RV5 Zaman 2010‐AS.

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 the first 14 days after each dose and every month thereafter for 1 year after the first dose with respect to intussusception and serious adverse events (active method). "Serious adverse events were classified with the US regulatory definition, in line with ICH guidance, and identified by monthly query and parental reporting at any time or identification by study staff in hospitals or clinics. Intussusception at any time was assessed with an additional detailed protocol. All these events were monitored by an independent, unmasked, data and safety monitoring board that met about twice a year during the course of the investigation. The board also provided guidance about enrolment and severity scoring"
Participants	Number: 2119 enrolled; 2036 randomized, 2016 evaluable Age range: 1 to 3 months (beginning); 3 to 6 months (end) Inclusion criteria: healthy infants aged 4 to 12 weeks. Breast‐feeding was not restricted and there was no enrolment restrictions based on HIV status, although HIV testing was not done Exclusion criteria: see above
Interventions	RV5 1. WC3 (RV5): 2 mL (6.7 to 12.4 x 107 PFU); 3 doses given 4 weeks apart; 1018 participants (randomized) 2. Placebo: 2 mL; 3 doses given 4 weeks apart; 1018 participants (randomized) Schedule: 3 doses given at 4‐week intervals
Outcomes	Clinical outcome measures (safety and efficacy) 1. Serious adverse events 2. Death due to serious adverse events 3. 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 4. 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 20‐point severity scale; scores > 11 were considered to indicate severe disease; measured up to 2 years follow‐up 5. All‐cause diarrhoea 6. All‐cause diarrhoea – severe 7. Reactogenicity *: symptoms of rotavirus illness, including fever, diarrhoea, and vomiting; measured for 7 days after each dose (review includes data from for the end of follow‐up) Data on fever and vomiting are provided only on figure 2 and data could not be extracted reliably Outcomes to measure immunogenicity 8. Seroconversion: serum rotavirus IgA responses (increases in level of serum rotavirus IgA ≥ 4‐fold) (review includes data from after dose 2)
Immunization status	All children in the study received the standard EPI vaccines (including oral poliovirus vaccine) starting at 6 weeks of age
Location	Sites in rural Matlab (Bangladesh) and urban and peri‐urban Nha Trang (Vietnam) WHO mortality strata B, D
Notes	This trial was conducted in Bangladesh and Vietnam; data reported separately by country can be found under RV5 Zaman 2010‐BGD and RV5 Zaman 2010‐VNM. Date: March 29, 2007 to March 31, 2009 Source of funding: funded by PATH (GAVI Alliance grant) and Merck
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Unique allocation numbers were designated at Merck as pentavalent rotavirus vaccine or placebo with computer generated block randomization, with block sizes of six"
Allocation concealment (selection bias)	Low risk	Quote: "Vaccine and placebo packages were then labelled with allocation numbers and provided to sites in identical presentations. Sites were instructed to assign allocation numbers to participants in sequential order as they were enrolled"
Blinding (performance bias and detection bias) All outcomes	Low risk	Participants and staff Quote: "Participants were enrolled by study staff, who remained masked to treatment assignment throughout the trial" Researchers Quote: "The statistician from Merck who analysed the data and the Merck and PATH protocol teams were masked to treatment assignment"
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	Low risk	No apparent other bias