Following promising findings in case reports and in small, uncontrolled trials, medications from three different pharmacologic classes were evaluated for fatigue persisting post-acute COVID-19 in a multisite, randomized controlled platform trial in the UK.1
"Fatigue most strongly predicted non-recovery in a previous study," explained Emma Wall, PhD, The Francis Crick Institute, University College London Hospitals NHS Trust, and Queen Mary University London, London, UK, and colleagues of the Writing Committee for the STIMULATE-ICP consortium, with "less than 15% of people with long COVID and severe fatigue recovered over 2 years."
The investigators selected rivaroxaban, colchicine, and famotidine-loratidine for the adaptive platform, open-label controlled trial based on reports supporting their potential benefit or putative mechanism of action in long COVID.The anticoagulant could mitigate reported abnormalities in complement and platelet systems and presence of fibrinoid-amyloid complexes. Colchicine may exert anti-inflammatory activity, with effects on the endothelial and myocardial inflammation that can occur in long COVID.The antihistamines could provide benefit by modifying mast-cell mediated inflammation.
The STIMULATE platform trial with these medications was nested in the Integrated Care Pathway (ICP) study of the specialized clinics and care protocols established in the UK for patients with long COVID.The ICP protocols were continued for the patients participating in the platform trial.Although it was hoped that there would be sufficient volunteers from the ICP clinics to populate the 3 medication groups and ICP-only control group, additional recruitment and trial clinics were required.
All participants had persistent, post-COVID-19 symptoms for at least 4 weeks without alternative explanation, as determined by a specialist clinician. The primary measure was the Fatigue Assessment Scale (FAS) compared to baseline at the 12 week completion of the medication regimens. The FAS at 24 weeks was a secondary measure. Adjustments were made for baseline fatigue and clinically relevant covariates.
The 12-week dosing regimens were: rivaroxaban 10mg daily (n=197); colchicine 500mcg twice daily (n=192); and famotidine 40mg with loratadine 10mg daily (n=193). As this was an open-label, pragmatic trial, the usual care/no trial medication control group (n=196) did include patients who received trial medications: 6 (3%) famotidine, 6 (3%) loratadine, and 2 (1%) colchicine.
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Colchicine and famotidine-loratadine produced modest short-term improvements in fatigue, with both treatments showing small but statistically significant reductions in Fatigue Assessment Scale (FAS) scores at 12 weeks compared with usual care.
Rivaroxaban did not improve long COVID-related fatigue, and by 24 weeks none of the three treatment groups demonstrated a sustained benefit over usual care.
The findings suggest that repurposed medications alone are unlikely to provide lasting relief for long COVID fatigue, highlighting the need for future studies evaluating targeted patient subgroups or combination treatment strategies.
Wall and colleagues defended the pragmatic, open-label design in which all participants continued to receive ICP care as usual, as a means to avoid the delays and costs of developing placebo control to match across all trial arms, and "to retain the trust of our patient population, many of whom experienced substantial stigma and barriers to care, reducing their trust in researchers and clinicians."
The investigators reported that at 12 weeks, compared to the ICP care control group, there was small, statistically significant FAS reduction in the colchicine and famotidine-loratadine groups (-1.49 [95% CI -2.92 to -0.041] and -1.48 [-2.88 to -0.08], respectively); but not with rivaroxaban.At 24 weeks, there were no statistically significant differences between groups, with all demonstrating some reduction in fatigue.
Although the investigators suggest that future trials could find benefit from these or other repurposed medications in specific subgroups of patients with long COVID, or possibly in combination therapies, they conclude "long-term long COVID symptom benefit is unlikely with these drugs alone".
Reference
1. Wall EC, Prescott G, Dehbi HM, and members of the Writing Committee for STIMULATE-ICP consortium. Efficacy and safety of rivaroxaban, colchicine, and famotidine-loratadine with specialist supportive clinical care for fatigue in patients with post-COVID-19 condition in the UK: a multisite, open-label, randomised controlled trial. Lancet Infect Dis. 2026, online July 8. https://doi.org/10.1016/S1473-3099(26)00242-2. Accessed July 10, 2026.
