RV5 Clark 2004‐USA

Methods	RCT Length of follow‐up: up to 1 year (season) Adverse event data collection methods: episodes of fever (subjective assessment of fever), vomiting, diarrhoea, behavioural changes, and any other adverse experiences during the 14 days after each dose were also reported on the diary card (passive method); parents were asked to report any serious adverse experience immediately to the study site (passive method); telephone call made to each participant 14 days after each vaccination to ask about serious adverse experiences (active method)
Participants	Number: 439 enrolled; 416 evaluable Age range: 1 to 3 months (beginning); 3 to 6 months (end) Inclusion criteria: healthy infants approximately 2 to 6 months of age were enrolled and followed for episodes of acute gastroenteritis Exclusion criteria: known hypersensitivity to any component of the rotavirus vaccine; known or suspected immunologic impairment; prior administration of any rotavirus vaccine; fever at time of vaccination (> 38.1 °C rectal); history of chronic diarrhoea or failure to thrive; clinical evidence of gastrointestinal illness; receipt of any other vaccines within 14 days; immunocompromised resident in the home; or any condition, which, in the opinion of the investigator, might interfere with the evaluation of the study objectives
Interventions	RV5 1. WC3 (RV5): 107 PFU; 3 doses at 6 to 8 week intervals; 218 participants (randomized) 2. Placebo: 3 doses at 6 to 8 week intervals; 221 participants (randomized)
Outcomes	Clinical outcome measures (safety and efficacy) 1. Rotavirus diarrhoea: case of rotavirus disease in a study participant defined as ≥ 3 watery or looser‐than‐normal stools within a 24‐hour period or forceful vomiting, or both, occurring at least 14 days after the third dose of vaccine/placebo and identification of rotavirus in a stool specimen obtained within 14 days of symptom onset; measured up to 1 year 2. Severe rotavirus diarrhoea: based on a clinical scoring system for evaluating the severity of an episode of infant acute gastroenteritis (0 to 24 points) they consider severe above 16 points; measured up to 1 year 3. Dropouts: measured up to 1 year 4. Serious adverse events: serious adverse experiences included death, life‐threatening events, and experiences that resulted in hospitalization, persistent disability, or that prolonged a hospitalization; deaths or any serious adverse experiences judged to be vaccine‐related were recorded for the duration of the study; measured up to 1 year, including intussusception (data from correspondence with Merck, Merck 2012). 5. Reactogenicity: all participants were followed for clinical adverse experiences for 14 days after each vaccination 6. Adverse events requiring discontinuation; measured up to 1 year Outcomes to measure immunogenicity 7. Viral shedding: stools were collected to evaluate vaccine strain shedding among subsets of infants at different time periods after each dose (review includes data from after dose 3) 8. Seroconversion: pre‐vaccination and post‐vaccination sera assayed for anti‐rotavirus immunoglobulin A (IgA) and anti‐rotavirus IgG (units/mL, based on pooled human serum standards); ≥ 3‐fold rise in titre from baseline to after dose 3 (review includes data from after dose 3)
Immunization status	Receipt of any other vaccines within 14 days was not allowed.
Location	10 study sites in the USA WHO mortality stratum A
Notes	Date: August 1993 to June 1994 Source of funding: Merck & Co., Inc.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "Infants who met all eligibility criteria were randomly assigned in a 1:1 ratio". No further details.
Allocation concealment (selection bias)	Unclear risk	No details
Blinding (performance bias and detection bias) All outcomes	Low risk	Quote: "The vials of vaccine and placebo were visibly indistinguishable" Quote: "The placebo was identical to the vaccine except that it did not contain the rotavirus reassortants". Investigators, study personnel (internal and external), and parents/guardians were blinded throughout trial. (Merck 2012)
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Insufficient reporting of attrition/exclusions
Selective reporting (reporting bias)	High risk	≥ 1 outcome of interest reported incompletely Quote: "Only wild‐type (ie, non‐vaccine related) rotavirus cases were considered for the primary case definition"
Other bias	Unclear risk	Not enough detail to make a judgement