Three drugs all ineffective for COVID-19 according to RCT – Hospital Healthcare Europe

Three drugs, metformin, ivermectin and fluvoxamine are of limited effectiveness at preventing either hypoxia or hospitalisation or an emergency department visit in patients with COVID-19 according to the findings of a COVID-OUT, a recent randomised, placebo-controlled trial with all three medicines.

Before the introduction of COVID-19 vaccines, research efforts were directed towards repurposing existing medicines to treat the virus. Metformin was one such drug and some work revealed how the drug has an anti-thrombotic effect and was highly effective at inhibiting platelet activation. Moreover, other in vitro work found that metformin inhibited NLRP3 inflammasome activation and interleukin (IL)-1 production in cultured and alveolar macrophages along with inflammasome-independent IL-6 secretion, thus attenuating lipopolysaccharide and COVID-19-induced acute respiratory distress syndrome. Taken together, these data point to a possible role for the drug in the treatment of COVID-19 and which was supported by a retrospective analysis which showed that outpatient metformin use was associated with lower mortality and a trend towards decreased admission for COVID-19. Similarly, a systematic review found that fluvoxamine showed a high probability of being associated with reduced hospitalisation in outpatients with COVID-19. Finally, a Cochrane review concluded that uncertainty remains over the efficacy and safety of ivermectin used to treat or prevent COVID-19.

In trying to gather more evidence for the effectiveness of all three drugs in COVID-19, the COVID-OUT trialists, undertook a randomised, placebo-controlled trial with all three drugs. Eligible patients were non-hospitalised individuals who were enrolled within 3 days of a positive test for the virus and within 7 days of symptom onset. In addition, individuals were either overweight or obese, making them at high risk of severe disease if infected with COVID-19. Metformin was given at a dose of 1500 mg for 14 days (after a period of dose escalation over 6 days), fluvoxamine at a dose of 50 mg twice daily and ivermectin at a dose of 390 to 470 g per kilogram per day for 3 days. The primary event was severe COVID-19 over the 14 days of the trial, defined as a composite of hypoxia (< 93% oxygen saturation), emergency department visit, hospitalisation or death. The main secondary outcomes were the individual components of the composite primary outcome.

Metformin, ivermectin, fluvoxamine and COVID-19 outcomes

A total of 1323 participants with a median age of 46 years (56% female) of whom 52% were vaccinated against COVID-19, were enrolled and randomised to one of the three treatments or placebo. The median body mass index of participants was 30.

The adjusted odds ratio for the primary event with metformin was 0.84 (95% CI 0.66 1.09, p = 0.19), 1.09 (95% CI 0.76 1.45, p = 0.78) for ivermectin and 0.94 (95% CI 0.66 1.36, p = 0.75) for fluvoxamine. There were also no significant differences for each of the three drugs based on the secondary outcomes apart from a reduction in emergency department visits for metformin (odds ratio = 0.84, 95% CI 0.35 0.94) and while this finding was statistically significant, the authors made clear that since this was pre-specified as a secondary outcome, the result warranted further trial evidence.

Participants were also asked to self-rate the severity of daily symptoms during the study and these were not reduced any faster with the three drugs compared to placebo.

The authors concluded that none of the three drugs significantly prevented the primary event compared to placebo although the effect of metformin on emergency department visits warranted further investigation.

CitationBramante CT et al. Randomized Trial of Metformin, Ivermectin, and Fluvoxamine for Covid-19 N Eng J Med 2022

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Three drugs all ineffective for COVID-19 according to RCT - Hospital Healthcare Europe