Veenhoven 2003.

Methods	This study was performed in parallel with van Kempen 2006, but analysed separately due to differences in study population. Randomised: yes, at individual level Design: standard parallel‐group design Intention‐to‐treat: yes Follow‐up: 18 months, starting 1 month after completion of the vaccination scheme
Participants	N: 383 children with a history of AOM Age: between 1 and 7 years Setting: a general hospital (Spaarne Hospital, Haarlem) and a tertiary care hospital (Wilhelmina Children's Hospital of the University Medical Centre Utrecht) in the Netherlands Inclusion criteria: children aged 1 to 7 years with a history of AOM defined as 2 or more AOM episodes in the year before study entry. The number of previous AOM episodes was based on parental report and on clinical confirmation of the diagnosis by a physician. Exclusion criteria: children with immunodeficiency, cystic fibrosis, immotile cilia syndrome, craniofacial abnormalities, chromosomal abnormalities such as Down's syndrome, and severe adverse events during previous vaccinations Baseline characteristics: described and balanced (Table 1 of trial publication)
Interventions	Children were randomly allocated to either CRM197‐PCV7 followed by a PPV23 or a hepatitis A or B vaccine. Children aged 12 to 24 months in the pneumococcal vaccination group received PCV7 twice with a 1‐month interval, followed 6 months later by PPV23. The control vaccine group received 3 hepatitis B vaccinations (Engerix‐B) according to a similar time schedule. Children aged 25 to 84 months in the pneumococcal vaccine group received 1 dose of PCV7 followed 7 months later by PPV23. The control group received hepatitis A vaccine (Havrix) twice. Tx: CRM197‐PCV7 plus PPV23; N = 190 (N = 190 included in ITT analysis) C: hepatitis A or hepatitis B vaccine; N = 193 (N = 193 included in ITT analysis) Additional vaccines: not described
Outcomes	Primary outcome: number of clinical AOM episodes during 18‐month follow‐up Secondary outcomes: number of AOM episodes due to the 7 pneumococcal serotypes included in the PCV7 vaccine and nasopharyngeal carriage of conjugate vaccine serotypes, serious adverse events Parents were instructed to visit the study clinics or their GP, ENT surgeon, or paediatrician to assess symptoms suggesting AOM. Physicians registered signs and symptoms of every AOM episode on standard registration forms and were unaware of treatment allocation. AOM was defined according to the guideline issued by the Dutch College of General Practitioners, i.e. presence of an abnormal tympanic membrane on otoscopy (red, dull, or bulging) or otorrhoea and at least 1 of the following signs or symptoms of acute infection: acute earache, new‐onset otorrhoea, irritability, or fever greater than 38.5 °C rectally or 38.0 °C axillary.
Funding sources	The study was supported by the Netherlands Organisation for Health Research and Development (ZonMw) and the Dutch Health Insurance Company Zilveren Kruis‐Achmea as part of the OMAVAX‐trial. Wyeth‐Lederle Vaccines and Pediatrics provided the pneumococcal vaccines, and GlaxoSmithKline provided the hepatitis A vaccines.
Declarations of interest	The authors declared no conflicts of interest.
Notes	Participants lost to follow‐up:total: 1/383 (0.3%); all children included in ITT analysis Participants lost to follow‐up:Tx: 0/190 (0%) Participants lost to follow‐up:C: 1/193 (0.5%)
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Table of random numbers that identified the vaccine scheme, randomisation stratified according to age (12 to 24 months versus 25 to 84 months) and number of previous AOM episodes per year (2 to 3 versus 4 or more episodes)
Allocation concealment (selection bias)	Unclear risk	No method of allocation concealment was described.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Vaccine was administered to the child by a study nurse, so that parents and physicians were unaware of treatment allocation.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Parents were instructed to visit the study clinics or their family physician, otolaryngologist, or paediatrician to assess symptoms suggesting AOM. Physicians registered signs and symptoms of every AOM episode on standard registration forms and were unaware of treatment allocation. AOM was defined according to the guideline issued by the Dutch College of General Practitioners.
Incomplete outcome data (attrition bias) All outcomes	Low risk	All randomised children were included in ITT analysis.
Selective reporting (reporting bias)	Unclear risk	No study protocol available.
Other bias	Low risk	No other sources of bias identified.