Critical appraisal:Burn J, Gerdes AM, Macrae F, Mecklin JP, Moeslein G, Olschwang S, et al 2011 1

Risk of bias assessment: Randomised Controlled Trial (Cochrane risk of bias tool)

Random sequence generation

Describe the method used to generate the allocation sequence in sufficient detail to allow an assessment of whether it should produce comparable groups.

Randomization was computer-generated. The study centers were categorized into six geographic groups — Americas, southern Europe (the Iberian Peninsula and Italy), northern Europe, South Africa, the United Kingdom, and the Pacific Rim (Australia and Hong Kong). Block randomization (in blocks of 16) was performed separately for each group of centers to ensure balance across the four main study groups.

What was the risk of bias from the random sequence generation?

Low

Allocation concealment

Describe the method used to conceal the allocation sequence in sufficient detail to determine whether intervention allocations could have been foreseen in advance of or during, enrolment.

The investigators and patients were unaware of the study-group assignments. Dispensing and related records were managed by the Newcastle Hospitals NHS Foundation Trust Pharmacy. After colonoscopic examination at study entry, packs containing the study drugs were sent directly to the participants or local clinicians and thereafter were sent every 6 months, when compliance data were collected.

What was the risk of bias from the allocation concealment?

Low

Blinding

Describe all measures used, if any, to blind outcome assessors from knowledge of which intervention a participant received. Provide any information relating to whether the intended blinding was effective.

The investigators and patients were unaware of the study-group assignments. Dispensing and related records were managed by the Newcastle Hospitals NHS Foundation Trust Pharmacy.

What was the risk of bias from the blinding of participants and personnel and outcome assessors?

Low

Incomplete outcome data

Describe the completeness of outcome data for each main outcome, including attrition and exlusions from the analysis. State whether attrition and exclusions were reported, the numbers in each intervention group (compared with total randomized participants), reasons for attrition/exclusions where reported, and any re-inclusions in analyses performed by the review authors.

We recruited 1009 eligible patients. The analysis excluded 263 participants (26%); 72 withdrew before the colonoscopic examination at study entry, and 191 withdrew before the follow-up colonoscopic examination. The remaining 746 participants were included in the analysis. There were no notable differences between the patients who were recruited and those who completed the study. A total of 671 included in this long term follow up data set.

What was the risk of bias from incomplete outcome data?

Low

Selective outcome reporting

State how the possibility of selective outcome reporting was examined by the review authors and what was found.

The primary outcome of CAPP2 was development of colorectal cancer; the secondary outcomes were development of colorectal adenomas or the development of other Lynch syndrome-related cancers, or both. This analysis focused on 861 CAPP2 participants randomly assigned to aspirin or aspirin placebo from entry until the latest date for which the recruiters had information about cancer diagnosis—a timepoint usually corresponding to the date of last surveillance attendance. Our analysis included Lynch syndrome cancers that were included in the earlier report,3 those that occurred subsequent to exit from the intervention phase, and all cancers that occurred in people without an exit colonoscopy, which excluded them from the statistical analysis in our earlier report.3 As a result of dispersed international recruitment and because routine surveillance was provided by local health-care teams, records of adenoma occurrence in CAPP2 participants subsequent to the intervention phase are incomplete. Similarly, no details of adverse events were available postintervention; during the intervention phase, adverse events in the aspirin and placebo groups were similar (webappendix p 2).3 There was also no signifi cant difference in compliance (ie, proportion of scheduled tablets not taken during the intervention phase) between the aspirin and aspirin placebo groups for participants with complete inter vention phase data (χ²(1)=1·27, p=0·20).

What was the risk of bias from selective outcome reporting? Assessments should be made for each main outcome (or class of outcomes).

Low