RV1 Steele 2008‐ZAF

Methods	RCT Length of follow‐up: up to 6 months after last vaccine given Adverse event data collection methods: "The infants were monitored for at least 30 min after each vaccination. Parents received a diary card to record information daily about solicited general symptoms (fever, fussiness/irritability, diarrhoea, vomiting, loss of appetite or cough/runny nose) for 15 days after each dose of RIX4414 or placebo, and any other adverse events occurring until the next study visit. Weekly supervision was done by Health Care Workers from Madibeng District Health Centre. The study physician or his staff questioned the parents on their child’s health and verified the completed diary card at each visit"
Participants	Number: 450 enrolled; 406 evaluable 2 cohorts were vaccinated: 1st cohort before the rotavirus season (271 participants); 2nd cohort after the rotavirus season (179) participants Age range: 1 to 3 months (beginning); 3 to 6 months (end) Inclusion criteria: healthy infants, born after a normal gestation period of ≥ 36 weeks; 5 to 10 weeks of age at the time of the first study visit; free of obvious health problems as established by medical history and clinical examination before entering into the study. There were no restrictions on feeding the infants before or after vaccination Exclusion criteria: infants were excluded if they had a clinically significant history of gastrointestinal disease or malformation, had received vaccines or treatment prohibited by the protocol, were immuno‐compromised or were in household contact with an immunosuppressed individual or pregnant woman. BCG and OPV vaccinations at birth were allowed according to the local EPI schedule. Vaccination was postponed if the infant had fever (≥ 37.5 ºC axillary or ≥ 38 ºC rectal) or gastroenteritis within the previous 7 days
Interventions	RV1 1. RIX4414 (RV1): 105 FFU; 2 doses given 1 month apart; 300 participants (randomized) 1.1. RV1 vaccine + oral polio vaccine + diphtheria‐tetanus‐acellular pertussis/H. influenzae type b vaccine 1.2. RV1 vaccine + oral polio vaccine placebo + diphtheria‐tetanus‐acellular pertussis inactivated polio‐H. influenzae type b vaccine 1.3. RV1 placebo + diphtheria‐tetanus‐acellular pertussis inactivated polio‐H. influenzae type b vaccine 2. Placebo: 2 doses given 1 month apart; 150 participants (randomized)
Outcomes	Clinical outcome measures (safety and efficacy) 1. Reactogenicity (see Adverse event data collection methods above) 2. Serious adverse events: Infants who experienced a serious adverse event and required hospitalization were admitted at the local district hospital in the study sites or at Ga‐Rankuwa Hospital, the referral hospital for the study site and surrounding areas. Parents were informed on the symptoms of intussusception and were instructed to contact the study physician or clinic if any signs of intussusception became apparent. Any suspected cases were immediately referred to Ga‐Rankuwa Hospital. All serious adverse events were reported to the sponsor and the Ethics committees and followed up until resolved. Parents were contacted 6 months after the second dose of RIX4414 or placebo to obtain information on any serious adverse events since the final study visit. All serious adverse events were reviewed periodically by an independent safety monitoring committee 3. All‐cause death 4. Dropouts 5. Adverse events resulting in discontinuation Outcomes to measure immunogenicity 6. Vaccine virus shedding: vaccine virus in stool sample (review includes data from combined time points) 7. Seroconversion: appearance of anti‐rotavirus IgA antibody (concentration ≥ 20 U/mL) in participants negative for rotavirus before vaccination (review includes data from 289 participants)
Immunization status	Diphtheria‐tetanus‐acellular pertussis, polio virus, and H. influenzae type b co‐administered in trial
Location	Madibeng District, North West Province, South Africa WHO mortality stratum E
Notes	Date: 1st cohort started from 22 November 2001; 2nd cohort from 23 October 2002 to 15 October 2003 Source of funding: The study (e‐Track 444563‐014/NCT00346892) was sponsored by a public‐private partnership RAPID and GSK Biologicals. The RAPID partnership consists of public sector partners (including the WHO, US Agency for International Development, National Institutes of Health, Children’s Vaccine Programme and the Centers for Disease Control), academic institutions (International Centre for Diarrhoeal Disease Research, Bangladesh and Medical University of Southern Africa) and GlaxoSmithKline Biologicals.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Very likely Quote: "This study was conducted under the WHO RAPID (Rotavirus Action Partnership for Immunization and Development) programme that facilitates conduct of rotavirus vaccine trials in developing countries, specifically in Africa and Asia, to address specific developing country needs. The RAPID partnership consists of public sector partners (including the WHO, US Agency for International Development, National Institutes of Health, Children’s Vaccine Programme and the Centers for Disease Control), academic institutions (International Centre for Diarrhoeal Disease Research, Bangladesh and Medical University of Southern Africa) and GlaxoSmithKline Biologicals"
Allocation concealment (selection bias)	Low risk	Likely to be adequate: treatment masked to investigators Quote: "a unique randomization number identified the vials to be administered to the same subject" and "subjects were administered the vaccine dose with the lowest treatment number available at the study centre"
Blinding (performance bias and detection bias) All outcomes	Unclear risk	Blinding of oral polio vaccine co‐administration not completely blinded Quote: "OPV and its placebo used in the first cohort were identical in appearance allowing for double blinding while this was not possible in the second cohort due to differences in appearance of OPV and its placebo"
Incomplete outcome data (attrition bias) All outcomes	Low risk	Quote: "All infants who had received at least one dose of RIX4414 or placebo (total vaccinated cohort) were included in the primary analysis of reactogenicity"
Selective reporting (reporting bias)	Low risk	All prespecified outcomes reported
Other bias	Low risk	No apparent other bias