Two repurposed drug regimens produced small improvements in fatigue during treatment but no sustained benefit after treatment ended, while a third showed no significant benefit in adults with long COVID, according to a large randomized controlled trial conducted at 12 specialist clinics in the United Kingdom.
The phase 3, open-label STIMULATE-ICP drug trial evaluated colchicine, rivaroxaban and a combination of famotidine and loratadine in adults with long COVID who had not been hospitalized during their initial COVID-19 illness. All participants received usual specialist-led long COVID care, according to research published in The Lancet Infectious Diseases.
"Overall, our data do not support widespread clinical use of these drugs for fatigue reduction in long COVID, but our study does provide a framework to support second-generation, precision medicine, placebo-controlled trials of new and repurposed drugs and drug combinations for long COVID-associated fatigue," wrote first author Emma C. Wall, PhD, of the Francis Crick Institute, the NIHR University College London Hospitals Biomedical Research Centre and the Division of Infection and Immunity at University College London, and colleagues.
The STIMULATE-ICP consortium randomly assigned 778 participants to receive colchicine 500 μg twice daily, rivaroxaban 10 mg once daily, famotidine 40 mg with loratadine 10 mg once daily, or no study drug for 12 weeks. The mean participant age was 46 years, 64% were female and 12% were from an ethnic group other than White. Participants had experienced long COVID symptoms for a median of 775 days and reported a median of nine symptoms. At enrollment, the mean Fatigue Assessment Scale score was 36.8 on a 10-50 scale, with higher scores indicating greater fatigue and a change of more than 10% considered clinically meaningful.
At 12 weeks, mean fatigue scores decreased by 4.3 points across all study groups, from 36.8 to 32.5. Compared with no study drug, adjusted Fatigue Assessment Scale scores were an additional 1.49 points lower with colchicine (95% CI, –2.92 to –0.06; P=0.041) and 1.48 points lower with famotidine-loratadine (95% CI, –2.88 to –0.08; P=0.038). The 1.06-point reduction with rivaroxaban was not statistically significant (95% CI, –2.47 to 0.35; P=0.139).
However, these differences were small and were not sustained after drug cessation. At 24 weeks — 12 weeks after treatment ended — fatigue scores did not differ significantly between any drug group and the usual-care group. Sensitivity analyses also weakened the evidence for benefit: differences associated with colchicine and famotidine-loratadine were no longer statistically significant when missing data were imputed or when analyses were limited to participants who completed the full treatment period.
Adverse events were more frequent among participants assigned study drugs. Gastrointestinal events occurred in 14% of participants receiving colchicine, while minor bleeding or heavy menstrual bleeding occurred in 13% of those receiving rivaroxaban. Ten serious adverse events requiring hospitalization occurred in eight participants (1.0%), including five events in three participants assigned rivaroxaban, but investigators judged none to be related to the study drugs.
The findings do not support use of these drugs alone for sustained management of long COVID fatigue, according to the researchers. Although fatigue improved by a clinically meaningful amount across all groups, including participants who received no study drug, the trial was not designed to determine whether that improvement resulted from specialist supportive care, the natural course of long COVID or other factors. The investigators said future trials should evaluate repurposed drugs in defined patient subgroups, combination therapies and different models of care.
The researchers noted that the open-label design was a limitation, particularly because the primary outcome, fatigue, was patient reported. The lack of masking could have affected participants’ perceptions of treatment benefit.
Emma C. Wall reported participating in the RECLAIM trial’s Data Safety and Monitoring Board for the RECLAIM trial, and Rachael A. Evans reported receiving speaker fees from Moderna and BMJ Best Practice, a grant from Genentech (Roche), as well as payments from the Scottish COVID-19 Inquiry and the UK Covid-19 Inquiry. All other study authors declared no competing interests. Funding was provided by the UK National Institute for Health and Care Research.
