Common Drugs Basically Flunk for Long COVID Fatigue

An anti-inflammatory pill and the combination of a heartburn drug and an antihistamine marginally improved severe long COVID fatigue over usual care, and only in the short-term, according to an open-label randomized trial from the U.K.

Compared with usual care with a long COVID specialist alone, adding daily treatment with the common drugs (colchicine or famotidine-loratadine) led to statistically significant improvements in patient-reported Fatigue Assessment Scale (FAS) scores over 12 weeks, but the differences were small and of marginal clinical significance:

• Colchicine: 1.49 points lower (P=0.041)
• Famotidine-loratadine: 1.48 points lower (P=0.038)

Furthermore, those differences were no longer significant 12 weeks after stopping the interventions, reported Amitava Banerjee, DPhil, of University College London, and colleagues of the STIMULATE-ICP consortium, in Lancet Infectious Diseases.

A third investigational arm testing the anticoagulant rivaroxaban (Xarelto) showed no benefit at either 12 or 24 weeks.

“Overall, our data do not support widespread clinical use of these drugs for fatigue reduction in long COVID,” Banerjee and colleagues wrote. “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.”

Long COVID has no FDA-approved treatments, nor are there validated disease-specific primary outcome measures that can be used in clinical trials, noted Tiffany Walker, MD, of Emory University School of Medicine in Atlanta, in an accompanying editorial.

Of note, in another recent trial, the antidepressant fluvoxamine showed benefit for reducing long COVID-associated fatigue, whereas metformin flopped. And a Japanese trial did not support donepezil (Aricept) in treating fatigue and psychological symptoms of long COVID.

While the current study’s treatment effects on fatigue were marginal, a larger effect could have been masked by symptom fluctuations, according to Walker. “It is possible that the drug effect seen here would be more robust if symptom severity variations were addressed,” she wrote, noting that trials are needed that account for symptom fluctuations and long COVID features such as post-exertional malaise.

All groups in the study, including the control arm, showed FAS score improvements from baseline, which potentially highlights “the importance of high-quality specialist care, including rehabilitation and pacing support, in obtaining meaningful clinical improvement,” Banerjee and colleagues wrote.

“Our report of improvement in fatigue with usual long COVID care provided by specialist NHS [National Health Service] clinics is in line with our previous observational evaluation of U.K. services, and serves as an important addition to growing evidence supporting a multifaceted approach to long COVID rehabilitation,” the study authors noted. “Our trial was done across 12 sites with broadly consistent care models, informed by NHS long COVID guidelines, in a broadly U.K.-representative population. All sites were led by clinicians with long COVID expertise, and all provided rehabilitation advice and support in addition to the trial interventions.”

The STIMULATE-ICP trial enrolled adults from August 2022 to August 2024 who were diagnosed with long COVID; the trial excluded those with a previous COVID hospitalization.

A total of 778 patients were randomized to 12 weeks of twice-daily colchicine (500 µg), once-daily famotidine (40 mg) and loratadine (10 mg), once-daily rivaroxaban (10 mg), or no drug. All patients received usual care from a long COVID specialist and ongoing community support.

Mean patient age was 46 years, 64% were women, 88% were white, and 97% had received at least one COVID vaccine dose. The median number of long COVID symptoms was nine, median symptom duration was 775 days, and the mean FAS score at baseline was 36.8, indicating severe baseline fatigue.

The medications patients most commonly reported using to manage long COVID symptoms were salbutamol, inhaled beclometasone dipropionate and formoterol fumarate dihydrate (sold as Fostair in the U.K.), magnesium, famotidine, ibuprofen, fexofenadine, amitriptyline, cetirizine (Zyrtec), N-acetylcysteine, nattokinase, and naltrexone.

The primary outcome was fatigue at 12 weeks on FAS, with a decline greater than 10% considered a minimally clinically important difference.

Across all trial groups, mean FAS scores dropped from 36.8 to 32.5 from baseline to 12 weeks on the scale of 10-50 points. Scores fell 4.4 points in the colchicine group, 4.8 points for famotidine-loratadine, 4.4 points for rivaroxaban, and 3.3 points for the no-drug group.

The intervention period ended after 12 weeks, marking study drug cessation. By week 24, FAS scores had crept up in the three drug groups from their week-12 lows, reaching 32.7 in the colchicine group, 33.4 in the famotidine-loratadine group, and 33.4 in the rivaroxaban group. The no-drug group saw a slight improvement, with a FAS score decline from 34.2 to 34.1.

Roughly one-quarter of study participants reported an adverse event, with most being mild or moderate. Adverse event rates were highest in the rivaroxaban group (36%), followed by colchicine (30%), famotidine-loratadine (26%), and usual care only (11%).

Study limitations included an inability to separate the effects of SARS-CoV-2 exposures, vaccination, or repeated infection on fatigue scores. The open-label trial also may have been subject to placebo effects and expectation bias.

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