT may also seeN indeSendent e[Sert medical oSinion as dictated by 
the occurrence of certain events  
It is e[Sected that the enrolment Zill be comSleted over aSSro[imately 6 months and total study 
duration for each SarticiSant Zill be 35 months 
 
ST8D< POP8LATION 
. 
Description of Study Site 	 Population 
The study Zill be conducted at *eorJe Clinic in LusaNa Zhere CIDRZ has a research facility This 
Research Unit is located on the Sremises of a busy Sublic clinic that offers all basic outSatient 
services includinJ Jeneral OPD, MCH, ART, Sharmacy and allied Srimary care services in a Seri
urban settinJ The center has a catchment SoSulation of 15,230 This study site is at a tySical Seri
urban clinic settinJ in LusaNa, and SarticiSants Zill be recruited as they randomly attend the health 
facility  
After necessary aSSrovals are in Slace, the CIDRZ Community Advisory Board Zill facilitate 
meetinJs in the community Zith Ney Jate NeeSers and interest JrouSs in order to inform them about 
the study This is the mechanism that is also used to address any community issues that may arise 
durinJ the course of the study :ith a catchment SoSulation of over 10,000 and more than 600 
antenatal attendances each month, *eorJe clinic has sufficient number of healthy infants to be 
screened Zith Sarental consent in order to enroll 50 infants in the study ParticiSants Zill be 68 
ZeeN 256 days both inclusive old healthy infants Parents attendinJ clinics for the vaccination 
of their infants Zill be aSSroached for their child’s enrollment in the study A siJned Zritten form 
consent Zill be obtained before any trialrelated Srocedures are Serformed   
)inal eliJibility determination Zill deSend on the results of the medical history and clinical 
e[amination, fulfillment of eliJibility criteria, and aSSroSriate understandinJ of the study 
InvestiJators should alZays use Jood clinical MudJment in considerinJ a SarticiSant’s overall 
fitness for inclusion in the trial Some SarticiSants may not be aSSroSriate for the study even if 
they meet all inclusion e[clusion criteria )or instance, medical, occuSational or other conditions 
Sresent in the Sarents may maNe safety evaluations difficult or maNe the infants Soor candidates 
for retention All infants tarJeted for enrollment Zill need to have Sarents Zho can comSrehend 
the SurSose of the study and Srovide Zritten informed consent In addition, the families should be 
resident in the area Zithout Slans to leave the area durinJ the course of the study 
. 
Inclusion Criteria 
 
)ulfillment of all of the folloZinJ criteria is reTuired to acceSt an infant in the study: 
1 Healthy infant as established by medical history and clinical e[amination before enterinJ the 
study 

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2 AJe: 68 ZeeNs 256 days, both days inclusive confirmed by Immuni]ation Record 
3 Infants received aJeaSSroSriate (PI vaccines till enrolment  
 Ability and ZillinJness to Srovide informed consent as Ser local consentinJ Srocedures 
5 Parent can be contacted on Shone and confirms intention to remain in the study area Zith the 
SarticiSant durinJ the study Seriod 
. 
(xclusion Criteria 
Any of the folloZinJ Zill e[clude an infant from the study:  
1 Presence of diarrhea or vomitinJ in the Srevious 2 hours or on the day of enrolment 
temSorary e[clusion 
2 Presence of fever on the day of enrolment temSorary e[clusion  
3 Acute disease at the time of enrolment temSorary e[clusion 
 Concurrent SarticiSation in another clinical trial throuJhout the entire timeframe of this study 
5 Presence of severe malnutrition ZeiJhtforheiJht ]score  3SD median 
6 Any systemic disorder cardiovascular, Sulmonary, heSatic, renal, Jastrointestinal, 
hematoloJical, endocrine, immunoloJical, dermatoloJical, neuroloJical, cancer or 
autoimmune disease as determined by medical history andor Shysical e[amination Zhich 
Zould comSromise the child’s health or is liNely to result in nonconformance to the Srotocol  
 History of conJenital abdominal disorders, intussusceStion, abdominal surJery 
8 .noZn or susSected imSairment of immunoloJical function based on medical history and 
Shysical e[amination 
 Prior receiSt or intent to receive rotavirus and other aJe sSecified (PI vaccines outside of the 
study center and durinJ study SarticiSation  
10 A NnoZn sensitivity or allerJy to any comSonent of the study vaccine 
11 Clinically detectable siJnificant conJenital or Jenetic defect 
12 History of Sersistent diarrhea defined as diarrhea more than 1 days 
13 ParticiSant’s Sarents not able, available or ZillinJ to acceSt active folloZuS by the study staff  
1 Has received any immunoJlobulin theraSy andor blood Sroducts since birth or Slanned 
administration durinJ the study Seriod 
15 History of chronic administration defined as more than 1 days of immunosuSSressants 
includinJ corticosteroids Infants on inhaled or toSical steroids may be Sermitted to SarticiSate 
in the study  
16 History of any neuroloJic disorders or sei]ures  
1 Any medical condition in the Sarentsinfants that, in the MudJment of the investiJator, Zould 
interfere Zith or serves as a contraindication to Srotocol adherence or a SarticiSant’s 
Sarent’sleJally acceStable reSresentative’s ability to Jive informed consent 

Protocol Number ± CVIA 066  
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18 ParticiSant is a direct descendant child or Jrandchild of any Serson emSloyed by the SSonsor, 
the CRO, the PI or study site Sersonnel 
. 
Continued (ligibility Confirmation for SubseTuent Vaccination 
The folloZinJ events constitute absolute contraindications to rotavirus vaccination and all 
SarticiSants should be evaluated for these before further administration of the study vaccine If any 
of these events occur durinJ the study, the SarticiSant must not receive additional doses of the 
vaccine but should be aSSroSriately folloZed uS for safety by the InvestiJator 
x 
HySersensitivity reaction folloZinJ the administration of the study vaccine 
x 
Any uncorrected conJenital malformation of the Jastrointestinal tract such as MecNel’s 
diverticulum Zhich is diaJnosed after the first vaccination and that Zould SredisSose for 
intussusceStion 
x 
Infants Zith any history of intussusceStion  
x 
Severe combined immunodeficiency SCID 
x 
Detection of one or more of the e[clusion criteria durinJ dosinJ Seriod  
The folloZinJ events constitute contraindications to administration of the study vaccine at that 
Soint in time if any of these events occur at the time scheduled for vaccination, the SarticiSant 
may be vaccinated at a later date, Zithin the time ZindoZ sSecified in the Srotocol, or ZithdraZn 
at the discretion of the InvestiJator 
x 
Acute disease and  or fever at the time of vaccination 
x 
Acute disease is defined as the Sresence of a moderate or severe illness Zith or Zithout 
fever All vaccines can be administered to Sersons Zith a minor illness such as mild 
uSSer resSiratory infection Zithout fever 
x 
)ever is defined as temSerature 35C 5) on a[illary settinJ  
x 
*astroenteritis Zithin 2 hours SrecedinJ the study vaccine administration 
.5 
Reasons for :ithdrawal 
ParticiSants have the riJht to decline study treatment or Srocedures for any reason and at any time 
durinJ the study  If a SarticiSant declines further vaccination or study Srocedures but continues 
in the study for safety assessment  this Zill be recorded as a study deviation and the reason Zill 
be clearly documented in the source document  The SarticiSant Zill be encouraJed to comSlete 
the remaininJ aSSlicable safetyrelated folloZuS to comSlete safety folloZuS for atleast 28 days 
after last dose and immunoJenicity blood draZ at the end of safety folloZuS  If the SarticiSant 
does not Zish to remain in the study by declininJ any folloZuSs or Srocedures, the SarticiSant 
can choose to ZithdraZ consent and be ZithdraZn from the study  
The SarticiSants may be ZithdraZn from the study for any of the folloZinJ reasons: 
x 
If Sarent of SarticiSant Zishes to ZithdraZ consent 
x 
If the PrinciSal InvestiJator PI decides that ZithdraZal is in the best interest of the 
SarticiSant 

Protocol Number ± CVIA 066  
Version Number: 01 Version Date: 11 July, 2018 
 
Confidential                                                        PaJe  of  
 
x 
SiJnificant noncomSliance Zith treatment reJimen or trial reTuirements 
x 
ParticiSant is lost to folloZuS 
x 
The sSonsormanufacturer recommends to terminate the study 
In all cases, Zhere the SarticiSant is ZithdraZn from the study the reason for ZithdraZal Zill be 
documented in an aSSroSriate section of the eCR)  HoZever, the data collected uS to the last 
contact Zill be Sart of the analysis In the event of ZithdraZal from study, reasonable efforts should 
be made to conduct the folloZinJ Srocedures: 
x 
RevieZ diary card if still in use Srior to ZithdraZal 
x 
USdatinJ any onJoinJ A(SA(s that remain onJoinJ at time of SarticiSant’s last visit Srior to 
ZithdraZal  
x 
4uery about A(s, SA(s and concomitant medications if the interval betZeen the SarticiSant’s 
last visit and the time of ZithdraZal is Zithin the Srotocoldefined reSortinJ Seriod 
x 
Conduct Shysical e[amination 
x 
Collect blood for immunoloJic testinJ if ZithdraZal occurs before end of study 
x 
USdate contact information 
5 
ST8D< PROD8CTS  
5. 
Study Vaccine  
5.. Product Description 
TZo formulations of Rotavirus vaccine manufactured by Bharat Biotech International Ltd Zill be 
used in the study Both the formulations are monovalent vaccines containinJ susSension of 1050 
))U live rotavirus 116( SreSared in Vero cells Based on the dual classification system usinJ * 
and P surface Sroteins, 116( is classified as *P>11@ tySe Both the vaccines are ready to use no 
reconstitution or dilution is reTuired 
Rotari[® is a live attenuated RI;1 strain of human rotavirus of the *1P>8@ tySe and Zill be 
used as an internal control The vaccine is ready to use no reconstitution or dilution is reTuired 
Rotari[® is a *S. BioloJicals’ licensed rotavirus vaccine Zhich has been revieZed by :HO and 
has been aSSroved and included in the :HO SreTualified list of vaccines 
Details of the vaccines are Srovided beloZ: 
ROTAVAC® 
(Frozen 
formulation) 
This is the licensed and :HO SreTualified rotavirus vaccine from 
Bharat Biotech International Limited The vaccine is a live, attenuated 
*P>11@ monovalent vaccine at a dose of 05 mL containinJ NLT loJ 
1050 focus forminJ units ))U Ser dose The vaccine should be stored 
at 20C Before administration, liTuid fro]en vaccine vial Zill be shifted 
from 20C to room temSerature for thaZinJ The liTuid vaccine Zill be 
administered Ser oral 
Manufactured by Bharat Biotech International Limited, India 

Protocol Number ± CVIA 066  
Version Number: 01 Version Date: 11 July, 2018 
 
Confidential                                                        PaJe  of  
 
ROTAVAC 5CM 
(liTuid 
formulation) 
The vaccine is a live, attenuated *P>11@ monovalent vaccine to be 
administered in a dose of 05 mL containinJ NLT loJ 1050 focus 
forminJ units ))U Ser dose Since this is a fully liTuid vaccine stored 
at 28qC, no thaZinJ is reTuired before administration The liTuid 
vaccine Zill be administered Ser oral  
Manufactured by Bharat Biotech International Limited, India 
Rotarix® 
This is the licensed and :HO SreTualified rotavirus vaccine from *S. 
BioloJicals Rotari[ is a live attenuated RI;1 strain of human 
rotavirus of the *1P>8@ tySe containinJ not less than 1060 CCID50 cell 
culture infectious dose 50 of the RI; 1 strain of human rotavirus 
15 ml of the liTuid vaccine Zill be administered Ser oral 
Manufactured by *la[oSmith.line Vaccines, BelJium 
5.. Manufacturer   
ROTAVAC® and ROTAVAC 5CM are manufactured by Bharat Biotech International Ltd  
Rotari[® is manufactured by *S. BioloJicals 
5.. Presentation and Formulation   
ROTAVAC® is a liTuid in fro]en form In liTuid form, the vaccine is Jenerally SinN in colour and 
may sometimes chanJe to oranJe or liJht yelloZ in colour This chanJe in colour does not imSact 
the Tuality of vaccine ROTAVAC® is SacNed in USP tySe l Jlass vials and Zill be suSSlied as 
multi dose vials containinJ 5 25 mL vial or 10 doses 5 mL vial of the vaccine Ser vial 
(ach dose of 05 mL 5 DroSs contains 
Ingredient  
4uantity  0.5 mL 
Rotavirus 116( BulN, Live Attenuated  
NLT 1050 ))U 
Potassium PhosShate Monobasic USPBP  
0258 mJ 
Potassium PhosShate Dibasic USPBP  
0625 mJ 
Sucrose USPBP  
331 mJ 
Potassium LJlutamate Monohydrate USPBP  
10 mJ 
Neomycin SulShate USPBP  
15 ȝJ 
.anamycin SulShate USPBP  
15 ȝJ 
Dulbecco
s Modified (aJle
s Medium DM(M   mJ 
:ater for InMections USPBP  
Ts 
SH ranJe: 2 to 80 
ROTAVAC® vials suSSlied throuJh BBIL comes Zith a Vaccine Vial Monitor2 VVM2 dot to 
Juide its usaJe The e[Siry date of the vaccine is indicated on the label and SacNaJinJ A Sicture 
of the SrototySe vial and label has been Srovided beloZ: 

Protocol Number ± CVIA 066  
Version Number: 01 Version Date: 11 July, 2018 
 
Confidential                                                        PaJe  of  
 
 
 
An additional label to comSly Zith the reJulatory reTuirements Zill be Sasted on the carton of the 
vaccine A temSlate has been Srovided beloZ:  
FOR CLINICAL TRIAL 8S( ONL< 
 
Protocol Number: CVIA 066               
SSonsor: Centre for Infectious Disease 
Research in Zambia, LusaNa, Zambia, 10101 
Site:  *eorJe Research Clinic, Centre for 
Infectious Disease Research in Zambia, 
LusaNa, Zambia, 10101 
 
ROTAVAC 5CM is a fully liTuid vaccine and is Jenerally SinN in colour and may sometimes 
chanJe to oranJe or liJht yelloZ in color This chanJe in colour does not imSact the Tuality of 
vaccine ROTAVAC 5CM is SacNed in USP tySe l Jlass vials and Zill be suSSlied as sinJle dose 
*lass Vials 2mL containinJ 05 mL of the vaccine  
(ach dose of 05 mL 5 DroSs contains 
Ingredient  
Reference  
Rotavirus 116( BulN, Live Attenuated 
NLT 1050 ))U 
.anamycin acid sulShate  
IP  
Neomycin sulShate  
USP  
Sucrose  
USP  
Trehalose  
InHouse  
Lactalbumin hydrolysate LAH  
InHouse  
Human Albumin  
IPBP  
Di Potassium hydroJen orthoShosShatePotassium 
PhosShate dibasic  
USP  
Potassium di hydroJen orthoShosShate Potassium 
PhosShate Monobasic  
USP  
Tri sodium citrate dihydrate  
USP  
:ater for InMection  
IPBPInHouse  
SH ranJe: 2 to 80 
A temSlate of the label for has been Srovided beloZ: 
 

Protocol Number ± CVIA 066  
Version Number: 01 Version Date: 11 July, 2018 
 
Confidential                                                        PaJe 5 of  
 
FOR CLINICAL TRIAL 8S( ONL<  
Protocol No.: CVIA 066                            
ROTAVAC 5CM® 
Instructions for use and route of administration:  
)or oral administration only Not for inMection  
Directions of storage:  
Store at 28qC 
Batch No: ;;  
 
MfJ Date: 
 
 
([Siry date: 
Manufactured by: Bharat Biotech International Ltd, *enome Valley, ShameerSet,  
Hyderabad, TelanJana, India500 08 
Sponsor: Centre for Infectious Disease Research in Zambia, LusaNa, Zambia, 10101 
Site: *eorJe Research Clinic, Centre for Infectious Disease Research in Zambia, 
LusaNa, Zambia, 10101 
 
Rotarix® is Sresented as a clear, colourless liTuid susSension in a sTuee]able tube Solyethylene 
fitted Zith a membrane and a tube caS SolySroSylene The vaccine is meant for oral 
administration and is free of visible Sarticles (ach tube contains 15 ml of the vaccine Zhich 
maybe SacNed in SacN si]es of 1, 10 or 50 
1 dose 15 ml contains: 
Ingredient  
4uantity 
Human rotavirus RI;1 strain live, 
attenuated 
not 
less 
than 
1060 
CCID50 
([ciSients: Sucrose, Disodium AdiSate, Dulbecco’s Modified (aJle 
Medium DM(M, sterile Zater 
Produced on Vero cells 
 

Protocol Number ± CVIA 066  
Version Number: 01 Version Date: 11 July, 2018 
 
Confidential                                                        PaJe 6 of  
 
An additional label to comSly Zith the reJulatory reTuirements Zill be Sasted on the carton of 
the vaccine A temSlate label has been Srovided beloZ:  
FOR CLINICAL TRIAL 8S( ONL< 
 
Protocol Number: CVIA 066               
SSonsor: Centre for Infectious Disease Research in 
Zambia, LusaNa, Zambia, 10101 
Site:  *eorJe Research Clinic, Centre for Infectious 
Disease Research in Zambia, LusaNa, Zambia, 10101 
5.. Stability and Storage 
The e[Siry date of the vaccine Zill be indicated on the label and the SacNaJinJ The vaccines 
should not be mi[ed Zith any other medicinal Sroductsactive immuni]inJ aJents 
ROTAVAC® should be stored at 20 C in a deeS free]er Zith a SoZer bacNuS It is absolutely 
critical to ensure that the storaJe conditions sSecified above are comSlied Zith The vaccine should 
be thaZed before and used immediately after oSeninJ ROTAVAC® should be transSorted in a 
vaccine carrier usinJ conditioned Jel SacNs Zith temSerature maintained at 28 C Any unused 
vaccine after 8 hours of thaZinJ should be discarded 
ROTAVAC 5CM and Rotari[® should be stored at 28 C in a refriJerator Zith a SoZer bacNuS 
The vaccine should be transSorted in a vaccine carrier usinJ conditioned Jel SacNs Zith 
temSerature maintained at 28 C It is absolutely critical to ensure comSliance Zith the storaJe 
conditions sSecified above  
)ree]inJ is not recommended for storaJe of Rotari[® The vaccine should be used immediately 
after oSeninJ The vaccine should be stored in the oriJinal SacNaJe, in order to Srotect from liJht 
5..5 The Vaccine Vial Monitor 
Vaccine Vial Monitor2 VVM2 dot is on the seal of the ROTAVAC® vials suSSlied throuJh 
BBIL This is a time temSerature sensitive dot that Srovides an indication of the cumulative heat 
to Zhich the vial has been e[Sosed It Zarns the end user Zhen e[Sosure to heat is liNely to have 
deJraded the vaccine beyond an acceStable level 
 
 

Protocol Number ± CVIA 066  
Version Number: 01 Version Date: 11 July, 2018 
 
Confidential                                                        PaJe  of  
 
InterSretation of VVM2: )ocus on the central sTuare Its colour Zill chanJe SroJressively As lonJ 
as the colour of this sTuare is liJhter than the colour of the rinJ, the vaccine can be used As soon 
as the colour of the central sTuare is the same colour as the rinJ or of a darNer colour than the rinJ, 
the vial should be discarded 
The Vaccine Vial Monitor VVM is also Sart of the label used for all Rotari[® batches suSSlied 
by *la[oSmith.line BioloJicals The colour dot that aSSears on the label of the tube is a VVM 
This is a timetemSerature sensitive dot that Srovides an indication of the cumulative heat to Zhich 
the tube has been e[Sosed It Zarns the end user Zhen e[Sosure to heat is liNely to have deJraded 
the vaccine beyond an acceStable level 
To interSret the VVM status the colour of the central sTuare should be observed and decisions on 
use are e[actly the same as described for Rotavac® above  
5. 
Dose Preparation and Administration 
The InvestiJational Medicinal Products IMP Zill be SreSared and administered by desiJnated 
Tualified staff only to infants included in this study The vaccine Zill be administered as Ser the 
randomi]ation list  
The date and time of the IMP administration must be recorded The InvestiJator must tracN 
vaccines received, used and Zasted and Zill retain all unused or e[Sired Sroducts 
ROTAVAC®, ROTAVAC 5CM and Rotarix® for oral use only and should under no 
circumstances be inMected.  
The investiJational Sroducts must not be mi[ed Zith other medicinal Sroducts  
ROTAVAC® and ROTAVAC 5CM instructions for use: 
x 
The aSSroSriate dosinJ vial to be chosen  
x 
ChecN the e[Siry date 
x 
InsSect visually for any foreiJn Sarticulate matter and  or abnormal Shysical aSSearance Srior 
to administration In the event of either beinJ observed, discard the vaccine vial  
x 
ChecN the vial has not been damaJed nor is already oSen 
x 
ChecN the VVM2 on the seal and let the vaccine to thaZ to liTuid state before administration 
aSSlicable for fro]en ROTAVAC® formulation only  
x 
Pull out the aluminum seal alonJ the indicated marN and tear it off 
x 
Pull out the rubber stoSSer 
x 
Connect the droSSer firmly on the vial 
x 
OSen the droSSer tiS 
x 
The vaccine should be administered immediately after oSeninJ 
x 
Seat the child leaninJ sliJhtly bacNZards .eeS droSSer at 5 deJrees and administer 5 droSs 
in the mouth of the baby toZard the inner cheeN Note that ROTAVAC 5CM comes as a 05ml 
sinJle dose vial and all the contents should be administered to one child 

Protocol Number ± CVIA 066  
Version Number: 01 Version Date: 11 July, 2018 
 
Confidential                                                        PaJe  of  
 
x 
Observe the child for at least 30 minutes for any immediate reactions 
Please refer to PacNaJe Insert of ROTAVAC® for more information on administration of the 
vaccine 
 
Rotarix® instructions for use 
x 
The aSSroSriate dosinJ tube to be chosen  
x 
ChecN the e[Siry date 
x 
InsSect visually for any foreiJn Sarticulate matter and  or abnormal Shysical aSSearance Srior 
to administration In the event of either beinJ observed, discard the vaccine  
x 
ChecN the tube has not been damaJed nor is already oSen 
x 
ChecN the liTuid is clear and colorless, Zithout any Sarticles in it 
x 
ChecN the VVM2 on the label  
x 
Hold the tube uSriJht and reSeatedly flicN the toS of the tube until it is clear of any liTuid 
x 
.eeS the tube held uSriJht and hold the side of tube 
x 
There is a small sSiNe inside the toS of the caS  in the center Turn the caS uSside doZn 180 
and Sress the caS doZn to Sierce the membrane Then lift off the caS 
x 
ChecN the membrane has been Sierced and there is a hole at the toS of the tube 

Protocol Number ± CVIA 066  
Version Number: 01 Version Date: 11 July, 2018 
 
Confidential                                                        PaJe  of  
 
x 
Administer the vaccine immediately 
x 
Seat the child leaninJ sliJhtly bacNZards 
x 
STuee]e the liTuid Jently into the side of the child’s mouth  toZards the inside of their cheeN 
x 
<ou may need to sTuee]e the tube a feZ times to Jet all of the vaccine out  it is oNay if a droS 
remains in the tiS of the tube 
x 
Observe the child for 30 minutes for any immediate reactions 
Please refer to PacNaJe Insert of Rotari[® for more information on administration of the vaccine 
If a child sSits uS or reJurJitates most of the vaccine based on investiJator’s discretion Zithin 5 
minutes of administration, a sinJle reSlacement dose Zill be administered and the event Zill be 
recorded in the source documents and eCR) The SarticiSant should continue to receive remaininJ 
doses in the recommended series  
5. 
Accountability and disposal 
5.. Vaccine supply 
Bharat Biotech International Limited Zill suSSly sufficient Tuantities of study vaccines 
ROTAVAC® and ROTAVAC 5CM to alloZ comSletion of this study only after the I(C and 
reJulatory aSSroval of final Srotocol Rotari[® Zill be Srocured locally from the commercial 
marNet by the SSonsor CIDRZ Local reJulatory reTuirements reTuire that an additional label 
³)or Clinical Trial Use ONL<´ be added to the vaccine lots intended for research studies The 
Sroduct commercial SacNaJinJ or aSSroSriate SacNaJe Zill be unaltered and remain visible to 
maintain the inteJrity of the Sroducts The batch numbers, e[Siry dates and Shysical descriStion 
of investiJational Sroducts Zill also be included in the study reSort  
The vaccines Zill be labeled accordinJ to the local reJulations and reTuirements of study Srotocol 
All labels Zill contain the folloZinJ minimum information: 
x ImSrint ³)or Clinical Trial Use Only´  
x .it Number if aSSlicablestudy vaccine name 
x Name and Address of Manufacturer, 
x Protocol number 
x Store betZeen 28 oC or 20 oC, 
x Batch Number, 
x ([Siry Date, 
x ImSrint ³)or Oral use only´ 
x Name and address of Site 
USon receiSt of the study suSSlies, an inventory must be Serformed by the desiJnated study staff 
at site It is imSortant that the desiJnated study staff verifies that the shiSment contains all the items 
noted in the shiSment inventory Any damaJed or unusable study Sroduct in a Jiven shiSment Zill 
be documented in the study files The InvestiJator must notify Bharat Biotech International 

Protocol Number ± CVIA 066  
Version Number: 01 Version Date: 11 July, 2018 
 
Confidential                                                        PaJe 50 of  
 
Limited immediately of any damaJed or unusable investiJational Sroducts that Zere suSSlied to 
the InvestiJator’s site The IMP must be stored as Ser the storaJe instructions, Zhich Zill be under 
close temSerature monitorinJ and connected to a source Zith reliable bacN uS SoZer ChanJes in 
temSerature outside the alloZed ranJe should be immediately reSorted and any vaccine lots 
e[SeriencinJ such out of ranJe chanJes Zill be brouJht to the attention of Bharat Biotech 
International Limited for determination of Srocedures to folloZ  
In case there is any temSerature e[cursion durinJ shiSment or storaJe, folloZ the steSs Jiven 
beloZ:  
1 4uarantine the shiSment in aSSroSriate storaJe area 28C or 20C 
2 Inform immediately to Site Monitor and BBIL  desiJnee about e[cursion 
3 Send comSleted acNnoZledJment forms to BBIL  desiJnee 
 :ait to hear on usaJe decision from BBIL 
5 In case BBIL confirms use, release investiJational Sroducts for study use  
6 In case usaJe decision is µTo be ReMected’, transfer the investiJational Sroducts to reMected 
area 
The loJistic Srovider’s desiJnee Zill Srovide temSerature data to PATHBBIL for each shiSment 
TemSerature recorded for storaJe Zill be revieZed by the monitor durinJ monitorinJ visits  
After administration, the study staff Zill comSlete accountability label on the carton and store the 
used Sroducts at desiJnated area A monitor from the CRO Zill verify the use of investiJational 
Sroducts as Ser the randomi]ation list and also the accountability of investiJational Sroducts 
The site PI or desiJnee must maintain 100 accountability for all investiJational Sroducts 
received and disSensed durinJ his or her entire SarticiSation in the study ProSer druJ 
accountability includes, but is not limited to:  
x )reTuently verifyinJ that actual inventory matches documented inventory  
x VerifyinJ that all containers used  broNen  unused  lost are documented accurately on the 
loJ  
x VerifyinJ that reTuired fields are comSleted accurately and leJibly  
If any disSensinJ errors or discreSancies are discovered, PATHBBIL must be notified 
immediately  
5.. Dispensing 
After the inclusion and e[clusion criteria checN, the PI or desiJnated Sersonnel must confirm the 
eliJibility and then randomi]e the SarticiSant The Srocedure for randomi]ation Zill be desiJned 
to minimi]e allocation bias in the study DesiJnated Sersonnel Zill SreSare and administer the IP 
as Ser the instructions resSectinJ randomi]ation The used IMP tubesvials must be NeSt for 
accountability )or ROTAVAC® multi dose vial, only one dose to be used for one SarticiSant Used 
vials Zith remaininJ vaccines should be NeSt at room temSerature for accountability  

Protocol Number ± CVIA 066  
Version Number: 01 Version Date: 11 July, 2018 
 
Confidential                                                        PaJe 5 of  
 
5.. Return or destruction 
The site Zill receive instruction from BBILPATH DesiJnee reJardinJ the final disSosition of 
used and unused IMP tubesvials The used IMP containers must be NeSt seSarately for the 
accountability At the comSletion of the study after the last visit of the last SarticiSant, there Zill 
be a final reconciliation of IMP shiSSed, IMP consumed, and IMP remaininJ Any discreSancies 
noted Zill be investiJated, resolved, and documented All the unused and used vialstubes Zill be 
destroyed on site after PATHBBIL aSSroval Destruction of IMP at site Zill be documented 
includinJ ZAMRA Sermit to destroy the Sroducts in the study files and certificate Zill be 
Srovided to PATHBBIL  
6 
ST8D< PROC(D8R(S 
A manual Zill be develoSed and maintained at site Zith detailed descriStions of the Srocedures 
involved All relevant study team members Zill have documented traininJ on their resSective 
resSonsibilities to be undertaNen in the study 
6. 
Recruitment 
ParticiSants Zill be 68 ZeeN 256 days both days inclusive old healthy infants at enrolment  
(liJible Sarent those above the aJe of 18 years ie leJal aJe for consentinJ in Zambia to younJ 
infants Zill be aSSroached durinJ the initial visit to MCH of *eorJe Health Centre by the study 
nurses Zith information about the study in the local lanJuaJe of choice Those Jenerally interested 
Zill be invited to ZalN to the research unit Zithin 20 meters of the clinic Sremises for more detailed 
information durinJ Zhich motivated mothers Zill be recruited and taNen throuJh the Zritten 
informed consent Srocess by the study nurse The standard oSeratinJ Srocedures Zill folloZ *ood 
Clinical Practice and ethical norms of research includinJ confidentiality, Srovision of adeTuate 
information and alloZinJ sufficient time for ansZerinJ Tuestions, voluntariness and clear 
information to confirm that there are no Senalties Zhatsoever for refusal to SarticiSate )or illiterate 
SarticiSants, an indeSendent, literate individual Zill Zitness and validate the informed consent 
Srocess A comSrehension test for the SarticiSant information Zill be administered to assess 
NnoZledJe and understandinJ of the basic study information, and only those meetinJ the minimum 
threshold score  out of 10 Zill Sroceed to siJn the consent Those scorinJ less, Zill have 
information readministered and Zill taNe the comSrehension test aJain This Zill be reSeated only 
once 
InvestiJators should alZays use Jood clinical MudJment in considerinJ a SarticiSant’s overall 
fitness for inclusion in the trial Some SarticiSants may not be aSSroSriate for the study even if 
they meet all inclusion  e[clusion criteria )or instance, medical, occuSational or other conditions 
Sresent in the Sarents may maNe safety evaluations difficult or maNe the infants Soor candidates 
for retention All infants tarJeted for enrollment Zill need to have Sarents LeJally AcceStable 
ReSresentative Zho can comSrehend the SurSose of the study and Srovide Zritten informed 
consent In addition, the families should be resident in the area Zithout Slans to leave the area 
durinJ the course of the study 
Sufficient number of healthy infants Zill be screened Zith Sarental consent to enroll 50 infants 
in the study It is e[Sected that the recruitment Zill be comSleted over a Seriod of 6 months 

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6. 
Study visits 
Children Zill be seen at the study clinic on the day of screeninJenrollmentfirst vaccination, visits 
for second and third vaccinations, if aSSlicable, and folloZ uS visit  ZeeNs after the third dose of 
ROTAVACROTAVAC 5CM and second dose for those in the Rotari[® arm BeloZ is a detailed 
descriStion of study activities on each scheduled visit day 
6.. Day 0 ±Screening(nrolment Visit 
ScreeninJ and enrolment Zill be done on the same day An information sheet aSSroved by I(CIRB 
Zith details of the study Zill be Srovided and discussed Zith the families If the family is interested 
in SarticiSatinJ in the study a ParticiSant ID Zill be assiJned and the study Shysician Zill counsel 
the Sarent and siJned consent Zill be obtained before any trialrelated Srocedures After obtaininJ 
Zritten consent for the study, SarticiSants Zill be screened for eliJibility throuJh medical history 
revieZ and Jeneral Shysical e[amination To assess the eliJibility, the folloZinJ Srocedures Zill 
be conducted: 
Demographic data: This Zill include aJe, ethnicity, Jender, date of birth, birth ZeiJht NJ, 
Sresent ZeiJht NJ, and lenJth cm A coSy of the Children’s Clinic Card Zill be taNen as a source 
document  
ComSlete address of the Sarent Zill be recorded 
Medical History: This Zill include history of SarticiSation in a druJ research studyclinical trial, 
immuni]ation history, any onJoinJ diarrhea or other illness It Zill also include Sast medical 
history vaccination history surJical history Srevious hosSitali]ations history of any allerJy to 
druJs, vaccines current medication history and family history, includinJ history of 
immunodeficiency in any household member  
Physical (xamination: Physical e[amination Zill include vital siJns a[illary temSerature, heart 
rate and resSiratory rate and systematic e[amination of head and necN, sNin, eye, ears, nose, and 
throat (NT, cardiovascular system CVS, resSiratory system RS, Jastrointestinal system 
*IS, Jenitourinary system *US, central nervous system CNS, and musculosNeletal system 
ParticiSants Zho failed screeninJ Zill be recorded on screeninJ SaJes of the eCR) documentinJ 
reason for failure 
(nrollment procedures: The day of the child’s first study vaccination is desiJnated as study Day 
0 The folloZinJ Srocedures Zill be conducted on this day: 
1 Reconfirm eliJibility: If screeninJ and enrolmentvaccination are conducted seSarately, a 
tarJeted symStombased Shysical e[am Zith vital siJns a[illary temSerature, heart rate and 
resSiratory rate, and brief medical history uSdate Zill be Serformed Srior to vaccination to 
ensure continued eliJibility  
2 Randomi]ation: Once eliJibility is ascertained, the child Zould be assiJned a randomi]ation 
code Zhich Zill assiJn himher to receive either ROTAVAC®, ROTAVAC 5CM or Rotari[® 
The SarticiSants Zill receive same treatment at all the aSSlicable vaccination visits  
3 Blood collection: Collect baseline blood samSle of uS to 2 ml for immunoJenicity assessment 
 Vaccination: Vaccination Zill be done Zhen the child comes bacN to normal state after blood 
collection The SarticiSant Zill receive a dose of either ROTAVAC®, ROTAVAC 5CM or 

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Rotari[® as assiJned by the randomi]ation schedule Vaccines Zill ONL< be administered if 
SarticiSant does not meet any contraindication to vaccine administration DurinJ each 
vaccination visit, a section of study ZorNsheeteCR) Zill be comSleted that records 
information about vaccines received, date and time ProSer accountability of all vaccines Zill 
be maintained  
5 Concomitant Vaccination and Other Treatments: All SarticiSants Zill receive other (PI 
vaccinations concomitantly as Ser the national immuni]ation schedule the research nurses Zill 
ensure that all study SarticiSants receive the due vaccines on schedule Use of SrescriStion 
medications and any treatments  Srocedures durinJ the study Seriod Zill be recorded on source 
documents  eCR) The name of SrescriStion medication and duration of treatment should be 
recorded in the eCR), if available  
6 Immediate PostVaccination ReactoJenicity Assessment: After each dosinJ, all SarticiSants 
Zill be observed at the clinic site for 30 minutes to checN for any immediate A(s includinJ 
any eSisodes of vomitinJ and allerJic reaction to vaccine After 30 minutes Sostvaccination 
observation Seriod, vital siJns Zill be measured if indicated, a tarJeted Shysical e[amination 
Zill be Serformed Clinically siJnificant abnormal findinJs on tarJeted Shysical e[amination 
and vital siJns Zill be reSorted in the CR) as an unsolicited A(  
 Provide diJital thermometer and the Sostimmuni]ation diary card PIDC to record, from the 
day of vaccination and daily for ne[t si[ days, any solicited reactions, includinJ diarrhea, fever, 
vomitinJ, decreased aSSetite, irritability, and decreased activity level Train the Sarents to 
comSlete the PIDC  
8 Parents Zill be instructed that if an A( reTuirinJ medical attention is identified durinJ the 
study, Sarents Zill contact a study ShysiciandesiJnee and aSSroSriate medical care Zill be 
Jiven Also, at all times betZeen first and last visit, unsolicited A(s and or SA(s includinJ 
intussusceStion Zill be recorded in eCR) and manaJed medically as needed 
 Inform the Sarent on the safety folloZ uS home visit by the field officer on days 2 	 , and 
advise himher on the ne[t clinic visit after 28 days  
 
Safety Follow-8p:  Parents Zill be shoZn hoZ to fill in the PIDC for  days day 06 after 
vaccination Study staff Zill maNe a Shysical home visit on Days 2 1 day and Day  1 day 
to determine the child’s health status and to suSSort comSletion of the PIDC In case the child 
e[Seriences any illness durinJ this Seriod, they Zill be referred to the study clinic for further 
evaluation and treatment ComSleted PIDC can be collected by the field officer at this visit or the 
Sarent can brinJ it to the site at the ne[t visit, if Sarents Zere not available durinJ the home visit 
The data in the PIDC collected by the Sarents Zill be revieZed by the study ShysiciandesiJnee 
and entered in the CR) Any solicited reaction e[tendinJ beyond  days after vaccination Zill also 
be recorded on the PIDCCR) Zith date of resolution if available and the hiJhest severity durinJ 
the occurrence Also, at all times betZeen first and last visit, unsolicited A(s and  or SA(s 
includinJ intussusceStion Zill be recorded in eCR) and manaJed medically as needed  
6.. Second Visit (Day ) 
The date for this visit Zill be calculated 28 days from the date of the first study vaccination A 
ma[imum ZindoZ Seriod of  days Zill be alloZed for this visit Parents Zill be contacted by 

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Shone a day before the visit to remind them of the aSSointment ParticiSants Zho miss the 
scheduled visit date Zill be SromSted to reschedule for the missed immuni]ations and ensure that 
(PI vaccines and investiJational vaccines are administered in a timely manner The folloZinJ 
Srocedures Zill be carried out at this visit: 
1 ChecN for any adverse events since last visit and record them in the source note and eCR) 
USdate medical history includinJ folloZuS of Srior A(s 
2 Collection and revieZ of the diary cards if not already collected by field ZorNer earlier   
3 ChecN for useadministration of any medicationvaccine since last visit Any medication taNen 
for the treatment of the illness or vaccine administered Zill also be recorded in the relevant 
section of the CR) 
 Conduct Shysical e[amination and vital e[amination 
5 ChecN for any contraindication to vaccination Reschedule visit if the infant is e[SeriencinJ an 
illness that is temSorary contraindication to vaccination  
6 Vaccines Zill be administered if SarticiSant does not meet any contraindication to 
InvestiJational Medicinal Product IMP administration The SarticiSant Zill receive a dose of 
either ROTAVAC®, ROTAVAC 5CM or Rotari[® as assiJned by the randomi]ation schedule 
DurinJ each vaccination visit, a section of study ZorNsheeteCR) Zill be comSleted that 
records information about vaccines received, date and time  
 Procedures 5 under section 621 above Zill be reSeated   
8 Remind the Sarent of the safety folloZ uS visit by the field officer on days 30 	 35, and advise 
himher on the ne[t clinic visit after 28 days  
6.. Third Visit (Day 56)  
The date for this visit Zill be calculated 28 days from the date of last vaccination A ma[imum 
ZindoZ Seriod of  days Zill be alloZed for each of these visits Parents Zill be contacted by 
Shone a day before the visit to remind them of the aSSointment ParticiSants Zho miss the 
scheduled visit date Zill be SromSted to reschedule for the missed immuni]ations and ensure that 
(PI vaccines and IMPs are administered in a timely manner The folloZinJ Srocedures Zill be 
carried out at this visit: 
1 ChecN for any adverse events since last visit and record them in the source note and eCR) 
USdate medical history includinJ folloZuS of Srior A(s  
2 ChecN for useadministration of any medicationvaccine since last visit Any medication taNen 
for the treatment of the illness or vaccine administered Zill also be recorded in the relevant 
section of the ZorNsheeteCR) 
3 Conduct Shysical e[amination and vital e[amination 
 )or SarticiSants in the Rotari[® arm 
x RevieZuSdate address and contact details 
x Collection and revieZ the diary cards if not already collected by field ZorNer earlier  
x Perform Shysical e[amination  

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x Obtain uS to 2 ml of blood for immunoloJical assays  
x (nsure all onJoinJ SA(s are folloZed uS as Ser the Srotocol 
x RevieZ vaccination history and advise the Sarent on further vaccination of the infant 
x )ill uS the study terminationcomSletion form This Zill be the final study visit for 
SarticiSants in the Rotari[® arm 
5 )or SarticiSants in the ROTAVAC®, ROTAVAC 5CM arms 
x ChecN for any contraindication to vaccination Reschedule visit if the infant is e[SeriencinJ 
an illness that is temSorary contraindication to vaccination  
x Collection and revieZ of the diary cards if not already collected by field ZorNer earlier 
Vaccines Zill be administered if SarticiSant does not meet any contraindication to IMP 
administration The SarticiSant Zill receive a dose of either ROTAVAC or ROTAVAC 
5CM as assiJned by the randomi]ation schedule DurinJ each vaccination visit, a section 
of study ZorNsheeteCR) Zill be comSleted that records information about vaccines 
received, date and time  
x Procedures 5 under section 621 above Zill be reSeated 
x Remind the Sarent of the safety folloZ uS visit by the field officer on days 58 	 63, and 
advise himher on the ne[t clinic visit after 28 days 
6.. Fourth Visit (Day ) 
aSSlicable only for ROTAVAC® and ROTAVAC 5CM arms 
The date for this visit Zill be calculated 28 days from the date of last vaccination A ma[imum 
ZindoZ Seriod of  days Zill be alloZed for this visit Parents Zill be contacted for the 
SarticiSants Zho miss the scheduled visit date The folloZinJ Srocedures Zill be conducted: 
1 RevieZ  uSdate address and contact details 
2 ChecN for any adverse events since last visit and record them in the source note and eCR) 
USdate medical history includinJ folloZuS of Srior SA(s (nsure all onJoinJ A(s are 
folloZed uS as Ser the Srotocol 
3 Collection and revieZ of the diary cards if not already collected by field ZorNer earlier  
 ChecN for useadministration of any medicationvaccine since last visit Any medication taNen 
for the treatment of the illness or vaccine administered Zill also be recorded in the relevant 
section of the CR) 
5 Perform Shysical e[amination RevieZ vaccination history and advise the Sarent on further 
vaccination of the infant  
6 Collect uS to 2 ml of blood for immunoloJical assays 
 RevieZ vaccination history and advise the Sarent on future vaccination of the infant 
8 ComSlete the study terminationcomSletion form 

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6..5 Interim Contacts and Visits 
Interim contacts and visits those betZeen reJularly scheduled folloZ uS visits may be Serformed 
at SarticiSant’s Sarent’s reTuest or as deemed necessary by the investiJator or desiJnee at any time 
durinJ the study Parents Zill be asNed to brinJ the child to the clinic at any time betZeen visits if 
they have any condition that reTuires medical attention All interim contacts and visits Zill be 
documented in SarticiSant’s study records and on aSSlicable case reSort forms as ³Unscheduled 
visits´   
6..6 Management of Serious Adverse (vents including Intussusception 
The research team Zill be available onsite at all times durinJ normal ZorNinJ hours and Zill be 
able to Srovide basic services for outSatient care In case of serious conditions that reTuire 
admission to the tertiary hosSital, a study vehicle stationed onsite Zill be available to Srovide 
ambulance service for timely travel Medical Sersonnel at the sites Zill be trained on screeninJ 
tools to SromStly identify and assess any susSected cases of intussusceStion The Ney symStoms 
include bloody stools, continuous vomitinJ, abdominal distension andor abdominal ³lumSs´ 
Children SresentinJ Zith any susSected symStoms or siJns Zill be SromStly escorted for 
consultation Zith a Sediatrician or Sediatric surJeon or referred for hosSitali]ation Parents Zill be 
instructed by staff to NeeS close Zatch of the symStoms noted above and contact study staff if they 
are detected The study team Zill be obliJed to ensure raSid consultation Zith the team led by the 
Sediatric surJeon Zho leads the intussusceStion surveillance ZorN at the university teachinJ 
hosSital Any access fees related to diaJnosis and care for these cases Zill be taNen by the SSonsor 
A SA( form Zill be comSleted for all cases of intussusceStion and notified to authorities as Zell 
as the Protocol Safety RevieZ Team PSRT immediately, and folloZon full reSort as soon as the 
case is ascertained 
6.. Schedule of events 
The schedule of events  assessments Serformed durinJ the trial is Srovided beloZ: 
Visit 
V 
V 
V 
V 
Time point 
D0 
D 
D56 
D 
Interval 
6- 
weeNs 
V 
() 
days 
V 
() 
days 
V 
() 
days 
Information Srocess and Zritten informed 
consent 
; 
 
 
 
Collect baseline demoJraShic data 
; 
 
 
 
CollectrevieZ medical history 
; 
 
 
 
Perform Shysical and vital siJns e[amination 
;a 
; 
; 
; 
ChecN inclusion e[clusion criteria 
; 
 
 
 
ChecN ZithdraZal criteria 
 
;  
;  
;  
ParticiSant enrollment and Randomi]ation 
; 
 
 
 

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Visit 
V 
V 
V 
V 
Time point 
D0 
D 
D56 
D 
Interval 
6- 
weeNs 
V 
() 
days 
V 
() 
days 
V 
() 
days 
Collect blood samSle for immunoJenicity 
testinJ 
; 
Pre
dosinJ 
 
;c 
 
;b 
 
Study vaccination alonJ Zith (PI vaccination 
; 
; 
;b 
 
ChecN 
contraindications, 
ZarninJs 
and 
Srecautions to vaccine receiSt 
 
; 
;b 
 
Observe for immediate adverse events for 30 
minutes Sost vaccination 
; 
; 
;b 
 
Perform Sostvaccination Vital e[amination and 
tarJeted Shysical e[amination if reTuired 
; 
; 
;b 
 
Issue and Instruct SarticiSant’s ParentLAR on 
use of diary card 
; 
; 
;b 
 
Record solicited A(s for  days Sostvaccination 
; 
; 
;b 
 
Safety folloZ uS Sost vaccination by social 
ZorNer 
;d 
;d 
;db 
 
Record unsolicited A(s , includinJ SA(s  
; 
; 
; 
;b 
Record 
any 
concomitant 
medicationsvaccinations 
; 
; 
; 
;b 
RevieZ interim medical history and record any 
intercurrent medical conditions 
 
; 
; 
;b 
ParticiSant comSletion of study 
 
 
;c 
;b 
D   day PR(   Srevaccination A(   adverse events, SA(   serious adverse event  
a SymStombased P( to be Serformed if screeninJ is beinJ reSeated and there is any chanJe in 
health since last screeninJ  
b Not aSSlicable for SarticiSants in Rotari[ arm 
c ASSlicable only for SarticiSants in Rotari[ arm 
 d This includes visit by the health ZorNer to the Sarent on day 2 and  after vaccination  
  

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6. 
Study Termination  
6.. (nd of Trial According to the Protocol 
The end of the trial is defined as the date of the last contact of the last SarticiSant in the trial, 
accordinJ to the trial scheme 
6.. Suspension andor Premature Termination of the Trial 
CIDRZ in consultation Zith PATH retains the riJht to temSorarily susSend or Srematurely 
discontinue this study at any time related to safety, administrative, or other reasons includinJ but 
not limited to the folloZinJ: 
x 
RisN to SarticiSant’s safety  
x 
A(s occur Zith such severity and freTuency that the SroSosed schedule can no lonJer be 
adhered to 
x 
The scientific Tuestion is no lonJer relevant or the obMectives Zill not be met ie sloZ 
accrual  
x 
)ailure to comSly Zith *CP or terms of Clinical Trial AJreement 
x 
RisNs that cannot be adeTuately Tuantified  
x 
(thical concerns raised by the local community or local medical care  health care authorities  
x 
)ailure to remedy deficiencies identified throuJh site monitorinJ, substandard data or failure 
to meet identified SSonsor Serformance standards 
x 
The manufacturer decides to discontinue the develoSment of the formulation 
x 
It becomes aSSarent that SarticiSant enrollment is unsatisfactory Zith resSect to Tuality and  
or Tuantity  
x 
Data recordinJ is inaccurate and  or incomSlete on a chronic basis 
Documentation e[SlaininJ Sremature termination of the study must be forZarded to the Site, 
ReJulatory Authority, and (thics Committee in accordance Zith local Juidelines If the study is 
stoSSed or susSended Srematurely, a summary reSort Zill be submitted by Centre for Infectious 
Disease Research in Zambia to inform the reJulatory authorities and the ethics committee 
Institutional RevieZ Board overseeinJ the study about the decision and the reasons for termination 
or susSension The summary reSort Zill Srovide a brief descriStion of the study, the number of 
SarticiSants e[Sosed to the vaccine, dose and duration of e[Sosure, details of adverse druJ 
reactions if any, and the reason for discontinuation of the study If such action is taNen, all efforts 
must be made to ensure the safety of the SarticiSants enrolled in the study )or all SarticiSants 
enrolled in the study, safety folloZuS Zill be conducted as decided by the PSRT or as advised by 
the (CIRB or the MOH In case of Sremature study or study clinic closure, the monitor Zill 
conduct all activities as indicated in the close out visit 
6. 
Lost to follow-up 
To Srevent lost to folloZuS, the study team Zill ensure that valid contact details are obtained Srior 
to enrolment, includinJ a Shysical visit to the SarticiSant’s home at the end of visit Also, the 

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SarticiSant’s Sarent Zill be reminded by Shone at least one day before their scheduled visit  In the 
event of a missed visit, the SarticiSant Zill be contacted by Shone if that fails, a home visit Zithin 
3 days of the scheduled visit Zill be made by the field ZorNer  A SarticiSant Zho cannot be located 
after at least 3 documented contact efforts and have missed 2 consecutive visits Zill be considered 
lost to folloZuS  (fforts to contact Zill be documented in source documents  Any SarticiSant 
Zho failed to attend the final study visit Zill also be classified as lost to folloZuS  There Zill be 
no reSlacement for SarticiSant Zho are lost to folloZuS   
6.5 
8se of concomitant vaccine(s)medication during the study 
Routine childhood vaccines mandated by (PI should be Jiven concomitantly Zith the study 
vaccine as Ser the national immuni]ation schedule All infants Zill receive all (PI vaccines as Ser 
routine schedule The (PI schedule consists of administerinJ DiShtheria, Tetanus, Pertussis, 
+DHPRSKLOXV LQIOXHQ]DH W\SH E and HeSatitis B vaccine DTZPHibHeSB, Pneumococcal 
conMuJate vaccine and OPV at 6, 10 and 1 ZeeNs and IPV at ZeeN 1 Zhen sZitched to in 
Zambia The study SarticiSants may receive additional doses of OPV as reTuired durinJ sSecial 
immuni]ation rounds  BC* vaccine Zill be offered to infants Zho did not receive it at birth 
Concomitant and other vaccines used durinJ the study Zill be reSorted in the Concomitant 
vaccination section of the CR)  
The Sarents of the children should inform the PI or desiJnee about intaNe of any druJ taNen for the 
treatment of an illness occurrinJ since first vaccination until end of folloZuS Seriod Use of 
SrescriStion medications and any treatments  Srocedures durinJ the study Seriod Zill be recorded 
on source documents and Concomitant Medication CR) 
6.6 
8nblinding procedure 
The study Zill be conducted under oSenlabel condition This means that the Satient, clinical site, 
CRO, sSonsor and PATH Zill be unblinded to the treatment assiJnments Therefore, unblindinJ 
Srocedures are not aSSlicable  The study laboratory Zill be NeSt blinded for the treatment 
administered until the end of testinJ 
6. 
Clinical procedures  
Vital Signs 
x 
TemSerature in deJrees Celsius recorded to the nearest 01 deJree Zill be measured by 
a[illary thermometer for infants  
x 
ResSiratory rate Zill be recorded in breaths Ser minute  
x 
Heart rate in beats Ser minute Zill be measured manually 
x 
HeiJhtlenJth Zill be measured and recorded to the nearest 01 cm  
x 
:eiJht Zill be measured in NJ and recorded to the nearest 001 NJ  
Physical (xamination 
)ull Shysical e[amination Zill include assessment of vital siJns, head, eyes, ears, nose, 
oroSharyn[, necN, chest auscultation, lymSh nodes necN, suSraclavicular, a[illary, inJuinal, 

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abdomen auscultation and SalSation, Jenitourinary, musculosNeletal, sNin esSecially inMection 
sites, and neuroloJical  
Targeted physical examination 
A focused Shysical e[amination based on symStoms reSorted by the SarticiSant and the Sresence 
or absence of solicited adverse events collected to assess vaccine reactoJenicity  
Medical History 
A comSrehensive medical history Zill be collected includinJ details of any Srevious vaccinations 
and reaction to vaccinations, SarticiSation in clinical trials, surJery, Srevious hosSitali]ation, 
allerJy to fooddruJs, current medication and history of any chronic or recurrent medical 
conditions 
An interval medical history Zill consist of inTuirinJ reJardinJ chanJes since the last medical 
history discussion healthcare events, siJns, symStoms and chanJes in use of SrescriStion or 
nonSrescriStion druJs or herbal SreSarations 
6. 
Termination of withdrawn study participant 
A SarticiSant Zho can no lonJer continue Zith the study for Zhatever reason, Zill need to be 
concluded in the eCR) via the termination SaJe Zhich Zill marN the close of the case The Sossible 
reasons Zill include: 
1 Voluntary ZithdraZal from the study by the SarticiSant 
2 InvestiJator decides to ZithdraZ the SarticiSant from the study for safety or other clinical 
reasons 
3  ParticiSant is confirmed as lost to folloZ uS 
This site SrinciSal investiJator must revieZ each case and confirm the status before comSletion of 
the termination form 
 
LA%ORATOR< (VAL8ATIONS R(48IR(M(NTS 
. 
Sample collection, distribution and storage 
To Tuantitate antibody concentrations elicited by the study vaccines, a baseline blood samSle Zill 
be collected from all SarticiSants before the first vaccination and four ZeeNs after the last 
vaccination after 3rd dose for ROTAVAC®ROTAVAC 5CM and after 2nd dose for Rotari[®  
Clinicians and e[Serienced nurseShlebotomists Zill be trained in aSSroSriate samSle collection 
methods ASSroSriate aseStic Srocedures Zill be emSloyed Zith aSSroSriate needles and syrinJes 
in Slace for samSle collection Srocedure A ma[imum of 2 ml of blood, from a SeriSheral vein, 
Zill be collected by an aseStic techniTue into Jel SST tubes A ma[imum of 2 attemSts Zill be 
made for collection of the blood samSle SamSlinJ attemSt Zill not be reSeated in case the team is 
not able to collect the samSle on this day Clotted blood in the tube Zill be centrifuJed to obtain 
serum DesiJnated laboratory Sersonnel at the site Zill aliTuot the samSles into tZo aliTuots before 
storaJe Serum Zill be distributed in the tZo aliTuots such that the Srimary receives at least 05 ml 
of the serum and the remaininJ is transferred to the second cryotube All serum samSles Zill be 
labelled aSSroSriately The tZo samSles Zill be stored in seSarate controlled free]ers at or beloZ 

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±20qC until the time of shiSment to the testinJ laboratories These free]ers Zill have bacNuS SoZer 
source in case of outaJe on the national SoZer Jrid All handlinJ Zill be done to Srevent 
unnecessary free]ethaZ cycles ie, bacNuS samSles should not be thaZed unless reTuired for 
testinJ TemSerature monitorinJ Zill be done to assure maintenance of cold chain and sSecimen 
Tuality One aliTuot each Zill be sent seSarately to each of the tZo testinJ laboratories ie, 
laboratory at CMC Vellore, India and CCHMC, Cincinnati, USA at or beloZ ±20qC usinJ 
validated SacNaJinJ and temSerature monitors The testinJ laboratories Zill be resSonsible for 
testinJ for antirotavirus IJA antibodies see beloZ and storinJ of samSles till study comSletion  
The SSonsor Zill be resSonsible for obtaininJ the aSSroSriate Material Transfer AJreement MTA 
from the local National Health Research Authority 
. 
Immunological laboratory assays  
SeroloJical assays for Tuantification of antirotavirus IJA antibodies by (LISA Zill be Serformed 
at the folloZinJ labs 
Name of Laboratory 
Assay sSecification 
Number of SarticiSants Pre and Post
vaccination samSles 
ROTAVAC® ROTAVAC 
5CM 
Rotari[® 
The :ellcome Trust 
Research Laboratory, 
Christian 
Medical 
ColleJe, Vellore, India 
(stimation of serum anti
rotavirus IJA antibodies by 
(LISA usinJ :C3 as the 
viral lysate 
All 
All 
All 
Cincinnati 
Children
s 
HosSital 
Medical 
Center 
CCHMC, 
Division of Infectious 
Diseases, 
Cincinnati, 
Ohio, USA 
(stimation of serum anti
rotavirus IJA antibodies by 
(LISA usinJ 812 as the 
viral lysate 
50  
50  
50  
 
If Zarranted, the samSles may be subMected to additional tests to e[Slain the immune resSonses 
seen in the Srimary analysis 
. 
Assays Tualification, standardization, validation 
The :ellcome Trust Research Laboratory, Christian Medical ColleJe, Vellore, India has a 
validated assay to measure serum antirotavirus IJA antibodies usinJ :C3 as the lysate Zhich has 
been used in earlier clinical trials of ROTAVAC® vaccines Cincinnati Children
s HosSital Medical 
Center CCHMC,  Division of Infectious Diseases, Cincinnati, Ohio, USA also has a validated 

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assay for estimatinJ serum antirotavirus IJA antibodies usinJ 812 as the viral lysate Zhich is 
the Sarent strain of Rotari[® vaccine 
. 
Future use of stored samples 
Any remaininJ serum samSles Zill be retained for a ma[imum of 5 years at the laboratories in case 
further investiJations are reTuired after comSletion of the study No Jenetic testinJ Zill be 
Serformed on samSles collected in the study After this Seriod these samSles Zill be destroyed 
after Zritten communication from PATH   
.5 
%iohazard containment 
As bloodborne SathoJens can infect throuJh contact Zith contaminated needles, blood, and blood 
Sroducts, aSSroSriate Srecautions Zill be emSloyed by all Sersonnel in shiSSinJ and handlinJ of 
all sSecimens for this study as recommended All bioloJical sSecimens Zill be transSorted usinJ 
aSSroSriate SacNaJinJ All danJerous Joods or materials, includinJ diaJnostic sSecimens and 
infectious substances, must be transSorted accordinJ to instructions detailed in the International 
Air TransSort Association IATA DanJerous *oods ReJulations Bioha]ard Zaste Zill be 
contained accordinJ to institutional, transSortationcarrier, and all other aSSlicable reJulations All 
danJerous Joods or materials, includinJ diaJnostic sSecimens and infectious substances, must be 
transSorted accordinJ to instructions detailed in the International Air TransSort Association 
IATA DanJerous *oods ReJulations Bioha]ardous Zaste Zill be contained accordinJ to 
institutional, transSortationcarrier, and all other aSSlicable reJulations   
 
SAF(T< ASS(SSM(NT AND R(PORTIN* 
. 
Definitions 
.. Adverse (vent (A() 
An adverse event is any untoZard medical occurrence in a SarticiSant after administration of the 
investiJational vaccine and that does not necessarily have a causal relationshiS Zith the 
investiJational vaccine  An A( can therefore be any unfavorable and unintended siJn includinJ 
abnormal laboratory findinJs, symStoms, Shysical e[aminations, or disease temSorally associated 
Zith the use of the investiJational vaccine, Zhether or not related to the investiJational vaccine  
This definition includes e[acerbations of Sree[istinJ conditions  Stable Sree[istinJ conditions 
Zhich do not chanJe in nature or severity durinJ the study are not considered A(s hoZever, these 
should be reSorted as Sart of the medical history An A( does not include:  
x 
Medical or surJical Srocedures eJ, surJery, endoscoSy, transfusion, but the condition that 
leads to the Srocedure is an A(  
x 
Situations Zhere an untoZard medical occurrence has not occurred eJ, hosSitali]ation for 
elective surJery, social and  or convenience admissions  
x 
Overdose of either study druJ or concomitant medication Zithout any siJns or symStoms 
Solicited A(s are SresSecific local and systemic adverse events that are common or NnoZn to be 
associated Zith vaccination and that are actively monitored as indicators of vaccine reactoJenicity  
InvestiJators Zill not be reTuired to assess causality of solicited adverse events if the onset is 

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durinJ the solicitation Seriods  Solicited adverse events Zith onset after the solicitation Seriod Zill 
be caStured as unsolicited A(s 
)or this trial, immediate A(s Zill be assessed by study staff 30 minutes after each vaccination and 
solicited A(s Zill be assessed daily for  days after each vaccination by the SarticiSants  
ParticiSants Zill be Srovided a diary to record the Sresence or absence of solicited A(s, severity 
of the solicited A( and use of concomitant medication   
In this study only systemic solicited events of fever, diarrhea, vomitinJ, decreased aSSetite, 
irritability, and decreased activity level Zill be monitored Local reactions to (PI vaccination Zill 
not be considered solicited events and should be reSorted as unsolicited A(s  
8nsolicited A(s are any A(s reSorted sSontaneously by the SarticiSant, observed by the study 
Sersonnel durinJ study visits or those identified durinJ revieZ of medical records or source 
documents Unsolicited A(s are not sSecified for active monitorinJ, but sSontaneously reSorted 
as untoZard events occurrinJ in a SarticiSant All such events Zill be recorded on the µAdverse 
event’ SaJes of the eCR) 
.. Adverse drug reaction (ICH)  Suspected Adverse Reaction (FDA) 
An adverse druJ reaction ADR is any A( in Zhich the casual relationshiS to the investiJational 
vaccine is at least a reasonable Sossibility, ie, the relationshiS cannot be ruled out HavinJ a 
reasonable susSected causal relationshiS to the investiJational vaccine Tualify as ADR  The 
conceSt of ³reasonable causal relationshiS´ is meant to convey in Jeneral that there are facts 
evidence or arJuments to suJJest a causal relationshiS  
8nexpected adverse drug reaction is an adverse reaction, the nature or severity of Zhich is not 
consistent Zith the information in the Sroduct information eJ, InvestiJator
s Brochure for an 
unaSSroved investiJational Sroduct or SacNaJe insertsummary of Sroduct characteristics for an 
aSSroved Sroduct 
.. Serious Adverse (vent (SA()  
A SA( is any untoZard medical occurrence that: 
x 
Results in death, 
x 
Is life threateninJ,       
x 
ReTuires inSatient hosSitali]ation or SrolonJation of e[istinJ hosSitali]ation, 
x 
Results in Sersistent or siJnificant disability  incaSacity,  
x 
Is a conJenital anomaly or a birth defect, 
x 
Medically imSortant event 
NOT(: InvestiJatorconfirmed cases of intussusceStion Zill Tualify as SA( in the study and Zill 
be reSorted on the SA( form The term lifethreateninJ in the definition of serious refers to an 
event in Zhich the Satient Zas at risN of death at the time of the event it does not refer to an event 
Zhich hySothetically miJht have caused death if it Zere more severe 
Medical and scientific MudJment should be e[ercised in decidinJ Zhether e[Sedited reSortinJ is 
aSSroSriate in other situations, such as imSortant medical events that may not be immediately life

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threateninJ or result in death or hosSitali]ation but may MeoSardi]e the Satient or may reTuire 
intervention to Srevent one of the other outcomes listed in the definition above These should also 
usually be considered serious ([amSles of such events are intensive treatment in an emerJency 
room or at home for allerJic bronchosSasm blood dyscrasias or convulsions that do not result in 
hosSitali]ation or develoSment of druJ deSendency or druJ abuse  
HosSitali]ation is an official admission to a hosSital HosSitali]ation or SrolonJation of a 
hosSitali]ation constitutes a criterion for an A( to be serious hoZever, it is not in itself considered 
a SA( In absence of an A(, a hosSitali]ation or SrolonJation of a hosSitali]ation should not be 
reSorted as a SA( by the InvestiJator throuJh a SA( form, e[amSles of such situations include: 
x 
A hosSitali]ation or SrolonJation of hosSitali]ation is needed for a Srocedure reTuired by the 
Srotocol 
x 
HosSitali]ation or SrolonJation of hosSitali]ation is Sart of a routine Srocedure folloZed by 
the center eJ, stent removal after surJery This should be recorded in the study file 
x 
A hosSitali]ation for a Sree[istinJ condition that has not Zorsened 
x 
HosSitali]ation for social reasons 
Disability is defined as a substantial disruStion in a Serson’s ability to conduct normal life 
functions  
.. Reporting Period and Parameter 
Safety events are reSorted from the time of the first study vaccination throuJh comSletion of the 
study at  ZeeNs after the final vaccination  SSecifically,  
x 
Immediate adverse events Zill be collected for 30 minutes after each vaccination  
x 
Solicited A(s to assess systemic reactoJenicity Zill be collected for  days after each 
vaccination  If a solicited A( started durinJ the  days Day 06 Sost vaccination and 
continues beyond the  days it Zill continue to be reSorted as a solicited A(   
x 
Unsolicited A(s and SA(s Zill be collected from day 0 uS to four ZeeNs after last vaccination 
inclusive Any medical condition that is Sresent at the time that the SarticiSant is screened Zill 
be considered as baseline and not reSorted as an A( A(s characteri]ed as intermittent reTuire 
documentation of onset and duration of each eSisode No sSecific safety laboratory tests are 
Slanned in the study hoZever, clinical and laboratory investiJations conducted in order to 
diaJnose or treat a condition in a study SarticiSant Zill Zarrant documentation of all the Ney 
laboratory results (vents Zill be folloZed for outcome information until resolution or 
stabili]ation 
. 
Severity of Adverse (vents 
Severity of solicited reactions Zill be Jraded as folloZs: 
Reaction 
Intensity grade Parameter 
)ever C 
0Normal 
A[illary temSerature  35C 
1 Mild 
A[illary temSerature  35 ±  380C 

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2Moderate 
A[illary temSerature ! 380 ±  30C 
3 Severe 
A[illary temSerature ! 30C  
Diarrhea 
0Normal 
0  2 looser than normal stools  day 
1 Mild 
3 looser than normal stools  day 
2Moderate 
   5 looser than normal stools  day 
3 Severe 
 t 6 looser than normal stools  day 
VomitinJ 
0Normal 
Normal no emesis 
1 Mild 
1 eSisode of vomitinJ  day 
2Moderate 
2 eSisodes of vomitinJ  day 
3 Severe 
t 3 eSisodes of vomitinJ  day 
Decreased aSSetite 
0Normal 
ASSetite as usual 
1 Mild 
(atinJbreast feedinJ less than usual  no effect on 
normal activity 
2Moderate 
(atinJbreast feedinJ less than usual  interferes Zith 
normal activity 
3 Severe 
Not eatinJbreast feedinJ at all 
Irritability 
0Normal 
Normal Behaviour as usual 
1 Mild 
CryinJ more than usual Zith no effect on normal activity 
2Moderate 
CryinJ more than usual that interferes Zith normal 
activity 
3 Severe 
Sersistent cryinJ and the child could not be comforted 
and that Srevents normal activity 
Decreased 
activity 
level 
0Normal 
Behaviour as usual 
1 Mild 
DroZsiness easily tolerated 
2Moderate 
DroZsiness that interferes Zith normal activity 
3 Severe 
DroZsiness that Srevents normal activity 
The severity of all unsolicited A(s  SA(s occurrinJ durinJ the course of the study Zill be Jraded 
as Ser the Juidance document by Division of AIDS DAIDS Table for *radinJ the  Severity of 
Adult and Pediatric Adverse (vents, corrected version 21, July 201, of the US National Institute 
of Health as attached as ASSendi[ 2 to the Srotocol Severity of unsolicited A(s and SA(s not 
included in the JradinJ system mentioned above Zill be Jraded as folloZs: 
*rade 1  Mild  Mild symStoms causinJ no or minimal interference Zith usual social 	 functional 
activities Zith intervention not indicated  

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*rade 2  Moderate  Moderate symStoms causinJ Jreater than minimal interference Zith usual 
social 	 functional activities Zith intervention indicated 
*rade 3  Severe  Severe symStoms causinJ inability to Serform usual social 	 functional 
activities Zith intervention or hosSitali]ation indicated 
*rade   Potentially Life ThreateninJ  Potentially lifethreateninJ symStoms Zith intervention 
indicated to Srevent Sermanent imSairment, Sersistent disability, or death the InvestiJator should 
not Jrade a reaction as lifethreateninJ if had it occurred in a more severe form then it miJht have 
caused death 
*rade 5  Death All A(s leadinJ to death are *rade 5 events 
Definitions: 
Usual Social 	 )unctional Activities: Activities that are aJe and culturally aSSroSriate, such as 
social interactions, Slay activities, or learninJ tasNs 
Medical Intervention: Use of SharmacoloJic or bioloJic aJents for treatment of an A( 
An A( that is assessed as severe should not be confused Zith the term SA( Severity is a cateJory 
utili]ed for ratinJ the intensity of an event and both A(s and SA(s can be assessed as severe  
A(s are Jraded Zith the Zorst severity Jrade durinJ the illnesssymStoms 
. 
Causality of Adverse (vent  
The study investiJators Zill determine the causal relationshiS betZeen the study Sroduct and the 
A(  The causality assessment is made on the basis of the available information at the time of 
reSortinJ and can be subseTuently chanJed accordinJ to folloZuS information  DetermininJ of 
causality is based on clinical MudJment and should taNe into consideration the folloZinJ factors: 
x 
Is there a temSoral timebased relationshiS betZeen the event and administration of the 
investiJational Sroduct" 
x 
Is there a Slausible bioloJical mechanism for the investiJational Sroduct to cause the A(" 
x 
Is there a Sossible alternative etioloJy for the A( such as concurrent illness, concomitant 
medications"  
x 
Are there Srevious reSorts of similar A(s associated Zith the investiJational Sroduct or other 
vaccines in the same class" 
)or this study, the investiJators must classify the causality of the A( accordinJ to the cateJories 
defined beloZ:  
Related: There is a reasonable Sossibility that the Sroduct caused the event ³Reasonable 
Sossibility´ means that there is evidence to suJJest a causal relationshiS betZeen the study Sroduct 
and the A( 
Not Related: There is not a reasonable Sossibility that the administration of the study Sroduct 
caused the event 
Assessment of causal relationshiS should be recorded in the A( and SA( forms 

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. 
Follow-up of Adverse (vent 
ParticiSants Zill be monitored throuJhout the study Seriod for adverse events A(s come to the 
attention of site clinicians throuJh interim medical histories, Shysical e[aminations and laboratory 
testinJ conducted to investiJate other illnesses or routine tests The Sossible occurrence of any A( 
and SA( Zill also be asNed durinJ the scheduled study visits In addition, the Sarents Zill be 
advised to contact study staff immediately at any time throuJhout the study Seriod if their child 
e[Seriences an A( All adverse events Zill be closely monitored in the safety monitorinJ 
Srocesses 
A(s Zill be manaJed in accordance Zith Jood medical Sractices by the clinical study site team 
Zho Zill assess and treat or refer the SarticiSant for medical care as aSSroSriate :here feasible 
and medically aSSroSriate, the Sarent Zill be encouraJed to seeN medical care at the facility Zhere 
the study clinician is based, and to reTuest that the clinician be contacted uSon their arrival If 
needed to monitor or treat an adverse event, additional study visits may be conducted  
All A(s and SA(s Zill be folloZed until resolution, until the condition stabili]es, or until the 
SarticiSant’s SarticiSation in the study ends, Zhichever is earlier Once resolved or stabili]ed, the 
aSSroSriate A(  SA( forms Zill be uSdated ParticiSants Zho have an onJoinJ study Sroduct
related A(SA( at study comSletion or at discontinuation from the study Zill be folloZed by the 
PI or his desiJnee until the event is resolved or determined to be irreversible, chronic, or stable by 
the PI The InvestiJator Zill ensure that folloZuS includes any suSSlemental investiJations as 
may be indicated to elucidate the nature and  or causality of the A( or SA( This may include 
additional laboratory tests or investiJations, histoSatholoJical e[aminations or consultation Zith 
other health care Srofessionals  
PATH may reTuest that the InvestiJator Serform or arranJe for the conduct of suSSlemental 
laboratory analysis and  or evaluations to elucidate as fully as Sossible the nature and or causality 
of the A( or SA( The InvestiJator is obliJed to comSly Zith this reTuest if Mustifiable Site 
InvestiJators Zill maNe sure that the reTuired diaJnostic tools eJ, ultrasound and surJical 
treatment for intussusceStion are readily available for the study SarticiSants under his Zatch If a 
SarticiSant dies durinJ the study Seriod or durinJ a recoJni]ed folloZuS Seriod, attemSts should 
be made to Srovide a coSy of any Sostmortem findinJs, includinJ histoSatholoJy The uSdated 
SA( form should be sent to the PSRT Zithin the time frames outlined in section 82 
The outcome of adverse event Zill be assessed as at the time of last observation as Ser the folloZinJ 
cateJories:  
x 
Recoveredresolved Zithout seTuelae  
x 
Recoveredresolved Zith seTuelae 
x 
OnJoinJ at the end of the study 
x 
Stabili]ed 
x 
Death 
x 
UnNnoZn  The outcome of the A( is not NnoZn 

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.5 
*eneral *uidance on Recording Adverse (vents  
To imSrove the Tuality and Srecision of acTuired A( data, the PI should observe the folloZinJ 
Juidelines: 
x All A(s and SA(s Zill be recorded in the source document and eCR) for all SarticiSants 
throuJhout the study SarticiSation  
x A solicited symStom reSorted durinJ the solicitation Seriod as a SA( should be recorded on 
the PIDC and SA( forms  
x :henever Sossible, use recoJni]ed medical terms Zhen recordinJ A(s on the A( CR)  Do 
not use colloTuialisms andor abbreviations 
x If NnoZn, record the diaJnosis ie, disease or syndrome rather than comSonent siJns, 
symStoms and laboratory values eJ, record conJestive heart failure rather than dysSnea, 
rales, and cyanosis  HoZever, siJns and symStoms that are considered unrelated to an 
encountered syndrome or disease should be recorded as individual A(s eJ, if conJestive 
heart failure and severe headache are observed at the same time, each event should be recorded 
as an individual A( 
x A(s occurrinJ secondary to other events eJ, seTuelae should be identified by the Srimary 
cause A ³Srimary´ A(, if clearly identifiable, Jenerally reSresents the most accurate clinical 
term to record  If a Srimary serious A( SA( is recorded, events occurrinJ secondary to the 
Srimary event should be described in the narrative descriStion of the case 
 
 
)or e[amSle: 
            Acute *astroenteritiso   Diarrheao   NaSSy Rash   
 
 
The Srimary A( here is acute Jastroenteritis 
x Death is an outcome of an event  The event that resulted in the death should be recorded and 
reSorted on the SA( CR) 
x )or hosSitali]ations for surJical or diaJnostic Srocedures, the illness leadinJ to the surJical or 
diaJnostic Srocedure should be recorded as the SA(, not the Srocedure itself  The Srocedure 
should be caStured in the case narrative as Sart of the action taNen in resSonse to the illness 
x :hile no routine safety laboratories Zill be Serformed under this Srotocol, any abnormal 
laboratory findinJs eJ, clinical chemistry, hematoloJy or other abnormal assessments eJ, 
electrocardioJram, vital siJns that the study team may be aZare of are not Ser se reSorted as 
A(s HoZever, abnormal findinJs that are deemed clinically siJnificant or are associated Zith 
siJns and  or symStoms must be recorded as A(s if they meet the definition of an A( and 
recorded as a SA( if they meet the criteria of beinJ serious as described Sreviously Clinically 
siJnificant abnormal laboratory or other abnormal findinJs that are detected after study druJ 
administration or that are Sresent at baseline and Zorsen folloZinJ the administration of study 
druJ are included as A(s and SA(s if serious The InvestiJator should e[ercise his or her 
medical MudJment in decidinJ Zhether an abnormal laboratory findinJ or other abnormal 
assessment is clinically siJnificant Usually, the abnormality should be associated Zith a 
clinically evident siJn or symStom, or be liNely to result in an evident siJn or symStom in the 
near term, to be considered clinically siJnificant 

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.6 
Reporting of SA( 
.6. Investigator Reporting to Sponsor 
:ithin 2 hours of an investiJator’s aZareness of a SA( as defined in the Srotocol, a SA( form 
must be comSleted and submitted to PATH and SSonsor as Ser reSortinJ reTuirement An SOP 
Zill be develoSed to include the contact details of PATH and CIDRZ and Zill contain sSecific 
details of the Srocess includinJ timelines  
The investiJator must not Zait to collect additional information to fully document the event before 
submittinJ the SA( form :hen additional information become available folloZuS submission 
must be comSleted  The initial SA( form should be comSleted Zith all information NnoZn at the 
time and should include as much information as Sossible on the folloZinJ: 
x 
Name and contact of the investiJator submittinJ the A(SA( reSort 
x 
ParticiSant ID number  
x 
Date SarticiSant received study vaccines, includinJ cohort JrouS if aSSlicable     
x 
DescriStion of the serious adverse event and date of event onset 
x 
InvestiJator’s assessment of severity, causality and e[Sectedness  
x 
Action taNen and current status 
x 
If available, any diaJnostic test reSorts or hosSital records that may helS the PATH to evaluate 
the SA(  
The investiJator Zill be resSonsible for notifyinJ UNZABR(C and :IRB throuJh PATH as Ser 
the resSective (CIRB’s reSortinJ reTuirement  
The sSonsor and PATH must be notified, Zithin 15 calendar days after first NnoZledJe by the 
investiJator, Zhen there is a suJJestion of a chanJe in the nature, severity or freTuency of e[Sected 
adverse druJ reactions or Zhen neZ risN factors are identified The basis on Zhich these 
assessments are made should be included An SOP Zill be develoSed to include sSecific details of 
resSonsibilities of the Sersonnel, Srocess and timelines 
.6. Notification and Review of SA(s 
The Medical monitor PATH is resSonsible for evaluatinJ SA(s submitted by the investiJator 
and for notifyinJ the Srotocol safety revieZ team PSRT Zithin 2 hours to convene an e[Sedited 
PSRT revieZ if any criteria outlined in section 2 or 3 is met  The PSRT Zill be resSonsible 
for revieZinJ adeTuacy of information and Tuery investiJator team to suSSlement information or 
act as a consultant if reTuired on treatment aSSroach The medical monitor must also indicate 
Zhether heshe concurs Zith the details of the reSort Srovided by the site PI The medical monitor 
Zill also be resSonsible for conductinJ the e[Sectedness analysis of the SA( and inform the team 
on the reSortinJ reTuirement for ZAMRA Medical monitor from PATH servinJ as technical 
consultants Zill Srovide technical Juidance reJardinJ SA( manaJement includinJ classification 
and reSortinJ 

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.6. Sponsor Reporting to Regulatory Agency 
The SSonsor Zill be resSonsible for safety reSortinJ to the aSSroSriate reJulatory authorities Zithin 
the sSecified time Seriod of notification  
x 
All fatal and lifethreateninJ, serious, une[Sected adverse druJ reactions should be reSorted 
Zithin  calendar days after first NnoZledJe by the aSSlicant The initial notification must be 
folloZed by as comSlete a reSort as Sossible, Zithin an additional 8 calendar days  
x 
Serious, une[Sected adverse druJ reactions that are not fatal or lifethreateninJ must be 
reSorted as soon as Sossible, and not later than 15 calendar days after first NnoZledJe by the 
aSSlicant 
x 
Adverse druJ reaction that are serious and already NnoZn described in InvestiJator’s 
Brochure or the Summary of Product characteristics SPCPrescribinJ Information there Zill 
be no fi[ed time limit set These cases Zill be reSorted as soon as the necessary information 
is available 
x 
Any information, that may in any Zay influence the benefitrisN assessment of a medicine or 
that Zould be sufficient to consider chanJes in the administration of the medicine or in the 
overall conduct of a clinical trial, must be reSorted to the PSRT The aSSlicant must submit 
this information to the PSRT Zithin three calendar days of first NnoZledJe by the aSSlicant 
 
SAF(T< OV(RSI*HT 
)or this study, a diliJent mechanism for revieZ of safety of the SarticiSants Zill be created  It Zill 
ensure safety oversiJht by the site PI and Protocol Safety RevieZ Team PSRT Zith the Srovision 
of e[Sedited revieZ by the team in case hiJh Jrade A(s are reSorted The study also has Srovisions 
for referrinJ to infectious disease sSecialists in case a consultation is recommended by the PSRT   
. 
Routine Reviews by Principal Investigator  
The study site InvestiJators Zill be resSonsible for continuous close safety monitorinJ of all study 
SarticiSants, and for alertinJ the Srotocol team if concerns arise or if criteria for e[Sedited revieZ 
of safety data are met  
. 
Routine Reviews by Protocol Safety Review Team (PSRT) 
An internal team, the PSRT, Zill be established to e[amine safety at Seriodic intervals The 
Protocol Safety RevieZ Team PSRT, a JrouS of Shysicians Zhich includes the SrinciSal 
investiJator, other Shysicians from the site and the medical officers from PATH Zill routinely 
monitor safety throuJhout the duration of the trial The PSRT Zill be chaired by a PATH Medical 
Officer and may seeN additional indeSendent e[Sert medical oSinion as dictated by needs The 
CRO statistician Zith assistance from the data manaJement staff Zill SreSare safety reSorts for 
revieZ by the PSRT  These reSorts Zill Srovide at a minimum the folloZinJ information:  1 
accrual and SarticiSant status data Zith reJard to comSletion of study vaccinations and study visits 
and 2 summaries of solicited and unsolicited adverse events durinJ the revieZ Seriod 3 ReSorted 
SA(s 
The PSRT safety revieZ Zill be conducted by teleconference occurrinJ aSSro[imately fortniJhtly 
to monthly deSendinJ on rate of enrolment durinJ the vaccination Shase of the study and as 

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needed thereafter for the remainder of the study  An e[Sedited safety revieZ Zill be carried out 
Zithin 36 hours of submission of the safety information for the safety events listed beloZ:  
(vent and relationshiS to study aJent  
Severity *rade  
SA(, related  
All Jrades  
A case of IntussusceStion 
All Jrades 
Unsolicited A(, related  
 and above 
 As assessed by investiJator or Medical Monitor 
The assiJned medical monitorofficer Zill be resSonsible for informinJ the other members and 
conveninJ the meetinJ The PSRT may seeN indeSendent e[Sert medical oSinion as dictated by 
the occurrence of certain events  
In addition to safety revieZ, the PSRT may elect to discuss trial conduct issues that imSact study 
inteJrity and SarticiSant safety  These may include but not limited to data Tuality, critical 
monitorinJ findinJs, study Sroduct, research sSecimens, etc  The PI or medical monitor Zill also 
notify the PSRT for ad hoc safety revieZs Zhenever it is aZare of SA( or adverse events that meet 
SresSecified study Sause criteria as Ser Section 3 
The reSorts and their analysis by the PSRT Zill be submitted to the various (CsIRBs, if needed 
The Terms of Reference for the PSRT Zill be develoSed as an SOP 
. 
Study Pause Rule 
This study has no formal Sause rules HoZever, if durinJ the e[Sedited safety revieZs, the PSRT 
identifies safety concerns that Zarrant a safety Sause, the PSRT Zill notify the SSonsor, PATH 
and BBIL ([amSles of safety concerns Zhich may be considered but may not necessarily triJJer 
automatic Sause include: 
x 
TZo or more SarticiSants e[Serience the same related serious adverse event over a Seriod of 
tZo ZeeNs 
x 
TZo or more SarticiSants e[SeriencinJ a Jrade  solicited systemic adverse event over a 
Seriod of tZo ZeeNs 
x 
TZo or more SarticiSants Zith the same severe Jrade 3 solicited systemic adverse event or 
laboratory abnormality, Zithin seven days 
x 
Any case of intussusceStion Zith DiaJnostic Certainty Level 1 as Ser BriJhton Collaboration 
IntussusceStion :orNinJ *rouS Zithin 30 days of vaccination 
BriJhton collaboration definition of Diagnostic Certainty Level of intussusceStion 
 SurJical criteria: The demonstration of invaJination of the intestine at surJery 
andor  
 RadioloJic criteria: The demonstration of invaJination of the intestine by either air or liTuid contrast enema or the 
demonstration of an intraabdominal mass by ultrasound Zith tarJet siJn or douJhnut siJn on transverses section and 
a SseudoNidney or sandZich siJn on lonJitudinal section that is Sroven to be reduced by hydrostatic enema on Sost 
reduction ultrasound 
andor  AutoSsy criteria: the demonstration of invaJination of the intestine at autoSsy 
Based on the criteria if a decision is made to Sause the study, all enrollment and further 
vaccinations Zill be Saused, SendinJ consultation Zith indeSendent infectious disease e[Sert, (C 
and ZAMRA  

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PATHCIDRZ retains the riJht to temSorarily susSend or Srematurely discontinue this study at 
any time related to safety If the study is stoSSed or susSended Srematurely, the sSonsor CIDRZ 
Zill inform the (C and ZAMRA about the decision and the reasons for termination or susSension 
If such action is taNen, all efforts must be made to ensure the safety of the SarticiSants enrolled in 
the study In case of Sremature study or study clinic closure, the monitor Zill conduct all activities 
as indicated in the close out monitorinJ visit   
. 
Study Pause Procedure 
At scheduled study revieZ, the PSRT may also identify adverse events that could Sotentially 
Tualify as Sause criteria 
If the PI or desiJnee, the medical monitor or any other member of the PSRT identifies and 
SroSose the study be Saused on a discretionary basis, all vaccinations and enrollment Zill be 
susSended The PSRT revieZs Zill be summari]ed Zith consensus recommendations to the study 
SSonsor as to Zhether there are safety concerns and Zhether the study should continue Zithout 
chanJe, be modified, or be stoSSed 
If at any time, a decision is made to discontinue administration of study Sroduct in all SarticiSants, 
e[Seditious notification Zill be Srovided by the SSonsor to the ZAMRA and the (C Zithin 8 
hours 
If the SSonsor restarts the study after PSRT revieZ and recommendation, enrollment and 
vaccination may resume   
0 DATA HANDLIN* AND R(CORD.((PIN* 
The PrinciSal InvestiJator is resSonsible for assurinJ that the data collected are comSlete, leJible, 
attributable, accurate, and recorded in a timely manner Data collection is the resSonsibility of the 
clinical trial staff at the site under the suServision of the site PI  HardcoSies of the study visit 
ZorNsheets Zill be Srovided for use as source document ZorNsheets for recordinJ data for each 
SarticiSant enrolled in the study  Data recorded in the eCR) should be consistent Zith source 
documents, and a Tuality control Slan Zill be Sut in Slace to ensure the same All source documents 
includinJ laboratory reSorts must be revieZed by the clinical team and data entry staff, Zho Zill 
ensure that they are accurate and comSlete  Adverse events must be Jraded, assessed for severity 
and causality, and revieZed by the site PI or desiJnee 
The Data ManaJement CRO DMC is resSonsible for data manaJement activities, includinJ 
settinJ uS the data base, allocation of access to various teams Zith aSSroSriate access authority 
levels, Tuality revieZ, analysis, and reSortinJ of the study data accordinJ to SOPs 
The study site Zill maintain aSSroSriate medical and research records for this trial, in comSliance 
Zith ICH*CP, reJulatory, sSonsor and institutional reTuirements for the Srotection of 
confidentiality of SarticiSants 
0. 
Definitions 
0.. Source Data 
All information in oriJinal records and certified coSies of oriJinal records or clinical findinJs, 
observations, or other activities in a clinical trial necessary for the reconstruction and evaluation 

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of the trial Source data are contained in source documents oriJinal records or certified coSies  
ICH (6 section 151, 
0.. Source Documents 
)or this study source documents Zould include but are not limited to: 
x 
Documentation of the study eliJibility evaluation 
x 
SiJned Informed Consent Documents 
x 
Visit documentation that includes dates of study visits and dates of study vaccinations  
x 
ReSorted laboratory results 
x 
A( evaluations  
x 
Concomitant medications  
x 
Post Immuni]ation Diary Card PIDC 
x 
Certified coSies of hosSital records 
x 
Study visit ZorNsheets   
0. 
Data Capture Methods (Case Report Form Development and Completion) 
The clinical data in source documents Zill be continuously entered directly into a 21 C)R Part 11
comSliant (lectronic Data CaSture (DC system by trained and Tualified study staff  The eCR) 
for the (DC system Zill be develoSed by the Data ManaJement CRO Zho Zill also Srovide 
traininJ in the use of the system :rite access to the system Zill be limited to authori]ed 
InvestiJators  subInvestiJators  study staff and the system Zill automatically NeeS an audit trail 
of all entries and corrections in the eCR) Read access to the SarticiSant data Zill be restricted to 
authori]ed staff ZorNinJ Zithin the SroMect team The data system includes internal Tuality checNs, 
such as automatic ranJe checNs, to identify data that aSSear inconsistent, incomSlete, or inaccurate  
Clinical data for each SarticiSant Zill be entered directly into the eCR) from the source documents 
It is the site PIs’ resSonsibility to ensure the accuracy, comSleteness, and timelines of the data 
reSorted in the SarticiSant’s eCR) and any suSSortinJ documentation All source documents 
should be comSleted in a neat, leJible manner to ensure accurate interSretation of data Source 
documentation suSSortinJ the eCR) data should document the dates and details of study 
Srocedures, A(s and SarticiSant status The study database Zill identify study SarticiSants only by 
a study identification number and Zill not contain any identifyinJ information such as name, 
address or Sersonal contact information, or any other reJional  state  national identification 
number The site PIsinstitutions Zill maintain all information in the eCR)s and all source 
documents that suSSort the data collected from each SarticiSant in a secure area and treated as 
confidential material The confidentiality of records that could identify SarticiSants must be 
Srotected, resSectinJ the Srivacy and confidentiality rules in accordance Zith the aSSlicable 
reJulatory reTuirements )or electronic CR)s, revieZ and aSSroval  siJnature is comSleted 
electronically throuJh the electronic data caSture tool (ach individual havinJ Zrite access to 
electronic CR)s must meet the PATH’s traininJ reTuirements and must only access the electronic 
data caSture tool usinJ the uniTue user account Srovided by the SSonsor User accounts are not to 
be shared or reassiJned to other individuals 

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The site PI Zill retain all essential documents and a CDROM coSy of the eCR) data after the 
study is closed and the Clinical Study ReSort is comSleted or at such time that the site no lonJer 
has access to the electronic data system 
0. 
Data Management 
The DMC resSonsible for data manaJement Zill develoS a Data ManaJement Plan DMP and 
corresSondinJ database comSliant Zith International Conference on Harmoni]ation ICH 
reTuirements for aSSroval by PATH before imSlementation  The Plan Zill describe roles of 
staNeholders and sSecific Srocedures to ensure aSSroSriate handlinJ of data at all steSs of the data 
manaJement Srocess to assure a valid and hiJhTuality database at the end of the study, ready for 
analysis 
(ntered data Zill be verified by an indeSendent monitorinJ CRO Zho Zill Tuery the site for 
Sotential discreSancies The site InvestiJator, or desiJnee, Zill be resSonsible for resolution of 
Tueries and aSSroSriate documented chanJes in the database DMC Zill Serform all activities as 
Ser their standard oSeratinJ Srocedures SOPs All study sSecific Srocesses Zill be described in 
the Data ManaJement Plan DMP CodinJ of medical history and adverse events Zill be 
Serformed usinJ MedDRA and codinJ of medications Zill be Serformed usinJ :HO DruJ 
Dictionary eCR)s and any suSSortinJ documentation should be available for retrieval or revieZ 
at any Jiven time 
The (lectronic Data CaSture System (DC Zill detect and flaJ univariate data discreSancies or 
inconsistencies to alert the InvestiJator  desiJnee and Srovide a satisfactory resolution Zithin the 
(DC The Data ManaJer shall revieZ all the discreSancies to ensure corrective and Sreventive 
actions In addition, the Medical RevieZers Zill also revieZ data for medical inconsistencies and 
Jenerate manual Tueries if reTuired or Tueries can be routed throuJh DMC folloZinJ medical 
revieZ After comSletion of data codinJ and resolution of all the Tueries in the database, the 
database Zill be declared as comSlete and accurate and Zill be locNed for final statistical analysis 
0. 
Retention of Study Records 
The site PIs are resSonsible for retaininJ study records until 5 years after the investiJation is 
discontinued or comSleted and the UNZABR(C, NHRA and ZAMRA is notified No records Zill 
be destroyed Zithout the Zritten consent of PATH PATH Zill inform the InvestiJator in ZritinJ 
of the need for record retention and Zill notify the InvestiJator in ZritinJ Zhen the trial related 
records are no lonJer needed 
These records are also to be maintained in comSliance Zith local (C and local authority medical 
records retention reTuirements, Zhichever is lonJest StoraJe of all trialrelated documents Zill be 
such that confidentiality Zill be strictly maintained to the e[tent reTuired by local laZ 
 STATISTICAL CONSID(RATIONS 
. 
Overview and *eneral Considerations  
An outline of the statistical analyses is described in the folloZinJ sections A formal statistical 
analysis Slan SAP that contains full details of all Slanned analyses Zill be created and finali]ed 
Srior to database locN All statistical analyses Zill be Serformed usinJ SAS® softZare version  
or later 

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Serum antirotavirus IJA antibody concentrations beloZ the loZest limit of Tuantitation LLO4 
ie, beloZ the startinJ dilution of assay recorded as ³ LLO4´ Zill be set to half that limit ie, 
LLO4  2 In case of that the concentration is above the uSSer limit of Tuantitation ULO4, an 
actual value reSorted Zill be used  
. 
Randomization Procedures 
Healthy infants Zill be randomi]ed to receive one of the three study vaccines in a 1:1:1 ratio )or 
vaccine allocation, a randomi]ation blocNinJ scheme Zill be used in order to ensure that balance 
betZeen vaccine JrouSs Zill be maintained Infants Zill be randomi]ed seTuentially in the order 
that they are enrolled The randomi]ation scheme that contains a SarticiSant identification number 
and the corresSondinJ randomi]ation assiJnment Zill be Jenerated usinJ comSuter softZare Srior 
to the initiation of the study and Srovided to the desiJnated site Sersonnel 
. 
Sample Size and Power 
The immunoJenicity of the study vaccines Zill be Srimarily assessed by Jeometric mean 
concentrations *MCs of serum antirotavirus IJA antibodies at 28 days after the last dose of the 
study vaccine, alonJ Zith its tZosided 5 confidence interval CI, by e[SonentiatinJ the 
corresSondinJ loJ10transformed mean and its tZosided 5 CI limits 
Table 2 beloZ Sresents the Srecision of the 5 CI of the *MC in loJ10transformed scale Ser 
JrouS under different assumStions of JrouS si]es and assumed standard deviation SD of loJ10
transformed antirotavirus IJA concentrations 
Table 2. The half width of a two-sided 95% CI of the GMC in log10-transformed scale based on 
various group sizes and assumed standard deviation (SD) of log10-transformed anti-rotavirus IgA 
concentrations 
Assumed 
SD 
of 
loJ10transformed 
antirotavirus 
IJA 
concentrations 
Number of evaluable SarticiSants Ser JrouS 
120 
5 
150 
050 
000 
0085 
0081 
055 
00 
00 
008 
0.60 
0108 
0.0 
00 
065 
011 
0111 
0105 
00 
012 
011 
0113 
:ith a samSle si]e of 150 for each JrouS and an assumed SD of loJ10transformed antirotavirus 
IJA concentrations of 060, the half Zidth of a tZosided 5 CI for antirotavirus IJA *MC Zill 
be 0102 in loJ10transformed scale for each JrouS, assuminJ a droSout rate of 10  
PoZer to shoZ that the ratio of antirotavirus IJA *MCs in ROTAVAC 5CM JrouS to that in 
ROTAVAC® JrouS is at least 05 Zas calculated usinJ tZosamSle ttest accordinJ to various 

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JrouS si]es, different assumed SDs of loJ10transferred antirotavirus IJA concentrations and eTual 
true underlyinJ Jeometric mean and is Srovided in Table 3 
Table 3. Power to show comparability of immune response in terms of GMCs for rotavirus-specific 
serum IgA antibody concentrations between ROTAVAC 5CM and ROTAVAC® groups, based on 
various group sizes, different assumed SD of log10 anti-rotavirus IgA concentrations, and equal 
true geometric mean 
Assumed SD of log0 
anti-rotavirus 
IgA 
concentrations 
Number of evaluable 
participants 
per 
group 
Power to demonstrate that the lower limit 
of 5 CI of the ratio of *MC between 
groups is !  
050 
120 vs 120 
! 
135 vs 135 
! 
150 vs 150 
! 
055 
120 vs 120 
 
135 vs 135 
 
150 vs 150 
! 
0.60 
120 vs 120 
 
5 vs. 5 
 
150 vs 150 
 
065 
120 vs 120 
5 
135 vs 135 
 
150 vs 150 
8 
00 
120 vs 120 
1 
135 vs 135 
 
150 vs 150 
6 
AssuminJ the true standard deviation of loJ10transformed antirotavirus IJA concentration is 
beloZ than or eTual to 060, Zith a samSle si]e of 150 and a droSout rate of 10 Ser JrouS 135 
evaluable SarticiSants Ser JrouS, the study has SoZer of 8 to detect at least 05 of *MC ratio 
betZeen ROTAVAC®5CM and ROTAVAC® JrouSs  
:ith 150 infants vaccinated Ser JrouS, this study desiJn alloZs a Jreater than 0 chance of 
observinJ at least one A( if true incidence is 153 Conversely, if no A(s are observed in 150 
vaccine reciSients, the study Zill be able to rule out A(s occurrinJ at a rate of aSSro[imately 25 
or above based on the uSSer bound of the tZosided 5 CI  
. 
Analysis Populations 
.. (nrolled Population  
The enrolled SoSulation is defined as all screened SarticiSants Zho Srovide informed consent and 
are eliJible for study SarticiSation, reJardless of the SarticiSant’s randomi]ation and treatment 
status in the study 
.. Full Analysis population  
The full analysis SoSulation is defined as all SarticiSants in the enrolled SoSulation Zho Zere 
randomi]ed, received a study vaccination, and Srovided at least one evaluable serum samSle The 

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analysis based on this SoSulation Zill serve as suSSortive results for all immunoJenicity 
obMectives 
ParticiSants in the )ull Analysis )A SoSulation Zill be analy]ed ³as randomi]ed´, ie accordinJ 
the vaccine a SarticiSant Zas desiJnated to receive, Zhich may be different from the vaccine that 
the SarticiSant actually received 
.. Per Protocol population  
The SerSrotocol SoSulation is defined as all SarticiSants in the )A SoSulation Zho correctly 
received study vaccine Ser randomi]ation Zith no maMor Srotocol deviations that are determined 
to Sotentially interfere Zith the immunoJenicity assessment of the study vaccines This SoSulation 
Zill serve as the Srimary analysis SoSulation for all immunoJenicity obMectives 
Due to unSredictability of some irreJularities, the criteria for e[clusion of SarticiSants from the 
Per Protocol PP SoSulation Zill be determined before the database is locNed 
.. Safety population  
The safety SoSulation is defined as all SarticiSants in the enrolled SoSulation Zho received a study 
vaccination and had any safety data available ParticiSants in the safety SoSulation Zill be analy]ed 
as ³treated´, ie accordinJ to the actual vaccine received at the first dose All safety analyses Zill 
be Serformed usinJ this SoSulation The denominators for different safety endSoints may vary 
accordinJ to the number of SarticiSants Zith available data for the sSecific endSoint )or instance, 
the solicited systemic adverse event endSoints Zill be based only on those Zho have the 
corresSondinJ CR) data reJardless of other safety folloZuS data  
.5 
Analytical Methodology 
.5. Analysis of demographics and other baseline characteristics 
DemoJraShic and baseline characteristics aJe, ethnicity, se[, lenJth, and ZeiJht Zill be tabulated 
by vaccine JrouS on the )A SoSulation If more than 10 of the )A SoSulation is e[cluded from 
the PP SoSulation, the descriStion and comSarability of the vaccine JrouSs at baseline Zill be 
reSeated on the PP SoSulation 
Continuous variables, such as aJe, lenJth, and ZeiJht, Zill be described as number of SarticiSants, 
mean, standard deviation SD, minimum, median, and ma[imum CateJorical variables, such as 
ethnicity and se[, Zill be described by number of SarticiSants and SercentaJe for each vaccine 
JrouS *rouS comSarison Zill be Serformed to confirm Zhether the vaccine JrouSs are similar 
Zith reJard to demoJraShic and baseline characteristics, usinJ ANOVA or )isher’s e[act test as 
aSSroSriate 
Medical history Zill be tabulated by Medical Dictionary for ReJulatory Activities MedDRA 
system orJan class SOC and Sreferred term for each vaccine JrouS Medications taNen uS to 1 
month Srior to enrolment Zill be summari]ed by anatomical theraSeutic chemical ATC 
classification and Sreferred druJ name coded by :HO DruJ Dictionary :HO DD for each 
vaccine JrouS 

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.5. Analysis of primary obMective 
The *MCs of serum antirotavirus IJA antibodies at 28 days after the last dose of ROTAVAC® 
or ROTAVAC 5CM Zill be calculated alonJ Zith its tZosided 5 CI, by e[SonentiatinJ the 
corresSondinJ loJ10transformed mean and its tZosided 5 CI limits 
To comSare the immunoJenicity of ROTAVAC® and ROTAVAC 5CM at 28 days folloZinJ the 
last dose of the study vaccine, the folloZinJ hySothesis Zill be tested, 
H0: *MCROTAVAC 5CM  *MCROTAVAC®  ò 
H1: *MCROTAVAC 5CM  *MCROTAVAC® ! ò 
The test Zill be done at 28 days folloZinJ the last dose of ROTAVAC 5CM and ROTAVAC® and 
Zill be conducted Zith onesided Zith a tySe I error rate of 0025 The ratio of the Sostvaccination 
antirotavirus IJA *MCs betZeen the ROTAVAC 5CM and ROTAVAC® JrouSs Zill be Srovided 
Zith its tZosided 5 CI The loJ10transformed antirotavirus IJA concentrations Zill be used 
to construct a tZosided 5 CI for the mean difference betZeen the tZo study JrouSs usinJ t
distribution The mean difference and corresSondinJ 5 CI limits Zill be e[Sonentiated to obtain 
the *MC ratio and the corresSondinJ 5 CI If the loZer limit of the 5 CI of the ratio of 
*MCs betZeen the ROTAVAC 5CM and ROTAVAC® JrouSs is larJer than 12, ROTAVAC 
5CM is considered to be noninferior to ROTAVAC® 
The comSarison of the *MCs betZeen the tZo study vaccines Zill be also Serformed usinJ 
analysis of covariance ANCOVA method Zith loJ10transformed antirotavirus IJA 
concentrations as the deSendent variable, the vaccine JrouS as the e[Slanatory variable, and loJ10
transformed baseline concentrations as a covariate This adMusted analysis Zill be considered as 
suSSortive 
The SercentaJe of SarticiSants Zith seroconversion, seroSositivity, and seroresSonse Zill be 
comSuted for the ROTAVAC 5CM and ROTAVAC® JrouSs alonJ Zith e[act tZosided 5 CIs 
based on CloSSerPearson method The difference in the SercentaJe betZeen the tZo JrouSs Zill 
be Srovided alonJ Zith its tZosided 5 CI obtained by Miettinen and Nurminen method  
The *eometric Mean )old Rise *M)R *MC Sost vaccination  *MC at baseline Zill be 
Srovided Zith its tZosided 5 CIs, by e[SonentiatinJ the difference in means of loJ10
transformed antirotavirus IJA concentrations betZeen Sost vaccination and baseline and its tZo
sided 5 CI that Zill be obtained by Saired ttest method 
In addition, a reverse cumulative distribution RCD curve Zill be created by vaccine JrouS and 
visit 
.5. Analysis of secondary obMectives 
.5.. Analysis of secondary safety obMective  
The SercentaJe of SarticiSants Zith safety endSoints alonJ Zith its e[act tZo sided 5 CI based 
on CloSSerPearson method  Zill be Srovided for each vaccine JrouS 
Reactogenicity: 

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The number and SercentaJe of SarticiSants e[SeriencinJ immediate adverse events Zithin 30 
minutes Sost each vaccination and solicited Sostvaccination reactoJenicity fever, diarrhea, 
vomitinJ, decreased aSSetite, irritability, decreased activity level durinJ the day Seriod after 
each vaccine Zill be tabulated by vaccine JrouS and severity )or the SercentaJe, an e[act tZo
sided 5 CI Zill be Srovided usinJ CloSSerPearson method  
8nsolicited A(s: 
The number and SercentaJe of SarticiSants e[SeriencinJ immediate adverse events Zithin 30 
minutes, unsolicited A(s and SA(s includinJ intussusceStion reSorted throuJh  ZeeNs after the 
last vaccination Zill be Srovided by vaccine JrouS, severity, and causality )or the SercentaJe, an 
e[act tZosided 5 CI Zill be Srovided usinJ CloSSerPearson method  
The oriJinal verbatim terms used by investiJators to identify adverse events on case reSort forms 
CR)s Zill be coded accordinJ to MedDRA dictionary A(s includinJ SA(s Zill be summari]ed 
and classified by SOC and Sreferred term of the MedDRA dictionary They Zill be disSlayed by 
vaccine JrouS as both freTuencies and SercentaJes 
The analysis of unsolicited adverse events comSrises the folloZinJ cateJories: 
x 
Any unsolicited A(s 
x 
Related unsolicited A(s 
x 
SA(s 
x 
Related SA(s 
x 
Unsolicited A(s leadinJ to ZithdraZal from the study 
x 
Unsolicited A(s leadinJ to ZithdraZal from study vaccination but remaininJ in the study 
x 
Unsolicited A(s leadinJ to hosSitali]ation 
x 
Any A(s leadinJ to death 
All reSorted A(s that start after vaccination Zill be tabulated If a Jiven disease is already reSorted 
as onJoinJ at the first visit on the medical history SaJes, it Zill be counted and tabulated as a 
vaccine emerJent adverse event only if it Zorsens after the immuni]ation Zith the study vaccine 
:hen an adverse event occurs more than once for a SarticiSant, the ma[imal severity and stronJest 
relationshiS to the vaccine JrouS Zill be counted    
SA(s and discontinuation due to A(s Zill be described in detail by vaccine JrouS 
Data listinJs of all adverse events Zill be Srovided by SarticiSant 
 
The medications taNen durinJ study Seriod Zill be coded usinJ :HO DD The concomitant 
medications tZill be tabulated by ATC classification and Sreferred druJ name of :HO DD for 
each vaccine JrouS 

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.5.. Analysis of secondary immunogenicity obMective 
The immunoJenicity analysis for Rotari[® Zill be descriStive The *MC and *M)R Zill be 
comSuted for the Rotari[® JrouS alonJ Zith its tZosided 5 CI usinJ the same methods outlined 
in Section 1152 The SercentaJe of SarticiSants Zith seroconversion, seroSositivity, and 
seroresSonse Zill be Srovided for the Rotari[® JrouS alonJ Zith its e[act tZosided 5 CI usinJ 
CloSSerPearson method 
A reverse cumulative distribution RCD curve Zill be created for Rotari[® JrouS by visit 
.5. Analysis of exploratory obMective 
The e[Sloratory analysis conducted on immune resSonse measured by (LISA usinJ 812 *1P8 
virus as a substrate in a subset of the samSles collected 50 Ser JrouS Zill be descriStive *MCs 
of serum antirotavirus IJA antibodies usinJ 812 virus as a substrate Zill be calculated for each 
JrouS alonJ Zith its tZosided 5 CI, by e[SonentiatinJ the corresSondinJ loJ10transformed 
mean and its tZosided 5 CI limits 
The SercentaJe of SarticiSants Zith seroconversion and seroSositivity Zill be Srovided for each 
JrouS alonJ Zith its e[act tZosided 5 CI usinJ CloSSerPearson method 
*M)R Zill be Srovided Zith its tZosided 5 CIs, by e[SonentiatinJ the difference in means of 
loJ10transformed antirotavirus IJA concentrations usinJ 812 virus as a substrate betZeen Sost 
vaccination and baseline and its tZosided 5 CI that Zill be obtained by Saired ttest method 
.5.5 Multiplicity 
No multiSlicity adMustment Zill be carried out as ROTAVAC 5CM and ROTAVAC® Zill be 
Srimarily comSared based on a sinJle Srimary endSoint 
.5.6 Handling of Dropouts and Missing Data 
MissinJ immunoJenicity data Zill not be imSuted and Zill be analy]ed as if they Zere missinJ 
randomly 
Over the Zhole study Seriod, the number and SercentaJe of SarticiSants Zho ZithdraZ from the 
study Zill be Srovided by treatment JrouS All ZithdraZn SarticiSants Sostrandomi]ation Zill be 
further described reJardinJ their time to droSout and their reasons for ZithdraZal )or SarticiSants 
Zho ZithdraZ from the study, their data collected before ZithdraZal Zill be analy]ed under full 
analysis )A SoSulation and safety SoSulation as aSSlicable 
.6 
Analysis SeTuence 
No interim analysis is Slanned for this study A final analysis on all safety and immunoJenicity 
data Zill be Serformed after the study ends and database is cleaned and locNed  
  48ALIT< ASS8RANC( AND 48ALIT< CONTROL 
*uidance on internal and e[ternal Srocesses to assure effective Srotocol imSlementation, Tuality 
of the research conducted and comSliance Zith sSonsorPATH’s and aSSlicable reJulatory 
reTuirements 

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. 
*eneral Considerations 
The study Zill be conducted in full comSliance Zith the Srotocol and ICH *CP to Srovide Sublic 
assurance that the riJhts, safety, and ZellbeinJ of trial SarticiSants are Srotected, and that the 
clinical trial data are credible To ensure Tuality and standardi]ation, the site Zill develoS Standard 
OSeration Procedures SOPs for Ney Srotocol Srocedures and conduct the study Juided by the 
study Manual of Procedures or other Zritten Juidelines The site Zill also develoS routine 
oSerational checNs to verify that critical Srotocol reTuirements and Srocedures are e[ecuted 
correctly and comSletely at the time the ZorN is beinJ Serformed  Prior to the initiation of the 
study, PATH and  or the CRO deleJated by PATH Zill conduct Srotocol traininJ, includinJ 
aSSlicable SOPs, for study staff 
The investiJational site Zill Srovide direct access to all trialrelated site, source datadocuments, 
and reSorts for the SurSose of monitorinJ and auditinJ by the PATHdesiJnee, and insSection by 
local IRB(C and reJulatory authorities 
. 
(xternal Monitoring 
PATHdesiJnee is resSonsible for ensurinJ that the study is conducted in accordance Zith ICH 
*CP and reJulatory reTuirements  )or this SurSose, monitors under contract from PATH Zill 
Srovide e[ternal monitorinJ for this study  A site initiation visit Zill be conducted Srior to 
beJinninJ the study, and monitorinJ Zill be conducted at initiation, durinJ, and at closeout of the 
study  DurinJ the course of the study monitors Zill visit the clinical site at intervals to verify 
comSliance to the Srotocol comSleteness, accuracy, and consistency of the data and study Sroduct 
accountability adherence to ICH *CP and aSSlicable reJulations  As needed and Zhen 
aSSroSriate, the monitors Zill also Srovide clarifications, additional traininJ to helS the site resolve 
issues identified durinJ the monitorinJ visit  As aSSroSriate and informed by risN assessment, 
remote centrali]ed monitorinJ activities may be considered in Slace of or to suSSlement onsite 
monitorinJ  These may include analysis of data Tuality eJ missinJ or inconsistent data, outlier 
data, identify data trend not easily detected by onsite monitorinJ and Serformance metrics eJ, 
screeninJ or ZithdraZal rates, eliJibility violations, timeliness and accuracy of data submission  
The e[tent and freTuencies of the monitorinJ visits Zill be described in a seSarate Study 
MonitorinJ Plan develoSed Srior to study initiation  The investiJator Zill be notified in advance 
of the scheduled monitorinJ visit  The monitor should have access to all trial related locations, 
SarticiSant medical records, study Sroduct accountability and other studyrelated records needed 
to conduct monitorinJ activities The PATHdesiJnee Zill share the findinJs of the monitorinJ 
visit, includinJ any corrective actions, Zith the site investiJator The site PI and the monitor must 
aJree to cooSerate to ensure that any Sroblems detected in the course of these monitorinJ visits are 
resolved in a Sredefined timeframe  
. 
Independent Auditing 
PATH or its desiJnee may audit the study to ensure that study Srocedures and data collected 
comSly Zith the Srotocol and aSSlicable SOPs at the clinical site and that data are correct and 
comSlete The site PI Zill Sermit auditors emSloyees of the PATH or emSloyee of a comSany 
desiJnated by the PATH to verify source data validation of the reJularly monitored clinical study 
The auditors Zill comSare the entries in the eCR)s Zith the source data and evaluate the study site 

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for its adherence to the clinical study Srotocol and *CP Juidelines and aSSlicable reJulatory 
reTuirements 
. 
Regulatory Agency Inspection 
The site PI must be aZare that reJulatory authorities, includinJ (CIRB may Zish to insSect the 
site to verify the validity and inteJrity of the study data and Srotection of human research 
SarticiSants  The site PI Zill notify the SSonsor, and PATH Zithin 2 hours folloZinJ contact by 
a reJulatory authority The site PI must maNe the relevant records available for insSection and Zill 
be available to resSond to reasonable reTuests and audit Tueries made by authori]ed reSresentatives 
of reJulatory aJencies The site PI Zill Srovide the SSonsor and PATH Zith coSies of all 
corresSondence that may affect the revieZ of the current study or his Tualification as an 
investiJator in clinical studies DurinJ the audits or insSections, the SarticiSant’s confidentiality 
Zill be maintained at all times to the e[tent Sermitted by the laZ Site visit loJs Zill be maintained 
at the study site to document all visits PATH Zill Srovide any needed assistance in resSondinJ to 
reJulatory audits or corresSondence 
 (THICAL CONSID(RATIONS (AND INFORM(D CONS(NT) 
. 
(thical Standards 
This study Zill be conducted in accordance Zith the ethical SrinciSles set forth in the :orld 
Medical Association Declaration of HelsinNi  The Council for International OrJani]ations of 
Medical Sciences CIOMS International (thical *uidelines for Biomedical Research InvolvinJ 
Human ParticiSant and in conformity Zith ICH *CP and ³*uidelines on ReJulatinJ the Conduct 
of Clinical Trial in Human ParticiSants´ as set forth by Zambia Medicines ReJulatory Authority 
ZAMRA 
NB The Declaration of HelsinNi Srovides detail on Zhat must be included in a Srotocol: fundinJ, 
sSonsorshiS, affiliations and Sotential conflicts of interest, incentives to SarticiSate, comSensation 
for harm and Sosttrial access to druJs and care 
International (thical *uidelines for Biomedical Research InvolvinJ Human Trial SarticiSants 
CIOMS 2002 also Srovides Juidance on ethical reTuirements  
. 
(thical Review 
This study Zill be conducted under the ausSices of the University of Zambia Biomedical Research 
(thics Committee In addition, the study Zill also be revieZed by :estern Institutional RevieZ 
Board and an aSSroval Zould be reTuired before initiation of enrolment 
These committees Zill revieZ and aSSrove the Srotocol, informed consent form, and any 
recruitment materials advertisinJ or informational material includinJ any modifications to these 
documents Srior to, or durinJ the study  All chanJes to the Srotocol or informed consent form 
must be revieZed and aSSroved by the I(C, :IRB and PATH Srior to imSlementation, e[ceSt 
Zhere necessary to eliminate aSSarent immediate ha]ard to study SarticiSants  The investiJator is 
also resSonsible for obtaininJ continuinJ revieZ throuJhout the duration of the study in accordance 
Zith e[istinJ reJulations The site Zill be resSonsible for submittinJ to and obtaininJ initial and 
subseTuent annualbiannual revieZ aSSroval from the UNZABR(C, NHRA and ZAMRA as 
aSSlicable  

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. 
Informed Consent Process 
(liJible Sarent those above the aJe of 18 years ie leJal aJe for consentinJ in ZambiaLAR of 
Sotential SarticiSants Zill tySically be aSSroached durinJ routine child immuni]ation clinics by 
study staff Zith Jeneral information about the study Those interested, Zill be invited to the 
Research Unit Zithin 20 meters of the clinic and Zill be offered further information about the 
study Motivated SarentsLAR Zill then be Srovided one on one study information in the local 
lanJuaJe of their choice They Zill be taNen over the aSSroved SarticiSant information sheet JoinJ 
throuJh details of Zhat the study is about, Zhat is reTuired to SarticiSate, Srocedures, benefits of 
SarticiSation and risNs involved, number of clinic visits reTuired etc  
The SarticiSant’s SarentLAR Zill be Jiven a coSy of the IC) and alloZed amSle time to read the 
consent form, encouraJed to asN Tuestions about the study, have the Tuestions ansZered and then 
be Jiven time to decide if she Zould liNe to have herhis child SarticiSate in the study It Zill be 
emShasi]ed that SarticiSation is voluntary, and that the SarticiSantSarent has the riJht to decline 
to SarticiSate or subseTuently ZithdraZ from the study at any time Zithout SreMudice 
A simSle comSrehension test Zill be administered at the end of the session ParticiSant’s 
SarentLAR scorinJ at least  out of 10 basic Tuestions Zill be deemed sufficiently informed, and 
those scorinJ less Zill be taNen throuJh the SarticiSant information aJain reSeat Zill be done only 
once until they are able to Sass the comSrehension test After this, the Sarent or aSSroSriate leJally 
acceStable reSresentative Zill be reTuired to siJn tZo oriJinals of the IC) one for the study file, 
and another for themselves to NeeS 
Those Zho are illiterate Zill reTuire an indeSendent Zitness of their choice to siJn attestinJ to the 
Srocess Zhile the SarentLAR Zill be reTuired to thumb Srint the form 
. 
Participant Confidentiality  
The investiJators, PATH and all staff from orJani]ations involved Zith the imSlementation of the 
trial must ensure that the SarticiSant’s confidentiality is maintained Personal identifiers Zill not 
be included in any study reSort  All study records Zill be NeSt confidential to the e[tent Srovided 
by national and local laZs  Medical records containinJ identifyinJ information may be made 
available for revieZ Zhen the study is monitored by the sSonsordesiJnee or an authori]ed 
reJulatory aJency  Direct access may include e[amininJ, analy]inJ, verifyinJ, and reSroducinJ 
any records and reSorts that are imSortant to the evaluation of the study 
:hen aSSroSriate and to the e[tent Sossible, study Srocedures Zill be conducted in Srivate to 
Srotect SarticiSant Srivacy and confidentiality   
All studyrelated information Zill be stored securely at the study site All SarticiSant information 
Zill be stored in locNed file cabinets in areas Zith access limited to study staff  Data collection, 
Srocess, and administrative forms, laboratory sSecimens, and other reSorts Zill be identified by a 
coded number only to maintain SarticiSant confidentiality  All records that contain names or other 
Sersonal identifiers, such as locator forms and informed consent forms, Zill be stored seSarately 
from study records identified by code number  All local databases Zill be secured Zith SassZord
Srotected access systems  )orms, lists, loJbooNs, aSSointment booNs, and any other listinJs that 
linN ParticiSant ID numbers to other identifyinJ information Zill be stored in a seSarate, locNed 
file in an area Zith limited access  ParticiSants’ study information Zill not be released Zithout 
their Zritten Sermission, e[ceSt as necessary for monitorinJ 

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.5 
Reimbursement 
ParticiSants Zill be comSensated for their time and effort in this study, and be reimbursed for travel 
to study visits There is no direct Sayment for SarticiSatinJ in this study HoZever, a 
reimbursement 
 has been 
SroSosed for aSSroval by the ethics committee This amount is e[Sected to be reasonably sufficient 
to comSensate for time, inconvenience and travel cost, and yet not too much to unduly induce them 
into SarticiSatinJ This information Zill be Srovided in the SarticiSant information sheet    
ParticiSantsSarents of study SarticiSants Zill not be charJed for study medication, research clinic 
visits, researchrelated e[aminations, or researchrelated laboratory tests 
.6 
RisN and %enefits 
%enefits to Study Participants  
Potential benefits to enrolled SarticiSants in the current trial could be Srotection from rotavirus 
Jastroenteritis, the identification of undetected medical conditions durinJ medical e[amination, 
education about rotavirus and diarrhea and its Srevention and treatment, education on Sersonal 
hyJiene and access to medical care for the SarticiSant for any illnesses occurrinJ durinJ the trial 
Seriod 
Potential RisNs  
Physical RisNs: The main risNs of this study are risNs of rotavirus vaccines to cause some side 
effects includinJ develoSment of fever, vomitinJ, diarrhea, couJh, runny nose, irritability and rash 
In babies, natural rotavirus infection can cause diarrhea, vomitinJ and fever It is Sossible that 
enrolled SarticiSants may have a feZ looser than usual stools, cry or have a sliJhtly hiJher than 
usual temSerature for a day or tZo after vaccination Zith the attenuated rotavirus vaccine These 
events are similar to those reSorted in other rotavirus vaccine clinical trials These Zill be e[Slained 
to Sarents in the consent form 
Serious or allerJic reactions also may be Sossible This risN is addressed by tryinJ to screen out 
any children Zith NnoZn allerJic reactions to vaccines in the Sast and Zho may have an allerJy to 
one of the comSonents of the vaccine Should an allerJic reaction occur Zith vaccination, the study 
clinic Zill folloZ its SOP for handlinJ medical emerJencies and have suSSortive medicines in 
Slace, in addition to trained staff  
PostmarNetinJ studies suJJest that intussusceStion may be associated Zith the licensed rotavirus 
vaccines at a loZ rate Zith an attributable risN for intussusceStion of the rotavirus vaccine betZeen 
1 Ser 100,000 vaccinated infants The huJe benefit in terms of number of lives saved as a result 
of e[cellent efficacy of these vaccines aJainst rotavirus diarrhea outZeiJh the small Sotential risN 
of intussusceStion and therefore the vaccine continues to be recommended for immuni]ation 
schedules of all countries  
Collection of blood sSecimens may cause some discomfort to SarticiSants VeniSuncture is 
sometimes associated Zith discomfort, Sain, bleedinJ, bruisinJ, redness, sZellinJ, local hardness, 
andor infection at the Suncture site This risN Zill be mitiJated by ensurinJ that only study staff 
members adeTuately trained in safe draZinJ of blood, conduct this Srocedure 

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In the case of e[Sected and une[Sected reactions after the use of vaccines, study SarticiSants Zill 
receive aSSroSriate medical care and treatment The sSonsor CIDRZ Zill ensure coveraJe for the 
cost of medical treatment and resolve these cases accordinJ to current standard of care in Zambia  
To minimi]e risN to the SarticiSants and early identification and treatment of side effects the 
folloZinJ assessments are Slanned in the Srotocol 
x 
Conduct of study Srocedures liNe administration of vaccines, safety assessment and blood 
draZs by staff trained in these Srocedures and in this aJe JrouS  
x 
MonitorinJ of SarticiSants closely for 30 minutes after vaccination and SrovidinJ emerJency 
care for any immediate reactions If medical issues arise that cannot be manaJed by the clinic 
SerforminJ the study, the study doctor Zill refer the SarticiSant to an aSSroSriate clinic outside 
of the institution 
x 
TeleShonic call and visit of heath care ZorNer to infant’s home tZice Zithin  days of each 
vaccine dose  
x 
ReJular folloZ uS of all infants Zith severe and serious adverse events  
RisNs to Privacy: Anyone SarticiSatinJ in research usinJ their real name and medical information 
can face a loss of Srivacy These risNs are mitiJated by usinJ uniTue IDs in Slace of a SarticiSant’s 
name, restrictinJ access to study information, and not naminJ or identifyinJ a SarticiSant in any 
Sublication  
Foregoing approved rotavirus Vaccination: Rotari[® is beinJ Srovided free of cost by the 
national immuni]ation Slan Zhereas ROTAVAC® and ROTAVAC 5CM have not yet been studied 
or aSSroved for use in Zambia  HoZever, ROTAVAC® has been administered to more than 12,000 
children in clinical trials in India includinJ one study SrovinJ efficacy of the vaccine and another 
study SrovinJ noninferiority of immune resSonse vs Rotari[® and has already been administered 
to millions of children in India under national immuni]ation Slan  ROTAVAC 5CM has the same 
virus strain as ROTAVAC® Zith addition of some stabili]ers and e[ciSients of *RAS cateJory 
and the immune resSonse has been shoZn to be similar to :HO aSSroved ROTAVAC® vaccine 
TZo third of the SarticiSants Zill receive either ROTAVAC® or ROTAVAC 5CM vaccine Zhich 
has not been studied in Zambian SoSulation and the immune resSonse cannot be Sredicted If the 
immune resSonse in the SoSulation is not as Ser the e[Sectation, then there is a risN that the infant 
may not be Srotected aJainst rotavirus infections  
. 
Compensation for Research Related InMury 
The SSonsor CIDRZ Zill Srovide aSSroSriate treatment for inMuries directly attributable to 
SarticiSation Clinical trial insurance in favor of SarticiSants Zill be undertaNen to cover inMury and 
other trial related eventualities includinJ comSensation for disability and death Information about 
this Zill be Srovided in the SarticiSant information as Zell as hoZ to access it 
 PROTOCOL MODIFICATIONS AND AM(NDM(NTS 
The Srotocol Zill not be amended Zithout Srior Zritten aSSroval from PATH In case the Srotocol 
is amended, the InvestiJator Zill submit and, Zhere necessary, obtain aSSroval from the (thics 
Committee for all Srotocol amendments and chanJes to the IC) document Submission and 
aSSroval of the amended Srotocol to ZAMRA Zill be the resSonsibility of the sSonsor  

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. 
Administrative Modifications 
Administrative or technical modifications liNe chanJe in study team or teleShone numbers, Zhich 
do not have an imSact on the SarticiSant
s health or influence study outcome Zill be communicated 
in ZritinJ and filed to UNZABR(C and :IRB throuJh PATH as an amendment to the Srotocol 
by the investiJator  
. 
Clinical Modifications 
Modifications affectinJ or interferinJ Zith the SarticiSant
s health interests and involvinJ chanJes 
in the desiJn of the study or its scientific siJnificance or Tuality or safety Zill reTuire Srotocol 
amendments and neZ aSSrovals by NHRA, ZAMRA, UNZABR(C and :IRB The SSonsor, 
PATH and InvestiJator Zill aJree to imSlement  adhere to such modifications only after Zritten 
aSSroval from ZAMRA and UNZABR(C  
These reTuirements for aSSroval should in no Zay Srevent any immediate action from beinJ taNen 
by the InvestiJator in the interests of SreservinJ the safety of all SarticiSants included in the trial 
If an immediate chanJe to the Srotocol is felt to be necessary by the InvestiJator and is 
imSlemented by him for safety reasons, the SSonsor and PATH should be notified immediately 
The I(C  IRB should be informed immediately  
. 
Protocol Deviations and Violations 
Any chanJes from SrotocolsSecified Srocedures and studyrelated SOPs occurrinJ durinJ the 
conduct of the trial Zill be documented and reSorted as Srotocol violations or deviations  
A Protocol Violation is any deSarture from the aSSroved Srotocol, trial documents or any other 
information relatinJ to the conduct of the study Zhich may affect the safety of trial SarticiSants or 
the study outcomes ([amSles include ZronJ randomi]ation or enrolment of SarticiSants that do 
not meet inclusion  e[clusion criteria   
A Protocol Deviation is any deSarture from the aSSroved Srotocol, trial documents or any other 
information relatinJ to the conduct of the trial that does not result in harm to the trial SarticiSants 
and does not siJnificantly affect the study outcomes ([amSles of deviations include a Srotocol 
visit date outside the study visit ZindoZ or an isolated incident of a missed or incomSlete study 
Srocedure or study evaluation Serious or reSeated Srotocol violations or deviations Zill reTuire 
assessment of the root cause and imSlementation of corrective and Sreventive action Slans They 
may constitute Jrounds to interruSt the trial at a study site  
The noncomSliance may be either on the Sart of the SarticiSant, the investiJator, or the study clinic 
staff As a result of any deviations, corrective actions are to be develoSed by the site and 
imSlemented SromStly Trial Srocedures shall not be chanJed Zithout the consent of PATH 
Deviations of the Srotocol Zill be e[amined on an individual basis, taNinJ into account recorded 
information for the reasons that the deviation occurred  
It is the resSonsibility of the site to use continuous viJilance to identify and reSort deviations to 
CRO in a timely manner after identification If reTuired, reSorts of Srotocol deviations must be 
sent to the research ethics committees overseeinJ the research The PI and hisher staff are 
resSonsible for NnoZinJ and adherinJ to their research ethics committee’sIRB’s reTuirements  

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To limit the Sotential for Srotocol deviations, the trial site Zill receive traininJ or retraininJ, as 
necessary on Srotocol imSlementation and Zill oSerate accordinJ to Zritten Srocedures 
5 FINANCIN* AND INS8RANC( 
The trial is suSSorted by a Jrant from Bill and Melinda Jates )oundation to PATH under 
OSSortunity ID: OPP11685  ROTAVAC® and ROTAVAC 5CM vaccine are Srovided by 
Bharat Biotech International Ltd, India  
The sSonsor Zill secure insurance that comSlies Zith local reJulatory reTuirements to cover for 
research related inMury  The vaccine manufacturer Zill selfinsure aJainst Sroduct liability 
6 P8%LICATION POLIC< 
It is understood by the investiJators that the information Jenerated in this study Zill be used by 
PATH in connection Zith the develoSmentuse of the Sroduct and therefore may be disclosed to 
Jovernment reJulatory aJencies in various countries  PATH and manufacturer also recoJni]es 
the imSortance of communicatinJ study findinJs and therefore encouraJes their Sublication in 
reSutable scientific Mournals and Sresentation at seminars or conferences, Zhile SrotectinJ the 
inteJrity of the onJoinJ trial  Any Sublication, lecture, manuscriSts of the findinJs of this study 
by any individual involved Zith the study Zill be Joverned by the Srocedure outlined in the 
Clinical Trial AJreement   :ithin any Sresentation or Sublication, confidentiality of individual 
SarticiSants Zill be maintained, Zith identification by SarticiSant code number and initials, if 
aSSlicable 
 

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 LIT(RAT8R( CIT(D 
1. 
Tate JE, Burton AH, Boschi-Pinto C, Parashar UD, World Health Organization-Coordinated Global 
Rotavirus Surveillance N. Global, Regional, and National Estimates of Rotavirus Mortality in Children <5 
Years of Age, 2000-2013. Clin Infect Dis 2016;62 Suppl 2:S96-S105. 
2. 
Atherly DE, Lewis KD, Tate J, Parashar UD, Rheingans RD. Projected health and economic impact 
of rotavirus vaccination in GAVI-eligible countries: 2011-2030. Vaccine 2012;30 Suppl 1:A7-14. 
3. 
Beres LK, Tate JE, Njobvu L, et al. A Preliminary Assessment of Rotavirus Vaccine Effectiveness 
in Zambia. Clin Infect Dis 2016;62 Suppl 2:S175-82. 
4. 
WHO. 
Rotavirus 
deaths 
by 
Country. 
Available 
at 
http://wwwwhoint/entity/immunization/monitoring_surveillance/rotavirus_deaths_by_country_2000-
2013xlsx?ua=1 Accessed on 08-02-2018 2013. 
5. 
Liu L, Johnson HL, Cousens S, et al. Global, regional, and national causes of child mortality: an 
updated systematic analysis for 2010 with time trends since 2000. Lancet 2012;379:2151-61. 
6. 
Chilengi R, Simuyandi M, Beach L, et al. Association of Maternal Immunity with Rotavirus Vaccine 
Immunogenicity in Zambian Infants. PLoS One 2016;11:e0150100. 
7. 
Tate JE, Yen C, Steiner CA, Cortese MM, Parashar UD. Intussusception Rates Before and After 
the Introduction of Rotavirus Vaccine. Pediatrics 2016;138. 
8. 
Madhi SA, Cunliffe NA, Steele D, et al. Effect of human rotavirus vaccine on severe diarrhea in 
African infants. N Engl J Med 2010;362:289-98. 
9. 
Armah GE, Sow SO, Breiman RF, et al. Efficacy of pentavalent rotavirus vaccine against severe 
rotavirus gastroenteritis in infants in developing countries in sub-Saharan Africa: a randomised, double-
blind, placebo-controlled trial. Lancet 2010;376:606-14. 
10. 
Zaman K, Dang DA, Victor JC, et al. Efficacy of pentavalent rotavirus vaccine against severe 
rotavirus gastroenteritis in infants in developing countries in Asia: a randomised, double-blind, placebo-
controlled trial. Lancet 2010;376:615-23. 
11. 
Bhandari N, Rongsen-Chandola T, Bavdekar A, et al. Efficacy of a monovalent human-bovine 
(116E) rotavirus vaccine in Indian infants: a randomised, double-blind, placebo-controlled trial. Lancet 
2014;383:2136-43. 
12. 
Isanaka S, Guindo O, Langendorf C, et al. Efficacy of a Low-Cost, Heat-Stable Oral Rotavirus 
Vaccine in Niger. N Engl J Med 2017;376:1121-30. 
13. 
Mpabalwani EM, Simwaka CJ, Mwenda JM, et al. Impact of Rotavirus Vaccination on Diarrheal 
Hospitalizations in Children Aged <5 Years in Lusaka, Zambia. Clin Infect Dis 2016;62 Suppl 2:S183-7. 
14. 
Bishop R. Discovery of rotavirus: Implications for child health. J Gastroenterol Hepatol 2009;24 
Suppl 3:S81-5. 
15. 
Santos N, Hoshino Y. Global distribution of rotavirus serotypes/genotypes and its implication for 
the development and implementation of an effective rotavirus vaccine. Rev Med Virol 2005;15:29-56. 
16. 
Kang G, Arora R, Chitambar SD, et al. Multicenter, hospital-based surveillance of rotavirus disease 
and strains among indian children aged <5 years. J Infect Dis 2009;200 Suppl 1:S147-53. 
17. 
Rodrigo C, Salman N, Tatochenko V, Meszner Z, Giaquinto C. Recommendations for rotavirus 
vaccination: A worldwide perspective. Vaccine 2010;28:5100-8. 
18. 
Simpson E, Wittet S, Bonilla J, Gamazina K, Cooley L, Winkler JL. Use of formative research in 
developing a knowledge translation approach to rotavirus vaccine introduction in developing countries. 
BMC Public Health 2007;7:281. 
19. 
Levy K, Hubbard AE, Eisenberg JN. Seasonality of rotavirus disease in the tropics: a systematic 
review and meta-analysis. Int J Epidemiol 2009;38:1487-96. 
20. 
Atchison CJ, Tam CC, Hajat S, van Pelt W, Cowden JM, Lopman BA. Temperature-dependent 
transmission of rotavirus in Great Britain and The Netherlands. Proc Biol Sci 2010;277:933-42. 
21. 
Velazquez FR, Matson DO, Calva JJ, et al. Rotavirus infection in infants as protection against 
subsequent infections. N Engl J Med 1996;335:1022-8. 
22. 
Ruiz-Palacios GM, Perez-Schael I, Velazquez FR, et al. Safety and efficacy of an attenuated 
vaccine against severe rotavirus gastroenteritis. N Engl J Med 2006;354:11-22. 
23. 
Bhandari N, Rongsen-Chandola T, Bavdekar A, et al. Efficacy of a monovalent human-bovine 
(116E) rotavirus vaccine in Indian children in the second year of life. Vaccine 2014;32 Suppl 1:A110-6. 
24. 
Ward RL, Bernstein DI. Protection against rotavirus disease after natural rotavirus infection. US 
Rotavirus Vaccine Efficacy Group. J Infect Dis 1994;169:900-4. 

Protocol Number ± CVIA 066  
Version Number: 01 Version Date: 11 July, 2018 
 
Confidential                                                        PaJe  of  
 
25. 
Bhan MK, Lew JF, Sazawal S, Das BK, Gentsch JR, Glass RI. Protection conferred by neonatal 
rotavirus infection against subsequent rotavirus diarrhea. J Infect Dis 1993;168:282-7. 
26. 
Aiyar J, Bhan MK, Bhandari N, Kumar R, Raj P, Sazawal S. Rotavirus-specific antibody response 
in saliva of infants with rotavirus diarrhea. J Infect Dis 1990;162:1383-4. 
27. 
Appaiahgari MB, Glass R, Singh S, et al. Transplacental rotavirus IgG interferes with immune 
response to live oral rotavirus vaccine ORV-116E in Indian infants. Vaccine 2014;32:651-6. 
28. 
Bishop RF, Barnes GL, Cipriani E, Lund JS. Clinical immunity after neonatal rotavirus infection. A 
prospective longitudinal study in young children. N Engl J Med 1983;309:72-6. 
29. 
Glass RI, Bhan MK, Ray P, et al. Development of candidate rotavirus vaccines derived from 
neonatal strains in India. J Infect Dis 2005;192 Suppl 1:S30-5. 
30. 
Ing DJ, Glass RI, Woods PA, et al. Immunogenicity of tetravalent rhesus rotavirus vaccine 
administered with buffer and oral polio vaccine. Am J Dis Child 1991;145:892-7. 
31. 
Clark HF, Burke CJ, Volkin DB, et al. Safety, immunogenicity and efficacy in healthy infants of G1 
and G2 human reassortant rotavirus vaccine in a new stabilizer/buffer liquid formulation. Pediatr Infect Dis 
J 2003;22:914-20. 
32. 
Kerdpanich A, Chokephaibulkit K, Watanaveeradej V, et al. Immunogenicity of a live-attenuated 
human rotavirus RIX4414 vaccine with or without buffering agent. Hum Vaccin 2010;6. 
33. 
Estes MK, Graham DY, Smith EM, Gerba CP. Rotavirus stability and inactivation. J Gen Virol 
1979;43:403-9. 
34. 
Weiss C, Clark HF. Rapid inactivation of rotaviruses by exposure to acid buffer or acidic gastric 
juice. J Gen Virol 1985;66 ( Pt 12):2725-30. 
35. 
Feng N, Burns JW, Bracy L, Greenberg HB. Comparison of mucosal and systemic humoral immune 
responses and subsequent protection in mice orally inoculated with a homologous or a heterologous 
rotavirus. J Virol 1994;68:7766-73. 
36. 
Graham DY, Dufour GR, Estes MK. Minimal infective dose of rotavirus. Arch Virol 1987;92:261-71. 
37. 
 Rotarix 
(Product 
Information). 
(Accessed 
21 
February, 
2018, 
at 
https://www.gsk.com.au/resources.ashx/vaccineproductschilddataproinfo/116/FileName/32AE8B6050D22
D6F9145C3F882B3238B/PI_Rotarix.pdf.) 
38. 
Rotateq 
(Product 
Information). 
(Accessed 
21 
February, 
2018, 
at 
https://www.merck.com/product/usa/pi_circulars/r/rotateq/rotateq_pi.pdf.) 
39. 
PATH welcomes new promising study results for rotavirus vaccine candidate. (Accessed 21 
February, 2018, at http://www.path.org/news/press-room/804/.) 
40. 
Bharat Biotech receives National Technology Award for Rotavac from President of India. 
Pharmabizcom:http://www.pharmabiz.com/NewsDetails.aspx?aid=108851&sid=2. Accessed on 14-05-
2018. 
41. 
Ward RL, Kirkwood CD, Sander DS, et al. Reductions in cross-neutralizing antibody responses in 
infants after attenuation of the human rotavirus vaccine candidate 89-12. J Infect Dis 2006;194:1729-36. 
42. 
Mandomando I, Weldegebriel G, de Deus N, Mwenda JM. Feasibility of using regional sentinel 
surveillance to monitor the rotavirus vaccine impact, effectiveness and intussusception incidence in the 
African Region. Vaccine 2017;35:1663-7. 
43. 
Bhandari N, Sharma P, Glass RI, et al. Safety and immunogenicity of two live attenuated human 
rotavirus vaccine candidates, 116E and I321, in infants: results of a randomised controlled trial. Vaccine 
2006;24:5817-23. 
44. 
Bhandari N, Sharma P, Taneja S, et al. A dose-escalation safety and immunogenicity study of live 
attenuated oral rotavirus vaccine 116E in infants: a randomized, double-blind, placebo-controlled trial. J 
Infect Dis 2009;200:421-9. 
45. 
Chandola TR, Taneja S, Goyal N, et al. ROTAVAC((R)) does not interfere with the immune 
response to childhood vaccines in Indian infants: A randomized placebo controlled trial. Heliyon 
2017;3:e00302. 
46. 
Ella R, Bobba R, Muralidhar S, Babji S, Vadrevu KM, Bhan MK. A Phase 4, multicentre, 
randomized, single-blind clinical trial to evaluate the immunogenicity of the live, attenuated, oral rotavirus 
vaccine (116E), ROTAVAC(R), administered simultaneously with or without the buffering agent in healthy 
infants in India. Hum Vaccin Immunother 2018:1-9. 

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APP(NDI;  - D(CLARATION OF H(LSIN.I 
 
(thical Principles for Medical Research Involving Human SubMects 
 
AdoSted by the 18th :MA *eneral Assembly, HelsinNi, )inland, June 16 
and amended by the: 
2th :MA *eneral Assembly, ToNyo, JaSan, October 15 
35th :MA *eneral Assembly, Venice, Italy, October 183 
1st :MA *eneral Assembly, HonJ .onJ, SeStember 18 
8th :MA *eneral Assembly, Somerset :est, ReSublic of South Africa, October 16 
52nd :MA *eneral Assembly, (dinburJh, Scotland, October 2000  
53rd :MA *eneral Assembly, :ashinJton DC, USA, October 2002 Note of Clarification 
added 
55th :MA *eneral Assembly, ToNyo, JaSan, October 200 Note of Clarification added 
5th :MA *eneral Assembly, Seoul, ReSublic of .orea, October 2008 
6th :MA *eneral Assembly, )ortale]a, Bra]il, October 2013 
Preamble 
1 The :orld Medical Association :MA has develoSed the Declaration of HelsinNi as a 
statement of ethical SrinciSles for medical research involvinJ human subMects, includinJ research 
on identifiable human material and data 
            The Declaration is intended to be read as a Zhole and each of its constituent SaraJraShs 
should be aSSlied Zith consideration of all other relevant SaraJraShs 
2  Consistent Zith the mandate of the :MA, the Declaration is addressed Srimarily to Shysicians 
The :MA encouraJes others Zho are involved in medical research involvinJ human subMects to 
adoSt these SrinciSles  
*eneral Principles 
3 The Declaration of *eneva of the :MA binds the Shysician Zith the Zords, ³The health of my 
Satient Zill be my first consideration,´ and the International Code of Medical (thics declares that, 
³A Shysician shall act in the Satient
s best interest Zhen SrovidinJ medical care´ 
  It is the duty of the Shysician to Sromote and safeJuard the health, ZellbeinJ and riJhts of 
Satients, includinJ those Zho are involved in medical research The Shysician
s NnoZledJe and 
conscience are dedicated to the fulfilment of this duty 
5  Medical SroJress is based on research that ultimately must include studies involvinJ human 
subMects 
6 The Srimary SurSose of medical research involvinJ human subMects is to understand the causes, 
develoSment and effects of diseases and imSrove Sreventive, diaJnostic and theraSeutic 
interventions methods, Srocedures and treatments (ven the best Sroven interventions must be 
evaluated continually throuJh research for their safety, effectiveness, efficiency, accessibility and 
Tuality 
 Medical research is subMect to ethical standards that Sromote and ensure resSect for all human 
subMects and Srotect their health and riJhts 
8  :hile the Srimary SurSose of medical research is to Jenerate neZ NnoZledJe, this Joal can 
never taNe Srecedence over the riJhts and interests of individual research subMects 
 It is the duty of Shysicians Zho are involved in medical research to Srotect the life, health, 
diJnity, inteJrity, riJht to selfdetermination, Srivacy, and confidentiality of Sersonal information 
of research subMects The resSonsibility for the Srotection of research subMects must alZays rest 

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Zith the Shysician or other health care Srofessionals and never Zith the research subMects, even 
thouJh they have Jiven consent 
10 Physicians must consider the ethical, leJal and reJulatory norms and standards for research 
involvinJ human subMects in their oZn countries as Zell as aSSlicable international norms and 
standards No national or international ethical, leJal or reJulatory reTuirement should reduce or 
eliminate any of the Srotections for research subMects set forth in this Declaration 
11 Medical research should be conducted in a manner that minimises Sossible harm to the 
environment 
12  Medical research involvinJ human subMects must be conducted only by individuals Zith the 
aSSroSriate ethics and scientific education, traininJ and Tualifications Research on Satients or 
healthy volunteers reTuires the suServision of a comSetent and aSSroSriately Tualified Shysician 
or other health care Srofessional 
13 *rouSs that are underreSresented in medical research should be Srovided aSSroSriate access 
to SarticiSation in research 
1 Physicians Zho combine medical research Zith medical care should involve their Satients in 
research only to the e[tent that this is Mustified by its Sotential Sreventive, diaJnostic or theraSeutic 
value and if the Shysician has Jood reason to believe that SarticiSation in the research study Zill 
not adversely affect the health of the Satients Zho serve as research subMects 
15  ASSroSriate comSensation and treatment for subMects Zho are harmed as a result of 
SarticiSatinJ in research must be ensured 
RisNs, %urdens and %enefits  
16 In medical Sractice and in medical research, most interventions involve risNs and burdens 
           Medical research involvinJ human subMects may only be conducted if the imSortance of the 
obMective outZeiJhs the risNs and burdens to the research subMects 
1  All medical research involvinJ human subMects must be Sreceded by careful assessment of 
Sredictable risNs and burdens to the individuals and JrouSs involved in the research in comSarison 
Zith foreseeable benefits to them and to other individuals or JrouSs affected by the condition under 
investiJation 
           Measures to minimise the risNs must be imSlemented The risNs must be continuously 
monitored, assessed and documented by the researcher  
18 Physicians may not be involved in a research study involvinJ human subMects unless they are 
confident that the risNs have been adeTuately assessed and can be satisfactorily manaJed 
           :hen the risNs are found to outZeiJh the Sotential benefits or Zhen there is conclusive 
Sroof of definitive outcomes, Shysicians must assess Zhether to continue, modify or immediately 
stoS the study            
Vulnerable *roups and Individuals 
1 Some JrouSs and individuals are Sarticularly vulnerable and may have an increased liNelihood 
of beinJ ZronJed or of incurrinJ additional harm 
       All vulnerable JrouSs and individuals should receive sSecifically considered Srotection 
20  Medical research Zith a vulnerable JrouS is only Mustified if the research is resSonsive to the 
health needs or Sriorities of this JrouS and the research cannot be carried out in a nonvulnerable 
JrouS In addition, this JrouS should stand to benefit from the NnoZledJe, Sractices or 
interventions that result from the research 
Scientific ReTuirements and Research Protocols  
21  Medical research involvinJ human subMects must conform to Jenerally acceSted scientific 
SrinciSles, be based on a thorouJh NnoZledJe of the scientific literature, other relevant sources of 

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information, and adeTuate laboratory and, as aSSroSriate, animal e[Serimentation The Zelfare of 
animals used for research must be resSected 
22 The desiJn and Serformance of each research study involvinJ human subMects must be clearly 
described and Mustified in a research Srotocol 
           The Srotocol should contain a statement of the ethical considerations involved and should 
indicate hoZ the SrinciSles in this Declaration have been addressed The Srotocol should include 
information reJardinJ fundinJ, SSonsors, institutional affiliations, Sotential conflicts of interest, 
incentives for subMects and information reJardinJ Srovisions for treatinJ and  or comSensatinJ 
subMects Zho are harmed as a conseTuence of SarticiSation in the research study 
           In clinical trials, the Srotocol must also describe aSSroSriate arranJements for Sosttrial 
Srovisions 
Research (thics Committees 
23 The research Srotocol must be submitted for consideration, comment, Juidance and aSSroval 
to the concerned research ethics committee before the study beJins This committee must be 
transSarent in its functioninJ, must be indeSendent of the researcher, the SSonsor and any other 
undue influence and must be duly Tualified It must taNe into consideration the laZs and reJulations 
of the country or countries in Zhich the research is to be Serformed as Zell as aSSlicable 
international norms and standards but these must not be alloZed to reduce or eliminate any of the 
Srotections for research subMects set forth in this Declaration  
           The committee must have the riJht to monitor onJoinJ studies The researcher must Srovide 
monitorinJ information to the committee, esSecially information about any serious adverse events 
No amendment to the Srotocol may be made Zithout consideration and aSSroval by the committee 
After the end of the study, the researchers must submit a final reSort to the committee containinJ 
a summary of the study’s findinJs and conclusions  
Privacy and Confidentiality  
2 (very Srecaution must be taNen to Srotect the Srivacy of research subMects and the 
confidentiality of their Sersonal information 
Informed Consent  
25 ParticiSation by individuals caSable of JivinJ informed consent as subMects in medical research 
must be voluntary AlthouJh it may be aSSroSriate to consult family members or community 
leaders, no individual caSable of JivinJ informed consent may be enrolled in a research study 
unless he or she freely aJrees 
26 In medical research involvinJ human subMects caSable of JivinJ informed consent, each 
Sotential subMect must be adeTuately informed of the aims, methods, sources of fundinJ, any 
Sossible conflicts of interest, institutional affiliations of the researcher, the anticiSated benefits and 
Sotential risNs of the study and the discomfort it may entail, Soststudy Srovisions and any other 
relevant asSects of the study The Sotential subMect must be informed of the riJht to refuse to 
SarticiSate in the study or to ZithdraZ consent to SarticiSate at any time Zithout reSrisal SSecial 
attention should be Jiven to the sSecific information needs of individual Sotential subMects as Zell 
as to the methods used to deliver the information 
           After ensurinJ that the Sotential subMect has understood the information, the Shysician or 
another aSSroSriately Tualified individual must then seeN the Sotential subMect’s freelyJiven 
informed consent, Sreferably in ZritinJ If the consent cannot be e[Sressed in ZritinJ, the non
Zritten consent must be formally documented and Zitnessed       
           All medical research subMects should be Jiven the oStion of beinJ informed about the Jeneral 
outcome and results of the study 

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2 :hen seeNinJ informed consent for SarticiSation in a research study the Shysician must be 
Sarticularly cautious if the Sotential subMect is in a deSendent relationshiS Zith the Shysician or 
may consent under duress In such situations the informed consent must be souJht by an 
aSSroSriately Tualified individual Zho is comSletely indeSendent of this relationshiS 
28 )or a Sotential research subMect Zho is incaSable of JivinJ informed consent, the Shysician 
must seeN informed consent from the leJally authorised reSresentative These individuals must not 
be included in a research study that has no liNelihood of benefit for them unless it is intended to 
Sromote the health of the JrouS reSresented by the Sotential subMect, the research cannot instead 
be Serformed Zith Sersons caSable of SrovidinJ informed consent, and the research entails only 
minimal risN and minimal burden 
2 :hen a Sotential research subMect Zho is deemed incaSable of JivinJ informed consent is able 
to Jive assent to decisions about SarticiSation in research, the Shysician must seeN that assent in 
addition to the consent of the leJally authorised reSresentative The Sotential subMect’s dissent 
should be resSected 
30  Research involvinJ subMects Zho are Shysically or mentally incaSable of JivinJ consent, for 
e[amSle, unconscious Satients, may be done only if the Shysical or mental condition that Srevents 
JivinJ informed consent is a necessary characteristic of the research JrouS In such circumstances 
the Shysician must seeN informed consent from the leJally authorised reSresentative If no such 
reSresentative is available and if the research cannot be delayed, the study may Sroceed Zithout 
informed consent Srovided that the sSecific reasons for involvinJ subMects Zith a condition that 
renders them unable to Jive informed consent have been stated in the research Srotocol and the 
study has been aSSroved by a research ethics committee Consent to remain in the research must 
be obtained as soon as Sossible from the subMect or a leJally authorised reSresentative 
31 The Shysician must fully inform the Satient Zhich asSects of their care are related to the 
research The refusal of a Satient to SarticiSate in a study or the Satient’s decision to ZithdraZ 
from the study must never adversely affect the SatientShysician relationshiS 
32 )or medical research usinJ identifiable human material or data, such as research on material 
or data contained in biobanNs or similar reSositories, Shysicians must seeN informed consent for 
its collection, storaJe and  or reuse There may be e[ceStional situations Zhere consent Zould be 
imSossible or imSracticable to obtain for such research In such situations the research may be 
done only after consideration and aSSroval of a research ethics committee 
8se of Placebo 
33 The benefits, risNs, burdens and effectiveness of a neZ intervention must be tested aJainst 
those of the best Sroven interventions, e[ceSt in the folloZinJ circumstances: 
           :here no Sroven intervention e[ists, the use of Slacebo, or no intervention, is acceStable 
or 
           :here for comSellinJ and scientifically sound methodoloJical reasons the use of any 
intervention less effective than the best Sroven one, the use of Slacebo, or no intervention is 
necessary to determine the efficacy or safety of an intervention and the Satients Zho receive any 
intervention less effective than the best Sroven one, Slacebo, or no intervention Zill not be subMect 
to additional risNs of serious or irreversible harm as a result of not receivinJ the best Sroven 
intervention  
           ([treme care must be taNen to avoid abuse of this oStion 
Post-Trial Provisions 
3 In advance of a clinical trial, SSonsors, researchers and host country Jovernments should maNe 
Srovisions for Sosttrial access for all SarticiSants Zho still need an intervention identified as 

Protocol Number ± CVIA 066  
Version Number: 01 Version Date: 11 July, 2018 
Confidential                 
PaJe 5 of 5 
 
beneficial in the trial This information must also be disclosed to SarticiSants durinJ the informed 
consent Srocess 
Research Registration and Publication and Dissemination of Results 
35 (very research study involvinJ human subMects must be reJistered in a Sublicly accessible 
database before recruitment of the first subMect 
36 Researchers, authors, SSonsors, editors and Sublishers all have ethical obliJations Zith reJard 
to the Sublication and dissemination of the results of research Researchers have a duty to maNe 
Sublicly available the results of their research on human subMects and are accountable for the 
comSleteness and accuracy of their reSorts All Sarties should adhere to acceSted Juidelines for 
ethical reSortinJ NeJative and inconclusive as Zell as Sositive results must be Sublished or 
otherZise made Sublicly available Sources of fundinJ, institutional affiliations and conflicts of 
interest must be declared in the Sublication ReSorts of research not in accordance Zith the 
SrinciSles of this Declaration should not be acceSted for Sublication 
8nproven Interventions in Clinical Practice 
3 In the treatment of an individual Satient, Zhere Sroven interventions do not e[ist or other 
NnoZn interventions have been ineffective, the Shysician, after seeNinJ e[Sert advice, Zith 
informed consent from the Satient or a leJally authorised reSresentative, may use an unSroven 
intervention if in the Shysician
s MudJement it offers hoSe of savinJ life, reestablishinJ health or 
alleviatinJ sufferinJ This intervention should subseTuently be made the obMect of research, 
desiJned to evaluate its safety and efficacy In all cases, neZ information must be recorded and, 
Zhere aSSroSriate, made Sublicly available

Protocol Number ± CVIA 066  
Version Number: 01 Version Date: 11 July, 2018 
Confidential 
PaJe  of  
 
APP(NDI;  ± APPLICA%L( D(FINITIONS FOR *RADIN* OF A(S 
 
The severity of all unsolicited A(s Zill be assessed by the investiJator based on the Juidance 
Srovided in Division of AIDS DAIDS Table for *radinJ the Severity of Adult and Pediatric 
Adverse (vents, corrected version 21, July 201, of the US National Institute of Health The 
aSSlicable symStoms and their adaSted definitions has been Srovided beloZ:  
PARAM(T(R  
*RAD(  MILD  
*RAD(  
MOD(RAT(  
*RAD(  
S(V(R(  
*RAD(  
POT(NTIALL< 
LIF(-
THR(AT(NIN*  
Diarrhea  
 
LiTuid stools more 
unformed 
than 
usual 
but 
usual 
number of stools  
LiTuid stools Zith 
increased number of 
stools 
OR 
Mild 
dehydration  
LiTuid stools Zith 
moderate 
dehydration  
LifethreateninJ 
conseTuences eJ, 
liTuid 
stools 
resultinJ in severe 
dehydration, 
hySotensive shocN  
VomitinJ  
Transient or 
intermittent AND 
No or minimal 
interference Zith 
oral intaNe  
)reTuent eSisodes 
Zith no or mild 
dehydration  
Persistent vomitinJ 
Zith aJJressive 
rehydration 
indicated eJ, IV 
fluids  
LifethreateninJ 
conseTuences eJ, 
hySotensive shocN  
Sei]ures  
 
Sei]ure lastinJ  5 
minutes Zith  2 
hours Sostictal state  
Sei]ure lastinJ 5 to 
 20 minutes Zith  
2 hours Sostictal 
state  
Sei]ure lastinJ  20 
minutes OR ! 2 
hours Sostictal state  
ProlonJed and 
reSetitive sei]ures 
eJ, status 
eSileSticus OR 
Difficult to control 
eJ, refractory 
eSileSsy  
Acute AllerJic 
Reaction  
Locali]ed urticaria 
Zheals Zith no 
medical intervention 
indicated  
Locali]ed urticaria 
Zith intervention 
indicated OR Mild 
anJioedema Zith no 
intervention 
indicated  
*enerali]ed 
urticaria OR 
AnJioedema Zith 
intervention 
indicated OR 
SymStoms of mild 
bronchosSasm  
Acute anaShyla[is 
OR LifethreateninJ 
bronchosSasm OR 
LarynJeal edema  
)ever a[illary 
temSeratures  
 35 ±  380C 
! 380 ±  30C 
! 30 ±  00C 
 00C 
InMection Site 
Tenderness  
 
Tenderness causinJ 
no or minimal 
limitation of use of 
limb  
Tenderness causinJ 
Jreater than 
minimal limitation 
of use of limb  
Tenderness causinJ 
inability to Serform 
usual social 	 
functional activities  
Tenderness causinJ 
inability to Serform 
basic selfcare 
function OR 
HosSitali]ation 
indicated  
InMection Site 
(rythema or 
Redness 
5HSRUW RQO\ RQH 
 25 cm in 
diameter  
! 25 cm in 
diameter Zith  
50 surface area of 
the e[tremity 
seJment involved 
eJ, uSSer arm or 
thiJh  
 50 surface area 
of the e[tremity 
seJment involved 
eJ, uSSer arm or 
thiJh OR 
Ulceration OR 
Secondary infection 
OR Phlebitis OR 
Sterile abscess OR 
DrainaJe  
Potentially life
threateninJ 
conseTuences eJ, 
abscess, e[foliative 
dermatitis, necrosis 
involvinJ dermis or 
deeSer tissue  

Protocol Number ± CVIA 066  
Version Number: 01 Version Date: 11 July, 2018 
Confidential 
PaJe  of  
 
InMection Site 
Induration or 
SZellinJ  
5HSRUW RQO\ RQH  
 
Same 
as 
for 
InMection 
Site 
(rythema 
or 
Redness  
Same 
as 
for 
InMection 
Site 
(rythema 
or 
Redness  
Same 
as 
for 
InMection 
Site 
(rythema 
or 
Redness  
Same 
as 
for 
InMection 
Site 
(rythema 
or 
Redness  
*rade 5Death All A(s leadinJ to death are *rade 5 events 
 
 

Addendum to Protocol: CVIA 066 
Number: 01 Dated: 25 October, 2018 
 
 
 Confidential                                       PaJe  of  
Addendum to Protocol: CVIA 066 
 
An Open-label, Randomized, Controlled, Single Centre, Phase IIb 
Study to Assess the Immunogenicity, Reactogenicity and Safety of 
Three Live Oral Rotavirus Vaccines, ROTAVAC®, ROTAVAC 
5CM and Rotarix® in Healthy Zambian Infants. 
 
Addendum Number: 0 Dated 5, October, 0  
 
The SurSose of this addendum is to emShasi]e the chanJes that are to be made in the study 
Srotocol, version number 10 Version date: date 11 July, 2018 
Namely, after the above mentioned version of the Srotocol Zas submitted and aSSroved by 
University of Zambian Biomedical (thics Committee for the CIDRZ Srotocol to be conducted at 
*eorJe Health Centre and Zambia Medicines ReJulatory Authority ZAMRA,  minor chanJes 
are to be imSlemented in the Srotocol 
 
The folloZinJ outlines these chanJes: 
 
Place Zithin 
the document 
Section 
Present te[t 
CorrecteduSdated te[t 
Title SaJe 
NA 
Trial ReJistration: 
Submission in Srocess 
Trial ReJistration: 
ClinicalTrialJov study 
reference no NCT03602053  
PaJe 12 
NeZ addition 
Administrative 
structure 
NA 
Clinical Research Officer 
PATH  15th )loor, Dr 
*oSal Das BhaZan,  
28, 
BaraNhamba 
Road, 
ConnauJht Place,  
NeZ Delhi  110001 India 
Phone: 
 
(mail: 
 
PaJe 10, 6 
ParticiSatinJ 
Institutions 
513 Presentation 
and )ormulation 
*eorJe Research Clinic   
 
 

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