RV1 Vesikari 2004b‐FIN

Methods	RCT Unbalanced randomization (2:1) Length of follow‐up: 1 and 2 years of follow‐up are reported Adverse event data collection methods: to assess reactogenicity, parents recorded daily on diary cards rectal temperature, any diarrhoea, vomiting, irritability, and loss of appetite for 15 days after each vaccination. Any other symptoms or signs occurring during a 43‐day follow‐up period after each vaccination were recorded as unsolicited symptoms (or signs) (passive method)
Participants	Number: 405 enrolled; 372 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 to 42 weeks; 6 to 12 weeks of age at the time of the first dose of the study vaccination course; free of obvious health problems as established by medical history and clinical examination before entering into the study Exclusion criteria: premature labour; vaccination was delayed if infant had fever (rectal temperature > 38 °C) or had gastroenteritis within the previous 7 days
Interventions	RV1 1. RIX4414 (RV1): 104.7 PFU; 2 doses given 2 months apart; 270 participants (randomized) 2. Placebo: 2 doses given 2 months apart; 135 participants (randomized) Feeding was not allowed for 1 hour before administration of the study vaccine
Outcomes	Clinical outcome measures (safety and efficacy) 1. Rotavirus diarrhoea: occurrence of rotavirus gastroenteritis during the period starting from 2 weeks after dose 2 until the end of the first rotavirus season following vaccination as detected by RT‐PCR in stool samples; occurrence of asymptomatic rotavirus infections during the period starting from 1 month after dose 2 until the end of each rotavirus season following vaccination; G type of the wild rotavirus strain by RT‐PCR; measured at 1 year (first report) and 2 years (second report) 2. Reactogenicity: for each type of solicited symptom, occurrence of the symptom within the 15‐day solicited follow‐up period after each dose; measured at 15 days after each dose 3. Adverse events requiring discontinuation: occurrence of unsolicited symptoms within 42 days after each dose, according to WHO's classification; measured 42 days after each dose 4. Serious adverse events: no definition; measured at all follow‐ups 5. All‐cause diarrhoea: gastroenteritis was defined as diarrhoea (≥ 3 looser‐than‐normal stools within any day) and/or vomiting (≥ 1 episodes of forceful emptying of partially digested stomach contents > 1 hour after feeding within any day); 2 occurrences of gastroenteritis were classified as separate episodes if there were ≥ 5 symptom‐free days between them 6. Severe rotavirus diarrhoea: score of < 7 prospectively defined as mild; score of 7 to 10 as moderate; and a score > 11 as severe 7. Rotavirus diarrhoea resulting in hospitalization 8. All‐cause death 9. Dropouts Outcomes to measure immunogenicity 10. Seroconversion: anti‐rotavirus antibody IgA concentration of ≥ 20 units/mL in infants negative for this before the first dose (review includes data from 1 month after dose 2)
Immunization status	Infant routine vaccinations (diphtheria tetanus toxoids‐pertussis, H. influenzae type b, and inactivated poliovirus vaccines) were separated from the study vaccines by at least 2 weeks
Location	6 centres in Finland WHO mortality stratum A
Notes	Date: 21 August 2000 to 11 July 2002 Source of funding: GlaxoSmithKline Biologicals Other: GSK 444663/004 (rota‐004annex) reports a second year extension of the study
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Eligible infants were randomly assigned (2:1 ratio) to 2 study groups according to a computer‐generated randomization list to receive the vaccine or placebo by mouth"
Allocation concealment (selection bias)	Low risk	Likely to be adequate: treatment masked to investigators Quote: "A randomisation or subject number identified uniquely the vaccine dose to be administered to each subject", and "subjects were administered the vaccine dose with the lowest number available at the study site"
Blinding (performance bias and detection bias) All outcomes	Low risk	Quote: "The placebo had the same constituents and identical appearance as the active vaccine, but did not contain the vaccine virus"
Incomplete outcome data (attrition bias) All outcomes	Low risk	33/405 participants dropped out of the study, balanced between groups with reasons provided
Selective reporting (reporting bias)	Low risk	All prespecified outcomes reported
Other bias	Unclear risk	No information