Kryscio 2017.

Methods	PREADVISE (Prevention of Alzheimer's Disease by Vitamin E and Selenium Trial) Ancillary study to SELECT (primary aim prevention of prostate cancer) Began as a double‐blind RCT in 2002, transformed into a cohort study from 2009‐15 Randomised, double‐blind, 2 x 2 factorial design
Participants	Location: 130 SELECT clinical sites in the US, Canada and Puerto Rico Recruitment: 7540 non‐dementia men already enrolled in SELECT were recruited into PREADVISE between 2002 and 2008. 7338 had at least one follow‐up visit. 4271 consented to continue annual telephone follow‐up after the RCT was closed and supplements stopped in 2009/10. Of these, 3786 were screened by telephone at least once. Number randomised: 7540 Participant characteristics: Age: Mean (SD) 67.5 (5.3) at PREADVISE baseline Gender: all participants were male Inclusion criteria: SELECT participants aged 62 years and over (age 60 years if black) Exclusion criteria: dementia, active neurologic and/or neuropsychiatric conditions that affect cognition, as well as history of serious head injury (> 30‐minute loss of consciousness within the last five years prior to enrolment) and substance abuse
Interventions	Supplements were taken for 5.4 ± 1.2 years 2 x 2 factorial design: vitamin E 400 IU/day, selenium 200 mcg/day, placebo
Outcomes	Dementia incidence was the primary outcome of PREADVISE. It was determined by one of two methods. First tier screening was the Memory Impairment Screen (MIS). A score ≤ 5/8 triggered a second tier screen which was the expanded Consortium to Establish a Registry in Alzheimer's Disease (CERADe) battery during the RCT and the modified Telephone Interview for Cognitive Status (TICSm) during the cohort study. Method 1: Participants with T score ≤ 35 on CERADe or total score ≤ 35 on TICSm were encouraged to obtain a memory work‐up and share medical records with PREADVISE. Medical records were reviewed by a team of 2‐3 expert neurologists and 2‐3 expert neuropsychologists to determine a consensus diagnosis. Method 2: Participants who did not obtain a memory work‐up were assessed by additional measures collected during the study: AD8 Dementia Screening Interview, self‐reported medical history, self‐reported medication use, and cognitive test scores including the MIS, CERAD T Score, NYU Paragraph Delayed Recall, and TICSm. An AD8 ≥ 1 (at any time during follow‐up) plus a self‐reported dementia diagnosis, use of a memory enhancing prescription drug (i.e. donepezil, rivastigmine, galantamine, memantine), or cognitive score ≥ 1.5 standard deviations below expected performance yielded a dementia diagnosis. The diagnosis date was assigned to the earliest event.
Notes	"PREADVISE was ancillary to SELECT, a randomized controlled trial of the same antioxidant supplements for preventing prostate cancer. SELECT closed in 2009 due to a futility analysis." "The RCT was scheduled to continue supplements until 2012 but in September 2008, the SELECT Data and Safety Monitoring Committee recommended that supplements be discontinued due to lack of efficacy on prostate cancer incidence. Study sites closed over the next two years, during which time both PREADVISE and SELECT transitioned into cohort studies. RCT participants were asked to continue in the cohort study .." PREADVISE had intended to recruit 10,400 men to achieve 80% power to detect a hazard ratio of 0.6. Power was reduced by under‐recruitment, loss of sites and participants when RCT closed, and difficulties with case ascertainment.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"Randomized". No details. Large multisite cancer prevention trial. Likely adequate
Allocation concealment (selection bias)	Low risk	No details. Large multisite cancer prevention trial. Likely adequate
Blinding of participants and personnel (performance bias) All outcomes	Low risk	"Double‐blind". No details. Likely adequate
Blinding of outcome assessment (detection bias) All outcomes	Low risk	"Double‐blind". No details. Likely adequate
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	The transition from RCT to cohort study was associated with loss of approximately half the participants to follow‐up. "Fortunately ... the major cost was sample size (reduction in person‐years of follow‐up) since no new large selection biases were introduced." "All PREADVISE participants who completed at least one follow‐up visit were included in the current analyses (intent‐to‐treat analysis, ITT), whether they participated in just the RCT or both the RCT and cohort studies."
Selective reporting (reporting bias)	Low risk
Other bias	Low risk	"... despite randomization occurring at SELECT baseline rather than PREADVISE enrolment, there were no perceivable differences between study arms in terms of medical history, APOE ɛ4 genotype, or initial MIS."