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.
STIMULATE-ICP consortium
Post-acute sequelae of COVID-19 or post-COVID-19 condition (also known as long COVID) affects 1-5% of adults globally, most commonly with fatigue, and no evidence-based therapies are available. We aimed to evaluate the efficacy of repurposed medications in fatigue management in adults with long COVID. We did a phase 3, four-group, randomised, controlled, adaptive platform, open-label drug trial nested within a pragmatic, multicentre, cluster-randomised trial of an integrated care pathway (ICP) for long COVID across 12 UK National Health Service (NHS) specialist long COVID care clinics in the UK. Participants had to be adults (>18 years) with long COVID who had not been hospitalised with COVID-19. In addition to NHS specialist-led long COVID care (hereafter, usual care), participants in the ICP trial could receive multiorgan MRI and clinical decision support and/or app-based rehabilitation. Initially, participants in the ICP trial were invited to enrol in the drug trial, but slow recruitment to the drug trial led to establishment of additional drug-only trial sites. Participants enrolled at either ICP trial sites or drug-only trial sites were randomly assigned (1:1:1:1) to receive colchicine 500 μg twice daily, rivaroxaban 10 mg once daily, famotidine 40 mg with loratadine 10 mg once daily, or no drug for 12 weeks. All participants received usual care. Randomisation was done electronically in blocks (various block sizes) and stratified by site, birth sex, ICP trial group allocation, and being a new or previous patient of a drug-only site. The primary endpoint was 12-week fatigue, assessed with the Fatigue Assessment Scale (FAS; with scores ranging from 10 [no fatigue] to 50 [debilitating fatigue], and a >10% change considered clinically meaningful) among randomly assigned individuals who had available baseline and 12-week data, adjusting for baseline fatigue and clinically relevant covariates. Secondary endpoints included 24-week FAS. The nested drug trial is registered, ISRCTN10665760. The trial is complete. Of 6035 eligible participants, 778 (383 co-enrolled in the ICP trial and 395 directly enrolled in the drug trial) were randomly assigned between Aug 22, 2022, and Aug 7, 2024 to colchicine (n=192), famotidine-loratadine (n=193), rivaroxaban (n=197), or no drug (usual long COVID care only; n=196). The mean age of participants was 46 years (SD 12·4), 495 (64%) of 778 were female, and 91 (12%) were from a non-White ethnic group. Across all trial groups, there was severe baseline fatigue (mean FAS score 36·8 [SD 7·49]) and a clinically relevant mean FAS reduction of 4·3 points to 32·5 (SD 9·13) at 12 weeks. Adjusted analyses showed small, statistically significant FAS reductions in the colchicine (-1·49 points [95% CI -2·92 to -0·06], p=0·041) and famotidine-loratadine (-1·48 points [-2·88 to -0·08], p=0·038) groups, but not in the rivaroxaban group (-1·06 points [-2·47 to 0·35, p=0·139), compared with no study drug at 12 weeks. However, 24-week FAS scores, 12 weeks after drug cessation, were not significantly different between groups. Treatment was well tolerated, with ten serious adverse events (requiring hospitalisation but unrelated to trial drugs) reported in eight (1·0%) of the 778 participants, five of which were in three participants in the rivaroxaban group. In participants with long COVID, severe fatigue reduced in all study groups-including the no drug group-over 12 weeks, with small additional reductions in the colchicine and famotidine-loratadine groups compared with the no drug group. Modest effects on FAS were not sustained after drug withdrawal. Long-term long COVID symptom benefit is unlikely with these drugs alone. Future trials could investigate the use of these or other repurposed drugs in specific subgroups of patients with long COVID, combination therapies, and how care is delivered. UK National Institute for Health and Care Research.