RV5 Ciarlet 2009‐EU.

Methods	RCT Length of follow‐up: up to 42 days after last dose Adverse event data collection methods: see outcome measures; passive method used for reactogenicity, and active method used for serious adverse events
Participants	Number: 403 enrolled; 403 evaluable Age range: 1 to 3 months (beginning); 3 to 6 months (end) Inclusion criteria: healthy infants, aged 6 to 12 weeks; mothers negative for hepatitis B surface antigen; no known history of congenital abdominal disorders; intussusception, or abdominal surgery; no known or suspected impairment of immunological function; no history of seizure with or without fever; no known hypersensitivity to any component of rotavirus vaccine or INFANRIX hexa; no prior receipt of any rotavirus, DTaP, DTP, H. influenzae type b, Hepatitis B, injectable poliovirus vaccine, or oral polio vaccine during the course of the study, within 42 days before first dose of RV5 or before final blood draw (42 days after dose 3); no fever, with a rectal temperature < 38.1 °C (< 100.5 °F) at the time of immunization; no history of known rotavirus disease, chronic diarrhoea, or failure to thrive; no clinical evidence of active gastrointestinal illness; no prior receipt of intramuscular, oral, or intravenous corticosteroids treatment within 2 weeks before vaccination; did not reside in a household with an immunocompromised person; no receipt of a blood transfusion or blood products, including immunoglobulin; did not participate in another clinical study within 42 days before or during current study; could be adequately followed for safety Exclusion criteria: as above
Interventions	RV5 1. WC3 (RV5) plus Infanrix hexa: RV5 (2 mL; 3 doses given 4 to 6 weeks apart); 201 participants (randomized) 2. Placebo plus Infanrix hexa: placebo (2 mL; 3 doses given 4 to 6 weeks apart); 202 participants (randomized) Infanrix hexa: comes in 2 parts; first part is a white, milky liquid (0.5 mL) in a pre‐filled syringe that consists of the combined diphtheria, tetanus, pertussis, hepatitis b, and inactivated poliovirus vaccine; second part is the H. influenzae type b vaccine and is a white pellet in a separate glass vial; both parts mixed together before being injected intramuscularly
Outcomes	Clinical outcome measures (safety and efficacy) 1. Reactogenicity: in both groups, at each study visit, parents/legal guardians received Vaccination Report Cards (VRCs) which they completed for 7 days with information on fever, diarrhoea, and vomiting starting from the day of office visit and returned completed VRCs to the study site at the next visit 2. Serious adverse events: parents/legal guardians of all participants were contacted by telephone or home visit on approximately day 14 after each office visit in either group for safety follow‐up and asked about all serious adverse experiences; measured up to 42 days 3. All‐cause death 4. Adverse events resulting in discontinuation Outcomes to measure immunogenicity None specific to review
Immunization status	Hepatitis B vaccine, diphtheria‐tetanus‐acellular pertussis, polio virus, and H. influenzae type b co‐administered
Location	26 study sites in Austria, Belgium, and Germany WHO mortality stratum A
Notes	Date: 22 February 2006 to 13 November 2006 Source of funding: Merck & Co., Inc. Other: only data about serious adverse events and adverse events leading to discontinuation are provided
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated randomized 1:1 to receive hexavalent vaccine concomitantly with either RV5 (RotaTeq) or placebo (Merck 2012)
Allocation concealment (selection bias)	Low risk	Allocation numbers were generated for participants, investigators, adults, and parents/guardians of children were blinded throughout trial (Merck 2012)
Blinding (performance bias and detection bias) All outcomes	Low risk	RV5 was visibly indistinguishable from placebo, investigators, parents/guardians and study personnel (internal and external) were blinded throughout trial (Merck 2012)
Incomplete outcome data (attrition bias) All outcomes	Low risk	Quote: "In both treatment groups (RV5+Hexavalent and Placebo+Hexavalent), ˜84% of the infants reported 1 or more adverse events within 14 days after vaccination.  One subject discontinued in the concomitant‐use group because of abdominal pain (considered non‐serious)" (Merck 2012)
Selective reporting (reporting bias)	High risk	Not all prespecified outcomes reported
Other bias	Unclear risk	No details