Drug therapy falls short for long COVID fatigue

Clinical takeaway: Continue to prioritize multidisciplinary long COVID care for patients with persistent fatigue. Current evidence does not support routine use of repurposed drug therapy, although small short-term benefits warrant further study.

Long COVID fatigue remains one of the most challenging symptoms to treat, and there are currently no FDA-approved drug therapies. In one of the largest randomized treatment trials to date, commonly used medications provided only modest, short-lived improvements beyond specialist supportive care, reinforcing that comprehensive multidisciplinary long COVID management remains the foundation of treatment.

The STIMULATE-ICP trial enrolled 778 adults with persistent long COVID who had not been hospitalized for their initial COVID-19 illness. Participants, who had experienced symptoms for more than two years on average and had severe baseline fatigue, were randomized to receive specialist supportive care alone or specialist care plus one of three repurposed drug treatments (colchicine, a combination of famotidine and loratadine, or rivaroxaban) for 12 weeks.

Patients in all treatment groups, including those receiving specialist supportive care alone, experienced clinically meaningful improvements in fatigue over 12 weeks. Compared with specialist care alone, colchicine and the combination of famotidine and loratadine provided only modest, short-term additional benefit. This advantage disappeared 12 weeks after treatment stopped, and rivaroxaban showed no benefit.

“We tested potential medicines based on the most promising theories of how to improve long Covid when we started out in 2021. Our findings suggest these drugs alone are unlikely to be the answer to long Covid fatigue. Antihistamines and the anti-inflammatory drug, colchicine, did provide a small benefit, but this did not last once participants stopped taking them and so they are unlikely to improve symptoms over the long term on their own,” said study author Professor Amitava Banerjee.

The open-label design means placebo effects cannot be excluded. However, in an accompanying commentary, Tiffany A. Walker, MD, MPH, assistant professor of medicine in the Division of Infectious Diseases at Emory University School of Medicine, said the trial represents an important step in building the evidence base for long COVID treatment despite its modest results. She wrote that the findings support future placebo-controlled trials, comparative effectiveness studies, and more targeted treatment approaches to identify which patients are most likely to benefit from specific therapies.

Source: Wall E, et al. (2026 July 8) Lancet Infect Dis. 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