Black 2000.

Study characteristics
Methods	Randomised: yes, at individual level Design: standard parallel‐group design Intention‐to‐treat: yes Follow‐up: 6 to 31 months
Participants	N: 37,868 healthy infants Age: 2 months Setting: 23 medical centres within Northern California Kaiser Permanente (NCKP), USA Inclusion criteria: healthy children aged 2 months Exclusion criteria: children with sickle cell disease, known immunodeficiency, any serious chronic or progressive disease, a history of seizures, or a history of either pneumococcal or meningococcal disease Baseline characteristics: not described
Interventions	Children were randomly allocated to either CRM197‐PCV7 or a meningococcus type C conjugate vaccine (10 µg of group C oligosaccharide conjugated to carrier protein CRM197; MenC) at 2, 4, 6 and 12 to 15 months of age Tx: CRM197‐PCV7; N = 18,927 received 1 dose or more of the vaccine (unclear how many children were included in otitis media analyses) C: MenC; N = 18,941 received 1 dose or more of the vaccine (unclear how many children were included in otitis media analyses) Additional vaccines: routine childhood vaccines were administered at the recommended ages: DTwP or DTaP; oral poliovirus vaccine or inactivated poliovirus vaccine; Hib; hepatitis B; measles‐mumps‐rubella vaccine; varicella. Initially all participants received a vaccine combining Haemophilus b conjugate and DTwP into the opposite leg and oral poliovirus vaccine concurrently. When recommendations changed, the protocol was amended to allow administration of DTaP and inactivated poliovirus vaccine. Vaccines not given concomitantly were given at least 2 weeks apart from study vaccine.
Outcomes	Primary outcome: invasive pneumococcal disease caused by vaccine serotypes Secondary outcomes: number of otitis media episodes in fully vaccinated per protocol; number of otitis media visits; time to recurrent otitis media (defined as 3 or more episodes in 6 months or 4 or more in 12 months); number of tympanostomy tubes placements; number of cases of spontaneously draining ruptured tympanic membranes with culture of a vaccine serotype pneumococcus; safety (local and systemic reactions at 48 to 72 hours after vaccination, uncommon events requiring medical attention 30 days and 60 days after vaccination, and mortality) Clinical diagnoses of AOM were obtained from computerised data sources using diagnoses registered by emergency physicians and paediatricians in the NCKP population. Each clinic visit constituted a new episode unless it was classified as a follow‐up visit. A visit < 21 days after another otitis media visit was always considered a follow‐up visit. A visit 42 days or more after the most recent otitis media visit was considered a new episode. Visits occurring between 21 and 42 days, if the appointment was made < 3 days in advance, were considered new episodes.
Funding sources	The study was supported by an unrestricted grant from Wyeth(‐Ayerst); authors were employed at Kaiser Permanente Vaccine Study Center (Oakland), Wyeth Lederle Vaccines and Pediatrics (Pearl River), University of Pennsylvania (Philadelphia), and Vanderbilt University Medical Center (Nashville).
Declarations of interest	Not described; authors were employed at Kaiser Permanente Vaccine Study Center (Oakland), Wyeth Lederle Vaccines and Pediatrics (Pearl River), University of Pennsylvania (Philadelphia), and Vanderbilt University Medical Center (Nashville)
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Method of random sequence generation not described
Allocation concealment (selection bias)	Unclear risk	No method of allocation concealment described
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Indicated as a double‐blind study, but insufficient details provided to ensure blinding of participants and personnel
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Clinical diagnoses of AOM were obtained from computerised data sources using diagnoses registered by emergency physicians and paediatricians (non‐trialists).
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Unclear how many children were included in otitis media analyses
Selective reporting (reporting bias)	Unclear risk	Study protocol is not available. Otitis media endpoint (efficacy against otitis media episodes) is reported as a secondary endpoint.
Other bias	Unclear risk	Study enrolment was stopped as a result of prespecified interim analysis.