Prymula 2006.

Study characteristics
Methods	Randomised: yes, at individual level Design: standard parallel‐group design Intention‐to‐treat: yes, both ITT and per‐protocol analysis described Follow‐up: efficacy follow‐up started on the day of the first dose of study vaccine (for ITT analysis) or 2 weeks after the third vaccine dose (for the per‐protocol analysis) and continued until 24 to 27 months of age
Participants	N: 4968 healthy infants Age: between 6 weeks and 5 months Setting: 27 paediatric centres in the Czech Republic and 23 in Slovakia Inclusion criteria: healthy children aged between 6 weeks and 5 months with no acute illness Exclusion criteria: use of any investigational or non‐registered drug or vaccine other than the study vaccines within 30 days preceding first dose of the study vaccines; previous vaccination against Streptococcus pneumoniae; fever (defined as a rectal temperature of 38 °C or higher or temperature by other routes of 37.5 °C or higher); history of allergic disease or reactions likely to be exacerbated by any component of the study vaccines; other conditions that might potentially interfere with the interpretation of study outcomes according to the investigator Baseline characteristics: described and balanced (Table 1 of trial publication)
Interventions	Children were randomly allocated to either PHiD‐CV11 or a hepatitis A vaccine (containing 720 ELISA units of inactivated hepatitis A virus antigen (strain HM 175)) at about 3, 4, 5 and 12 to 15 months of age. Tx: PHiD‐CV11; N = 2489 (N = 2455 included in per‐protocol cohort for efficacy) C: hepatitis A vaccine; N = 2479 (N = 2452 included in per‐protocol cohort for efficacy) Additional vaccines: a concomitant hexavalent diphtheria‐tetanus‐3‐component acellular pertussis‐hepatitis B‐inactivated poliovirus types 1, 2, and 3 Haemophilus influenzae type b (DTPa‐HBV‐IPV/Hib) vaccine was offered to all study participants, followed by a booster dose at age 15 to 18 months
Outcomes	Primary outcome: first episode of AOM caused by vaccine pneumococcal serotypes Secondary outcomes: first episode of AOM caused by non‐typeable H influenzae, any all‐cause AOM episodes, any vaccine‐type AOM episodes, any cross‐reactive serotypes AOM, any non‐vaccine‐type AOM, safety (adverse events arising within 31 days of vaccination, and serious adverse events occurring throughout the study period). There was no active surveillance. Unscheduled doctor visits could take place any time during follow‐up according to standard local practice (parents consulting their local paediatrician in case of illness of their child). Parents were advised to consult their paediatrician if their child was sick, had ear pain, or had spontaneous ear discharge. Children with suspected AOM were immediately referred to ENT surgeons. AOM was defined as either abnormal findings of the tympanic membrane at otoscopy (i.e. redness, bulging, loss of light reflex) or the presence of middle ear effusion as shown by simple or pneumatic otoscopy or by microscopy together with at least 2 of the following signs or symptoms: ear pain, ear discharge, hearing loss, fever, lethargy, irritability, anorexia, vomiting, or diarrhoea. These signs or symptoms had to be present for a maximum of 14 days. For children with repeated doctor visits, a new episode of AOM was judged to have started if more than 30 days had elapsed since the beginning of the previous episode. Additionally, for categories defined according to bacterial pathogen or serotype, a new episode was judged to have started if any interval had elapsed since the beginning of an episode caused by a different bacterial pathogen or serotype. Recurrent AOM was defined as 3 or more AOM episodes in the last 6 months or 4 or more in the last 12 months.
Funding sources	The study was supported by GlaxoSmithKline Biologicals, Rixensart, Belgium.
Declarations of interest	Dr Prymula is a consultant to GlaxoSmithKline and other pharmaceutical companies, and has received travel grants or honoraria paid by healthcare companies within the past 3 years. 7 co‐authors are employees of GlaxoSmithKline Biologicals, of which 4 own shares in GlaxoSmithKline.
Notes	Participants lost to follow‐up:total: 61/4968 (1.2%) did not complete the follow‐up period specified in the protocol Participants lost to follow‐up:Tx: 34/2489 (1.4%) did not complete the follow‐up period specified in the protocol Participants lost to follow‐up:C: 27/2479 (1.1%) 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	Computer‐generated random list
Allocation concealment (selection bias)	Low risk	Randomisation (1:1) was done with a study‐specific central randomisation system via the internet which, on receipt of the infant's initials and birth date, determined the vaccine number to be used.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Indicated as a double‐blinded study. The sponsor numbered the vaccine supplies. However, it is unknown whether the appearance of the vaccines was similar at the time of administration.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Visits during efficacy follow‐up were according to standard local clinical practice. When AOM was suspected, children were referred to ENT surgeons.
Incomplete outcome data (attrition bias) All outcomes	Low risk	No reporting of reasons for dropout or loss to follow‐up. This is not expected to have a major impact on outcome since 98.6% in the PHiD‐CV11 and 98.9% in the control group completed the follow‐up as specified in the protocol.
Selective reporting (reporting bias)	Low risk	Prespecified outcomes (primary and secondary) are listed in ClinicalTrials.gov.
Other bias	Low risk	Study enrolment was stopped as a result of prespecified interim analysis. No other sources of bias identified.