Outcome measures in long COVID clinical trials: a review

Long COVID is a multisystem disease that affects approximately 10% of people after a SARS-CoV-2 infection. In the absence of curative treatment, high-quality clinical treatment trials are urgently needed for long COVID. There is significant overlap between long COVID and other infection-associated chronic conditions, in particular myalgic encephalomyelitis. As such, trial design for long COVID can benefit from prior experience in this field. In this review we explore outcome measures in long COVID and myalgic encephalomyelitis clinical trials to survey current practices, and provide recommendations for future clinical trials. PubMed and Clinicaltrials.gov were searched for clinical trials on long COVID and myalgic encephalomyelitis that featured a biomedical intervention. 37 myalgic encephalomyelitis and 68 long COVID trials were identified that used 397 outcome measures in total. We then critically assessed the relevance of these outcome measures for patients.

Long COVID trial design could be improved by incorporating outcomes that address important symptom clusters such as post-exertional malaise, dysautonomia and mast cell activation. Clinical assessments, physical tests and biomarkers can supplement patient reported outcome measure data, if safety, feasibility and applicability are carefully considered. Lastly, safety of the intervention is rarely adequately evaluated. We recommend a concerted effort to include patient input at all steps of clinical trial design, execution and evaluation.