RV5 Vesikari 2006b‐INT

Methods	RCT Length of follow‐up: up to 43 days for safety outcomes, and up to 2 years for efficacy outcomes Adverse event data collection methods: active surveillance was used to obtain safety data; parents or legal guardians were contacted on days 7, 14, and 42 after each dose and every 6 weeks thereafter for 1 year after the first dose with respect to intussusception and serious adverse events (active method)
Participants	Number: 70,301 enrolled and 69,274 randomized (efficacy study subpopulation of 5673); 57,134 evaluable for safety outcomes; for efficacy outcomes, 4512 evaluable in year 1 and 1569 evaluable in year 2 Age range: 1 to 3 months (beginning); 3 to 6 months (end) Inclusion criteria: healthy infants between 6 and 12 weeks of chronological age were eligible regardless of gestational age; no known history of congenital abdominal disorders, intussusception, or abdominal surgery; no known or suspected impairment of immunological function; no known hypersensitivity to any component of the rotavirus vaccine; no prior receipt of any rotavirus vaccine; no fever, with a rectal temperature ≥ 38.1 °C (≥ 100.5 °F) at the time of immunization; no history of known prior rotavirus disease, chronic diarrhoea, or failure to thrive; no clinical evidence of active gastrointestinal illness; no receipt of intramuscular, oral, or intravenous corticosteroid treatment within the 2 weeks before vaccination; did not reside in a household with an immunocompromised person; no prior receipt of a blood transfusion or blood products, including immunoglobulins; no receipt of oral poliovirus vaccine during the course of the study or within 42 days prior to the first dose of vaccine/placebo Exclusion criteria: see above for details Special group: infants born at < 36 weeks of gestational age were considered premature and infants born at < 32 weeks of gestational age were considered extremely premature; no formal safety or efficacy hypotheses were prespecified for premature infants
Interventions	RV5 1. WC3 (RV5): 2 mL (6.7 to 12.4 x 107 PFU); 3 doses given 4 to 10 weeks apart; 34,644 participants (randomized) 2. Placebo: 2 mL; 3 doses given 4 to 10 weeks apart; 34,630 participants (randomized)
Outcomes	Clinical outcome measures (safety and efficacy) 1. Rotavirus diarrhoea: case definition for rotavirus gastroenteritis required participants to meet both of the following criteria: (1) ≥ 3 watery or looser‐than‐normal stools within a 24‐hour period or forceful vomiting, or both, and (2) rotavirus detected by EIA in a stool specimen taken within 14 days after the onset of symptoms. Only naturally‐occurring "rotavirus AGEs" caused by the composite of the human rotavirus G‐serotypes in the vaccine (G1, G2, G3, and G4) occurring through the first rotavirus season that began at least 14 days following the third vaccination were included in the primary analysis; measured up to 2 years follow‐up 2. Severe rotavirus diarrhoea: an established clinical scoring system based on the intensity and duration of fever, vomiting, diarrhoea, and changes in behaviour used to categorize episodes of rotavirus gastroenteritis on a 24‐point severity scale; scores > 16 were considered to indicate severe disease; measured up to 2 years follow‐up 3. Emergency department visit: hospitalizations and emergency department visits for acute gastroenteritis; measured up to 1 year of follow‐up 4. All‐cause hospital admission: see above; measured up to 1 year of follow‐up 5. All‐cause mortality: measured up to 1 year of follow‐up 6. Dropouts: no definition; measured up to 2 years follow‐up 7. Serious adverse events: monitored for at least 42 days after each dose for serious adverse events, including intussusception. All suspected cases of intussusception were reported to an independent, blinded adjudication committee, which included a paediatric surgeon, a paediatric radiologist, and a paediatrician with extensive experience in emergency medicine. The committee adjudicated potential cases of intussusception according to a prespecified case definition that required confirmation of the diagnosis by radiography or at surgery or autopsy; measured up to 1 year of follow‐up. Final intussusception results taken from CDC report (CDC 2010) 8. Reactogenicity: not defined; measured up to 43 days after vaccine 9. Adverse events requiring discontinuation: not defined; measured up to 1 year of follow‐up 10. Rotavirus diarrhoea resulting in hospitalization Outcomes to measure immunogenicity 11. Seroconversion: defined as an increase in the antibody titre by a factor of ≥ 3 from baseline (review includes data from 14 days after dose 3)
Immunization status	Administration of other licensed childhood vaccines and breast‐feeding were not restricted; for a subset of participants in the USA (U.A. concomitant use cohort), Merck also provided the licensed paediatric vaccines that were administered concomitantly (same day) with RV5 or placebo, which included Comvax, Infanrix, Ipol, and Prevnar
Location	356 primary study sites in Belgium, Costa Rica, Finland, Germany, Guatemala, Italy, Jamaica, Mexico, Puerto Rico, Sweden, Taiwan, and the USA WHO mortality strata A, B, D
Notes	Date: 12 January 2001 to 6 October 2004 Source of funding: Merck & Co., Inc. Other: there is a full report on premature babies that will be data‐extracted separately
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated randomized 1:1 to receive either RV5 (RotaTeq) or placebo (Merck 2012)
Allocation concealment (selection bias)	Low risk	Allocation numbers were generated for participants; investigators and parents/guardians were blinded throughout trial (Merck 2012)
Blinding (performance bias and detection bias) All outcomes	Low risk	Participants and key personnel Quote: "Randomized, multicenter, double blinded (operated under in‐house blinding procedures), placebo controlled, safety and efficacy trial. The placebo was an exact match minus the virus"
Incomplete outcome data (attrition bias) All outcomes	Low risk	Missing data balanced across groups
Selective reporting (reporting bias)	Low risk	Prespecified outcomes reported
Other bias	Unclear risk	Difficult to judge, as some important information about randomization/allocation concealment are not provided