Amantadine in early COVID-19 enhances recovery

In unvaccinated patients at the early stage of a SARS-CoV-2 infection, treatment with amantadine in a placebo-controlled study of 200 enrolled patients, enhanced recovery and was safe during the prolonged follow-up. This can be explained by the antiviral activity of amantadine and its potential effects on the central nervous system (CNS) including neurotransmitter modulation.

Amantadine may display anti-viral activity against the SARS-CoV-2 virus, but even more important are its potential CNS effects including neurotransmitter modulation and anti-inflammatory activity, stated Prof. Konrad Rejdak (Medical University of Lublin, Poland) [1].

The phase 3 COV-PREVENT trial (NCT04854759) assessed the efficacy and safety of amantadine in the prevention of COVID-19 progression to acute respiratory failure and neurological complications. The study enrolled 200 patients from 8 Polish centres who were positive for SARS-CoV-2 and had 1 or more risk factors for clinical complications of the infection, such as obesity, hypertension, or pulmonary disease. Exclusion criteria included an infection severe enough to meet the study's primary endpoint of clinical worsening, and a WHO score of 4 or more, implying oxygen therapy during hospitalisation.

Of 200 enrolled participants, 111 were randomised to amantadine (n=54) or placebo (n=57), administered orally at a dose of 100 mg twice daily (morning and noon) for 14 days. The mean age was 48 years, 53% were men, and 54% of participants were hospitalised. The randomised phase was followed by an open-label phase (days 15–210), in which participants were offered an additional 14 days of treatment with amantadine at 100 mg once daily. The primary outcome measure was clinical worsening: moderate/severe dyspnoea, drop in O₂-saturation, and/or reaching a WHO score of 4 or more at day 15.

According to Prof. Rejdak, SARS-CoV-2 generally remained mild between days 1–15. In the amantadine and placebo groups, 0 and 4 (8%) patients progressed to WHO score >4, respectively; 3 (6.1%) and 4 (8%) progressed to WHO=4. “However, more patients progressed to a higher WHO score in the placebo group than in the amantadine group”, observed Prof. Rejdak, adding that these differences were not significant. There was, however, a significant difference in the number of recovered patients (WHO=0) in favour of amantadine versus placebo (63.3% vs 40%; see Table).

Table: Disease progression/death (WHO≥4) or recovery (WHO=0) from COVID-19 in observation between days 1–15, and survival in extended follow-up until day 210 [1]



“In a logistic regression analysis, treatment with amantadine was significantly associated with favourable outcomes (P=0.028),” Prof. Rejdak noted. In patients with 1–2 risk factors, the relative benefit was 1.29 (95% CI 0.83–1.99); in patients with 3–4 risk factors, the relative benefit was higher at 4.09 (95% CI 1.15–14.57). Neurological outcomes improved as well in the amantadine group, including depression, sleepiness, sense of taste and smell, and fatigue. Amantadine was well tolerated and was not associated with more side effects than placebo.

1. Rejdak K, et al. Amantadine in early COVID-19: a randomised, placebo-controlled, double-blind, phase 3 trial. EAN 2023 Annual Meeting, 1–4 July, Budapest, Hungary.

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Posted on 7 September 202315 February 2024