RNA polymerase inhibitor enisamium for treatment of moderate COVID-19 patients: a randomized, placebo-controlled, multicenter, double-blind phase 3 clinical trial

Background Enisamium (trade name Amizon® MAX) is an orally available therapeutic that inhibits influenza A virus and SARS-CoV-2 replication and improves influenza patient recovery. We aimed to evaluate the clinical efficacy of enisamium treatment combined with standard care compared to standard care plus treatment with a placebo control in adult, hospitalized patients with moderate COVID-19 requiring external oxygen. This trial was registered with [ClinicalTrials.gov][1] under [NCT04682873][2]. Methods The study was a phase three, multi-center, double-blind, randomized, placebo-controlled trial conducted in 14 clinical centers. Hospitalized patients aged ≥18 years with laboratory-confirmed SARS-CoV-2 infection were eligible. Patients were randomly assigned to receive either enisamium (500 mg per dose, 4 times a day) or a placebo. The treatment lasted ≤7 days in case of early discharge from the hospital, or loss of the patient’s ability to swallow due to the need for ventilation. All patients received standard of care as deemed necessary by the investigator and the health status of each patient. All patients received standard of care as deemed necessary by the investigator and each patient’s health status. The primary outcome was an improvement of at least two points on an 8-point, modified WHO severity rating (SR) scale within 29 days of randomization. The primary and safety outcomes were analyzed in accordance to the intention-to-treat (ITT) principle. Findings A total of 592 patients were enrolled and randomized between May 2020 and March 2021. Only patients with a baseline SR of 4 (285 subjects or 48.1%) were included in the ITT analysis. Patients with a baseline SR of 5 were excluded as the interim analysis did not show relevant differences between the enisamium group and placebo in this sub-group. The patients with a baseline SR of 4 were divided into two groups: 142 (49.8%) were assigned to the enisamium group and 143 (50.2%) to the placebo group. No differences were observed between the safety or patient tolerability profiles of the enisamium and placebo treatment. Analysis of the ITT population showed that if patients were treated within 4 days of the onset of COVID-19 symptoms, the median time to improvement was 8 for the enisamium group and 13 days for the placebo group (p = 0.0051). For patients treated within 7 days of the onset of COVID-19 symptoms, the median time to improvement was 10 days for the enisamium group and 11 days for the placebo group (p = 0.0035). Comparison of groups using a stratified one-sided Logrank criterion (adjustment using stratification by age categories: “<40 years”, “40-<65 years” and “≥65 years”) showed statistically significant differences between the groups (p = 0.00945, one-sided). Interpretation Enisamium is safe to use in COVID-19 patients. In COVID-19 patients that did not require supplementary oxygen (SR = 5), standard treatment was sufficient to aid recovery and enisamium did not offer significant clinical benefits. However, we found that standard care combined with enisamium offers a significant clinical benefit when given to patients with moderate COVID-19 requiring supplementary oxygen (SR = 4), if enisamium is given within 7 days of the onset of symptoms. These data suggest that enisamium therapy can be used as therapy against SARS-CoV-2 infection in these patients. Funding Farmak JSC, Wellcome Trust, and Royal Society. ### Competing Interest Statement A.T.V. has received grants from the National Institutes of Health, the Wellcome Trust, and the Royal Society. V.M. and A.G. are employees of Farmak JSC. J.M., H.S. received personal fees from Pharmalog Institut fuer klinische Forschung GmbH as subcontracted service CRO. L.M. received personal fees from Regenold GmbH as subcontracted consultant. A.T.V. was previously employed by the University of Cambridge. The University of Cambridge received consulting fees for the experiments and analyses performed by A.T.V. ### Clinical Trial NCT04682873 ### Funding Statement The clinical trial and medical analysis was funded by Farmak. A.T.V. is supported by joint Wellcome Trust and Royal Society grant 206579/Z/17/Z. For the purpose of Open Access, the authors have applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was approved by the Ethics Commission of the Regional Clinical Hospital of Ivano-Frankivsk Regional Council on 12.05.2020. The protocol and materials of the clinical trial were approved by the CEB (Ministry of Health [MOH] of Ukraine; approval number 2949, December 18, 2020). The registration number of the study in [ClinicalTrials.gov][1] is [NCT04682873][2]. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes The data analyzed and presented in this study are available from P.B. and V.M. on reasonable request, providing the request meets local ethical and research criteria. Patient data will be anonymized, and study documents will be redacted to protect the privacy of trial participants. The study protocol is available upon request. [1]: http://ClinicalTrials.gov [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT04682873&atom=%2Fmedrxiv%2Fearly%2F2022%2F08%2F23%2F2022.08.21.22279036.atom