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 rocess
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
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 Patho en ...... 21 1 3 Descri tion of Study Vaccine ...... 22 1 3 1 Immune Res onses to Rotavirus Vaccines ...... 24 1 3 2 Potential Safety Ris s 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® 20 C ...... 27 1 5 2 ROTAVAC 5C ...... 31 1 5 3 ROTAVAC 5CM ...... 32 1 6 Potential Ris s and or Benefits of Study Vaccine ...... 33 1 Overall Develo ment Strate y ...... 34 1 8 Study Rationale ...... 34 2 H POTH S S, OBJ CTIV S AND NDPOINTS ...... 35 2 1 Study Hy otheses ...... 35 2 2 Study Ob ectives ...... 35 2 2 1 Primary Ob ective ...... 35 2 2 2 Secondary Ob ectives ...... 35 2 2 3 loratory Ob ective...... 35 2 3 Study nd oints ...... 35 2 3 1 Primary nd oint ...... 35 2 3 2 Secondary nd oints ...... 36 2 3 3 loratory nd oints: ...... 36 3 STUD D SI N ...... 37 STUD POPULATION ...... 39 1 Descri tion of Study Site Po ulation ...... 39 2 Inclusion Criteria ...... 39 3 clusion Criteria ...... 40 Continued li ibility Confirmation for Subse uent Vaccination ...... 41 5 Reasons for ithdra al ...... 41 5 STUD PRODUCT S ...... 42 5 1 Study Vaccine ...... 42 5 1 1 Product Descri tion ...... 42 5 1 2 Manufacturer ...... 43 5 1 3 Presentation and ormulation ...... 43
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5 1 Stability and Stora e ...... 46 5 1 5 The Vaccine Vial Monitor2 ...... 46 5 2 Dose Pre aration and Administration ...... 47 5 3 Accountability and dis osal ...... 49 5 3 1 Vaccine su ly ...... 49 5 3 2 Dis ensin ...... 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 Screenin 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 Mana ement of Serious Adverse vents includin Intussusce tion ...... 56 6 2 Schedule of events ...... 56 6 3 Study Termination ...... 58 6 3 1 nd of Trial Accordin to the Protocol ...... 58 6 3 2 Sus ension and or Premature Termination of the Trial ...... 58 6 Lost to follo u ...... 58 6 5 Use of concomitant vaccine s medication durin the study ...... 59 6 6 Unblindin rocedure ...... 59 6 Clinical rocedures ...... 59 6 8 Termination of ithdra n study artici ant ...... 60 LABORATOR VALUATIONS R UIR M NTS ...... 60 1 Sam le collection, distribution and stora e ...... 60 2 Immunolo ical laboratory assays ...... 61 3 Assays ualification, standardi ation, validation ...... 61 uture use of stored sam les ...... 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 dru reaction ICH Sus ected Adverse Reaction DA ...... 63 8 1 3 Serious Adverse vent SA ...... 63 8 1 Re ortin Period and Parameter ...... 64 8 2 Severity of Adverse vents ...... 64 8 3 Causality of Adverse vent ...... 66 8 ollo u of Adverse vent ...... 67 8 5 eneral uidance on Recordin Adverse vents ...... 68 8 6 Re ortin of SA ...... 69 8 6 1 Investi ator Re ortin to S onsor ...... 69 8 6 2 Notification and Revie of SA s ...... 69 8 6 3 S onsor Re ortin to Re ulatory A ency ...... 70 SA T OV RSI HT ...... 70
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Protocol Number CVIA 066 Version Number: 01 Version Date: 11 July, 2018
1 Routine Revie s by Princi al Investi ator ...... 70 2 Routine Revie s by Protocol Safety Revie 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 Ca ture Methods Case Re ort orm Develo ment and Com letion ...... 73 10 3 Data Mana ement ...... 74 10 Retention of Study Records ...... 74 11 STATISTICAL CONSID RATIONS ...... 74 11 1 Overvie and eneral Considerations ...... 74 11 2 Randomi ation Procedures ...... 75 11 3 Sam le Si e and Po er...... 75 11 Analysis Po ulations ...... 76 11 1 nrolled Po ulation ...... 76 11 2 ull Analysis o ulation ...... 76 11 3 Per Protocol o ulation ...... 77 11 Safety o ulation ...... 77 11 5 Analytical Methodolo y ...... 77 11 5 1 Analysis of demo ra hics and other baseline characteristics ...... 77 11 5 2 Analysis of rimary ob ective ...... 78 11 5 3 Analysis of secondary ob ectives ...... 78 11 5 Analysis of e loratory ob ective ...... 80 11 5 5 Multi licity ...... 80 11 5 6 Handlin of Dro outs and Missin Data ...... 80 11 6 Analysis Se uence ...... 80 12 UALIT ASSURANC AND UALIT CONTROL ...... 80 12 1 eneral Considerations ...... 81 12 2 ternal Monitorin ...... 81 12 3 Inde endent Auditin ...... 81 12 Re ulatory A ency Ins ection ...... 82 13 THICAL CONSID RATIONS AND IN ORM D CONS NT ...... 82 13 1 thical Standards ...... 82 13 2 thical Revie ...... 82 13 3 Informed Consent Process ...... 83 13 Partici ant Confidentiality ...... 83 13 5 Reimbursement ...... 84 13 6 Ris and Benefits ...... 84 13 Com ensation for Research Related In ury ...... 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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Protocol Number CVIA 066 Version Number: 01 Version Date: 11 July, 2018
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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Protocol Number CVIA 066 Version Number: 01 Version Date: 11 July, 2018
A R VIATIONS AND ACRON MS
A Adverse vents A I Adverse vents ollo in Immuni ation A Acute astroenteritis AIIMS All India Institute of Medical Sciences ART Anti Retroviral Treatment ANC Acid Neutrali in Ca acity BBIL Bharat Biotech International Limited BM Bill Melinda ates oundation CCHMC Cincinnati Children s Hos ital Medical Center CCID Cell Culture Infectious Dose CDC Centers for Disease Control CDSCO Central Dru s Standard Control Or ani ation C R Code of ederal Re ulations CI Confidence interval CIDRZ Centre for Infectious Disease Research in Zambia CIOMS Council for International Or ani ations of Medical Sciences CM Centimeter CMC Christian Medical Colle e CR Case Re ort orm CRO Contract Research Or ani ation DMC Data Mana ement Centre DBT De artment of Biotechnolo y DM M Dulbecco’s Modified a le Medium DMP Data Mana ement Plan DT P Di htheria, Tetanus, Pertussis hole cell C thics Committee DC lectronic Data Ca ture LISA n yme lin ed immunosorbent assay PI anded Pro ram on Immuni ation A ull Analysis DA ood and Dru Administration U ocus ormin Units CP ood Clinical Practices MC eometric Mean Concentration M R eometric Mean old Rise MT eometric Mean Titer RAS enerally Reco ni ed as Safe S la oSmith line He B He atitis B Hib I C Inde endent thics Committee IATA International Air Trans ort Association I Immuno lobulin IMP Investi ational Medicinal Products
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Protocol Number CVIA 066 Version Number: 01 Version Date: 11 July, 2018
IRB Institutional Revie Board ICH International Council for Harmonisation of Technical Re uirements for Pharmaceuticals for Human Use IMP Investi ational Medicinal Product ilo ram LLO Lo er Limit of uantification MCH Maternal and Child Health MedDRA Medical Dictionary for Re ulatory Activities m milli ram mL milliliter MOH Ministry of Health MTA Material Transfer A reement NIAID National Institute of Aller y and Infectious Diseases NHRA National Health Research Authority NLT Not Less Than NSP Non Structural Protein OPD Out Patient De artment ORS Oral Rehydration Solution ORT Oral Rehydration Thera y ORV Oral Rotavirus Vaccine PIDC Post Immuni ation Diary Card PP Per rotocol PSRT Protocol Safety Revie Team RCD Reverse Cumulative Distribution RV Rotavirus astroenteritis SA Serious Adverse vent SA Strate ic Advisory rou of erts on Immuni ation SAP Statistical Analysis Plan SAS Society for A lied Studies SCID Severe Combined Immunodeficiency SCR Seroconversion Rate SD Standard Deviation SDMC Statistical Data Mana ement Center SIIPL Serum Institute of India Private Limited SOC System Or an Class SOP Standard O eratin Procedure s SPC Summary of Product characteristics SST Serum Se arator Tubes ST Serum Se arator tubes ULO U er Limit of uantification UNZABR C University of Zambia Biomedical Research thics Committee VP Viral Protein VVM Vaccine Vial Monitor HO orld Health Or ani ation HO DD HO Dru Dictionary ZAMRA Zambia Medicines Re ulatory Authority
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Protocol Number CVIA 066 Version Number: 01 Version Date: 11 July, 2018
STAT M NT OF COMPLIANC The study ill be carried out in accordance ith ood Clinical Practice CP as re uired by the follo in : International Conference on Harmonisation ICH uidance for CP 6 orld Medical Association MA Declaration of Helsin i thical Princi les for Research Involvin Human Sub ects Oct 2013 or subse uent amendments A licable Rules of Zambia All ey ersonnel all individuals res onsible for the desi n and conduct of this study have com leted Human Sub ects Protection Trainin , Res onsible Conduct of Research RCR trainin and ICH CP trainin
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Protocol Number CVIA 066 Version Number: 01 Version Date: 11 July, 2018
ROL S AND CONTACT INFORMATION
PARTICIPATIN INSTIT TIONS
Centre for Infectious Disease Research in Zambia, Lusa a, Zambia, 10101 Sponsor Phone: mail:i
PATH 2201 estla e Avenue, Suite 200 In Collaboration with Seattle, A 8121, USA
Phone: mail:
Bharat Biotech International Ltd enome Valley, Shameer et, Vaccine Manufacturer Hyderabad 5000 8, Telan ana, India Phone: mail:
Clinical Trial Site eor e Research Clinic, Centre for Infectious Disease Research in Zambia, Lusa a, Zambia, 10101 Phone: mail:
Research Laboratories The ellcome Trust Research Laboratory, De artment of astrointestinal Sciences, Christian Medical Colle e, Vellore 632 00 , Tamil Nadu, India Phone: mail:
Cincinnati Children s Hos ital Medical Center CCHMC
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Protocol Number CVIA 066 Version Number: 01 Version Date: 11 July, 2018
Division of Infectious Diseases Cincinnati, Ohio, USA Phone: mail:
Contract Research Clinical Operations Organizations amily Health International HI 360 35 Blac ell Street, Suite 200 Durham, NC 2 01 USA Phone: ebsite: fhi360 or
Data Management and iostatistics Dia noSearch Life Sciences Private Limited 02, Dosti Pinnacle, , Road No 22, a le state, Thane 0060 , India Phone: mail:
thics Committee University of Zambia Biomedical Research thics Committee UNZABR C
P O Bo 50110 Lusa a Phone: mail:
estern IRB 101 3 th Avenue S Suite 120 Puyallu , A 83 2115 Phone: mail:
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Protocol Number CVIA 066 Version Number: 01 Version Date: 11 July, 2018
ADMINISTRATIV STR CT R
Principal Investigator Chief Scientific Officer Centre for Infectious Disease Research in Zambia, Lusa a, Zambia, 10101 Phone: mail:
Sponsor Representative Head Research O erations Centre for Infectious Disease Research in Zambia, Lusa a, Zambia, 10101 Phone: mail:
PATH s Medical Officer Senior Medical Officer PATH 15th loor, Dr o al Das Bha an, 28, Bara hamba Road, Connau ht Place, Ne Delhi 110001 India Phone: mail:
Vaccine Manufacturer Representative ecutive Director Bharat Biotech International Limited, enome Valley, Shameer et, Hyderabad, Telan ana Phone: mail:
Protocol Statistician Biostatistician PATH 2201 estla e Avenue, Suite 200
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Protocol Number CVIA 066 Version Number: 01 Version Date: 11 July, 2018
Seattle, A 8121 USA Phone: mail:
Clinical Operations Specialist Senior Clinical Research Officer, Center for Vaccine Innovation and Access CVIA PATH 2201 estla e Avenue, Suite 200, Seattle, A 8121, USA Phone: mail:
Pharmacist of Record Head of Pharmacy Centre for Infectious Disease Research in Zambia Lusa a, Zambia, 10101 Phone: mail:
Immunology Laboratories The ellcome Trust Research Laboratory De artment of astrointestinal Sciences Christian Medical Colle e Vellore 632 00 , Tamil Nadu, India Tel: mail:
Cincinnati Children s Hos ital Medical Center CCHMC Division of Infectious Diseases Cincinnati, Ohio Phone: mail:
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Protocol Number CVIA 066 Version Number: 01 Version Date: 11 July, 2018
Contract Research Clinical Operation Organizations
Pro ect Mana er HI 360 Valley Rd, Chancery Bld, P O Bo 38835 00623 Nairobi, enya Phone: mail:
Data Management and iostatistics
Pro ect Mana er Dia noSearch Life Sciences Private Limited 02, Dosti Pinnacle, , Road No 22, a le state, Thane 0060 , India Phone: mail:
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Protocol Number CVIA 066 Version Number: 01 Version Date: 11 July, 2018
PROTOCOL S MMAR
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 ROTAVAC®: Bharat Biotech International Ltd s licensed and HO Products re ualified rotavirus vaccine, ROTAVAC® is a live, attenuated P 11 monovalent vaccine at a dose of 0 5mL NLT lo 105 0 focus formin units U er dose, to be administered orally The vaccine is recommended to be stored at 20 C ROTAVAC® 5CM: Bharat Biotech International Ltd s ne Rotavirus vaccine, ROTAVAC 5CM is a live, attenuated P 11 monovalent vaccine at a dose of 0 5mL NLT lo 105 0 focus formin units U er dose, to be administered orally The vaccine is recommended to be stored at 2 8 C Rotarix®: S Biolo icals’ licensed rotavirus vaccine, Rotari ® is a live attenuated RI 1 strain of human rotavirus of the 1P 8 ty e containin not less than 106 0 CCID50 cell culture infectious dose 50 of the RI 1 strain of human rotavirus 1 5 ml of the li uid vaccine administered orally The vaccine is recommended to be stored at 2 8 C
Study Hypotheses Immunogenicity ROTAVAC® and ROTAVAC 5CM administered as a 3 dose series induce com arable immune res onse in healthy African infants Safety ROTAVAC® and ROTAVAC 5CM administered as a 3 dose series are both safe and ell tolerated in healthy African infants
Study Ob ectives Primary Ob ective: Immunogenicity To evaluate and com are the immuno enicity of ROTAVAC® and ROTAVAC® 5CM, 28 days after the last dose of the vaccine, hen administered to infants in a three dose schedule at 6, 10 and 1 ee s of a e
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Protocol Number CVIA 066 Version Number: 01 Version Date: 11 July, 2018
Secondary Ob ectives: Safety To assess the reacto enicity days after each vaccination and safety ee s after the last vaccination of the ROTAVAC® and ROTAVAC® 5CM, hen administered to infants in a three dose schedule at 6, 10 and 1 ee s of a e and Rotari ®, hen administered to infants in a t o dose schedule at 6 and 10 ee s of a e Immunogenicity To evaluate the immuno enicity of Rotari ® 28 days after the last dose of the vaccine, hen administered to infants in a t o dose schedule at 6 and 10 ee s of a e xploratory Ob ective: To evaluate the immuno enicity of the three vaccines by LISA usin 8 12 1P8 virus as a substrate in a subset of the sam les collected
Study ndpoints Primary ndpoint: Immunogenicity: eometric mean concentrations MCs of serum anti rotavirus I A antibodies, 28 days after the last dose of a study vaccine, as measured by en yme lin ed immunosorbent assay LISA usin C3 as the viral lysate Secondary ndpoints: Safety The secondary safety end oints ill include: Immediate adverse events, ithin 30 minutes’ ost vaccination Solicited ost vaccination reacto enicity fever, diarrhea, vomitin , decreased a etite, irritability, decreased activity level durin the day eriod Day 0 6 after each vaccination Unsolicited A s from first vaccination throu h ee s after the last vaccination SA s, includin intussusce tion from first vaccination throu h ee s after the last vaccination of each study artici ant Immunogenicity The secondary immuno enicity end oints anti rotavirus I A usin C3 as the Lysate ill be as follo s: 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 ost vaccination serum anti rotavirus I A antibody concentration of at least 20 U mL if a baseline
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Protocol Number CVIA 066 Version Number: 01 Version Date: 11 July, 2018
concentration is 20 U mL or a ost vaccination serum anti rotavirus I A antibody concentration of 2 fold baseline level if a baseline concentration is 20 U mL Sero ositivity rate at baseline and 28 days after last dose of study vaccine Day 8 for ROTAVAC® and ROTAVAC 5CM and Day 56 for Rotari ® Sero ositivity is defined as serum anti rotavirus I A antibody concentration 20 U mL Serores onse rate 28 days after last dose of study vaccine Day 8 for ROTAVAC® and ROTAVAC 5CM and Day 56 for Rotari ® Serores onse ill be assessed as a four fold, three fold and t o fold rise in antibody concentration from baseline 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 ® ith reference to baseline xploratory ndpoints: The e loratory end oints based on anti rotavirus I A antibodies measured by LISA usin 8 12 as the viral lysate in a subset of sam les ill be as follo s: MCs of serum anti rotavirus I A antibodies 28 days after the last dose of study vaccine Seroconversion rate 28 days after last dose of study vaccine Seroconversion is defined as a ost vaccination serum anti rotavirus I A antibody concentration of at least 20 U mL if a baseline concentration is 20 U mL or a ost vaccination serum anti rotavirus I A antibody concentration of 2 fold baseline level if a baseline concentration is 20 U mL Sero ositivity rate at baseline and 28 days after last dose of study vaccine Sero ositivity is defined as serum anti rotavirus I A antibody concentration 20 U mL M R that is a ratio of MCs at 28 days after last dose of study vaccine ith reference to baseline
Study Design This study is desi ned as a Phase IIb, sin le center, randomi ed, controlled, o en label study ith 3 rou s of infants n 150 er rou receivin either three doses of ROTAVAC® three doses of ROTAVAC 5CM or t o doses of Rotari ® 50 artici ants ill be randomi ed 1:1:1 to receive ROTAVAC®, ROTAVAC 5CM or Rotari ® The three doses of ROTAVAC® and ROTAVAC 5CM ill be administered at 6, 10 and 1 ee s of a e hereas t o doses of Rotari ® ill be administered at 6 and 10 ee s of a e All vaccines ill be administered concomitantly ith PI vaccines includin Di htheria, Tetanus, Pertussis,
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Protocol Number CVIA 066 Version Number: 01 Version Date: 11 July, 2018
and He atitis B vaccine DT P Hib He B , Pneumococcal con u ate vaccine and OPV at 6, 10 and 1 ee s and IPV at ee 1 hen s itched to in Zambia The artici ants ill be monitored for 30 minutes follo in vaccine administration for immediate adverse events A blood sam le ill be obtained from all the artici atin infants before first vaccination and four ee s after the last vaccine dose This ould mean that the blood sam le ill be collected at a ro imately 1 ee s of a e for infants in the Rotari ® arm and 18 ee s for infants in the ROTAVAC® rou s nhanced assive Active surveillance for vaccine reacto enicity solicited reactions over the day eriod after each vaccination ill be conducted on all infants In addition, surveillance for unsolicited A s, SA s includin intussusce tion ill be carried out over the eriod bet een first vaccination and four ee s after the last vaccination on all infants The study ill com are the immuno enicity of the t o formulations of ROTAVAC® i e ROTAVAC® vs ROTAVAC 5CM and ill descri tively analy e the immune res onse to Rotari ®
Study population 50 infants 150 er arm , 6 8 ee s of a e ill be enrolled in the study All enrolments ill be done in a sin le centre in Zambia
Number of One At the CIDRZ Research Unit at eor e Health Centre in Lusa a participating sites
Study Duration A ro imately 12 months
Participant 3 5 months er artici ant includin follo u eriod of 28 days Duration after the last vaccination
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Protocol Number CVIA 066 Version Number: 01 Version Date: 11 July, 2018
AC RO ND AND RATIONAL
. urden of Disease Diarrhea is a ma or cause of death amon children under five years of a e lobally 1 Rotavirus is the leadin cause of severe diarrhea, resultin in an estimated 215 000 ran e, 1 000 233 000 deaths in 2013 hich corres onds to 3 of all deaths in children 5 years of a e The lar est number of rotavirus deaths occurred in sub Saharan Africa, here the number is estimated at 121 000 ran e, 111 000 131 000 deaths in 2013 Rotavirus deaths decreased at a slo er rate in sub Saharan Africa than in the other re ions, resultin in an increasin ro ortion of all rotavirus deaths occurrin in this re ion from 3 in 2000 to 56 3 in 2013 1 More than 0 of rotavirus deaths occurred in countries eli ible for avi su ort 2 i ure 1 Mortality rate due to rotavirus disease amon children 5 years of a e, by country, 2013
Diarrhea is the third leadin cause of child death in Zambia U to one third of diarrhea cases resultin in hos itali ation and or death are caused by vaccine reventable rotavirus 3 In line ith the orld avera es, in 2013, Zambia re orted a total of 563 diarrhea related deaths of hich 38 2 diarrheas ere ositive for rotavirus This corres onds to a ro imately 3 of all cause mortality in children less than 5 years of a e Nearly all children, re ardless of eo ra hic location or economic status, are infected ith rotavirus before their third birthday, but children in lo income countries are far more li ely to be infected earlier in life and, because access to ur ent care can be limited or unavailable in rural, im overished settin s, they are more li ely to develo severe disease and die 5 Studies conducted in Zambia have re orted sero ositivity rate in a ro imately 25 of the infants rior to vaccination 6
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Protocol Number CVIA 066 Version Number: 01 Version Date: 11 July, 2018
Hi h rotavirus mortality rates still revail in lo income countries in s ite of the si nificant im act of oral rehydration thera y ORT and the eneral im rovement in sanitary conditions Such hi h mortality rates are li ely associated ith the elevated incidence of malnutrition, other co morbidities and ith limited access to a ro riate medical care In addition to causin loss of lives, rotavirus laces a heavy burden on health care systems and on families ith rohibitive medical care costs and loss of roductivity for adults ta in care of sic children Standard methods of sanitation such as antibacterial soa s are not 100 effective in illin the virus, and because lo numbers of viruses can cause infection, transmission is common even ith ood hy iene ractices The most effective antise tics a ainst rotavirus are alcohols, hich have been found to reduce the number of viruses on the hands by reater than Ho ever, ta ater alone, or ta ater ith re ular soa reduces the titer by only 2 8 Thus, rotavirus vaccination is no recommended for use in every country in the orld and should be a art of a com rehensive strate y to control diarrheal diseases ith the scalin u of both revention romotion of early and e clusive breastfeedin , hand ashin ith soa , im roved ater and sanitation and treatment ac a es includin lo osmolarity ORS and inc Rotavirus vaccine im lementation in settin s of hi h child mortality in Africa and Asia is ust be innin to occur, and the real lifesavin otential of vaccination has yet to be reali ed The ublic health im act of rotavirus vaccination has been demonstrated in several countries or e am le, in the USA, a measurable decrease as seen in the number of rotavirus astroenteritis hos itali ations accom anied by a su ested herd effect rotectin older non vaccinated children, hile in Me ico a decline of u to 50 in diarrheal deaths in children 5 years of a e as attributed directly to the use of the vaccine HO continues to recommend that the first dose of either RotaTe ® or Rotari ® be administered as soon as ossible after 6 ee s of a e, alon ith DTP vaccination A art from a lo ris of intussusce tion 1 to 5 er 100 000 infants vaccinated the current rotavirus vaccines are considered safe and ell tolerated In lo income countries, vaccine efficacy can be lo er than in industriali ed settin s, similar to other live oral vaccines, ho ever, due to the hi h rates of severe diarrhea, this modest efficacy still translates into hi h ublic health im act, thereby ma in rotavirus vaccination hi hly cost effective in hi h mortality settin s Live attenuated oral rotavirus vaccines ere first develo ed for hi h income countries and have been sho n to have modest efficacy in develo in countries in the ran e of 0 to 60 8 12 In countries in Africa hich had introduced rotavirus vaccination, the African rotavirus surveillance net or has re orted a si nificant dro in the ro ortion of hos itali ed rotavirus diarrhea amon children less than five years of a e The surveillance re orted a direct correlation of this effect ith the time hen rotavirus vaccine as introduced In the countries that introduced rotavirus vaccine by 2013 R anda, Tan ania, Zambia and thio ia , avera e rotavirus vaccine covera e reached u to 0 in 2015 and rotavirus ositivity decreased from 35 in 2010 to 1 in year 2015 Understandably, the covera e as lo er in year 2015 in countries hich im lemented vaccination after year 2013 ith only 51 in year 2015 but in these countries too, the avera e rotavirus ositivity decreased from 1 in 2013 to 25 in 2015 hence rovin the advanta es of im lementin rotavirus vaccination in ro rammatic settin s Rotari ® as introduced in the routine ublic health immuni ation ro ram in Lusa a, Zambia, in January 2012 and as rolled out country ide in November 2013 A study in Lusa a Zambia re orted that follo in rotavirus vaccine introduction, seasonal ea s of rotavirus and all cause A ere smaller The study observed a si nificant reduction in A associated in hos ital morbidity and mortality follo in
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Protocol Number CVIA 066 Version Number: 01 Version Date: 11 July, 2018 rotavirus vaccine introduction The reatest reduction as seen in infants 1 year ho accounted for 8 of rotavirus hos itali ations rior to vaccine introduction 13 Another case control study in Zambia re orted a Vaccine ffectiveness of around 26 a ainst rotavirus diarrhea of all severity and around 56 a ainst hos itali ed children concludin that rotavirus vaccines are more effective a ainst disease of increased severity of illness com ared ith milder disease 3 Three rotavirus vaccines, Rotari ® S , RotaTe ® Merc and ROTAVAC® BBIL are currently HO re ualified ith Rotari ® and RotaTe ® bein idely available One other vaccine, ROTASIIL® SIIPL , has been licensed in India and may be evaluated for HO re ualification Althou h Rotari ® and RotaTe ® are considered effective in reventin severe astrointestinal disease and are currently more idely available and have been demonstrated to be safe and effective in lo income, hi h burden o ulations, they are not affordable in develo in countries The recent lobal recommendation by the orld Health Or ani ation HO ’s Strate ic Advisory rou of erts on Immuni ation SA for the inclusion of rotavirus vaccines in all national immuni ation ro rams and considered a riority articularly in countries in South and Southeast Asia and sub Saharan Africa is e ected to further increase demand, but economic barriers to access remain, and vaccine su ly continues to be an issue for the countries in most need To address this, it is critical that a mature mar et for rotavirus vaccines, includin manufacturers from develo in countries, develo s as uic ly as ossible At US 1 er dose, initially, ROTAVAC® is substantially less e ensive than other available rotavirus vaccines
. Pathogen Rotavirus as identified in 1 3 from the small intestine s e ithelial cells of children ho are affected by diarrhea 1 Humans are mainly infected by s ecies A, B, and C amon the available ei ht s ecies A, B, C, D, , , , and H , but more than 0 of diarrheal infections are caused by s ecies A The rotavirus enome, shelled ith three roteins a core, inner membrane, and outer ca sid , contains an 11 se mented double stranded enome Both structural roteins VP1 VP , VP6, VP and non structural rotein NSP1 NSP are encoded by rotaviral RNA ene se ment, but only ene se ment 11 codes for NSP5 and NSP6 The outer shell that is used to characteri e the rotavirus strain is formed by VP a lyco rotein rotein and VP a rotease cleaved rotein P rotein The combination of and P roteins is mediated by VP and VP structural rotein due to its inde endent nature of se re ation 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 roteins It is sus ected that clinical rotection robably involves mucosal intestinal , systemic antibody res onse, and cell mediated immunity, ho ever it is difficult to reali e the mechanism of rotection, as ell as duration of rotection a ainst rotavirus infection 15,16 The e act mechanism of rotavirus infection ithin the ublic health community is relatively un no n1 ,18 Probably, rotavirus diarrhea is multi factorial, ith malabsor tion and secretion com onents, and may have other com onents su ested to be related to villus ischemia and intestinal motility The rotavirus mostly refer to infect durin cool and dry seasons ith infection sho in ea s in inter to cause diarrhea 1 ,20 The molecular mechanisms underlyin the ra id induction of heteroty ic rotective immunity to rotavirus, hich rovides the basis for the efficacy of licensed monovalent rotavirus vaccines, have
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Protocol Number CVIA 066 Version Number: 01 Version Date: 11 July, 2018 remained un no n idemiolo ic and clinical studies demonstrate that heteroty ic rotective immunity is enerated after a sin le rotavirus infection21 or immuni ation 22,23
. Description of Study Vaccine Several studies have documented that the first rotavirus infection in infants rotects a ainst severe diarrhea durin reinfection 21,2 In the mid 1 80s, neonates born at the All India Institute of Medical Sciences Ne Delhi ere commonly infected ith a rotavirus strain before hos ital dischar e that as later encoded 116 These infants remained asym tomatic and e erienced 6 fe er e isodes of rotavirus diarrhea than did a cohort of babies born at the same institute ho ere not neonatally infected A reater reduction in the severity of diarrhea as observed in the neonatally infected than the non infected neonates Because infection ith strain 116 did not cause diarrhea in ne borns and as not found in older atients ith diarrhea, it a eared to be naturally attenuated urthermore, the strain re ell in the infant ut, induced rotavirus s ecific immuno lobulin I A or I M antibody res onses, and offered clinical rotection 25,26 hile rotaviruses do not commonly infect infants in the first fe months of life, this strain as uni ue in that it re in the resence of trans lacental antibodies from the mother2 Human neonatal strains similar to Rotavirus 116 iven alone are li ely to rotect children a ainst a variety of rotavirus strains of different seroty es 28 Bharat Biotech International Limited Hyderabad, India develo ed the oral rotavirus vaccine ORV 116 to address the need for a safe, effective, and affordable vaccine for India and the develo in orld as a art of the Indo US Vaccine Action Pro ram and ith technical su ort from the De artment of Biotechnolo y India , the US Centers for Disease Control and Prevention CDC , the National Institutes of Health, Stanford University, and PATH 2 The vaccine as successfully develo ed and named as ROTAVAC® urther, clinical trials in India roved the efficacy of ROTAVAC® in reventin severe rotavirus astroenteritis ROTAVAC® as licensed by CDSCO National Re ulatory A ency in 201 ROTAVAC® as initially a roved as a 3 dose re imen to be iven ith routine childhood vaccines at 6, 10, and 1 ee s of a e alon ith 2 5 mL citrate bicarbonate buffer to facilitate assa e throu h the acidic contents of the u er astrointestinal tract Several studies have been carried out to e amine the role of buffer on the erformance 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 althou h natural transmission of rotavirus occurs via the faecal oral route and occurs in the resence of un neutrali ed astric acid It is also ostulated that the human infant stomach ith hi her H levels a ro imately 3 2 com ared to adults a ro imately 1 0 may be more ermissive for the survival of rotavirus In addition, in humans, homolo ous rotaviruses human ori in rotavirus in a human are much more 1000 fold infectious than heterolo ous rotavirus non human ori in rotavirus in a human and only very small uantities of homolo ous rotavirus 10 infectious doses or less are enerally able to cause infection, immune res onse and illness 35,36 In eneral, the results have been found to be mi ed in nature and all commercial vaccines use bufferin com onents either as art of the formulation RotaTe ® and Rotari ®, in some mar ets or reconstituted at the time of administration Rotasiil® in India and Rotari ® in some mar ets hich ose several lo istic and ro rammatic challen es in terms of either havin to se arately trans ort and store the bufferin diluent, and administer relatively lar e volumes 1 5 to 2 16 mL of reconstituted or ready to use vaccine orally to infants 3 3 rom a vaccine administration oint of vie for infants, lo dose volumes, ty ically
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Protocol Number CVIA 066 Version Number: 01 Version Date: 11 July, 2018 around 0 5 mL, are referred Immuni ation ro rams refer vaccines that are ready to use and do not re uire reconstitution or administration of se arate com onents, such as a diluent or a buffer, to minimi e errors in administration Considerin the human ori in of 116 strain, hich belon s to the and P 11 enoty es and the a e at immuni ation, it as hy othesi ed that the strain may re licate and the vaccine may confer immunity ithout a buffer administration as it as initially recovered from an asym tomatic neonate urther, the hi h H stability of the 116 strain also su ests that the challen e of remi in the vaccine ith the buffer before administration could be avoided, and hence by ass any ro rammatic challen e hen bein administered alon the other vaccines in The anded Pro ram on Immuni ation PI In vie of this, and su orted by the results of a clinical study demonstratin similar immune res onse achieved by ROTAVAC® hen administered ith and ithout antacid buffer, ROTAVAC® ithout buffer as also a roved and the vaccine as licensed on 30 A r 2015 and is no available for commercial use ROTAVAC® has a dosin volume of 0 5 ml dose ith the inherent acid neutrali in ca acity of the vaccine eliminatin the need to administer an al ali buffer se arately rior to the vaccine Hence the cold chain foot rint of these vaccines is mar edly reduced ith the cold chain volume of ROTAVAC® bein bet een 3 2 2 cm3 dose hereas the same is bet een 6 25 5 26 for RotaTe ® and 1 12 115 3 cm3 dose er vial for Rotari ® The vaccine as still recommended to be stored at 20 C The overnment of India has rolled out rotavirus vaccination as art of the PI in a hased manner and ROTAVAC® is bein used for this ur ose in fe of the states in India Till date, the com any has su lied 35 million doses to the PI ro ram in India It has also initiated su ly of HO Pre ualified the vaccine to UNIC and other immuni ation ro rams orld ide 0 BBIL further undertoo the develo ment of a li uid formulation of the vaccine, ROTAVAC 5C that is stable at 2 8 C for over 2 months thereby ma in it amenable for easier stora e and trans ort This formulation contains the same rotavirus strain 116 as in ROTAVAC® These formulations also have sufficient Acid Neutrali in Ca acity ANC to neutrali e the astric uices in stomach, thus, su ortin survival of the vaccine virus The formulation as chan ed by addition of e ci ients and stabili ers belon in to the enerally re arded as Safe RAS cate ory urther to this and based on the ROTAVAC® clinical trial results ithout buffer, formulation of ROTAVAC 5C 1 5 mL as modified to 0 5mL volume and the internal buffer com onents ere removed, hich later as named as ROTAVAC® 5CM, a li uid formulation that is stable at 2 8 C stora e tem erature ROTAVAC 5CM is ithout buffer and has additional e ci ients and stabili ers same as in ROTAVAC 5C, ith established safety and immuno enicity that belon to RAS cate ory and additionally any ne safety concerns are not antici ated ROTAVAC 5CM vaccine formulation also has e cellent stability at 25 C and 3 C The advanta es ith such li uid formulations include stability at 2 8 C hich ma es the vaccine amenable for easier stora e and trans ort, and the acid neutrali in ca acity hich eliminates the need to administer an al ali buffer se arately rior to the vaccine International Patents have been ranted in several countries includin India, USA, U and South Africa for these ROTAVAC® vaccine formulations The dia ram belo describes the develo ment of ROTAVAC® formulations
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Protocol Number CVIA 066 Version Number: 01 Version Date: 11 July, 2018
. . Immune Responses to Rotavirus Vaccines Challen e of adult volunteers ith ild ty e rotavirus strains and trials of live rotavirus vaccines have sho n a correlation bet een re e istin rotavirus antibodies, articularly I A, and the ability of the viruses to infect corres ondin ly, serum res onses after live virus challen e resultin in infection include a si nificant increase in antibody levels, I A in articular Testin antibodies in serum of infants under months of a e, before they receive a live vaccine, has demonstrated the resence of si nificant amounts of anti rotavirus s ecific I of maternal ori in, the half life of hich is such that by the fourth month such antibodies are barely detectable On the other hand, I A antibodies are no n not to cross the lacenta and therefore are not resent in re immune serum unless natural infection has occurred Accordin ly, the induction of an I A serores onse is the best available tool to assess the immuno enicity of any rotavirus vaccines An LISA based anti rotavirus I A, develo ed and validated by ard, et al , at the Cincinnati Children’s Hos ital Medical Center CCHMC and later ada ted to use in multi le laboratories, has become the standard test to evaluate immune res onses to rotavirus vaccine 1 hen evaluated in develo ed countries, all reviously licensed vaccines RotaShield®, Rotari ®, and RotaTe ® ere sho n to induce a 3 or fold res onse de endin on the study analysis in 80 or more
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Protocol Number CVIA 066 Version Number: 01 Version Date: 11 July, 2018 of the artici ants ith corres ondin eometric mean concentrations MCs 100 Ho ever, hen tested in resource oor countries, and in arallel to their diminished efficacy in these countries, both the serores onse rates as ell as the MCs are reatly diminished ith serores onse rates in some cases belo 0 and MCs as lo as 30 Note, ho ever, that in s ite of this arallelism, no correlation has been found bet een I A res onses and efficacy levels Conversely, in some studies immuno enicity rates have been hi her than the efficacy rates or instance, the serores onse rates for Rotari ® in Vietnam study have been a ro imately ith efficacy rates of a ro imately 6 A study conducted in Zambia re orted 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 Ris s of Rotavirus Vaccines Ris of vaccination ith live attenuated rotaviruses include develo ment of fever, diarrhea or vomitin as a conse uence of the ro th of the virus in the child’s intestine, ho ever, all the animal and animal human rotavirus reassortants tested to date at similar or hi her titers to those used ith ROTAVAC® have seen adverse events li e fever, diarrhea, cou h, vomitin , irritability, otitis media, naso haryn itis, bronchos asm, cryin and rash bein re orted as common adverse events In babies, natural rotavirus infection can cause diarrhea, vomitin and fever these occurrences have been self contained and of easy mana ement 3 ,38 Shortly after the introduction of RotaShield® in the US, the vaccine as associated ith a very small increase in the incidence of intussusce tion after vaccination, articularly follo in the first vaccine dose in older infants This led to ithholdin any subse uent use of this vaccine and ut a si nificant burden on future rotavirus vaccine develo ers to demonstrate ith a reasonable de ree of certainty that their candidates ere not associated ith this outcome Both Rotari ® and RotaTe ® under ent lar e safety studies in tens of thousands of children in hich the occurrence of intussusce tion as closely follo ed The hi h level of efficacy observed in those studies, alon ith the vaccine safety rofile and lac of association ith intussusce tion ere sufficient to achieve licensure in many countries Additional ost mar etin studies initially su ested that intussusce tion mi ht still be associated ith the licensed vaccines, but at much lo er rates than could have been detected in the clinical trials A recently com leted study in the US, here ost vaccination surveillance as conducted in 3 3 ee old infants after the administration of over 50,000 doses of the RotaTe ® vaccine, sho ed a lac of association bet een vaccination and the occurrence of intussusce tion in the eriods of 1 to or 1 to 30 days ost vaccination 22 The HO resently su orts seven Rotari ® vaccine usin countries includin Zambia , and another four countries that are usin the RotaTe ® vaccine, to systematically collect surveillance data on intussusce tion, and other Adverse events follo in immuni ation A I Tools for systematic collection of data are readily available for enhanced surveillance 2
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Protocol Number CVIA 066 Version Number: 01 Version Date: 11 July, 2018
. Summary of Nonclinical Studies of Study Vaccine To icolo y studies for oral rotavirus 116 vaccine ere conducted in S iss Albino Mice, S ra ue Da ley Rat, ischer 3 Rats and rabbits The reclinical to icity studies of Rotavirus 116 ormulations ere conducted in RCC Laboratories, a LP certified testin facility and CPCS A and AAALAC Accredited animal facility The characteri ation from these studies identified that the vaccine did not dama e any or an structurally or functionally in animals The Summary details of the studies erformed for Oral Rotavirus 116 vaccine formulations is tabulated belo : Study atch number Dose Composition A 28 Day Re eated Dose T 11002 Sucrose 0 , Trehalose0 5 , HA To icity Study of T o 106 0 U 0 5mL 0 35 , LAH 1 , 3mM Ca, ormulations of Oral Citrate 0 052 M, Rotavirus 116 Vaccine, Live Potassium Phos hate 0 1 M, Attenuated in S iss Albino T 11012 Sucrose 30 , Lactose 5 , HA Mice 106 0 U 1 0mL 0 35 , LAH 0 5 , 3mM Ca, Citrate 0 03 M, Bicarbonate 0 3 Dosin : Day 0, 3, 6, , 12, 15 M and day 28 Re eated Dose 28 Days Oral 61 Z13001 Sucrose 0 , Trehalose 0 5 , To icity Study ith Oral 106 10 U 1 5 mL LAH 0 5 , HA 0 35 , Rotavirus 116 e Vaccine, II 1 1 M Potassium Phos hate eneration our 61 Z13002 Sucrose 50 , Trehalose 0 5 , ormulations In S ra ue 106 15 U 1 5 mL LAH 0 5 , HSA 0 35 , 0 053 M Da ley Rat Trisodium Citrate, 0 1 M Dosin : Day 0, day , day 1 Potassium Phos hate and day 21 61 Z13003 Sucrose 50 , Trehalose 0 5 , 106 18 U 1 5 mL LAH 1 0 , HSA 0 35 , 0 15M Re eated Dose 28 Days Oral Trisodium Citrate, 0 3M Potassium To icity Study ith Oral Phos hate Rotavirus 116 Vaccine, II 61 Z1300 Sucrose 55 , Trehalose 0 8 , eneration our 105 3 U 1 5 mL LAH 1 0 , 0 15 M Trisodium ormulations in Rabbits Citrate, 0 3 M Potassium Phos hate Dosin : Day 0, day , day 1 61DA13001 Reference 105 38 U 0 5 mL and day 21 28 Day Re eated Oral Dose 61 Z13001 Sucrose 0 , Trehalose 0 5 , Proof of Conce t Study ith 106 10 U 1 5 mL LAH 0 5 , HA 0 35 , 1 1 M Oral Rotavirus 116 Vaccine, Potassium Phos hate Ii eneration T o 61 Z1300 Sucrose 55 , Trehalose 0 8 , ormulations in ischer 3 105 3 U 1 5 mL LAH 1 0 , 0 15 M Trisodium Rats Citrate, 0 3 M Potassium Phos hate Dosin : Day 0, day 1 and day 61DA13001 Reference 105 38 U 0 5 mL 28
In the above studies all animals in the rou s ere observed and e amined for clinical si ns, o hthalmosco y, body ei hts and food consum tion, clinical atholo y, or an ei hts and histo atholo y of the reserved or ans and tissues The studies revealed no adverse findin s in
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Protocol Number CVIA 066 Version Number: 01 Version Date: 11 July, 2018 any of the Oral Rotavirus 116 Vaccine treated animals, and all the formulations ere com arable ith reference test item In conclusion, under the conditions of these studies, 28 day re eated oral dose ith Oral Rotavirus 116 formulations revealed no adverse findin s in any treated animals, hen com ared ith the lacebo The studies ere initiated in 0 5 mL formulations and later on in continuation of develo in formulation ith buffer herein the dose volume is 1 5 mL The ro osed ROTAVAC 5CM has similar e ci ients as in 61 Z13001 and T 11002 and differ only in the concentration Buffer com osition is similar to 61 Z1300 herein the buffer system is citrate hos hate Dose volume and concentration of buffer system and e ci ients did not affect the results of the studies Hence it is roved that the e ci ients and buffer system used for ROTAVAC 5CM ere 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® (- 0 C) The early clinical develo ment of A M Vaccine 116 in adults, children and infants ere a collaborative effort bet een the Society for A lied Studies SAS , AIIMS, NIAID and PATH The results of these studies, hich ere conducted amon adults, children a es 2 to 12 years, and infants a es 6 to ee s, rovided the basis for BBIL to further develo the vaccine The follo in are the studies that ere conducted ith ROTAVAC®
Table . List of clinical trials of ROTAVAC® Clinical trial N Formulation Location ndpoint Status Phase Phase 1: 30 116 or I321 105 0 U India Safety Com leted adults or Placebo Phase 1: 30 India Safety Com leted children Phase 1: 0 India Safety and Com leted infants immuno enicity Phase 1b 2a: 360 116 , 10 0 ffu or 105 0 India Safety and Com leted infants ffu or Placebo immuno enicity Phase 3: 6800 116 105 0 ffu ith India fficacy Com leted infants buffer or Placebo Phase 3: 1356 116 105 0 ffu ith India Lot to lot Com leted infants buffer or consistency and Placebo interference ith childhood vaccines Phase : 00 ROTAVAC® ithout India Immuno enicity Com leted infants buffer and safety
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Protocol Number CVIA 066 Version Number: 01 Version Date: 11 July, 2018
ROTAVAC® ith buffer administered 5 minutes before ROTAVAC® ith buffer administered simultaneously Phase : 6 ROTAVAC® or India Immuno enicity Com leted infants Rotari ® and safety Phase 3 6 5 ROTAVAC® or Rotavac India Reacto enicity Com leted loratory: 5C 1 5 ml or Rotavac and Safety infants 5C 2 0 ml Phase 3 1,302 ROTAVAC® or Rotavac India Immuno enicity Com leted Confirmatory: 5C 2 0 ml , Lot 1 2 and safety infants Phase 3: 360 ROTAVAC® or India Safety and Com leted infants ROTAVAC 5CM immuno enicity In these studies, ROTAVAC® ithout buffer as used
Phase Study in Healthy Adults in India A hase 1 randomi ed, double blind, lacebo controlled, safety and immuno enicity study as conducted in healthy adults A total of 30 volunteers a ed 18 5 years received a sin le oral dose of either the 116 or I321 105 0 U or Placebo accordin to a 1:1:1 vaccine: vaccine: lacebo randomi ation Vaccine or lacebo as administered orally after consumin 2 sodium bicarbonate dissolved in 120 ml sterile ater to buffer stomach acidity The study evaluated safety and immuno enicity of the study vaccines and sheddin of the vaccine virus No vaccine related SA as re orted Intussusce tion as not re orted by any artici ant None of the artici ants shed rotavirus in stools as ascertained throu h anti en detection ny me Lin ed Immunosorbent Assay LISA None of the artici ants seroconverted i e had a fold rise in rotavirus s ecific I A Both vaccines re licated oorly in adults and a eared to be safe
Phase Study in Healthy Children in India A hase 1 study ith similar study desi n as the adult study above as conducted in healthy children a ed 2 12 years This study also did not re ort any vaccine related SA or case of intussusce tion Sym toms such as fever, diarrhea, vomitin ere rare and not differentially distributed Mild abdominal ain as more common in the study vaccine rou s, but only one child re uired medication Both vaccines re licated oorly in children and a eared to be safe None of the artici ants shed rotavirus in stools as e amined by anti en detection LISA One artici ant seroconverted i e had a fold rise in rotavirus s ecific I A in the 116 rou the baseline concentration in this child as lo
Phase Study in Healthy Infants in India This study as a hase 1 randomi ed, double blind, safety and immuno enicity study of live, attenuated neonatal rotavirus vaccine candidate strains 116 or I321 in healthy non malnourished infants a ed 8 12 ee s The study enrolled 0 infants ith 30 infants each receivin 116 or I321 vaccines 105 0 fluorescence focus units, ffu in 1 ml or lacebo UIP vaccines ere not administered concomitantly The study evaluated safety and immuno enicity of the study vaccines
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Protocol Number CVIA 066 Version Number: 01 Version Date: 11 July, 2018 and sheddin of the vaccine virus ected adverse events such as fever, diarrhea associated ith vomitin and diarrhea not associated ith vomitin ere similar in both rou s Virus as shed on day 3 or , by t o out of 30 infants in the lacebo rou , one out of 2 in I321 rou and 12 out of 30 in 116 rou infants In the er rotocol analysis, the ro ortion of infants sho in fold rise in I A antibody durin 28 days ost administration of vaccine lacebo as five out of 30 16 in the lacebo rou , nine out of 28 32 1 in I321 rou and 16 out of 30 53 3 in 116 rou The study concluded that 116 strain is attenuated, clinically safe and hi hly immuno enic ith a sin le dose 3
Phase b a Study in Healthy Infants in India A fro en 0 C Rotavirus 116 candidate vaccine roduced by BBIL su orted by De artment of Biotechnolo y DBT and PATH as tested in a dose ran in study for safety and immuno enicity in infants 8 20 ee s of a e The randomi ed, double blind lacebo controlled trial tested t o doses of the ORV 116 , 10 0 ffu and 105 0 ffu Infants received a dose of either vaccine at 8, 12, and 16 ee s, se arately from routine vaccines There ere no vaccine related serious adverse events, and no si nificant differences in clinical adverse events or laboratory to icity ere observed bet een vaccine and lacebo reci ients The seroconversion rates ith the 105 0 ffu dose ere 6 5 vs 23 3 ith a sin le dose and 8 and 28 1 after three doses in the vaccine and lacebo rou s, res ectively These ere si nificantly hi her than the lo er dose These results led to selection of three doses of the vaccine candidate in a dose of 1 105 U dose for the hase III efficacy study
Phase Study in Infants in India The fro en 20 C Rotavirus 116 candidate vaccine roduced by BBIL su orted by De artment of Biotechnolo y DBT and PATH has been tested in an efficacy study in infants The hase 3 ivotal efficacy study as a double blind lacebo controlled, multicenter trial enrollin 6 infants The infants ere randomi ed to receive three doses of vaccine 116 105 0ffu or lacebo at 6, 10, and 1 ee s of a e The rimary outcome as severe rotavirus astroenteritis ith 11 oints on the Vesi ari scale Based on the incidence in the t o arms, vaccine efficacy a ainst severe rotavirus astroenteritis in children in the first year of life as calculated as 56 3 5 CI 36 to 6 hereas it as only mar inally less at 8 in the second year of life Overall efficacy u to 2 years of a e as 55 1 0 0001 The study estimated that the number of infants needed to be immuni ed to revent one e isode of severe RV in the first 2 years of life as 0 and for RV of any severity, it as 21 Seroconversion rates ere analysed usin 2 , 3 and fold res onse The I A immune res onse rates ere moderate fold 3 , 2 fold 56 3 and 3 fold 6 Viral sheddin as hi hest on day 3 or after dose 1 2 The The rotection offered by the vaccine durin the first 2 years of life as a ainst the array of commonly circulatin enoty es includin 1P 8 , 2P , 12P 6 , 12P 8 and P , althou h 116 vaccine has an unusual P 11 enoty e that is rarely associated ith clinical disease in India or other countries This su ests that the vaccine could offer si nificant rotection in varyin eo ra hical settin s over time SA s, deaths and cases of intussusce tion ere similar bet een vaccine and lacebo rou s 23
Phase Lot Consistency and Non-Interference with Childhood Vaccines Study in India This is a lacebo controlled study desi ned to assess non interference of ORV 116 to the childhood vaccines namely entavalent vaccine and oral olio vaccine , hen co administered at
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Protocol Number CVIA 066 Version Number: 01 Version Date: 11 July, 2018
6 , 10 1 and 1 18 ee s of a e and clinical consistency in the immune res onses to the three roduction lots of ORV 116 This study demonstrated that three doses of ROTAVAC® can be safely co administered ith three doses of entavalent vaccine and oral olio vaccine ithout diminishin an infant’s serum antibody res onses to each com onent of these vaccines The three ROTAVAC® lots tested ere roven to be not different as statistical clinical e uivalence across them as established ROTAVAC® is enerally ell tolerated ith res ect to solicited adverse events of s ecial interest fever, vomitin , diarrhea, cou h, listlessness or less active, runny nose, irritability, and rash There as no case of intussusce tion associated ith the administration of ROTAVAC® 5
Based on romisin results of the hase 3, safety and efficacy clinical trial of the oral rotavirus human 116 strain ORV 116 , ROTAVAC® ith buffer , manufactured by Bharat Biotech International Limited, Hyderabad, India, it as licensed in India in 201
Phase ith and ithout uffer Study in Infants in India This as a sin le blind study to evaluate the immuno enicity and safety of ROTAVAC® A total of 00 artici ants ere enrolled in the study in three different treatment rou s ith 1:1:1 ratio ROTAVAC® as administered in a 3 dose series ith and ithout buffer to healthy infants Immuno enicity as tested in terms of MCs of serum anti rotavirus I A and seroconversion in all three treatment rou s Seroconversion as defined as achievement of ost vaccination titer of 20 U mL in infants ith re vaccination titer of 20 U mL or achievement of a 2 fold rise in their ost vaccination titer if re vaccination titers ere 20 U mL Immune res onse in three treatment rou s is com arable ith no statistically si nificant difference detected Seroconversion and MCs achieved in rou II ROTAVAC® administered ithout buffer as similar to that in the other t o treatment rou s here ROTAVAC® is administered ith buffer Post vaccination anti rotavirus I A MCs in the rou to hich ROTAVAC® as administered ithout buffer as 20 U mL in com arison to 1 6 U mL and 1 2 U mL in the t o rou s hich received antacid buffer 5 minutes rior to vaccine and simultaneously mi ed ith vaccine, res ectively Similarly, the three fold seroconversion observed in the rou s that received ROTAVAC® ithout antacid buffer and ith buffer ere bet een 2 5 and 2 2 ROTAVAC® vaccine as ell tolerated in all three treatment rou s that received the vaccine ith or ithout the antacid buffer The reacto enicity and safety ith res ect to solicited and unsolicited adverse events ere com arable across the three rou s ith no statistically si nificant difference 6
Phase Comparator Study Immuno enicity and safety of ROTAVAC® as com ared ith a HO re ualified rotavirus vaccine Rotari ® in a se arate hase IV, multicenter, o en labelled, randomi ed clinical trial in healthy infants in India our hundred and si ty four infants a ed 6 8 ee s ere e ually randomi ed to receive 3 doses of ROTAVAC® rou I or 2 dose Rotari ® rou II Infants in rou 1 ere vaccinated on day 0, day 28 and day 56 ith 3 doses of ROTAVAC® and infants in rou II ere vaccinated on day 0 and day 28 ith 2 doses of Rotari ® The t o rou s ere com ared for differences in serolo ical res onses and safety Seroconversion as defined as achievement of ost vaccination titer of 20 U mL in infants ith re vaccination titer of 20 U mL or achievement of a 2 fold rise in their ost vaccination titer if re vaccination titers ere
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Protocol Number CVIA 066 Version Number: 01 Version Date: 11 July, 2018
20 U mL Seroconversion as re orted in 3 1 artici ants and 30 6 artici ants in rou I and II res ectively Anti rotavirus eometric mean concentration MC as 20 and 2 8 for rou I and II res ectively The ro ortion of infants ho achieved fourfold rise in antibodies from baseline as 25 and 21 in rou I and II res ectively Adverse vents ere ca tured and analy ed for the entire study o ulation A total of 100 and 106 artici ants in the treatment ROTAVAC® and ROTARI ® rou s re orted at least one adverse event The distribution of solicited, unsolicited, and serious adverse events as similar across rou s The study demonstrated immunolo ical non inferiority ith the com arator Rotari ® ith a clinically acce table safety rofile Data on file CTRI 2015 12 006 28 The study results clearly establish that buffer administration is not re uired to ensure the immuno enicity of the vaccine Not havin buffer also addresses the ro rammatic issues, such as incorrect reconstitution of a vaccine, tem orary unavailability of the buffer, and reduction of the cold chain foot rint, etc ith due im ortance to all these findin s, ROTAVAC® ithout buffer as licensed in India in the year 2015 This formulation as included in the HO list of re ualified vaccines on 5th January 2018 The formulation still re uired stora e and trans ortation at 20 C
.5. ROTAVAC 5C The currently licensed fro en ROTAVAC® vaccine needed to be stored and trans orted at 20 C BBIL has been en a ed since 200 in the develo ment of a li uid formulation that is stable at 2 8 C stora e tem erature over 2 months and also has sufficient Acid Neutrali in Ca acity ANC to neutrali e the astric uices in the stomach, thus su ortin survival of the vaccine virus This chan es the formulation by addition of e ci ients and stabili ers belon in to the RAS enerally Reco ni ed as Safe cate ory The advanta es ith this formulation are t ofold: 1 ROTAVAC 5C is a stable li uid vaccine that offers many advanta es as discussed later 2 the acid neutrali in ca acity eliminates the need to administer an al ali buffer se arately rior to the vaccine ROTAVAC 5C contains the same rotavirus strain 116 as in ROTAVAC® International Patents have been ranted in several countries includin India, USA, U and South Africa for these rotavirus vaccine formulations
Phase xploratory Study In this hase 3 e loratory study, 6 8 ee old healthy infants n 6 5 ere 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 ere no statistically si nificant differences in the re and ost vaccination I A concentrations bet een the ROTAVAC 5C 1 and 2 and ROTAVAC® arms mean baseline concentration 20 , 22 3 and 2 2 U mL res ectively 0 8 com arin all arms and ost vaccination concentration 63 5, 5 1 and 6 0 U mL, res ectively 0 12 com arin 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 Si nificantly reater ro ortions of healthy infants seroconverted in the ROTAVAC® arm com ared to the ROTAVAC 5C 1 arm 0 0085 There as no si nificant difference in seroconversion rates bet een the ROTAVAC® and ROTAVAC 5C 2 formulation 0 8 Adverse event rates ere 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 ma ority of these adverse events ere re orted ithin seven days of
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Protocol Number CVIA 066 Version Number: 01 Version Date: 11 July, 2018 the study vaccine administration There as no statistically si nificant difference in the ro ortion of healthy infants e eriencin adverse events bet een those receivin either ROTAVAC 5C formulation 1 or 2 and those receivin ROTAVAC® 0 10 The safety rofile of both ROTAVAC 5C formulations 1 and 2 as found to be similar to the ROTAVAC® formulation e er healthy infants e erienced astrointestinal disturbances ith the ROTAVAC 5C 2 mL 2 formulation com ared to the ROTAVAC 1 5 mL 1 formulation There ere no A s leadin to discontinuation, no A s leadin to death, and no cases of intussusce tion 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 hase 3 confirmatory study, 6 8 ee old healthy infants n 1302 ere 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 ere no statistically si nificant differences in the re and ost vaccination I A concentrations bet een 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®, res ectively 0 2 5 Seroconversion fold or reater increase in I A 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 bet een arms as not statistically si nificant 0 8156 There ere 861 healthy infants ho e erienced 2, 8 adverse events Of these, 30 infants e erienced 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 0 86 The ma ority of adverse events occurred ithin days of vaccine administration There ere no adverse events leadin to discontinuation, no deaths and no cases of intussusce tion re orted durin this study Non inferiority a ainst the ROTAVAC® formulation as established usin t o sided 5 confidence intervals for the MC ratio bet een ROTAVAC 5C all lots combined to ROTAVAC®, re uirin a lo er limit reater than 0 50 Data on ile CTRI 2015 02 0055
.5. ROTAVAC 5CM urther to this and based on the ROTAVAC clinical trial results ithout buffer, formulation of ROTAVAC 5C 1 5 mL ormulation 1 Z as modified to 0 5mL volume and the internal buffer com onents ere removed, hich later as named as ROTAVAC 5CM, a li uid formulation that is stable at 2 8 C 5 3 C stora e tem erature ROTAVAC 5CM is ithout buffer and has additional e ci ients and stabili ers same as in ormulation 1 Z, ith established safety and immuno enicity that belon to RAS enerally Reco ni ed as Safe Cate ory and ne safety concerns are not antici ated The ROTAVAC 5CM vaccine has also been filed for international atents
Phase Study A hase 3, multicenter, randomi ed, o en labeled clinical study as conducted to evaluate the immuno enicity, reacto enicity and safety of ROTAVAC 5CM stored at 2 8 C , in com arison
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Protocol Number CVIA 066 Version Number: 01 Version Date: 11 July, 2018
ith ROTAVAC® stored at 20oC in healthy infants a ed 6 8 ee s The study enrolled 360 artici ants hich ere randomi ed in the t o rou s in a ratio of 3: 1 ith 2 0 artici ants in the ROTAVAC 5CM arm and 0 in the ROTAVAC® arm Both formulations ere administered in a dose of 0 5 ml at 6, 10 and 1 ee s of a e alon ith routine childhood vaccinations Blood sam les for immuno enicity analysis ere collected before first vaccination and ee s after last vaccination The ost vaccination MCs re orted in the ROTAVAC 5CM and ROTAVAC® rou s ere 18 0 and 1 55, res ectively The ratio of MC ROTAVAC 5CM ROTAVAC® as estimated as 0 81 and the lo er bound of t o sided 5 CI as found to fall in the 2 fold mar in bounds of 0 5 to 2 Hence the t o vaccines ere assessed to be e uivalent Also, the t o vaccines ere found to be similar hen 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 , t o fold rise 38 31 vs 31 25 for ROTAVAC 5CM and ROTAVAC® arms, res ectively The adverse events ere, Pain at the site of in ection 3 22 and 38 6 , Redness at the site of in ection 3 60 and 32 5 , S ellin at the site of in ection 32 0 and 3 50 , cryin 1 83 and 1 and fever 65 0 and 6 05 in ROTAVAC 5CM and ROTAVAC® rou s res ectively Many of these may be ascribed to routine childhood immuni ation administered concomitantly No case of intussusce tion as re orted amon the study o ulation ho ere administrated ith either of t o vaccines Overall, this study demonstrated that immuno enicity and safety rofiles of both vaccines ROTAVAC 5CM and ROTAVAC® as similar Data on file Data on ile CTRI 2016 11 00 81
.6 Potential Ris s and or enefits of Study Vaccine ROTAVAC 5CM is the ne t eneration formulation of ROTAVAC® and has the same virus strain as ROTAVAC® ith addition of some stabili ers and e ci ients of RAS cate ory ROTAVAC® and ROTAVAC 5CM have been e tensively studied in re clinical and clinical studies ROTAVAC® has been administered to more than ,000 children in clinical trials in India includin one study demonstratin efficacy of the vaccine and another study demonstratin non inferiority of immune res onse vs Rotari In these studies, ROTAVAC® as found to be efficacious efficacy of 55 1 u to 2 years of a e and immuno enic The ivotal study had active surveillance for adverse events and the vaccine as found to be safe ROTAVAC 5CM has been sho n to be e ually immuno enic as ROTAVAC Based on these data ROTAVAC® has been licensed in India and as recently included in the HO list of re ualified vaccines It has already been administered to millions of children in India under the national immuni ation lan ithout any ma or concern The otential ris for the vaccine include commonly re orted adverse events li e fever, vomitin , diarrhea, cou h, runny nose, irritability and rash In babies, natural rotavirus infection can cause diarrhea, vomitin and fever It is ossible that enrolled artici ants may have a fe looser than usual stools, cry, or have a sli htly hi her than usual tem erature for a day or t o after vaccination ith the attenuated rotavirus vaccine These events are similar to those re orted in other rotavirus vaccine clinical trials In the Phase 3 efficacy study, 11 intussusce tion cases as defined by Bri hton rade 1 have been re orted 8 of 532 artici ants in vaccine rou and 3 of the 223 in lacebo rou None occurred ithin 30 days of a vaccine dose and all ere re orted only after the third dose The intussusce tion events follo in the third dose occurred bet een 112 and 58 days ost vaccination in the vaccine rou and bet een 36 and 605 days in the lacebo rou Ten of the cases ere rotavirus ne ative hen tested for resence of rotavirus anti en in stools by LISA None of the four rotavirus ositive cases had the vaccine virus strain
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Protocol Number CVIA 066 Version Number: 01 Version Date: 11 July, 2018
Since the earlier studies ere erformed in India another develo in country it can be e ected that the vaccine ill be similarly beneficial in Zambia, and ill have similar safety rofile
. Overall Development Strategy ROTAVAC® is indicated for active immuni ation of infants from the a e of 6 ee s for the revention of astroenteritis due to rotavirus hen administered as a 3 dose series ROTAVAC® has been licensed in India in 201 and has been included on the HO list of re ualified vaccines since early 2018 These milestones ere achieved based on the data enerated in India This trial ill enerate immuno enicity and safety data on ROTAVAC® and ROTAVAC 5CM outside of India to su ort HO SA olicy recommendations and country level decision ma in
. Study Rationale This study has been desi ned to com are ROTAVAC 5CM ith the ne ly HO re ualified vaccine ROTAVAC® amon infants in Africa our hundred and fifty infants, 6 8 ee s of a e ill be enrolled and randomi ed to receive either three doses of ROTAVAC® or ROTAVAC 5CM, four ee s a art, at 6, 10 and 1 ee s of a e or t o doses of Rotari ® current standard of care in Zambia , four ee s a art at 6 and 10 ee s of a e The main ur ose of this study is to assess the immuno enicity of a full course of the t o formulations of ROTAVAC®, i e , ROTAVAC® and ROTAVAC 5CM and to assess the safety and reacto enicity of the vaccine amon African infants Rotari ® has been included as the third arm since it is bein used for routine immuni ation of children in Zambia and holds the vast ma ority of the AVI eli ible country mar et share This arm ill act as an internal control to validate immune res onse of ROTAVAC® and ROTAVAC 5CM hich are bein tested for the first time in African continent The study ill also assess the safety and reacto enicity of a full immuni ation course and of each dose of the study vaccines, ith the aim of describin its safety in Zambia Because Rotari ® is a t o dose human rotavirus vaccine and ROTAVAC® and ROTAVAC 5CM are three dose human rotavirus vaccines, ma imi in com arability of immuno enicity data is a critical driver of the desi n and tests to be used In order to ensure ma imal com arability, blood sam lin time oints in a three dose arm i e ROTAVAC® and ROTAVAC 5CM are at 18 ee s of a e, and for Rotari ® at 1 ee s of a e i e ee s after last dose ROTAVAC® has already been studied in a similar study desi n in studies conducted in Indian o ulation This trial ill enerate immuno enicity and safety data on ROTAVAC® and ROTAVAC 5CM outside of India to su ort HO SA olicy recommendations and country level decision ma in At the conclusion of the study, PATH, ublic health leaders and site investi ator s , to ether ith Bill Melinda ates oundation BM officers ill su ort BBIL in communication of results to lobal and national olicyma ers and to the lobal ublic health community Presentation of data to Zambian Ministry of Health, HO and in eer revie ed o en access ublications ill be ey audiences tar eted for communication of results Primary immuno enicity analysis of all sam les ill be based on a validated LISA hich uses strain C3 as a substrate The same test as also used for clinical trials su ortin licensure of the ROTAVAC® ithout buffer in India and for HO re ualification of the vaccine A subset of the sam les 50 airs arm collected ill also be tested by a validated LISA hich uses strain 8 12 1P8 virus as a substrate Strain 8 12 as the isolated strain that as used to develo the Rotari ® Vaccine Since no correlation bet een the t o assays has been established and it is
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Protocol Number CVIA 066 Version Number: 01 Version Date: 11 July, 2018 e ected that tests em loyin heterolo ous strains as substrate may ive lo er concentrations, no ithin rou or bet een assay com arisons ill be done
H POTH S S, O CTIV S AND NDPOINTS
. Study Hypotheses Immunogenicity ROTAVAC® and ROTAVAC 5CM administered as a 3 dose series induce com arable immune res onse in healthy African infants Safety ROTAVAC® and ROTAVAC 5CM administered as a 3 dose series are both safe and ell tolerated in healthy African infants
. Study Ob ectives
. . Primary Ob ective Immunogenicity To evaluate and com are the immuno enicity of ROTAVAC® and ROTAVAC 5CM 28 days after the last dose of the vaccine, hen administered to infants in a three dose schedule at 6, 10 and 1 ee s of a e
. . Secondary Ob ectives Safety To assess the reacto enicity days after each vaccination and safety ee s after the last vaccination of the ROTAVAC® and ROTAVAC 5CM, hen administered to infants in a three dose schedule at 6, 10 and 1 ee s of a e and Rotari ®, hen administered to infants in a t o dose schedule at 6 and 10 ee s of a e Immunogenicity To evaluate the immuno enicity of Rotari ® 28 days after the last dose of the vaccine, hen administered to infants in a t o dose schedule at 6 and 10 ee s of a e
. . xploratory Ob ective To evaluate the immuno enicity of the three vaccines by LISA usin 8 12 1P8 virus as a substrate in a subset of the sam les collected
. Study ndpoints
. . Primary ndpoint Immunogenicity:
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Protocol Number CVIA 066 Version Number: 01 Version Date: 11 July, 2018
eometric mean concentrations MCs of serum anti rotavirus I A antibodies 28 days after the last dose of a study vaccine, as measured by en yme lin ed immunosorbent assay LISA usin C3 as the viral lysate
. . Secondary ndpoints Safety The secondary safety end oints ill include: Immediate adverse events, ithin 30 minutes ost vaccination Solicited ost vaccination reacto enicity fever, diarrhea, vomitin , decreased a etite, irritability, decreased activity level durin the day eriod Day 0 6 after each vaccination Unsolicited A s from first vaccination throu h ee s after the last vaccination SA s, includin intussusce tion from first vaccination throu h ee s after the last vaccination of each study artici ant Immunogenicity The secondary immuno enicity end oint anti rotavirus I A usin C3 as the Lysate ill be as follo s: Seroconversion rate 28 days after last dose of study vaccine Day 8 for ROTAVAC® and ROTAVAC 5CM and Day 56 for Rotari ® Seroconversion ill be defined as a ost vaccination serum anti rotavirus antibody I A concentration of at least 20 U mL if a baseline concentration is 20 U mL or a ost vaccination serum anti rotavirus I A concentration of 2 fold baseline level if a baseline concentration is 20 U mL Sero ositivity rate at baseline and 28 days after last dose of study vaccine Day 8 for ROTAVAC® and ROTAVAC 5CM and Day 56 for Rotari ® Sero ositivity is defined as serum anti rotavirus I A antibody concentration 20 U mL Serores onse rate 28 days after last dose of study vaccine Day 8 for ROTAVAC® and ROTAVAC 5CM and Day 56 for Rotari ® Serores onse ill be assessed as a four fold, three fold and t o fold rise in antibody concentration from baseline 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 ® ith reference to baseline
. . xploratory ndpoints: The e loratory end oints based on anti rotavirus I A antibodies measured by LISA usin 8 12 as the viral lysate in a subset of sam les ill be as follo s: MCs of serum anti rotavirus I A antibodies 28 days after the last dose of study vaccine Seroconversion rate 28 days after last dose of study vaccine Seroconversion is defined as a ost vaccination serum anti rotavirus I A antibody concentration of at least 20 U mL if a baseline concentration is 20 U mL or a ost vaccination serum anti rotavirus I A antibody concentration of 2 fold baseline level if a baseline concentration is 20 U mL
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Protocol Number CVIA 066 Version Number: 01 Version Date: 11 July, 2018
Sero ositivity rate at baseline and 28 days after last dose of study vaccine Sero ositivity is defined as serum anti rotavirus I A antibody concentration 20 U mL M R that is a ratio of MCs at 28 days after last dose of study vaccine ith reference to baseline
ST D D SI N This study is desi ned as a Phase IIb, sin le center, randomi ed, active controlled, o en label study enrollin a total of 50 healthy infants 6 8 ee s 2 56 days of a e Pros ective artici ants, hose arent or le al uardian si n an informed consent form and ass the test of understandin , ill be assessed for eli ibility to artici ate in the study Screenin for eli ibility ill include solicitation of medical history, assessment of vital si ns, and hysical e amination If the artici ant is found to be eli ible, the infants ill be allocated to one of the three rou s in a ratio of 1:1:1 n 150 er rou to receive either three doses of ROTAVAC®, three doses of ROTAVAC 5CM or t o doses of Rotari ® ee s a art minimum interval of ee s and ma imum of 5 ee s Allocation of treatment to individual artici ants ill be based on a randomi ation schedule develo ed in coordination ith the data mana ement or ani ation for unbiased randomi ation of artici ants to the treatments Three doses of ROTAVAC® and ROTAVAC 5CM ill be administered at 6, 10 and 1 ee s of a e hereas t o doses of Rotari ® ill be administered at 6 and 10 ee s of a e see table belo All vaccines ill be administered concomitantly ith PI vaccines includin Di htheria, Tetanus, Pertussis, and He atitis B vaccine DT P Hib He B , Pneumococcal con u ate vaccine and OPV at 6, 10 and 1 ee s and IPV at ee 1 hen s itched to in Zambia Should any chan es to the PI schedule in the Zambia occur before or durin the study the vaccines iven alon side the study vaccines ill be allo ed to reflect the current ro ram ithout a rotocol amendment unless this is considered to interfere ith the assessment of the study end oints in any ay The artici ants ill be monitored for 30 minutes follo in vaccine administration for immediate adverse events li e ana hyla is, vomitin etc roup No of Visit 1 Visit 2 Visit 3 artici ants 6 8 ee s V1 28 days 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 immuno enicity, a blood sam le ill be obtained from all the artici atin infants before first vaccination and four ee s 1 ee after the last vaccine dose This ould mean that the blood sam le ill be collected at a ro imately 1 ee s of a e for infants in the Rotari ® arm and 18 ee s for infants in the ROTAVAC rou s Serum Anti rotavirus I A antibodies ill be analy ed at ellcome Trust Research Laboratory, Christian Medical Colle e, Vellore, India usin a validated LISA hich uses C3 virus as a substrate A subset of sam les 50 sam le airs er arm ill also be analy ed by another LISA usin the Rotari s ecific strain 8 12 as a lysate at Cincinnati Children s Hos ital Medical Center CCHMC , Cincinnati, Ohio, USA The study ill com are the immuno enicity of the t o
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Protocol Number CVIA 066 Version Number: 01 Version Date: 11 July, 2018 formulations of ROTAVAC® i e ROTAVAC® vs ROTAVAC 5CM in terms of MCs and ill describe ithout com arin the immune res onse to Rotari ® Study Schema
nhanced assive Active surveillance for vaccine reacto enicity solicited reactions over the day eriod after each vaccination ill be conducted on all infants In addition, surveillance for unsolicited A s, SA s includin intussusce tion ill be carried out over the eriod bet een first vaccination and four ee s after the last vaccination on all infants Partici ants ill be evaluated for: Immediate adverse events ithin 30 minutes ost vaccination days ost vaccination reacto enicity, i e , the occurrence of solicited reactions fever, diarrhea, vomitin , decreased a etite, irritability, decreased activity level after each vaccination Unsolicited A s from first vaccination throu h four ee s after the last vaccination Incidence of serious adverse events SA s includin intussusce tion, from first vaccination throu h four ee s after the last vaccination or evaluation of ost vaccination reacto enicity, the arent ill be iven a di ital thermometer and a Post Immuni ation Diary Card PIDC coverin Days 0 6 Day 0 day of vaccination They ill be instructed to record their child’s a illary tem erature as ell as other solicited reactions on the PIDC for days ost vaccination Study staff ill ma e a home visit on Days 2 1 day and Day 1 day to determine health status and to su ort com letion of the PIDC as ell as ca ture information on the PIDC recorded to date Com leted PIDC ill be collected by
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Protocol Number CVIA 066 Version Number: 01 Version Date: 11 July, 2018 the field officer on the Day 1 day follo in vaccination The data in the PIDC collected by the arents ill be revie ed by the study hysician desi nee and entered in the CR All SA s ill be re orted follo in established re ulatory re uirements Safety ill be monitored by on site clinical staff and routinely by a Protocol Safety Revie Team PSRT , an internal rou of hysicians hich includes the Investi ator team and PATH Medical Officers The PSRT ill have rovision of e edited meetin that could be tri ered by re ortin of redefined A s The PSRT may also see inde endent e ert medical o inion as dictated by the occurrence of certain events It is e ected that the enrolment ill be com leted over a ro imately 6 months and total study duration for each artici ant ill be 3 5 months
ST D POP LATION
. Description of Study Site Population The study ill be conducted at eor e Clinic in Lusa a here CIDRZ has a research facility This Research Unit is located on the remises of a busy ublic clinic that offers all basic out atient services includin eneral OPD, MCH, ART, harmacy and allied rimary care services in a eri urban settin The center has a catchment o ulation of 1 5,230 This study site is at a ty ical eri urban clinic settin in Lusa a, and artici ants ill be recruited as they randomly attend the health facility After necessary a rovals are in lace, the CIDRZ Community Advisory Board ill facilitate meetin s in the community ith ey ate ee ers and interest rou s in order to inform them about the study This is the mechanism that is also used to address any community issues that may arise durin the course of the study ith a catchment o ulation of over 1 0,000 and more than 600 antenatal attendances each month, eor e clinic has sufficient number of healthy infants to be screened ith arental consent in order to enroll 50 infants in the study Partici ants ill be 6 8 ee 2 56 days both inclusive old healthy infants Parents attendin clinics for the vaccination of their infants ill be a roached for their child’s enrollment in the study A si ned ritten form consent ill be obtained before any trial related rocedures are erformed inal eli ibility determination ill de end on the results of the medical history and clinical e amination, fulfillment of eli ibility criteria, and a ro riate understandin of the study Investi ators should al ays use ood clinical ud ment in considerin a artici ant’s overall fitness for inclusion in the trial Some artici ants may not be a ro riate for the study even if they meet all inclusion e clusion criteria or instance, medical, occu ational or other conditions resent in the arents may ma e safety evaluations difficult or ma e the infants oor candidates for retention All infants tar eted for enrollment ill need to have arents ho can com rehend the ur ose of the study and rovide ritten informed consent In addition, the families should be resident in the area ithout lans to leave the area durin the course of the study
. Inclusion Criteria ulfillment of all of the follo in criteria is re uired to acce t an infant in the study: 1 Healthy infant as established by medical history and clinical e amination before enterin the study
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2 A e: 6 8 ee s 2 56 days, both days inclusive confirmed by Immuni ation Record 3 Infants received a e a ro riate PI vaccines till enrolment Ability and illin ness to rovide informed consent as er local consentin rocedures 5 Parent can be contacted on hone and confirms intention to remain in the study area ith the artici ant durin the study eriod
. xclusion Criteria Any of the follo in ill e clude an infant from the study: 1 Presence of diarrhea or vomitin in the revious 2 hours or on the day of enrolment tem orary e clusion 2 Presence of fever on the day of enrolment tem orary e clusion 3 Acute disease at the time of enrolment tem orary e clusion Concurrent artici ation in another clinical trial throu hout the entire timeframe of this study 5 Presence of severe malnutrition ei ht for hei ht score 3SD median 6 Any systemic disorder cardiovascular, ulmonary, he atic, renal, astrointestinal, hematolo ical, endocrine, immunolo ical, dermatolo ical, neurolo ical, cancer or autoimmune disease as determined by medical history and or hysical e amination hich ould com romise the child’s health or is li ely to result in non conformance to the rotocol History of con enital abdominal disorders, intussusce tion, abdominal sur ery 8 no n or sus ected im airment of immunolo ical function based on medical history and hysical e amination Prior recei t or intent to receive rotavirus and other a e s ecified PI vaccines outside of the study center and durin study artici ation 10 A no n sensitivity or aller y to any com onent of the study vaccine 11 Clinically detectable si nificant con enital or enetic defect 12 History of ersistent diarrhea defined as diarrhea more than 1 days 13 Partici ant’s arents not able, available or illin to acce t active follo u by the study staff 1 Has received any immuno lobulin thera y and or blood roducts since birth or lanned administration durin the study eriod 15 History of chronic administration defined as more than 1 days of immunosu ressants includin corticosteroids Infants on inhaled or to ical steroids may be ermitted to artici ate in the study 16 History of any neurolo ic disorders or sei ures 1 Any medical condition in the arents infants that, in the ud ment of the investi ator, ould interfere ith or serves as a contraindication to rotocol adherence or a artici ant’s arent’s le ally acce table re resentative’s ability to ive informed consent
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18 Partici ant is a direct descendant child or randchild of any erson em loyed by the S onsor, the CRO, the PI or study site ersonnel
. Continued ligibility Confirmation for Subse uent Vaccination The follo in events constitute absolute contraindications to rotavirus vaccination and all artici ants should be evaluated for these before further administration of the study vaccine If any of these events occur durin the study, the artici ant must not receive additional doses of the vaccine but should be a ro riately follo ed u for safety by the Investi ator Hy ersensitivity reaction follo in the administration of the study vaccine Any uncorrected con enital malformation of the astrointestinal tract such as Mec el’s diverticulum hich is dia nosed after the first vaccination and that ould redis ose for intussusce tion Infants ith any history of intussusce tion Severe combined immunodeficiency SCID Detection of one or more of the e clusion criteria durin dosin eriod The follo in events constitute contraindications to administration of the study vaccine at that oint in time if any of these events occur at the time scheduled for vaccination, the artici ant may be vaccinated at a later date, ithin the time indo s ecified in the rotocol, or ithdra n at the discretion of the Investi ator Acute disease and or fever at the time of vaccination Acute disease is defined as the resence of a moderate or severe illness ith or ithout fever All vaccines can be administered to ersons ith a minor illness such as mild u er res iratory infection ithout fever ever is defined as tem erature 3 5 C 5 on a illary settin astroenteritis ithin 2 hours recedin the study vaccine administration
.5 Reasons for ithdrawal Partici ants have the ri ht to decline study treatment or rocedures for any reason and at any time durin the study If a artici ant declines further vaccination or study rocedures but continues in the study for safety assessment this ill be recorded as a study deviation and the reason ill be clearly documented in the source document The artici ant ill be encoura ed to com lete the remainin a licable safety related follo u to com lete safety follo u for atleast 28 days after last dose and immuno enicity blood dra at the end of safety follo u If the artici ant does not ish to remain in the study by declinin any follo u s or rocedures, the artici ant can choose to ithdra consent and be ithdra n from the study The artici ants may be ithdra n from the study for any of the follo in reasons: If arent of artici ant ishes to ithdra consent If the Princi al Investi ator PI decides that ithdra al is in the best interest of the artici ant
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Protocol Number CVIA 066 Version Number: 01 Version Date: 11 July, 2018
Si nificant non com liance ith treatment re imen or trial re uirements Partici ant is lost to follo u The s onsor manufacturer recommends to terminate the study In all cases, here the artici ant is ithdra n from the study the reason for ithdra al ill be documented in an a ro riate section of the eCR Ho ever, the data collected u to the last contact ill be art of the analysis In the event of ithdra al from study, reasonable efforts should be made to conduct the follo in rocedures: Revie diary card if still in use rior to ithdra al U datin any on oin A SA s that remain on oin at time of artici ant’s last visit rior to ithdra al uery about A s, SA s and concomitant medications if the interval bet een the artici ant’s last visit and the time of ithdra al is ithin the rotocol defined re ortin eriod Conduct hysical e amination Collect blood for immunolo ic testin if ithdra al occurs before end of study U date contact information
5 ST D PROD CT S
5. Study Vaccine
5. . Product Description T o formulations of Rotavirus vaccine manufactured by Bharat Biotech International Ltd ill be used in the study Both the formulations are monovalent vaccines containin sus ension of 105 0 U live rotavirus 116 re ared in Vero cells Based on the dual classification system usin and P surface roteins, 116 is classified as P 11 ty e Both the vaccines are ready to use no reconstitution or dilution is re uired Rotari ® is a live attenuated RI 1 strain of human rotavirus of the 1P 8 ty e and ill be used as an internal control The vaccine is ready to use no reconstitution or dilution is re uired Rotari ® is a S Biolo icals’ licensed rotavirus vaccine hich has been revie ed by HO and has been a roved and included in the HO re ualified list of vaccines Details of the vaccines are rovided belo : This is the licensed and HO re ualified rotavirus vaccine from Bharat Biotech International Limited The vaccine is a live, attenuated
® P 11 monovalent vaccine at a dose of 0 5 mL containin NLT lo ROTAVAC 105 0 focus formin units U er dose The vaccine should be stored (Frozen at 20 C Before administration, li uid fro en vaccine vial ill be shifted formulation) from 20 C to room tem erature for tha in The li uid vaccine ill be administered er oral Manufactured by Bharat Biotech International Limited, India
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Protocol Number CVIA 066 Version Number: 01 Version Date: 11 July, 2018
The vaccine is a live, attenuated P 11 monovalent vaccine to be administered in a dose of 0 5 mL containin NLT lo 105 0 focus ROTAVAC 5CM formin units U er dose Since this is a fully li uid vaccine stored (li uid at 2 8 C, no tha in is re uired before administration The li uid formulation) vaccine ill be administered er oral Manufactured by Bharat Biotech International Limited, India This is the licensed and HO re ualified rotavirus vaccine from S Biolo icals Rotari is a live attenuated RI 1 strain of human 6 0 ® rotavirus of the 1P 8 ty e containin not less than 10 CCID50 cell Rotarix culture infectious dose 50 of the RI 1 strain of human rotavirus 1 5 ml of the li uid vaccine ill be administered er oral Manufactured by la oSmith line Vaccines, Bel ium
5. . Manufacturer ROTAVAC® and ROTAVAC 5CM are manufactured by Bharat Biotech International Ltd Rotari ® is manufactured by S Biolo icals
5. . Presentation and Formulation ROTAVAC® is a li uid in fro en form In li uid form, the vaccine is enerally in in colour and may sometimes chan e to oran e or li ht yello in colour This chan e in colour does not im act the uality of vaccine ROTAVAC® is ac ed in USP ty e l lass vials and ill be su lied as multi dose vials containin 5 2 5 mL vial or 10 doses 5 mL vial of the vaccine er vial ach dose of 0 5 mL 5 Dro s contains Ingredient uantity 0.5 mL Rotavirus 116 Bul , Live Attenuated NLT 105 0 U Potassium Phos hate Monobasic USP BP 0 258 m Potassium Phos hate Dibasic USP BP 0 625 m Sucrose USP BP 3 31 m Potassium L lutamate Monohydrate USP BP 1 0 m Neomycin Sul hate USP BP 15 anamycin Sul hate USP BP 15 Dulbecco s Modified a le s Medium DM M m ater for In ections USP BP s H ran e: 2 to 8 0 ROTAVAC® vials su lied throu h BBIL comes ith a Vaccine Vial Monitor2 VVM2 dot to uide its usa e The e iry date of the vaccine is indicated on the label and ac a in A icture of the rototy e vial and label has been rovided belo :
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Protocol Number CVIA 066 Version Number: 01 Version Date: 11 July, 2018
An additional label to com ly ith the re ulatory re uirements ill be asted on the carton of the vaccine A tem late has been rovided belo : FOR CLINICAL TRIAL S ONL
Protocol Number: CVIA 066 S onsor: Centre for Infectious Disease Research in Zambia, Lusa a, Zambia, 10101 Site: eor e Research Clinic, Centre for Infectious Disease Research in Zambia, Lusa a, Zambia, 10101
ROTAVAC 5CM is a fully li uid vaccine and is enerally in in colour and may sometimes chan e to oran e or li ht yello in color This chan e in colour does not im act the uality of vaccine ROTAVAC 5CM is ac ed in USP ty e l lass vials and ill be su lied as sin le dose lass Vials 2mL containin 0 5 mL of the vaccine ach dose of 0 5 mL 5 Dro s contains Ingredient Reference Rotavirus 116 Bul , Live Attenuated NLT 105 0 U anamycin acid sul hate IP Neomycin sul hate USP Sucrose USP Trehalose In House Lactalbumin hydrolysate LAH In House Human Albumin IP BP Di Potassium hydro en ortho hos hate Potassium USP Phos hate dibasic Potassium di hydro en ortho hos hate Potassium USP Phos hate Monobasic Tri sodium citrate dihydrate USP ater for In ection IP BP In House H ran e: 2 to 8 0 A tem late of the label for has been rovided belo :
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Protocol Number CVIA 066 Version Number: 01 Version Date: 11 July, 2018
FOR CLINICAL TRIAL S ONL Protocol No.: CVIA 066 ROTAVAC 5CM® Instructions for use and route of administration: or oral administration only Not for in ection Directions of storage: Store at 2 8 C Batch No: Mf Date: iry date: Manufactured by: Bharat Biotech International Ltd, enome Valley, Shameer et, Hyderabad, Telan ana, India 500 0 8 Sponsor: Centre for Infectious Disease Research in Zambia, Lusa a, Zambia, 10101 Site: eor e Research Clinic, Centre for Infectious Disease Research in Zambia, Lusa a, Zambia, 10101
Rotarix® is resented as a clear, colourless li uid sus ension in a s uee able tube olyethylene fitted ith a membrane and a tube ca oly ro ylene The vaccine is meant for oral administration and is free of visible articles ach tube contains 1 5 ml of the vaccine hich maybe ac ed in ac si es of 1, 10 or 50 1 dose 1 5 ml contains: Ingredient uantity Human rotavirus RI 1 strain live, not less than 106 0 attenuated CCID50 ci ients: Sucrose, Di sodium Adi ate, Dulbecco’s Modified a le Medium DM M , sterile ater Produced on Vero cells
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Protocol Number CVIA 066 Version Number: 01 Version Date: 11 July, 2018
An additional label to com ly ith the re ulatory re uirements ill be asted on the carton of the vaccine A tem late label has been rovided belo : FOR CLINICAL TRIAL S ONL
Protocol Number: CVIA 066 S onsor: Centre for Infectious Disease Research in Zambia, Lusa a, Zambia, 10101 Site: eor e Research Clinic, Centre for Infectious Disease Research in Zambia, Lusa a, Zambia, 10101
5. . Stability and Storage The e iry date of the vaccine ill be indicated on the label and the ac a in The vaccines should not be mi ed ith any other medicinal roducts active immuni in a ents ROTAVAC® should be stored at 20 C in a dee free er ith a o er bac u It is absolutely critical to ensure that the stora e conditions s ecified above are com lied ith The vaccine should be tha ed before and used immediately after o enin ROTAVAC® should be trans orted in a vaccine carrier usin conditioned el ac s ith tem erature maintained at 2 8 C Any unused vaccine after 8 hours of tha in should be discarded ROTAVAC 5CM and Rotari ® should be stored at 2 8 C in a refri erator ith a o er bac u The vaccine should be trans orted in a vaccine carrier usin conditioned el ac s ith tem erature maintained at 2 8 C It is absolutely critical to ensure com liance ith the stora e conditions s ecified above ree in is not recommended for stora e of Rotari ® The vaccine should be used immediately after o enin The vaccine should be stored in the ori inal ac a e, in order to rotect from li ht
5. .5 The Vaccine Vial Monitor Vaccine Vial Monitor2 VVM2 dot is on the seal of the ROTAVAC® vials su lied throu h BBIL This is a time tem erature sensitive dot that rovides an indication of the cumulative heat to hich the vial has been e osed It arns the end user hen e osure to heat is li ely to have de raded the vaccine beyond an acce table level
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Protocol Number CVIA 066 Version Number: 01 Version Date: 11 July, 2018
Inter retation of VVM2: ocus on the central s uare Its colour ill chan e ro ressively As lon as the colour of this s uare is li hter than the colour of the rin , the vaccine can be used As soon as the colour of the central s uare is the same colour as the rin or of a dar er colour than the rin , the vial should be discarded The Vaccine Vial Monitor VVM is also art of the label used for all Rotari ® batches su lied by la oSmith line Biolo icals The colour dot that a ears on the label of the tube is a VVM This is a time tem erature sensitive dot that rovides an indication of the cumulative heat to hich the tube has been e osed It arns the end user hen e osure to heat is li ely to have de raded the vaccine beyond an acce table level To inter ret the VVM status the colour of the central s uare should be observed and decisions on use are e actly the same as described for Rotavac® above
5. Dose Preparation and Administration The Investi ational Medicinal Products IMP ill be re ared and administered by desi nated ualified staff only to infants included in this study The vaccine ill be administered as er the randomi ation list The date and time of the IMP administration must be recorded The Investi ator must trac vaccines received, used and asted and ill retain all unused or e ired roducts ROTAVAC®, ROTAVAC 5CM and Rotarix® for oral use only and should under no circumstances be in ected. The investi ational roducts must not be mi ed ith other medicinal roducts ROTAVAC® and ROTAVAC 5CM instructions for use: The a ro riate dosin vial to be chosen Chec the e iry date Ins ect visually for any forei n articulate matter and or abnormal hysical a earance rior to administration In the event of either bein observed, discard the vaccine vial Chec the vial has not been dama ed nor is already o en Chec the VVM2 on the seal and let the vaccine to tha to li uid state before administration a licable for fro en ROTAVAC® formulation only Pull out the aluminum seal alon the indicated mar and tear it off Pull out the rubber sto er Connect the dro er firmly on the vial O en the dro er ti The vaccine should be administered immediately after o enin Seat the child leanin sli htly bac ards ee dro er at 5 de rees and administer 5 dro s in the mouth of the baby to ard the inner chee Note that ROTAVAC 5CM comes as a 0 5ml sin le dose vial and all the contents should be administered to one child
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Protocol Number CVIA 066 Version Number: 01 Version Date: 11 July, 2018
Observe the child for at least 30 minutes for any immediate reactions Please refer to Pac a e Insert of ROTAVAC® for more information on administration of the vaccine
Rotarix® instructions for use The a ro riate dosin tube to be chosen Chec the e iry date Ins ect visually for any forei n articulate matter and or abnormal hysical a earance rior to administration In the event of either bein observed, discard the vaccine Chec the tube has not been dama ed nor is already o en Chec the li uid is clear and colorless, ithout any articles in it Chec the VVM2 on the label Hold the tube u ri ht and re eatedly flic the to of the tube until it is clear of any li uid ee the tube held u ri ht and hold the side of tube There is a small s i e inside the to of the ca in the center Turn the ca u side do n 180 and ress the ca do n to ierce the membrane Then lift off the ca Chec the membrane has been ierced and there is a hole at the to of the tube
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Protocol Number CVIA 066 Version Number: 01 Version Date: 11 July, 2018
Administer the vaccine immediately Seat the child leanin sli htly bac ards S uee e the li uid ently into the side of the child’s mouth to ards the inside of their chee ou may need to s uee e the tube a fe times to et all of the vaccine out it is o ay if a dro remains in the ti of the tube Observe the child for 30 minutes for any immediate reactions Please refer to Pac a e Insert of Rotari ® for more information on administration of the vaccine If a child s its u or re ur itates most of the vaccine based on investi ator’s discretion ithin 5 minutes of administration, a sin le re lacement dose ill be administered and the event ill be recorded in the source documents and eCR The artici ant should continue to receive remainin doses in the recommended series
5. Accountability and disposal
5. . Vaccine supply Bharat Biotech International Limited ill su ly sufficient uantities of study vaccines ROTAVAC® and ROTAVAC 5CM to allo com letion of this study only after the I C and re ulatory a roval of final rotocol Rotari ® ill be rocured locally from the commercial mar et by the S onsor CIDRZ Local re ulatory re uirements re uire that an additional label or Clinical Trial Use ONL be added to the vaccine lots intended for research studies The roduct commercial ac a in or a ro riate ac a e ill be unaltered and remain visible to maintain the inte rity of the roducts The batch numbers, e iry dates and hysical descri tion of investi ational roducts ill also be included in the study re ort The vaccines ill be labeled accordin to the local re ulations and re uirements of study rotocol All labels ill contain the follo in minimum information: Im rint or Clinical Trial Use Only it Number if a licable study vaccine name Name and Address of Manufacturer, Protocol number Store bet een 2 8 oC or 20 oC, Batch Number, iry Date, Im rint or Oral use only Name and address of Site U on recei t of the study su lies, an inventory must be erformed by the desi nated study staff at site It is im ortant that the desi nated study staff verifies that the shi ment contains all the items noted in the shi ment inventory Any dama ed or unusable study roduct in a iven shi ment ill be documented in the study files The Investi ator must notify Bharat Biotech International
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Protocol Number CVIA 066 Version Number: 01 Version Date: 11 July, 2018
Limited immediately of any dama ed or unusable investi ational roducts that ere su lied to the Investi ator’s site The IMP must be stored as er the stora e instructions, hich ill be under close tem erature monitorin and connected to a source ith reliable bac u o er Chan es in tem erature outside the allo ed ran e should be immediately re orted and any vaccine lots e eriencin such out of ran e chan es ill be brou ht to the attention of Bharat Biotech International Limited for determination of rocedures to follo In case there is any tem erature e cursion durin shi ment or stora e, follo the ste s iven belo : 1 uarantine the shi ment in a ro riate stora e area 2 8 C or 20 C 2 Inform immediately to Site Monitor and BBIL desi nee about e cursion 3 Send com leted ac no led ment forms to BBIL desi nee ait to hear on usa e decision from BBIL 5 In case BBIL confirms use, release investi ational roducts for study use 6 In case usa e decision is To be Re ected’, transfer the investi ational roducts to re ected area The lo istic rovider’s desi nee ill rovide tem erature data to PATH BBIL for each shi ment Tem erature recorded for stora e ill be revie ed by the monitor durin monitorin visits After administration, the study staff ill com lete accountability label on the carton and store the used roducts at desi nated area A monitor from the CRO ill verify the use of investi ational roducts as er the randomi ation list and also the accountability of investi ational roducts The site PI or desi nee must maintain 100 accountability for all investi ational roducts received and dis ensed durin his or her entire artici ation in the study Pro er dru accountability includes, but is not limited to: re uently verifyin that actual inventory matches documented inventory Verifyin that all containers used bro en unused lost are documented accurately on the lo Verifyin that re uired fields are com leted accurately and le ibly If any dis ensin errors or discre ancies are discovered, PATH BBIL must be notified immediately
5. . Dispensing After the inclusion and e clusion criteria chec , the PI or desi nated ersonnel must confirm the eli ibility and then randomi e the artici ant The rocedure for randomi ation ill be desi ned to minimi e allocation bias in the study Desi nated ersonnel ill re are and administer the IP as er the instructions res ectin randomi ation The used IMP tubes vials must be e t for accountability or ROTAVAC® multi dose vial, only one dose to be used for one artici ant Used vials ith remainin vaccines should be e t at room tem erature for accountability
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Protocol Number CVIA 066 Version Number: 01 Version Date: 11 July, 2018
5. . Return or destruction The site ill receive instruction from BBIL PATH Desi nee re ardin the final dis osition of used and unused IMP tubes vials The used IMP containers must be e t se arately for the accountability At the com letion of the study after the last visit of the last artici ant , there ill be a final reconciliation of IMP shi ed, IMP consumed, and IMP remainin Any discre ancies noted ill be investi ated, resolved, and documented All the unused and used vials tubes ill be destroyed on site after PATH BBIL a roval Destruction of IMP at site ill be documented includin ZAMRA ermit to destroy the roducts in the study files and certificate ill be rovided to PATH BBIL
6 ST D PROC D R S A manual ill be develo ed and maintained at site ith detailed descri tions of the rocedures involved All relevant study team members ill have documented trainin on their res ective res onsibilities to be underta en in the study
6. Recruitment Partici ants ill be 6 8 ee 2 56 days both days inclusive old healthy infants at enrolment li ible arent those above the a e of 18 years i e le al a e for consentin in Zambia to youn infants ill be a roached durin the initial visit to MCH of eor e Health Centre by the study nurses ith information about the study in the local lan ua e of choice Those enerally interested ill be invited to al to the research unit ithin 20 meters of the clinic remises for more detailed information durin hich motivated mothers ill be recruited and ta en throu h the ritten informed consent rocess by the study nurse The standard o eratin rocedures ill follo ood Clinical Practice and ethical norms of research includin confidentiality, rovision of ade uate information and allo in sufficient time for ans erin uestions, voluntariness and clear information to confirm that there are no enalties hatsoever for refusal to artici ate or illiterate artici ants, an inde endent, literate individual ill itness and validate the informed consent rocess A com rehension test for the artici ant information ill be administered to assess no led e and understandin of the basic study information, and only those meetin the minimum threshold score out of 10 ill roceed to si n the consent Those scorin less, ill have information re administered and ill ta e the com rehension test a ain This ill be re eated only once Investi ators should al ays use ood clinical ud ment in considerin a artici ant’s overall fitness for inclusion in the trial Some artici ants may not be a ro riate for the study even if they meet all inclusion e clusion criteria or instance, medical, occu ational or other conditions resent in the arents may ma e safety evaluations difficult or ma e the infants oor candidates for retention All infants tar eted for enrollment ill need to have arents Le ally Acce table Re resentative ho can com rehend the ur ose of the study and rovide ritten informed consent In addition, the families should be resident in the area ithout lans to leave the area durin the course of the study Sufficient number of healthy infants ill be screened ith arental consent to enroll 50 infants in the study It is e ected that the recruitment ill be com leted over a eriod of 6 months
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Protocol Number CVIA 066 Version Number: 01 Version Date: 11 July, 2018
6. Study visits Children ill be seen at the study clinic on the day of screenin enrollment first vaccination, visits for second and third vaccinations, if a licable, and follo u visit ee s after the third dose of ROTAVAC ROTAVAC 5CM and second dose for those in the Rotari ® arm Belo is a detailed descri tion of study activities on each scheduled visit day
6. . Day 0 Screening nrolment Visit Screenin and enrolment ill be done on the same day An information sheet a roved by I C IRB ith details of the study ill be rovided and discussed ith the families If the family is interested in artici atin in the study a Partici ant ID ill be assi ned and the study hysician ill counsel the arent and si ned consent ill be obtained before any trial related rocedures After obtainin ritten consent for the study, artici ants ill be screened for eli ibility throu h medical history revie and eneral hysical e amination To assess the eli ibility, the follo in rocedures ill be conducted: Demographic data: This ill include a e, ethnicity, ender, date of birth, birth ei ht , resent ei ht , and len th cm A co y of the Children’s Clinic Card ill be ta en as a source document Com lete address of the arent ill be recorded Medical History: This ill include history of artici ation in a dru research study clinical trial, immuni ation history, any on oin diarrhea or other illness It ill also include ast medical history vaccination history sur ical history revious hos itali ations history of any aller y to dru s, vaccines current medication history and family history, includin history of immunodeficiency in any household member Physical xamination: Physical e amination ill include vital si ns a illary tem erature, heart rate and res iratory rate and systematic e amination of head and nec , s in, eye, ears, nose, and throat NT , cardiovascular system CVS , res iratory system RS , astrointestinal system IS , enito urinary system US , central nervous system CNS , and musculos eletal system Partici ants ho failed screenin ill be recorded on screenin a es of the eCR documentin reason for failure nrollment procedures: The day of the child’s first study vaccination is desi nated as study Day 0 The follo in rocedures ill be conducted on this day: 1 Reconfirm eli ibility: If screenin and enrolment vaccination are conducted se arately, a tar eted sym tom based hysical e am ith vital si ns a illary tem erature, heart rate and res iratory rate , and brief medical history u date ill be erformed rior to vaccination to ensure continued eli ibility 2 Randomi ation: Once eli ibility is ascertained, the child ould be assi ned a randomi ation code hich ill assi n him her to receive either ROTAVAC®, ROTAVAC 5CM or Rotari ® The artici ants ill receive same treatment at all the a licable vaccination visits 3 Blood collection: Collect baseline blood sam le of u to 2 ml for immuno enicity assessment Vaccination: Vaccination ill be done hen the child comes bac to normal state after blood collection The artici ant ill receive a dose of either ROTAVAC®, ROTAVAC 5CM or
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Protocol Number CVIA 066 Version Number: 01 Version Date: 11 July, 2018
Rotari ® as assi ned by the randomi ation schedule Vaccines ill ONL be administered if artici ant does not meet any contraindication to vaccine administration Durin each vaccination visit, a section of study or sheet eCR ill be com leted that records information about vaccines received, date and time Pro er accountability of all vaccines ill be maintained 5 Concomitant Vaccination and Other Treatments: All artici ants ill receive other PI vaccinations concomitantly as er the national immuni ation schedule the research nurses ill ensure that all study artici ants receive the due vaccines on schedule Use of rescri tion medications and any treatments rocedures durin the study eriod ill be recorded on source documents eCR The name of rescri tion medication and duration of treatment should be recorded in the eCR , if available 6 Immediate Post Vaccination Reacto enicity Assessment: After each dosin , all artici ants ill be observed at the clinic site for 30 minutes to chec for any immediate A s includin any e isodes of vomitin and aller ic reaction to vaccine After 30 minutes ost vaccination observation eriod, vital si ns ill be measured if indicated, a tar eted hysical e amination ill be erformed Clinically si nificant abnormal findin s on tar eted hysical e amination and vital si ns ill be re orted in the CR as an unsolicited A Provide di ital thermometer and the ost immuni ation diary card PIDC to record, from the day of vaccination and daily for ne t si days, any solicited reactions, includin diarrhea, fever, vomitin , decreased a etite, irritability, and decreased activity level Train the arents to com lete the PIDC 8 Parents ill be instructed that if an A re uirin medical attention is identified durin the study, arent s ill contact a study hysician desi nee and a ro riate medical care ill be iven Also, at all times bet een first and last visit, unsolicited A s and or SA s includin intussusce tion ill be recorded in eCR and mana ed medically as needed Inform the arent on the safety follo u home visit by the field officer on days 2 , and advise him her on the ne t clinic visit after 28 days
Safety Follow- p: Parents ill be sho n ho to fill in the PIDC for days day 0 6 after vaccination Study staff ill ma e a hysical home visit on Days 2 1 day and Day 1 day to determine the child’s health status and to su ort com letion of the PIDC In case the child e eriences any illness durin this eriod, they ill be referred to the study clinic for further evaluation and treatment Com leted PIDC can be collected by the field officer at this visit or the arent can brin it to the site at the ne t visit, if arents ere not available durin the home visit The data in the PIDC collected by the arents ill be revie ed by the study hysician desi nee and entered in the CR Any solicited reaction e tendin beyond days after vaccination ill also be recorded on the PIDC CR ith date of resolution if available and the hi hest severity durin the occurrence Also, at all times bet een first and last visit, unsolicited A s and or SA s includin intussusce tion ill be recorded in eCR and mana ed medically as needed
6. . Second Visit (Day ) The date for this visit ill be calculated 28 days from the date of the first study vaccination A ma imum indo eriod of days ill be allo ed for this visit Parents ill be contacted by
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Protocol Number CVIA 066 Version Number: 01 Version Date: 11 July, 2018
hone a day before the visit to remind them of the a ointment Partici ants ho miss the scheduled visit date ill be rom ted to re schedule for the missed immuni ations and ensure that PI vaccines and investi ational vaccines are administered in a timely manner The follo in rocedures ill be carried out at this visit: 1 Chec for any adverse events since last visit and record them in the source note and eCR U date medical history includin follo u of rior A s 2 Collection and revie of the diary cards if not already collected by field or er earlier 3 Chec for use administration of any medication vaccine since last visit Any medication ta en for the treatment of the illness or vaccine administered ill also be recorded in the relevant section of the CR Conduct hysical e amination and vital e amination 5 Chec for any contraindication to vaccination Reschedule visit if the infant is e eriencin an illness that is tem orary contraindication to vaccination 6 Vaccines ill be administered if artici ant does not meet any contraindication to Investi ational Medicinal Product IMP administration The artici ant ill receive a dose of either ROTAVAC®, ROTAVAC 5CM or Rotari ® as assi ned by the randomi ation schedule Durin each vaccination visit, a section of study or sheet eCR ill be com leted that records information about vaccines received, date and time Procedures 5 under section 6 2 1 above ill be re eated 8 Remind the arent of the safety follo u 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 ill be calculated 28 days from the date of last vaccination A ma imum indo eriod of days ill be allo ed for each of these visits Parents ill be contacted by hone a day before the visit to remind them of the a ointment Partici ants ho miss the scheduled visit date ill be rom ted to re schedule for the missed immuni ations and ensure that PI vaccines and IMPs are administered in a timely manner The follo in rocedures ill be carried out at this visit: 1 Chec for any adverse events since last visit and record them in the source note and eCR U date medical history includin follo u of rior A s 2 Chec for use administration of any medication vaccine since last visit Any medication ta en for the treatment of the illness or vaccine administered ill also be recorded in the relevant section of the or sheet eCR 3 Conduct hysical e amination and vital e amination or artici ants in the Rotari ® arm Revie u date address and contact details Collection and revie the diary cards if not already collected by field or er earlier Perform hysical e amination
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Obtain u to 2 ml of blood for immunolo ical assays nsure all on oin SA s are follo ed u as er the rotocol Revie vaccination history and advise the arent on further vaccination of the infant ill u the study termination com letion form This ill be the final study visit for artici ants in the Rotari ® arm 5 or artici ants in the ROTAVAC®, ROTAVAC 5CM arms Chec for any contraindication to vaccination Reschedule visit if the infant is e eriencin an illness that is tem orary contraindication to vaccination Collection and revie of the diary cards if not already collected by field or er earlier Vaccines ill be administered if artici ant does not meet any contraindication to IMP administration The artici ant ill receive a dose of either ROTAVAC or ROTAVAC 5CM as assi ned by the randomi ation schedule Durin each vaccination visit, a section of study or sheet eCR ill be com leted that records information about vaccines received, date and time Procedures 5 under section 6 2 1 above ill be re eated Remind the arent of the safety follo u 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 ) a licable only for ROTAVAC® and ROTAVAC 5CM arms The date for this visit ill be calculated 28 days from the date of last vaccination A ma imum indo eriod of days ill be allo ed for this visit Parents ill be contacted for the artici ants ho miss the scheduled visit date The follo in rocedures ill be conducted: 1 Revie u date address and contact details 2 Chec for any adverse events since last visit and record them in the source note and eCR U date medical history includin follo u of rior SA s nsure all on oin A s are follo ed u as er the rotocol 3 Collection and revie of the diary cards if not already collected by field or er earlier Chec for use administration of any medication vaccine since last visit Any medication ta en for the treatment of the illness or vaccine administered ill also be recorded in the relevant section of the CR 5 Perform hysical e amination Revie vaccination history and advise the arent on further vaccination of the infant 6 Collect u to 2 ml of blood for immunolo ical assays Revie vaccination history and advise the arent on future vaccination of the infant 8 Com lete the study termination com letion form
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6. .5 Interim Contacts and Visits Interim contacts and visits those bet een re ularly scheduled follo u visits may be erformed at artici ant’s arent’s re uest or as deemed necessary by the investi ator or desi nee at any time durin the study Parents ill be as ed to brin the child to the clinic at any time bet een visits if they have any condition that re uires medical attention All interim contacts and visits ill be documented in artici ant’s study records and on a licable case re ort forms as Unscheduled visits
6. .6 Management of Serious Adverse vents including Intussusception The research team ill be available on site at all times durin normal or in hours and ill be able to rovide basic services for out atient care In case of serious conditions that re uire admission to the tertiary hos ital, a study vehicle stationed on site ill be available to rovide ambulance service for timely travel Medical ersonnel at the sites ill be trained on screenin tools to rom tly identify and assess any sus ected cases of intussusce tion The ey sym toms include bloody stools, continuous vomitin , abdominal distension and or abdominal lum s Children resentin ith any sus ected sym toms or si ns ill be rom tly escorted for consultation ith a ediatrician or ediatric sur eon or referred for hos itali ation Parents ill be instructed by staff to ee close atch of the sym toms noted above and contact study staff if they are detected The study team ill be obli ed to ensure ra id consultation ith the team led by the ediatric sur eon ho leads the intussusce tion surveillance or at the university teachin hos ital Any access fees related to dia nosis and care for these cases ill be ta en by the S onsor A SA form ill be com leted for all cases of intussusce tion and notified to authorities as ell as the Protocol Safety Revie Team PSRT immediately, and follo on full re ort as soon as the case is ascertained
6. . Schedule of events The schedule of events assessments erformed durin the trial is rovided belo : Visit V V V V Time point D0 D D56 D V V V 6- Interval ( ) ( ) ( ) wee s days days days Information rocess and ritten informed consent Collect baseline demo ra hic data Collect revie medical history Perform hysical and vital si ns e amination a Chec inclusion e clusion criteria Chec ithdra al criteria Partici ant enrollment and Randomi ation
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Protocol Number CVIA 066 Version Number: 01 Version Date: 11 July, 2018
Visit V V V V Time point D0 D D56 D V V V 6- Interval ( ) ( ) ( ) wee s days days days Collect blood sam le for immuno enicity c b Pre testin dosin Study vaccination alon ith PI vaccination b Chec contraindications, arnin s and b recautions to vaccine recei t Observe for immediate adverse events for 30 b minutes ost vaccination Perform ost vaccination Vital e amination and b tar eted hysical e amination if re uired Issue and Instruct artici ant’s Parent LAR on b use of diary card Record solicited A s for days ost vaccination b Safety follo u ost vaccination by social d d db or er Record unsolicited A s , includin SA s b Record any concomitant b medications vaccinations Revie interim medical history and record any b intercurrent medical conditions Partici ant com letion of study c b D day PR re vaccination A adverse events, SA serious adverse event a Sym tom based P to be erformed if screenin is bein re eated and there is any chan e in health since last screenin b Not a licable for artici ants in Rotari arm c A licable only for artici ants in Rotari arm d This includes visit by the health or er to the arent 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 artici ant in the trial, accordin to the trial scheme
6. . Suspension and or Premature Termination of the Trial CIDRZ in consultation ith PATH retains the ri ht to tem orarily sus end or rematurely discontinue this study at any time related to safety, administrative, or other reasons includin but not limited to the follo in : Ris to artici ant’s safety A s occur ith such severity and fre uency that the ro osed schedule can no lon er be adhered to The scientific uestion is no lon er relevant or the ob ectives ill not be met i e slo accrual ailure to com ly ith CP or terms of Clinical Trial A reement Ris s that cannot be ade uately uantified thical concerns raised by the local community or local medical care health care authorities ailure to remedy deficiencies identified throu h site monitorin , substandard data or failure to meet identified S onsor erformance standards The manufacturer decides to discontinue the develo ment of the formulation It becomes a arent that artici ant enrollment is unsatisfactory ith res ect to uality and or uantity Data recordin is inaccurate and or incom lete on a chronic basis Documentation e lainin remature termination of the study must be for arded to the Site, Re ulatory Authority, and thics Committee in accordance ith local uidelines If the study is sto ed or sus ended rematurely, a summary re ort ill be submitted by Centre for Infectious Disease Research in Zambia to inform the re ulatory authorities and the ethics committee Institutional Revie Board overseein the study about the decision and the reasons for termination or sus ension The summary re ort ill rovide a brief descri tion of the study, the number of artici ants e osed to the vaccine, dose and duration of e osure, details of adverse dru reactions if any, and the reason for discontinuation of the study If such action is ta en, all efforts must be made to ensure the safety of the artici ants enrolled in the study or all artici ants enrolled in the study, safety follo u ill be conducted as decided by the PSRT or as advised by the C IRB or the MOH In case of remature study or study clinic closure, the monitor ill conduct all activities as indicated in the close out visit
6. Lost to follow-up To revent lost to follo u , the study team ill ensure that valid contact details are obtained rior to enrolment, includin a hysical visit to the artici ant’s home at the end of visit Also, the
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artici ant’s arent ill be reminded by hone at least one day before their scheduled visit In the event of a missed visit, the artici ant ill be contacted by hone if that fails, a home visit ithin 3 days of the scheduled visit ill be made by the field or er A artici ant ho cannot be located after at least 3 documented contact efforts and have missed 2 consecutive visits ill be considered lost to follo u fforts to contact ill be documented in source documents Any artici ant ho failed to attend the final study visit ill also be classified as lost to follo u There ill be no re lacement for artici ant ho are lost to follo u
6.5 se of concomitant vaccine(s) medication during the study Routine childhood vaccines mandated by PI should be iven concomitantly ith the study vaccine as er the national immuni ation schedule All infants ill receive all PI vaccines as er routine schedule The PI schedule consists of administerin Di htheria, Tetanus, Pertussis, and He atitis B vaccine DT P Hib He B , Pneumococcal con u ate vaccine and OPV at 6, 10 and 1 ee s and IPV at ee 1 hen s itched to in Zambia The study artici ants may receive additional doses of OPV as re uired durin s ecial immuni ation rounds BC vaccine ill be offered to infants ho did not receive it at birth Concomitant and other vaccines used durin the study ill be re orted in the Concomitant vaccination section of the CR The arents of the children should inform the PI or desi nee about inta e of any dru ta en for the treatment of an illness occurrin since first vaccination until end of follo u eriod Use of rescri tion medications and any treatments rocedures durin the study eriod ill be recorded on source documents and Concomitant Medication CR
6.6 nblinding procedure The study ill be conducted under o en label condition This means that the atient, clinical site, CRO, s onsor and PATH ill be unblinded to the treatment assi nments Therefore, unblindin rocedures are not a licable The study laboratory ill be e t blinded for the treatment administered until the end of testin
6. Clinical procedures Vital Signs Tem erature in de rees Celsius recorded to the nearest 0 1 de ree ill be measured by a illary thermometer for infants Res iratory rate ill be recorded in breaths er minute Heart rate in beats er minute ill be measured manually Hei ht len th ill be measured and recorded to the nearest 0 1 cm ei ht ill be measured in and recorded to the nearest 0 01 Physical xamination ull hysical e amination ill include assessment of vital si ns, head, eyes, ears, nose, oro haryn , nec , chest auscultation , lym h nodes nec , su raclavicular, a illary, in uinal ,
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Protocol Number CVIA 066 Version Number: 01 Version Date: 11 July, 2018 abdomen auscultation and al ation , enitourinary, musculos eletal, s in es ecially in ection sites , and neurolo ical Targeted physical examination A focused hysical e amination based on sym toms re orted by the artici ant and the resence or absence of solicited adverse events collected to assess vaccine reacto enicity Medical History A com rehensive medical history ill be collected includin details of any revious vaccinations and reaction to vaccinations, artici ation in clinical trials, sur ery, revious hos itali ation, aller y to food dru s, current medication and history of any chronic or recurrent medical conditions An interval medical history ill consist of in uirin re ardin chan es since the last medical history discussion healthcare events, si ns, sym toms and chan es in use of rescri tion or non rescri tion dru s or herbal re arations
6. Termination of withdrawn study participant A artici ant ho can no lon er continue ith the study for hatever reason, ill need to be concluded in the eCR via the termination a e hich ill mar the close of the case The ossible reasons ill include: 1 Voluntary ithdra al from the study by the artici ant 2 Investi ator decides to ithdra the artici ant from the study for safety or other clinical reasons 3 Partici ant is confirmed as lost to follo u This site rinci al investi ator must revie each case and confirm the status before com letion of the termination form
LA ORATOR VAL ATIONS R IR M NTS
. Sample collection, distribution and storage To uantitate antibody concentrations elicited by the study vaccines, a baseline blood sam le ill be collected from all artici ants before the first vaccination and four ee s after the last vaccination after 3rd dose for ROTAVAC® ROTAVAC 5CM and after 2nd dose for Rotari ® Clinicians and e erienced nurse hlebotomists ill be trained in a ro riate sam le collection methods A ro riate ase tic rocedures ill be em loyed ith a ro riate needles and syrin es in lace for sam le collection rocedure A ma imum of 2 ml of blood, from a eri heral vein, ill be collected by an ase tic techni ue into el SST tubes A ma imum of 2 attem ts ill be made for collection of the blood sam le Sam lin attem t ill not be re eated in case the team is not able to collect the sam le on this day Clotted blood in the tube ill be centrifu ed to obtain serum Desi nated laboratory ersonnel at the site ill ali uot the sam les into t o ali uots before stora e Serum ill be distributed in the t o ali uots such that the rimary receives at least 0 5 ml of the serum and the remainin is transferred to the second cryotube All serum sam les ill be labelled a ro riately The t o sam les ill be stored in se arate controlled free ers at or belo
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20 C until the time of shi ment to the testin laboratories These free ers ill have bac u o er source in case of outa e on the national o er rid All handlin ill be done to revent unnecessary free e tha cycles i e , bac u sam les should not be tha ed unless re uired for testin Tem erature monitorin ill be done to assure maintenance of cold chain and s ecimen uality One ali uot each ill be sent se arately to each of the t o testin laboratories i e , laboratory at CMC Vellore, India and CCHMC, Cincinnati, USA at or belo 20 C usin validated ac a in and tem erature monitors The testin laboratories ill be res onsible for testin for anti rotavirus I A antibodies see belo and storin of sam les till study com letion The S onsor ill be res onsible for obtainin the a ro riate Material Transfer A reement MTA from the local National Health Research Authority
. Immunological laboratory assays Serolo ical assays for uantification of anti rotavirus I A antibodies by LISA ill be erformed at the follo in labs Name of Laboratory Assay s ecification Number of artici ants Pre and Post vaccination sam les ROTAVAC® ROTAVAC Rotari ® 5CM The ellcome Trust stimation of serum anti All All All Research Laboratory, rotavirus I A antibodies by Christian Medical LISA usin C3 as the Colle e, Vellore, India viral lysate Cincinnati Children s stimation of serum anti 50 50 50 Hos ital Medical rotavirus I A antibodies by Center CCHMC , LISA usin 8 12 as the Division of Infectious viral lysate Diseases, Cincinnati, Ohio, USA
If arranted, the sam les may be sub ected to additional tests to e lain the immune res onses seen in the rimary analysis
. Assays ualification, standardization, validation The ellcome Trust Research Laboratory, Christian Medical Colle e, Vellore, India has a validated assay to measure serum anti rotavirus I A antibodies usin C3 as the lysate hich has been used in earlier clinical trials of ROTAVAC® vaccines Cincinnati Children s Hos ital Medical Center CCHMC , Division of Infectious Diseases, Cincinnati, Ohio, USA also has a validated
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Protocol Number CVIA 066 Version Number: 01 Version Date: 11 July, 2018 assay for estimatin serum anti rotavirus I A antibodies usin 8 12 as the viral lysate hich is the arent strain of Rotari ® vaccine
. Future use of stored samples Any remainin serum sam les ill be retained for a ma imum of 5 years at the laboratories in case further investi ations are re uired after com letion of the study No enetic testin ill be erformed on sam les collected in the study After this eriod these sam les ill be destroyed after ritten communication from PATH
.5 iohazard containment As blood borne atho ens can infect throu h contact ith contaminated needles, blood, and blood roducts, a ro riate recautions ill be em loyed by all ersonnel in shi in and handlin of all s ecimens for this study as recommended All biolo ical s ecimens ill be trans orted usin a ro riate ac a in All dan erous oods or materials, includin dia nostic s ecimens and infectious substances, must be trans orted accordin to instructions detailed in the International Air Trans ort Association IATA Dan erous oods Re ulations Bioha ard aste ill be contained accordin to institutional, trans ortation carrier, and all other a licable re ulations All dan erous oods or materials, includin dia nostic s ecimens and infectious substances, must be trans orted accordin to instructions detailed in the International Air Trans ort Association IATA Dan erous oods Re ulations Bioha ardous aste ill be contained accordin to institutional, trans ortation carrier, and all other a licable re ulations
SAF T ASS SSM NT AND R PORTIN
. Definitions
. . Adverse vent (A ) An adverse event is any unto ard medical occurrence in a artici ant after administration of the investi ational vaccine and that does not necessarily have a causal relationshi ith the investi ational vaccine An A can therefore be any unfavorable and unintended si n includin abnormal laboratory findin s , sym toms, hysical e aminations, or disease tem orally associated ith the use of the investi ational vaccine, hether or not related to the investi ational vaccine This definition includes e acerbations of re e istin conditions Stable re e istin conditions hich do not chan e in nature or severity durin the study are not considered A s ho ever, these should be re orted as art of the medical history An A does not include: Medical or sur ical rocedures e , sur ery, endosco y, transfusion , but the condition that leads to the rocedure is an A Situations here an unto ard medical occurrence has not occurred e , hos itali ation for elective sur ery, social and or convenience admissions Overdose of either study dru or concomitant medication ithout any si ns or sym toms Solicited A s are re s ecific local and systemic adverse events that are common or no n to be associated ith vaccination and that are actively monitored as indicators of vaccine reacto enicity Investi ators ill not be re uired to assess causality of solicited adverse events if the onset is
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Protocol Number CVIA 066 Version Number: 01 Version Date: 11 July, 2018 durin the solicitation eriods Solicited adverse events ith onset after the solicitation eriod ill be ca tured as unsolicited A s or this trial, immediate A s ill be assessed by study staff 30 minutes after each vaccination and solicited A s ill be assessed daily for days after each vaccination by the artici ants Partici ants ill be rovided a diary to record the resence 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, vomitin , decreased a etite, irritability, and decreased activity level ill be monitored Local reactions to PI vaccination ill not be considered solicited events and should be re orted as unsolicited A s nsolicited A s are any A s re orted s ontaneously by the artici ant, observed by the study ersonnel durin study visits or those identified durin revie of medical records or source documents Unsolicited A s are not s ecified for active monitorin , but s ontaneously re orted as unto ard events occurrin in a artici ant All such events ill be recorded on the Adverse event’ a es of the eCR
. . Adverse drug reaction (ICH) Suspected Adverse Reaction (FDA) An adverse dru reaction ADR is any A in hich the casual relationshi to the investi ational vaccine is at least a reasonable ossibility, i e , the relationshi cannot be ruled out Havin a reasonable sus ected causal relationshi to the investi ational vaccine ualify as ADR The conce t of reasonable causal relationshi is meant to convey in eneral that there are facts evidence or ar uments to su est a causal relationshi nexpected adverse drug reaction is an adverse reaction, the nature or severity of hich is not consistent ith the information in the roduct information e , Investi ator s Brochure for an una roved investi ational roduct or ac a e insert summary of roduct characteristics for an a roved roduct
. . Serious Adverse vent (SA ) A SA is any unto ard medical occurrence that: Results in death, Is life threatenin , Re uires in atient hos itali ation or rolon ation of e istin hos itali ation , Results in ersistent or si nificant disability inca acity, Is a con enital anomaly or a birth defect, Medically im ortant event NOT : Investi ator confirmed cases of intussusce tion ill ualify as SA in the study and ill be re orted on the SA form The term life threatenin in the definition of serious refers to an event in hich the atient as at ris of death at the time of the event it does not refer to an event hich hy othetically mi ht have caused death if it ere more severe Medical and scientific ud ment should be e ercised in decidin hether e edited re ortin is a ro riate in other situations, such as im ortant medical events that may not be immediately life
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Protocol Number CVIA 066 Version Number: 01 Version Date: 11 July, 2018 threatenin or result in death or hos itali ation but may eo ardi e the atient or may re uire intervention to revent one of the other outcomes listed in the definition above These should also usually be considered serious am les of such events are intensive treatment in an emer ency room or at home for aller ic bronchos asm blood dyscrasias or convulsions that do not result in hos itali ation or develo ment of dru de endency or dru abuse Hos itali ation is an official admission to a hos ital Hos itali ation or rolon ation of a hos itali ation constitutes a criterion for an A to be serious ho ever, it is not in itself considered a SA In absence of an A , a hos itali ation or rolon ation of a hos itali ation should not be re orted as a SA by the Investi ator throu h a SA form, e am les of such situations include: A hos itali ation or rolon ation of hos itali ation is needed for a rocedure re uired by the rotocol Hos itali ation or rolon ation of hos itali ation is art of a routine rocedure follo ed by the center e , stent removal after sur ery This should be recorded in the study file A hos itali ation for a re e istin condition that has not orsened Hos itali ation for social reasons Disability is defined as a substantial disru tion in a erson’s ability to conduct normal life functions
. . Reporting Period and Parameter Safety events are re orted from the time of the first study vaccination throu h com letion of the study at ee s after the final vaccination S ecifically, Immediate adverse events ill be collected for 30 minutes after each vaccination Solicited A s to assess systemic reacto enicity ill be collected for days after each vaccination If a solicited A started durin the days Day 0 6 ost vaccination and continues beyond the days it ill continue to be re orted as a solicited A Unsolicited A s and SA s ill be collected from day 0 u to four ee s after last vaccination inclusive Any medical condition that is resent at the time that the artici ant is screened ill be considered as baseline and not re orted as an A A s characteri ed as intermittent re uire documentation of onset and duration of each e isode No s ecific safety laboratory tests are lanned in the study ho ever, clinical and laboratory investi ations conducted in order to dia nose or treat a condition in a study artici ant ill arrant documentation of all the ey laboratory results vents ill be follo ed for outcome information until resolution or stabili ation
. Severity of Adverse vents Severity of solicited reactions ill be raded as follo s: Reaction Intensity grade Parameter ever C 0 Normal A illary tem erature 3 5 C 1 Mild A illary tem erature 3 5 38 0 C
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2 Moderate A illary tem erature 38 0 3 0 C 3 Severe A illary tem erature 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 6 looser than normal stools day Vomitin 0 Normal Normal no emesis 1 Mild 1 e isode of vomitin day 2 Moderate 2 e isodes of vomitin day 3 Severe 3 e isodes of vomitin day Decreased a etite 0 Normal A etite as usual 1 Mild atin breast feedin less than usual no effect on normal activity 2 Moderate atin breast feedin less than usual interferes ith normal activity 3 Severe Not eatin breast feedin at all Irritability 0 Normal Normal Behaviour as usual 1 Mild Cryin more than usual ith no effect on normal activity 2 Moderate Cryin more than usual that interferes ith normal activity 3 Severe ersistent cryin and the child could not be comforted and that revents normal activity Decreased activity 0 Normal Behaviour as usual level 1 Mild Dro siness easily tolerated 2 Moderate Dro siness that interferes ith normal activity 3 Severe Dro siness that revents normal activity The severity of all unsolicited A s SA s occurrin durin the course of the study ill be raded as er the uidance document by Division of AIDS DAIDS Table for radin the Severity of Adult and Pediatric Adverse vents, corrected version 2 1, July 201 , of the US National Institute of Health as attached as A endi 2 to the rotocol Severity of unsolicited A s and SA s not included in the radin system mentioned above ill be raded as follo s: rade 1 Mild Mild sym toms causin no or minimal interference ith usual social functional activities ith intervention not indicated
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rade 2 Moderate Moderate sym toms causin reater than minimal interference ith usual social functional activities ith intervention indicated rade 3 Severe Severe sym toms causin inability to erform usual social functional activities ith intervention or hos itali ation indicated rade Potentially Life Threatenin Potentially life threatenin sym toms ith intervention indicated to revent ermanent im airment, ersistent disability, or death the Investi ator should not rade a reaction as life threatenin if had it occurred in a more severe form then it mi ht have caused death rade 5 Death All A s leadin to death are rade 5 events Definitions: Usual Social unctional Activities: Activities that are a e and culturally a ro riate, such as social interactions, lay activities, or learnin tas s Medical Intervention: Use of harmacolo ic or biolo ic a ent s for treatment of an A An A that is assessed as severe should not be confused ith the term SA Severity is a cate ory utili ed for ratin the intensity of an event and both A s and SA s can be assessed as severe A s are raded ith the orst severity rade durin the illness sym toms
. Causality of Adverse vent The study investi ator s ill determine the causal relationshi bet een the study roduct and the A The causality assessment is made on the basis of the available information at the time of re ortin and can be subse uently chan ed accordin to follo u information Determinin of causality is based on clinical ud ment and should ta e into consideration the follo in factors: Is there a tem oral time based relationshi bet een the event and administration of the investi ational roduct Is there a lausible biolo ical mechanism for the investi ational roduct to cause the A Is there a ossible alternative etiolo y for the A such as concurrent illness, concomitant medications Are there revious re orts of similar A s associated ith the investi ational roduct or other vaccines in the same class or this study, the investi ator s must classify the causality of the A accordin to the cate ories defined belo : Related: There is a reasonable ossibility that the roduct caused the event Reasonable ossibility means that there is evidence to su est a causal relationshi bet een the study roduct and the A Not Related: There is not a reasonable ossibility that the administration of the study roduct caused the event Assessment of causal relationshi should be recorded in the A and SA forms
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. Follow-up of Adverse vent Partici ants ill be monitored throu hout the study eriod for adverse events A s come to the attention of site clinicians throu h interim medical histories, hysical e aminations and laboratory testin conducted to investi ate other illnesses or routine tests The ossible occurrence of any A and SA ill also be as ed durin the scheduled study visits In addition, the arents ill be advised to contact study staff immediately at any time throu hout the study eriod if their child e eriences an A All adverse events ill be closely monitored in the safety monitorin rocesses A s ill be mana ed in accordance ith ood medical ractices by the clinical study site team ho ill assess and treat or refer the artici ant for medical care as a ro riate here feasible and medically a ro riate, the arent ill be encoura ed to see medical care at the facility here the study clinician is based, and to re uest that the clinician be contacted u on their arrival If needed to monitor or treat an adverse event, additional study visits may be conducted All A s and SA s ill be follo ed until resolution, until the condition stabili es, or until the artici ant’s artici ation in the study ends, hichever is earlier Once resolved or stabili ed, the a ro riate A SA form s ill be u dated Partici ants ho have an on oin study roduct related A SA at study com letion or at discontinuation from the study ill be follo ed by the PI or his desi nee until the event is resolved or determined to be irreversible, chronic, or stable by the PI The Investi ator ill ensure that follo u includes any su lemental investi ations as may be indicated to elucidate the nature and or causality of the A or SA This may include additional laboratory tests or investi ations, histo atholo ical e aminations or consultation ith other health care rofessionals PATH may re uest that the Investi ator erform or arran e for the conduct of su lemental laboratory analysis and or evaluations to elucidate as fully as ossible the nature and or causality of the A or SA The Investi ator is obli ed to com ly ith this re uest if ustifiable Site Investi ators ill ma e sure that the re uired dia nostic tools e , ultrasound and sur ical treatment for intussusce tion are readily available for the study artici ants under his atch If a artici ant dies durin the study eriod or durin a reco ni ed follo u eriod, attem ts should be made to rovide a co y of any ost mortem findin s, includin histo atholo y The u dated SA form should be sent to the PSRT ithin the time frames outlined in section 8 2 The outcome of adverse event ill be assessed as at the time of last observation as er the follo in cate ories: Recovered resolved ithout se uelae Recovered resolved ith se uelae On oin at the end of the study Stabili ed Death Un no n The outcome of the A is not no n
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Protocol Number CVIA 066 Version Number: 01 Version Date: 11 July, 2018
.5 eneral uidance on Recording Adverse vents To im rove the uality and recision of ac uired A data, the PI should observe the follo in uidelines: All A s and SA s ill be recorded in the source document and eCR for all artici ants throu hout the study artici ation A solicited sym tom re orted durin the solicitation eriod as a SA should be recorded on the PIDC and SA forms henever ossible, use reco ni ed medical terms hen recordin A s on the A CR Do not use collo uialisms and or abbreviations If no n, record the dia nosis i e , disease or syndrome rather than com onent si ns, sym toms and laboratory values e , record con estive heart failure rather than dys nea, rales, and cyanosis Ho ever, si ns and sym toms that are considered unrelated to an encountered syndrome or disease should be recorded as individual A s e , if con estive heart failure and severe headache are observed at the same time, each event should be recorded as an individual A A s occurrin secondary to other events e , se uelae should be identified by the rimary cause A rimary A , if clearly identifiable, enerally re resents the most accurate clinical term to record If a rimary serious A SA is recorded, events occurrin secondary to the rimary event should be described in the narrative descri tion of the case or e am le: Acute astroenteritis Diarrhea Na y Rash The rimary A here is acute astroenteritis Death is an outcome of an event The event that resulted in the death should be recorded and re orted on the SA CR or hos itali ations for sur ical or dia nostic rocedures, the illness leadin to the sur ical or dia nostic rocedure should be recorded as the SA , not the rocedure itself The rocedure should be ca tured in the case narrative as art of the action ta en in res onse to the illness hile no routine safety laboratories ill be erformed under this rotocol, any abnormal laboratory findin s e , clinical chemistry, hematolo y or other abnormal assessments e , electrocardio ram, vital si ns that the study team may be a are of are not er se re orted as A s Ho ever, abnormal findin s that are deemed clinically si nificant or are associated ith si ns and or sym toms 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 bein serious as described reviously Clinically si nificant abnormal laboratory or other abnormal findin s that are detected after study dru administration or that are resent at baseline and orsen follo in the administration of study dru are included as A s and SA s if serious The Investi ator should e ercise his or her medical ud ment in decidin hether an abnormal laboratory findin or other abnormal assessment is clinically si nificant Usually, the abnormality should be associated ith a clinically evident si n or sym tom, or be li ely to result in an evident si n or sym tom in the near term, to be considered clinically si nificant
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Protocol Number CVIA 066 Version Number: 01 Version Date: 11 July, 2018
.6 Reporting of SA
.6. Investigator Reporting to Sponsor ithin 2 hours of an investi ator’s a areness of a SA as defined in the rotocol, a SA form must be com leted and submitted to PATH and S onsor as er re ortin re uirement An SOP ill be develo ed to include the contact details of PATH and CIDRZ and ill contain s ecific details of the rocess includin timelines The investi ator must not ait to collect additional information to fully document the event before submittin the SA form hen additional information become available follo u submission must be com leted The initial SA form should be com leted ith all information no n at the time and should include as much information as ossible on the follo in : Name and contact of the investi ator submittin the A SA re ort Partici ant ID number Date artici ant received study vaccine s, includin cohort rou if a licable Descri tion of the serious adverse event and date of event onset Investi ator’s assessment of severity, causality and e ectedness Action ta en and current status If available, any dia nostic test re orts or hos ital records that may hel the PATH to evaluate the SA The investi ator ill be res onsible for notifyin UNZABR C and IRB throu h PATH as er the res ective C IRB’s re ortin re uirement The s onsor and PATH must be notified, ithin 15 calendar days after first no led e by the investi ator, hen there is a su estion of a chan e in the nature, severity or fre uency of e ected adverse dru reactions or hen ne ris factors are identified The basis on hich these assessments are made should be included An SOP ill be develo ed to include s ecific details of res onsibilities of the ersonnel, rocess and timelines
.6. Notification and Review of SA s The Medical monitor PATH is res onsible for evaluatin SA s submitted by the investi ator and for notifyin the rotocol safety revie team PSRT ithin 2 hours to convene an e edited PSRT revie if any criteria outlined in section 2 or 3 is met The PSRT ill be res onsible for revie in ade uacy of information and uery investi ator team to su lement information or act as a consultant if re uired on treatment a roach The medical monitor must also indicate hether he she concurs ith the details of the re ort rovided by the site PI The medical monitor ill also be res onsible for conductin the e ectedness analysis of the SA and inform the team on the re ortin re uirement for ZAMRA Medical monitor from PATH servin as technical consultants ill rovide technical uidance re ardin SA mana ement includin classification and re ortin
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Protocol Number CVIA 066 Version Number: 01 Version Date: 11 July, 2018
.6. Sponsor Reporting to Regulatory Agency The S onsor ill be res onsible for safety re ortin to the a ro riate re ulatory authorities ithin the s ecified time eriod of notification All fatal and life threatenin , serious, une ected adverse dru reactions should be re orted ithin calendar days after first no led e by the a licant The initial notification must be follo ed by as com lete a re ort as ossible, ithin an additional 8 calendar days Serious, une ected adverse dru reactions that are not fatal or life threatenin must be re orted as soon as ossible, and not later than 15 calendar days after first no led e by the a licant Adverse dru reaction that are serious and already no n described in Investi ator’s Brochure or the Summary of Product characteristics SPC Prescribin Information there ill be no fi ed time limit set These cases ill be re orted as soon as the necessary information is available Any information, that may in any ay influence the benefit ris assessment of a medicine or that ould be sufficient to consider chan es in the administration of the medicine or in the overall conduct of a clinical trial, must be re orted to the PSRT The a licant must submit this information to the PSRT ithin three calendar days of first no led e by the a licant
SAF T OV RSI HT or this study, a dili ent mechanism for revie of safety of the artici ants ill be created It ill ensure safety oversi ht by the site PI and Protocol Safety Revie Team PSRT ith the rovision of e edited revie by the team in case hi h rade A s are re orted The study also has rovisions for referrin to infectious disease s ecialists in case a consultation is recommended by the PSRT
. Routine Reviews by Principal Investigator The study site Investi ators ill be res onsible for continuous close safety monitorin of all study artici ants, and for alertin the rotocol team if concerns arise or if criteria for e edited revie of safety data are met
. Routine Reviews by Protocol Safety Review Team (PSRT) An internal team, the PSRT, ill be established to e amine safety at eriodic intervals The Protocol Safety Revie Team PSRT , a rou of hysicians hich includes the rinci al investi ator, other hysicians from the site and the medical officer s from PATH ill routinely monitor safety throu hout the duration of the trial The PSRT ill be chaired by a PATH Medical Officer and may see additional inde endent e ert medical o inion as dictated by needs The CRO statistician ith assistance from the data mana ement staff ill re are safety re orts for revie by the PSRT These re orts ill rovide at a minimum the follo in information: 1 accrual and artici ant status data ith re ard to com letion of study vaccinations and study visits and 2 summaries of solicited and unsolicited adverse events durin the revie eriod 3 Re orted SA s The PSRT safety revie ill be conducted by teleconference occurrin a ro imately fortni htly to monthly de endin on rate of enrolment durin the vaccination hase of the study and as
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Protocol Number CVIA 066 Version Number: 01 Version Date: 11 July, 2018 needed thereafter for the remainder of the study An e edited safety revie ill be carried out ithin 36 hours of submission of the safety information for the safety events listed belo : vent and relationshi to study a ent Severity rade SA , related All rades A case of Intussusce tion All rades Unsolicited A , related and above As assessed by investi ator or Medical Monitor The assi ned medical monitor officer ill be res onsible for informin the other members and convenin the meetin The PSRT may see inde endent e ert medical o inion as dictated by the occurrence of certain events In addition to safety revie , the PSRT may elect to discuss trial conduct issues that im act study inte rity and artici ant safety These may include but not limited to data uality, critical monitorin findin s, study roduct, research s ecimens, etc The PI or medical monitor ill also notify the PSRT for ad hoc safety revie s henever it is a are of SA or adverse events that meet re s ecified study ause criteria as er Section 3 The re orts and their analysis by the PSRT ill be submitted to the various Cs IRBs, if needed The Terms of Reference for the PSRT ill be develo ed as an SOP
. Study Pause Rule This study has no formal ause rules Ho ever, if durin the e edited safety revie s, the PSRT identifies safety concerns that arrant a safety ause, the PSRT ill notify the S onsor, PATH and BBIL am les of safety concerns hich may be considered but may not necessarily tri er automatic ause include: T o or more artici ants e erience the same related serious adverse event over a eriod of t o ee s T o or more artici ants e eriencin a rade solicited systemic adverse event over a eriod of t o ee s T o or more artici ants ith the same severe rade 3 solicited systemic adverse event or laboratory abnormality, ithin seven days Any case of intussusce tion ith Dia nostic Certainty Level 1 as er Bri hton Collaboration Intussusce tion or in rou ithin 30 days of vaccination Bri hton collaboration definition of Diagnostic Certainty Level of intussusce tion Sur ical criteria: The demonstration of inva ination of the intestine at sur ery and or Radiolo ic criteria: The demonstration of inva ination of the intestine by either air or li uid contrast enema or the demonstration of an intra abdominal mass by ultrasound ith tar et si n or dou hnut si n on transverses section and a seudo idney or sand ich si n on lon itudinal section that is roven to be reduced by hydrostatic enema on ost reduction ultrasound and or Auto sy criteria: the demonstration of inva ination of the intestine at auto sy Based on the criteria if a decision is made to ause the study, all enrollment and further vaccinations ill be aused, endin consultation ith inde endent infectious disease e ert, C and ZAMRA
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PATH CIDRZ retains the ri ht to tem orarily sus end or rematurely discontinue this study at any time related to safety If the study is sto ed or sus ended rematurely, the s onsor CIDRZ ill inform the C and ZAMRA about the decision and the reasons for termination or sus ension If such action is ta en, all efforts must be made to ensure the safety of the artici ants enrolled in the study In case of remature study or study clinic closure, the monitor ill conduct all activities as indicated in the close out monitorin visit
. Study Pause Procedure At scheduled study revie , the PSRT may also identify adverse events that could otentially ualify as ause criteria If the PI or desi nee , the medical monitor or any other member of the PSRT identifies and ro ose the study be aused on a discretionary basis, all vaccinations and enrollment ill be sus ended The PSRT revie s ill be summari ed ith consensus recommendations to the study S onsor as to hether there are safety concerns and hether the study should continue ithout chan e, be modified, or be sto ed If at any time, a decision is made to discontinue administration of study roduct in all artici ants, e editious notification ill be rovided by the S onsor to the ZAMRA and the C ithin 8 hours If the S onsor re starts the study after PSRT revie and recommendation, enrollment and vaccination may resume
0 DATA HANDLIN AND R CORD PIN The Princi al Investi ator is res onsible for assurin that the data collected are com lete, le ible, attributable, accurate, and recorded in a timely manner Data collection is the res onsibility of the clinical trial staff at the site under the su ervision of the site PI Hardco ies of the study visit or sheets ill be rovided for use as source document or sheets for recordin data for each artici ant enrolled in the study Data recorded in the eCR should be consistent ith source documents, and a uality control lan ill be ut in lace to ensure the same All source documents includin laboratory re orts must be revie ed by the clinical team and data entry staff, ho ill ensure that they are accurate and com lete Adverse events must be raded, assessed for severity and causality, and revie ed by the site PI or desi nee The Data Mana ement CRO DMC is res onsible for data mana ement activities, includin settin u the data base, allocation of access to various teams ith a ro riate access authority levels, uality revie , analysis, and re ortin of the study data accordin to SOPs The study site ill maintain a ro riate medical and research records for this trial, in com liance ith ICH CP, re ulatory, s onsor and institutional re uirements for the rotection of confidentiality of artici ants
0. Definitions
0. . Source Data All information in ori inal records and certified co ies of ori inal records or clinical findin s, observations, or other activities in a clinical trial necessary for the reconstruction and evaluation
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Protocol Number CVIA 066 Version Number: 01 Version Date: 11 July, 2018 of the trial Source data are contained in source documents ori inal records or certified co ies ICH 6 section 1 51 ,
0. . Source Documents or this study source documents ould include but are not limited to: Documentation of the study eli ibility evaluation Si ned Informed Consent Documents Visit documentation that includes dates of study visits and dates of study vaccinations Re orted laboratory results A evaluations Concomitant medications Post Immuni ation Diary Card PIDC Certified co ies of hos ital records Study visit or sheets
0. Data Capture Methods (Case Report Form Development and Completion) The clinical data in source documents ill be continuously entered directly into a 21 C R Part 11 com liant lectronic Data Ca ture DC system by trained and ualified study staff The eCR for the DC system ill be develo ed by the Data Mana ement CRO ho ill also rovide trainin in the use of the system rite access to the system ill be limited to authori ed Investi ators sub Investi ators study staff and the system ill automatically ee an audit trail of all entries and corrections in the eCR Read access to the artici ant data ill be restricted to authori ed staff or in ithin the ro ect team The data system includes internal uality chec s, such as automatic ran e chec s, to identify data that a ear inconsistent, incom lete, or inaccurate Clinical data for each artici ant ill be entered directly into the eCR from the source documents It is the site PIs’ res onsibility to ensure the accuracy, com leteness, and timelines of the data re orted in the artici ant’s eCR and any su ortin documentation All source documents should be com leted in a neat, le ible manner to ensure accurate inter retation of data Source documentation su ortin the eCR data should document the dates and details of study rocedures, A s and artici ant status The study database ill identify study artici ants only by a study identification number and ill not contain any identifyin information such as name, address or ersonal contact information, or any other re ional state national identification number The site PIs institutions ill maintain all information in the eCR s and all source documents that su ort the data collected from each artici ant in a secure area and treated as confidential material The confidentiality of records that could identify artici ants must be rotected, res ectin the rivacy and confidentiality rules in accordance ith the a licable re ulatory re uirement s or electronic CR s, revie and a roval si nature is com leted electronically throu h the electronic data ca ture tool ach individual havin rite access to electronic CR s must meet the PATH’s trainin re uirements and must only access the electronic data ca ture tool usin the uni ue user account rovided by the S onsor User accounts are not to be shared or reassi ned to other individuals
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The site PI ill retain all essential documents and a CD ROM co y of the eCR data after the study is closed and the Clinical Study Re ort is com leted or at such time that the site no lon er has access to the electronic data system
0. Data Management The DMC res onsible for data mana ement ill develo a Data Mana ement Plan DMP and corres ondin database com liant ith International Conference on Harmoni ation ICH re uirements for a roval by PATH before im lementation The Plan ill describe roles of sta eholders and s ecific rocedures to ensure a ro riate handlin of data at all ste s of the data mana ement rocess to assure a valid and hi h uality database at the end of the study, ready for analysis ntered data ill be verified by an inde endent monitorin CRO ho ill uery the site for otential discre ancies The site Investi ator, or desi nee, ill be res onsible for resolution of ueries and a ro riate documented chan es in the database DMC ill erform all activities as er their standard o eratin rocedures SOPs All study s ecific rocesses ill be described in the Data Mana ement Plan DMP Codin of medical history and adverse events ill be erformed usin MedDRA and codin of medications ill be erformed usin HO Dru Dictionary eCR s and any su ortin documentation should be available for retrieval or revie at any iven time The lectronic Data Ca ture System DC ill detect and fla univariate data discre ancies or inconsistencies to alert the Investi ator desi nee and rovide a satisfactory resolution ithin the DC The Data Mana er shall revie all the discre ancies to ensure corrective and reventive actions In addition, the Medical Revie ers ill also revie data for medical inconsistencies and enerate manual ueries if re uired or ueries can be routed throu h DMC follo in medical revie After com letion of data codin and resolution of all the ueries in the database, the database ill be declared as com lete and accurate and ill be loc ed for final statistical analysis
0. Retention of Study Records The site PIs are res onsible for retainin study records until 5 years after the investi ation is discontinued or com leted and the UNZABR C, NHRA and ZAMRA is notified No records ill be destroyed ithout the ritten consent of PATH PATH ill inform the Investi ator in ritin of the need for record retention and ill notify the Investi ator in ritin hen the trial related records are no lon er needed These records are also to be maintained in com liance ith local C and local authority medical records retention re uirements, hichever is lon est Stora e of all trial related documents ill be such that confidentiality ill be strictly maintained to the e tent re uired by local la
STATISTICAL CONSID RATIONS
. Overview and eneral Considerations An outline of the statistical analyses is described in the follo in sections A formal statistical analysis lan SAP that contains full details of all lanned analyses ill be created and finali ed rior to database loc All statistical analyses ill be erformed usin SAS® soft are version or later
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Serum anti rotavirus I A antibody concentrations belo the lo est limit of uantitation LLO i e , belo the startin dilution of assay recorded as LLO ill be set to half that limit i e , LLO 2 In case of that the concentration is above the u er limit of uantitation ULO , an actual value re orted ill be used
. Randomization Procedures Healthy infants ill be randomi ed to receive one of the three study vaccines in a 1:1:1 ratio or vaccine allocation, a randomi ation bloc in scheme ill be used in order to ensure that balance bet een vaccine rou s ill be maintained Infants ill be randomi ed se uentially in the order that they are enrolled The randomi ation scheme that contains a artici ant identification number and the corres ondin randomi ation assi nment ill be enerated usin com uter soft are rior to the initiation of the study and rovided to the desi nated site ersonnel
. Sample Size and Power The immuno enicity of the study vaccines ill be rimarily assessed by eometric mean concentrations MCs of serum anti rotavirus I A antibodies at 28 days after the last dose of the study vaccine, alon ith its t o sided 5 confidence interval CI , by e onentiatin the corres ondin lo 10 transformed mean and its t o sided 5 CI limits Table 2 belo resents the recision of the 5 CI of the MC in lo 10 transformed scale er rou under different assum tions of rou si es and assumed standard deviation SD of lo 10 transformed anti rotavirus I A 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 Number of evaluable artici ants er rou lo 10 transformed anti rotavirus I A 120 5 150 concentrations
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 sam le si e of 150 for each rou and an assumed SD of lo 10 transformed anti rotavirus I A concentrations of 0 60, the half idth of a t o sided 5 CI for anti rotavirus I A MC ill be 0 102 in lo 10 transformed scale for each rou , assumin a dro out rate of 10 Po er to sho that the ratio of anti rotavirus I A MCs in ROTAVAC 5CM rou to that in ROTAVAC® rou is at least 0 5 as calculated usin t o sam le t test accordin to various
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rou si es, different assumed SDs of lo 10 transferred anti rotavirus I A concentrations and e ual true underlyin eometric mean and is rovided 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 Number of evaluable Power to demonstrate that the lower limit anti-rotavirus IgA participants per of 5 CI of the ratio of MC between concentrations group 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
Assumin the true standard deviation of lo 10 transformed anti rotavirus I A concentration is belo than or e ual to 0 60, ith a sam le si e of 150 and a dro out rate of 10 er rou 135 evaluable artici ants er rou , the study has o er of 8 to detect at least 0 5 of MC ratio bet een ROTAVAC®5CM and ROTAVAC® rou s ith 150 infants vaccinated er rou , this study desi n allo s a reater than 0 chance of observin at least one A if true incidence is 1 53 Conversely, if no A s are observed in 150 vaccine reci ients, the study ill be able to rule out A s occurrin at a rate of a ro imately 2 5 or above based on the u er bound of the t o sided 5 CI
. Analysis Populations
. . nrolled Population The enrolled o ulation is defined as all screened artici ants ho rovide informed consent and are eli ible for study artici ation, re ardless of the artici ant’s randomi ation and treatment status in the study
. . Full Analysis population The full analysis o ulation is defined as all artici ants in the enrolled o ulation ho ere randomi ed, received a study vaccination, and rovided at least one evaluable serum sam le The
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Protocol Number CVIA 066 Version Number: 01 Version Date: 11 July, 2018 analysis based on this o ulation ill serve as su ortive results for all immuno enicity ob ectives Partici ants in the ull Analysis A o ulation ill be analy ed as randomi ed , i e accordin the vaccine a artici ant as desi nated to receive, hich may be different from the vaccine that the artici ant actually received
. . Per Protocol population The er rotocol o ulation is defined as all artici ants in the A o ulation ho correctly received study vaccine er randomi ation ith no ma or rotocol deviations that are determined to otentially interfere ith the immuno enicity assessment of the study vaccines This o ulation ill serve as the rimary analysis o ulation for all immuno enicity ob ectives Due to un redictability of some irre ularities, the criteria for e clusion of artici ants from the Per Protocol PP o ulation ill be determined before the database is loc ed
. . Safety population The safety o ulation is defined as all artici ants in the enrolled o ulation ho received a study vaccination and had any safety data available Partici ants in the safety o ulation ill be analy ed as treated , i e accordin to the actual vaccine received at the first dose All safety analyses ill be erformed usin this o ulation The denominators for different safety end oints may vary accordin to the number of artici ants ith available data for the s ecific end oint or instance, the solicited systemic adverse event end oints ill be based only on those ho have the corres ondin CR data re ardless of other safety follo u data
.5 Analytical Methodology
.5. Analysis of demographics and other baseline characteristics Demo ra hic and baseline characteristics a e, ethnicity, se , len th, and ei ht ill be tabulated by vaccine rou on the A o ulation If more than 10 of the A o ulation is e cluded from the PP o ulation, the descri tion and com arability of the vaccine rou s at baseline ill be re eated on the PP o ulation Continuous variables, such as a e, len th, and ei ht, ill be described as number of artici ants, mean, standard deviation SD , minimum, median, and ma imum Cate orical variables, such as ethnicity and se , ill be described by number of artici ants and ercenta e for each vaccine rou rou com arison ill be erformed to confirm hether the vaccine rou s are similar ith re ard to demo ra hic and baseline characteristics, usin ANOVA or isher’s e act test as a ro riate Medical history ill be tabulated by Medical Dictionary for Re ulatory Activities MedDRA system or an class SOC and referred term for each vaccine rou Medications ta en u to 1 month rior to enrolment ill be summari ed by anatomical thera eutic chemical ATC classification and referred dru name coded by HO Dru Dictionary HO DD for each vaccine rou
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.5. Analysis of primary ob ective The MCs of serum anti rotavirus I A antibodies at 28 days after the last dose of ROTAVAC® or ROTAVAC 5CM ill be calculated alon ith its t o sided 5 CI, by e onentiatin the corres ondin lo 10 transformed mean and its t o sided 5 CI limits To com are the immuno enicity of ROTAVAC® and ROTAVAC 5CM at 28 days follo in the last dose of the study vaccine, the follo in hy othesis ill be tested, ® H0: MCROTAVAC 5CM MCROTAVAC ® H1: MCROTAVAC 5CM MCROTAVAC The test ill be done at 28 days follo in the last dose of ROTAVAC 5CM and ROTAVAC® and ill be conducted ith one sided ith a ty e I error rate of 0 025 The ratio of the ost vaccination anti rotavirus I A MCs bet een the ROTAVAC 5CM and ROTAVAC® rou s ill be rovided ith its t o sided 5 CI The lo 10 transformed anti rotavirus I A concentrations ill be used to construct a t o sided 5 CI for the mean difference bet een the t o study rou s usin t distribution The mean difference and corres ondin 5 CI limits ill be e onentiated to obtain the MC ratio and the corres ondin 5 CI If the lo er limit of the 5 CI of the ratio of MCs bet een the ROTAVAC 5CM and ROTAVAC® rou s is lar er than 1 2, ROTAVAC 5CM is considered to be non inferior to ROTAVAC® The com arison of the MCs bet een the t o study vaccines ill be also erformed usin analysis of covariance ANCOVA method ith lo 10 transformed anti rotavirus I A concentrations as the de endent variable, the vaccine rou as the e lanatory variable, and lo 10 transformed baseline concentrations as a covariate This ad usted analysis ill be considered as su ortive The ercenta e of artici ants ith seroconversion, sero ositivity, and serores onse ill be com uted for the ROTAVAC 5CM and ROTAVAC® rou s alon ith e act t o sided 5 CIs based on Clo er Pearson method The difference in the ercenta e bet een the t o rou s ill be rovided alon ith its t o sided 5 CI obtained by Miettinen and Nurminen method The eometric Mean old Rise M R MC ost vaccination MC at baseline ill be rovided ith its t o sided 5 CIs, by e onentiatin the difference in means of lo 10 transformed anti rotavirus I A concentrations bet een ost vaccination and baseline and its t o sided 5 CI that ill be obtained by aired t test method In addition, a reverse cumulative distribution RCD curve ill be created by vaccine rou and visit
.5. Analysis of secondary ob ectives .5. . Analysis of secondary safety ob ective
The ercenta e of artici ants ith safety end oints alon ith its e act t o sided 5 CI based on Clo er Pearson method ill be rovided for each vaccine rou Reactogenicity:
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The number and ercenta e of artici ants e eriencin immediate adverse events ithin 30 minutes ost each vaccination and solicited ost vaccination reacto enicity fever, diarrhea, vomitin , decreased a etite, irritability, decreased activity level durin the day eriod after each vaccine ill be tabulated by vaccine rou and severity or the ercenta e, an e act t o sided 5 CI ill be rovided usin Clo er Pearson method nsolicited A s:
The number and ercenta e of artici ants e eriencin immediate adverse events ithin 30 minutes, unsolicited A s and SA s includin intussusce tion re orted throu h ee s after the last vaccination ill be rovided by vaccine rou , severity, and causality or the ercenta e, an e act t o sided 5 CI ill be rovided usin Clo er Pearson method The ori inal verbatim terms used by investi ators to identify adverse events on case re ort forms CR s ill be coded accordin to MedDRA dictionary A s includin SA s ill be summari ed and classified by SOC and referred term of the MedDRA dictionary They ill be dis layed by vaccine rou as both fre uencies and ercenta es The analysis of unsolicited adverse events com rises the follo in cate ories: Any unsolicited A s Related unsolicited A s SA s Related SA s Unsolicited A s leadin to ithdra al from the study Unsolicited A s leadin to ithdra al from study vaccination but remainin in the study Unsolicited A s leadin to hos itali ation Any A s leadin to death All re orted A s that start after vaccination ill be tabulated If a iven disease is already re orted as on oin at the first visit on the medical history a es, it ill be counted and tabulated as a vaccine emer ent adverse event only if it orsens after the immuni ation ith the study vaccine hen an adverse event occurs more than once for a artici ant, the ma imal severity and stron est relationshi to the vaccine rou ill be counted SA s and discontinuation due to A s ill be described in detail by vaccine rou Data listin s of all adverse events ill be rovided by artici ant
The medications ta en durin study eriod ill be coded usin HO DD The concomitant medications t ill be tabulated by ATC classification and referred dru name of HO DD for each vaccine rou
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.5. . Analysis of secondary immunogenicity ob ective The immuno enicity analysis for Rotari ® ill be descri tive The MC and M R ill be com uted for the Rotari ® rou alon ith its t o sided 5 CI usin the same methods outlined in Section 11 5 2 The ercenta e of artici ants ith seroconversion, sero ositivity, and serores onse ill be rovided for the Rotari ® rou alon ith its e act t o sided 5 CI usin Clo er Pearson method A reverse cumulative distribution RCD curve ill be created for Rotari ® rou by visit
.5. Analysis of exploratory ob ective The e loratory analysis conducted on immune res onse measured by LISA usin 8 12 1P8 virus as a substrate in a subset of the sam les collected 50 er rou ill be descri tive MCs of serum anti rotavirus I A antibodies usin 8 12 virus as a substrate ill be calculated for each rou alon ith its t o sided 5 CI, by e onentiatin the corres ondin lo 10 transformed mean and its t o sided 5 CI limits The ercenta e of artici ants ith seroconversion and sero ositivity ill be rovided for each rou alon ith its e act t o sided 5 CI usin Clo er Pearson method M R ill be rovided ith its t o sided 5 CIs, by e onentiatin the difference in means of lo 10 transformed anti rotavirus I A concentrations usin 8 12 virus as a substrate bet een ost vaccination and baseline and its t o sided 5 CI that ill be obtained by aired t test method
.5.5 Multiplicity No multi licity ad ustment ill be carried out as ROTAVAC 5CM and ROTAVAC® ill be rimarily com ared based on a sin le rimary end oint
.5.6 Handling of Dropouts and Missing Data
Missin immuno enicity data ill not be im uted and ill be analy ed as if they ere missin randomly Over the hole study eriod, the number and ercenta e of artici ants ho ithdra from the study ill be rovided by treatment rou All ithdra n artici ants ost randomi ation ill be further described re ardin their time to dro out and their reasons for ithdra al or artici ants ho ithdra from the study, their data collected before ithdra al ill be analy ed under full analysis A o ulation and safety o ulation as a licable
.6 Analysis Se uence No interim analysis is lanned for this study A final analysis on all safety and immuno enicity data ill be erformed after the study ends and database is cleaned and loc ed
ALIT ASS RANC AND ALIT CONTROL uidance on internal and e ternal rocesses to assure effective rotocol im lementation, uality of the research conducted and com liance ith s onsor PATH’s and a licable re ulatory re uirements
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. eneral Considerations The study ill be conducted in full com liance ith the rotocol and ICH CP to rovide ublic assurance that the ri hts, safety, and ell bein of trial artici ants are rotected, and that the clinical trial data are credible To ensure uality and standardi ation, the site ill develo Standard O eration Procedures SOPs for ey rotocol rocedures and conduct the study uided by the study Manual of Procedures or other ritten uidelines The site ill also develo routine o erational chec s to verify that critical rotocol re uirements and rocedures are e ecuted correctly and com letely at the time the or is bein erformed Prior to the initiation of the study, PATH and or the CRO dele ated by PATH ill conduct rotocol trainin , includin a licable SOPs, for study staff The investi ational site ill rovide direct access to all trial related site, source data documents, and re orts for the ur ose of monitorin and auditin by the PATH desi nee, and ins ection by local IRB C and re ulatory authorities
. xternal Monitoring PATH desi nee is res onsible for ensurin that the study is conducted in accordance ith ICH CP and re ulatory re uirements or this ur ose, monitors under contract from PATH ill rovide e ternal monitorin for this study A site initiation visit ill be conducted rior to be innin the study, and monitorin ill be conducted at initiation, durin , and at closeout of the study Durin the course of the study monitors ill visit the clinical site at intervals to verify com liance to the rotocol com leteness, accuracy, and consistency of the data and study roduct accountability adherence to ICH CP and a licable re ulations As needed and hen a ro riate, the monitors ill also rovide clarifications, additional trainin to hel the site resolve issues identified durin the monitorin visit As a ro riate and informed by ris assessment, remote centrali ed monitorin activities may be considered in lace of or to su lement onsite monitorin These may include analysis of data uality e missin or inconsistent data, outlier data , identify data trend not easily detected by onsite monitorin and erformance metrics e , screenin or ithdra al rates, eli ibility violations, timeliness and accuracy of data submission The e tent and fre uencies of the monitorin visits ill be described in a se arate Study Monitorin Plan develo ed rior to study initiation The investi ator ill be notified in advance of the scheduled monitorin visit The monitor should have access to all trial related locations, artici ant medical records, study roduct accountability and other study related records needed to conduct monitorin activities The PATH desi nee ill share the findin s of the monitorin visit, includin any corrective actions, ith the site investi ator The site PI and the monitor must a ree to coo erate to ensure that any roblems detected in the course of these monitorin visits are resolved in a redefined timeframe
. Independent Auditing PATH or its desi nee may audit the study to ensure that study rocedures and data collected com ly ith the rotocol and a licable SOPs at the clinical site and that data are correct and com lete The site PI ill ermit auditors em loyees of the PATH or em loyee of a com any desi nated by the PATH to verify source data validation of the re ularly monitored clinical study The auditors ill com are the entries in the eCR s ith the source data and evaluate the study site
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. Regulatory Agency Inspection The site PI must be a are that re ulatory authorities, includin C IRB may ish to ins ect the site to verify the validity and inte rity of the study data and rotection of human research artici ants The site PI ill notify the S onsor, and PATH ithin 2 hours follo in contact by a re ulatory authority The site PI must ma e the relevant records available for ins ection and ill be available to res ond to reasonable re uests and audit ueries made by authori ed re resentatives of re ulatory a encies The site PI ill rovide the S onsor and PATH ith co ies of all corres ondence that may affect the revie of the current study or his ualification as an investi ator in clinical studies Durin the audits or ins ections, the artici ant’s confidentiality ill be maintained at all times to the e tent ermitted by the la Site visit lo s ill be maintained at the study site to document all visits PATH ill rovide any needed assistance in res ondin to re ulatory audits or corres ondence
THICAL CONSID RATIONS (AND INFORM D CONS NT)
. thical Standards This study ill be conducted in accordance ith the ethical rinci les set forth in the orld Medical Association Declaration of Helsin i The Council for International Or ani ations of Medical Sciences CIOMS International thical uidelines for Biomedical Research Involvin Human Partici ant and in conformity ith ICH CP and uidelines on Re ulatin the Conduct of Clinical Trial in Human Partici ants as set forth by Zambia Medicines Re ulatory Authority ZAMRA NB The Declaration of Helsin i rovides detail on hat must be included in a rotocol: fundin , s onsorshi , affiliations and otential conflicts of interest, incentives to artici ate, com ensation for harm and ost trial access to dru s and care International thical uidelines for Biomedical Research Involvin Human Trial artici ants CIOMS 2002 also rovides uidance on ethical re uirements
. thical Review This study ill be conducted under the aus ices of the University of Zambia Biomedical Research thics Committee In addition, the study ill also be revie ed by estern Institutional Revie Board and an a roval ould be re uired before initiation of enrolment These committees ill revie and a rove the rotocol, informed consent form, and any recruitment materials advertisin or informational material includin any modifications to these documents rior to, or durin the study All chan es to the rotocol or informed consent form must be revie ed and a roved by the I C, IRB and PATH rior to im lementation, e ce t here necessary to eliminate a arent immediate ha ard to study artici ants The investi ator is also res onsible for obtainin continuin revie throu hout the duration of the study in accordance ith e istin re ulations The site ill be res onsible for submittin to and obtainin initial and subse uent annual biannual revie a roval from the UNZABR C, NHRA and ZAMRA as a licable
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. Informed Consent Process li ible arent those above the a e of 18 years i e le al a e for consentin in Zambia LAR of otential artici ants ill ty ically be a roached durin routine child immuni ation clinics by study staff ith eneral information about the study Those interested, ill be invited to the Research Unit ithin 20 meters of the clinic and ill be offered further information about the study Motivated arents LAR ill then be rovided one on one study information in the local lan ua e of their choice They ill be ta en over the a roved artici ant information sheet oin throu h details of hat the study is about, hat is re uired to artici ate, rocedures, benefits of artici ation and ris s involved, number of clinic visits re uired etc The artici ant’s arent LAR ill be iven a co y of the IC and allo ed am le time to read the consent form, encoura ed to as uestions about the study, have the uestions ans ered and then be iven time to decide if s he ould li e to have her his child artici ate in the study It ill be em hasi ed that artici ation is voluntary, and that the artici ant arent has the ri ht to decline to artici ate or subse uently ithdra from the study at any time ithout re udice A sim le com rehension test ill be administered at the end of the session Partici ant’s arent LAR scorin at least out of 10 basic uestions ill be deemed sufficiently informed, and those scorin less ill be ta en throu h the artici ant information a ain re eat ill be done only once until they are able to ass the com rehension test After this, the arent or a ro riate le ally acce table re resentative ill be re uired to si n t o ori inals of the IC one for the study file, and another for themselves to ee Those ho are illiterate ill re uire an inde endent itness of their choice to si n attestin to the rocess hile the arent LAR ill be re uired to thumb rint the form
. Participant Confidentiality The investi ators, PATH and all staff from or ani ations involved ith the im lementation of the trial must ensure that the artici ant’s confidentiality is maintained Personal identifiers ill not be included in any study re ort All study records ill be e t confidential to the e tent rovided by national and local la s Medical records containin identifyin information may be made available for revie hen the study is monitored by the s onsor desi nee or an authori ed re ulatory a ency Direct access may include e aminin , analy in , verifyin , and re roducin any records and re orts that are im ortant to the evaluation of the study hen a ro riate and to the e tent ossible, study rocedures ill be conducted in rivate to rotect artici ant rivacy and confidentiality All study related information ill be stored securely at the study site All artici ant information ill be stored in loc ed file cabinets in areas ith access limited to study staff Data collection, rocess, and administrative forms, laboratory s ecimens, and other re orts ill be identified by a coded number only to maintain artici ant confidentiality All records that contain names or other ersonal identifiers, such as locator forms and informed consent forms, ill be stored se arately from study records identified by code number All local databases ill be secured ith ass ord rotected access systems orms, lists, lo boo s, a ointment boo s, and any other listin s that lin Partici ant ID numbers to other identifyin information ill be stored in a se arate, loc ed file in an area ith limited access Partici ants’ study information ill not be released ithout their ritten ermission, e ce t as necessary for monitorin
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.5 Reimbursement Partici ants ill be com ensated for their time and effort in this study, and be reimbursed for travel to study visits There is no direct ayment for artici atin in this study Ho ever, a reimbursement has been ro osed for a roval by the ethics committee This amount is e ected to be reasonably sufficient to com ensate for time, inconvenience and travel cost, and yet not too much to unduly induce them into artici atin This information ill be rovided in the artici ant information sheet Partici ants arents of study artici ants ill not be char ed for study medication, research clinic visits, research related e aminations, or research related laboratory tests
.6 Ris and enefits enefits to Study Participants Potential benefits to enrolled artici ants in the current trial could be rotection from rotavirus astroenteritis, the identification of undetected medical conditions durin medical e amination, education about rotavirus and diarrhea and its revention and treatment, education on ersonal hy iene and access to medical care for the artici ant for any illnesses occurrin durin the trial eriod Potential Ris s Physical Ris s: The main ris s of this study are ris s of rotavirus vaccines to cause some side effects includin develo ment of fever, vomitin , diarrhea, cou h, runny nose, irritability and rash In babies, natural rotavirus infection can cause diarrhea, vomitin and fever It is ossible that enrolled artici ants may have a fe looser than usual stools, cry or have a sli htly hi her than usual tem erature for a day or t o after vaccination ith the attenuated rotavirus vaccine These events are similar to those re orted in other rotavirus vaccine clinical trials These ill be e lained to arents in the consent form Serious or aller ic reactions also may be ossible This ris is addressed by tryin to screen out any children ith no n aller ic reactions to vaccines in the ast and ho may have an aller y to one of the com onents of the vaccine Should an aller ic reaction occur ith vaccination, the study clinic ill follo its SOP for handlin medical emer encies and have su ortive medicines in lace, in addition to trained staff Post mar etin studies su est that intussusce tion may be associated ith the licensed rotavirus vaccines at a lo rate ith an attributable ris for intussusce tion of the rotavirus vaccine bet een 1 er 100,000 vaccinated infants The hu e benefit in terms of number of lives saved as a result of e cellent efficacy of these vaccines a ainst rotavirus diarrhea out ei h the small otential ris of intussusce tion and therefore the vaccine continues to be recommended for immuni ation schedules of all countries Collection of blood s ecimens may cause some discomfort to artici ants Veni uncture is sometimes associated ith discomfort, ain, bleedin , bruisin , redness, s ellin , local hardness, and or infection at the uncture site This ris ill be miti ated by ensurin that only study staff members ade uately trained in safe dra in of blood, conduct this rocedure
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In the case of e ected and une ected reactions after the use of vaccines, study artici ants ill receive a ro riate medical care and treatment The s onsor CIDRZ ill ensure covera e for the cost of medical treatment and resolve these cases accordin to current standard of care in Zambia To minimi e ris to the artici ants and early identification and treatment of side effects the follo in assessments are lanned in the rotocol Conduct of study rocedures li e administration of vaccines, safety assessment and blood dra s by staff trained in these rocedures and in this a e rou Monitorin of artici ants closely for 30 minutes after vaccination and rovidin emer ency care for any immediate reactions If medical issues arise that cannot be mana ed by the clinic erformin the study, the study doctor ill refer the artici ant to an a ro riate clinic outside of the institution Tele honic call and visit of heath care or er to infant’s home t ice ithin days of each vaccine dose Re ular follo u of all infants ith severe and serious adverse events Ris s to Privacy: Anyone artici atin in research usin their real name and medical information can face a loss of rivacy These ris s are miti ated by usin uni ue IDs in lace of a artici ant’s name, restrictin access to study information, and not namin or identifyin a artici ant in any ublication Foregoing approved rotavirus Vaccination: Rotari ® is bein rovided free of cost by the national immuni ation lan hereas ROTAVAC® and ROTAVAC 5CM have not yet been studied or a roved for use in Zambia Ho ever, ROTAVAC® has been administered to more than 12,000 children in clinical trials in India includin one study rovin efficacy of the vaccine and another study rovin non inferiority of immune res onse vs Rotari ® and has already been administered to millions of children in India under national immuni ation lan ROTAVAC 5CM has the same virus strain as ROTAVAC® ith addition of some stabili ers and e ci ients of RAS cate ory and the immune res onse has been sho n to be similar to HO a roved ROTAVAC® vaccine T o third of the artici ants ill receive either ROTAVAC® or ROTAVAC 5CM vaccine hich has not been studied in Zambian o ulation and the immune res onse cannot be redicted If the immune res onse in the o ulation is not as er the e ectation, then there is a ris that the infant may not be rotected a ainst rotavirus infections
. Compensation for Research Related In ury The S onsor CIDRZ ill rovide a ro riate treatment for in uries directly attributable to artici ation Clinical trial insurance in favor of artici ants ill be underta en to cover in ury and other trial related eventualities includin com ensation for disability and death Information about this ill be rovided in the artici ant information as ell as ho to access it
PROTOCOL MODIFICATIONS AND AM NDM NTS The rotocol ill not be amended ithout rior ritten a roval from PATH In case the rotocol is amended, the Investi ator ill submit and, here necessary, obtain a roval from the thics Committee for all rotocol amendments and chan es to the IC document Submission and a roval of the amended rotocol to ZAMRA ill be the res onsibility of the s onsor
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. Administrative Modifications Administrative or technical modifications li e chan e in study team or tele hone numbers , hich do not have an im act on the artici ant s health or influence study outcome ill be communicated in ritin and filed to UNZABR C and IRB throu h PATH as an amendment to the rotocol by the investi ator
. Clinical Modifications Modifications affectin or interferin ith the artici ant s health interests and involvin chan es in the desi n of the study or its scientific si nificance or uality or safety ill re uire rotocol amendments and ne a rovals by NHRA, ZAMRA, UNZABR C and IRB The S onsor, PATH and Investi ator ill a ree to im lement adhere to such modifications only after ritten a roval from ZAMRA and UNZABR C These re uirements for a roval should in no ay revent any immediate action from bein ta en by the Investi ator in the interests of reservin the safety of all artici ants included in the trial If an immediate chan e to the rotocol is felt to be necessary by the Investi ator and is im lemented by him for safety reasons, the S onsor and PATH should be notified immediately The I C IRB should be informed immediately
. Protocol Deviations and Violations Any chan es from rotocol s ecified rocedures and study related SOPs occurrin durin the conduct of the trial ill be documented and re orted as rotocol violations or deviations A Protocol Violation is any de arture from the a roved rotocol, trial documents or any other information relatin to the conduct of the study hich may affect the safety of trial artici ants or the study outcomes am les include ron randomi ation or enrolment of artici ants that do not meet inclusion e clusion criteria A Protocol Deviation is any de arture from the a roved rotocol, trial documents or any other information relatin to the conduct of the trial that does not result in harm to the trial artici ants and does not si nificantly affect the study outcomes am les of deviations include a rotocol visit date outside the study visit indo or an isolated incident of a missed or incom lete study rocedure or study evaluation Serious or re eated rotocol violations or deviations ill re uire assessment of the root cause and im lementation of corrective and reventive action lans They may constitute rounds to interru t the trial at a study site The noncom liance may be either on the art of the artici ant, the investi ator, or the study clinic staff As a result of any deviations, corrective actions are to be develo ed by the site and im lemented rom tly Trial rocedures shall not be chan ed ithout the consent of PATH Deviations of the rotocol ill be e amined on an individual basis, ta in into account recorded information for the reason s that the deviation occurred It is the res onsibility of the site to use continuous vi ilance to identify and re ort deviations to CRO in a timely manner after identification If re uired, re orts of rotocol deviations must be sent to the research ethics committees overseein the research The PI and his her staff are res onsible for no in and adherin to their research ethics committee’s IRB’s re uirements
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To limit the otential for rotocol deviations, the trial site ill receive trainin or retrainin , as necessary on rotocol im lementation and ill o erate accordin to ritten rocedures
5 FINANCIN AND INS RANC The trial is su orted by a rant from Bill and Melinda ates oundation to PATH under O ortunity ID: OPP11685 ROTAVAC® and ROTAVAC 5CM vaccine are rovided by Bharat Biotech International Ltd , India The s onsor ill secure insurance that com lies ith local re ulatory re uirements to cover for research related in ury The vaccine manufacturer ill self insure a ainst roduct liability
6 P LICATION POLIC It is understood by the investi ators that the information enerated in this study ill be used by PATH in connection ith the develo ment use of the roduct and therefore may be disclosed to overnment re ulatory a encies in various countries PATH and manufacturer also reco ni es the im ortance of communicatin study findin s and therefore encoura es their ublication in re utable scientific ournals and resentation at seminars or conferences, hile rotectin the inte rity of the on oin trial Any ublication, lecture, manuscri ts of the findin s of this study by any individual involved ith the study ill be overned by the rocedure outlined in the Clinical Trial A reement ithin any resentation or ublication, confidentiality of individual artici ants ill be maintained, ith identification by artici ant code number and initials, if a licable
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LIT RAT R 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.
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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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Protocol Number CVIA 066 Version Number: 01 Version Date: 11 July, 2018
APP NDI - D CLARATION OF H LSIN I
thical Principles for Medical Research Involving Human Sub ects
Ado ted by the 18th MA eneral Assembly, Helsin i, inland, June 1 6 and amended by the: 2 th MA eneral Assembly, To yo, Ja an, October 1 5 35th MA eneral Assembly, Venice, Italy, October 1 83 1st MA eneral Assembly, Hon on , Se tember 1 8 8th MA eneral Assembly, Somerset est, Re ublic of South Africa, October 1 6 52nd MA eneral Assembly, dinbur h, Scotland, October 2000 53rd MA eneral Assembly, ashin ton DC, USA, October 2002 Note of Clarification added 55th MA eneral Assembly, To yo, Ja an, October 200 Note of Clarification added 5 th MA eneral Assembly, Seoul, Re ublic of orea, October 2008 6 th MA eneral Assembly, ortale a, Bra il, October 2013 Preamble 1 The orld Medical Association MA has develo ed the Declaration of Helsin i as a statement of ethical rinci les for medical research involvin human sub ects, includin research on identifiable human material and data The Declaration is intended to be read as a hole and each of its constituent ara ra hs should be a lied ith consideration of all other relevant ara ra hs 2 Consistent ith the mandate of the MA, the Declaration is addressed rimarily to hysicians The MA encoura es others ho are involved in medical research involvin human sub ects to ado t these rinci les eneral Principles 3 The Declaration of eneva of the MA binds the hysician ith the ords, The health of my atient ill be my first consideration, and the International Code of Medical thics declares that, A hysician shall act in the atient s best interest hen rovidin medical care It is the duty of the hysician to romote and safe uard the health, ell bein and ri hts of atients, includin those ho are involved in medical research The hysician s no led e and conscience are dedicated to the fulfilment of this duty 5 Medical ro ress is based on research that ultimately must include studies involvin human sub ects 6 The rimary ur ose of medical research involvin human sub ects is to understand the causes, develo ment and effects of diseases and im rove reventive, dia nostic and thera eutic interventions methods, rocedures and treatments ven the best roven interventions must be evaluated continually throu h research for their safety, effectiveness, efficiency, accessibility and uality Medical research is sub ect to ethical standards that romote and ensure res ect for all human sub ects and rotect their health and ri hts 8 hile the rimary ur ose of medical research is to enerate ne no led e, this oal can never ta e recedence over the ri hts and interests of individual research sub ects It is the duty of hysicians ho are involved in medical research to rotect the life, health, di nity, inte rity, ri ht to self determination, rivacy, and confidentiality of ersonal information of research sub ects The res onsibility for the rotection of research sub ects must al ays rest
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Protocol Number CVIA 066 Version Number: 01 Version Date: 11 July, 2018
ith the hysician or other health care rofessionals and never ith the research sub ects, even thou h they have iven consent 10 Physicians must consider the ethical, le al and re ulatory norms and standards for research involvin human sub ects in their o n countries as ell as a licable international norms and standards No national or international ethical, le al or re ulatory re uirement should reduce or eliminate any of the rotections for research sub ects set forth in this Declaration 11 Medical research should be conducted in a manner that minimises ossible harm to the environment 12 Medical research involvin human sub ects must be conducted only by individuals ith the a ro riate ethics and scientific education, trainin and ualifications Research on atients or healthy volunteers re uires the su ervision of a com etent and a ro riately ualified hysician or other health care rofessional 13 rou s that are underre resented in medical research should be rovided a ro riate access to artici ation in research 1 Physicians ho combine medical research ith medical care should involve their atients in research only to the e tent that this is ustified by its otential reventive, dia nostic or thera eutic value and if the hysician has ood reason to believe that artici ation in the research study ill not adversely affect the health of the atients ho serve as research sub ects 15 A ro riate com ensation and treatment for sub ects ho are harmed as a result of artici atin in research must be ensured Ris s, urdens and enefits 16 In medical ractice and in medical research, most interventions involve ris s and burdens Medical research involvin human sub ects may only be conducted if the im ortance of the ob ective out ei hs the ris s and burdens to the research sub ects 1 All medical research involvin human sub ects must be receded by careful assessment of redictable ris s and burdens to the individuals and rou s involved in the research in com arison ith foreseeable benefits to them and to other individuals or rou s affected by the condition under investi ation Measures to minimise the ris s must be im lemented The ris s must be continuously monitored, assessed and documented by the researcher 18 Physicians may not be involved in a research study involvin human sub ects unless they are confident that the ris s have been ade uately assessed and can be satisfactorily mana ed hen the ris s are found to out ei h the otential benefits or hen there is conclusive roof of definitive outcomes, hysicians must assess hether to continue, modify or immediately sto the study Vulnerable roups and Individuals 1 Some rou s and individuals are articularly vulnerable and may have an increased li elihood of bein ron ed or of incurrin additional harm All vulnerable rou s and individuals should receive s ecifically considered rotection 20 Medical research ith a vulnerable rou is only ustified if the research is res onsive to the health needs or riorities of this rou and the research cannot be carried out in a non vulnerable rou In addition, this rou should stand to benefit from the no led e, ractices or interventions that result from the research Scientific Re uirements and Research Protocols 21 Medical research involvin human sub ects must conform to enerally acce ted scientific rinci les, be based on a thorou h no led e of the scientific literature, other relevant sources of
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Protocol Number CVIA 066 Version Number: 01 Version Date: 11 July, 2018 information, and ade uate laboratory and, as a ro riate, animal e erimentation The elfare of animals used for research must be res ected 22 The desi n and erformance of each research study involvin human sub ects must be clearly described and ustified in a research rotocol The rotocol should contain a statement of the ethical considerations involved and should indicate ho the rinci les in this Declaration have been addressed The rotocol should include information re ardin fundin , S onsors, institutional affiliations, otential conflicts of interest, incentives for sub ects and information re ardin rovisions for treatin and or com ensatin sub ects ho are harmed as a conse uence of artici ation in the research study In clinical trials, the rotocol must also describe a ro riate arran ements for ost trial rovisions Research thics Committees 23 The research rotocol must be submitted for consideration, comment, uidance and a roval to the concerned research ethics committee before the study be ins This committee must be trans arent in its functionin , must be inde endent of the researcher, the S onsor and any other undue influence and must be duly ualified It must ta e into consideration the la s and re ulations of the country or countries in hich the research is to be erformed as ell as a licable international norms and standards but these must not be allo ed to reduce or eliminate any of the rotections for research sub ects set forth in this Declaration The committee must have the ri ht to monitor on oin studies The researcher must rovide monitorin information to the committee, es ecially information about any serious adverse events No amendment to the rotocol may be made ithout consideration and a roval by the committee After the end of the study, the researchers must submit a final re ort to the committee containin a summary of the study’s findin s and conclusions Privacy and Confidentiality 2 very recaution must be ta en to rotect the rivacy of research sub ects and the confidentiality of their ersonal information Informed Consent 25 Partici ation by individuals ca able of ivin informed consent as sub ects in medical research must be voluntary Althou h it may be a ro riate to consult family members or community leaders, no individual ca able of ivin informed consent may be enrolled in a research study unless he or she freely a rees 26 In medical research involvin human sub ects ca able of ivin informed consent, each otential sub ect must be ade uately informed of the aims, methods, sources of fundin , any ossible conflicts of interest, institutional affiliations of the researcher, the antici ated benefits and otential ris s of the study and the discomfort it may entail, ost study rovisions and any other relevant as ects of the study The otential sub ect must be informed of the ri ht to refuse to artici ate in the study or to ithdra consent to artici ate at any time ithout re risal S ecial attention should be iven to the s ecific information needs of individual otential sub ects as ell as to the methods used to deliver the information After ensurin that the otential sub ect has understood the information, the hysician or another a ro riately ualified individual must then see the otential sub ect’s freely iven informed consent, referably in ritin If the consent cannot be e ressed in ritin , the non ritten consent must be formally documented and itnessed All medical research sub ects should be iven the o tion of bein informed about the eneral outcome and results of the study
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Protocol Number CVIA 066 Version Number: 01 Version Date: 11 July, 2018
2 hen see in informed consent for artici ation in a research study the hysician must be articularly cautious if the otential sub ect is in a de endent relationshi ith the hysician or may consent under duress In such situations the informed consent must be sou ht by an a ro riately ualified individual ho is com letely inde endent of this relationshi 28 or a otential research sub ect ho is inca able of ivin informed consent, the hysician must see informed consent from the le ally authorised re resentative These individuals must not be included in a research study that has no li elihood of benefit for them unless it is intended to romote the health of the rou re resented by the otential sub ect, the research cannot instead be erformed ith ersons ca able of rovidin informed consent, and the research entails only minimal ris and minimal burden 2 hen a otential research sub ect ho is deemed inca able of ivin informed consent is able to ive assent to decisions about artici ation in research, the hysician must see that assent in addition to the consent of the le ally authorised re resentative The otential sub ect’s dissent should be res ected 30 Research involvin sub ects ho are hysically or mentally inca able of ivin consent, for e am le, unconscious atients, may be done only if the hysical or mental condition that revents ivin informed consent is a necessary characteristic of the research rou In such circumstances the hysician must see informed consent from the le ally authorised re resentative If no such re resentative is available and if the research cannot be delayed, the study may roceed ithout informed consent rovided that the s ecific reasons for involvin sub ects ith a condition that renders them unable to ive informed consent have been stated in the research rotocol and the study has been a roved by a research ethics committee Consent to remain in the research must be obtained as soon as ossible from the sub ect or a le ally authorised re resentative 31 The hysician must fully inform the atient hich as ects of their care are related to the research The refusal of a atient to artici ate in a study or the atient’s decision to ithdra from the study must never adversely affect the atient hysician relationshi 32 or medical research usin identifiable human material or data, such as research on material or data contained in bioban s or similar re ositories, hysicians must see informed consent for its collection, stora e and or reuse There may be e ce tional situations here consent ould be im ossible or im racticable to obtain for such research In such situations the research may be done only after consideration and a roval of a research ethics committee se of Placebo 33 The benefits, ris s, burdens and effectiveness of a ne intervention must be tested a ainst those of the best roven intervention s , e ce t in the follo in circumstances: here no roven intervention e ists, the use of lacebo, or no intervention, is acce table or here for com ellin and scientifically sound methodolo ical reasons the use of any intervention less effective than the best roven one, the use of lacebo, or no intervention is necessary to determine the efficacy or safety of an intervention and the atients ho receive any intervention less effective than the best roven one, lacebo, or no intervention ill not be sub ect to additional ris s of serious or irreversible harm as a result of not receivin the best roven intervention treme care must be ta en to avoid abuse of this o tion Post-Trial Provisions 3 In advance of a clinical trial, S onsors, researchers and host country overnments should ma e rovisions for ost trial access for all artici ants ho still need an intervention identified as
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Protocol Number CVIA 066 Version Number: 01 Version Date: 11 July, 2018 beneficial in the trial This information must also be disclosed to artici ants durin the informed consent rocess Research Registration and Publication and Dissemination of Results 35 very research study involvin human sub ects must be re istered in a ublicly accessible database before recruitment of the first sub ect 36 Researchers, authors, S onsors, editors and ublishers all have ethical obli ations ith re ard to the ublication and dissemination of the results of research Researchers have a duty to ma e ublicly available the results of their research on human sub ects and are accountable for the com leteness and accuracy of their re orts All arties should adhere to acce ted uidelines for ethical re ortin Ne ative and inconclusive as ell as ositive results must be ublished or other ise made ublicly available Sources of fundin , institutional affiliations and conflicts of interest must be declared in the ublication Re orts of research not in accordance ith the rinci les of this Declaration should not be acce ted for ublication nproven Interventions in Clinical Practice 3 In the treatment of an individual atient, here roven interventions do not e ist or other no n interventions have been ineffective, the hysician, after see in e ert advice, ith informed consent from the atient or a le ally authorised re resentative, may use an un roven intervention if in the hysician s ud ement it offers ho e of savin life, re establishin health or alleviatin sufferin This intervention should subse uently be made the ob ect of research, desi ned to evaluate its safety and efficacy In all cases, ne information must be recorded and, here a ro riate, made ublicly available
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Protocol Number CVIA 066 Version Number: 01 Version Date: 11 July, 2018
APP NDI APPLICA L D FINITIONS FOR RADIN OF A S
The severity of all unsolicited A s ill be assessed by the investi ator based on the uidance rovided in Division of AIDS DAIDS Table for radin the Severity of Adult and Pediatric Adverse vents, corrected version 2 1, July 201 , of the US National Institute of Health The a licable sym toms and their ada ted definitions has been rovided belo : PARAM T R RAD MILD RAD RAD RAD MOD RAT S V R POT NTIALL LIF - THR AT NIN Diarrhea Li uid stools more Li uid stools ith Li uid stools ith Life threatenin unformed than increased number of moderate conse uences e , usual but usual stools OR Mild dehydration li uid stools number of stools dehydration resultin in severe dehydration, hy otensive shoc Vomitin Transient or re uent e isodes Persistent vomitin Life threatenin intermittent AND ith no or mild ith a ressive conse uences e , No or minimal dehydration rehydration hy otensive shoc interference ith indicated e , IV oral inta e fluids Sei ures Sei ure lastin 5 Sei ure lastin 5 to Sei ure lastin 20 Prolon ed and minutes ith 2 20 minutes ith minutes OR 2 re etitive sei ures hours ostictal state 2 hours ostictal hours ostictal state e , status state e ile ticus OR Difficult to control e , refractory e ile sy Acute Aller ic Locali ed urticaria Locali ed urticaria enerali ed Acute ana hyla is Reaction heals ith no ith intervention urticaria OR OR Life threatenin medical intervention indicated OR Mild An ioedema ith bronchos asm OR indicated an ioedema ith no intervention Laryn eal edema intervention indicated OR indicated Sym toms of mild bronchos asm ever a illary 3 5 38 0 C 38 0 3 0 C 3 0 0 0 C 0 0 C tem eratures In ection Site Tenderness causin Tenderness causin Tenderness causin Tenderness causin Tenderness no or minimal reater than inability to erform inability to erform limitation of use of minimal limitation usual social basic self care limb of use of limb functional activities function OR Hos itali ation indicated In ection Site 2 5 cm in 2 5 cm in 50 surface area Potentially life rythema or diameter diameter ith of the e tremity threatenin Redness 50 surface area of se ment involved conse uences e , the e tremity e , u er arm or abscess, e foliative se ment involved thi h OR dermatitis, necrosis e , u er arm or Ulceration OR involvin dermis or thi h Secondary infection dee er tissue OR Phlebitis OR Sterile abscess OR Draina e
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Protocol Number CVIA 066 Version Number: 01 Version Date: 11 July, 2018
In ection Site Same as for Same as for Same as for Same as for Induration or In ection Site In ection Site In ection Site In ection Site S ellin rythema or rythema or rythema or rythema or Redness Redness Redness Redness
rade 5 Death All A s leadin to death are rade 5 events
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Addendum to Protocol: CVIA 066 Number: 01 Dated: 25 October, 2018
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 ur ose of this addendum is to em hasi e the chan es that are to be made in the study rotocol, version number 1 0 Version date: date 11 July, 2018 Namely, after the above mentioned version of the rotocol as submitted and a roved by University of Zambian Biomedical thics Committee for the CIDRZ rotocol to be conducted at eor e Health Centre and Zambia Medicines Re ulatory Authority ZAMRA , minor chan es are to be im lemented in the rotocol
The follo in outlines these chan es:
Place ithin Section Present te t Corrected u dated te t the document
Title a e NA Trial Re istration: Trial Re istration: Submission in rocess ClinicalTrial ov study reference no NCT03602053
Pa e 12 Administrative NA Ne addition structure Clinical Research Officer PATH 15th loor, Dr o al Das Bha an, 28, Bara hamba Road, Connau ht Place, Ne Delhi 110001 India Phone: mail:
Pa e 10, 6 Partici atin eor e Research Clinic Institutions 5 1 3 Presentation and ormulation
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