Tregnaghi 2014.

Study characteristics
Methods	This trial was part of Clinical Otitis Media and Pneumonia Study (COMPAS; clinicaltrials.gov/show/NCT00466947) to assess the efficacy of PHiD‐CV10 against IPD, CAP, and AOM in young Latin American children. Randomised: yes, at individual level Design: standard parallel‐group design Intention‐to‐treat: yes, both ITT and per‐protocol analysis described Follow‐up: total follow‐up duration 4 years
Participants	N: 23,821 healthy infants (for Panama, AOM cohort: 7359) Age: mean age 9 months Setting: well‐baby clinics at 5 sites (3 in Argentina, 1 in Colombia, and 1 in Panama); all countries are classified as upper‐middle economies Inclusion criteria: healthy children aged 6 to 16 weeks Exclusion criteria: use or planned use of any investigational or unregistered drug or vaccine other than the study vaccines; previous vaccination against diphtheria, tetanus, pertussis, Haemophilus influenzae type b, hepatitis A, and/or Streptococcus pneumoniae; history of allergic disease or reactions likely to be exacerbated by any components of the study vaccines; acute disease at time of enrolment; low birthweight (< 2500 g) not permitted for Colombia Baseline characteristics: described and balanced (Table 3 of trial publication)
Interventions	Children were randomly allocated to either PHiD‐CV10 or a hepatitis B vaccine at 2, 4, and 6 months followed by 1 dose of PHiD‐CV10 or hepatitis A vaccine at 15 to 18 months of age. Tx: PHiD‐CV10; N = 11,875 (N = 10,295 completed the follow‐up as specified in the protocol); for AOM cohort N = 3602 (N = 3010 completed the follow‐up as specified in the protocol) C: hepatitis B vaccine; N = 11,863 (N = 10,201 completed the follow‐up as specified in the protocol); for AOM cohort N = 3612 (N = 2979 completed the follow‐up as specified in the protocol) Additional vaccines: a combination vaccine containing diphtheria‐tetanus‐acellular pertussis‐inactivated polio and H influenzae type b (DTPa‐IPV/Hib) was given in the child's opposite thigh at the same visit as the pneumococcal vaccine at 2, 4, 6 and 15 to 18 months
Outcomes	Primary outcome: likely bacterial CAP Secondary outcomes: other CAP outcomes, first episode of clinically confirmed AOM, first episode of pathogen‐specific AOM, serious adverse events and mortality occurring throughout the study period. The AOM outcome was studied in Panama only (7357 of the 23,821 randomised children). Initially, AOM cases were captured only when parents sought medical attention for children with AOM symptoms. However, because of a lower‐than‐expected AOM rate, the surveillance was enhanced in July 2009 (2 years after start of enrolment) through regular telephone calls or home visits by study personnel who advised parents to visit the clinic if their child had symptoms suggestive of AOM. If the physician suspected AOM, the child was referred to 1 of the ENT surgeons involved in the trial. Clinically confirmed AOM was defined as either altered visual appearance of the tympanic membrane (e.g. redness, bulging, loss of light reflex) or the presence of middle ear effusion (by pneumatic otoscopy or otomicroscopy). Recent onset (duration of less than 5 days) of at least 2 of the following clinical symptoms was also required: ear pain, ear discharge, hearing loss, fever, lethargy, irritability, anorexia, vomiting, or diarrhoea. The severity of each AOM episode (mild, moderate, severe) was assessed by combining objective elements of the Friedman scale (the Ear Treatment Group‐five items (ETG‐5) and otoscopy scale with eight grades of severity (OS‐8)) with subjective elements in a clinical otologic scale. When middle ear fluid was suspected, tympanocentesis was performed, and bacterial presence was assessed by culture.
Funding sources	Sponsored by GlaxoSmithKline Biologicals, the vaccine developer and manufacturer. The data generated in the trial are subject to a confidentiality agreement between the investigators and the sponsor that allowed the investigators full access to the study data and included an obligation for GlaxoSmithKline Biologicals to permit publication without excessive delay.
Declarations of interest	Dr Sáez‐Llorens declares having received financial support from the study sponsor for travel to meetings, and his institution has received grants from Health Research International. Drs López and Calvo declare that their institutions have received support for travel to meetings and grants from the study sponsor. Dr Calvo declares that her institution has received consulting fee/honorary from the study sponsor. Dr Hausdorff is a patent coholder of PCV13 (no royalties). 9 co‐authors are employees of GlaxoSmithKline companies and own stock/stock options from the GlaxoSmithKline group of companies.
Notes	Participants lost to follow‐up:total: 592/3602 (16.4%) did not complete the follow‐up period specified in the protocol Participants lost to follow‐up:Tx: 633/3612 (17.5%) did not complete the follow‐up period specified in the protocol Participants lost to follow‐up:C: 1225/7214 (17.0%) 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	Quote: "The randomization list was generated by the sponsor using a standard SAS (SAS Institute) program and was used to number the vaccines. A randomization blocking scheme was used to ensure that balance between treatment groups was maintained"
Allocation concealment (selection bias)	Low risk	Quote: "Vaccine allocation at each site was performed using a central randomization system on the Internet (SBIR, GlaxoSmithKline Vaccines), and treatment was concealed from all study personnel"
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Vaccines were numbered by the sponsor, and treatment allocation was concealed from study personnel. There were minor differences in vaccine appearance, but vaccines were prepared and administered by personnel who took no further part in the study.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Vaccines were prepared and administered by personnel who took no further part in the study. Parents/guardians of participating children and study personnel involved in data gathering, processing, and analysis and safety assessment were blind to vaccine allocation.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Almost all randomised children were included in ITT analysis.
Selective reporting (reporting bias)	Low risk	Prespecified outcomes listed at clinicaltrials.gov/show/NCT00466947.
Other bias	Low risk	No other sources of bias identified.