Amantadine in unvaccinated patients with early, mild to moderate COVID-19: A randomized, placebo-controlled, double-blind trial.
COVID-19
amantadine
neurological and psychiatric complications
outcome
trial
Journal
European journal of neurology
ISSN: 1468-1331
Titre abrégé: Eur J Neurol
Pays: England
ID NLM: 9506311
Informations de publication
Date de publication:
Jan 2024
Jan 2024
Historique:
revised:
24
07
2023
received:
26
06
2023
accepted:
08
08
2023
pubmed:
16
8
2023
medline:
16
8
2023
entrez:
16
8
2023
Statut:
ppublish
Résumé
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. 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. 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. 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.
Sections du résumé
BACKGROUND AND PURPOSE
OBJECTIVE
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
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
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
CONCLUSIONS
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.
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
e16045Subventions
Organisme : Agencja Badań Medycznych
Informations de copyright
© 2023 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.
Références
Petersen E, Koopmans M, Go U, et al. Comparing SARS-CoV-2 with SARS-CoV and influenza pandemics. Lancet Infect Dis. 2020;20:e238-e244.
Brenner SR. The potential of memantine and related adamantanes such as amantadine, to reduce the neurotoxic effects of COVID-19, including ARDS and to reduce viral replication through lysosomal effects. J Med Virol. 2020;92:2341-2342.
Tipton PW, Wszolek ZK. What can Parkinson's disease teach us about COVID-19? Neurol Neurochir Pol. 2020;54:204-206.
Nisar T, Sutherland-Foggio H, Husar W. Antiviral amantadine. Lancet Neurol. 2019;18:1080.
Danysz W, Dekundy A, Scheschonka A, Riederer P. Amantadine: reappraisal of the timeless diamond-target updates and novel therapeutic potentials. J Neural Transm (Vienna). 2021;128:127-169.
Pahwa R. Amantadine: an old drug reborn. Lancet Neurol. 2021;20:975-977.
Rejdak K, Grieb P. Adamantanes might be protective from COVID-19 in patients with neurological diseases: multiple sclerosis, parkinsonism and cognitive impairment. Mult Scler Relat Disord. 2020;42:102163.
Grieb P, Rejdak K. Are central nervous system drugs displaying anti-inflammatory activity suitable for early treatment of COVID-19? Folia Neuropathol. 2021;59:113-120.
Grieb P, Swiatkiewicz M, Prus K, Rejdak K. Hypoxia may be a determinative factor in COVID-19 progression. Curr Res Pharmacol Drug Discov. 2021;2:100030.
Smieszek SP, Przychodzen BP, Polymeropoulos MH. Amantadine disrupts lysosomal gene expression: a hypothesis for COVID19 treatment. Int J Antimicrob Agents. 2020;55:106004.
Toft-Bertelsen TL, Jeppesen MG, Tzortzini E, et al. Amantadine has potential for the treatment of COVID-19 because it inhibits known and novel ion channels encoded by SARS-CoV-2. Commun Biol. 2021;4:1347.
Fink K, Nitsche A, Neumann M, Grossegesse M, Eisele KH, Danysz W. Amantadine inhibits SARS-CoV-2 in vitro. Viruses. 2021;13:539.
Mancilla-Galindo J, García-Méndez JÓ, Márquez-Sánchez J, et al. All-cause mortality among patients treated with repurposed antivirals and antibiotics for COVID-19 in Mexico City: a real-world observational study. EXCLI J. 2021;20:199-222.
Aranda-Abreu GE, Aranda-Martínez JD, Araújo R, Hernández-Aguilar ME, Herrera-Covarrubias D, Rojas-Durán F. Observational study of people infected with SARS-Cov-2, treated with amantadine. Pharmacol Rep. 2020;72:1538-1541.
Kamel WA, Kamel MI, Alhasawi A, Elmasry S, AlHamdan F, al-Hashel JY. Effect of pre-exposure use of amantadine on COVID-19 infection: a hospital-based cohort study in patients with Parkinson's disease or multiple sclerosis. Front Neurol. 2021;12:704186.
Barczyk A, Czajkowska-Malinowska M, Farnik M, et al. Efficacy of oral amantadine among patients hospitalised with COVID-19: a randomised, double-blind, placebo-controlled, multicentre study. Respir Med. 2023;212:107198.
Chober D, Czajkowski Z, Aksak-Wąs B, et al. Improved survival in intensive care unit in severe COVID-19 associated with amantadine use - retrospective study. Int J Infect Dis. 2022;124:143-151.
Rejdak K, Fiedor P, Bonek R, et al. 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 desing. Contemp Clin Trials. 2022;116:106755.
World Health Organization. WHO R&D Blueprint. Novel coronavirus. COVID-19 therapeutic trial synopsis. https://www.who.int/docs/default-source/blue-print/covid-19-therapeutic-trial-synopsis.pdf
Krupp LB, LaRocca NG, Muir-Nash J, Steinberg AD. The fatigue severity scale. Application to patients with multiple sclerosis and systemic lupus erythematosus. Arch Neurol. 1989;46:1121-1123.
Beck AT, Ward CH, Mendelson M, Mock J, Erbaugh J. An inventory for measuring depression. Arch Gen Psychiatry. 1961;4:561-571.
Haxel BR, Bertz-Duffy S, Fruth K, Letzel S, Mann WJ, Muttray A. Comparison of subjective olfaction ratings in patients with and without olfactory disorders. J Laryngol Otol. 2012;126:692-697.
Johns MW. A new method for measuring daytime sleepiness: the Epworth Sleepiness Scale. Sleep. 1991;14:540-545.
Little JW, Hall WJ, Douglas RG Jr, et al. Amantadine effect on peripheral airways abnormalities in influenza. A study in 15 students with natural influenza a infection. Ann Intern Med. 1976;85:177-182.
Cunha BA. Amantadine may be lifesaving in severe influenza A. Clin Infect Dis. 2006;43:1372-1373.
Nakagawa T, Wada H, Sekizawa K, Arai H, Sasaki H. Amantadine and pneumonia. Lancet. 1999;353:1157.
Weis N, Bollerup S, Sund JD, et al. Amantadine for COVID-19 treatment (ACT) study: a randomized, double-blinded, placebo-controlled clinical trial. Clin Microbiol Infect. 2023; S1198-743X(23)00301-4. doi:10.1016/j.cmi.2023.06.023
Dangayach NS, Newcombe V, Sonnenville R. Acute neurologic complications of COVID-19 and postacute sequelae of COVID-19. Crit Care Clin. 2022;38:553-570.
Taquet M, Sillett R, Zhu L, et al. Neurological and psychiatric risk trajectories after SARS-CoV-2 infection: an analysis of 2-year retrospective cohort studies including 1 284 437 patients. Lancet Psychiatry. 2022;9:815-827.
Butterworth RF. Potential for the repurposing of adamantane antivirals for COVID-19. Drugs R D. 2021;21:267-272.
Müller T, Riederer P, Kuhn W. Aminoadamantanes: from treatment of Parkinson's and Alzheimer's disease to symptom amelioration of long COVID-19 syndrome? Expert Rev Clin Pharmacol. 2023;16:101-107.