In a recent study posted to the medRxiv* preprint server, researchers evaluated the efficacy of the anti-inflammatory drug dimethyl fumarate (DMF) in treating coronavirus disease 2019 (COVID-19) as part of an early phase, randomized, controlled assessment trial in the United Kingdom (UK).
Pulmonary inflammation and the increase in circulating inflammatory markers such as interleukin-6 and C-reactive protein are commonly observed during severe outcomes of COVID-19. Various immunomodulatory treatments, such as interleukin-6 inhibitors, Janus kinase inhibitors, and corticosteroids, have been used to limit severe COVID-19-related mortality.
Studies have shown that a part of the innate immune system called inflammasomes plays a major role in inducing proinflammatory cytokine release and pyroptosis. Specifically, the nucleotide oligomerization domain (NOD)-like receptor (NLR) family pyrin domain containing 3 (NLRP3) inflammasome has been associated with severe COVID-19.
Dimethyl fumarate has displayed anti-inflammatory effects against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in vitro and is thought to inhibit NLRP3 inflammasome activation. However, there have been no clinical trials until now to test the efficacy of DMF in reducing inflammation in COVID-19 patients.
About the study
In the present study, the efficacy of DMF was tested as part of the randomized evaluation of COVID-19 therapy (RECOVERY) trial being carried out in 177 UK hospitals funded by the National Institute for Health and Care Research Clinical Research Network and 15 non-U.K. hospitals. Of the 177 hospitals, 27 participated in the DMF trials.
Eligible participants were 18 years old or above, with suspected or confirmed COVID-19 and no medical history, which might put them at risk during the DMF trial. Pregnant women were excluded from the study.
Half the participants were randomly assigned to the usual standard of care, while the other randomized half was administered DMF along with standard care. Oral doses of 125 mg were administered every 12 hours for the first four days, and then the dosage was increased to 250 mg twice daily for the next eight days or until discharge.
The measured primary outcome was the clinical status on the fifth day based on an ordinal scale with seven categories ranging from hospital discharge to mortality. The secondary outcomes were measured based on various parameters, including clinical status improvement time, peripheral blood oxygenation, C-reactive protein levels on the fifth day, and time to discharge.
The results indicated that DMF had no beneficial effects on the fifth-day clinical status of the 357 patients who received DMF along with standard care. Treatment with DMF did not result in any significant improvement in secondary outcomes either. However, although 13% of the patients experienced rashes, flushing, and gastrointestinal side effects commonly associated with DMF, no new adverse reactions were observed.
Although DMF has been effective in inhibiting inflammasomes in vitro and has been successful in halving relapse rates in multiple sclerosis and treating psoriasis, it had no noticeable in vivo effects on COVID-19 outcomes. The authors believe that while DMF is known to inhibit inflammasome activation pathways, the progression of COVID-19 symptoms might not be directly related to these pathways. The other immunomodulators used in standard care could also have affected the efficacy of DMF.
While other adverse reactions, such as abnormal liver function test scores and transaminitis, were observed, the participants in the only standard care group also exhibited these reactions, suggesting that DMF was not the cause.
The study had some limitations, including a sample size not large enough to observe varied effects among a diverse group of patients or to evaluate a reduction in mortality rates. Moreover, the authors believe that since the trial was open-label, the knowledge about the treatment could have affected the outcomes.
Overall, the evaluation of dimethyl fumarate during the RECOVERY clinical trials showed no discernible effects in improving the clinical status of COVID-19 patients compared to the standard treatment methods. There were no improvements in the secondary outcomes, such as time of discharge, blood oxygenation, or C-reactive protein levels.
Common DMF-associated side effects such as rashes and gastrointestinal reactions were observed, but no new adverse reactions occurred. In conclusion, the clinical trial results do not recommend DMF as a potential COVID-19 treatment option.
medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.