RV1 Steele 2010b‐ZAF

Methods	RCT Length of follow‐up: up to 6 months after last dose of vaccine or placebo 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: 475 participants enrolled; 420 evaluable 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; 6 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, and mothers had confirmed negative HIV status 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 immuno‐suppressed individual or pregnant woman. BCG and OPV vaccinations at birth were allowed according to the local EPI schedule. Infants with acute disease at the time of enrolment or gastroenteritis (diarrhoea) within 7 days before administration of the study vaccine were also excluded. In addition, vaccination was postponed if the infant had fever (≥ 37.5 °C axillary or ≥ 38 °C rectal) or gastroenteritis within the previous 7 days
Interventions	RV1 1. RIX4414 (RV1): at least 106.0 PFU CCID50 1.1. 2 doses, 1 month apart (at 10 and 14 weeks) plus 1 dose of placebo (at 6 weeks); 190 participants (randomized) 1.2. 3 doses, 1 month apart (at 6, 10, and 14 weeks of age); 189 participants (randomized) 2. Placebo: 3 doses, 1 month apart (at 6, 10, and 14 weeks of age); 96 participants (randomized) Schedule: Visits 1 (Dose 1), 2 (Dose 2), 3 (Dose 3), 4 and 5 correspond to months 0, 1, 2, 4, and 8 to 11 in the schedule
Outcomes	Clinical outcome measures (safety and efficacy) 1. Reactogenicity: for each type of solicited symptom, occurrence of the symptom within the 15‐day (days 0 to 14) solicited follow‐up period after each dose; occurrence of unsolicited adverse events within 43 days (days 0 to 42) after each dose, according to MedDRA classification; measured up to 43 days after vaccine/placebo 2. Serious adverse events: occurrence throughout entire study period; measured up to 6 months 5. All‐cause death: fatal adverse events measured up to 6 months 6. Dropouts: measured up to 6 months 7. Adverse events resulting in discontinuation Outcomes to measure immunogenicity 8. Viral shedding: presence of rotavirus in any stool sample (review includes data from combined time points (these combined data for 2 and 3 doses)) 9. Seroconversion: appearance of anti‐rotavirus IgA antibody concentration ≥ 20 U/mL in participants negative for rotavirus before first dose (review includes data from 1 month after dose 1 and 2 months after dose 3)
Immunization status	Infants received routine vaccinations according to the local EPI schedule in South Africa. BCG and OPV vaccinations were given at birth; all other routine vaccinations (including diphtheria‐tetanus toxoids‐whole cell pertussis, hepatitis B, H. influenzae type b, and OPV) were administered concomitantly with the study vaccine. All of the infants received a dose of OPV concomitantly with each dose of study vaccine or placebo at all administration times
Location	7 centres in South Africa WHO mortality stratum E
Notes	Study known as RIX GSK[013] 2007‐AF in previously published versions of this review Date: 5 September 2003 to 25 October 2004 Source of funding: GlaxoSmithKline Biologicals Study rationale: "The aim of this study was to determine if there was a difference in immune response between the two different schedules that were tested"
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Very likely. This study was conducted under the auspices of WHO (eTrack 444563/013/NCT00383903)
Allocation concealment (selection bias)	Low risk	Likely to be adequate: treatment masked to investigators Quote: "a randomization number uniquely identified the three vials to be administered to the same subject" and "subjects were administered the vaccine dose with the lowest number available at the study centre"
Blinding (performance bias and detection bias) All outcomes	Low risk	Quote: "The placebo was similar to RIX4414 in appearance and contained the same constituents as the active vaccine except that it did not contain the vaccine virus"
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