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Clinical Trial
. 2024 May 6;92(3):202-217.
doi: 10.3390/arm92030021.

RNA Polymerase Inhibitor Enisamium for Treatment of Moderate COVID-19 Patients: A Randomized, Placebo-Controlled, Multicenter, Double-Blind Phase 3 Clinical Trial

Olga Holubovska  1 , Pavlo Babich  2 , Alla Mironenko  3 , Jens Milde  4 , Yuriy Lebed  5 , Holger Stammer  4 , Lutz Mueller  6 , Aartjan J W Te Velthuis  7   8 , Victor Margitich  9 , Andrew Goy  9
Affiliations
Clinical Trial

RNA Polymerase Inhibitor Enisamium for Treatment of Moderate COVID-19 Patients: A Randomized, Placebo-Controlled, Multicenter, Double-Blind Phase 3 Clinical Trial

Olga Holubovska et al. Adv Respir Med. .

Abstract

Enisamium is an orally available therapeutic that inhibits influenza A virus and SARS-CoV-2 replication. We evaluated the clinical efficacy of enisamium treatment combined with standard care in adult, hospitalized patients with moderate COVID-19 requiring external oxygen. Hospitalized patients with laboratory-confirmed SARS-CoV-2 infection were randomly assigned to receive either enisamium (500 mg per dose, four times a day) or a placebo. The primary outcome was an improvement of at least two points on an eight-point severity rating (SR) scale within 29 days of randomization. We initially set out to study the effect of enisamium on patients with a baseline SR of 4 or 5. However, because the study was started early in the COVID-19 pandemic, and COVID-19 had been insufficiently studied at the start of our study, an interim analysis was performed alongside a conditional power analysis in order to ensure patient safety and assess whether the treatment was likely to be beneficial for one or both groups. Following this analysis, a beneficial effect was observed for patients with an SR of 4 only, i.e., patients with moderate COVID-19 requiring supplementary oxygen. The study was continued for these COVID-19 patients. Overall, a total of 592 patients were enrolled and randomized between May 2020 and March 2021. 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. An analysis of the population showed that if patients were treated within 4 days of the onset of COVID-19 symptoms (n = 33), the median time to improvement was 8 days for the enisamium group and 13 days for the placebo group (p = 0.005). For patients treated within 10 days of the onset of COVID-19 symptoms (n = 154), the median time to improvement was 10 days for the enisamium group and 12 days for the placebo group (p = 0.002). Our findings suggest that enisamium is safe to use with COVID-19 patients, and that the observed clinical benefit of enisamium is worth reporting and studying in detail.

Keywords: Amizon; COVID-19; FAV00A; RNA polymerase; SARS-CoV-2; antiviral; clinical trial.

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Conflict of interest statement

A.T.V. 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. and H.S. received personal fees from Pharmalog Institut für klinische Forschung GmbH as subcontracted service CRO. L.M. received personal fees from Regenold GmbH as a subcontracted consultant. A.J.W.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.J.W.t.V.

Figures

Figure 1
Figure 1
Structure of enisamium and its active metabolite VR17-04.
Figure 2
Figure 2
Overview of patient recruitment, randomization, testing, and treatment. (A) Timeline of patient recruitment, randomization, and treatment. (B) Timeline of patient testing. (C) Schematic overview of patient recruitment, randomization, and treatment. (a) This number of patients was included according to both versions of the study protocol. The first version of the protocol allowed the inclusion of patients with an SR = 4 and SR = 5. Patients with an SR = 4 were included in the active and control groups. Patients with an SR = 5 were not included in the efficacy analysis, but they were included in the safety analysis. (b) Patients who received enisamium or placebo were included in the efficacy and safety analyses, while (c) those who did not were excluded. (d) Presence of renal dysfunction. These data were obtained from a patient’s medical history, which was, for some patients, disclosed to the researchers after visit 1 and randomization. In these situations (with evidence of renal dysfunction prior to enrolment), the enrolled patient was removed from the ITT population.
Figure 3
Figure 3
Kaplan–Meier plots. Kaplan–Meier estimates of the cumulative proportion of patients that achieved the primary endpoint in (A) the overall patient population (n = 258), (B) patients in the age category “<40 years” (n = 32), (C) patients in the age category “40–<65 years” (n = 174), (D) patients in the age category “≥65 years” (n = 79), (E) patients randomized within <5 days of symptom onset (n = 33), and (F) patients aged ≥ 50 years randomized within <10 days of symptom onset (n = 154).
Figure 4
Figure 4
Patients testing positive or showing a deterioration in their SR score. (A) Percentage of patients on day 15. (B) Percentage of patients with a change in SR from 4 to 3 after randomization. (C) Percentage of patients testing positive for SARS-CoV-2 RNA via RT-qPCR on day 15, which is representative of the other days.
Figure 5
Figure 5
Proportions of patients with decreased cough on days 3 to 5. (A) Proportion of patients with decreased cough on day 3, (B) day 4, and (C) day 5.
See this image and copyright information in PMC

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