Table 1.

Inclusion and exclusion rules applied to compounds and clinical trials for selection into the evaluation

Inclusion and exclusion criteria
Report of trial failure must be between 2004 and 2021, inclusive; ongoing trials or recently completed trials without reported results were excluded.
Interventional trials that utilized placebo-controlled, randomized, parallel assigned and blinded trial design were included; factorial and crossover designs were accepted; observational and open-label trials were excluded.
Trials of medical foods were included; but studies of medical devices, behavioral interventions, vitamins, and general dietary supplements were excluded.
Phase II and III trials were included (as efficacy was the focus); phase I/II trials were treated as a phase II; phase II/III and phase III/IV trials were treated in the same way as a phase III.
Only AD dementia trials were examined, not other types of dementias; the full spectrum of preclinical/prodromal to severe AD were included.
Phase III trials must use a cognition measure as the primary clinical endpoint; non-dementia indications (e.g., depression, agitation, aggression, sleep disturbances) were excluded.
For phase II trials, cognition or function measures were not necessary as the primary endpoint, and studies of only AD biomarker measurements (as a surrogate endpoint) were included.
Evidence for phase III compound failures were from scientific publications or news releases, or reported compound discontinuation in AD databases (e.g., Alzforum, AdisInsight). Compounds with phase III trial failures were included in the evaluation, even if the sponsor is continuing development with additional trials.
Evidence for phase II compound failures were from scientific publications or news releases, reports of compound discontinuation in AD databases (e.g., Alzforum, AdisInsight), or removal of compound information from company’s R&D pipeline. Inactive or unknown status, or complete lack of follow-up information was not sufficient to be a failure.
Phase III trials that were extensions of another phase III were not included as separate entries.
Trials in which failure occurred as a result of safety issues were included.