RV5 Block 2007‐EU/USA

Methods	RCT Length of follow‐up: up to 42 days for safety/immunogenicity; up to 1 year for efficacy Adverse event data collection methods: parents or guardians contacted by the study site on day 7, day 14, and day 42 after each vaccination and asked about serious adverse events (active method); parents or guardians were provided diary cards and were instructed to record daily temperatures for the infant for 7 days after each vaccination (passive method)
Participants	Number: 1312 enrolled; 1200 evaluable Age range: 1 to 3 months (beginning); 3 to 6 months (end) Inclusion criteria: healthy infants, 6 through 12 weeks of age, who had 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 before first dose of vaccine/placebo; any infant who could not be adequately followed for safety by telephone or home visit; and no condition, which, in the opinion of the investigator, may have interfered with the evaluation of the study objectives Exclusion criteria: see above
Interventions	RV5 1. WC3 (RV5): 1.1 x 107 PFU; 651 participants (randomized) 2. Placebo: 661 participants (randomized) Schedule: 3 doses given 4 to 10 weeks apart
Outcomes	Clinical outcome measures (safety and efficacy) 1. Serious adverse events: potential cases of intussusception were adjudicated by an independent blinded committee; all study personnel remained blinded to the treatment arm and adjudication results of the potential intussusception cases; data on cases of intussusception, deaths, or other serious adverse events determined to be vaccine‐related by the investigator were collected throughout the trial; measured up to 42 days, and up to 1 year (for vaccine‐related serious adverse events) 2. Reactogenicity: no definition; measured up to 42 days 3. Dropouts: no definition: measured up to 1 year 4. Rotavirus diarrhoea: case of rotavirus gastroenteritis defined as meeting both of the following criteria: (a) > 3 watery or looser‐than‐normal stools within a 24‐hour period or forceful vomiting, or both; and (b) rotavirus antigen detection by EIA in the stool sample. Primary analysis of efficacy included only cases caused by naturally‐occurring rotavirus of serotypes G1, G2, G3, or G4 as confirmed by RT‐PCR occurring at least 14 days after the third dose 5. Severe rotavirus diarrhoea: each episode graded on a 24‐point scale, where a score < 8 designated as mild, > 8 as moderate‐and‐severe, and > 16 as a severe disease 6. All‐cause death 7. Adverse events resulting in discontinuation Outcomes to measure immunogenicity 8. Seroconversion: pre‐vaccination and post‐vaccination sera analyzed for serotype‐specific rotavirus neutralizing antibody and for serum anti‐rotavirus immunoglobulin A (IgA) (review includes data from after dose 3)
Immunization status	Use of oral poliovirus vaccine during the course of the study or within 42 days before first dose of vaccine/placebo was an exclusion criterion; administration of other vaccines permitted
Location	30 sites; 27 in USA, and 3 in Finland WHO mortality stratum A
Notes	Date: 24 September 2002 (first participant in) to 11 February 2004 Source of funding: Merck & Co., Inc.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Enrolled infants were randomly assigned 1:1 by using computer‐generated allocation schedules to receive either vaccine or visibly indistinguishable placebo in a sucrose citrate buffer administered orally as three 2‐mL doses 4 to 10 weeks apart"
Allocation concealment (selection bias)	Low risk	Sequential identical containers (see quote above)
Blinding (performance bias and detection bias) All outcomes	Low risk	Quote:"This randomized, clinical trial blinded to investigator, parent or guardian, and sponsor" "The placebo was identical to the vaccine except that it did not contain the rotavirus reassortants or trace trypsin"
Incomplete outcome data (attrition bias) All outcomes	Low risk	Missing data balanced across groups
Selective reporting (reporting bias)	High risk	Key expected outcome (episodes of gastroenteritis) not included
Other bias	Unclear risk	Relevant information needed for assessment not provided