Long COVID has created a worldwide public health crisis and has no approved treatments or validated biomarkers. We summarize the current challenges and considerations of outcome selection in Long COVID trials, along with recommendations for current trial design and future endpoint validation, with a focus on post-exertional malaise (PEM). We make five overarching recommendations for Long COVID clinical trials: 1) thorough characterisation of baseline disease; 2) collection of longitudinal data; 3) design of a placebo arm to enable comparison of treatment effect relative to the disease natural history; 4) accounting for, and when feasible, measuring PEM; 5) balancing severity, duration, and relevant phenotypes across trial arms and within subgroups to be analysed. We present a list of outcomes that may be considered for Long COVID clinical trials, with a focus on PEM. Crucially, the field of Long COVID clinical trials urgently needs funding and research effort investment to develop and validate outcomes concomitantly with clinical trial research.

Long COVID

Endpoints

Outcomes

Clinical trials

Biomarkers

© 2025 The Author(s). Published by Elsevier B.V.