Amantadine in unvaccinated patients with early, mild to moderate COVID-19: A randomized, placebo-controlled, double-blind trial.

BACKGROUND AND PURPOSE: Adamantanes were listed as an interesting option as an early intervention against COVID-19. We aimed to evaluate the effectiveness of amantadine in preventing the progression of COVID-19 and its neurological sequelae. METHODS: Unvaccinated patients with confirmed SARS-CoV-2 infection within 5 days were enrolled. Subjects were randomized (50:50) to amantadine (AMD; 100 mg twice daily) or placebo (PLB) for 14 days. The Ordinal Scale for Clinical Improvement of the World Health Organization (OSCI-WHO) was the primary measure. Secondary endpoints included assessment for fatigue; depression, disorders of smell and taste, and sleepiness on Days 1 and 15. RESULTS: We enrolled 99 patients (49 AMD and 50 PLB). Disease progression (OSCI-WHO = 4) was observed in 6% (AMD) and 8% (PLB) patients (p > 0.05) with further deterioration (OSCI-WHO〉4) in 0% (AMD) and 8% (PLB) patients (p > 0.05). Complete recovery on Day 15 was 60% higher in the AMD compared with the PLB group (p = 0.025). There was improvement in taste (AMD: p = 0.003; PLB: p = 0.0001) and smell (AMD: p = 0.005; PLB: p = 0.0004) but not in fatigue in both groups. Improvement was observed in the AMD (p = 0.010) but not in the PLB group (p = 0.058) when assessing depression as well as sleepiness (AMD: p = 0.0002; PLB: p = 0.341). There was one death in the PLB group (2.0%) and none in the AMD group (p > 0.05) until Day 210. Overall, the drug was well tolerated. CONCLUSION: The central effects of amantadine on the nervous system with reduction of sleepiness and depression might have had a supportive effect on faster recovery in early COVID-19 patients.

The use of amantadine in the prevention of progression and treatment of COVID-19 symptoms in patients infected with the SARS-CoV-2 virus (COV-PREVENT): Study rationale and design.

BACKGROUND: COVID-19, a disease caused by infection with the SARS-CoV-2 virus, is asymptomatic or mildly symptomatic in most cases. Some patients, usually burdened with risk factors develop acute respiratory failure and other organ dysfunction. In such cases, the mortality rate is very high despite the use of intensive therapy. Amantadine has complex activity including antiviral, antiinflammatory and dopaminergic effects. This clinical trial will assess the efficacy and safety of amantadine in the prevention of COVID-19 progression toward acute respiratory failure and neurological complications. METHODS AND RESULTS: The trial will enroll 200 patients who are positive for SARS-CoV-2 infection and have one or more risk factors for worsening the disease. These patients will be included as hospitalized or ambulatory subjects for early treatment of illness. The recruitment will take place in 8 centers covering different regions of Poland. For 14 days they will be given either 200 mg of amantadine a day or placebo. Our hypothesis is a considerable reduction in the number of patients with progression toward respiratory insufficiency or neurological complications thanks to the treatment of amantadine. CONCLUSIONS: Demonstrating the efficacy and safety of amantadine treatment in improving the clinical condition of patients diagnosed with COVID-19 is of great importance in combating the effects of the pandemic. It has potential to influence on the severity and course of neurological complications, which are very common and persist long after the infection as long-COVID syndrome. CLINICAL TRIAL REGISTRATION: www. CLINICALTRIALS: gov identification no. NCT04854759; Eudra CT number: 2021-001144-98 (dated 27 February 2021).