Eskola 2001.

Study characteristics
Methods	This trial was part of a study including Kilpi 2003 (FinOM Vaccine Trial). Both Eskola 2001 and Kilpi 2003 used the same control group (hepatitis B vaccine containing 5 μg of recombinant hepatitis B surface protein) but a different treatment group, each with a different PCV7 type. Eskola 2001 used CRM197‐PCV7, whilst Kilpi 2003 used OMPC‐PCV7. Randomised: yes, at individual level Design: standard parallel‐group design Intention‐to‐treat: yes, both ITT and per‐protocol analysis described Follow‐up: 22 consecutive months (children were followed up to 24 months of age)
Participants	N: 1662 healthy infants Age: 2 months Setting: 8 study clinics in the communities of Tampere, Kangsala, and Nokia, Finland Inclusion criteria: healthy children aged 2 months Exclusion criteria: not described Baseline characteristics: described and balanced (Table 1 of trial publication)
Interventions	Children were randomly allocated to either CRM197‐PCV or a hepatitis B vaccine at 2, 4, 6 and 12 to 15 months of age. Tx: CRM197‐PCV; N = 831 (N = 786 completed the follow‐up as specified in the protocol) C: hepatitis B vaccine; N = 831 (N = 794 completed the follow‐up as specified in the protocol) Additional vaccines: a combination vaccine containing whole‐cell DTP and Hib was given in the child's opposite thigh at the same visit as the pneumococcal vaccine at 2, 4, and 6 months of age. In half of the study clinics, the carrier protein in the DTP and Haemophilus influenzae vaccine was CRM197, whilst in the other half it was tetanus toxoid. Inactivated poliovirus vaccine was given at 7 months of age and again at the same time as the fourth dose of the study vaccine at 12 months of age. Measles–mumps–rubella vaccine was administered at 18 months.
Outcomes	Primary outcome: number of AOM episodes due to the pneumococcal serotypes included in the vaccine Secondary outcomes: number of all‐cause AOM episodes, culture‐confirmed and pathogen‐specific AOM episodes; preventing first and subsequent AOM episodes; number of children with recurrent AOM episodes (defined as 3 or more AOM episodes in the last 6 months or 4 or more in the last 12 months); serious adverse events, safety (pain, local and systemic reactions within 3 days after vaccination, unexpected events after vaccination and mortality) All children attended 1 of the study clinics for enrolment at 2 months of age and thereafter at 4, 6, 7, 12, 13, 18, and 24 months. Parents were encouraged to bring their child to the study clinic for evaluation of symptoms suggesting respiratory infection or AOM. AOM was diagnosed by otoscopy (visibly abnormal tympanic membrane in terms of colour, position, or mobility, suggesting middle ear effusion) and the presence of at least 1 of the following symptoms or signs of acute infection: fever, earache, irritability, diarrhoea, vomiting, acute otorrhoea not caused by otitis externa, and other symptoms of respiratory infection. For the overall and pathogen‐specific AOM episodes, a new episode was considered to have started if at least 30 days had elapsed since the beginning of the previous episode. For AOM episodes according to serotype, a new episode was considered to have started if 30 days had elapsed since the beginning of an episode due to the same serotype, or if any interval had elapsed since the beginning of an episode due to a different serotype. If more than 1 serotype was recovered from the middle ear fluid at the same time, only 1 episode was considered to have started.
Funding sources	Supported by Merck, Pasteur Mérieux Connaught, and Wyeth‐Lederle Vaccines and Pediatrics
Declarations of interest	Dr Eskola and Dr Kilpi have served as consultants to Wyeth‐Lederle Vaccines.
Notes	Participants lost to follow‐up:total: 82/1662 (4.9%) did not complete the follow‐up period specified in the protocol Participants lost to follow‐up:Tx: 45/831 (5.4%) did not complete the follow‐up period specified in the protocol Participants lost to follow‐up:C: 37/831 (4.5%) did not complete the follow‐up period specified in the protocol
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	6 letters corresponding to the 3 treatment options were randomly allocated to consecutive participant identification numbers, using an allocation of 1:1:1 and a block size of 12 (see Kilpi 2003).
Allocation concealment (selection bias)	Low risk	Individual treatment assignments were kept in sealed envelopes until vaccination (see Kilpi 2003).
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Use of vaccinators who were not otherwise involved in the trial follow‐up. Letter code was destroyed immediately after vaccination (see Kilpi 2003).
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Assessment of the outcome was done according to a strict definition of AOM. Assessment was performed by personnel other than those who vaccinated the children (vaccinators were not otherwise involved in the trial follow‐up) (see Kilpi 2003).
Incomplete outcome data (attrition bias) All outcomes	Low risk	Reasons for dropout or lost to follow‐up, or both, were not reported. This is not expected to have a major impact on outcome since 94.6% in the CRM197‐PCV7 and 95.5% in the control group completed the follow‐up as specified in the protocol.
Selective reporting (reporting bias)	Unclear risk	Prespecified outcomes (primary and secondary) are listed in ClinicalTrials.gov (although uploaded after study end).
Other bias	Low risk	No other sources of bias identified.