RV5 Vesikari 2006a‐FIN

Methods	RCT Length of follow‐up: 1 to 3 rotavirus seasons (1 to 3 years) Adverse event data collection methods: diary cards (passive method); telephone calls to parents/legal guardians to ask about serious adverse events (active method) Note: the per‐protocol population used for the primary efficacy analysis included 1496 participants after exclusion of 450 participants (23.1%). The modified intention‐to‐treat population used in a secondary efficacy analysis consisted of the 1647 participants, including protocol violators, who had any valid post‐dose 3 efficacy data
Participants	Number: 1946 enrolled; 1496 evaluable (after 2 years) Age range: 3 to 6 months (beginning); > 6 months (end) Inclusion criteria: healthy infants between 2 and 8 months of age Exclusion criteria: not described
Interventions	RV5 1. WC3 (RV5) 1.1. G1‐4, P1A (2.69 x 107, 7.92 x 106, 2.41 x 106); 3 doses given 4 to 8 weeks apart; 1027 participants (randomized) 1.2. G1‐4 (2.9 x 107); 3 doses given 4 to 8 weeks apart; 270 participants (randomized) 1.3. P1A (9.24 x 107); 3 doses given 4 to 8 weeks apart; 327 participants (randomized) 2. Placebo: 3 doses given 4 to 8 weeks apart; 322 participants (randomized) We excluded the 2 arms dealing with different G or P serotypes and compared a single arm to placebo
Outcomes	Clinical outcome measures (safety and efficacy) 1. Rotavirus diarrhoea: case definition for rotavirus gastroenteritis required: (1) ≥ 3 watery or looser‐than‐normal stools within a 24‐hour period or forceful vomiting, or both; and (2) rotavirus antigen detection by EIA. The primary analysis of efficacy considered episodes as positive only when caused by wild‐type rotavirus with a vaccine G serotype (G1, G2, G3, or G4) confirmed by PCR occurring at least 14 days after the third dose of vaccine; measured 1 to 3 years 2. Severe rotavirus diarrhoea: clinical scoring system based on the intensity and duration of symptoms of fever, vomiting, diarrhoea, and behavioural changes was used to rate the severity of gastroenteritis, using a 24‐point severity scale where a score of 1 to 8 was designated as mild, > 8 was designated as moderate‐and‐severe, and > 16 was designated as severe; measured 1 to 3 years 3. Reactogenicity: not defined other than all participants were followed for clinical adverse events for 42 days after each dose of vaccine or placebo; parents/guardians were provided with diary cards to record adverse events 4. Serious adverse events: not defined; noted that they were to be reported immediately. Parents/legal guardians were contacted by phone approximately 14 days after each dose and asked about serious adverse events. Data on deaths and serious adverse events judged by the investigator to be vaccine‐related were collected for the duration of the study (up to 42 days) 5. All‐cause death Outcomes to measure immunogenicity 6. Seroconversion: prevaccination and post‐vaccination sera assayed for rotavirus‐specific IgA by ELISA with seroconversion defined as ≥ 3‐fold rise in antibody titre from baseline to 2 weeks after dose 3 (review includes data from 14 days after dose 3)
Immunization status	Licensed vaccines could be administered throughout the study, but were not given on the same day as study vaccine; inactivated poliovirus vaccine was exclusively used in Finland at the time of the study
Location	4 sites (Tampere, Espoo, Lahti, Pori) in Finland WHO mortality stratum A
Notes	Date: June 1998 and June 2001 Source of funding: Merck & Co., Inc. Other: in total, 1946 infants (1300 in the first year and 646 in the second year of the study) were enrolled in the study and received at least the first dose of 1 of the 5 active vaccines or placebo. Overall, 1813 (93.2%) participants received 3 doses and were followed for ≥ 42 days after the final dose. 1800 participants (92.5%) were followed through the first rotavirus season after vaccination; 1740 participants (89.4%) were followed through a second rotavirus season. Of the 1300 participants enrolled in the first year, 880 (67.7%) were followed through a third rotavirus season
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated (Merck 2012)
Allocation concealment (selection bias)	Low risk	Allocation numbers were generated for participants; investigators and parents/guardians were blinded throughout trial (Merck 2012)
Blinding (performance bias and detection bias) All outcomes	Low risk	Sequential identical containers Quote: "The vials containing either vaccine or placebo were visibly indistinguishable." Participants and key personnel Quote: "This randomized clinical trial blinded to subject, investigator, parent/legal guardian, and sponsor. The placebo was identical to the vaccine except that it did not contain rotavirus reassortants or trace trypsin"
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
Other bias	Unclear risk	Insufficient information to assess