Amantadine for COVID-19 treatment (ACT study): a randomized, double-blinded, placebo-controlled clinical trial

The COVID-19 pandemic has revealed a severe need for effective antiviral treatment. The objectives of this study were to assess if preemptive treatment with amantadine for COVID-19 in non-hospitalized persons ≥40 years or adults with comorbidities was able to prevent disease progression and hospitalization. Primary outcomes were clinical status on day 14. Between 9 June 2021 and 27 January 2022, this randomized, double-blinded, placebo-controlled, single-center clinical trial included 242 subjects with a follow-up period of 90 days. Subjects were randomized 1:1 to either amantadine 100 mg or placebo twice daily for five days. The inclusion criteria were confirmed SARS-CoV-2 infection and at least one of (i) age ≥ 40 years, age ≥ 18 years (ii) and at least one comorbidity, or - (iii) and BMI ≥ 30. The study protocol was published at www. gov (unique protocol #02032021) and at www.clinicaltrialregister.eu (EudraCT-number 2021-001177-22). With 121 participants in each arm, we found no difference in the primary endpoint with 82 participants in the amantadine arm, and 92 participants in the placebo arm with no limitations to activities, respectively, and 25 and 37 with limitations to activities in the amantadine arm and the placebo arm respectively. No participants in either group were admitted to hospital or died. The Odds Ratio of having state severity increased by 1 in the amantadine group versus placebo was 1.8 (Confidence Interval 1.0-3.3, (p=0.051)). At day 7, one participant was hospitalized in each group; throughout the study this increased to five and three participants for amantadine versus placebo treatment (P=0.72). Similarly, at day 7, there was no difference in the status of oropharyngeal swabs. Most participants (108 in each group) were SARS-CoV-2 RNA positive (p=0.84). We found no effect of amantadine on disease progression of SARS-CoV-2 infection.