RV1 Phua 2009‐AS

Methods	RCT Length of follow‐up: 2 weeks post‐dose 2 to 3 years Adverse events data collection methods: passive method, using diary cards
Participants	Number: 10,708 enrolled; 10,519 evaluable Age range: 3 to 6 months Inclusion criteria: healthy infants 6 to 12 weeks of age in Hong Kong and Taiwan, or 11 to 17 weeks of age in Singapore at the time of the first dose Exclusion criteria: "they did not have a history of chronic administration of immunosuppressants since birth, any confirmed or suspected immunosuppressive or immunodeficient condition, history of allergic disease or reaction likely to be exacerbated by any vaccine component, had not received any investigational drugs/vaccines from 30 days before Dose 1 or planned use during the study, had not received immunoglobulins and/or blood products since birth or planned administration during the study period, did not have any clinically significant history of chronic gastrointestinal disease including any uncorrected congenital malformation of the gastrointestinal tract or other serious medical condition as determined by the investigator, and did not have first or second degree of consanguinity of parents"
Interventions	RV1 1. RIX4414 (RV1) 106 FFU; 5359 participants 2. Placebo; 5349 participants All vaccines given in 2 doses with a 1 to 2 month interval
Outcomes	Clinical outcome measures 1. All‐cause diarrhoea: a gastroenteritis episode was defined as occurrence of diarrhoea with or without vomiting (diarrhoea was defined as the passage of 3 or more looser‐than‐normal stool within a 24‐hour period) 2. Severe all‐cause diarrhoea: severe gastroenteritis was defined as an episode of diarrhoea with or without vomiting that required overnight hospitalization or rehydration therapy, or both (equivalent to WHO plan B or C) in a medical facility and with a score of 11 points on the 20‐point Vesikari scale 3. Rotavirus diarrhoea: stool samples collected during gastroenteritis episodes were tested for the presence of rotavirus using ELISA method (RotacloneTM, Meridian Bioscience) at GlaxoSmithKline Biologicals’ laboratories in Rixensart, Belgium. All rotavirus‐positive stool samples were tested by reverse transcriptase polymerase chain reaction (RT‐PCR) followed by reverse hybridization assay, and optional sequencing, at Delft Diagnostic Laboratory, The Netherlands, to determine G and P types, and differentiation of G1P[8] vaccine type 4. Severe rotavirus diarrhoea*: see above 5. Emergency department visit: active surveillance was conducted at hospitals and medical facilities in the study area to capture gastroenteritis episodes requiring hospitalization and/or re‐hydration therapy (equivalent to WHO plan B or C) in a medical facility from day of the first vaccine or placebo dose until the follow‐up visit at 24 months of age 6. Serious adverse events: intussusception and SAEs were followed during the study duration. A case of definite intussusception required confirmation at surgery or autopsy or by using imaging techniques such as gas or liquid contrast enema or abdominal ultrasound. Abstractable data for all serious adverse events and Kawasaki disease were only provided for the third year of follow‐up. Intussusception data for the third year follow‐up was not included in the analysis as the follow‐up population was smaller (RV1: 2/4272; placebo: 1/4226) 7. All‐cause deaths Outcomes to measure immunogenicity None *G types for severe rotavirus diarrhoea up to two years follow‐up was reported and added to the analyses, data for the third year was reported but not included in the analysis as the follow‐up population was smaller"
Immunization status	Infants received other routine paediatric immunizations (combined diphtheria toxoid‐tetanus toxoid‐acellular pertussis (DTPa) inactivated poliovirus (IPV) and H. influenzae type b (HiB) vaccine and hepatitis B vaccine (HBV)) during the study period according to local schedules. Almost all infants received BCG dose at birth. If oral polio vaccine (OPV) was given as part of the routine schedule in the participating countries, a time interval of 2 weeks was observed between the OPV doses and RIX4414 vaccine/placebo doses. One dose of oral polio vaccine (OPV) was given at birth in Hong Kong (99.8% participants) and Taiwan (0.7% participants). However, during the study period, > 95% of infants in the 3 countries received DTPa‐IPV‐HiB concomitantly with both doses of RIX4414 vaccine/placebo as per local schedules. 50.9% of participants were male and the study population was predominantly Chinese (76.3%).
Location	Hong Kong, Singapore, Taiwan WHO mortality stratum A
Notes	Date: 8 December 2003 to 31 August 2005 Funding: GlaxoSmithKline Other: all enrolled infants received the first dose of RIX4414 vaccine or placebo, and 10,551 (98.5%) received both doses
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	A randomization list was generated at GSK Biologicals, Rixensart, using a standard SAS® programme and was used to number the vaccines
Allocation concealment (selection bias)	Low risk	A randomization blocking scheme was used to ensure that the balance between treatments was maintained. Treatment allocation at the investigator sites was performed using a central randomization system on the Internet
Blinding (performance bias and detection bias) All outcomes	Low risk	Data analysis was performed at GSK Biologicals. The treatment code remains masked, except for statisticians and the database administrator
Incomplete outcome data (attrition bias) All outcomes	Low risk	Primary analysis of efficacy was performed from 2 weeks post‐dose 2 until 2 years of age on the ATP cohort that included participants who completed the full 2‐dose vaccination course and complied with the protocol. The total vaccinated cohort was used to calculate vaccine efficacy starting from the first dose onwards
Selective reporting (reporting bias)	Low risk	All expected outcomes included
Other bias	Low risk	No apparent other bias