Vesikari 2016.
| Methods | This trial was nested within the Finnish invasive pneumococcal disease vaccine trial (FinIP; clinicaltrials.gov/show/NCT00861380; Palmu 2013), a cluster‐randomised double‐blind trial to assess the efficacy of PHiD‐CV10 against IPD, all‐cause antibiotic‐purchases, tympanostomy tube placements, and vaccine‐preventable diseases. Randomised: yes, at cluster level Design: parallel‐group (4 groups) design Intention‐to‐treat: no, per‐protocol analysis Follow‐up – mean duration of follow‐up 18 months |
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| Participants |
N:– 5095 healthy infants Age: mean age at first dose 2.3 months Setting: 15 study centres in Finland Inclusion criteria: healthy children aged 6 weeks to 18 months Exclusion criteria: prior administration of pneumococcal vaccine, hepatitis A or B vaccine, any investigational or non‐registered product, contraindication to immunisation Baseline characteristics: described and balanced (Suppl. Table 1) |
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| Interventions | Children were randomly allocated (2:2:1:1) to either PHiD‐CV10 3 + 1, 2 + 1, control 3 + 1, control 2 + 1 (control vaccine was hepatitis B for children aged < 12 months or hepatitis A for those aged 12 months or above). Tx1: PHiD‐CV10 3 + 1; N = 1846 (N = 1846 completed the follow‐up as specified in the protocol) Tx2: PHiD‐CV10 2 + 1; N = 1313 (N = 942 completed the follow‐up as specified in the protocol) C1: hepatitis A or hepatitis B vaccine 3 + 1; N = 1073 (N = 468 completed the follow‐up as specified in the protocol) C2: hepatitis A or hepatitis B vaccine 2 + 1; N = 861 (N = 861 completed the follow‐up as specified in the protocol) Additional vaccines: a combination vaccine containing diphtheria‐tetanus‐acellular pertussis‐inactivated polio and Haemophilus influenzae type b (DTPa‐IPV/Hib) and human rotavirus vaccine were given at the same visit as the pneumococcal vaccine at 3 and 5 months. The DTPa‐IPV/Hib vaccine was also co‐administered at 11 to 12 months of age. |
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| Outcomes |
Primary outcome – parent‐reported, physician‐confirmed all‐cause AOM (stratified to 1 or more AOM episodes and overall AOM) Secondary outcomes: parent‐reported, physician‐confirmed all‐cause AOM with antibiotic prescription (stratified to 1 or more AOM episodes and overall AOM), serious adverse events occurring throughout the study period Parents were asked by automatic text message every 2 weeks if their child had had a physician‐confirmed AOM diagnosis. If no contact could be made, AOM status was checked at the next study visit. |
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| Funding sources | GlaxoSmithKline Biologicals SA was the funding source and was involved in all stages of the study conduct and analysis. GlaxoSmithKline Biologicals SA also took responsibility for all costs associated with the development and publishing of this article. | |
| Declarations of interest | Dr Vesikari declares that he received payment from the GlaxoSmithKline group of companies and other vaccine manufacturers for board membership, consultancy, and attending meetings; the institution of Dr Kaijalainen received grants from the GlaxoSmithKline group of companies. 7 co‐authors are employees of the GlaxoSmithKline group of companies. Dr Hezareh is a consultant for Chiltern International for the GlaxoSmithKline group of companies. Dr Puumalainen was a GlaxoSmithKline group of companies employee during the study. 4 co‐authors declare stock and stock options ownership in the GlaxoSmithKline group of companies, and 1 co‐author declares shares ownership in the GlaxoSmithKline group of companies. Dr Forsten and Dr Seppä declare no conflicts of interest. | |
| Notes |
Participants lost to follow‐up:total: 976/5093 (19.2%) did not complete the follow‐up period specified in the protocol Participants lost to follow‐up:Tx1: 0/1846 (0%) did not complete the follow‐up period specified in the protocol Participants lost to follow‐up:Tx2: 371/1313 (28.3%) did not complete the follow‐up period specified in the protocol Participants lost to follow‐up:C1: 605/1073 (56.4%) did not complete the follow‐up period specified in the protocol Participants lost to follow‐up:C2: 0/861 (0%) did not complete the follow‐up period specified in the protocol |
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| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote: "Clusters were randomized (2:2:1:1: PHiD‐CV 3+1, PHiD‐CV 2+1, control 3+1, control 2+1) using a blocking scheme, stratified according to cluster size (below/above average), urbanity (urban/rural), and Tampere University Vaccine Research Centre trial enrolment" |
| Allocation concealment (selection bias) | Low risk | Quote: "For nested study participants, individual randomization codes were used, aligned with cluster randomization based on place of residence" |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Stated that this was a double‐blind trial, but no further details provided |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Stated that this was a double‐blind trial, but no further details provided |
| Incomplete outcome data (attrition bias) All outcomes | High risk | Substantial number of participants not included in analysis due to “randomization error” |
| Selective reporting (reporting bias) | Low risk | Prespecified outcomes listed in clinicaltrials.gov/show/NCT00839254. |
| Other bias | Low risk | No other sources of bias identified. |
Ab: antibiotics AOM: acute otitis media C: control CAP: community‐acquired pneumonia CRM197‐PCV7: 7‐valent pneumococcal conjugate vaccine conjugated to carrier protein CRM197 CRM197‐PCV9: 9‐valent pneumococcal conjugate vaccine conjugated to carrier protein CRM197 DCC: day‐care centre DTaP: diphtheria‐tetanus toxoid‐acellular pertussis vaccine DTP: diphtheria‐tetanus toxoid‐pertussis vaccine DTwP: diphtheria‐tetanus toxoid‐whole cell pertussis vaccine ELISA: enzyme‐linked immunosorbent assay
ENT: ear, nose, and throat GP: general practitioner HBV/placebo: hepatitis B virus vaccination plus placebo vaccine Hib: Haemophilus influenzae type b ICPC: International Classification of Primary Care IgA: immunoglobulin A IgG: immunoglobulin G IPD: invasive pneumococcal disease ITT: intention‐to‐treat MenC: meningococcus type C conjugate vaccine N: number NaCl: sodium chloride OM: otitis media OMPC‐PCV7: 7‐valent pneumococcal conjugate vaccine conjugated to the outer membrane protein complex of Neisseria meningitidis serogroup B PCR: polymerase chain reaction PCV: pneumococcal conjugate vaccine PHiD‐CV10: 10‐valent pneumococcal conjugate vaccine conjugated to protein D (surface lipoprotein of non‐typeable Haemophilus influenzae) PHiD‐CV11: 11‐valent pneumococcal conjugate vaccine conjugated to protein D (surface lipoprotein of non‐typeable Haemophilus influenzae) PPV23: 23‐valent pneumococcal polysaccharide vaccine RTI: respiratory tract infection TIV: trivalent influenza vaccine TIV/CRM197‐PCV7: trivalent influenza vaccine plus 7‐valent pneumococcal conjugate vaccine conjugated to carrier protein CRM197 TIV/placebo: trivalent influenza vaccine plus placebo vaccine Tx: treatment