RV1 Vesikari 2007a‐EU

Methods	RCT Length of follow‐up: 1 and 2 years of follow‐up in all countries, and a third year follow‐up in Finland (GSK109810) Adverse event data collection methods: "active surveillance for gastroenteritis episodes and serious adverse events from the day of the first vaccine or placebo dose (8 September 2004) until the follow‐up visit at the end of the second rotavirus epidemic season (10 August 2006) ... Study staff contacted parents every week" (active method); "During every episode, we asked parents to record in a daily diary card the number of looser than normal stools, axillary or rectal temperature, number of vomiting episodes, any rehydration or other medication administered, and any medical attention (defined as medical personnel contact, advice, or visit; emergency room contact or visit; or admission)" (passive method)
Participants	Number: 3994 enrolled; 3848 evaluable Age range: 1 to 3 months (beginning); 3 to 6 months (end) Inclusion criteria: healthy infants aged 6 to 14 weeks who weighed > 2000 g at birth Exclusion criteria: acute disease at the time of enrolment; history of chronic administration of immunosuppressants since birth; received any vaccines or treatments prohibited by the protocol; or had any disorders or illnesses excluded by the protocol
Interventions	RV1 1. RIX4414 (RV1): 106.5 PFU; 2 doses given 1 or 2 months apart; 2646 participants (randomized) 2. Placebo: 2 doses given 1 or 2 months apart; 1348 participants (randomized)
Outcomes	Clinical outcome measures (safety and efficacy) 1. All‐cause diarrhoea: gastroenteritis defined as diarrhoea characterized by at least 3 looser‐than‐normal stools within a day, with or without vomiting; measured 2 weeks after dose 2 until end of 2 years follow‐up 2. Rotavirus diarrhoea: trialists deemed a gastroenteritis episode to be caused by rotavirus if a rotavirus strain was identified in a stool sample collected during the episode or within 7 days after resolution of symptoms, or before the next episode if fewer than 7 days had fallen between the end of 1 episode and the start of the next, in cases of multiple episodes; measured 2 weeks after dose 2 until end of 2 years follow‐up 3. Severe rotavirus diarrhoea: score < 7 was defined prospectively as mild, score of 7 to 10 as moderate, and a score of ≥ 11 as severe 4. Severe all‐cause diarrhoea: as for severe rotavirus diarrhoea 5. Emergency department visit: no definition 6. All‐cause hospitalization admission: no definition 7. Serious adverse events: no definition 8. Rotavirus diarrhoea resulting in hospitalization 9. Rotavirus diarrhoea requiring medical attention (defined as "medical personnel contact, advice, or visit; emergency room contact or visit; or admission") 10. Reactogenicity Outcomes to measure immunogenicity 11. Seroconversion: appearance of anti‐rotavirus IgA antibody concentration ≥ 20 U/mL in participants seronegative for rotavirus before vaccination (review includes data from 1 to 2 months after dose 2)
Immunization status	Concomitant vaccines included 7 valent pneumococcal polysaccharide conjugate vaccine (Prevenar) and meningococcal group c conjugate vaccine (Meningitec); Hepatitis B vaccine, diphtheria‐tetanus‐acellular pertussis, polio virus, and H. influenzae type b vaccines were co‐administered
Location	98 centres in 6 European countries (Czech Republic, Finland, France, Germany, Italy, and Spain) WHO mortality stratum A
Notes	Date: 12 February 2007 to 08 August 2007 Source of funding: funded by GlaxoSmithKline Biologicals Other: vaccination postponed if baby either had a temperature of ≥ 37.5 °C (axillary) or of 38.0 °C (rectal) or had gastroenteritis within 7 days before planned vaccination Study aim: "to assess the efficacy and safety of HRV [RV1] vaccine during the 3rd year of age in subjects primed with a 2‐dose schedule in study 102247, with the first dose administered at the age of 6 to 14 weeks"
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "GSK Biologicals provided vaccine supplies that were numbered with a computer‐generated randomization list"
Allocation concealment (selection bias)	Low risk	Quote: "randomization was done by a central Internet randomization system. Infants were randomly allocated in a 2/1 ratio two doses of either RIX4414 or placebo"
Blinding (performance bias and detection bias) All outcomes	Low risk	Quote: "Treatment allocation remained concealed from investigators and the parents of participating infants throughout the study"
Incomplete outcome data (attrition bias) All outcomes	Low risk	Missing data imputed appropriately
Selective reporting (reporting bias)	Unclear risk	Data are provided only for rotavirus gastroenteritis and for severe gastroenteritis, not for all gastroenteritis episodes
Other bias	Unclear risk	No information